ALDRIN/DIELDRIN US. DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry N Federal Recycling Program ‘2 Printed on Recycled Paper ' PUBLIC HEALTH LIBRARY /u;z;:sfi¥ i UBRARY "NW” 0! CALIFORNIA TOXICOLOGICAL PROFILE FOR ALDRIN/DIELDRIN Prepared by: Clement International Corporation Under Contract No. 205-88-0608 Prepared for: US. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry April 1993 CAT.FOR PUBLIC HEALTH DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. UPDATE STATEMENT A Toxicological Profile for aldrin and dieldrin was released on May 1989. This edition supersedes any previously released draft or final profile. Toxicological profiles are revised and republished as necessary, but no less than once every three years. For information regarding the update status of previously released profiles, contact ATSDR at: Agency for Toxic Substances and Disease Registry Division of Toxicology/Toxicology Information Branch 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 FOREWORD The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) extended and amended the Comprehensive Environmental Response. Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare toxicological profiles for hazardous substances which are most commonly found at facilities on the CERCLA National Priorities List and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). The lists of the 250 most significant hazardous substances were published in the Federal Register on April 17, 1987, on October 20, 1988, on October 26, 1989, on October 17, 1990, and on October 17, 1991. A revised list of 275 substances was published on October 28. 1992. Section 104(i)(3) of CERCLA, as amended. directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the lists. Each profile must include the following: (A) The examination, summary, and interpretation of available toxicological information and epidemiological evaluations on a hazardous substance in order to ascertain the levels of significant human exposure for the substance and the associated acute, subacute. and chronic health effects. (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure which present a significant risk to human health of acute. subacute. and chronic health effects. (C) Where appropriate, identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. This toxicological profile is prepared in accordance with guidelines developed by ATSDR and EPA. The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. The ATSDR toxicological profile is intended to characterize succinctly the toxicological and adverse health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature (that has been peer-reviewed) that describes a hazardous substance’s toxicological properties. Other pertinent literature is also presented but described in less detail than the key studies. The profile is not intended to be an exhaustive document; however. more comprehensive sources of specialty information are referenced. Each toxicological profile begins with a public health statement, which describes in nontechnical language a substance‘s relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance’s health effects is described in a health effects summary. Data needs that are of significance to protection of public health will be identified by ATSDR and EPA. The focus of the profiles is on health and toxicological information; therefore. we have included this information in the beginning of the document. vi Foreword The principal audiences for the toxicological profiles are health professionals at the federal. state. and local levels. interested private sector orgmiizations and groups. and members of the public. This profile reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR. the Centers for Disease Control and Prevention (CDC). and other federal agencies. It has also been reviewed by a panel of nongovemment peer reviewers and is being made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. William L. Roper. M.D.. Administrator Agency for Toxic Substances and Disease Registry vii CONTRIBUTORS CHEMICAL MANAGER(S)/AUTHORS(S): Michael Brown, M.P.H. ATSDR, Division of Toxicology, Atlanta, GA Carolyn Rabe, Ph.D. Clement International Corporation, Fairfax, VA THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 1. 2. Green Border Review. Green Border review assures the consistency with ATSDR policy. Health Effects Review. The Health Effects Review Committee examines the health effects chapter of each profile for consistency and accuracy in interpreting health effects and classifying endpoints. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to substance-specific minimal risk levels (MRLs), reviews the health effects database of each profile, and makes recommendations for derivation of MRLs. Quality Assurance Review. The Quality Assurance Branch assures that consistency across profiles is maintained, identifies any significant problems in format or content, and establishes that Guidance has been followed. CONTENTS FOREWORD ......................................................... v CONTRIBUTORS ....................................................... vii LIST OF FIGURES ..................................................... xiii LIST OF TABLES ....................................................... xv 1. PUBLIC HEALTH STATEMENT .......................................... 1 1.1 WHAT ARE ALDRIN AND DIELDRIN? ................................. 1 1.2 WHAT HAPPENS TO ALDRIN AND DH-ELDRIN WHEN THEY ENTER THE ENVIRONMENT? ................................................ 2 1.3 HOW MIGHT I BE EXPOSED TO ALDRIN OR DIELDRIN? .................... 3 1.4 HOW CAN ALDRIN AND DIELDRIN ENTER AND LEAVE MY BODY? ........... 3 1.5 HOW CAN ALDRIN AND DIELDRIN AFFECT MY HEALTH? .................. 4 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO ALDRIN OR DIELDRIN? ........................................... 5 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? ............................................... 5 1.8 WHERE CAN I GET MORE INFORMATION? ............................. 6 2. HEALTH EFFECTS ................................................... 7 2.1 INTRODUCTION ................................................ 7 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ................ 7 2.2.1 Inhalation Exposure .......................................... 8 2.2.1.1 Death ............................................. 8 2.2.1.2 Systemic Effects ...................................... 9 2.2.1.3 Immunological Effects .................................. 11 2.2.1.4 Neurological Effects ................................... 11 2.2.1.5 Developmental Effects ............ ‘ ...................... 12 2.2.1.6 Reproductive Effects ................................... 12 2.2.1.7 Genotoxic Effects ..................................... 12 2.2.1.8 Cancer ............................................ 13 2.2.2 Oral Exposure .............................................. 13 2.2.2.1 Death ............................................. 13 2.2.2.2 Systemic Effects ...................................... 14 2.2.2.3 Immunological Effects .................................. 37 2.2.2.4 Neurological Effects ................................... 37 2.2.2.5 Developmental Effects .................................. 39 2.2.2.6 Reproductive Effects ................................... 41 2.2.2.7 Genotoxic Effects ..................................... 42 2.2.2.8 Cancer ............................................ 43 2.2.3 Dermal Exposure ............................................ 44 2.2.3.1 Death ............................................. 44 2.2.3.2 Systemic Effects ...................................... 45 2.2.3.3 Immunological Effects .................................. 51 2.2.3.4 Neurological Effects . . ' ................................. 51 2.2.3.5 Developmental Effects .................................. 52 3. 4. 5. 2.2.3.6 Reproductive Effects ................................... 53 2.2.3.7 Genotoxic Effects ..................................... 53 2.2.3.8 Cancer ............................................ 53 2.3 TOXICOKINETICS ............................................... 54 2.3.1 Absorption ................................................ 54 2.3.1.1 Inhalation Exposure .................................... 54 2.3.1.2 Oral Exposure ....................................... 54 2.3.1.3 Dermal Exposure ..................................... 55 2.3.2 Distribution ............................................... 55 2.3.2.1 Inhalation Exposure .................................... 55 2.3.2.2 Oral Exposure ....................................... 55 2.3.2.3 Dermal Exposure ..................................... 57 2.3.2.4 Other Routes of Exposure ................................ 57 2.3.3 Metabolism ............................................... 57 2.3.3.1 Inhalation Exposure .................................... 57 2.3.3.2 Oral Exposure ....................................... 58 2.3.3.3 Dermal Exposure ..................................... 60 2.3.4 Excretion ................................................. 60 2.3.4.1 Inhalation Exposure .................................... 60 2.3.4.2 Oral Exposure ....................................... 60 2.3.4.3 Dermal Exposure ..................................... 62 2.3.4.4 Other Routes of Exposure ................................ 62 2.4 RELEVANCE TO PUBLIC HEALTH ................................... 62 2.5 BIOMARKERS OF EXPOSURE AND EFFECT ............................. 71 2.5.1 Biomarkers Used to Identify or Quantify Exposure to Aldrin or Dieldrin ......... 72 2.5.2 Biomarkers Used to Characterize Effects Caused by Aldrin or Dieldrin .......... 73 2.6 INTERACTIONS WITH OTHER CHEMICALS ............................. 73 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ..................... 74 2.8 METHODS FOR REDUCING TOXIC EFFECTS ............................ 75 2.8.1 Reducing Absorption Following Exposure ............................ 75 2.8.2 Reducing Body Burden ........................................ 75 2.8.3 Interfering with the Mechanism of Action for Toxic Effects ................. 76 2.9 ADEQUACY OF THE DATABASE .................................... 77 2.9.1 Existing Information on Health Effects of Aldrin or Dieldrin ................ 77 2.9.2 Identification of Data Needs . . . . . . . . . . . . . . ....................... 79 2.9.3 On-going Studies ............................................ 86 CHEMICAL AND PHYSICAL INFORMATION ................................. 89 3.1 CHEMICAL IDENTITY ............................................ 89 3.2 PHYSICAL AND CHEMICAL PROPERTIES ............................... 89 PRODUCTION, IMPORT, USE, AND DISPOSAL ............................... 93 4.1 PRODUCTION .................................................. 93 4.2 IMPORT/EXPORT ................................................ 93 4.3 USE ......................................................... 93 4.4 DISPOSAL .................................................... 94 POTENTIAL FOR HUMAN EXPOSURE ..................................... 95 5.1 OVERVIEW .................................................... 95 5.2 RELEASES TO THE ENVIRONMENT .................................. 95 5.2.1 Air .................................................... 95 xi 5.2.2 Water ................................................... 95 5.2.3 Soil .................................................... 98 5.3 ENVIRONMENTAL FATE .......................................... 98 5.3.1 Transport and Partitioning ...................................... 98 5.3.2 Transformation and Degradation .................................. 101 5.3.2.1 Air .............................................. 101 5.3.2.2 Water ............................................ 101 5.3.2.3 Soil .............................................. 102 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............... 103 5.4.1 Air .................................................... 103 5.4.2 Water ................................................... 103 5.4.3 Soil .................................................... 105 5.4.4 Other Environmental Media ..................................... 105 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .................. 106 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .................... 110 5.7 ADEQUACY OF THE DATABASE .................................... 112 5.7.1 Identification of Data Needs ..................................... 112 5.7.2 On-going Studies ............................................ 114 6. ANALYTICAL METHODS .............................................. 115 6.1 BIOLOGICAL MATERIALS ......................................... 115 6.2 ENVIRONMENTAL SAMPLES ....................................... 115 6.3 ADEQUACY OF THE DATABASE .................................... 121 6.3.1 Identification of Data Needs ..................................... 121 6.3.2 On-going Studies ............................................ 121 7. REGULATIONS AND ADVISORIES ........................................ 123 8. REFERENCES ...................................................... 135 9. GLOSSARY ........................................................ 181 APPENDICES A. USER’S GUIDE ................................................. A-1 B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS .......................... B-l C. PEER REVIEW .................................................. C-l 2-1 2-2 2-3 xiii LIST OF FIGURES Levels of Significant Exposure to Aldrin - Oral ................................. 19 Levels of Significant Exposure to Dieldrin - Oral ................................ 29 Proposed Metabolic Pathway for Aldrin and Dieldrin ............................. 59 Existing Information on Health Effects of Aldrin/Dieldrin ........................... 78 Frequency of NFL Sites with Aldrin Contamination .............................. 96 Frequency of NFL Sites with Dieldrin Contamination ............................. 97 XV LIST OF TABLES Levels of Significant Exposure to Aldrin - Oral ................................. 15 Levels of Significant Exposure to Dieldrin - Oral ................................ 21 Levels of Significant Exposure to Aldrin - Dermal ............................... 46 Levels of Significant Exposure to Dieldrin - Dermal .............................. 47 Genotoxicity of Aldrin/Dieldrin 13M ...................................... 69 Genotoxicity of Aldrin/Dieldrin M7112 ..................................... 7O On-going Studies on Aldrin and Dieldrin ..................................... 87 Chemical Identity of Aldrin and Dieldrin ..................................... 90 Physical and Chemical Properties of Aldrin and Dieldrin ........................... 91 Dieldrin Residues in Adult Dietary Components (1980—1982) ........................ 109 Calculated Dietary Intakes of Dieldrin for Three Population Groups .................... 111 Analytical Methods for Determining Aldrin/Dieldrin in Biological Materials ............... 116 Analytical Methods for Determining Aldrin/Dieldrin in Environmental Samples ............. 118 Regulations and Guidelines Applicable to Aldrin ................................ 124 Regulations and Guidelines Applicable to Dieldrin ............................... 129 Recommended Action Levels for Total Residues of Aldrin and Dieldrin ................. 134 1. PUBLIC HEALTH STATEMENT This Statement was prepared to give you information about aldrin and dieldrin and to emphasize the human health effects that may result from exposure to them. The Environmental Protection Agency (EPA) has identified 1,300 sites on its National Priorities List (NPL). Aldrin has been found in at least 36 of these sites. Dieldrin has been found in at least 162 of these sites. However, we do not know how many of the 1,300 NPL sites have been evaluated for aldrin or dieldrin. As EPA evaluates more sites, the number of sites at which aldrin and dieldrin are found may change. This information is important for you to know because aldrin and dieldrin may cause harmful health effects and because these sites are potential or actual sources of human exposure to aldrin and dieldrin. When a chemical is released from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment as a chemical emission. This emission, which is also called a release, does not always lead to exposure. You can be exposed to a chemical only when you come into contact with the chemical. You may be exposed to it in the environment by breathing, eating, or drinking substances containing the chemical or from skin contact with it. If you are exposed to a hazardous chemical such as aldrin or dieldrin, several factors will determine whether harmful health effects will occur and what the type and severity of those health effects will be. These factors include the dose (how much), the duration (how long), the route or pathway by which you are exposed (breathing, eating, drinking, or skin contact), the other chemicals to which you are exposed, and your individual characteristics such as age, sex, nutritional status, family traits, lifestyle, and state of health. 1.1 WHAT ARE ALDRIN AND DIELDRIN? Aldrin and dieldrin are the common names of two structurally similar compounds that are used as insecticides. They are chemicals that are made in the laboratory and do not occur naturally in the environment. The scientific name for aldrin is 1,2,3,4,10,10- hexachloro-1,4,4a,5,8,8a-hexahydro-1,4-endo,exo-5,8-dimethanonaphthalene. The ab- breviation for the scientific name for aldrin is HHDN. Technical-grade aldrin contains not less than 85.5% aldrin. The trade names used for aldrin include Aldrec, Aldrex, Drinox, Octalene, Seedrin, and Compound 118. The scientific name for dieldrin is 1,2,3,4,10,10-hexachloro-6,7-epoxy-1,4,4a,5,6,7,8,8a-octahydro-1,4-endo,exo-5,8- dimethanonaphthalene. The abbreviation for the scientific name for dieldrin is HEOD. Technical-grade dieldrin contains not less than 85% dieldrin. The trade names used for dieldrin include Alvit, Dieldrix, Octalox, Quintox, and Red Shield. 2 1. PUBLIC HEALTH STATEMENT Pure aldrin and dieldrin are white powders. Technical-grade aldrin and dieldrin are tan powders. Aldrin and dieldrin slowly evaporate in the air. Aldrin evaporates more readily than dieldrin. Both aldrin and dieldrin have mild chemical odors. You might find aldrin and dieldrin in the soil, in water, or in the air near hazardous waste sites. You might also find aldrin and dieldrin in plants and animals near hazardous waste sites. Aldrin and dieldrin are no longer used. From the 19505 until 1970, aldrin and dieldrin were used extensively as insecticides on crops such as corn and cotton. The US. Department of Agriculture canceled all uses of aldrin and dieldrin in 1970. In 1972, however, EPA approved aldrin and dieldrin for killing termites. Use of aldrin and dieldrin to control termites continued until 1987. In 1987, the manufacturer voluntarily canceled the registration for use in controlling termites. In this profile, the two chemicals are discussed together because aldrin readily changes into dieldrin once it enters either the environment or your body. More information on the chemical and physical properties of aldrin and dieldrin is found in Chapter 3. More information on the production and use of aldrin and dieldrin is found in Chapter 4. 1.2 WHAT HAPPENS TO ALDRIN AND DIELDRIN WHEN THEY ENTER THE ENVIRONMENT? Aldrin and dieldrin can enter the environment from accidental spills or leaks from storage containers at waste sites. In the past, aldrin and dieldrin entered the environment when farmers used them to kill pests on crops and when exterminators used them to kill termites. Aldrin and dieldrin are still present in the environment from these past uses. Sunlight and bacteria in the environment can change aldrin to dieldrin. Therefore, you can find dieldrin in places where aldrin was originally released. Dieldrin in soil or water breaks down slowly. Dieldrin sticks to soil very strongly and may stay there unchanged for many years. Water does not wash dieldrin off of soil easily. Dieldrin does not dissolve in water very well; thus, you can find very little dieldrin in water. Most dieldrin in the environment attaches to soil. It also attaches to sediments at the bottoms of lakes, ponds, and streams. Dieldrin can travel large distances by attaching to dust and traveling in the wind. Dieldrin can evaporate slowly from surface water or soil. Dieldrin in the air changes to photodieldrin within a few days. We know very little about the harmful health effects of photodieldrin. Plants take up dieldrin from the soil. Most of the dieldrin in plants is in the roots. Fish or animals that eat dieldrin-contaminated materials store a large amount of the dieldrin in their fat. Animals or fish that eat other animals have levels of dieldrin in their fat many times higher than animals or fish that eat plants. For more information, see Chapters 4 and 5. 3 1. PUBLIC HEALTH STATEMENT 1.3 HOW MIGHT I BE EXPOSED TO ALDRIN OR DIELDRIN? For most people, exposure to aldrin and dieldrin occurs when they eat contaminated foods. Contaminated foods might include fish or shellfish from contaminated lakes or streams, root crops, dairy products, and meats. Exposure to aldrin and dieldrin also occurs when you drink water, breathe air, or touch contaminated soil at hazardous waste sites. Skin contact and breathing of aldrin and dieldrin by workers who used these chemicals to kill insects were at one time common. However, aldrin and dieldrin are no longer used to kill insects. Some people who live in homes that were treated for termites with aldrin or dieldrin may breathe in these chemicals several years after the houses were treated. Exposure to aldrin is limited because aldrin is changed very quickly to dieldrin in the environment. Dieldrin stays in the environment for a long time. Most dieldrin in the environment is in soil or in animal fat. Levels of aldrin and dieldrin in air and water are very low. Levels in air and water are about 0.000001 parts of aldrin or dieldrin in 1 million parts of air or water (ppm). Background levels of dieldrin in soil are about 0.001 ppm. This is 1,000 times higher than background levels in air and water. Contamination of groundwater and soil at hazardous waste sites is limited. Only 0.71% of groundwater samples and 1.42% of soil samples had levels of aldrin or dieldrin above background. The average level of dieldrin in contaminated groundwater was 0.0004 ppm. The average level of dieldrin in contaminated soil was 0.057 ppm. The average level of aldrin in contaminated soil was 0.019 ppm. Contaminated fish contained about 0.030—0.050 ppm of dieldrin. The estimated average daily human intake of dieldrin from the air is 0.02 nanograms per kilogram of body weight (ng/kg/day). The 1982-1984 estimated daily intake from food is 10 ng/kg/day for infants and 16 ng/kg/day for young children. The estimated daily food intake for adults is 7-8 ng/kg/day. One nanogram is one million times less than 1 milligram. Refer to Chapter 5 for more information. 1.4 HOW CAN ALDRIN AND DIELDRIN ENTER AND LEAVE MY BODY? Aldrin can enter your bloodstream through your lungs when you breathe air. It can also enter through your stomach after eating food or drinking water containing it, or it can enter through your skin. Dieldrin can enter your bloodstream through your lungs, stomach, or skin. Exposure to aldrin or dieldrin around hazardous waste sites can occur by breathing contaminated air or touching contaminated soil. Exposure around hazardous waste sites can also occur by eating contaminated food or drinking contaminated water. Exposure of the general population most likely occurs through eating food contaminated with aldrin or dieldrin. Exposure of some infants occurs by drinking mother’s milk containing aldrin or dieldrin. Studies in animals show that both aldrin and dieldrin enter the body quickly after exposure. Once aldrin is inside your body, it quickly breaks down 4 1. PUBLIC HEALTH STATEMENT to dieldrin. Dieldrin then stays in your fat for a long time. Dieldrin can break down to other products. Most dieldrin and its breakdown products leave your body in the feces. Some breakdown products can also leave in the urine. It can take many weeks or years for all of the compound to leave your body. Chapter 2 contains more information on how aldrin and dieldrin enter and leave the body. 1.5 HOW CAN ALDRIN AND DIELDRIN AFFECT MY HEALTH? Aldrin and dieldrin cause similar adverse health effects. Exposure to very high levels of aldrin or dieldrin for a short time causes convulsions or kidney damage. One very young child died from drinking a solution containing a very high level of dieldrin. Another very young child died after eating food contaminated with aldrin. Exposure for a long time to somewhat lower levels of aldrin or dieldrin also causes convulsions. This occurs because aldrin and dieldrin build up in our bodies. Exposure to moderate levels of aldrin or dieldrin for a long time also causes headaches, dizziness, irritability, vomiting, or uncontrollable muscle movements. Some sensitive people develop a condition in which aldrin or dieldrin causes the body to destroy its own blood cells. We do not know whether aldrin or dieldrin affects the ability of men to father children. We also do not know whether aldrin or dieldrin causes birth defects or cancer in people. The International Agency for Research on Cancer has determined that aldrin and dieldrin are not classifiable as to their carcinogenicity to humans. The EPA has determined that aldrin and dieldrin are probable human carcinogens. Animal studies show effects of aldrin and dieldrin on the nervous system and on the kidneys similar to those seen in people. Results from animal studies also show additional effects of aldrin and dieldrin. We do not know whether these effects also occur in people. Animal studies show that aldrin and dieldrin cause increases in liver enzymes and liver weight. Also, animal studies show that exposure to moderate levels of aldrin and dieldrin for a short time causes decreased ability to fight infections. In addition, animals born to mothers who have eaten aldrin or dieldrin do not live very long. This results, in part, from the newly born animals being poisoned by aldrin or dieldrin in the mother’s milk. Studies in animals give conflicting information about whether aldrin and dieldrin causes birth defects. Studies in animals also give conflicting information about whether aldrin and dieldrin make it more difficult for male animals to reproduce. Some studies show that aldrin and dieldrin may damage sperm. Studies in animals show that mice that eat aldrin or dieldrin develop liver tumors. See Chapter 2 for more information. 5 1. PUBLIC HEALTH STATEMENT 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO ALDRIN OR DIELDRIN? Your body rapidly converts aldrin into dieldrin after it enters your body. Therefore, you can determine exposure to either aldrin or dieldrin by measuring the amount of dieldrin in your body. Laboratory tests can detect dieldrin in your blood, fat, breast milk, and body tissues after exposure to sufficiently high levels. Blood samples are used most often because they are easy to obtain. The blood test is simple and does not confuse exposure to aldrin or dieldrin with exposure to other chemicals. It is not routinely done at your doctor’s office. The amount of dieldrin in your body decreases slowly over time after an exposure is over. Blood levels remain elevated for a long time after the exposure has occurred. Therefore, elevated blood levels of dieldrin do not indicate whether exposure occurred recently or some time in the past. Some studies in people show that blood levels may predict whether harmful effects on the nervous system will occur. These studies predict that blood levels above 0.20 milligrams (mg) of dieldrin in a liter (L) of blood may produce harmful effects such as convulsions or uncontrollable muscle movements. See Chapters 2 and 6 for more information. 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The federal government has developed regulatory standards and guidelines to protect people from the harmful health effects of aldrin and dieldrin. In 1974, EPA banned all uses of aldrin or dieldrin except as a termite killer. In 1981, EPA required labeling changes to warn against applying these chemicals near water supplies, heating ducts, or crawl spaces. They also warned against applying them too frequently. EPA concludes that the maximum amount of aldrin and dieldrin present in bodies of water from which you drink water and eat seafood should not exceed 74 picograms per liter (pg/L, one billion times less than 1 mg/L) of aldrin or 71 pg/L of dieldrin. In theory, this would limit the risk for developing cancer to one in a million. If you do not drink water from the same source as you get seafood, the maximum amount of aldrin and dieldrin present in the water from which you get the seafood should not exceed 79 pg/L for aldrin or 76 pg/L for dieldrin. The Food and Drug Administration (FDA) regulates the residues of aldrin and dieldrin in raw foods. The allowable range for residues is from 0 to 0.1 ppm depending on the 6 1. PUBLIC HEALTH STATEMENT type of food product. This limits the intake of aldrin and dieldrin in food to levels considered to be safe. EPA has named aldrin and dieldrin as hazardous solid waste materials. If quantities greater than 1 pound enter the environment, the National Response Center of the federal government must be told immediately. The Occupational Safety and Health Administration (OSHA) recommended a maximum average amount of aldrin and dieldrin in the air in the workplace to protect workers. This amount is 250 micrograms in a cubic meter of air (pg/m‘) for an 8-hour workday over a 40-hour workweek. The National Institute for Occupational Safety and Health (NIOSH) recommended that exposure to aldrin and dieldrin be limited to the lowest amount that can be reliably measured. For more information, see Chapter 7. 1.8 WHERE CAN I GET MORE INFORMATION? If you have any more questions or concerns, please contact your community or state health or environmental quality department or: Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 This agency can also provide you with information on the location of the nearest occupational and environmental health clinic. These clinics specialize in the recognition, evaluation, and treatment of illnesses resulting from exposure to hazardous substances. 2. HEALTH EFFECTS 2.1 INTRODUCTION The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of aldrin/dieldrin and a depiction of significant exposure levels associated with various adverse health effects. It contains descriptions and evaluations of studies and presents levels of significant exposure for aldrin/dieldrin based on toxicological studies and epidemiological investigations. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure--inhalation, oral, and dermal-- and then by health effect--death, systemic, immunological, neurological, developmental, reproductive, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure periods--acute (14 days or less), intermediate (15—364 days), and chronic (365 days or more). Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse- effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects. These distinctions are intended to help the users of the document identify the levels of exposure at which adverse health effects start to appear. They should also help to determine whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown in the tables and figures may differ depending on the user’s perspective. For example, physicians concerned with the interpretation of clinical findings in exposed persons may be interested in levels of exposure associated with "serious" effects. Public health officials and project managers concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAEL) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels, MRI..s) may be of interest to health professionals and citizens alike. Levels of exposure associated with the carcinogenic effects of aldrin/dieldrin are indicated in Figures 2-1 and 2-2. Because cancer effects could occur at lower exposure levels, the figures also show a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10“1 to 107), as developed by EPA. Estimates of exposure levels posing minimal risk to humans (MRI..s) have been made, where data were believed reliable, for the most sensitive noncancer effect for each exposure duration. MRI..s include adjustments to reflect human variability and extrapolation of data from laboratory animals to humans. Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1989b), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised. 8 2. HEALTH EFFECTS 2.2.1 lnhalatlon Exposure Aldrin and dieldrin are structurally similar pesticides. The only difference between the structures of aldrin and dieldrin is the presence, in dieldrin, of an epoxide ring at the site of one of the carbon-carbon double bonds in aldrin. Because aldrin is rapidly metabolized to dieldrin in the body and converted to dieldrin in the environment, these two compounds are discussed together throughout this document. Virtually all of the studies presented in this section on inhalation exposure are either epidemiological reports of occupational exposure or case reports of either accidental or intentional poisonings. Extremely limited information was located regarding the effects of inhalation exposures of animals to aldrin or dieldrin. In many of the human and animal studies, inhalation exposure may occur simultaneously with dermal exposure. Thus, many of the effects reported in this section may be due, in part, to dermal exposure to aldrin or dieldrin. Furthermore, in occupational studies and case reports of poisonings, precise levels of exposure are not known. Thus, the results in this section are not presented in a table or figure. 2.2.1.1 Death No increase in mortality from any cause was reported in workers who had been employed in the manufacture of aldrin, dieldrin, endrin, and/or telodrin at a facility in the Netherlands for more than 4 years (cohort = 233 workers) (Van Raalte 1977; Versteeg and Jager 1973). Furthermore, in a 20-year follow-up of this population and expansion of the cohort to include workers exposed for at least 1 year between 1954 and 1970 (cohort = 570 workers), a lower than expected overall incidence of mortality was observed (de Jong 1991). Although the workers described by de Jong represented a unique population because they had been under observation for an average of 25.86 years, all of the studies described above are limited because of the small number of subjects used ($570 workers), uncertainty regarding exposure levels, and the potential exposure of the subjects to more than one of these pesticides and/or to other chemicals at the chemical manufacturing complex. Several of these studies have attempted to estimate exposures using blood levels. However, blood levels were not obtained for approximately 10 years (during what is expected to have been the period of heaviest exposures) and extrapolations were based on data obtained in astudy using constant daily low-level oral dosing (Hunter and Robinson 1967). It is unclear whether such extrapolations accurately reflect exposure levels in the occupational situation. Only two case studies were located regarding deaths that may have been attributable to occupational exposure to aldrin or dieldrin (Muirhead et a1. 1959; Pick et a1. 1965). One of these studies concerned a farmer with multiple exposures to insecticides that contained dieldrin. The farmer died in hemolytic crisis after developing immunohemolytic anemia (Muirhead et a1. 1959). Immunologic testing revealed a strong antigenic response to red blood cells coated with dieldrin. The other study concerned a worker from an orange grove who developed aplastic anemia and died following repeated exposures to aldrin during spraying (Pick et a1. 1965). In the latter study, the relationship between aldrin exposure and the aplastic anemia is considerably more tenuous, being linked only in that the onset of symptoms corresponded with spraying and the condition deteriorated upon subsequent exposure. Only very limited data were located regarding death in animals following inhalation exposure to aldrin or dieldrin. Cats, guinea pigs, rats, rabbits, and mice were exposed to aldrin vapors and particles generated by sublimating aldrin at 200°C (Treon et al. 1957b). Aldrin levels of 108 mg/m3 for 1 hour resulted in death in 9 out of 10 rats, 3 out of 4 rabbits, and 2 out of 10 mice. Cats and guinea 3pigs were less sensitive. One out of 1 cat and no guinea pigs died following exposure to 215 mg/m for 4 hours. Interpretation of the results of this study are limited in that sublimation may have resulted in the 9 2. HEALTH EFFECTS generation of atmospheres containing a higher proportion of volatile contaminants and thermal decomposition products than would be expected in atmospheres typical of most occupational exposures. 2.2.1.2 Systemlc Effects No studies were located regarding musculoskeletal effects in humans or animals after inhalation exposure to aldrin or dieldrin. Respiratory Effects. Extremely limited information is available regarding the respiratory effects of aldrin and dieldrin in humans after inhalation exposure. A study of workers with at least 4 years of employment in the manufacture of aldrin, dieldrin, endrin, or telodrin found no new pulmonary disease or deterioration of existing pulmonary disease (Jager 1970). Similarly, no increase in mortality from respiratory diseases was noted in workers employed for at least 1 year at the same plant during 1954—1970 when these workers were followed for at least 20 years (de Jong 1991). In contrast, in another study that examined workers involved in the manufacture of aldrin, dieldrin, and/or endrin for at least a year, a significantly increased incidence of pneumonia and other pulmonary diseases was found when compared to the incidence in US. white males (Ditraglia et al. 1981). However, all of these studies are limited by small sample size and the possible exposure of the workers to other chemicals and/or pesticides. Extremely limited data were located regarding respiratory effects in animals after inhalation exposure to aldrin or dieldrin. Cats, guinea pigs, rats, rabbits, and mice exposed to aldrin vapors and particles generated by sublimating aldrin at 200°C were reported to have exhibited symptoms indicative of mucous membrane irritation (Treon et al. 1957b). However, the exposure levels associated with these effects were not reported, and the contribution of thermal decomposition products or other volatile contaminants other than aldrin cannot be eliminated. Cardlovascular Effects. Very limited information is available regarding the cardiovascular effects of aldrin and dieldrin in humans after inhalation exposure. Suggestive evidence of an association between dieldrin and hypertension was obtained in a study examining disease incidence in patients with elevated fat levels of dieldrin (Radomski et al. 1968). However, the number of patients with hypertension in this study was low (eight cases), and elevated fat levels of other pesticide residues also correlated with hypertension. Furthermore, other studies did not support the correlation of hypertension with dieldrin exposure. For example, a study examining disease incidence in 2,620 pesticide-exposed workers reported no increase in the incidence of hypertension in workers with elevated serum dieldrin (Morgan et al. 1980). Also, workers involved in the manufacture of aldrin, dieldrin, endrin, or telodrin for at least 4 years had normal blood pressure (Jager 1970). Similarly, no increased mortality from circulatory system diseases was observed in the mortality study by de Jong (1991). All of these studies are limited because the subjects were exposed to a variety of other chemicals. » A slight, but significant, increase in serum cholesterol was observed in pesticide-exposed workers with elevated serum dieldrin (Morgan and Lin 1978). However, this study was limited in that the workers were occupationally exposed to a number of different pesticides and other chemicals including hydrocarbon solvents. No studies were located regarding cardiovascular effects in animals after inhalation exposure to aldrin or dieldrin. 10 2. HEALTH EFFECTS Gastrointestinal Effects. No increased mortality from digestive system causes was observed in a mortality study of workers employed in the manufacture of aldrin and dieldrin for at least 1 year between 1954 and 1970 (de Jong 1991). No studies were located regarding gastrointestinal effects in animals after inhalation exposure to aldrin or dieldrin. Hematological Effects. No abnormal values for hemoglobin, white blood cells, or erythrocyte sedimentation rate were found in workers who had been employed in the manufacture of aldrin, dieldrin, endrin, or telodrin for at least 4 years (Jager 1970). Similarly, no increase in blood diseases was observed in a morbidity study of workers employed at the plant described by Jager (1970) over the period of 1979 to 1990 (de Jong 1991). Also, workers who had been involved in either the manufacture or application of pesticides and who had elevated blood levels of dieldrin, had no hematological effects of clinical significance (Morgan and Lin 1978; Warnick and Carter 1972). These studies are limited by either potential exposure to other chemicals (de Jong 1991; Jager 1970; Morgan and Lin 1978) or by known exposure to other pesticides as demonstrated by elevated blood levels of "B—benzine [sic] hexachloride" (IS-benzene hexachloride), heptachlor epoxide, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (p,p’—DDT), 1,1,1-trichloro-2-(g-chlorophenyl)2-(p—chlorophenyl)ethane (g,p’-DDT), and 1,1-dichloro-2,2-bis(p-chloro- phenyl)ethene (p,p’-DDE) (Warnick and Carter 1972). A case of immunohemolytic anemia attributable to multiple dieldrin exposures was reported (Muirhead et al. 1959). Also, a worker from a grove where aldrin was sprayed developed aplastic anemia (Pick et al. 1965) and one person employed in the manufacture of aldrin and dieldrin between 1954 and 1970 died from aplastic anemia (de Jong 1991). However, it is unclear whether these cases of aplastic anemia were directly due to aldrin or dieldrin exposures because exposure to a variety of other chemicals was possible. Also, three cases of pancytopenia and one case of thrombocytopenia associated with exposure to dieldrin were reported during 1961 (AMA 1962). However, no assessment of whether dieldrin was the causative agent was provided in the report. No studies were located regarding hematologic effects in animals after inhalation exposure to aldrin or dieldrin. Hepatic Effects. Although a slight increase in serum hepatic enzymes (serum glutamate-oxaloacetate transaminase [SGOT] and serum glutamate-pyruvate transaminase [SGPT]) has been observed to correlate with serum dieldrin levels in one study of pesticide-exposed workers (Morgan and Lin 1978), no evidence of any hepatic effects of aldrin or dieldrin exposure have been observed in other studies of workers involved in either the manufacture (de Jong 1991; Hoogendam et al. 1965; Hunter et al. 1972; Jager 1970; van Sittert and de Jong 1987) or the manufacture or application (Morgan and Roan 1974; Warnick and Carter 1972) of these pesticides. Parameters that have been examined in the negative studies include serum hepatic enzyme activity (Hoogendam et al. 1965; Jager 1970; Morgan and Roan 1974; van Sittert and de Jong 1987; Warnick and Carter 1972), hepatic enlargement (Jager 1970), and tests intended to detect microsomal enzyme induction (Hunter et al. 1972; Jager 1970; Morgan and Roan 1974; van Sittert and de Jong 1987). All of the studies are limited by the potential exposure of the workers to other chemicals and/or organochlorine pesticides. No studies were located regarding hepatic effects in animals after inhalation exposure to aldrin or dieldrin. 11 2. HEALTH EFFECTS Renal Effects. No evidence of renal damage was seen in workers employed for 4 or more years in the manufacture of aldrin or dieldrin (Jager 1970). This study is limited by the potential exposure of the workers to other chemicals. No studies were located regarding renal effects in animals after inhalation exposure to aldrin or dieldrin. Dermal/Ocular Effects. No evidence of dermatitis was seen in workers employed for 4 or more years in the manufacture of aldrin, dieldrin, endrin, or telodrin (Jager 1970). This study is limited by the possible exposure of the workers to other chemicals. Extremely limited data were located regarding dermal/ocular effects in animals after inhalation exposure to aldrin or dieldrin. Cats, guinea pigs, rats, rabbits, and mice exposed to aldrin vapors and particles generated by sublimating aldrin at 200°C were reported to have exhibited symptoms indicative of mucous membrane irritation (Treon et al. 1957b). However, the exposure levels associated with these effects were not reported and the contribution of thermal decomposition products or other volatile contaminants other than aldrin cannot be eliminated. 2.2.1.3 Immunological Effects Limited information is available regarding the immunological effects of aldrin or dieldrin in humans after inhalation exposure. A case report was located concerning a pesticide sprayer who developed immunohemolytic anemia after multiple exposures to dieldrin, heptachlor, and toxaphene (Muirhead et al. 1959). Antibodies for dieldrin-coated or heptachlor-coated red blood cells were found in the subject’s serum. However, this study is limited because of the exposure of the subject to other pesticides. No studies were located regarding immunological effects in animals after inhalation exposure to aldrin or dieldrin. 2.2.1.4 Neurologlcal Effects Central nervous system excitation culminating in convulsions was the principal adverse effect noted in occupational studies of workers employed in either the application or manufacture of aldrin or dieldrin. In many cases, convulsions appeared suddenly and without prodromal signs (Hoogendam et al. 1965; Kazantis et al. 1964; Patel and Rao 1958). Electroencephalograms (EEGs) taken shortly after the convulsions revealed bilateral irregular alpha rhythms interrupted by spike and wave patterns (Avar and Czegledi-Janko 1970; Kazantis et al. 1964). In one case study of dieldrin sprayers who developed convulsions, the convulsive episodes did not follow known accidental overexposures (Patel and Rao 1958). Rather, the convulsions developed anywhere from 14 to 154 days after the first exposure to dieldrin. The time to onset was more rapid for those sprayers using the more concentrated spray. An accumulative type of intoxication was also reported in workers involved in the manufacture of aldrin, dieldrin, telodrin, or endrin (Jager 1970). In this report, convulsions were believed to have been caused by either accumulating levels of dieldrin in the blood or modest overexposures in the presence of subconvulsive accumulations of dieldrin. Other central nervous system symptoms reported by workers involved in the manufacture or application of aldrin and/or dieldrin included headaches (Jager 1970; Patel and Rao 1958), dizziness (Jager 1970), hyperirritability (Jager 1970; Kazantis et al. 1964), general malaise (Jager 1970), nausea and vomiting (Jager 1970; Kazantis et al. 1964), anorexia (Jager 1970), muscle twitching (Jager 1970; Patel and Rao 1958), and 12 2. HEALTH EFFECTS myoclonic jerking (Jager 1970; Kazantis et al. 1964). The more severe symptoms were accompanied by EEG patterns with bilateral spike and wave complexes and multiple spike and wave discharges in the alpha region (Jager 1970; Kazantis et al. 1964). Less severe symptoms were accompanied by bilateral theta (Jager 1970; Kazantis et al. 1964) and/or delta (Kazantis et al. 1964) wave discharges. In all cases in which follow-up of the subjects was reported, removal from the source of exposure caused a rapid physical recovery and a slower recovery of the EEG activity (within a year) to normal levels (Avar and Czegledi-Janko 1970; Hoogendam et al. 1962, 1965; Jager 1970; Kazantis et al. 1964). A morbidity study of workers employed in the manufacture of aldrin and dieldrin between 1979 and 1990 noted no degenerative disorders of the nervous system (de Jong 1991). However, this study reported significant increases in mental diseases among those <30 years old antI in those 46-50 years old. The diseases were classified as stress reactions, short-term depression, or sleep disorders. It is unclear whether these effects were the result of aldrin/dieldrin exposure. Results from a comprehensive neurological workup of 27 workers involved in either the manufacture or application of dieldrin were compared to those of a group of unexposed workers (Sandifer et al. 1981). Scores on five psychological tests were significantly different from those of the unexposed controls; however, the importance of the results was questioned by the authors because of differences in the degree of literacy between the two groups. Also, three exposed workers had abnormal electromyograms (EMGs) suggesting a peripheral neuropathy. However, EMGs were not obtained in the control group; thus, the significance of these results is unknown. No studies were located regarding neurological effects in animals after inhalation exposure to aldrin or dieldrin. 2.2.1.5 Developmental Effects No studies were located regarding developmental effects in humans or animals after inhalation exposure to aldrin or dieldrin. 2.2.1.6 Reproductive Effects No studies were located regarding reproductive effects in humans or animals after inhalation exposure to aldrin or dieldrin. 2.2.1.7 Genotoxlc Effects Sister chromatid exchanges and chromosomal aberrations were studied in a population of floriculturists occupationally exposed to several pesticides, including aldrin (Dulout et al. 1985). A statistically significant increase in sister chromatid exchanges was seen in workers with clinical symptoms of pesticide exposure as compared to those without symptoms. There was also an increase in exchange-type chromosome aberrations in this population when compared to nonfloriculturists. Interpretations based on this study are limited because the route and dose of exposure could not be determined, since the workers could have been exposed via inhalation or dermal contact following the spraying of the greenhouses with the pesticide aerosols. In addition, there was concomitant exposure to other organophosphorus, carbamate, and organochlorine insecticides. 13 2. HEALTH EFFECTS Lymphocytes from workers in a dieldrin manufacturing facility were examined for chromosome aberrations (Dean et al. 1975). No statistically significant differences in either chromatid-type or chromosome-type aberrations were seen in current workers when compared to former workers or to unexposed controls. While there was no occupational exposure to other pesticides in this study, the exposure could have occurer via inhalation and/or dermal contact. No studies were located regarding genotoxic effects in animals after inhalation exposure to aldrin or dieldrin. Other genotoxicity studies are discussed in Section 2.4. 2.2.1.8 Cancer A number of epidemiological studies were located that examined the incidence of cancer in workers exposed to aldrin or dieldrin. Workers who had been employed in the manufacture of aldrin, dieldrin, endrin, and/or telodrin for 4 or more years were evaluated by Van Raalte (1977) and again several years later by Ribbens (1985). Of the 232 workers studied by Ribbens (1985), 166 were studied by Van Raalte (1977). No evidence for a carcinogenic effect of aldrin or dieldrin was obtained in these studies. No correlation was observed between the incidence of cancer and the extent of exposure in the study by Van Raalte (1977). Also, the incidence of cancer in the workers studied by Ribbens (1985) was less than that found in the general population. Similarly, among 76 deaths of workers who were employed at the same plant for at least 1 year between 1954 and 1970, no increase was observed in mortality due to neoplasms in general; cancers of the stomach, large intestine, rectum, liver, pancreas, lung, prostate, bladder, or kidney; multiple myeloma; or leukemia (de Jong 1991). Additional analyses of the group of workers employed at the Netherlands pesticide manufacturing facility were performed by Sielken and Stevenson (1992). These authors found no increase in the likelihood of cancer mortalities in this population after analyzing the data using several paradigms and correcting for factors such as duration of exposure, duration of follow-up, and age at first exposure. However, these studies are limited by the small number of subjects studied and the potential exposure of these workers to a mixture of chemicals. A morbidity study of 570 workers employed in the manufacture of aldrin/dieldrin at the same facility between 1979 and 1990 also showed no increase in malignant neoplasms (de Jong 1991). In contrast, a significant increase in benign lesions (mainly subcutaneous lipomas) was observed in workers from this group aged 36—40 years. A separate group of workers employed in the manufacture of aldrin, dieldrin, and endrin had no significant increase in the incidence of cancer (Ditraglia et al. 1981). However, the authors concluded that too few deaths occurred in the group to draw any meaningful conclusions. No studies were located regarding cancer in animals after inhalation exposure to aldrin or dieldrin. 2.2.2 Oral Exposure 2.2.2.1 Death A 2-year-old child died a short time after consuming an unknown quantity of a 5% solution of dieldrin (Garrettson and Curley 1969). It is unclear from this report whether the child died during the severe convulsions produced by the dieldrin or during the postictal period (the period immediately following a seizure that is characterized by central nervous system depression). This child’s 4-year-old brother, who also consumed an unknown quantity of the 5% dieldrin solution, experienced severe convulsions but recovered completely. 14 2. HEALTH EFFECTS Of several persons who consumed wheat that had been mixed with aldrin and lindane for a period of 6-12 months, an infant female child died within a few hours after experiencing a severe generalized convulsion (Gupta 1975). The doses at which aldrin is acutely lethal in experimental animals are quite similar to lethal dieldrin doses. Oral LD50 values for single doses of aldrin in rats ranged from 39 to 64 mg/kg (Gaines 1960; Treon et al. 1952). Oral LD50 values for single doses of dieldrin in adult rats ranged from 37 to 46 mg/kg/day (Gaines 1960; Lu et al. 1965; Treon et al. 1952). Aldrin was lethal in females at a slightly lower dose when it was administered in solution in oil (LD50 = 48 mg/kg) than when it was administered in a kerosene vehicle (LD50 = 64 mg/kg) (Treon et al. 1952). The age of the animals appeared to influence the acute toxicity of a single administration of dieldrin. Newborn rats had a relatively high LD50 (168 mg/kg) (Lu et al. 1965); whereas 2-week-old rats had an LD50 of 25 mg/kg, which is somewhat lower that the adult LD50 value (Lu et al. 1965). When aldrin was widely used as an insecticide, several incidents were reported in which livestock died as the result of accidental mixing of unspecified amounts of aldrin with livestock feed (Buck and Van Note 1968). In an incident in which both calves and adult cattle were exposed, mortality occurred exclusively among the calves. Decreased survival in animals consuming aldrin and/or dieldrin over longer periods was seen at lower doses. Rats exposed to aldrin or dieldrin for 6 weeks exhibited an increase in mortality at doses of aldrin or dieldrin of 8 mg/kg/day (NCI 1978a). All rats consuming 15 mg/kg/day aldrin or dieldrin in the diet died by the end of the 2nd week of exposure (Treon et al. 1951a). When exposed for 2 years or more, rats exhibited decreased survival at doses of 2.5—5 mg/kg/day aldrin (Deichmann et al. 1970; Fitzhugh et al. 1964; Reuber 1980) or 0.5-2.5 mg/kg/day dieldrin (Deichmann et al. 1970; Fitzhugh et al. 1964; Harr et al. 1970; Reuber 1980). In intermediate- and chronic-duration studies, dogs and mice appeared to have a sensitivity to the lethal effects of aldrin and/or dieldrin that is similar to that of rats. All dogs given aldrin at doses of 0.89-1.78 mg/kg/day or dieldrin at doses of 1.95—4.24 mg/kg/day died or were killed in a moribund condition in a 9-month dietary study (Treon et al. 1951b). Dogs appeared to survive for longer periods if the dog was larger or older at the start of the study. Decreased survival in dogs exposed for 25 months was also observed at 1 mg/kg/day aldrin or 0.5 mg/kg/day of dieldrin (Fitzhugh et al. 1964). In mice, decreased survival was seen at 1.3 mg/kg/day of aldrin or dieldrin (Thorpe and Walker 1973; Walker et al. 1972). In contrast, hamsters appeared to be less sensitive to dieldrin. Slightly over 2 years of exposure to 14.94 mg/kg/day of dieldrin had no effect on hamster survival (Cabral et al. 1979). The highest NOAEL values, all LD50 values, and all reliable LOAEL values for death in each species and duration category are recorded for aldrin in Table 2—1 and for dieldrin in Table 2-2 and plotted for aldrin in Figure 2-1 and for dieldrin in Figure 2-2. 2.2.2.2 Systemlc Effects No studies were located regarding dermal/ocular effects in humans or animals after oral exposure to aldrin or dieldrin. The highest NOAEL values and all reliable LOAEL values for each study for each end point for dieldrin are recorded in Table 2-2 and plotted in Figure 2-2. TABLE 2-1. Levels of Significant Exposure to Aldrin - Oral LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure° Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference ACUTE EXPOSURE Death 1 Rat (G) 1 d 63.6 (LD50) Ireon et al. 1952 2 Rat (F) 2 uk 15 (20/20 died by the Treon et al. ad lib end of week 2) 1951a 3 Rat (ca) 1 x 39 (male L050) Gaines 1960 N 60 (female L050) 6 I. Rat (GO) 1 d 48.3 (L050) Treon et al. 5 1952 I 2} Neurological a 2 S Rat (GO) 3 d S 10 (convulsions) Mehrotra et al. 0’ 1x/d 1989 Developmental 6 Mouse (GO) 1 x 25 (webbed feet) Ottolenghi et Gd 9 al. 1974 7 Mouse (GO) 5-7 d 2b (increased seizure Al-Hachim 1971 threshold in offspring) 8 Hamster (G0) 1 x 50 (increased fetal Ottolenghi et Gd 7, 8 mortality) al. 1974 or 9 Reproductive 9 Mouse (G) 5 d 1.0 Epstein et al. 1972 91 TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figureu Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference INTERMEDIATE EXPOSURE Death 10 Rat (F) 6 wk 8 (2/10 died) NCI 1978a ad lib 11 Mouse (F) 6 uk 2.6 (2/10 died) NCI 1978a ad lib 12 Dog (F) 9 mo 0.89- (2/2 died) Treon et al. ad lib 1.78 1951b 13 Dog (C) 5 uk 1.5 (3/3 died-pre- Treon et al. 5d/Hk weanlings) 1955b Systemic 14 Rat (F) 27 wk Hepatic 1.25 Treon et al. ad lib Renal 1.25 1953b 15 009 (F) 9 mo Gastro 0.89- (vomiting) Treon et al. ad lib 1.78 1951b Hepatic 0.89- (moderate 1.78 hepatocellular degeneration) Neurological 16 Dog (F) 9 mo 0.89- (hypersensitivity; Treon et al. ad lib 1.78 tremors; 1951b convulsions; neuronal degeneration) $103153 HHVBH '2 9L TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figurea Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference CHRONIC EXPOSURE Death 17 Rat (F) 2 yr 5 (increased Fitzhugh et al. ad lib mortality) 1964 18 Rat (F) 31 mo 2.5 (decreased Deichmann et al. 7d/uk lifespan in 1970 females) Systemic 19 Rat (F) 2 yr Renal 0.5 (nephritis) Reuber 1980 20 Rat (F) 2 yr Hepatic 0.025c (hepatocellular Fitzhugh et al. ad lib vacuolation; 1964 ‘5 bile duct ; proliferation) Renal 0.5 2.5 (bladder hemorrhages) 21 Dog (F) 15.7 mo Hepatic 0.04- 0.12- (hyaline droplet Treon et al. 7d/uk 0.09 0.25 degeneration) 1955b 1-3x/d Renal 0.04- (vacuolation of 0.09 renal tubules) Neurological 22 Rat (F) 74-80 uk 1.5 (convulsions) NC! 1978a ad lib 23 Mouse (F) so uk 0.39 (hyper- MCI 1978: ad lib excitability) 3103533 HJJVEH '2 LL TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figurea Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Developmental 24 Rat (F) 3 gen 0.125 (increased mortality Treon et al. ad lib of offspring) 1954a Reproductive 25 Rat (F) 3 gen 0.625 (decreased number Treon et al. ad lib of litters) 1954a Cancer 26 Rat (F) 74-80 uk 1.5 (GEL-thyroid) NCI 1978a ad lib 27 Mouse (F) 2 yr 1.3 (GEL-liver) Davis and 7d/uk Fitzhugh 1962 28 Mouse (F) 80 wk 0.52 (GEL-liver) NC! 1978a ad lib ‘The number corresponds to entries in Figure 2-1. bUsed to derive an acute oral Minimal Risk Level (MRL) of 0.002 mg/kg/day; dose divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). cUsed to derive a chronic oral Minimal Risk Level (MRL) of 0.00003 mg/kg/day; dose divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). ad lib ad libitum; (C) = capsule; CEL = cancer effect level; d = day(s); (F) = feed; (G) = gavage (not specified); Gastro gastrointestinal; Gd = gestation day(s); gen = generation(s); (GO) = gavage (oil); L050 = lethal dose, 50% kill; LOAEL = louest-observed-adverse-effect level; mo = month(s); NOAEL = no-observed-adverse-effect level; wk = Heek(s); x = time(s); yr = year(s) SLOSJAS HlJVEH 'Z 91 FIGURE 2-1. Levels of Significant Exposure to Aldrin - Oral ACUTE INTERMEDIATE (<_1 4 Days) (1 5-364 Days) Systemic .98 0 (6‘3 f f g A"? 09 S 3 f 0" ‘4‘) 0° Q of 0 ~29? 0R 9") (Mg/1:13 — — —— —-—- =2; '3' I“ .3, 02v 08'" 10 - .51 .101 Osr .1 ¢7m .1“ 1m 1 ' I .120 0150 01500'4' 01" .160 I 09'" I . I 0.1 ' I I 0.01 '- I I I v 0.001 - 0.0001 b Kev ' R“ I LCSOILDSO °-°°°°‘ ‘ "‘ MW” 0 LOAEL ior serious cum (animals) - 3 W’ 0 LOAEL Ior loos scrim oiled: (anlmnls) : “mm" "3" '°"" '°' 0 NOAEL (animals) I effects 019m IMn cancer 9 CEL - Cancer E11001 Laval (animals) V The number next to each point 0011000000010 mm In Table 2-1. ' Doses mprmnttno Iowostdoootosted pormdymalproducod atumorigonic mponso anddonollmplytho oflntonoooinhmholdiorflnuneorond point. $103353 Hl1V3H '3 6i FIGURE 2-1 (Continued) CHRONIC (z 365 Days) Systemic 0 o”? ~2~ 9° 0° ‘9 (mg/kg/day) _ _ 100 - 10 - .17r Our 020, 1 . .22' .27". .26r 01m Ozor 023m .25'02em o_1 .- 02m .24, 0th 021d 10" ('20: 0.01 - r ' 10’5 Estimated : Human 0.001 l- . Ciincef I 10-8 Rusk Levels l 0.0001 - : 7 W 10‘ 0.00001 - Key V PM I LCSO/LDSO . "‘ MW“ 0 LOAELt0rserlousetlects(enimels) I Mlnimalrlsk Ievellcr Z :sz‘" O LOAELlorlessserlous effects (anlmels) : 0"th “berth!" 08W 0 NOAEL(enlmels) V O CEL - Cancer Eflect Level (animals) The number next to each point corresponds to entrles In Table 2-1. ‘ Doses represent the lowest dose tested per study that produced a tumorlgenlc response and do not lmpty the existence ot a threshold lor the cancer and polnt. $133553 H.L'IVE|H '3 TABLE 2-2. Levels of Significant Exposure to Dieldrin - Oral LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figurea Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference ACUTE EXPOSURE Death 1 Rat (GO) 1 x 168 (newborn-L050) Lu et al. 1965 2 Rat (G0) 1 x 37 (young adult-L050) Lu et al. 1965 3 Rat (GO) 4 d 9 (14—16 day old Lu et al. 1965 1x/d -L050) 4 Rat (GO) 1 x 46 (L050) Gaines 1960 5 Rat (GO) 1 x 25 (14-16 day old Lu et al. 1965 ~LDSO) 6 Rat (GO) 4 d 54.8 (young adult-L050) Lu et al. 1965 1x/d 7 Rat (F) 2 wk 15 (5/5 died by the end Treon et al. ad lib of week 2) 1951a 8 Rat (G0) 1 d 38.8 (L050) Treon et al. 19523 9 Rat (GO) 10 d 6 (13/32 dams died) Chernoff et al. 1x/d 1975 Gd 7-16 10 Mouse (F) 1-2 Hk 7.5 (4/4 died) Wright et al. ad lib 1972 Systemic 11 Rat (GO) 3 d Cardio 10 Mehrotra et al. 1x/d 1989 12 Rat (GO) 1 x Hepatic 30 (decreased lipid Kohli et al. peroxidation) 1977 5103553 HLWVEH 'Z 13 TABLE 2'2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figurea Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference 13 Rat (GO) 1 x Hepatic 26 (increased lipid Goel et al. 1988 peroxidation) 14 Mouse (F) 1-2 uk Hepatic 1.6 Hright et al. ad lib 1972 Immunological 15 Mouse (F) 2 wk 0.065b (impaired antigen Loose et al. ad lib processing) 1981 16 Mouse (GO) 2 x 16.6 (impaired T-cell Fournier et al. activity) 1988 17 Mouse (GO) 1 x 12 18 (increased Krzystyniak et lethality of al. 1985 infection) Neurological 18 Rat (GO) 1 x 8.4 16.7 (disrupted operant Burt 1975 behavior) 19 Rat (GO) 1 x 40 (hypothermia) 50 (convulsions) Wagner and Greene 1978 20 Rat (GO) 1 x 25 (increased evoked Hoolley et al. potentials) 1985 21 Rat (G0) 1 x 2.5 (disrupted operant Burt 1975 behavior) 22 Rat (GO) 1 x 0.5 (impaired Carlson and behavior) Rosellini 1987 23 Sheep (C) 4 d 20 (impaired Operant Sandler et al. behavior; EEG changes) 1969 SiOdeS HLWVBH '8 TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figurea Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Developmental 24 Rat (GO) 10 d 6 Chernoff et al. 1x/d 1975 Gd7-16 25 Mouse (G0) 13 d 2 (low glucose Costella and Gd6-18 level in Virgo 1980 neonates) 26 Mouse (GO) 1 x 15 (webbed foot; cleft Ottolenghi et Gd 9 palate) al. 1971. l" I 27 Mouse (GO) 10 d 1.5 3 (supernunerary chernoff et al. g 1x/d ribs) 1975 Z Gd7-16 I m 28 Hamster (GO) 1 x 30 (open eye; webbed Ottolenghi et i? Gd 7, 8 foot; cleft al. 1974 $3 or 9 palate; increased 0’ resorptions; increased fetal mortality) INTERMEDIATE EXPOSURE Death 29 Rat (F) 6 uk 16 (7/10 died) NCI 1978a ad lib 30 Mouse (F) 74 d 2.6 (increased Virgo and ad lib mortality) Belluard 1975 31 Mouse (F) 6 wk 2.6 (7/10 died) NCI 1978a ad lib 32 Dog (F) 9 mo 1.95- (3/3 died) Treon et al. ad lib 4.24 1951b 93 IABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figurea Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Systemic 33- Rat (F) 27 wk Hepatic 1.25 Treon et al. ad lib Renal 1.25 1953b 34 Rat (F) 85 d Hepatic 0.00035 Olson et al. 1x/d 1980 3S - Rat (F) 1-6 mo Hepatic 2 (decreased hepatic Shakoori et al. ' protein; areas of 1982 necrosis) 36 Rat (GO) 15 d Hepatic 5 (diffuse necrosis) Bandyopadhyay et 1x/d Renal 5 (glomerulonephritis; al. 1982b renal tubular nephrosis) 37 Rat (F) 6 mo Hepatic 10 (hepatocellular Ahmed et al. ad lib necrosis) 19863 Renal 10 (epithelial cell degeneration) 38 Mouse (F) 40 wk Hepatic 1.6 Hright et al. 1972 39 009 (F) 9 mo Gastro 0.73- 1.95- (vomiting) Treon et al. ad lib 1.85 4.24 1951b Hepatic 0.73- (moderate 1.85 hepatocellular degeneration) Innunological 40 Mouse (F) 10 wk 0.13 (increased Loose 1982 ad lib lethality of infections) 41 House (F) 3, 6, 0.13 (increased tumor Loose et al. 18 wk lethality) 1981 7d/uk 1x/d $103333 HlJVEH 'Z 93 IABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figurea Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Neurological 42 Rat (F) 60-120 d 0.025 0.25 (disrupted operant Burt 1975 behavior) 43 Rat (F) 60 d 0.5 (tremors) Mehrotra et al. ad lib 1988 44 Dog (F) 9 mo 0.73- (neuronal Treon et al. ad lib 1.85 degeneration 1951b convulsions) 45 Monkey (F) 55-109 d 0.01 0.1 (learning deficit) Smith et al. 1x/d 1976 Developmental 46 Mouse (F) 74 d 0.33 0.65 (increased pup Virgo and ad lib mortality) Bellward 1975 Reproductive 47 Mouse (F) 74 d 0.65 1.3 (decreased Virgo and ad lib fertility) Bellward 1975 48 Mouse (F) 74 d 0.65‘ 1.3 (long latency to Virgo and ad lib nursing) Bellward 1977 49 Mouse (F) 120 d 0.65 (decreased litter Good and Hare 1x/d size) 1969 CHRONIC EXPOSURE Death 50 Rat (F) 2 yr 2.5 (5/24 survived Fitzhugh et al. ad lib versus 12/24 in 1964 controls) $103533 HLWVSH 'Z 93 TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figurea Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference 51 Rat (F) 31 mo 1.5 (decreased survival Deichmann et al. in females) 1970 52 Mouse (F) 132 uk 1.3 (50% mortality Halker et al. 1x/d reached at 15 1972 months versus 20-24 months in controls) 53 Mouse (F) 128 wk 1.3 (decreased survival) Halker et al. 1x/d 1972 P9 Systemic I Si‘ 54 Human (C) 18 mo Hemato 0.003 Hunter and E; Hepatic 0.003 Robinson 1967 I n) "n 55 Rat (F) 2 yr Renal 2.5 5 (bladder Fitzhugh et al. ER ad lib hemorrhages) 1964 53 on 56 Rat (F) 2 yr Renal 2.5 (nephritis) Reuber 1980 57 Rat (F) 2 yr Hemato 0.5 Walker et al. ad lib Hepatic 0.5 1969 58 Mouse (F) 2 yr Hepatic 1.3 (liver Thorpe and hyperplasia) walker 1973 59 Mouse (F) 92 wk Hepatic 10 Tennekes et al. 7d/wk 1981 ad lib 60 Dog (C) 2 yr Hemato 0.05 Walker et al. 1x/d Hepatic 0.005c 0.05 (increased serum 1969 alkaline phosphatase) 93 TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figurea Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference 61 Dog (F) 15.7 mo Hepatic 0.14- Treon et al. 7d/wk 0.26 1955 1-3x/d Renal 0.14- (vacuolation of 0.26 renal tubules) 62 Monkey (F) 69 mo Hepatic 0.1 Wright et al. 1x/d 1978 Neurological 63 Human (C) 18 mo 0.003 Hunter and Robinson 1967 64 Rat (F) 59-80 wk 1.45 (hyper— NC] 19783 ad lib excitability) 65 Rat (F) 2 yr 0.05 0.5 (convulsions) Walker et al. ad lib 1969 66 Rat (F) 104- 0.5 2.5 (convulsions) NCI 1978b 105Hk ad lib 67 Mouse (F) 80 wk 0.33 (tremors) NC] 1978a ad lib 68 Dog (C) 2 yr 0.05 Walker et al. 1x/d 1969 Developmental 69 Rat (F) 3 gen 0.125 (increased Treon et al. ad lib mortality of 1954a offspring) Reproductive 70 Rat (F) 3 gen 0.125 (decreased Treon et al. ad lib number of 19543 litters) SiOdeS HLWVEH '8 £8 TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figurea Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Cancer 71 Mouse (F) 75 wk 1.3 (CEL--liver) Lipskey et al. ad lib 1989 72 Mouse (F) 132 wk 1.3 (CEL--liver) Walker et al. 1x/d 1972 73 Mouse (F) 80 wk 0.65 (CEL--liver) NCI 1978a ad lib 74 Mouse (F) 2 yr 1.3 (CEL--liver) Davis and 7d/uk Fitzhugh 1962 N I 75 Mouse (F) 85 wk 1.3 (CELuliver) Meierhenry et g ad lib al. 1983 E; I 76 Mouse (F) 140 wk 0.013 (decreased time Tennekes et al. In to tunor 1982 m development) {3 a) 77 Mouse (F) 128 wk 0.33 (CEL--liver) walker et al. 1x/d 1972 78 Mouse (F) 92 wk 1.3 (CEL--liver) Tennekes et al. 7d/wk 1981 ad lib aThe number corresponds to entries in Figure 2-2. bUsed to derive an acute oral Minimal Risk Level (MRL) of 0.00007 mg/kg/d; dose divided by an uncertainty factor of 1000 (10 for use of LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). cUsed to derive a chronic oral Minimal Risk Level (MRL) of 0.00005 mg/kg/d; dose divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). ad lib = ad libitum; (C) = capsule; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); EEG = electroencephalogram; (F) = feed; Gastro = gastrointestinal; Gd = gestation day(s); gen = generation(s); (GO) = gavage (oil); Hemato = hematological; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no-observed-adverse-effect level; wk = ueek(s); x = time(s); yr = year(s) 93 FIGURE 2-2. Levels of Significant Exposure to Dieldrin - Oral ACUTE (314 Days) Systemic fie 45> s "’ «5‘9 f ‘9 §' ° (394; 9 0°" (if x9 \s“ so" 0° (mg/kg/day) - 1,000 - I tr 100 F .8! 3: .4r '7' 191 019' 0m 0131 .283 5' 0 17m 13: flea 10 .. 16m .28!“ . .3, Ottr Hmow 10m .9' 024: 021' 827'“ 1 _ 014m zsmo 27m .22r 0.1 ’- 015m I 0.01 - I I I 0.001 - : l I 0.0001 \l/ Key 0.00001 ‘ 7 Ha: I LC50/L050 I m Mouse I Minlmal risk level for O LOAEL lor serious effects (animals) I h Rabblt ettects other than cancer 0 LOAEL for less serious ettects (animals) I s Harmter V 6 Dog 0 NOAEL (anlmals) k Monkey 9 CEL - Cancer Ellect Level (anlmals) a Sheep A NOAEL - Human The number next to each point corresponds to entrles In Table 2-2. ‘ Doses represent the lowest dose tested per study that produceda tumorlgenlc response and do not imply the exlstence of e threshold tor the cancer and polnt SLOSJJE HLWVEH 'Z 63 (me’ke’d-v) 1000 100 10 0.1 0.01 0.001 0.0001 0.00001 FIGURE 2-2 (Continued) INTERMEDIATE (15-364 Days) Systemic 3* e“ g f f" g" ff f? 0;“, «3 " ” 37r 7r . 836' 6! ”I! 31m 5' - .3” 039‘ 033m&3' 0:”, .47m 04m 039cl 0396 M 46m 04m 04m .49": a: «m _ .40"! .41!» .SK 042: n 05‘ OM! " Kev ' R" I LCSO/LDSO ' l Mnimel risk level lor rn Mouse . . - h Rm 0 LOAELior unous enacts (animals) . mm mm, mm m" s Ham” 0 LOAEL for Iesa serious meets (animals) I 6 Dog 0 NOAEL (am-nus) V k Mon”, 9 ca. - Cancer Eflea Level (minds) e Sheep A NOAEL - Human The number next to each point corresponds to enuies in Two 2-2. ' Doses represem the lowest dose tested per study he! produced a tumorigenic response and do not inply m existence of e Ihreshold for the me! end point. SiOEddE HLWVEH 'Z 09 (mo’ks’dlY) 1000 100 10 0.1 0.01 0.001 0.0001 0.00001 FIGURE 2-2 (Continued) CHRONIC (z 365 Days) Systemic O '9 ‘° 3 $ e 0° Q96? «9 0 59m 50! 055' .52": .53". 5" 058m 055' 056' O 57! O 57' 061d 0 62* 061d 0 God 0606 A54 0“” A54 I I I l I l I v Key ' “It I LCSOILDSO ' m Mouse . I MnimeI nsk level for h Rabbit O LOAEL tor senous ettects (enImaIs) . mm mm man we“ 0 LOAEL 101 less senous effects (enirnds) I s Hamster . V d Dog 0 NOAEL (amnals) k Monkey 0 CEL - Cancer Ettect Level (animals) e Sheep A NOAEL - Humm The number next to each point corresponds to entwies In TebIe 2-2. ' Doses represent the lowest dose tested per study that produced I tumongenic response and do not Imply the existence at a threshou tor the cancer end point 8103533 HDVEH '8 IS (meme/6'1) 1000 100 10 0.1 0.01 0.001 0.0001 0.00001 FIGURE 2-2 (Continued) CHRONIC (3 365 Days) 3’ fix” é. 3 if e 8:" 71m .72". .74m .75m Onm .57..“ 0“" 773$ .69 070' OS“ 065v 104 .76m 10-5 Estimated A” Human Cancer 10-0 Rtsk Levels 10-7 K_ev ' “It I Lesa/L050 ' m Mouse I Mnimel risklevellor n Rabbit O Loaeuorsonomertocuwrman) . mm “mm" m“ s Hamster 0 LOAELtorless senous ettectuenmls) I d Dog 0 NOAEL(animds) V k Monkey 0 GEL-Cancer EflectLeveHanlmals) a Sheep A NOAEL-Humut The number next to each point corresponds to entries in Table 2-2. ' Doses represent the lowest dose tested per study that produced I turnorigentc response and do not inply the existence of a threshold lor the cancer end point SlOSdzlEl HLTVEH '8 ZS 33 2. HEALTH EFFECTS Respiratory Effects. No studies were located regarding respiratory effects in humans after oral exposure to aldrin 0r dieldrin. Routine gross and microscopic examination of the lungs of rats consuming up to 15 mg/kg/day of aldrin or dieldrin for 6 months revealed no adverse effects on the lungs. Cardiovascular Effects. A young man who attempted suicide by consuming approximately 25.6 mg/kg of aldrin had extremely labile blood pressure upon admission to the hospital (Spiotta 1951). His electrocardiogram was normal. Another man who ingested 120 mg/kg of dieldrin had tachycardia and elevated blood pressure at the time of his admission to the hospital (Black 1974). Both men were suffering from convulsions at the time that these effects were observed; thus, it is possible that these cardiovascular effects may have been the result of altered activity in the central nervous system. In the case of the man who ingested 120 mg/kg of dieldrin, the cardiovascular effects were controlled with B—adrenergic blocking drugs, suggesting that the effects were due to increased sympathetic output (Black 1974) A correlation between adipose tissue levels of dieldrin and the incidence of hypertension was reported in a study of terminal hospital patients (Radomski et al. 1968). However, interpretation of these results is limited by the small number of cases of hypertension (eight cases) and the observation that the levels of a number of other pesticides in adipose tissues also correlated with the incidence of hypertension. Administration of dieldrin by gavage for 3 days resulted in decreased cardiac calmodulin levels at doses as low as 1 mg/kg/day and inhibition of cardiac Ca2+ATPase at doses as low as 10 mg/kg/day (Mehrortra et al. 1989). The authors suggested that such changes could adversely affect cardiac contractility, but no measurement of cardiac function were presented to support this hypothesis. Routine gross and histopathological examination of hearts from rats that ingested up to 15 mg/kg/day of aldrin or dieldrin for up to 6 months revealed no adverse effects (Treon et al. 1951a). Chronic exposure of rats to doses of dieldrin as low as 0.016 mg/kg/day was reported to cause fibrinoid degeneration, inflammation, endothelial proliferation, and perivascular edema in the small-to-medium-size arteries (Harr et al. 1970). However, this condition is known to occur spontaneously, no dose-response information was provided, and statistical analyses of these data were not presented. Also, the study by Harr et al. (1970) utilized a semisynthetic diet rather than standard rodent chow, and it is unclear whether such a diet may have affected the outcome of this study. Thus, the significance of this finding is unknown. Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after oral exposure to aldrin or dieldrin. Dogs that ingested lethal doses of aldrin (as low as 0.89—1.78 mg/kg/day over a period of 5—6 months) or dieldrin (as low as 1.95-4.24 mg/kg/day over a period of 11 days-1.3 months) during a 9-month study, vomited and became emaciated several days prior to death (Treon et al. 1951b). It is unclear whether the vomiting was directly due to gastrointestinal irritation. Hematological Effects. Volunteers consuming doses of dieldrin as high as 0.003 mg/kg/day for a period of 18 months experienced no adverse effects on the cellular elements of the blood or on plasma proteins (Hunter and Robinson 1967). Also, ingestion of 120 mg/kg of dieldrin followed by repeated stomach lavage produced no adverse effects on blood coagulation (Black 1974). 34 2. HEALTH EFFECTS One case of immunohemolytic anemia attributable to ingestion of dieldrin has been reported (Hamilton et al. 1978). Also, three cases of pancytopenia and one case of thrombocytopenia associated with exposure to dieldrin were reported during 1961 (AMA 1962; however, no assessment regarding whether dieldrin was the causative agent was provided in the report. No adverse effects on standard hematologic parameters were observed in either dogs or rats exposed to either aldrin or dieldrin for at least 2 years (Deichmann et al. 1967; Walker et al. 1969). However, evidence of slight adverse effects was observed in the blood forming tissues. Rats exposed to aldrin at 0.25 mg/kg/day for 25 months had moderate to marked congestion of the red pulp of the spleen and evidence of slight hemolysis (Deichmann et al. 1967). Also, dogs given doses as low as 1 mg/kg/day of either aldrin or dieldrin for 25 months had a reduced number of mature granulocytes and erythroid cells in the bone marrow (Fitzhugh et al. 1964). This study is limited, however, in that too few animals were tested (1-2 males and 1—2 females per dose). Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after oral exposure to aldrin or dieldrin. The only study that presented any adverse musculoskeletal effects of aldrin or dieldrin was a chronic study in rats (Harr et al. 1970). In this report, rats exposed to doses of dieldrin as low as 0.016 mg/kg/day had focal edema, coagulative necrosis, and chronic muscular inflammation. However, neither the relative number of affected animals nor statistical analyses of these data were presented to support these conclusions. Also, rats in this study received a semisynthetic diet rather than standard rodent chow. It is unclear whether the use of the semisynthetic diet may have affected the study outcome. Treatment of rats with 1.25 mg/kg/day of dieldrin for 60 days was reported to impair the performance of rats who had been trained to pull a weight up an inclined plane in order to receive food (Khairy 1960). Although the author attributed the impaired performance to a decrease in muscular efficiency, no attempt was made to determine whether the effect was neurological or muscular in origin. Thus, this effect cannot be established as a musculoskeletal effect. Hepatic Effects. Volunteers consuming up to 0.003 mg/kg/day of dieldrin for a period of 18 months had no adverse effects on the liver as determined by measuring serum hepatic enzyme activities (alkaline phosphatase and transaminases) (Hunter and Robinson 1967). However, a child who drank an unknown quantity of a 5% dieldrin solution and who experienced severe convulsions had evidence of liver dysfunction (Garrettson and Curley 1969). The half-life of phenobarbital in the child was greatly increased shortly after the initial intoxication, indicating a decreased ability of the liver to process the drug for excretion. Six months later, the phenobarbital half-life had returned to normal levels. However, serum alkaline phosphatase and thymol turbidity test results were elevated above normal levels. Evidence of liver damage (elevated serum transaminases) was also observed in a man 5 days after ingesting 120 mg/kg of dieldrin despite vigorous intervention to limit absorption (Black 1974). In the study by Black (1974), the dieldrin was a 15% solution in toluene. It is likely that the solution ingested by the child described by Garrettson and Curley (1969) also contained solvents and possibly emulsifiers. It is possible that the other ingredients in the dieldrin solutions contributed to the hepatic toxicity that was observed. A number of adaptive changes characteristically produced by halogenated hydrocarbon pesticides were observed in livers of dogs, mice, and rats exposed to aldrin and/or dieldrin. These changes include an increase in liver weight and/or size (Bandyopadhyay et al. 1982b; Deichmann et al. 1967, 1970; Fitzhugh et al. 1964; Kohli et al. 1977; Olson et al. 1980; Tennekes et al. 1981; Treon et al. 1951a, 1953b, 1955b; 35 2. HEALTH EFFECTS Walker et al. 1969; Walton et al. 1971; Wright et al. 1972), liver cell enlargement (Olson et al. 1980; Treon et al. 1951a, 1954b; Walker et al. 1972), cytoplasmic eosinophilia with migration of basophilic granules (Fitzhugh et al. 1964; Treon et al. 1951a, 1954b; Walker et al. 1969, 1972), an increase in the smooth endoplasmic reticulum (Wright et al. 1972), an increase in microsomal protein (Wright et al. 1972), an increase in cytochrome P-450 content (Walton et al. 1971; Wright et al. 1972, 1978), and/or an increase in microsomal enzyme activity (Den Tonkelaar and van Esch 1974; Kohli et al. 1977; Tennekes et al. 1981; Walton et al. 1971; Wright et al. 1972, 1978). Within 1 week, an increase in cytoplasmic vacuoles and smooth endoplasmic reticulum and increased microsomal protein and mixed-function oxidase activity were observed in rats exposed to 8 mg/kg/day or mice exposed to 1.6 mg/kg/day of dieldrin (Wright et a1. 1972). After 4 weeks of exposure to 2 mg/kg/day of dieldrin, similar effects were observed in dogs. In addition, liver cell enlargement and increased levels of cytochrome P-450 were apparent in rats and mice 4 weeks after exposure to 8 mg/kg/day and 1.6 mg/kg/day, respectively (Wright et al. 1972). Cessation of dosing with dieldrin allowed the reversal of these changes in these animals (Wright et al. 1972). The lowest dose at which an increase in liver-to-body- weight ratio was observed in rats was 0.00035 mg/kg/day of dieldrin for 85 days (Olson et al. 1980). However, this study was limited in that only one dose of dieldrin was tested and animals received limited rations during the last 15 days of the study to maintain their body weights below normal. Monkeys exposed to dieldrin for between 5 and 6 years had a more limited response than dogs, mice, or rats. Exposure to concentrations as high as 0.1 mg/kg/day of dieldrin produced increased mixed-function oxidase activity and cytochrome P-450 content in livers but no histologic changes in the liver that were observable by light or electron microscopy (Wright et al. 1972, 1978). In virtually all of these studies no other evidence of hepatic toxicity was reported; thus, these adaptive changes were not considered to be adverse. Mixed results regarding changes in hepatic lipid peroxidation have been observed. A single oral dose of 30 mg/kg was reported to decrease hepatic lipid peroxidation in male rats (Kohli et al. 1977). In contrast, a single oral dose of 26 mg/kg was reported to increase hepatic lipid peroxidation in female rats (Goel et al. 1988). It is unclear whether the difference between the outcomes of these two studies is entirely attributable to the use of different rats of different sexes. Limited evidence for adverse hepatic effects has been observed in rats in intermediate-duration studies following 1—6 months of exposure to 2 mg/kg/day of dieldrin (Shakoori et al. 1982), 6 months of exposure to 10 mg/kg/day of dieldrin (Ahmed et al. 19863), or 6 months of exposure to 15 mg/kg/day of aldrin or dieldrin (Treon et al. 19513). At 10 mg/kg/day, there was an increase in serum hepatic enzyme activity (alkaline phosphatase and/0r SGPT) with decreases in hepatic protein and areas of necrosis (Ahmed et al. 1986a). At 2 mg/kg/day, adverse effects were limited to decreased hepatic protein and some instances of necrosis (Shakoori et al. 1982). The statistical significance of the incidence of necrotic areas was not presented. Both of these studies are limited because only one dose of dieldrin was used. Rats that ingested 15 mg/kg/day of aldrin or dieldrin were reported to have scattered small foci of necrosis in their livers (Treon et al. 1951a). However, no statistics or incidence data were presented to support this conclusion. Dogs that ingested doses as low as 0.89—1.78 mg/kg/day of aldrin or 0.73—1.85 mg/kg/day of dieldrin had moderate parenchymatous degeneration (Treon et al. 1951b). The degeneration increased in severity with dose. This study is also limited by the small number of dogs used and the absence of statistics or histopathology data. Evidence for adverse hepatic effects has also been observed in chronic studies. Hyaline droplet degeneration was observed in the livers of dogs that ingested 0.12—0.25 mg/kg/day of aldrin for 15.7 months (Treon et al. 1955b). Similar effects were not observed in dogs that ingested 0.14—0.26 mg/kg/day of 36 2. HEALTH EFFECTS dieldrin over the same period. In dogs exposed to 1 mg/kg/day of aldrin or dieldrin for 25 months, slight- to—moderate fatty degeneration was observed (Fitzhugh et al. 1964). Also, in dogs given doses as low as 0.2 mg/kg/day of dieldrin for up to 1 year, degeneration was observed (Kitselman 1953). The degree of necrosis increased with dose. However, these studies are limited in that too few animals were tested (Fitzhugh et al. 1964; Kitselman 1953; Treon et al. 1955b). Both male and female dogs exposed to 0.05 mg/kg/day of dieldrin for 2 years had elevated serum alkaline phosphatase levels, and males at this dose had decreased serum proteins (Walker et a1. 1969). The possibility that increased serum alkaline phosphatase may not necessarily represent hepatic damage was raised by El-Aaser et al. (1972) when they showed that dogs exposed to 0.05-0.20 mg/kg/day of dieldrin for 1 year had increased serum alkaline phosphatase of hepatic origin but no increase in serum levels of 5’-nucleotidase (a hepatic membrane enzyme that should be elevated in the serum as a result of hepatic damage). Because hepatic levels of alkaline phosphatase increased in parallel with serum levels of alkaline phosphatase, these authors suggested that alkaline phosphatase may be transferred directly from the hepatocyte to the sinusoidal blood. Rats exposed to doses of dieldrin ranging from 0.016 to 0.063 mg/kg/day throughout their lifetime were reported to have developed hepatic lesions consisting of centrilobular degeneration and peripheral hyperplasia (Harr et al. 1970). Pyknosis of hepatocellular nuclei was also reported; however, no statistics, dose-response data, or incidence data were presented to support this conclusion. Also, the rats in this study received dieldrin in a semisynthetic diet, and it is unclear whether such a diet may have affected the study outcome. Rats exposed to aldrin or dieldrin at doses ranging from 0.025 to 7.5 mg/kg/day showed an increased severity of hepatocellular vacuolation and an increased incidence and severity of bile duct hyperplasia (Fitzhugh et al. 1964). However, it was unclear whether these effects were observed at all doses. Finally, mice exposed to 1.3 mg/kg/day for 2 years had livers with occasional necrotic areas (Thorpe and Walker 1973); this study is also limited because it is unclear whether the necrotic areas were secondary to tumor development, the incidence of these areas was not reported, and only one dose of dieldrin was tested. Renal Effects. A man who attempted suicide by consuming approximately 25.6 mg/kg of aldrin had elevated blood urea nitrogen, gross hematuria, and albuminuria upon admission to the hospital (Spiotta 1951). By 17 days after admission, levels of nitrogen, blood, and protein in the urine had returned to normal. Six weeks after the suicide attempt, the ability to concentrate the urine was determined to be poor. In contrast, a man who ingested 120 mg/kg of dieldrin had no evidence of renal damage (Black 1974). In both of these case reports, the actual dose available for absorption was unknown because efforts were made to limit absorption of the chemicals from the gastrointestinal tract. Adverse effects on the kidneys have been observed following exposure of rats and dogs to aldrin and/or dieldrin. Exposure of rats to 5 mg/kg/day of dieldrin for 15 days resulted in membranous glomerulonephritis, nephrosis in the proximal convoluted tubules, vacuolated cytoplasm, necrotic cells in the tubular lumen, and large intertubular spaces (Bandyopadhyay et al. 1982b). Similarly, exposure of rats to 10 mg/kg/day of dieldrin for 6 months in a single-dose level study resulted in degenerative changes in the epithelial cells of the kidney and lymphocyte and macrophage infiltration (Ahmed et al. 1986a). In contrast, rats ingesting 1.25 mg/kg/day of either aldrin or dieldrin for 27 weeks exhibited no adverse effects upon routine gross and microscopic examination (Treon et al. 1953b). Rats exposed to 0.25 mg/kg/day of dieldrin for 25 months in a single-dose level study showed slight lymphocyte infiltration, vascular congestion in the renal cortex, and hyaline casts in the renal tubules (Deichmann et al. 1967). Increases in the incidence and severity of nephritis were also observed in male rats exposed to doses as low as 0.5 mg/kg/day of aldrin or 0.125 mg/kg/day of dieldrin for 2 years (Fitzhugh et al. 1964; Harr et al. 1970; _ Reuber 1980). However, these studies are limited because no statistical analyses were presented to support 37 2. HEALTH EFFECTS these conclusions. Dogs exposed to doses of aldrin or dieldrin as low as 0.2 mg/kg/day also had degeneration of the renal tubules (Fitzhugh et al. 1964; Kitselman 1953), but these studies are limited by the absence of sufficient experimental detail, the lack of histopathological data on many of the animals, and the small number of animals tested. In the study by Fitzhugh et al. (1964), only one or two males and females were used per dose; in the study by Kitselman (1953), three dogs were used per dose. Slight vacuolation of the renal tubules was also reported in dogs exposed to doses as low as 0.14—0.26 mg/kg/day of dieldrin or 0.04-0.09 mg/kg/day of aldrin for 15.7 months, but this study was also limited by the small number of dogs used (Treon et al. 1955b). 2.2.2.3 Immunological Effects Limited information was located regarding immunological effects in humans after oral exposure to aldrin or dieldrin. A case report was located concerning a man who developed immunohemolytic anemia after eating fish that contained high levels of dieldrin (Hamilton et al. 1978). Testing of the patient’s serum revealed a positive antibody test for dieldrin-coated red blood cells. Immunosuppression by dieldrin has been reported in a number of studies in mice. An increase in lethality of mouse hepatitis virus 3 and a decrease in the antigenic response to the virus were observed in mice given a single oral dose of dieldrin (218 mg/kg) (Krzystyniak et al. 1985). Similarly, an increase in lethality of infections with the malaria parasite, Plasmodium berghei, or Leishmania tropica in mice was produced by treatment of the mice with dieldrin in the diet at doses as low as 0.13 mg/kg/day for 10 weeks (Loose 1982). Also, a decrease in tumor cell killing in mice was observed after dieldrin treatment with doses as low as 0.13 mg/kg/day for 3, 6, or 18 weeks (Loose et al. 1981). Since resistance to intracellular organisms and tumor cell killing require induction of cell-mediated immunity through thymus-derived lymphocyte (T-lymphocyte) interactions with macrophages, the effects of dieldrin consumption on the activity of these components of the response were tested. A decrease in antigen processing by alveolar macrophages was observed following consumption by mice of doses of dieldrin as low as 0.065 mg/kg/day for 2 weeks. This effect was observed in the absence of effects on macrophage respiration, phagocytic activity or capacity, and microbicidal activity (Loose et al. 1981). In addition, macrophages from dieldrin-treated (0.65 mg/kg/day for 10 weeks) mice were found to produce a soluble factor that induced T-lymphocyte suppressor cells (Loose 1982). Inhibition of lymphocyte proliferation was also seen in a mixed lymphocyte reaction test in which splenic cells from mice treated twice with 16.6 mg/kg dieldrin were combined with stimulator cells from control animals (Fournier et al. 1988). However, this study is limited because only one dose level of dieldrin was tested. All reliable LOAEL values for immunologic effects of dieldrin in mice in acute- and intermediate—duration studies are recorded in Table 2—2 and plotted in Figure 2-2. 2.2.2.4 Neurological Effects Case reports regarding accidental poisonings or suicide attempts provide the majority of the information on the neurological effects of aldrin and dieldrin by the oral route. Two children who consumed an unknown amount of a 5% dieldrin solution began to salivate heavily and developed convulsions within 15 minutes (Garrettson and Curley 1969). In the surviving child, the seizure episode lasted for 7.5 hours before being controlled by phenobarbital. EEG recordings taken from this child showed bursts of synchronous high-voltage slow waves. Both the child’s condition and the EEG recordings returned to normal with time. Convulsions also developed rapidly in a man who attempted suicide by consuming an 38 2. HEALTH EFFECTS estimated 25.6 mg/kg of aldrin (Spiotta 1951) and in a man who ingested 120 mg/kg of dieldrin (Black 1974). Anticonvulsants were given to control the seizures, but one man exhibited motor hyperexcitability and restlessness for several days (Spiotta 1951), and the other required muscle paralysis to sufficiently control the convulsions to allow artificial respiration (Black 1974). EEGs taken a few days after admission showed epileptiform activity, but the EEGs returned toward normal with time. A small group of persons who consumed wheat that had been mixed with aldrin and lindane over a period of 6—12 months developed a variety of central nervous system symptoms (Gupta 1975). These included bilateral myoclonic jerks, generalized seizures, auditory and visual auras, hyperexcitability, and irritability. In some cases, the onset of symptoms was abrupt. EEGs showed spike and wave activity and abnormal bursts of slow delta-wave discharges. After exposure was discontinued, the symptoms slowly improved. However, 1 year after exposure, infrequent myoclonic jerks were observed in several of the subjects. One subject also complained of memory loss and irritability, and a 7-year-old child was believed to have developed mild mental retardation as a result of the exposure. Although both aldrin and lindane had been mixed with the wheat, the author concluded that the effects observed were due to the aldrin exposure because in previous years wheat had been routinely mixed with lindane and consumed with no apparent adverse effects. Persistent headaches, irritability, and short-term memory loss were also reported following recovery from convulsions in a man who ingested 120 mg/kg of dieldrin (Black 1974). Dieldrin administered to volunteers daily for 18 months at doses as high as 0.003 mg/kg/day had no effect on central nervous system activity (as measured by EEG), peripheral nerve activity, or muscle activity (Hunter and Robinson 1967). Ingestion of aldrin and dieldrin most likely was not a significant route of exposure and therefore probably did not contribute significantly to the neurological effects observed in many of the occupational studies presented in Section 2.2.1.5. However, in the study by Patel and Rao (1958), the authors could not eliminate oral exposure by dieldrin since workers reportedly mixed the dieldrin solutions with their bare hands and some time later consumed food using their hands. Convulsions were also observed in rats given single doses of dieldrin ranging from 40 to 50 mg/kg (Wagner and Greene 1978; Woolley et al. 1985). When aldrin or dieldrin was administered to rats for 3 days, convulsions were observed at a dose of 10 mg/kg/day (Mehrotra et al. 1989). Transient hypothermia and anorexia were also observed following a single dose of 40 mg/kg (Woolley et a1. 1985). Long-term potentiation of limbic evoked potentials was observed following a single dose of 25 mg/kg, and subthreshold limbic stimulation caused convulsions following a single dose of 40 mg/kg (Woolley et al. 1985). Neurotoxic signs observed in cattle poisoned with unspecified dietary concentrations of aldrin included tremors, running, hyperirritability, and seizures (Buck and Van Note 1968). Operant behavior was disrupted in rats following single doses of dieldrin ranging from 0.5 to 16.7 mg/kg. The simpler paradigms of fixed interval responding and maze training were both impaired at doses as low as 16.7 mg/kg, whereas differential responding to low rates of reinforcement was impaired at 2.5 mg/kg (Burt 1975). Responses in an inescapable foot shock stress paradigm were impaired at doses as low as 0.5 mg/kg (Carlson and Rosellini 1987). In sheep, operant responding was decreased 38—76% during a 4-day treatment with 20 mg/kg/day dieldrin (Sandler et al. 1969). EEGs obtained during exposure showed high-voltage, slow wave activity. In studies of intermediate duration, operant behavior was disrupted at somewhat lower doses of dieldrin. Following 60-120 days of exposure of rats to 0.25 mg/kg/day, dieldrin significantly impaired maze training 39 2. HEALTH EFFECTS (Burt 1975). Monkeys also demonstrated impaired learning at similar doses (Smith et al. 1976). During treatment with 0.1 mg/kg/day for 55 days, monkeys had difficulty learning a successive discrimination reversal task. No effect on operant behavior in rats was observed following 0.025 mg/kg/day for 60—120 days. Sheep appeared to be somewhat less sensitive to the effects of dieldrin on behavior, although a small number of animals was used in these studies (Van Gelder 1975). The lowest dose at which sheep had impaired operant behavior was 2.5 mg/kg/day for 12 weeks. This was determined using an auditory signal detection test. Visual discrimination was not impaired until doses of 10 mg/kg/day were administered, and maze training and extinction of a conditioned avoidance response were not impaired at 15 mg/kg/day (Van Gelder 1975). Physical signs of neurotoxicity were observed in two single—dose level, intermediate-duration studies in rats. Tremors were observed in rats at a dose of 0.5 mg/kg/day for 60 days (Mehrotra et al. 1988) and hyperexcitability was observed at 2.5 mg/kg/day in an 8-week study (Wagner and Greene 1978). Dogs given aldrin at 0.89—1.78 mg/kg/day or dieldrin at 0.73-1.85 mg/kg/day for up to 9 months experienced neuronal degeneration in the cerebral cortex and convulsions (Treon et al. 1951b). At this dose, aldrin—treated dogs also exhibited hypersensitivity to stimulation, twitching, and tremors. At higher doses, the basal ganglia and cerebellum also exhibited degenerative changes. lrritability, tremors, and convulsions were observed in rats at dieldrin doses ranging from 0.5 to 2.5 mg/kg/day in several 1.5-2-year studies (NCI 19783, 1978b; Walker et al. 1969). No adverse effects were observed in rats at 0.05 mg/kg/day (Walker et al. 1969). Hyperexcitability was observed in rats exposed to aldrin at 1.45 mg/kg/day for 59-80 weeks. Mice showed slightly greater sensitivity, with hyperexcitability and tremors or fighting at 0.39 mg/kg/day aldrin or 0.33 mg/kg/day dieldrin in 80-week bioassays (NCI 1978a). EEGs taken from dogs exposed to 0.05 mg/kg/day for 2 years were normal (Walker et al. 1969). However, dogs were reported to develop convulsions when given 0.5 mg/kg/day for 25 months (Fitzhugh et a]. 1964), and neuronal degeneration was reported following 1 year of exposure to aldrin or dieldrin at 0.2 mg/kg/day (Kitselman 1953). However, both of these studies are limited by the small number of animals tested. The only other study that noted histopathological evidence of central nervous system damage was a 2-year study of the effects of dieldrin in rats (Harr et al. 1970). Cerebral edema and small foci of degeneration were reported in rats exposed to dieldrin at 0.016 mg/kg/day, but no statistical analysis of these results was presented. Also, the study by Harr et al. (1970) used a semisynthetic diet, and it is unclear whether the use of such a diet may have affected the study outcome. The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and duration category are recorded for aldrin in Table 2-1 and for dieldrin in Table 2-2 and plotted for aldrin in Figure 2-1 and for dieldrin in Figure 2-2. 2.2.2.5 Developmental Effects No studies were located regarding developmental effects in humans after oral exposure to aldrin or dieldrin. However, a study of dieldrin levels in women and their fetuses during labor revealed detectable levels of dieldrin in the placenta, amniotic fluid, and fetal blood (Polishuk et al. 1977b). These results suggest that dieldrin can pass through the human placenta and accumulate in the developing fetus. Conflicting results have been obtained in studies examining the ability of aldrin and dieldrin to cause external malformations or skeletal anomalies. Such effects have been observed in mice and hamsters 40 2. HEALTH EFFECTS following a single very large dose of aldrin or dieldrin in mid-gestation (Ottolenghi et al. 1974). Significant increases in cleft palate and webbed foot were observed in mice following a dose of 15 mg/kg of dieldrin or 25 mg/kg of aldrin on gestation day 9. Significant increases in cleft palate, open eye, and webbed foot were seen following a dose of 30 mg/kg of dieldrin or 50 mg/kg of aldrin on gestation days 7, 8, and/or 9 in hamsters. Fetal mortality was also significantly increased, and fetal weight was significantly decreased in hamsters. No information was provided regarding the health of maternal animals in this study. Also, this study is limited in that only a single dose of aldrin and dieldrin was tested. A significant increase in supernumerary ribs was observed in mice from dams exposed to 3 or 6 mg/kg/day dieldrin on gestation days 7—16 (Chernoff et al. 1975). In this study, these doses of dieldrin also caused an increase in the maternal liver-to-body-weight ratio. However, other studies examining developmental effects of aldrin and/or dieldrin have failed to observe similar malformations or anomalies. No developmental defects were observed in rats exposed to concentrations of dieldrin as high as 6 mg/kg/day from gestation day 7 to 16 (Chernoff et al. 1975). Also, no significant developmental effects were observed in mice exposed to doses of dieldrin as high as 4 mg/kg/day from gestation day 6 to 14 (Dix et al. 1977), although the number of litters tested in this study was somewhat low. Offspring of mice treated for 5-7 days during the third trimester of pregnancy with 2 or 4 mg/kg/day of aldrin had a significantly elevated electroconvulsive seizure shock threshold but had no disruption of the acquisition of a conditioned avoidance response (Al-Hachim 1971). In contrast, behavioral effects were observed in rat pups exposed to dieldrin from gestation day 5 until the pups were 70 days old (Olson et al. 1980). A significant improvement in swimming and maze running was observed in pups exposed to 0.00035 mg/kg/day. This dose of dieldrin is several orders of magnitude below any other close at which developmental effects have been observed. Interpretation of these results is difficult because the significance of improved performance in behavioral paradigms is unknown, and the study is limited because only one dose of dieldrin was tested. Increased postnatal mortality has been one of the most consistent developmental findings reported for aldrin and dieldrin. Mice exposed to dieldrin in the diet at doses as low as 0.65 mg/kg/day from 4 weeks prior to mating through weaning had significantly decreased pup survival (Virgo and Bellward 1975). Maternal mortality was unaffected in this study at doses below 2.6 mg/kg/day. A similar decrease in postnatal survival has been observed in rats and dogs exposed to aldrin and/or dieldrin by the oral route. Increased mortality of offspring during the first 5 days of life was observed at 0.125 mg/kg/day of either aldrin and dieldrin in the first mating of a three-generation reproduction study in rats (Treon et al. 1954a). Maternal mortality was unaffected at doses as high as 1.25 mg/kg/day of either aldrin or dieldrin. Similarly, rats exposed to dieldrin from the time that they were 28 days old to when they were mated at 146 days of age had decreased postnatal pup survival at doses as low as 0.125 mg/kg/day (Harr et al. 1970). Maternal mortality in this study was unaffected at doses below 0.5 mg/kg/day. This study is limited, however, in that no statistical analysis of the data was presented to confirm this assertion. Also, the rats in this study received a semisynthetic diet, and it is unclear whether such a diet may have affected the study outcome. Dogs exposed to doses of aldrin as low as 0.2 mg/kg/day or dieldrin at doses as low as 0.6 mg/kg/day for up to 1 year had poor litter survival (Kitselman 1953). In some instances, apparently normal puppies were born but died after a few days of nursing. Although maternal toxicity was not specifically addressed in this study, dogs receiving similar doses of aldrin and dieldrin had histopathological evidence of hepatic and renal toxicity. This study is also limited because too few dogs were tested, pregnancies were incidental to the study protocol, and thus adequate controls were not used. Dogs mated 2 weeks to 9 months after a 14-month exposure to doses of aldrin as low as 0.15 mg/kg/day also had high mortality among the offspring (Deichmann et al. 1971). However, this study was also limited by the small number of animals tested. 41 2. HEALTH EFFECTS A number of studies have been undertaken to assess the cause of the decreased pup survival. To test whether the decrease in pup survival was dependent on maternal postnatal care, a cross-fostering experiment was performed (Virgo and Bellward 1977). Mice born to dieldrin-exposed dams were nursed by untreated dams. Significantly decreased pup survival was also observed in this study at 0.65 mg/kg/day irrespective of whether pups were nursed by birth or foster maternal animals. In a single-dose level study of mice exposed in utero to 2 mg/kg/day between days 6 and 18 of gestation, examination was performed at varying times after birth. The rapid decrease in blood glucose and depletion of tissue glycogen stores were significant when compared to controls (Costella and Virgo 1980). These decreases were observed despite apparently normal gluconeogenesis. Cardiac failure, secondary to cardiac glycogen depletion, has been proposed as the cause of death (Costella and Virgo 1980). Histopathological examination of pups born to treated maternal animals was performed in two studies. Rat pups born to dams treated with dieldrin at doses as low as 0004-0008 mg/kg/day had neural lesions consisting of cerebral edema, internal and external hydrocephalus, and focal neuronal degeneration. Hepatic degeneration was seen in the pups of dams fed doses of dieldrin as low as 0.016 mg/kg/day (Harr et al. 1970). However, no information regarding the dose-dependency of these effects or the relative numbers of animals affected was reported. Also, the rats in this study received a semisynthetic diet, and it is unclear whether such a diet may have affected the study outcome. Offspring from dogs that had been treated with doses of aldrin as low as 0.2 mg/kg/day or dieldrin as low as 0.6 mg/kg/day had degeneration of hepatic and renal tissues (Kitselman 1953). Both of these studies are limited by the lack of supporting clinical chemistry data and the absence of statistical analyses of the histopathological data. Furthermore, in the study by Kitselman (1953), not all offspring were examined histopathologically. The highest NOAEL values and all reliable LOAEL values for developmental effects in animals after acute- or intermediate-duration exposure to dieldrin are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.6 Reproductive Effects Aldrin levels in blood and placental tissues of women who had premature labor or spontaneous abortions were significantly higher than in women with normal deliveries (Saxena et al. 1980). However, interpretation of this study is limited because levels of six other organochlorine pesticides were also significantly elevated and because other potential distinctions between the two groups that might have contributed to premature labor or abortion, such as smoking or alcohol consumption, were not addressed. Nevertheless, this observation suggests that aldrin can pass through the human placenta and accumulate in the developing fetus. Similarly, accumulation of dieldrin in the amniotic fluid and in the developing fetus has been reported by Polishuk et al. (1977b). Acute exposure of male mice to aldrin or dieldrin produced no adverse effects on reproduction. Male mice treated with doses of aldrin up to 1 mg/kg/day for a period of 5 days showed no significant effects in a dominant lethal study (Epstein 1972). Similarly, single oral doses of dieldrin ranging from 12.5 to 50 mg/kg had no significant effect on the number of pregnancies produced by male mice in a dominant lethal assay (Dean et al. 1975). A significant but slight decrease in fertility was observed in female mice exposed to 1.3 or 1.95 mg/kg/day of dieldrin from 4 weeks prior to mating through weaning (Virgo and Bellward 1975). In this study, males were exposed to test material only during the 2-week mating period. Similarly, rats receiving diet containing aldrin or dieldrin at doses of aldrin as low as 0.625 mg/kg/day and dieldrin as low as 0.125 mg/kg/day from the time they were 28 days old had decreased fertility (decreased number of litters) 42 2. HEALTH EFFECTS during the first mating of the parental generation in a three-generation reproduction study (Treon et al. 1954a). A subsequent mating of the parental rats receiving aldrin showed no reproductive effects, and those receiving dieldrin failed to show a consistent dose-related effect on fertility. At matings of the offspring, no effect on fertility (number of litters) was observed at 0.125 mg/kg/day; however, effects on fertility due to higher doses were difficult to assess because few offspring survived to be mated. In contrast, no consistent effect of doses of dieldrin as high as 2 mg/kg/day was found on the conception rate of rats exposed from the time they were 28 days old through the period of mating (initiated when the rats were 146 days old) (Harr et al. 1970). These results are limited in that no statistical analysis of the data was presented. In addition, mice exposed to 0.65 mg/kg/day of dieldrin for 30 days prior to mating and then for 90 days thereafter experienced no adverse effects on fertility, fecundity, or the length of gestation (Good and Ware 1969). The only adverse reproductive effect observed in this study was a slight decrease in litter size. However, this study is limited in that only one dose level of dieldrin was tested. A number of adverse reproductive effects were observed in dogs given either 0.15 or 0.30 mg/kg/day for 14 months prior to mating (Deichmann et al. 1971). These included delayed estrus, reduced libido, lack of mammary function and development, and an increased number of stillbirths. However, this study is limited by the small number of animals tested. Maternal behavior was adversely affected by dieldrin when mice were treated from 4 weeks prior to delivery until weaning. At 1.3 mg/kg/day, Virgo and Bellward (1977) observed a delay in the time before mice nursed their pups. Also, at doses of 1.95 mg/kg/day and above, some dieldrin-treated maternal animals violently shook the pups, ultimately killing them, and others neglected their litters (Virgo and Bellward 1975). At doses of dieldrin above 1.95 mg/kg/day, high maternal mortality was also observed in this study. The highest NOAEL for dieldrin and all reliable LOAEL values for reproductive effects in animals after acute- or intermediate-duration exposure to aldrin or dieldrin are recorded for aldrin in Table 2-1 and for dieldrin in Table 2-2 and plotted for aldrin in Figure 2-1 and for dieldrin in Figure 2-2. 2.2.2.7 Genotoxlc Effects No studies were located regarding genotoxic effects in humans after oral exposure to aldrin or dieldrin. Single doses of aldrin administered orally to three groups of male Swiss mice (13.0, 19.5, and 39.0 mg/kg) resulted in a statistically significant increase in the number of abnormal metaphases in dividing spermatocytes. There was also a significant increase at all doses of univalents, indicating a decreased pairing of meiotic chromosomes (Rani and Reddy 1986). Single doses of aldrin were administered orally to male rats and male and female mice (0.016, 0.011, and 0.008 mmol/kg, respectively). Deoxyribonucleic acid (DNA) synthesis in the liver was stimulated only in male mice (Busser and Lutz 1987). A dominant lethal assay was conducted using 40 male CF1 mice orally dosed with 12.5 or 25 mg/kg of dieldrin (Dean et al. 1975). The results of this assay indicated that the overall mean percentage of implantations was significantly reduced in the females mated with males receiving 12.5 mg/kg dieldrin. However, a second series of experiments showed that the overall mean of successful implantations was significantly higher in the 25-mg/kg group than in the controls. Several doses of both aldrin and dieldrin were tested in a dominant lethal study conducted in mice (Epstein et al. 1972). Dieldrin did not meet any 43 2. HEALTH EFFECTS criteria for mutagenic effects. Females mated to males exposed to aldrin did show some reduction in implantations, but these were judged to be nonsignificant upon statistical analysis. There are at present no in vivo data that indicate unequivocally that aldrin or dieldrin reacts directly with DNA to produce mutations in either the germ cells or in the somatic cells. The reduced meiotic pairing reported by Rani and Reddy (1986) does suggest that aldrin can cross the blood/testis barrier, but the results of Dean et al. (1975) offer no clear evidence that there are significant reactions with DNA Other genotoxicity studies are discussed in Section 2.4. 2.2.2.8 Cancer No studies were located regarding cancer in humans after oral exposure to aldrin or dieldrin. A few epidemiological studies have examined cancer mortality in workers employed in the manufacture of these pesticides. The results of these studies may be found in Sections 2.2.1.8 and 2.2.3.8. However, ingestion of aldrin or dieldrin is not thought to have been a significant source of exposure in these studies because manufacturing practices limit such exposures (Jager 1970). Several bioassays in mice were located that report a positive carcinogenic response of aldrin and/or dieldrin. With respect ,to aldrin, studies in two strains of mice (C3I-IeB/Fe and B6C3F1) show an increase in hepatic tumors with chronic exposure (Davis and Fitzhugh 1962; NCI 19783). A significant increase in the incidence of hepatocellular carcinoma was reported in males receiving 0.2 mg/kg/day of aldrin for 80 weeks (NCI 1978a). An increase in the incidence of hepatic cell adenomas at 1.3 mg/kg/day was also reported in a 2-year study by Davis and Fitzhugh (1962). Reevaluation of the histopathology data by Reuber (1980) and other pathologists indicated that most tumors classified by Davis and Fitzhugh (1962) as hepatic cell adenomas were hepatocellular carcinomas (Epstein 1975). With respect to dieldrin, bioassays in Balb/c, CFl, B6C3F1, C3HeB/Fe, C3H/I-Ie, and C57BL/6J mice have also shown an increase in the incidence of hepatocellular adenoma and/or carcinomas with chronic exposure. A study in B6C3F1 mice by NCI (1978a) showed a significant increase in the incidence of hepatocellular carcinoma with exposure of males to 0.65 mg/kg/day for 80 weeks. Studies also reporting an increased incidence of hepatocellular carcinomas in male mice in response to dieldrin exposure included an 85-week exposure of C3H/l-Ie, B6C3F1, and C57BL/6J mice to 1.3 mg/kg/day (Meierhenry et al. 1983) and a 92-week exposure of CF1 mice to 1.3 mg/kg/day (Tennekes et al. 1981). An increase in both hepatocellular adenomas (Type A tumors) and hepatocellular carcinomas (Type B tumors) in CF1 mice that ingested 1.3 mg/kg/day for 2 years was identified by Thorpe and Walker (1973). Similarly, a significant increase was observed in the incidences of both total tumors and Type B tumors in a 132-week study at 1.3 mg/kg/day and of total tumors in a 128-week study at 0.33 mg/kg/day in CF1 mice (Walker et al. 1972). In a 75-week study in Balb/c mice (Lipsky et al. 1989) and a 2-year study in C3HeB/Fe mice, (Davis and Fitzhugh 1962) increases in the incidence of hepatic cell adenoma were observed at 1.3 mg/kg/day. However, reexamination of the histopathology data by Reuber (1980) and other pathologists showed an increase in the incidence of hepatocellular carcinomas (Epstein 1975). Although reanalysis of the data presented in the Walker et al. (1972) study by Reuber also indicated a significant increase in pulmonary adenomas and carcinomas in female mice at 0.013 and 0.13 mg/kg/day and a significant increase in lymphoid and other tumors in female mice at 0.13 mg/kg/day (Epstein 1975), these conclusions were based on errors in the reporting of the number of females examined at 0.013 and 0.13 mg/kg/day (Hunt et al. 1975). 44 2. HEALTH EFFECTS In addition to producing an increase in the incidence of hepatocellular carcinomas in mice, dieldrin was also shown to significantly decrease the time to tumor development in mice at doses as low as 0.013 mg/kg/day in females and 0.13 mg/kg/day in males (Tennekes et al. 1982). Studies regarding the ability of aldrin and/or dieldrin to cause cancer in rats and hamsters have produced mostly negative results (Cabral et al. 1979; Deichmann et al. 1967, 1970; Fitzhugh et al. 1964; NCI 1978b; Walker et al. 1969). However, several of these studies have been determined to be flawed based on limited microscopic examination of animals (Fitzhugh et al. 1964; Walker et al. 1969), too few animals being used (Fitzhugh et al. 1964; NCI 1978b), and/or high levels of early mortality with insufficient numbers of animals surviving until termination of the study (Deichmann et al. 1970; Fitzhugh et al. 1964). Furthermore, reanalysis of the data from the study by Fitzhugh et al. (1964) revealed a significant increase in multiple- site tumors when doses of aldrin and dieldrin at or below 0.5 mg/kg/day were combined and an increased incidence of liver carcinomas at 5 mg/kg/day when data from both sexes were combined (Epstein 1975). A carcinogenic response was also observed in rats exposed to 1.5 mg/kg/day of aldrin for 80 weeks (NCI 1978a). These animals had a significantly increased incidence of follicular cell adenoma and carcinoma of the thyroid. Also, a significant increase in adrenal cortical adenomas was seen in female rats at this dose. However, these effects were not dose-dependent. Similarly, a significant increase in the combined incidence of adrenal cortical adenomas and carcinomas was observed in females given 1.45 mg/kg/day for 59 weeks but not in animals at the higher dose (NCI 1978a). This result was, however, discounted by the authors because of the historical variability of this result in control animals. The lowest dose that produced a tumorigenic response (Cancer Effect Levels, CELs) for each species and duration category of exposure to aldrin and dieldrin are recorded for aldrin in Table 2-1 and for dieldrin in Table 2-2 and plotted for aldrin in Figure 2-1 and for dieldrin in Figure 2-2. 2.2.3 Dermal Exposure As indicated in the section on inhalation exposure, it is often difficult to clearly separate dermal from inhalation exposures in many occupational studies. Thus, many of the findings described in the section on inhalation exposure are repeated here. 2.2.3.1 Death No increase in mortality from any cause was found in studies of workers who had been employed in the manufacture of aldrin, dieldrin, endrin, and/or telodrin at a facility in the Netherlands for more than 4 years (cohort = 233 workers) (Van Raalte 1977; Versteeg and Jager 1973). Furthermore, in a 20-year follow-up of this population and expansion of the cohort to include workers employed for at least 1 year during 1954-1970 (cohort = 570 workers), a lower than expected overall mortality was observed (de Jong 1991). Although the group of workers described by de Jong (1991) represents a unique population because they have been under medical supervision for an average of 25.86 years, all of the studies described above are limited because of the small number of subjects used (5570 workers) and the potential exposure of the subjects to more than one of these pesticides and/or to other chemicals at the chemical manufacturing complex. Several of these studies have attempted to estimate exposure levels using blood levels. However, blood levels were not obtained for approximately 10 years (during what is expected to have been the period of heaviest exposure) and extrapolations were based on data obtained in a study using constant daily low- level oral dosing (Hunter and Robinson 1967). It is unclear whether such extrapolations accurately reflect exposure levels in the occupational situation. Only two case studies were located regarding deaths that 45 2. HEALTH EFFECTS may have been attributable to occupational exposure to aldrin or dieldrin (Muirhead et al. 1959; Pick et al. 1965). One concerned a farmer with multiple exposures to insecticide containing dieldrin. The farmer died in hemolytic crisis after developing immunohemolytic anemia (Muirhead et al. 1959). Immunologic testing revealed a strong antigenic response of blood cells coated with dieldrin. The other concerned a worker from an orange grove who developed aplastic anemia and died following repeated exposures to aldrin during spraying (Pick et al. 1965). In the latter study, the relationship between aldrin exposure and the aplastic anemia is considerably more tenuous, being linked only in that the onset of symptoms corresponded with spraying and the condition deteriorated upon subsequent exposure. In rats, a single dermal application of aldrin in xylene was reported to produce death in 50% of the animals tested at 98 mg/kg/day (Gaines 1960). Dieldrin in xylene produced an LD50 value of 60 mg/kg/day in female rats and 90 mg/kg/day in male rats (Gaines 1960). However, this study is limited because the rats were not restrained, oral intake could not be eliminated, and the xylene vehicle has intrinsic dermal toxicity. A single 24-hour dermal exposure of rabbits to dry crystallized aldrin or dieldrin resulted in LD50 values between 600 and 1,250 mg/kg for both chemicals (Treon et al. 1953a). Similar results were obtained when these chemicals were prepared as oil solutions and maintained in contact with the skin for 24 hours. Also, sheep dipped in a solution of 200 mg/L of dieldrin (twice the recommended dose) experienced an 11% mortality rate within the lst month following exposure (Glastonbury et al. 1987). This study is limited because the preparation of dieldrin used was unsuitable for use in emulsions and may have been stripped from the bath during the dipping of the first sheep resulting in much higher doses for some animals than others. In addition, wool biting was observed among these sheep; this type of oral exposure may have contributed to the lethal effects. Dermal exposure of rabbits to aldrin or dieldrin (2 hours/day, 5 days/week, for 10 weeks) resulted in slightly greater lethality when these chemicals were prepared as solutions in oil and much greater lethality when the chemicals were administered as suspensions in kerosene than when crystallized material was placed directly in contact with the skin (Treon et al. 1953a). In the case of aldrin, three out of three rabbits survived exposure to average doses of 34—39 mg/kg/day during the 10-week period; one out of three died after exposure to 19-26 mg/kg/day in oil; and three out of three died after exposure to 19—27 mg/kg/day in kerosene. Crystallized dieldrin exposures of 39-41 mg/kg/day were survived by three out of three rabbits; but all rabbits died at 43-57 mg/kg/day in oil and 24—26 mg/‘kg/day in kerosene. The greater lethality of the kerosene suspensions may have been associated with greater absorption as a result of skin damage caused by the kerosene. The highest NOAEL values and all reliable LOAEL values for death in each species and duration category are recorded for aldrin in Table 2-3 and for dieldrin in Table 2-4. 2.2.3.2 Systemic Effects No studies were located regarding gastrointestinal or musculoskeletal effects in humans or animals after dermal exposure to aldrin or dieldrin. The highest NOAEL values for each study for dermal/ocular effects are recorded for aldrin in Table 2-3 and for dieldrin in Table 2-4. Respiratory Effects. Conflicting reports were located regarding the respiratory effects of aldrin and dieldrin in humans after dermal exposure. In a study of workers with at least 4 years of employment in the manufacture of aldrin, dieldrin, endrin, or telodrin, no new pulmonary disease or deterioration of TABLE 2-3. Levels of Significant Exposure to Aldrin - Dermal Exposure LOAEL (effect) duration/ NOAEL Less serious Serious Species frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference ACUTE EXPOSURE Death Rabbit 1 d 1250 (4/4 died) Treon et al. 24hr/d 1953a INTERMEDIATE EXPOSURE Death Rabbit 10 uk 120- (2/3 died-dry) Treon et al. 5d/uk 125 1953a 2hr/d 19-26 (1/3 died-oil solution) 4-5 (2/4 died-kerosene suspension) Systemic Rabbit 10 wk Derm/oc 221- Treon et al. Sd/Hk 320 1953a 2hr/d d = day(s); Derm/oc = adverse-effect level; uk = Heek(s) dermal/ocular; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed- SiOdeB HlJVBH '2 9V TABLE 2-4. Levels of significant Exposure to Dieldrin - Dermal LOAEL (effect) Exposure duration/ NOAEL Less serious Serious Species frequency System (mg/kg/day) (mg/kg/day) Reference ACUTE EXPOSURE Death Rabbit 1 d 360 (1/4 died-dry) Treon et al. 24hr/d 600 (1/4 died-oil 1953a solution) Systemic Human 4 d Derm/oc 0.5% Suskind 1959 24hr/d Immunological Human 4 d 0.5% Suskind 1959 24hr/d INTERMEDIATE EXPOSURE Death Rabbit 10 UK 97- (3/3 died-dry) Treon et al. 5d/Hk 174 1953a 2hr/d 43- (3/3 died-oil 57 solution) 4-5 (2/3 died-kerosene suspension) Systemic Rabbit 10 wk Derm/oc 97- Treon et al. 5d/uk 174 1953a 2hr/d SiOEddE HlJVBH '3 £7 TABLE 2-4 (Continued) Exposure LOAEL (effect) duration/ NOAEL Less serious Serious Species frequency System (mg/kglday) (mg/kg/day) (mg/kg/day) Reference Neurological Human 180 d 1.8 Fletcher et al. 5.5d/Hk 1959 6hr/d d = dayls); Derm/oc = dermal/ocular; hr = hour(s); LOAEL = louest-observed-adverse-effect level; NOAEL adverse-effect level; uk = ueek(s) no-observed- 8103333 HLWVSH ‘Z 49 2. HEALTH EFFECTS existing pulmonary disease were observed (Jager 1970). Similarly, no increase in mortality from respiratory diseases was noted in workers employed for at least 1 year at the same facility during 1954—1970 when these workers were followed for at least 20 years (de Jong 1991). In contrast, however, in another study that examined workers involved in the manufacture of aldrin, dieldrin, and/or endrin for at least a year, a significantly increased incidence of pneumonia and other pulmonary diseases was observed when the incidence in the exposed workers was compared to the incidence in US. white males (Ditraglia et al. 1981). Both studies are limited by the small sample size and the possible exposure of the workers to other chemicals and/or pesticides. In addition, inhalation exposure may have contributed to the production of these effects since exposures by both inhalation and dermal absorption are likely in these populations of workers. No effects on lung weight or pathology were found in a study in which rabbits were wrapped with material containing up to 0.04% dieldrin for up to 52 weeks (Witherup et al. 1961). However, this study is limited in that some animals from the study were treated with a variety of drugs to control "extraneous" diseases. Cardiovascular Effects. Limited information was available regarding the cardiovascular effects of aldrin or dieldrin in humans after dermal exposure. Suggestive evidence of an association between dieldrin and hypertension was obtained in a study examining the incidence of certain diseases in patients with elevated fat levels of dieldrin (Radomski et al. 1968). However, elevated fat levels of other pesticide residues also correlated with hypertension in this study. Furthermore, a study examining disease incidence in 2,620 workers exposed to a number of pesticides reported no increase in the incidence of hypertension in workers with elevated serum dieldrin (Morgan et al. 1980). The lack of a correlation between hypertension and aldrin or dieldrin exposure is also supported by the observation that workers involved in the manufacture of aldrin, dieldrin, endrin, or telodrin for at least 4 years had normal blood pressure (Jager 1970). Similarly, no increase in mortality from circulatory system diseases was observed in a mortality study by de Jong (1991). All of these studies are limited because the subjects were exposed to a variety of other chemicals. A slight, but significant, increase in serum cholesterol was observed in pesticide-exposed workers with elevated serum dieldrin (Morgan and Lin 1978). However, this study was limited in that the workers were occupationally exposed to a number of different pesticides and other chemicals including hydrocarbon solvents. No effects on heart weight or pathology were found in a study in which rabbits were wrapped with material containing up to 0.04% dieldrin for up to 52 weeks (Witherup et al. 1961). However, this study is limited in that some animals from the study were treated with a variety of drugs to control "extraneous" diseases. Gastrolntestinal Effects. No increased mortality from digestive system causes was observed in a mortality study of workers employed in the manufacture of aldrin and dieldrin for at least 1 year between 1954 and 1970 (de Jong 1991). No studies were located regarding gastrointestinal effects in animals after dermal exposure to aldrin or dieldrin. Hematological Effects. No abnormal values for hemoglobin, white blood cells, or erythrocyte sedimentation rate were found in workers who had been employed in the manufacture of aldrin, dieldrin, endrin, or telodrin for at least 4 years (Jager 1970). Similarly, no increase in blood diseases was observed in a morbidity study of workers employed at the same facility for at least 1 year (de Jong 1991). Also, 50 2. HEALTH EFFECTS workers who had been involved in either the manufacture or application of pesticides and who had significantly elevated blood levels of dieldrin compared to controls not employed in pesticide-related jobs had no hematological effects of clinical significance (Warnick and Carter 1972). These studies are limited by either potential exposure to other chemicals (Jager 1970) or by known exposure to other pesticides as demonstrated by elevated blood levels of B—benzine [sic] hexachloride (ls-benzene hexachloride), heptachlor epoxide, Elf-DDT, Q,p’-DDT, and p,p_’-DDE (Warnick and Carter 1972). A case of immunohemolytic anemia attributable to dieldrin exposure was reported (Muirhead et al. 1959). Also, a worker from a grove where aldrin was sprayed developed aplastic anemia (Pick et al. 1965), and one person employed in the manufacture of aldrin and dieldrin between 1954 and 1970 died from aplastic anemia (de Jong 1991). However, it is unclear whether these cases of aplastic anemia were directly due to aldrin or dieldrin exposures because exposure to a variety of other chemicals was possible. Three cases of pancytopenia and one case of thrombocytopenia associated with exposure to dieldrin were reported during 1961 (AMA 1962). However, no assessment regarding whether dieldrin was the causative agent was provided in the report. No studies were located regarding hematologic effects in animals after dermal exposure to aldrin or dieldrin. Hepatic Effects. Although a slight increase in serum hepatic enzymes (SGOT and SGPT) has been observed to correlate with serum dieldrin levels in pesticide-exposed workers (Morgan and Lin 1978), no evidence of any hepatic effects of aldrin or dieldrin exposure have been observed in other studies of workers involved in either the manufacture (de Jong 1991; Hoogendam et al. 1965; Hunter et al. 1972; Jager 1970; van Sittert and de Jong 1987) or the manufacture or application (Morgan and Roan 1974; Warnick and Carter 1972) of these pesticides. Parameters that have been examined in the negative studies include serum hepatic enzyme activity (Hoogendam et al. 1965; Jager 1970; Morgan and Roan 1974; van Sittert and de Jong 1987; Warnick and Carter 1972), hepatic enlargement (Jager 1970), and tests intended to detect microsomal enzyme induction (Hunter et al. 1972; Jager 1970; Morgan and Roan 1974; van Sittert and de Jong 1987). All of the studies are limited by the potential exposure of the workers to other chemicals and/or organochlorine pesticides. No effects on liver weight, serum proteins, thymol turbidity, serum alkaline phosphatase, or pathology were found in a study in which rabbits were wrapped with material containing up to 0.04% dieldrin for up to 52 weeks (Witherup et al. 1961). However, this study is limited in that some animals from the study were treated with a variety of drugs to control "extraneous“ diseases. Renal Effects. No evidence of renal damage was seen in workers employed for 4 or more years in the manufacture of aldrin, dieldrin, endrin, or telodrin (Jager 1970). However, this study is limited by the potential exposure of these workers to other chemicals. No studies were located regarding renal effects in animals after dermal exposure to aldrin or dieldrin. Dermal/Ocular Effects. Contact dermatitis was observed in police recruits wearing socks that had been moth-proofed with a solution containing dieldrin (Ross 1964). Several recruits had a positive patch test when tested against the moth-proofing agent. The outbreak of the dermatitis appeared to have been exacerbated by the presence of the particular dye used in the socks and by the fact that the recruits’ feet had sweated heavily. In contrast, no evidence of dermatitis was seen in volunteers who wore patches of cotton broadcloth or wool flannel impregnated with up to 0.5% dieldrin by weight for 4 days (Suskind 51 2. HEALTH EFFECTS 1959) or in workers employed for 4 or more years in the manufacture of aldrin, dieldrin, endrin, or telodrin (Jager 1970). The study by Jager (1970) is limited by the potential exposure of these workers to other chemicals. Application of up to 6,000 mg/kg of aldrin or 3,600 mg/kg of dieldrin as either the crystalline material or as a solution in oil to the skin of rabbits for 24 hours was reported to result in occasional very slight erythema, but the lowest doses associated with this effect were not reported (Treon et all 1953a). In contrast, no irritation was observed following application of 221-320 mg/kg/day aldrin or 97—174 mg/kg/day of dieldrin to the skin of rabbits for 2 hours/day, 5 days/week, for up to 10 weeks (Treon et al. 1953a). Also, no treatment-related effects were observed after microscopic examination of the skin of rabbits wrapped with wool fabric containing up to 0.04% dieldrin by weight for 52 weeks (Witherup et al. 1961). 2.2.3.3 Immunologlcal Effects Limited information is available regarding the immunological effects of aldrin and dieldrin in humans after dermal exposure. No sensitization was observed in volunteers who were reexposed to fabric containing up to 0.5% dieldrin 2 weeks following a 4-day exposure (Suskind 1959). However, a case report was located concerning a man who developed immunohemolytic anemia after multiple exposures to dieldrin, heptachlor, and toxaphene while spraying cotton fields (Muirhead et a1. 1959). Antibodies for dieldrin-coated or heptachlor-coated red blood cells were found in the subject’s serum. However, this study is limited because of the exposure of the subject to other pesticides. No studies were located regarding immunological effects in animals after dermal exposure to aldrin or dieldrin. All reliable LOAEL values for immunologic effects of dieldrin in humans in acute-duration studies are recorded in Table 24. 2.2.3.4 Neurologlcal Effects Central nervous System excitation culminating in convulsions was the principal toxic effect noted in occupational studies of workers employed in either the manufacture or application of aldrin or dieldrin. In many cases, convulsions appeared suddenly and without prodromal signs (Hoogendam et al. 1965; Kazantis et al. 1964; Patel and Rao 1958). EEGs taken shortly after the convulsions revealed bilateral irregular alpha rhythms interrupted by spike and wave patterns (Avar and Czegledi-Janko 1970; Kazantis et al. 1964). In the case of dieldrin sprayers who developed convulsions, the convulsive episodes did not follow known accidental overexposures (Patel and Rao 1958). Rather, the convulsions developed anywhere from 14 to 154 days after the first exposure to dieldrin. The time to onset was more rapid for sprayers using the more concentrated spray. An accumulative type of poisoning was also reported in workers involved in the manufacture of aldrin, dieldrin, telodrin, or endrin (Jager 1970). In this report, convulsions were believed to have been caused by either accumulating levels of dieldrin in the blood or modest overexposures in the presence of subconvulsive accumulations of dieldrin. Other central nervous system symptoms reported by workers involved in the manufacturer or application of aldrin and/or dieldrin included headaches (Jager 1970; Patel and Rao 1958), dizziness (Jager 1970), hyperirritability (Jager 1970; Kazantis et al. 1964), general malaise (Jager 1970), nausea and vomiting (Jager 1970; Kazantis et al. 1964), anorexia (Jager 1970), muscle twitching (Jager 1970; Patel and Rao 1958), and myoclonic jerking (Jager 1970; Jenkins and Toole 1964; Kazantis et al. 1964). The more severe symptoms 52 2. HEALTH EFFECTS were accompanied by EEG patterns with bilateral spike and wave complexes and multiple spike and wave discharges in the alpha region (Jager 1970; Kazantis et al. 1964). Less severe symptoms were accompanied by bilateral theta (Jager 1970; Kazantis et al. 1964) and/or delta (Kazantis et al. 1964) wave discharges. In all cases in which follow-up of the subjects was reported, removal from the source of exposure caused a rapid physical recovery and a slower recovery (within a year) of the EEG activity to normal levels (Avar and Czegledi-Janko 1970; Hoogendam et al. 1962, 1965; Jager 1970; Jenkins and Toole 1964; Kazantis et al. 1964). No symptoms of poisoning were observed in workers who were exposed to an estimated 1.8 mg/kg/day for 6 months at 6 hours per day for 5.5 days per week based on accumulation of dieldrin on absorbent pads that were attached to various surfaces on the workers (Fletcher et al. 1959). A morbidity study of workers employed in the manufacture of aldrin and dieldrin between 1979 and 1990 noted no degenerative disorders of the nervous system (de Jong 1991). However, this study reported significant increases in mental disorders among those <30 years old and in those 46—50 years old. The diseases were classified as stress reactions, short-term depression, or sleep disorders. It is unclear whether these effects were directly the result of aldrin or dieldrin exposure or may have had some other cause. Results of a comprehensive neurological work-up of 27 workers involved in either the manufacture or application of dieldrin were compared to those of unexposed workers (Sandifer et al. 1981). Scores on five psychological tests were significantly different from those of the unexposed controls; however, the importance of the results was questioned by the authors because of a lack of equality in the level of literacy of the two groups. Also, three exposed workers had abnormal EMGs suggesting a peripheral neuropathy. However, EMGs were not obtained in the control group; thus, the significance of these results is unknown. Tremors and convulsions were reported in a study examining the effects of acute dermal exposure to aldrin or dieldrin in rabbits (Treon et al. 1953a). However, the doses associated with these effects were not reported. Neurological symptoms including salivation, grinding of the teeth, and spasms were observed in rabbits that were dipped into an emulsion of dieldrin, xylene, Triton X4550, and water, at doses as low as 70 mg/kg once a week until death or termination of the experiment (Bundren et al. 1952). This study is limited in that no vehicle control was used and some dose levels were tested on a single animal. The highest NOAEL for neurological effects in humans in an intermediate-duration study is recorded in Table 2-4. 2.2.3.5 Developmental Effects No studies were located regarding developmental effects in humans after dermal exposure to aldrin or dieldrin. The only study located that referred to developmental effects following dermal exposure was a case report of a number of lambs that died either prior to or during parturition (Glastonbury et al. 1987). Ewes had been dipped in an aqueous emulsion of 210 mg/L of dieldrin on one occasion up to 4 months prior to giving birth. External appearance of the lambs was normal, but the lambs were small. Also, the brains of these lambs had an abnormal cerebellar structure. It is unclear whether these effects can be attributed 53 2. HEALTH EFFECTS entirely to dieldrin exposure since vitamin A deficiency was also observed in these sheep and vitamin A deficiency is known to cause fetal mortality. 2.2.3.6 Reproductlve Effects , No studies were located regarding reproductive effects in humans or animals after dermal exposure to aldrin or dieldrin. 2.2.3.7 Genotoxic Effects Sister chromatid exchanges and chromosomal aberrations were studied in a population of floriculturists occupationally exposed to several pesticides, including aldrin (Dulout et al. 1985). A statistically significant increase in sister chromatid exchanges was seen in workers with clinical symptoms of pesticide exposure when compared to those without symptoms. There was also an increase in exchange-type chromosome aberrations in this population when compared to nonfloriculturists. Interpretations based on this study are limited because the route and dose of exposure could not be determined, since the workers could have been exposed via inhalation or dermal contact following the spraying of the greenhouses with the pesticide aerosols. In addition, there was concomitant exposure to other organophosphorus, carbamate, and organochlorine insecticides. Lymphocytes from workers in a dieldrin manufacturing facility were examined for chromosome aberrations (Dean et al. 1975). No statistically significant differences in either chromatid- type or chromosome-type aberrations were seen in current workers when compared to former workers or to unexposed controls. While there was no occupational exposure to other pesticides in this study, the routes of exposure could have been inhalation and/or dermal. No studies were located regarding genotoxic effects in animals after dermal exposure to aldrin or dieldrin. Other genotoxicity studies are discussed in Section 2.4. 2.2.3.8 Cancer A limited number of epidemiological studies were located that examined the incidence of cancer in workers exposed to aldrin or dieldrin. Workers who had been employed in the manufacture of aldrin, dieldrin, endrin, and/or telodrin for 4 or more years between 1954 and 1968 were evaluated by Van Raalte (1977) and again several years later by Ribbens (1985). Of the 232 workers studied by Ribbens (1985), a subgroup of 166 workers were studied by Van Raalte (1977). The subgroup in the Van Raalte study (1977) consisted of workers who were exposed 15 years earlier. At the time of the study by Ribbens (1985), the average interval from initial exposure was 24 years. No evidence for a carcinogenic effect of aldrin or dieldrin was observed in these studies. No correlation was observed between the incidence of cancer and the extent of exposure in the study by Van Raalte (1977). Also, the incidence of cancer in the workers studied by Ribbens (1985) was less than that found in the general population. Similarly, when the cohort described by Ribbens (1985) and Van Raalte (1977) was expanded to cover workers with 1 or more years of exposure to aldrin or dieldrin between 1954 and 1970, no increase was observed in mortality due to neoplasms in general; cancers of the stomach, large intestine, rectum, liver, pancreas, lung, prostate, bladder, or kidney; multiple myeloma; or leukemia (de Jong 1991). An update and additional analyses of the group of workers described by de Jong (1991) have been performed by Sielken and Stevenson (1992). These authors found no increase in the likelihood of cancer mortalities in this population after analyzing the data using several paradigms and correcting for factors such as duration of exposure, duration of follow- up, and age at first exposure. However, these studies are limited by the small number of subjects studied 54 2. HEALTH EFFECTS and the potential exposure of these workers to a mixture of chemicals. A morbidity study of workers employed in the manufacture of aldrin and dieldrin at the same facility between 1979 and 1990 also showed no increase in malignant neoplasms (de Jong 1991). In contrast, a significant increase in benign lesions (mainly subcutaneous lipomas) was observed in workers from this group aged 36—40 years. A separate group of workers employed in the manufacture of aldrin, dieldrin, and endrin had no significant increase in the incidence of cancer (Ditraglia et al. 1981). This study included subjects whose initial employment ranged from <10 years to 220 years previously. However, the authors conclude that too few deaths occurred in the group to draw any meaningful conclusions. No studies were located regarding cancer in animals after dermal exposure to aldrin or dieldrin. 2.3 TOXICOKINETICS 2.3.1 Absorption 2.3.1.1 lnhalatlon Exposure Studies directly measuring absorption of aldrin or dieldrin in humans following inhalation exposure of known amounts of these pesticides were not located. However, results of a survey of women in pesticide- treated homes showed a correlation between the treatment and dieldrin levels in human breast milk (Stacey and Tatum 1985). Inhalation was suggested as the most probable route of exposure because absorption by skin contact with pesticide-treated surfaces was not believed to contribute significantly to the exposures. Measurable levels of aldrin and dieldrin in indoor air have been detected several years after pesticide treatment of homes (Dobbs and Williams 1983). In vivo studies on absorption following inhalation exposure of animals to aldrin/dieldrin were not located. In an in vitro study using isolated perfused rabbit lungs, aldrin (0.25, 0.50, 1.0, 1.5, 2.0, 2.5, and 3.0 pmol) was taken up by simple diffusion and then metabolized at a slower rate to dieldrin in the lung. Dieldrin was detected 3 minutes after initiation of the experiment. The rate of uptake of aldrin by the lung was biphasic consisting of a rapid phase followed by a slower phase, which could be related to the metabolic turnover of aldrin to dieldrin (Mehendale and El-Bassiouni 1975). 2.3.1.2 Oral Exposure Volunteers were fed dieldrin at concentrations of 0.0001, 0.0007, and 0.003 mg/kg/day for 18-24 months. A dose-related increase in blood and adipose tissue levels of dieldrin was found (Hunter and Robinson 1967; Hunter et al. 1969). However, no quantitative data specifically describing absorption of aldrin/dieldrin following oral exposure were found in the literature. Several metabolic studies indicate that dieldrin is absorbed from the gastrointestinal tract and is transported 'via the hepatic portal vein (Heath and Vandekar 1964). Following dosing with radiolabeled aldrin and dieldrin, high levels of radioactivity were detected in the liver, blood, and stomach and/or duodenum of dosed rats within 1-5 hours (Heath and Vandekar 1964; Iatropoulos et al. 1975). TWenty-four hours following a single oral administration to rats of 10 mg/kg, 50% of the dose was found in fat (Hayes 1974). 55 2. HEALTH EFFECTS 2.3.1.3 Dermal Exposure Although data are limited regarding absorption of aldrin and dieldrin following dermal exposure in humans, it appears to occur rapidly. Aldrin and dieldrin were first detected in urine 4 hours after dermal application of a single dose (0.004 mg/cmz) of aldrin and dieldrin, radiolabeled with carbon 14 (14C), to the forearm of six volunteers. Based on urinary 14C excretion, it was estimated that 7.8% of aldrin and 7. 7% of dieldrin was absorbed over a 5- -day period (Feldmann and Maibach 1974). The accuracy of these values is questionable since the dose used was small, the14C recovery in the urine was low, the major route of excretion was in the feces (not the urine), and a large individual variation in data was reported Aldrin was rapidly absorbed into the skin of female rats following dermal application at doses of 0.,006 0.06 and 0.6 mg/cm2 (Graham et al. 1987). Aldrin and dieldrin were detected in the skin 1 hour after aldrin application for all three dose levels. The amount absorbed was proportional to the dose applied. In vitro studies of rat skin strips incubated with aldrin showed absorption of aldrin was complete by 80 minutes (Graham et al. 1987). Absorption from fabric that had been impregnated with up to 0.04% dieldrin was also demonstrated in rabbits (Witherup et al. 1961). 2.3.2 DIstrIbutlon 2.3.2.1 lnhalatlon Exposure No studies were located regarding distribution following inhalation exposure to aldrin or dieldrin in humans or animals. 2.3.2.2 Oral Exposure Aldrin is rapidly converted to dieldrin. Distribution of dieldrin is initially general, but within a few hours it is redistributed primarily to fat. A study was conducted on volunteers who ingested dieldrin in doses of 0, 0.0001, 0.0007, or 0.003 mg/kg/day for 24 months (Hunter and Robinson 1967; Hunter et al. 1969). Dieldrin concentrations in blood and adipose tissue increased in a dose-related manner with a finite upper limit for the storage of dieldrin corresponding to a balance between the amount ingested and the amount eliminated daily. This was observed at about 15 months with the eventual body burden characteristic of a person and his particular daily intake (Hunter et al. 1969). The study also found that the concentrations of dieldrin in both adipose tissue and blood are proportional to the given daily dose (Hunter and Robinson 1967). The blood dieldrin concentrations increased by 4 and 10 times in the 0.0001- and 0.003-mg/kg/day dose groups, respectively, when compared to controls. Relationships were derived for the concentration of dieldrin in both adipose tissue and blood in terms of the given daily dosage. Using these relationships it was estimated that the exposure of the general population was equivalent to 0.025 mg/day (0.00033 mg/kg/day). For higher doses of dieldrin, a significant correlation existed between the concentration of dieldrin in blood and the concentration in adipose tissue. The average ratio of the concentration in the adipose tissue to that in the blood was 156:1 (Hunter and Robinson 1967). The existence of a functional relationship between the concentration of dieldrin in the adipose tissue and that in the blood gives strong support to the concept of a dynamic equilibrium in the distribution of dieldrin between these tissues. Animal experiments indicate that this type of equilibrium also exists between the concentrations in the blood and brain, and between those in the blood and liver. When dieldrin administration was terminated, its concentration in blood decreased exponentially following first order kinetics with an estimated half-life of approximately 369 days (range, 141—592 days) (Hunter et al. 1969). 56 2. HEALTH EFFECTS A study of the body burden of dieldrin showed that the bioconcentration and rate of elimination of dieldrin were related to the lipid mass of the individual (Hunter and Robinson 1967, 1968). The highest concentrations of dieldrin in adipose tissue were found in the leanest subjects, and these subjects also exhibited the smallest total body burden. On the other hand, the proportion of the total exposure dose retained in the adipose tissue was highest in those subjects with the greatest total body fat (Hunter and Robinson 1968). The study also showed no increase in the concentration of dieldrin in whole blood during surgical stress or in periods of complete fasting, and it was concluded that the body burden of this compound in the general population constitutes no danger of intoxication as a result of tissue catabolism in times of illness or weight loss (Hunter and Robinson 1968). Samples of brain, liver, and adipose tissue were collected from 29 randomly selected autopsies of people in Holland (DeVlieger et al. 1968). These people, with three exceptions, lived in an area where a plant manufacturing aldrin, dieldrin, and endrin is situated, but were not employed at that plant. The mean concentration of dieldrin in the white matter of the brain was significantly greater (0.0061 mg/kg) than that in the gray matter (0.0047 mg/kg). In comparison, the mean concentrations of dieldrin in the liver and adipose tissue were 0.03 and 0.17 mg/kg, respectively. Levels of dieldrin were detected in samples of adipose tissue taken from autopsy patients (Adeshina and Todd 1990; Ahmad et al. 1988; Holt et al. 1986). Dieldrin was detected at concentrations ranging from 0.36 to 0.13 mg/kg. No aldrin was detected. Placental transfer of dieldrin occurs (Polishuk et al. 1977b). A study of women and their offspring during labor showed higher concentrations of dieldrin in fetal blood than in the mother’s blood (1.22 mg/kg and 0.53 mg/kg, respectively). Dieldrin levels were also higher in the placenta (0.8 mg/kg) than in the uterus (0.54 mg/kg) (Polishuk et al. 1977b). Tissue distribution of 14C following single-dose oral administration of 14C-dieldrin (0.43 mg/kg) to rats indicated that the initial rapid uptake of 14C by the liver during the first 3 hours after dosing is followed by a biphasic decrease and redistribution of the compound among body tissues including adipose tissue, kidney, and lymph nodes, with the majority being distributed to the adipose tissue. During the redistribution process, the lymphatic system seems to be the major transport pathway; the parallel increase of lymph node and adipose tissue values indicated an equilibrium between lymph and depot fat (Iatropoulos et al. 1975). Between 24 and 48 hours after a single oral dose of dieldrin was administered to rats, the amount of dieldrin in fat increased to about 50% of the dose. Dieldrin’s affinity for fat is illustrated by the ratio of its concentration in fat to that in blood (>130:1) (Hayes 1974). In female rats fed 2.5 mg/kg/day for 6 months, the ratio of the concentrations of dieldrin in the blood, liver, and fat was 1:30:500, respectively (Deichmann et al. 1968). Most of the dieldrin absorbed through the skin of guinea pigs, dogs, and monkeys is accumulated in the subcutaneous fat (Sundaram et al. 1978a, 1978b). Species differences in tissue distribution of dieldrin in rodents have been reported (Hutson 1976). When male rats and mice were subjected to a single dose of 14C-dieldrin (3 mg/kg), liver and fat residues were higher in the mice than in the rats 8 days after ingestion. The liver concentration in mice (0.94 mg/kg) was about nine times higher than in rats (0.11 mg/kg). Fat samples in mice contained dieldrin levels (11.6 mg/kg) that were twice as high as the levels in rats (5.6 mg/kg) (Hutson 1976). Sex differences in tissue distribution of dieldrin in rodents have also been reported (Davison 1973; Walker et al. 1969). Female rats fed dieldrin (0.002, 0.01, 0.1 mg/kg/day) in their diet for 39 weeks had a higher proportion of the total dose in their carcasses than did male rats that were treated similarly (Davison 1973). Also, female rats fed dieldrin (0, 0.005, and 0.5 mg/kg/day) in their diet for 2 years had tissue concentrations of dieldrin between 2 and 10 times that of male rats fed the same dietary concentration (Walker et al. 1969). 57 2. HEALTH EFFECTS Following repeated dosing (2-104 weeks), an equilibrium or steady state is reached between the intake, storage, and excretion of dieldrin in various strains of rats and beagle dogs. Steady-state kinetics were determined by measuring both the level of radioactivity retained in fat, blood, liver, and brain and the percentage of the administered dose excreted at sublethal doses. The steady-state tissue concentration of dieldrin was dose- and time-dependent. In dogs receiving daily oral doses of 0.005 or 0.05 mg/kg/day dieldrin for 2 years, the steady-state blood residue levels were reached in 12—18 weeks or 18—30 weeks, respectively (Walker et al. 1969). In rats receiving 0.0002—2.5 mg/kg/day dieldrin in the diet, steady state was reached in 4—39 weeks; equilibrium was reached earlier in rats receiving higher doses of dieldrin (Baron and Walton 1971; Davison 1973; Ludwig et al. 1964; Walker et al. 1969). In rats receiving daily oral doses of 0.012 mg/kg/day 14C-aldrin for 3 months, steady state was reached in 53 days (Ludwig et al. 1964). In another study, the steady-state concentration in adipose tissues of rats receiving dietary concentrations of 1.25 mg/kg/day dieldrin for 8 weeks was reported to be 50 mg/kg dieldrin (Baron and Walton 1971). The elimination of dieldrin residues from the adipose tissue of rats subsequently placed on untreated diets was reasonably rapid with estimated half-lives reported to be 4.5 days (Baron and Walton 1971). The estimated half-lives for the adipose tissue and brain were 10.3 and 3 days, respectively, for rats on a basic diet for 12 weeks, following consumption of a diet containing 0.5 mg/kg/day dieldrin for 8 weeks (Robinson et al. 1969). The half-lives of dieldrin in the liver were estimated to be 1.3 and 10.2 days for the rapid and slower elimination, respectively, and similar values were estimated for the blood. The concentrations of dieldrin in adipose tissue were considerably greater than those in other tissues, with storage in the four tissues as follows: adipose tissue >> liver > brain > blood (Robinson et al. 1969). 2.3.2.3 Dermal Exposure No studies were located regarding distribution following dermal exposure to aldrin or dieldrin in humans. Guinea pigs exposed dermally to dieldrin at concentrations varying from 0.0001% to 0.1% for 6 months showed the highest tissue distribution in adipose tissue, with lower concentrations in the liver and brain (Sundaram et al. 1978b). Rabbits exposed to fabric containing up to 0.04% dieldrin for 52 weeks also showed slight accumulation in the omental and renal fat (Witherup et al. 1961). 2.3.2.4 Other Routes of Exposure The administration of dieldrin by the intraperitoneal route ensures more or less complete absorption. The 14C-residues in tissues of rats dosed by intraperitoneal injection with a total dose of 0.01, 0.1, or 1.0 mg/kg were distributed among the brain, blood, liver, and subcutaneous fat with the highest levels in the fat. Radioactivity excreted by groups given dieldrin by intraperitoneal injection was not significantly different from that of orally treated groups (Lay et al. 1982). 2.3.3 Metabolism 2.3.3.1 Inhalation Exposure No studies were located regarding metabolism following inhalation exposure to aldrin or dieldrin in humans. 58 2. HEALTH EFFECTS An in vitro study using rabbit lung perfusates showed that aldrin was metabolized to dieldrin within the endoplasmic reticulum. Aldrin metabolism was dose dependent. Up to 70% of aldrin was metabolized in 1 hour at low doses (53 pmol) (Mehendale and El-Bassiouni 1975). 2.3.3.2 Oral Exposure No studies were located specifically regarding metabolism following oral exposure to aldrin or dieldrin in humans. The initial and major step in the biotransformation of aldrin in experimental animals is the formation of the corresponding epoxide dieldrin (Wong and Terriere 1965). Aldrin is readily converted to dieldrin primarily in the liver by mixed-function oxidases (Wong and Terriere 1965) and to a lesser extent in the lung (Lang et al. 1986) and skin (Graham et al. 1987; Lang et al. 1986). The known metabolic pathways of aldrin and dieldrin in laboratory animals are presented in Figure 2.3. The formation of dieldrin by epoxidation of aldrin is a reaction catalyzed by monooxygenases in liver and lung microsomes. Aldrin epoxidation was studied in rat liver microsomes (Wolff et al. 1979). Microsomes from phenobarbital-treated rats showed a three-fold increase in dieldrin formation, whereas 3-methylcholanthrene treatment markedly depressed enzyme activity. Thus, cytochrome P-450, not cytochrome P-448, seems to be involved in epoxidation. In vitro studies compared the oxidation of aldrin to dieldrin in extrahepatic and hepatic tissues of rats (Lang et al. 1986). The authors tried to identify the pathway by which aldrin is metabolized in liver, lung, seminal vesicle, and subcutaneous granulation tissue. Many organs and tissues possess low cytochrome P-450 content. In these cases, an alternative oxidative pathway mediated by prostaglandin endoperoxide synthase (PES) might be more important. PES consists of a cyclooxygenase which catalyzes the bisdioxygenation of arachidonic acid to prostaglandin G2 (PGGZ). In a second step, a reduction by hydroperoxidase to prostaglandin H2 (PGI-Iz) occurs. The aldrin epoxidation was completely nicotine adenine dinucleotide phosphate (NADPH)-dependent in liver microsomes and hepatocytes. In lung microsomes, two pathways were involved. The NADPH-dependent activity was 1.5% and the arachidonic acid-dependent aldrin epoxidation was 0.3% of the activity found in the liver. In seminal vesicle microsomes and granulation tissue microsomes, aldrin epoxidation was stimulated by arachidonic acid and inhibited by indomethacin (a specific inhibitor of cyclooxygenase). These results suggest that aldrin was epoxidized by a prostaglandin synthase—mediated pathway in extrahepatic tissues as an alternative enzyme in the cytochrome P-450-dependent monooxygenases (Lang et al. 1986). In mammals, two major metabolism routes of dieldrin seem to be predominant: (1) direct oxidation by cytochrome oxidases, resulting in 9-hydroxydieldrin (the Chemical Abstract Service [CAS] numbering system equivalent of 12-hydroxydieldrin), and (2) the opening of the epoxide ring by epoxide hydrases, resulting in 6,7-trfls-dihydroxydihydroaldrin (the CAS numbering system equivalent of 4,5-tra_ns- dihydroxy—dihydroaldrin) (Muller et al. 1975). Dieldrin is hydroxylated to 9-hydroxydieldrin by liver microsomal monooxygenases in rats, and the reaction is inhibited by the addition of the monooxygenase inhibitor, sesamex (Matthews and Matsumura 1969). Metabolism of dieldrin is 3-4 times more rapid in male than in female rats (Matthews et al. 1971). The difference is attributed to the greater ability of males to metabolize dieldrin to its more polar metabolites, primarily 9-hydroxydieldrin. Species differences in rates of metabolism have been observed in rats and mice. The hydroxylation reaction occurs more rapidly in rats than it does in mice as indicated by a higher ratio in rats of 9-hydroxy-14C-dieldrin to 14C-dieldrin (Hutson 1976). 59 2. HEALTH EFFECTS -k FIGURE 2-3. Proposed Metabolic Pathway for Aldrin and Dieldrin Cl °‘ CI °' ca 0' 0| 0 CI mxygenase skeletal manangemem ' 01 c: c. —> 0' —> CI aldrin dieldrin pentachloroketone epoxldo hydralaso WWW Cl Cl 0| 0| 0| 0| cu Cl Cl Cl OH 0“ H H OH 6,7 - trans-dihydroxydihydroaldrin 9-hydroxydieldrin / gluouronide \ + duouronldo cu 6,7 - trans-dihydroxydihydroaldrin 0' 9 - hydroxydieldrin glucuronide glucuronide aldrin dicarboxylic acid 3(- Adapted from EPA 1987a 60 2. HEALTH EFFECTS The 9-hydroxydieldrin glucuronide is formed both in vivo and in vitro. It has been identified in the bile of rats (Chipman and Walker 1979); however, it is generally excreted in the feces in free form (Hutson 1976). The 9-hydroxydieldrin glucuronide is formed rapidly in vitro from dieldrin (which is hydroxylated first to 9-hydroxydieldrin) upon incubation with rat liver microsomes and uridine diphosphoglucuronic acid (Hutson 1976; Matthews et al. 1971). Dieldrin is also metabolized by epoxide hydrase to form 6,7-trfl-dihydroxydihydroaldrin, which was originally isolated and identified in rabbits and mice (Korte and Arent 1965) and later found also to form in other animals including rhesus monkeys and chimpanzees (Muller et al. 1975). The 67m- dihydroxydihydroaldrin glucuronide is formed in vitro in hepatic microsomal preparations from rabbits or rats in the presence of uridine diphosphoglucuronic acid and NADPH (Matthews and Matsumura 1969). 6,7-tr_an_s_-Dihydroxydihydroaldrin can be further oxidized to aldrin dicarboxylic acid or conjugated to glucuronic acid (Baldwin et a1. 1972; Hutson 1976). Pentachloroketone, also known as Klein’s metabolite, is a major urinary metabolite in male rats, but it is only found in trace amounts in the urine of female rats and male mice (Baldwin et al. 1972; Hutson 1976; Matthews et al. 1971). Pentachloroketone is formed by a skeletal rearrangement. It has been suggested that pentachloroketone is the product of rearrangement of the same intermediate that leads to 9-hydroxydieldrin (Bedford and Hutson 1976). 2.3.3.3 Dermal Exposure No studies were located regarding metabolism following dermal exposure to aldrin or dieldrin in humans. Data show that the skin is capable of metabolizing aldrin to the stable epoxide dieldrin (Graham et al. 1987). Dieldrin was detected in the skin of rats 1 hour after aldrin application at three dose levels (0.1, 1.0, and 10 mg/kg). The amount of conversion was greatest at the lowest dose levels suggesting enzyme saturation at higher doses. The authors concluded that, following topical application, up to 10% conversion of aldrin to dieldrin by skin enzymes can occur during percutaneous absorption (Graham et al. 1987). In vitro studies using mouse skin microsomal preparations and rat whole skin strips also showed that metabolism of aldrin to dieldrin took place in the skin (Graham et al. 1987). 2.3.4 Excretlon 2.3.4.1 lnhalatlon Exposure No studies were located regarding excretion following inhalation exposure to aldrin or dieldrin in humans or animals. 2.3.4.2 Oral Exposure Excretion in humans is primarily in the feces via the bile. 9—Hydroxydieldrin was found in the feces of seven workers occupationally exposed to aldrin and dieldrin (Richardson and Robinson 1971). An estimated half-life for dieldrin elimination is reported to be 369 days (Hunter et al. 1969). Dieldrin is also excreted via lactation in nursing mothers. Dieldrin concentrations of 19—26 ppb were found in breast milk (Schecter et al. 1989b). 61 2. HEALTH EFFECTS In rats dosed with 14C-aldrin at 0.012 mg/kg/day for 3 months, both aldrin and dieldrin were found in the feces, with lower concentrations of both compounds also found in the urine (Ludwig et al. 1964). Pentachloroketone was also detected in the urine of rats fed diets containing 1.25 mg/kg/day of aldrin (Klein et al. 1968). Following administration of single oral doses of 14C-dieldrin to rats, mice, monkeys, and chimpanzees, radioactivity accounting for 95%, 95%, 79%, and 79% of the dose, respectively, was excreted in the feces, which is the main route of excretion (Hutson 1976; Muller et al. 1975). The ratio of radioactivity excreted in the feces and in the urine is 19 in rats and mice and 3.8 in monkeys and chimpanzees (Miiller et al. 1975). Unchanged dieldrin and 9-hydroxydieldrin and its glucuronide are the major components in the feces of rats, monkeys, and chimpanzees, with lesser amounts of 6,7-dihydroxydihydroaldrin and aldrin dicarboxylic acid (Baldwin et al. 1972; Hutson 1976; Matthews et al. 1971; Miiller et al. 1975). 9-Hydroxydieldrin has also been found in the urine of monkeys given a single dose of 0.5 mg/kg of dieldrin (Miiller et al. 1975) and in mouse urine (Hutson 1976). Elimination of aldrin dicarboxylic acid occurs mainly in the urine of mice and rats (Baldwin et al. 1972; Hutson 1976) and in the feces of rats (Hutson 1976). Unchanged dieldrin was found in the feces of mice, rats, rabbits, and monkeys at concentrations ranging from 0.3% to 9.0% of the single dose administered (0.5 mg/kg) (Muller et al. 1975). Excretion of dieldrin is 3—4 times more rapid in male than in female rats (Matthews et a1. 1971). The difference was attributed to the greater ability of males to metabolize dieldrin to its more polar metabolites. An in vitro study using rat liver perfusates showed a sexual difference in the hepatic excretion of dieldrin. The appearance of radioactivity in the bile of livers of males was approximately three times as rapid as the appearance of radioactivity in the bile of livers of females (Klevay 1970). Species differences have been reported for the excretion of dieldrin and/or its metabolites between male CFE rats and male CF1 or LACG mice (Baldwin et al. 1972; Hutson 1976). Excretion was more rapid in the rat than in the mouse. The ratio of 9-hydroxy-14C-dieldrin to 14C-dieldrin was higher in rats than in mice, indicating a slightly more rapid excretion by the rat (Hutson 1976). In rabbits, films-dihydroxydihydroaldrin is the major metabolite excreted in the urine. Following administration of single oral doses of 14C-dieldrin to rabbits, elimination was greater in urine, accounting for 81—83% of the dose (Muller et al. 1975). 6,7-m—Dihydroxydihydroaldrin has also been identified in the urine of mice (Miiller et al. 1975). film-Dihydroxydihydroaldrin glucuronide has been identified in urine of rabbits and monkeys (Miiller et al. 1975). Pentachloroketone is the major component in rat urine (Baldwin et al. 1972; Hutson 1976; Matthews et al. 1971). The mouse, unlike the rat, does not appear to excrete pentachloroketone as a urinary metabolite. Pretreatment of CFE rats with dieldrin caused an enhancement of the urinary excretion of pentachloroketone, but no effect on the pattern of excretion of urinary metabolites could be detected when CF1 mice were given similar treatments (Baldwin et al. 1972). Aldrin dicarboxylic acid, unchanged dieldrin, and 9-hydroxydieldrin glucuronide have also been found in lower concentrations in the urine of rats (Hutson 1976; Muller et al. 1975). 62 2. HEALTH EFFECTS 2.3.4.3 Dermal Exposure No studies were located regarding excretion following dermal exposure to aldrin or dieldrin in humans or animals. 2.3.4.4 Other Routes of Exposure Elimination of 14C following intraperitoneal or intravenous injection of 14C-dieldrin to male rats was either approximately equal to or slightly less than that observed following oral dosing (between 70% and 80% of the total dose was excreted by 2 weeks postdosing) (Cole et al. 1970; Lay et al. 1982). Excretion occurred primarily in the feces (about 90%). Biliary elimination was measured experimentally following intraperitoneal administration. The rate of 14C elimination in the bile increased following pretreatment of rats with phenobarbital (Chipman and Walker 1979). 2.4 RELEVANCE TO PUBLIC HEALTH Exposure to aldrin or dieldrin at hazardous waste sites is possible via inhalation, oral, or dermal routes. Inhalation exposure and dermal exposure to these pesticides in air is possible because of their volatilization from contaminated surfaces. Oral exposure is possible through consumption of foods in which aldrin or dieldrin have bioconcentrated or biomagnified. These foods would include those obtained from plants grown on contaminated lands or animals living in contaminated areas. Oral exposure to aldrin or dieldrin could also occur through ingestion of contaminated water; however, the solubility of these pesticides in water is quite low. One source of exposure not related to living near a hazardous waste site is residue from the past use of aldrin or dieldrin for termite extermination. Although use for this application was voluntarily canceled by the manufacturer in 1987, aldrin and dieldrin levels in treated homes have been shown to decline slowly, with detectable levels present as many as 5 years after treatment. Exposure may also occur as a result of consumption of small amounts of aldrin or dieldrin found in commercial food products high in animal fat, such as dairy, fish, and meat products. This is the result of previous widespread use and the persistence in the environment of these pesticides. Current levels of these pesticides in food products are quite low. Information on the effects that occur in humans in response to aldrin or dieldrin exposure comes from case reports of accidental or intentional poisoning and from studies of workers occupationally exposed in either the manufacture or application of these pesticides. Acute high-level exposure of humans to aldrin or dieldrin has been observed to cause central nervous system excitation culminating in convulsions. In two very young children, death occurred either during the convulsions or shortly after the convulsions ceased. The other effect observed in humans after acute high- level exposure is renal toxicity. Longer—term exposure of humans in occupational settings has been associated with occasional cases of central nervous system intoxication, but other toxic effects in workers routinely handling these pesticides have not been reported. Two case reports of persons who developed immunohemolytic anemia after repeated exposure to aldrin or dieldrin were located, but this effect was not observed in other studies of 63 2. HEALTH EFFECTS larger populations of those employed in the manufacture or application of these pesticides, suggesting that this effect may be quite rare. For the most part, studies in animals support the observation of these toxic effects in humans. In addition, studies in animals indicate that other toxic effects may also be associated with exposure to sufficiently high levels of aldrin or dieldrin. These include hepatic degeneration, immunosuppression, increased postnatal mortality and possible teratogenesis, decreased reproductive function, and cancer. Death. Only two reports of death in humans resulting from inhalation or dermal exposure to aldrin or dieldrin were located (Muirhead et a1. 1959; Pick et a1. 1965). In one study, death was attributed to hemolytic crisis resulting from the development of immunohemolytic anemia (Muirhead et a1. 1959). In the other, death was attributed to aplastic anemia (Pick et a1. 1965). Other reports indicate that aldrin or dieldrin, at sufficiently high doses, can be acutely fatal to both humans and animals following ingestion. Two deaths in very young children were reported after accidental ingestion of unknown quantities of aldrin or dieldrin (Garrettson and Curley 1969; Gupta 1975). These deaths occurred either during or shortly after a convulsive episode. The oral dose required to cause death in humans is not known; however, it has been estimated to be 71 mg/kg (Hodge et a1. 1967). Animal studies indicate that a single dose of aldrin or dieldrin in the range of 30-60 mg/kg/day must be consumed in order to cause death (Gaines 1960; Lu et a1. 1965). Chronic studies in animals indicate that daily ingestion of 0.5-2.5 mg/kg/day of aldrin or dieldrin will significantly shorten survival (Deichmann et al. 1970; Fitzhugh et a1. 1964; Harr et a1. 1970; Reuber 1980; Thorpe and Walker 1973; Walker et a1. 1972). In mice, this decrease in survival may have been associated with the development of cancer; however, in rats, the association between the decrease in survival and a particular lesion is less clear. Death has also been observed in animals after dermal exposure to aldrin or dieldrin. In rats, the dermal dose necessary to cause death in 50% of the exposed animals was approximately twice the oral dose necessary to cause death in the same percentage of animals (Gaines 1960). It is extremely unlikely that sufficient levels of aldrin or dieldrin could be ingested acutely by persons living in the vicinity of hazardous waste sites to cause death. Furthermore, the low levels of aldrin or dieldrin likely to be present in air near such sites are substantially below the levels necessary to cause death. Systemic Effects Respiratory Effects. Conflicting data are available regarding adverse effects of aldrin or dieldrin on the respiratory tract in humans. In one study, a significant increase in the incidence of pneumonia and other pulmonary diseases was observed among workers employed in the manufacture of aldrin and dieldrin (Ditraglia et a]. 1981) but not in others (de Jong 1991; Jager 1970). However, all of these studies were limited by the small number of subjects included in the studies and potential exposures of the subjects to other chemicals. No studies in animals were available that corroborated either the absence or presence of potential respiratory effects. Thus, insufficient evidence exists to assess the relevance of these findings to public health. Cardiovascular Effects. Ingestion of a large quantity of aldrin (estimated to be 25.6 mg/kg) caused the blood pressure of a man who attempted suicide to fluctuate wildly (Spiotta 1951). The blood pressure fluctuations were observed in the presence of considerable central nervous system excitation and convulsions, but in the absence of any adverse effects on cardiac rhythms. Another man who attempted suicide by ingesting a large quantity of dieldrin had elevated blood pressure and tachycardia in conjunction 64 2. HEALTH EFFECTS with convulsions (Black 1974). In both of these cases, the effects were most likely associated with the convulsions and their disruption of central nervous system control of cardiovascular function. A correlation between elevated dieldrin levels in fat and the incidence of hypertension (Radomski et al. 1968) suggested an effect of dieldrin on blood pressure at nonconvulsive doses. However, this correlation has not been observed in other studies of persons occupationally exposed to aldrin or dieldrin (Morgan et al. 1980). Also, workers employed in the manufacture of aldrin and dieldrin had blood pressures within normal limits (Jager 1970). No animals studies were located that could either support or refute the effects of aldrin on blood pressure. One study examining the effects of dieldrin on the heart reported that acute exposure to relatively high doses of dieldrin caused a decrease in calmodulin levels and calcium ATPase activity in the heart (Mehrotra et al. 1989); however, the physiological significance of these findings is unknown. Thus, it appears that acute exposure to very high levels of aldrin or dieldrin may cause blood pressure lability, but it is unlikely that such levels would be consumed acutely in drinking water or foods, or be inhaled from contaminated air by those living in the vicinity of a hazardous waste site. Hematological Effects. With the exception of two reports of immunohemolytic anemia associated with an autoimmune response to dieldrin-coated red blood cells (Hamilton et al. 1978; Muirhead et al. 1959), no adverse effects of aldrin or dieldrin exposure on standard blood parameters have been clearly identified in workers employed in the manufacture or application of these pesticides (Jager 1970; Morgan and Lin 1978; Warnick and Carter 1972) or in animals exposed chronically (Deichmann et al. 1967; Walker et al. 1969). However, a limited number of reports of aplastic anemia in'persons exposed to aldrin or dieldrin have been published (AMA 1962; de Jong 1991; Pick et al. 1965). These reports are limited in that other potential causes for the aplastic anemia are possible. Also, in one study, reduced blood cell production by the bone marrow was observed after consumption of moderately high levels of aldrin or dieldrin (Fitzhugh et al. 1964). Because of study limitations, the significance of this finding is unknown. Thus, excluding the development of immunohemolytic anemia, it is unlikely that persons exposed to low levels of aldrin or dieldrin in the vicinity of a hazardous waste site will experience adverse hematological effects. Since no known threshold for the development of immunohemolytic anemia has been established, it is possible that susceptible persons living in the vicinity of hazardous waste sites may be exposed to sufficient quantities to trigger such an autoimmune response. Hepatic Effects. Adverse hepatic effects have not generally been observed in workers employed in the manufacture or application of aldrin or dieldrin (de Jong 1991; Hoogendam et al. 1965; Jager 1970; Morgan and Roan 1974; van Sittert and de Jong 1987; Warnick and Carter 1972), although a slight increase in SGOT and SGPT has been correlated with increased serum levels of dieldrin in pesticide- exposed workers (Morgan and Lin 1978). Liver injury was observed in a child who drank an unknown quantity of a 5% dieldrin solution (Garrettson and Curley 1969). However, the dieldrin solution most likely contained a substantial amount of solvent, and it is unclear whether the hepatic toxicity was directly due to the dieldrin or the solvent. The injury appeared to be reversible to some extent; however, the child was not followed for a sufficient period to determine whether the injury was completely reversible. Exposure of animals to moderate-to-high levels of aldrin or dieldrin over intermediate-to-chronic periods has also been reported to cause adverse effects such as elevated serum enzyme levels, decreased serum proteins, hyperplasia, bile duct proliferation, focal degeneration, and areas of necrosis in the liver (Ahmed et al. 1986a; Fitzhugh et al. 1964; Harr et al. 1970; Kitselman 1953; Thorpe and Walker 1973; Walker et al. 1969). Chronic exposure to sufficiently high levels of aldrin or dieldrin at hazardous waste sites may cause similar adverse hepatic effects. A chronic-duration oral MRL for aldrin of 3x10'5 mg/kg/day was derived based on a LOAEL for increased incidence of enlarged heptocytes with increased eosinophilia and peripheral migration of basophilic granules and possible increases in incidence and severity of heptocellular vacuolation and bile duct proliferation in rats (Fitzhugh et al. 1964). A chronic-duration oral MRL for 65 2. HEALTH EFFECTS dieldrin of 5x10'5 mg/kg/day was derived based on a NOAEL for increased serum alkaline phosphatase levels and decreased serum proteins in dogs (Walker et al. 1969). These degenerative effects are distinct from the adaptive changes observed in livers of a number of animal species in response to exposure to aldrin, dieldrin, or other chlorinated hydrocarbon pesticides. Such adaptive changes occur as a result of the induction of microsomal enzymes by aldrin or dieldrin and include increases in liver weight and/or size, liver cell enlargement, cytoplasmic eosinophilia, an increase in the smooth endoplasmic reticulum, an increase in microsomal protein, an increase in cytochrome P-450 content, and/or an increase in microsomal enzyme activity (Deichmann et al. 1967, 1970; Den Tonkelaar and van Esch 1974; Fitzhugh et al. 1964; Kohli et al. 1977; Olson et al. 1980; Tennekes et al. 1981; Walker et al. 1969, 1972; Walton et al. 1971; Wright et al. 1972, 1978). Studies of workers employed in the manufacture or application of aldrin or dieldrin have not shown evidence of microsomal enzyme induction (Jager 1970; Morgan and Roan 1974; van Sittert and de Jong 1987). However, studies have shown that species differences exist with respect to the magnitude of these changes. The most prolific changes have been observed in rats, with dogs, mice, and monkeys experiencing progressively lesser changes (Wright et al. 1972, 1978). It might be expected, based on the close evolutionary relationship between rhesus monkeys and humans, that limited enzyme induction might also occur in humans. Renal Effects. Although no adverse effects on renal function have been observed in workers employed in the manufacture or application of aldrin or dieldrin (Jager 1970), a man who attempted suicide by consuming a large quantity of aldrin had a transient increase in blood and protein in the urine and a longer-lasting decrease in the ability of the kidney to concentrate the urine (Spiotta 1951). Although a potential role of solvents in the solution that was ingested cannot be eliminated, this finding is supported to some extent by the observation of degenerative effects in kidneys of animals treated with aldrin or dieldrin for intermediate-to-chronic periods, although from several studies it is unclear whether the renal effects represent exacerbation of spontaneously occurring toxic nephropathy or a distinct renal lesion (Ahmed et al. 1986a; Deichmann et al. 1967; Fitzhugh et al. 1964; Harr et al. 1970; Reuber 1980). Thus, persons exposed to extremely high levels of aldrin or dieldrin may be at increased risk of renal toxicity, but it is less clear whether chronic exposure to low levels in the vicinity of hazardous waste sites might cause renal toxicity. Immunological Effects. TWO cases of immunohemolytic anemia resulting from dieldrin exposure were located. In one case, immunohemolytic anemia developed in a man who consumed dieldrin-contaminated fish (Hamilton et al. 1978), and, in the other case, a pesticide operator developed immunohemolytic anemia after multiple exposures to dieldrin and other pesticides (Muirhead et a]. 1959). No examples of this type of a response were observed in other studies of workers or animals exposed to aldrin or dieldrin. However, the existence of a positive immune reaction with dieldrin-coated erythrocytes in both of the case studies verified that dieldrin was the causative agent. Since the doses necessary to produce this effect have not been established, the possibility that susceptible persons living in the vicinity of hazardous waste sites may consume sufficient amounts of aldrin or dieldrin to trigger such an immune response cannot be excluded. Animal studies indicate immunosuppression may also be caused by acute- or intermediate-duration exposure to aldrin or dieldrin. Ingestion of dieldrin by laboratory animals results in a decreased resistance to infection and a decrease in tumor-cell-killing ability (Krzystyniak et al. 1985; Loose 1982; Loose et al. 1981). The suppression of the immune response appears to occur at the level of the cellular response. 66 2. HEALTH EFFECTS Studies in mice indicate that consumption of dieldrin interferes with macrophage processing of antigen, an initial step in cell-mediated immunity (Loose 1982; Loose et al. 1981). Numerous supporting studies, in which mice were given a single dose of dieldrin by intraperitoneal injection, produced similar results (Bernier et al. 1987, 1988; Fournier et al. 1986, 1988; Hugo et al. 1988a, 1988b; Jolicoeur et al. 1988; Krzystyniak et al. 1986, 1987, 1989). Thus, persons exposed to sufficiently high levels of aldrin or dieldrin at hazardous waste sites may be at risk for an unspecified degree of suppression of their immune systems. An acute-duration MRL for dieldrin of 7x10‘5 mg/kg/day was derived based on impaired antigen processing by macrophages (Loose et al. 1981). Neurological Effects. Central nervous system excitation is the primary adverse effect observed in humans in cases of aldrin or dieldrin intoxication. In cases of acute intoxication, in which a large amount of these pesticides is ingested over a short period of time, convulsions occur within several minutes after ingestion (Black 1974; Garrettson and Curley 1969; Spiotta 1951). In cases of longer-term exposures, where a slow rate of elimination from the body results in a gradual build-up of these agents in the blood to toxic levels, convulsions may also be produced (Hoogendam et al. 1965; Jager 1970; Kazantis et al. 1964; Patel and Rao 1958). However, during such longer-term exposures, other less-serious symptoms of central nervous system toxicity may also be observed including headaches, dizziness, hyperirritability, general malaise, nausea, vomiting, muscle twitching, or myoclonic jerking (Jager 1970; Kazantis et al. 1964; Patel and Rao 1958). Both acute- and longer-duration studies in animals support these findings (NCI 1978a, 1978b; Wagner and Greene 1978; Walker et al. 1969; Woolley et al. 1985). It is highly unlikely that high enough levels of aldrin or dieldrin could be absorbed acutely by persons living near hazardous waste sites to cause convulsions, but chronic exposure to sufficiently high levels may cause some of the less adverse central nervous system effects. Several studies in animals have been undertaken in an attempt to determine the mechanism underlying the central nervous system excitation. It is generally believed that the central nervous system excitation observed in animals results from a generalized activation of synaptic activity throughout the central nervous system; however, it has not been established whether aldrin and dieldrin act at the nerve terminal to facilitate neurotransmitter release or whether these agents cause excitation by depressing activity of inhibitory neurotransmitters within the central nervous system (Joy 1982; Shankland 1982). Facilitation of neurotransmitter release by dieldrin has been proposed to occur as the result of the ability of aldrin or dieldrin to inhibit brain calcium ATPases (Mehrotra et al. 1988, 1989). These enzymes are involved in pumping calcium out of the nerve terminal. By inhibiting their activity, aldrin and dieldrin would cause a build-up of intracellular levels of calcium and an enhancement of neurotransmitter release. Most recently, however, the role of aldrin and dieldrin in blocking inhibitory activity within the brain has received a great deal of attention as the probable mechanism underlying the central nervous system excitation. Based on the observed interaction of other cyclodiene insecticides with the inhibitory neurotransmitter, gamma aminobutyric acid (GABA) (Matsumura and Ghiasuddin 1983), numerous studies were undertaken to assess the effects of aldrin and dieldrin on GABA receptor function. Both in vitro experiments using rat brain membranes and intravenous or intraperitoneal administration of aldrin and dieldrin to rats have shown that these agents are capable of blocking the activity of GABA by blocking the influx of chloride through the GABAA receptor-ionophore complex (Abalis et al. 1986; Bloomquist and Soderlund 1985; Bloomquist et al. 1986; Cole and Casida 1986; Gant et al. 1987; Lawrence and Casida 1984; Obata et al. 1988). 67 2. HEALTH EFFECTS Developmental Effects. Studies in humans have not addressed whether adverse developmental effects occur as a result of exposure to aldrin or dieldrin. External malformations have been observed in a study in hamsters and mice using very high doses of dieldrin (Ottolenghi et al. 1974), but at doses 10 times lower, conflicting results regarding these types of effects were reported (Chernoff et al. 1975; Dix et al. 1977). Decreased postnatal survival following in utero exposure to dieldrin has been observed in a number of studies in laboratory animals (Harr et al. 1970; Kitselman 1953; Virgo and Bellward 1975, 1977). This decrease in survival does not appear to be dependent on exposure to this agent postnatally via the mothers’ milk or to effects of dieldrin on maternal behavior, although these factors appear to contribute to the postnatal mortality (Harr et al. 1970; Kitselman 1953; Virgo and Bellward 1975, 1977). However, the mechanism for the neonate lethality at present is not known. In addition, subtle changes in neurological function, such as changes in the electroconvulsive shock threshold, have been observed in offspring of mice treated with aldrin during pregnancy (Al-Hachim 1971). An acute-duration oral MRL for aldrin of 2x10'3 mg/kg/day was derived based on decreased pup weight and increased electroconvulsive shock threshold in pups from maternal mice exposed during gestation. Insufficient evidence exists to speculate whether exposure of parents to aldrin or dieldrin at hazardous waste sites may cause teratogenic effects, but the possibility that exposure of mothers to sufficiently high amounts of aldrin or dieldrin may cause adverse effects on the neonate cannot be excluded. Reproductive Effects. Studies in humans have not addressed whether adverse reproductive effects occur as a result of exposure to aldrin or dieldrin. However, decreased fertility was observed in several (but not all) studies in which aldrin or dieldrin was administered to maternal or paternal animals by the oral route (Dean et al. 1975; Epstein et al. 1972; Good and Ware 1969; Harr et al. 1970; Virgo and Bellward 1975). In additional studies of reproductive toxicity following intraperitoneal injection of aldrin, investigators have observed several adverse effects of this agent on the male reproductive system (Chatterjee et al. 1988a, 1988b, 1988c). These findings include decreased sperm count, degeneration of germ cells, decreased weights of seminal vesicles and prostate and coagulating glands, decreased seminiferous tubule diameter, decreased plasma and testicular testosterone, decreased prostatic fructose content and acid phosphatase activity, and decreased plasma luteinizing hormone (LH) and follicular stimulating hormone (FSH). Also, in vitro studies conducted using rat prostate tissue have shown that dieldrin blocks binding of the androgen, 5a-dihydro-testosterone, to a protein fraction of the prostate (Wakeling et al. 1973). These findings may provide clues regarding the mechanism of the decreased fertility in males. Based on the findings reported in these studies, an adverse effect of exposure to sufficiently high levels of aldrin 0r dieldrin on male fertility cannot be excluded. Genotoxlc Effects. In vitro studies assaying for genotoxicity of aldrin or dieldrin have been conducted in several species. Significant increases in chromosome aberrations have been reported in cultured human lung cells. Similar results have been observed in bone marrow cells of mice treated intraperitoneally with dieldrin (Majumdar et al. 1976). Sister chromatid exchanges were significantly increased in Chinese hamster ovary cells at doses that caused marked cell cycle delay when tested both with and without S9 (Galloway et al. 1987). However, no chromosome aberrations were seen in this study. In addition, only 3 of 4,800 cells from 48 Chinese hamsters exposed via intraperitoneal injection of 60 mg/kg of dieldrin showed aberrant chromosomes (Dean et al. 1975). Mitotic gene conversion in Saccharomyces cerevisiae was negative in a host-mediated assay in which adult male CF1 mice were orally dosed for 5 consecutive days with 5 or 10 mg/kg of dieldrin (Dean et al. 1975). Micronuclei formation was increased in Tradescantia by 3.81 ppm dieldrin, but aldrin yielded negative results (Sandhu et al. 1989). The authors speculated that the immiscibility of aldrin in water contributed to the negative findings of that chemical. 68 2. HEALTH EFFECTS Gene mutation has been reported to be positive in Chinese hamster V79 cells (Ahmed et al. 1977b) and in Salmonella (Ennever and Rosenkranz 1986; Majumdar et al. 1977) but negative in Aspergillus nidulans (Crebelli et al. 1986). Gene mutation in several strains of Salmonella has also been reported to be negative, with and without activation (De Flora et al. 1984; Glatt et al. 1983; Haworth et al. 1983; Marshall et al. 1976), but weakly positive results were reported in Salmonella following photoactivation with ultraviolet light (De Flora et al. 1989). Most of the available evidence indicates that aldrin and dieldrin do not act directly on the DNA. There is some evidence that the activity of several specific transfer ribonucleic acids (tRNAs) is depressed by exposure to dieldrin, but it is uncertain whether this is due to decreased synthesis or to direct inactivation (Chung and Williams 1986). Other possible mechanisms for the cellular effects of aldrin and dieldrin include increasing unscheduled DNA synthesis (UDS), since a positive effect has been reported in SV-40 transformed human cells in culture (Ahmed et al. 1977a). However, UDS assays have been negative in both rat (Probst et al. 1981) and mouse (Klaunig et al. 1984) primary hepatocyte cultures. Another possible mechanism for the action of aldrin and dieldrin involves the inhibition of metabolic cooperation and gap junctional intercellular communication. These effects have been reported in both Chinese hamster cells (Jone et al. 1985; Kurata et al. 1982; Trosko et al. 1987) and in human teratocarcinoma cells (Wade et al. 1986; Zhong-Xiang et al. 1986). While these effects are epigenetic, rather than genotoxic, these processes may offer insight into cellular changes in metabolism and proliferation that could explain cell cycle changes and the disparate results of genotoxicity assays. Key 13 1M). genotoxicity studies are presented in Table 2-5, and in vitro genotoxicity studies are presented in Table 2-6. Cancer. Epidemiological studies have been inadequate to determine whether aldrin or dieldrin cause cancer in exposed human populations because of the small sample sizes studied and the exposure of subjects to a variety of chemicals in addition to aldrin or dieldrin. However, several studies in mice demonstrate the ability of aldrin and/or dieldrin to cause hepatocellular carcinoma (Davis and Fitzhugh 1962; Meierhenry et al. 1983; NCI 19783; Tennekes et al. 1981; Thorpe and Walker 1973; Walker et al. 1972). The finding of liver tumors in mice withstood the EPA (1986c) criteria for downgrading the significance of such tumors because (1) the tumors were observed in a dose-dependent manner in both male and female mice, (2) in some studies the carcinogenic response was "unmistakably strong," and (3) tumors were observed in strains with both low and high incidences of spontaneous liver tumors (EPA 1987a). In addition, a study in rats provided suggestive evidence that thyroid tumors may be associated with aldrin exposure (NCI 1978a). Although several other studies in rats reported negative findings (Deichmann et al. 1967, 1970; Fitzhugh et al. 1964; NCI 1978b; Walker et al. 1969), deficiencies of these studies may have limited their ability to adequately detect carcinogenicity. Thus, the possibility exists that aldrin and dieldrin may cause cancer in humans. Based on the conclusion that sufficient animal evidence for carcinogenicity existed, EPA has classified both aldrin and dieldrin as B2, probable human carcinogens. An upper-bound ql' (cancer potency factor) of 17 (mg/kg/day)‘1 for oral exposure to aldrin was estimated by EPA (1987f) based on the geometric mean of three cancer potency values calculated from studies by Davis (1965), Davis and Fitzhugh (1962), and NCI (1978a). Insufficient data were available to develop such a value for exposure by the inhalation route, but based on the oral data, an upper-bound q,‘ of 0.0049 (pg/m3)'1 was extrapolated (EPA 1987f; IRIS 1990). TABLE 2-5. Genotoxicity of Aldrin/Dieldrin In Vivo Results With Without Species (test system) End point activation activation Reference Human (occupational cohort) Sister chromatid exchange NA + Dulout et al. 1985 Chromosome aberrations NA + Dulout et al. 1985 Human (occupational cohort) Chromosome aberrations NA — Dean et al. 1975 Swiss mice (male) Decreased meiotic NA + Rani and Reddy 1986 chromosome pairing Increased abnormal NA + Rani and Reddy 1986 metaphases Chinese hamsters (intraperitoneal Chromosome aberrations NA — Dean et al. 1975 exposure) Mice (intraperitoneal exposure) Chromosome aberrations NA + .Majumdar et al. 1976 — = negative result; + = positive result; NA = not applicable SiOEfldE H.L'|V3H ‘Z 69 TABLE 2-6. Genotoxicity of Aldrin/Dieldrin In Vitro $103533 H.L'1V3H '2 Results With Without Species (test system) End point activation activation Reference Chinese hamster ovary cells Sister chromatid exchange + + Galloway et al. 1987 Chromosome aberrations — — Chinese hamster V79 cells Gene mutation NA + Ahmed et al. 1977b Cultured human lung cells Chromosome aberrations NA + Majumdar et al. 1976 Saccharomyces cerevisiae Mitotic gene conversion NA - Dean et al. 1975 Tradescantia Micronuclei formation NA + Sandhu et al. 1989 (dieldrin) NA — (aldrin) Salmonella typhimurium Gene mutation + + Ennevar and Rosenkranz 1986; Majundar et al. 1977 — — DeFlora et a1. 1984; Glatt et al. 1983; Haworth et al. 1983; Marshall et al. 1976 (+) DeFlora et al. 1989 (photoactivation) Aspergillus nidulans NA — Crebelli et al. 1986 Transformed human cells Increased unscheduled DNA NA + Ahmed et al. 1977a Rat hepatocyte Mouse hepatocyte synthesis NA NA Probst et al. 1981 Klauniget al. 1984 — = negative result; + = positive result; (+) = weakly positive result; DNA = deoxyribonucleic acid; NA = not applicable 0/. 71 2. HEALTH EFFECTS Similarly, an upper-bound q,’ of 16 (mg/kg/day)’1 for oral exposure to dieldrin (IRIS 1990) was estimated by EPA (1987g) based on the geometric mean of 13 cancer potency values calculated from studies by Davis (1965), Meierhenry et al. (1983), NCI (1978a), Tennekes et al. (1981), Thorpe and Walker (1973), and Walker et al. (1972). Insufficient data were available to develop such a value for exposure by the inhalation route, but based on the oral data, an upper bound q; of 0.0046 (pg/m3)1 was extrapolated (EPA 1987g; IRIS 1990). Available data on the genotoxicity of aldrin and dieldrin indicate that these agents do not cause cancer by a mutagenic mechanism. Most recent data indicate that aldrin and dieldrin may act as tumor promoters (Jone et al. 1985; Kurata et al. 1982; Trosko et al. 1987; Wade et al. 1986; van Ravenzwaay and Kunz 1988; Zhong-Xiang et al. 1986). Some tumor promoters act by facilitating the proliferation of previously initiated preneoplastic cells. During the proliferative activity, genetic material from a preneoplastic cell may undergo further change allowing the progression from a preneoplastic state to a neoplastic state. Aldrin and dieldrin are believed to enhance proliferation, at least in part, by inhibiting gap junctional communication between cells. This inhibition of gap junctional communication may relieve the cell from inhibitory proliferative control. Support for this hypothesis comes from work demonstrating species and strain specificity with regard to the ability of aldrin and dieldrin to inhibit gap junctional communication and facilitate cellular hyperplasia and neoplasia (Klaunig and Ruch 1987; Klaunig et al. 1990; Ruch and Klaunig 1986). In these studies, dieldrin effectively inhibited gap junctional communication only in strains and species in which this agent had previously been shown to be carcinogenic. Similar strain and species correlations between inhibition of gap junctional communication and tumorigenicity have been observed for other tumor promoters. Whether aldrin and dieldrin to inhibit gap junctional communication in human tissues is unknown. 2.5 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target niolecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time biologic samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to aldrin or dieldrin are discussed in Section 2.5.1. Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. 72 2. HEALTH EFFECTS Note that these markers are often not substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by aldrin or dieldrin are discussed in Section 2.5.2. A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, biologically effective dose, or target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.7, "Populations That Are Unusually Susceptible." 2.5.1 Biomarkers Used to Identify or Quantify Exposure to Aldrin or Dieldrin Exposure to aldrin and dieldrin is measured almost exclusively by determining the level of dieldrin in the blood. Because aldrin is rapidly converted to dieldrin in the body, the detection of aldrin in body tissues is rare. Blood levels of dieldrin are specific for aldrin and dieldrin. Dieldrin levels measured in blood samples of members of the general population in the United States between 1976 and 1980 in the National Health and Nutrition Examination Survey (NHANES II) were found to be approximately 1.4 ppb (Murphy and Harvey 1985; Stehr-Green 1989). It is likely that current baseline blood levels in the general population would be lower. Detection of dieldrin in the blood may indicate either recent or past exposure to aldrin or dieldrin. Dieldrin would be detected in the blood either immediately after inhalation, oral, or dermal absorption or as stores of dieldrin are slowly released from adipose tissue. In humans, dieldrin has a relatively long half— life in the body (Hunter and Robinson 1967; Hunter et al. 1969; Jager 1970). Hunter et al. (1969) calculated a mean half-life of 396 days, and Jager (1970) estimated a mean half life of 266 days. Thus, exposures of sufficient magnitude occurring several years earlier may still be detected in the blood. Because dieldrin rapidly redistributes to adipose tissue, the highest levels of dieldrin are found in fat (except immediately after exposure). Thus, fat levels of dieldrin are also a good source for identifying exposure to aldrin or dieldrin. However, obtaining fat samples requires at least minor surgery; therefore, this method is not commonly used. The 1982 Human Adipose Tissue Survey found dieldrin present in adipose tissue at a mean concentration of 458 ppb. It is likely that current levels would be lower. Because of its high fat content, breast-milk levels of dieldrin may give some information about prior exposures and accumulation of dieldrin in fatty tissues. Breast-milk levels of dieldrin may be lowered by frequent nursing (Ackerman 1980). Following relatively long-term exposure to constant levels of aldrin or dieldrin, a steady state of body levels of dieldrin is achieved (Hunter and Robinson 1967; Hunter et al. 1969). Thus, when repeated and regular exposure is known to have occurred, the exposure level may be calculated from blood or fat levels using the equations described by Hunter et al. (1969) (exposure level equals the blood level divided by 0.086 or the fat level divided by 0.0185). The metabolite of dieldrin, 9-hydroxydieldrin, has been detected in human feces (Richardson and Robinson 1971). However, this metabolite has not been routinely used to identify or quantify exposure to aldrin or dieldrin. 73 2. HEALTH EFFECTS Prior to the use of blood levels to monitor exposure to aldrin and dieldrin, EEGs were used to monitor workers for possible overexposure to these substances (Hoogendam et al. 1962, 1965; Jager 1970). However, this technique is most reliable when a baseline EEG recording from each subject has been obtained prior to exposure. Also, any centrally acting neuroexcitatory substance could produce EEG changes similar to those produced by aldrin or dieldrin, limiting the specificity of this technique. 2.5.2 Biomarkers Used to Characterize Effects Caused by Aldrin or Dieldrin Although none of the following effects are specific for aldrin or dieldrin, measurement of a number of parameters may provide useful information when exposure to aldrin or dieldrin is suspected. In animals, microsomal enzyme induction is one of the earliest and most sensitive effects caused by organochlorine pesticides such as aldrin and dieldrin (Wright et al. 1972). Several indicators have been used to try to assess microsomal enzyme induction in humans following exposure to aldrin or dieldrin. These indicators include urinary levels of D-glucaric acid, the ratio of urinary 6-13-hydroxycortisol to 17-hydroxy- corticosteroids, and blood levels of p,p’-DDE (Jager 1970; Morgan and Roan 1974). Other substances such as barbiturates, phenytoin, chlorbutanol, aminopyrine, phenylbutazone, progesterone, and contraceptive steroids as well as other organochlorine pesticides also cause microsomal enzyme induction and cause changes in these parameters (Morgan and Roan 1974). Central nervous system excitation culminating in convulsions is, in some cases, the only symptom of aldrin or dieldrin intoxication. EEG changes in occupationally exposed workers have been monitored in the past in an attempt to detect central nervous system changes prior to the onset of convulsions (Jager 1970). Characteristic changes include bilateral synchronous spikes, spike and wave complexes, and slow theta waves (Avar and Czegledi-Janko 1970; Garrettson and Curley 1969; Hoogendam et al. 1962, 1965; Jager 1970; Kazantis et al. 1964; Spiotta 1951); however, these changes are not specific for aldrin or dieldrin overexposure and may be produced by several neuroexcitatory substances. A good correlation between blood levels of dieldrin and central nervous system toxicity has been established (Brown et al. 1964; Jager 1970). Thus, blood levels in excess of 0.2 mg/L are frequently associated with adverse central nervous system effects. Studies of immune activity have not routinely been done in humans to assess immunosuppression caused by aldrin and dieldrin, but studies indicate that measurements of cytotoxic T—lymphocyte activity or of macrophage-antigen processing may be good indicators of the adverse effects of aldrin and dieldrin on the immune system (Loose 1982; Loose et al. 1981). However, such tests would not be specific for aldrin- or dieldrin-mediated immunosuppression. Another potential adverse effect of aldrin and dieldrin on the immune system that has been reported only twice is the induction of immunohemolytic anemia. A Coomb’s test can be used to measure the ability of the subject’s serum to cause a positive immune reaction with dieldrin-coated red blood cells (Hamilton et al. 1978). 2.6 INTERACTIONS WITH OTHER CHEMICALS Limited information is available regarding the influence of other chemicals on the toxicity of aldrin and dieldrin. Administration of the pesticides Aramite, DDT, and methoxychlor with aldrin to rats did not cause an increase over the incidence of cancer observed in the presence of aldrin alone (Deichmann et al. 1967). However, no increase in cancer incidence was observed with any of these substances administered 74 2. HEALTH EFFECTS singly. Thus, it is unclear whether the conditions of this assay were adequate to detect an additive or synergistic effect if it existed. Induction of microsomal enzymes by ochratoxin, a mycotoxin, was observed to enhance conversion of aldrin to dieldrin (Farb et al. 1973). Also, induction of microsomal enzymes by the pesticides hexachlorobenzene and DDT caused a decrease in storage in adipose tissue and/or an increased rate of excretion of the metabolites of aldrin and dieldrin in the feces and urine (Clark et a1. 1981; Street and Chadwick 1967). However, these studies did not present information regarding the effects of these interactions on the toxicity of aldrin or dieldrin. Thus, it is unknown whether the changes in the pharmacokinetics of aldrin and dieldrin affected their toxicity. 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A susceptible population will exhibit a different or enhanced response to aldrin or dieldrin than will most persons exposed to the same level of aldrin or dieldrin in the environment. Reasons include genetic make- up, developmental stage, health and nutritional status, and chemical exposure history. These parameters result in decreased function of the detoxification and excretory processes (mainly hepatic and renal) or the pre-existing compromised function of target organs. For these reasons we expect the elderly with declining organ function and the youngest of the population with immature and developing organs will generally be more vulnerable to toxic substances than healthy adults. Populations who are at greater risk due to their unusually high exposure are discussed in Section 5.6, "Populations With Potentially High Exposure." Review of the literature regarding toxic effects of aldrin and dieldrin did not reveal any populations that are known to be unusually sensitive to aldrin or dieldrin. However, some populations that may potentially demonstrate unusual sensitivity include the very young with immature hepatic detoxification systems, persons with impaired liver function, and persons with impaired immune function. Aldrin and dieldrin are metabolized in the liver primarily by microsomal mixed-function oxidases. To some extent, the oxidized metabolites 9-hydroxydieldrin and 6,7-m—dihydroxydihydroaldrin are conjugated with glucuronide prior to excretion (Matthews and Matsumura 1969). In the very young, the microsomal enzyme system and the enzyme systems responsible for glucuronide conjugation operate at levels below those in adults (Calabrese 1978). Thus, the very young may experience increased toxic effects due to the decreased rates of excretion. Similarly, persons with impaired liver function may also experience increased toxicity because of their limited ability to fully metabolize aldrin or dieldrin. The suggestive evidence of bioconcentration of dieldrin in the fetus ‘(Polishuk et al. 1977b) and the possibility of consumption of contaminated breast milk by infants indicate that these groups have an increased risk, because they may have higher body burdens of these pesticides than adults. Persons suffering from compromised immune function may demonstrate an increased susceptibility to infections because of the ability of aldrin and dieldrin to impair cellular immunity (Krzystyniak et al. 1985; Loose 1982; Loose et a1. 1981). Infants and children may also be susceptible because the human immune system does not reach maturity until 10-12 years of age (Calabrese 1978). Although aldrin and dieldrin cause central nervous system excitation leading, in some cases, to convulsions, no evidence of an enhanced susceptibility to the excitatory effects of aldrin or dieldrin in persons with preexisting anomalous EEGs was observed (Jager 1970). 75 2. HEALTH EFFECTS 2.8 METHODS FOR REDUCING TOXIC EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to aldrin and dieldrin. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to aldrin and dieldrin. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. Most of the strategies discussed in the following sections apply to acute high-dose exposures. Some decontamination and treatment recommendations for persons acutely exposed may be inappropriate in the chronic exposure setting. Methods to reduce toxic effects should not be applied indiscriminately to individuals exposed to all doses of aldrin and dieldrin. If clinical effects are observed, only treatments appropriate for the patient’s clinical status should be administered. 2.8.1 Reducing Absorption Following Exposure General recommendations reported for reducing absorption following acute high-dose exposure to aldrin and dieldrin include removing the individual from the source of exposure and decontaminating exposed skin using alcohol or soap and water (HSDB 1992). Dermal absorption is fairly efficient, so decontamination attempts should be accomplished quickly. An initial soap and water wash, followed by an alcohol wash, followed by a second soap and water wash have been suggested for decontaminating skin and hair after aldrin or dieldrin exposure (Hall and Rumack 1992), but it is unclear whether this represents any true improvement over thorough washing with soap and water. A number of strategies have been suggested to minimize absorption from the gastrointestinal tract. Ipecac-induced emesis has been suggested for gastric emptying, although there is a risk of pulmonary aspiration of gastric contents and resultant pneumonitis from hydrocarbon solvents due to potential early onset of unconsciousness or convulsions (HSDB 1992). When emesis is contraindicated, gastric lavage has been suggested as an alternative method for emptying the stomach if ingestion was recent (within 60-90 minutes) (Klaassen 1990). A cuffed endotracheal tube is recommended if hydrocarbon solvents were also ingested. Since activated charcoal can adsorb aldrin and dieldrin, it has also been commonly used as a method for reducing intestinal uptake following ingestion (HSDB 1992). Another method for reducing absorption is the use of a cathartic; activated charcoal is frequently given mixed as a slurry with one of the saline cathartics or sorbitol (Hall and Rumack 1992; HSDB 1992). The mechanism by which aldrin and dieldrin are absorbed from the gastrointestinal tract is unknown; however, their highly lipophilic nature suggests dissolution in the cell membrane. 2.8.2 Reducing Body Burden There are no proven or accepted strategies for reducing the body burden of dieldrin. A majority of dieldrin’s final metabolites are conjugated with glucuronic acid in the liver; most excretion is in the bile, with smaller amounts in the urine (Richardson and Robinson 1971). Fecal metabolites have been measured but not quantitatively compared with metabolites secreted through the bile duct; thus, it is unclear whether enterohepatic recirculation occurs. However, some biliary metabolites, such as 9-hydroxydieldrin glucuronide, seem to be deconjugated by gut microfloral glucuronidases since they are excreted in the feces in aglycone form (Chipman and Walker 1979; Hutson 1976). Deconjugation frequently favors enterohepatic recirculation (Sipes and Gandolfi 1991). If significant enterohepatic recirculation could be demonstrated, methods to interfere with the reabsorption from the gut into the systemic circulation might be effective in accelerating the excretion of aldrin and dieldrin metabolites. There are several possible strategies for reducing intestinal resorption of bile excretions; the simplest is 76 2. HEALTH EFFECTS repeated doses of activated charcoal (without cathartics) (Levy 1982). Another strategy, which has been effective in experiments with another lipophilic xenobiotic, chlordecone, is the oral administration of the anion exchange resin, cholestryamine (Boylan et al. 1978). However, it effectiveness with aldrin or dieldrin poisoning is unknown. The pharmacokinetics of aldrin and dieldrin are not completely understood. Once absorbed by the gastrointestinal tract, these pesticides are transported to the liver via the portal vein (Heath and Vandekar 1964). They are found mainly in the liver for the first 3 hours but have also been found in the blood, lymph, kidneys, fetus, and adipose tissue (Heath and Vandekar 1964; Iatropoulos et al. 1975). The interval immediately after absorption may be a window of opportunity for removing the xenobiotic from the circulation before it partitions into adipose tissue. Potential strategies include hemodialysis and hemoperfusion (Klaassen 1990). However, the large molecular weights and lipophilic nature of these compounds argues against effective removal by hemodialysis. Another potential strategy for removal would be to attempt to increase dieldrin excretion by enhancing its metabolism. Dieldrin’s metabolism to 9-hydroxydieldrin and excretion are substantially greater in male than in female rats (Matthews et al. 1971), indicating that a specific form of cytochrome P450 may be more prevalent in male rats. If the specific form(s) of cytochrome P450 responsible for the more rapid metabolism and excretion could be identified, specific inducers could be used to speed dieldrin’s excretion in humans (Sipes and Gandolfi 1991). Long-term storage is in adipose tissue, primarily in the form of dieldrin (Hutson 1976), but initially some residues are also found in the liver and brain. It is unclear whether detrimental effects would be expected from this storage, although there is equilibrium between dieldrin in fat and blood. Release of dieldrin from fat has not resulted in a significant health hazard in people with low body burdens of dieldrin (Hunter and Robinson 1986). 2.8.3 lnterferlng wlth the Mechanism of Actlon for Toxlc Effects The mechanism for aldrin and dieldrin toxicity is not equally well understood for all target organs. The central nervous system is the most sensitive target for acute toxicity; aldrin and dieldrin are stimulants that can cause excitation, convulsions, and seizures (Wagner and Greene 1978; Woolley et al. 1985). There are multiple theories about the mechanism of action; it is unclear whether dieldrin facilitates excitatory neurotransmitter release or interferes with inhibitory neurotransmitter action. One hypothesis is that the majority of dieldrin’s neurotoxicity is due to its interactions with a receptor for the inhibitory neurotransmitter GABA. Dieldrin is thought to be a competitive inhibitor of binding to the GABA-A receptor TBPS binding site (Lawrence and Casida 1984), and in vitro experiments have shown that it blocks the chloride channel in GABA-A receptor complex (Abalis et al. 1986; Bloomquist and Soderlund 1985; Bloomquist et al. 1986; Cole and Casida 1986; Gant et al. 1987; Lawrence and Casida 1984; Obata et al. 1988). Administration of benzodiazepines, which act at the GABA receptor to potentiate GABA binding (Bloom 1990), has been suggested as a method for treating aldrin- or dieldrin- induced seizures (HSDB 1992). This standard method of reducing central nervous system excitation might be acting at the same molecular site as dieldrin and, thus, specifically interfering with its mechanism of action. If GABA-A receptor interactions are the major mechanism of central nervous system toxicity, potential research approaches for interfering with the mechanism of action would include the use of agonists such as muscimol or GABA to compete for binding at the receptor, inhibitors of GABA re-uptake such as guvacine or nipecotic acid, and blocking GABA catabolism with aminooxyacetic acid (Bloom 1990). Although benzodiazepines are safer, barbiturates also act at the GABA receptor to potentiate GABA binding and might reduce the central nervous system toxicity of dieldrin (Bloom 1990). Phenytoin has been used for seizures refractory to treatment with diazepam or barbiturate (Hall and Rumack 1992). 77 2. HEALTH EFFECTS Adrenergic B—blockers were used effectively to control blood pressure in a dieldrin-poisoned individual (Black 1974), suggesting that such treatment may be effective in other dieldrin-poisonings where elevated blood pressure occurs. A potential investigative strategy to reduce aldrin toxicity might be to channel aldrin metabolism to the liver where it is more likely to immediately continue to be metabolized to less toxic metabolites. While most conversion of aldrin to dieldrin occurs in the liver, some aldrin is converted to dieldrin outside of the liver. Since further metabolism and conjugation of dieldrin for excretion take place mainly in the liver, any dieldrin created outside the liver has a greater chance of causing toxic effects. Aldrin is converted to dieldrin outside the liver by the more ubiquitous prostaglandin endoperoxidase synthetase. A possible method for reducing the extrahepatic transformation of aldrin to dieldrin would be to inhibit the activity of prostaglandin endoperoxidase synthetase with the cyclooxygenase inhibitors aspirin and indomethacin. Also, ascorbic acid supplementation during dieldrin treatment has been observed to partially reduce the hepatic and renal toxicity of dieldrin treatment in experimental animals (Bandyopadhyay et al. 1982b). However, the reproducibility, effectiveness in humans, and potential mechanism for the reduction in toxicity are unknown. Mitigation strategies that may be developed in the future for other lipophilic pesticides should be considered for their applicability to aldrin and dieldrin. 2.9 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of aldrin or dieldrin is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of aldrin or dieldrin. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce or eliminate the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 2.9.1 Exlstlng lnformatlon on Health Effects of Aldrln or Dleldrln The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to aldrin or dieldrin are summarized in Figure 2-4. The purpose of this figure is to illustrate the existing information concerning the health effects of aldrin or dieldrin. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not imply anything about the quality of the study or studies. Gaps in this figure should not be interpreted as "data needs" information (i.e., data gaps that must necessarily be filled). The vast majority of the literature reviewed concerning the health effects of aldrin and dieldrin in humans described case reports and chronic-duration studies of workers employed in either the manufacture or application of aldrin or dieldrin and case reports of accidental or intentional ingestion of aldrin, dieldrin, 78 2. HEALTH EFFECTS FIGURE 2-4. Existing Information on Health Effects of AIdrin/Dieldrin SETEinlcf 63’ fig 3 of 3° a (Pg @ #3" 0° «9* 0°“? (3’3 Inhalation . . . . 0 C 0 Oral . C C C C . Dermal . .0 O O O O O 0 HUMAN ’ SYSTEMIC 936° '0 689$ $0 ‘0 of 3% 3“? $49 «3° 39°“ of? £9 060$ of Inhalation . . Oral .CCCCCCCCO Dermal . C C C C C ANIMAL 0 Existing Studies 79 2. HEALTH EFFECTS or food contaminated with either of these agents. For those employed in either the manufacture or application of these pesticides, the predominant routes of exposure would be inhalation and dermal, whereas for accidental or intentional poisonings the major route of exposure would be oral. Thus, information on acute- and intermediate-duration exposures comes almost exclusively from oral exposure data, whereas information on longer-term exposures comes almost exclusively from inhalation and dermal exposure data. Information from occupational studies is frequently limited by a lack of data regarding quantification of doses of the chemical in question and potential exposures to other pesticides or otherchemicals. Also, data from case reports of poisoning by ingestion of these agents is often limited by a lack of information on the amount consumed. No information is available regarding developmental effects or reproductive effects in humans by any route or regarding genotoxic or cancer effects by the oral route. Virtually all of the data regarding the health effects of aldrin and dieldrin in animals were obtained from studies in which these agents were administered orally. Very little information is available regarding the health effects of inhalation exposure, and far less information is available regarding dermal exposure than for oral exposure. Because persons living near hazardous waste sites and those with aldrin- or dieldrin- treated homes may be exposed via the inhalation or dermal routes, additional information on the effects via these routes would be valuable. 2.9.2 identification of Data Needs Acute-Duration Exposure. Populations in areas that contain hazardous waste sites may be exposed to aldrin or dieldrin for brief periods. Exposure would most likely occur by the inhalation or oral routes, but dermal exposure is also possible. There are acute-duration oral exposure data in humans from cases of accidental or intentional poisonings that indicate that the central nervous system is a major target organ of aldrin and dieldrin toxicity by the oral route. Convulsions have been observed following ingestion of very high concentrations of aldrin and dieldrin (Black 1974; Garrettson and Curley 1969; Spiotta 1951). Also, acute oral exposure in humans has been reported to cause renal toxicity (Spiotta 1951). Renal toxicity has not been reported in studies in animals after acute-duration ingestion of high concentrations of aldrin or dieldrin; however, the number of studies examining systemic effects associated with acute- duration exposures is quite limited. Studies in laboratory animals examining the effects of ingestion of aldrin or dieldrin have supported the conclusion that the nervous system is a major target organ of aldrin and dieldrin toxicity (Burt 1975; Carlson and Rosellini 1987; Mehrotra et al. 1989; Treon et al. 1953a; Wagner and Greene 1978; Woolley et al. 1985). In such studies, convulsions as well as impaired responding in operant behavioral paradigms were reported. In addition, immune suppression (Krzystyniak et al. 1985; Loose et al. 1981), developmental toxicity (Al-Hachim 1971; Ottolenghi et al. 1974), and adaptive changes in the liver (Wright et al. 1972) have been observed in acutely exposed animals. Results of these studies indicate that the immune system may be the most sensitive target organ for the effects of brief oral exposures to aldrin or dieldrin. An acute-duration oral MRL was derived for dieldrin based on its suppression of cellular immunity (Loose et al. 1981). An acute-duration oral MRL was derived for aldrin based on a decreased body weight and electroconvulsive shock threshold in offspring of treated mice (Al-Hachim 1971). No information is available regarding acute-duration inhalation exposure to aldrin or dieldrin in humans, and extremely limited information is available from studies in animals (Treon et al. 1957b). Although the volatility of aldrin and dieldrin is quite low and levels in the atmosphere are expected to be quite low, absorption of these compounds by the lungs occurs to a significant extent (Mehendale and El-Bassiouni 1975). Toxicokinetic data do not indicate that dissimilar target organs would be affected as a result of 80 2. HEALTH EFFECTS inhalation exposure to aldrin or dieldrin. Thus, additional studies examining the effects of acute inhalation exposure to saturating concentrations of aldrin or dieldrin would be helpful in determining whether toxic effects would occur as a result of brief inhalation exposure. Information regarding the acute effects of dermal exposure of aldrin or dieldrin is limited to lethality studies in animals (Gaines 1960; Treon et al. 1953a). Dermal exposure to aldrin and dieldrin is possible in contaminated soil, and toxicokinetic studies indicate that dermally applied aldrin and dieldrin are absorbed (Feldmann and Maibach 1974; Graham et al. 1987; Witherup et al. 1961). Toxicokinetic data do not suggest that dissimilar target organs would be affected as a result of dermal exposure. Thus, studies examining the effects of acute dermal exposure to aldrin or dieldrin would be useful. Intermediate-Duration Exposure. Few reports were located regarding effects in humans after intermediate-duration exposure to aldrin or dieldrin by any route. In one study, exposure was by the oral route (Gupta 1975). In two other studies, exposure most likely occurred as the result of combined inhalation and dermal (and possibly oral) exposures (Fletcher et al. 1959; Patel and Rao 1958). These studies showed that the nervous system is a major target organ in humans after intermediate-duration exposures. Studies in laboratory animals confirm this observation (Burt 1975; Mehrotra et al. 1988; Smith et al. 1976; Treon et al. 1951b; Wagner and Greene 1978). Other targets identified in intermediate- duration oral studies in animals include the immune system (Loose 1982), the developing neonate (Al-Hachim 1971; Deichmann et al. 1971; Harr et al. 1970; Treon et al. 1954a; Virgo and Bellward 1975), the reproductive system (Treon et al. 1954a; Virgo and Bellward 1975, 1977), the kidney (Ahmed et al. 1986a; Bandyopadhyay et al. 1982b), and the liver (Ahmed et al. 1986a; Shakoori et al. 1982; Treon et al. 1951a, 1951b). Insufficient data were located to calculate an intermediate-duration oral MRL for aldrin or dieldrin. No data were located regarding intermediate-duration inhalation exposures in animals, and human exposure levels were not quantified. Therefore, no intermediate-duration inhalation MRL was derived for either aldrin or dieldrin. Also, only limited information was located regarding lethality, neurological effects, and dermal effects after intermediate-duration dermal exposures (Bundren et al. 1952; Treon et al. 1953a). As noted above, absorption occurs by both the inhalation and dermal routes, and toxicokinetic data indicate that similar target organs would be affected following exposure to either route; thus, additional studies examining the effects of aldrin and dieldrin by the inhalation and dermal routes would be helpful. Chronic-Duration Exposure and Cancer. A number of epidemiological studies have been conducted on workers exposed chronically to aldrin and dieldrin (de Jong 1991; Ditraglia et al. 1981; Hoogendam et al. 1965; Jager 1970; Morgan and Lin 1978; Morgan et al. 1980; Sandifer et al. 1981; Van Raalte 1977; Van Sittert and de Jong 1987; Versteeg and Jager 1973; Warnick and Carter 1972). In these studies, doses are usually not well quantified, and concomitant inhalation, dermal, and possibly oral exposures have occurred. However, it is difficult to recommend a population for future epidemiological studies of effects caused by chronic-duration inhalation, oral, or dermal exposure because (1) these agents have not been manufactured in the United States since 1974, and (2) those who have been employed in applying the remaining stocks of these agents are likely to have been exposed to a variety of other pesticides. Data from the existing epidemiological studies indicate that the nervous system is also a major target organ for chronic inhalation, dermal, and possibly oral exposures in humans (Hoogendam et al. 1962, 1965; Jager 1970; Sandifer et al. 1981). Chronic oral studies in animals also indicate that the nervous system is a major target organ (Fitzhugh et al. 1964; Han .et al. 1970; Kitselman 1953; NCI 1978a, 1978b; Walker et al. 1969). In addition, chronic studies in animals demonstrate adverse effects of aldrin and dieldrin on the kidney (Deichmann et al. 1967; Fitzhugh et al. 1964; Harr et al. 1970; Treon et al. 1955b) and liver (Fitzhugh et 81 2. HEALTH EFFECTS al. 1964; Kitselman 1953; Thorpe and Walker 1973; Treon et al. 1955b; Walker et al. 1969). A chronic-duration oral MRL was derived for aldrin based on evidence for microsomal enzyme induction with possible hepatocellular vacuolation and bile duct proliferation (Fitzhugh et al. 1964). A chronic-duration oral MRL was derived for dieldrin based on increased serum alkaline phosphatase levels and decreased serum proteins in dogs (Walker et al. 1969). No chronic animal studies were located for the inhalation route; only one animal study was located examining the effects of chronic dermal exposure (Witherup et al. 1961). Studies examining the effects caused by low-level chronic exposures by both the inhalation and oral routes would be valuable for determining whether such exposures could cause toxicity in populations exposed to aldrin and dieldrin near hazardous waste sites for extended periods. Epidemiological studies examining the incidence of cancer in workers exposed to aldrin and dieldrin have not shown that these agents are carcinogenic in humans (de Jong 1991; Ditraglia et al. 1981; Ribbens 1985; Van Raalte 1977). However, these studies are limited by the small sample sizes studied and the exposure of workers to other chemicals. Several studies in mice have shown that oral exposure to aldrin or dieldrin cause an increase in the incidence of malignant liver tumors (Davis and Fitzhugh 1962; Meierhenry et al. 1983; NCI 1978a; Tennekes et al. 1981; Davis and Fitzhugh 1962; Thorpe and Walker 1973; Walker et al. 1972). However, studies in rats (Cabral et al. 1979; Deichmann et al. 1967, 1970; Fitzhugh et al. 1964; NCI 1978b; Walker et al. 1969) have been either equivocal or flawed. Additional studies by the oral route in a species other than the mouse would help clarify the carcinogenic potential of aldrin and dieldrin. If species differences are found to exist in the ability of these agents to enhance carcinogenicity, additional studies attempting to define the species-specific protective mechanism would be informative for predicting human susceptibility. Also, studies by routes other than oral would clarify whether inhalation or dermal exposures could also cause cancer. Toxicokinetic data do not indicate that any different response would be expected following exposures by these routes. Mechanistic studies indicate that aldrin and dieldrin act as tumor promoters presumably through their ability to inhibit intercellular gap junctional communication (Klaunig and Ruch 1987; Klaunig et al. 1990; Ruch and Klaunig 1986). Additional studies, using aldrin or dieldrin, that clarify the steps involved between inhibition of gap junctional communication and the appearance of tumors would be useful for understanding the apparent increase in cancer incidence. Genotoxicity. There were only two studies on in vivo exposure of humans to aldrin or dieldrin. Both were limited due to concomitant exposure to other pesticides and inconclusive route and dose of exposure (Dean et al. 1975; Dulout et al. 1985). Additional genotoxicity assays using tissues from humans exposed in vivo would be useful if these were accompanied by adequate quantitative exposure measurements. Numerous studies investigating the in vitro genotoxic effects of aldrin or dieldrin were available in the current literature (Ahmed et al. 1977a, 1977b; Crebelli et al. 1986; Dean et al. 1975; De Flora et al. 1984, 1989; Ennever and Rosenkranz 1986; Galloway et al. 1987; Glatt et al. 1983; Haworth et al. 1983; Klaunig et al. 1984; Majumdar et al. 1976, 1977; Marshall et al. 1976; Probst et al. 1981; Sandhu et al. 1989). They provide no conclusive evidence for genotoxic effects, particularly for direct action on the DNA molecule. The positive studies are primarily from the same research group, and while differences in results could be due to different concentrations used, different strains of test species, or other laboratory protocol differences, it would be useful to have independent confirmation or refutation of these studies using adequate techniques (especially in mammalian systems). Results of such studies would provide useful information on potential genotoxic effects in humans. Reproductive Toxicity. One study in humans attempted to correlate blood levels of dieldrin with premature labor or spontaneous abortions in pregnant women (Saxena et al. 1980); however, this study failed to establish causality. No other human data regarding reproductive effects of aldrin or dieldrin were 82 2. HEALTH EFFECTS located. Studies in laboratory animals exposed orally to aldrin or dieldrin present conflicting data on the ability of these agents to cause decreased fertility (Dean et al. 1975; Epstein et al. 1972; Good and Ware 1969; Harr et al. 1970; Treon et al. 1954a; Virgo and Bellward 1975). Some of these studies are limited. Additional studies examining the effects of oral exposure to aldrin or dieldrin would be helpful for clarifying this issue. No studies in animals were found regarding reproductive effects of exposure by the inhalation or dermal routes. Thus, studies examining effects on reproduction by inhalation or dermal exposure would also be useful. Animal studies performed using intraperitoneal injection of aldrin demonstrate adverse effects on male reproductive capacity (Chatterjee et al. 1988a, 1988b, 1988c). Additional studies examining fertility in animals exposed by the oral, dermal, or inhalation routes would be helpful in determining whether the effects are specific to intraperitoneal injection. Developmental Toxicity. No human studies are available on developmental effects for any exposure route. Similarly, no studies are available for animals exposed via the inhalation route, and negligible information is available for animals exposed via the dermal route (Glastonbury et al. 1987). Several studies report a decrease in postnatal survival for offspring of dogs, rats, and mice exposed to aldrin or dieldrin by the oral route (Deichmann et al. 1971; Harr et a1. 1970; Kitselman 1953; Treon et al. 1954a; Virgo and Bellward 1975), although many of these studies are flawed. Additional studies assessing postnatal survival after maternal exposure by all three routes would be helpful. Also, additional studies attempting to clarify the mechanism of the postnatal mortality would be informative. Adverse developmental effects have been observed following maternal oral exposure to aldrin (Al-Hachim 1971), and an acute-duration oral MRL for aldrin was derived based on the decrease in pup body weight and increased electroconvulsive shock threshold of pups observed in this study. Teratogenic effects have been observed in only a limited number of the studies performed to assess developmental toxicity (Ottolenghi et al. 1974); additional well-conducted studies examining this parameter may help clarify this issue. Immunotoxlcity. Isolated cases of dieldrin-induced immunohemolytic anemia have been reported in humans exposed by the inhalation, oral, and dermal routes (Hamilton et al. 1978; Muirhead et al. 1959). However, in epidemiological studies of workers exposed to these substances, similar effects have not been reported (de Jong 1991; Jager 1970). Thus, this effect may be idiosyncratic in nature. As large populations exposed to aldrin or dieldrin may be difficult to find, this response may be better studied in one of the strains of mice known to have a propensity for developing autoimmune diseases. Studies in animals via the oral (Krzystyniak et al. 1985; Loose 1982; Loose et al. 1981) and intraperitoneal routes (Bernier et al. 1987, 1988; Fournier et al. 1986, 1988; Hugo et al. 1988a, 1988b; Jolicoeur et al. 1988; Krzystyniak et al. 1986, 1987, 1989) indicate that aldrin and dieldrin may be immunosuppressive agents, at least during acute- and short intermediate-duration exposures. An acute-duration MRL was developed for dieldrin based on suppression of antigen processing by macrophages (Loose et al. 1981). These studies have also examined the mechanism for the immune suppression. However, additional studies examining potential longer-term effects on the immune system by all three routes as well as short-term effects by the inhalation and dermal routes would be important for estimating human susceptibility for populations exposed for varying amounts of time at hazardous waste sites. Neurotoxicity. Numerous human studies across all three routes indicate that the central nervous system is a major target of aldrin and dieldrin toxicity (Black 1974; Garrettson and Curley 1969; Hoogendam et al. 1965; Jager 1970; Kazantis et al. 1964; Patel and Rao 1958; Spiotta 1951). Studies in animals tend to support these findings, although studies in animals have been primarily by the oral route (Mehrotra et al. 1989; NCI 1978a, 1978b; Treon et al. 1951b, 1953a; Wagner and Greene 1978; Walker et al. 1969; Woolley et al. 1985). Both in vitro and in vivo studies in animals have provided a well-defined mechanism of action for neuroexcitation (Abalis et al. 1986; Bloomquist and Soderlund 1985; Bloomquist et al. 1986; Cole and 83 2. HEALTH EFFECTS Casida 1986; Gant et al. 1987; Lawrence and Casida 1984; Matsumura and Ghiasuddin 1983; Obata et al. 1988; Shankland 1982). Reports of human intoxication have provided information regarding blood levels that may be associated with the production of severe neurotoxic symptoms (convulsions, muscle jerks) (Brown et al. 1964; Jager 1970). However, information regarding the mechanism of action suggests that more subtle adverse effects of neurologic origin may be produced by aldrin and dieldrin. Thus, studies focusing on less severe forms of neurotoxicity (i.e., affective changes) may be informative. Studies in animals using behavioral paradigms designed to detect such changes or studies in persons exposed to aldrin or dieldrin would be useful for further defining these effects and the exposure levels associated with them. Epldemlological and Human Dosimetry Studies. Human studies on aldrin and dieldrin consist of either case reports of accidental or intentional poisonings (Black 1974; Garrettson and Curley 1969; Hoogendam et al. 1965; Kazantis et al. 1964; Patel and Rao 1958; Spiotta 1951) or epidemiological studies of workers employed in the manufacture or application of these agents (de Jong 1991; Ditraglia et al. 1981; Hoogendam et al. 1965; Jager 1970; Morgan and Lin 1978; Morgan et al. 1980; Sandifer et al. 1981; Van Raalte 1977; van Sittert and de Jong 1987; Versteeg and Jager 1973; Warnick and Carter 1972). Exposures in the case reports are virtually all oral, whereas exposures in the epidemiological studies are mainly inhalation and dermal, with very slight potential for accidental oral intake. Locating populations for future epidemiological studies may be difficult because aldrin and dieldrin have not been manufactured in the United States since 1974 and the use of these agents has been restricted to termite extermination. Also, because aldrin and dieldrin have not been imported into the United States since 1985, use has been limited to the use of remaining pre-1985 stocks. Thus, at the present time, very few persons are likely to be exposed to aldrin or dieldrin. The only subgroups of the population with possible exposure are termite exterminators and persons who have recently had their homes exterminated. If such groups are located, information regarding immunologic, reproductive, and developmental effects and correlation of these effects with blood levels of dieldrin associated with exposure would be useful. Biomarkers of Exposure and Effect. Exposure to aldrin and dieldrin is currently measured almost exclusively by determining the level of dieldrin in the blood (Jager 1970). This measure is specific for both aldrin and dieldrin. However, because aldrin is rapidly converted to dieldrin in the body (Wong and Tenure 1965; Wong and Terrier 1965), it is impossible to determine which of the two substances caused the blood levels of dieldrin to rise. Because dieldrin has a long half-life of elimination in humans (Hunter and Robinson 1967; Hunter et al. 1969; Jager 1970), measurement of dieldrin levels in the blood does not give any information about whether an acute-, intermediate-, or chronic-term exposure has occurred, whether such exposures have occurred recently, or whether a substantial period of time has elapsed since exposure occurred. The sensitivity of this biomarker of exposure appears to be sufficient to measure even background levels in the population; thus, no new biomarkers of exposure appear to be needed at this time. The central nervous system excitation resulting from aldrin or dieldrin exposure can be monitored, to a great extent, by monitoring EEG changes (Hoogendam et al. 1962, 1965; Jager 1970). Characteristic changes include bilateral synchronous spikes, spike and wave complexes, and slow theta and delta waves (Avar and Czegledi-Janko 1970; Garrettson and Curley 1969; Hoogendam et al. 1962, 1965; Jager 1970; Kazantis et al. 1964; Spiotta 1951). However, similar changes may be recorded in cases of central nervous system excitation caused by other agents. Thus, this measure is not specific for aldrin- or dieldrin-induced neurotoxicity. Blood levels of dieldrin have been correlated with adverse neurological effects caused by aldrin and dieldrin (Brown et al. 1964; Jager 1970). Such a measurement may also be used to monitor for adverse neurotoxic effects caused by these agents. Also, as understanding of the fundamental 84 2. HEALTH EFFECTS mechanism by which aldrin and dieldrin cause central nervous system excitation develops, tests may be developed to specifically monitor for the underlying neurological changes caused by aldrin and dieldrin. No tests specific for aldrin- or dieldrin-induced toxic effects on the liver or kidney exist; however, standard liver and kidney function tests should be able to identify the hepatic or renal toxicity that is produced. Microsomal enzyme induction may be measured by determining a number of parameters such as urinary levels of D-glucaric acid, the ratio of urinary 6-E-hydroxycortisol to 17-hydroxycorticosteroids, and blood levels of p_,p’-DDE. However, these tests are not specific for aldrin or dieldrin. Immune suppression of the type produced by aldrin or dieldrin may be detected by challenge with a T-lymphocyte-dependent antigen; however, this test also is not specific for aldrin or dieldrin. Absorptlon, DIstrlbutlon, Metabollsm, and Excretlon. Human and animal data are available that show that aldrin and dieldrin are absorbed across after exposure via all three routes (Feldmann and Maibach 1974; Graham et al. 1987; Hayes 1974; Heath and Vandekar 1964; Hunter and Robinson 1967; Hunter et al. 1969; Mehendale and El-Bassiouni 1975; Stacey and Tatum 1985). Quantitative data on the absorption of aldrin and dieldrin in humans and animals following exposure via all routes are limited. Animal studies indicate that aldrin and dieldrin are absorbed rather quickly and that the amount absorbed is proportional to the dose applied for the oral and dermal routes (Graham et al. 1987; Heath and Vandekar 1964; Iatropoulos et al. 1975). However, data concerning absorption rates are needed for all three routes. Because of the limited number of absorption studies for all three routes in general, it would be helpful to have additional quantitative data in animals that might serve as a basis for estimates of absorption in humans. No studies were located regarding distribution following inhalation exposure to aldrin or dieldrin in humans or animals. Data on distribution via the dermal route for humans were not located. However, numerous data exist that describe distribution after oral administration of aldrin or dieldrin (Adeshina and Todd 1990; Ahmad et al. 1988; Deichmann et al. 1968; DeVlieger et al. 1968; Hayes 1974; Holt et al. 1986; Hunter and Robinson 1967, 1968; Hunter et al. 1969; Iatropoulos et al. 1975). These studies indicate that dieldrin is distributed in the blood to adipose tissue, brain, and liver tissues, and is then redistributed primarily to fat. Concentrations of dieldrin have been shown to increase in a dose-related manner in blood and adipose tissues of humans and eventually reach a steady state (Hunter and Robinson 1967; Hunter et al. 1969). Kinetic studies in rats and dogs support these findings and provide further information on steady state kinetics following repeated dosing (Baron and Walton 1971; Davison 1973; Ludwig et al. 1964; Walker et al. 1969). Because data are sufficient regarding distribution following oral exposure to aldrin or dieldrin, no more studies via this route are needed. However, inhalation and dermal studies investigating distribution would be valuable because the potential exists for exposure to occur in humans via these routes. No studies were located regarding metabolism of aldrin or dieldrin in humans and animals via the inhalation route. Also, human data on metabolism via the oral and dermal routes were not located. Metabolism has been characterized in animals following oral exposure (Baldwin et al. 1972; Bedford and Hutson 1976; Chipman and Walker 1979; Hutson 1976; Korte and Arent 1965; Matthews and Matsumura 1969; Matthews et al. 1971; Miiller et al. 1975; Wolff et al. 1979; Wong and Tenure 1965; Wong and Terrier 1965). Sex-related and species differences have been observed in metabolism in animals (Baldwin et al. 1972; Hutson 1976; Korte and Arent 1965; Matthews and Matsumura 1969; Matthews et al. 1971). Because differences in metabolism may occur with differences in the route of exposure, it would be useful to have more data on inhalation and dermal metabolic studies as a comparison with the available oral studies. 85 2. HEALTH EFFECTS No human or animal data were located regarding excretion following inhalation or dermal exposure to aldrin or dieldrin. There are, however, a number of studies in animals (Baldwin et al. 1972; Hutson 1976; Klein et al. 1968; Klevay 1970; Ludwig et al. 1964; Matthews et al. 1971; Muller et al. 1975) and a limited number of studies in humans (Hunter et al. 1969; Richardson and Robinson 1971; Schecter et al. 1989b) that describe excretion following oral exposure to aldrin or dieldrin. These studies are sufficient to characterize excretion following oral exposure to aldrin or dieldrin. These studies show quantitatively that the metabolites are excreted primarily in the feces in both humans and animals. Species and sex-related differences in excretion of metabolites have been observed following oral exposure in animals (Baldwin et al. 1972; Hutson 1976; Klein et al. 1968; Klevay 1970; Ludwig et al. 1964; Matthews et al. 1971; Muller et al. 1975). Also, sex-related and species differences have been observed in the rates of excretion. Studies on excretion following inhalation and dermal exposure to aldrin or dieldrin would be useful to determine if excretion patterns vary with different routes. Comparative Toxlcoklnetlcs. Numerous studies using a variety of animal species indicate that the kinetics of aldrin and dieldrin differ across species (Baldwin et al. 1972; Hutson 1976; Klein et al. 1968; Klevay 1970; Ludwig et al. 1964; Matthews et al. 1971; Muller et al. 1975). The differences are primarily quantitative. Although the kinetic data alone do not allow for the identification of target organs common to humans and animals, the distribution data coupled with toxicity data appear to suggest that target organs are similar. Interspecies differences and sex-related differences in rats and mice have been observed for the metabolism and excretion of aldrin and dieldrin. These interspecies differences coupled with a lack of data across different routes indicate that it may be difficult to compare the kinetics of aldrin or dieldrin in animals with that in humans. Further studies across several species and via all three exposure routes would be useful in determining similarities and differences between humans and animals. Methods for Reduclng Toxlc Effects. The mechanism by which aldrin and dieldrin are absorbed from the gastrointestinal tract is unknown but is presumed to involve dissolution in the cell membrane. Current methods for reducing absorption from the gastrointestinal tract involve removing these chemicals from the site of absorption (HSDB 1992; Klaassen 1990). Additional studies examining the method of absorption would provide valuable information for developing methods that interfere with gastrointestinal absorption. Numerous studies have examined the distribution of aldrin and dieldrin after gastrointestinal absorption (Adeshina and Todd 1990; Ahmad et al. 1988; Deichmann et al. 1968; DeVlieger et a1. 1968; Hayes 1974; Holt et al. 1986; Hunter and Robinson 1967, 1968; Hunter et al. 1969; Iatropoulos et al. 1975). Additional studies on distribution are not necessary at this time. No established method exists for reducing the body burden of aldrin and dieldrin. However, available information indicates that reducing enterohepatic recirculation or removal from the blood before these chemicals partition to tissue may be effective (Chipman and Walker 1979; Heath and Vandekar 1964; Iatropolous et al. 1975; Richardson and Robinson 1971; Sipes and Gandolfi 1991). Studies examining the effectiveness of repeated doses of activated charcoal, cholestyramine, hemodialysis, and hemoperfusion in reducing body burden would be useful. The neurotoxicity of aldrin and dieldrin is believed to result, at least in part, from interference with GABA function (Abalis et al. 1986; Bloomquist and Soderlund 1985; Bloomquist et al. 1986; Cole and Casida 1986; Gant et al. 1987; Lawrence and Casida 1984; Obata et al. 1988), and benzodiazepines and barbiturates have been effective in mitigating some of the neurological symptoms of aldrin and dieldrin overexposures (Black 1974; Garrettson and Curley 1969; Spiotta 1951). However, additional studies examining the effectiveness of potentiating the GABAergic function in mitigating aldrin and dieldrin’s neurologic effects would be helpful. A decrease in the hepatic and renal effects of dieldrin has been observed when animals received ascorbic acid supplements during dieldrin treatment (Bandyopadhyay et al. 1982b). Further study clarifying this effect and identifying a potential mechanism for the mitigating effects of ascorbic acid would be valuable. 86 2. HEALTH EFFECTS 2.9.3 On-golng Studles On-going studies regarding the health effects of aldrin and/or dieldrin were reported in the Federal Research in Progress File (FEDRIP 1990a, 1990b) database and SCISearch (1990). Table 2-7 presents a summary of on-going studies that address the health effects of aldrin or dieldrin. 87 2. HEALTH EFFECTS Table 2-7. On-going Studies on Aldrin and Dieldrin‘ Research Investigator Affiliation description Sponsor J. Carlson Albany Medical College Environmental chemicals stress and NIEHS of Union University, behavioral toxicity in rats Albany, New York B. Mehrotra Tougaloo College, Role of glutamate and GABA NIGMS Tougaloo, Mississippi receptors in the neurotoxicity of cyclodienes R. Roth Michigan State Volatile organic chemicals and NIEHS University, East Lansing, neutrophil function Michigan L. Uphouse Texas Woman’s Neuro-reproductive effects of NIEHS University, Denton, chlorinated pesticides in rats Texas aDerived from FEDRIP 1990a, 1990b GABA = gamma aminobutyric acid; NIEHS = National Institute of Environmental Science; NIGMS = National Institute of General Medical Sciences 89 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Information regarding the chemical identities of aldrin and dieldrin is located in Table 3—1. This information includes synonyms, chemical formulas and structures, and identification numbers. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Information regarding the physical and chemical properties of aldrin and dieldrin is located in Table 3-2. 90 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-1. Chemical Identity of Aldrin and Dieldrini1 Characteristic Aldrin Dieldrin Synonym(s) 1,2,3,4,10,10— 1,2,3,4,10,10- hexachloro- hexachloro-6,7- 1,4,4oz,5,8,8a-hexahydro- epoxy-1,4,4a,5, 1,4-endo,exo-5,8— 6,7,8,8a-octa- dimethanonaphthalene; hydro-1,4-endo, HHDN exo-5,8- dimethanonaph- Registered trade name(s) Chemical formula Chemical structure Identification numbers: CAS registry NIOSH RTECS EPA hazardous waste OHM/T ADS DOT/UN/NA/IMCO shipping HSDB NCI Aldrec; Aldrex; Drinox; Octalene; Seedrin; Compound 118 C12H8Cl6 c ClCl Cl QC! 309-00-2 102150000 P004 7215090 IMO6.1 NA2762 199 C00044 thalene; HEOD Alvit; Dieldrix; Octalox; Quintox; Red Shieldb clesaéo 60-57-1 0 101750000 P037 7216516 NA2761 322 C00124 8All information obtained from HSDB 1990a or 1990b unless otherwise noted bOHM/TADS 1990b cVerschueren 1983 CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSl—I = National Institute for Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances 91 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-2. Physical and Chemical Properties of Aldrin and Dieldrina Property Aldrin Dieldrin Molecular weight 364.93 380.93 Color White (pure); White (pure); tan (technical grade) tan (technical grade) Physical state Crystalline solid Crystalline solid Melting point Boiling point Density Odor Odor threshold: Water Air Solubility: Water at 25°C Organic solvents Partition coefficients: L02 Kow Log Koo Vapor pressure: at 20°C at 25°C Henry’s law constant: at 25°C Autoignition temperature Flashpoint Flammability limits Conversion factors Explosive limits 104°C (pure); 40-60°C (technical grade) 145°Cc 1.70 g/L at 20°Cb Mild chemical odor No data 0.017 mg/kg° 0.20 mg/L Very soluble in .most organic solvents 3.01 4.69c 7.5x10'5 mmHg 1.4x10'4 mmHg 3.211104 atm-m3/mol° No data No data No data 1 ppm = 14.96 mg/m3 at 25°C, 1 atm Stable“ 17S—176‘C (pure); 95°C (technical grade)b 330°Cd 1.75 g/L at 25°C° Mild chemical odor No data 0.041 mg/kg° 0.18 mg/L Very soluble in benzene; slightly soluble in acetone, alcohol, and ether 4.55d 3.87 1.78x10‘7 mmHgf 7.78x10-7 mmHg 1.511(10'5 atm-m3/mold No data No data Nonflammablef 1 ppm = 15.61 mg/m3 at 25°C, 1 atm3 Stablef 8All information obtained from HSDB 1990a or 1990b unless otherwise noted bHayes 1982 °CHEMFATE 1985a dCI-IEMFATE 1985b °Verschueren 1983 fOTM/TADS 1985b gEPA 1987a “OTM/TADS 1985a 93 4. PRODUCTION, IMPORT, USE, AND DISPOSAL 4.1 PRODUCTION Aldrin was first synthesized in the United States as a pesticide in 1948 (EPA 1986d). Aldrin and dieldrin have not been produced in the United States since 1974 (Sittig 1985). It is not known how much aldrin and dieldrin are presently stored in the United States. Aldrin and dieldrin were previously manufactured and sold in the United States by only one firm, the Shell Chemical Company (EPA 1986d). There was no information available from the 1988 Toxic Chemical Release Inventory (TR188) database concerning aldrin or dieldrin manufacture, use, or release into the environment in 1988 (TRI88 1990). Aldrin was manufactured by the Dials-Alder condensation of hexachlorocyclopentadiene with bicyclo[2.2.1]- 2,5-heptadiene. The final condensation reaction was usually performed at approximately 120°C and at atmospheric pressure. Excess bicycloheptadiene was removed by distillation. The final product was usually further purified by recrystallization (Sittig 1980). In 1967, the composition of technical-grade aldrin was reported to be as follows: 90.5% hexachlorohexahydrodimethanonaphthalene (HHDN); 3.5% other polychlorohexahydrodimethanonaphthalene compounds (isodrin); 0.6% hexachlorobutadiene; 0.5% octachlorotetrahydromethanoindene (chlordane); 0.5% octachlorocyclopentene; 0.3% toluene; 0.2% hexachlorocyclopentadiene; 0.1% HHDN di-adduct; <0.1% hexachloroethane; <0.1% bicycloheptadiene and 3.6% other compounds (IARC 1974a). Dieldrin was manufactured by the epoxidation of aldrin. The epoxidation of aldrin was obtained by reacting it either with a peracid (producing dieldrin and an acid byproduct) or with hydrogen peroxide and a tungstic oxide catalyst (producing dieldrin and water) (Sittig 1980). Peracetic acid and perbenzoic acid were generally used as the peracid acid (HSDB 1990b). When using a peracid, the epoxidation reaction was performed noncatalytically or with an acid catalyst such as sulfuric acid or phosphoric acid. When using hydrogen peroxide, tungsten trioxide was generally used as the catalyst (Sittig 1980). 4.2 IMPORT/EXPORT Before the 1974 near-total ban by EPA on aldrin and dieldrin use, aldrin and dieldrin were not imported into the United States. Aldrin was imported from Shell International (Holland) for formulation and limited use in the United States from 1974 to 1985, except when imports were temporarily ceased in 1979 and 1980. Between 1981 and 1985, an estimated 1-1.5 million pounds of aldrin were imported annually. EPA reports that aldrin has not been imported since 1985 (EPA 1986d). No information could be found that explicitly provided information about dieldrin importation. No information could be found regarding the exportation of aldrin or dieldrin. 4.3 USE Aldrin and dieldrin are active against insects by contact or ingestion (Hayes 1982). Thus, their primary use in the past was for control of corn pests by application to soil and in the citrus industry (EPA 1980a). Other past uses include general crop protection from insects; timber preservation; and termite-proofing of plastic and rubber coverings of electrical and telecommunication cables, and of plywood and building boards (Worthington and Walker 1983). In 1966, aldrin use in the United States peaked at 19 million pounds, but by 1970, use had decreased to 10.5 million pounds. During this same period (1966-1970), annual dieldrin use dropped from 1 million pounds to 670,000 pounds. These decreases were attributed primarily 94 4. PRODUCTION, IMPORT. USE. AND DISPOSAL to increased insect resistance to the two chemicals, and to the development and availability of more effective and environmentally safer pesticides (EPA 1980a). In 1970, the US. Department of Agriculture canceled all uses of aldrin and dieldrin based on the concern that these chemicals could cause severe aquatic environmental change and are potentially carcinogenic (EPA 1980a). Early in 1971, EPA initiated cancellation proceedings for aldrin and dieldrin, but did not order the suspension of aldrin and dieldrin use. In 1972, under the authority of the Federal Insecticide, Fungicide, and Rodenticide Act as amended by the Federal Pesticide Control Act of 1972, an EPA order lifted the cancellation of aldrin and dieldrin use in three cases: subsurface ground insertion for termite control; dipping of nonfood plant roots and tops; and moth-proofing in manufacturing processes using completely closed systems (EPA 1980a, 1986d). In 1974, these last two registered uses were voluntarily abandoned by the registrant, Shell Chemical Company (EPA 1986d). Also in 1974, EPA issued a final decision canceling all uses of aldrin and dieldrin except those exempted in 1972. The final registered use of aldrin and dieldrin (as termiticides) was voluntarily canceled by Shell Chemical Company in 1987 (EPA 1989a). Thus, all uses of aldrin and dieldrin are canceled (EPA 1990b). 4.4 DISPOSAL Aldrin and dieldrin are classified as hazardous wastes (EPA 1988a, 1990c). Subtitle C of the Resource Conservation and Recovery Act of 1976 (RCRA) creates a comprehensive program for the safe management of hazardous waste. Section 3004 of RCRA requires owners and operators of facilities that treat, store, or dispose of hazardous waste to comply with standards established by EPA that are "necessary to protect human health and the environment" (EPA 1987h). The Chemical Manufacturers Association recommends disposing of aldrin and dieldrin by incineration (HSDB 1990b). Incineration by rotary kiln (at 820—1,600°C), liquid injection (at 650—1,600°C), and fluidized bed (at 450-980°C), with residence times of seconds for gases and liquids and hours for solids, is recommended (HSDB 1990a). Aldrin and dieldrin are often embedded in polyethylene (HSDB 1990a) or mixed with vermiculite, sodium bicarbonate, or a sand-soda ash mixture prior to incineration (OHM/TADS 1990a). The incineration of these chemicals emits highly toxic fumes of hydrogen chloride and chlorinated breakdown products (HSDB 1990a). Thus, incinerators used for disposal of aldrin and dieldrin must have an acid scrubber and an after-burner (OHM/TADS 1990a). Also, prior to incineration, local air and fire authorities must be contacted (OHM/TADS 1990a, 1990b). Another recommended disposal method for aldrin and dieldrin is burying the chemicals in landfills. Contaminated material should be buried 8—12 feet underground in an isolated area away from water supplies, with a layer of clay, a layer of lye, and a second layer of clay beneath the wastes (OHM/TADS 1990a). Gravity filtration of solids, followed by dual-media filtration of the liquids, followed by activated carbon adsorption (100-300 pounds of carbon per pound of soluble material) is also an approved disposal method (OHM/TADS 1990b). Finally, disposal of small amounts of aldrin and dieldrin can be accomplished through degradation by active metals (sodium or lithium) in liquid ammonia (HSDB 1990b; Sittig 1985). 95 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW In 1970, the registrations of aldrin and dieldrin as pesticides were canceled by the US. Department of Agriculture (EPA 1980a). Restrictions on their use as termiticides, for dipping of non-food plant roots and tops, and for moth-proofing were lifted by EPA in 1972. In 1974, the latter two uses were voluntarily canceled by the manufacturer (EPA 1986b). In 1987, the use of aldrin and dieldrin as termiticides was canceled (EPA 1989a). Aldrin is readily converted to dieldrin, which is ubiquitous in the environment. Dieldrin persists because it is more resistant to biotransformation and abiotic degradation than aldrin, and as a result, it is found in low levels in all media, even at a distance from the site of concentration. Dieldrin bioconcentrates and biomagnifies through the terrestrial and aquatic food chains. Transport of aldrin and dieldrin in soils is minimal because these compounds tend to bind tightly to soil; however, they both can volatilize from soil. Most dieldrin and aldrin found in surface water are the result of runoff from contaminated soil. Aldrin undergoes photolysis to dieldrin, which in turn may be degraded by ultraviolet radiation or microbial action into the more persistent photodieldrin. Past agricultural uses of aldrin and dieldrin have resulted in persisting soil residues and uptake in a wide range of crops. Because of the persistence and potential for bioaccumulation of dieldrin, exposure of the general population may occur through ingestion of contaminated water or food products. Many people have also been exposed to aldrin and dieldrin in their homes from past termite treatment. Aldrin and dieldrin have been detected at 36 and 162 of the 1,300 NPL sites, respectively (HAZDAT 1992). The frequency of these sites within the United States can be seen in Figures 5-1 and 5-2. 5.2 RELEASES TO THE ENVIRONMENT Aldrin and dieldrin use and production in the United States have been canceled by EPA (EPA 1990b). However, the persistent nature of these previously widely used compounds suggests an environmental background level that is slowly decreasing. Aldrin and dieldrin are included on the most recent Toxic Chemical Release Inventory (TRI88) as reportable chemicals when released or transferred from TRI88 facilities. However, EPA received no TR188 forms for aldrin or dieldrin, indicating that no reportable releases to the environment occurred in 1988. 5.2.1 Air Past application of aldrin and dieldrin for termite control is a continuing source of contamination of indoor air. In addition, these compounds may be released to the atmosphere from previously treated soil particulates and contaminated surface waters. Release of aldrin and dieldrin into the air may also occur as a result of atmospheric dispersal of contaminated soils at NPL sites. 5.2.2 Water Aldrin and dieldrin may be released to surface waters as a result of runoff from contaminated soils. Dieldrin was not detected in samples of surface waters taken at any of the NFL sites included in the Contract Laboratory Program Statistical Database (CLPSD). However, dieldrin was detected in 0.71% of FIGURE 5— 1. FREQUENCY OF NPL SITES WITH ALDRIN CONTAMINATION * aunsoaxa NVWflH HOJ 'IVI.LN3.LOd '9 FREQUENCY 33593 1 To 2 SITES m a To 5 SITES , 7 To 11 SITES _ E1 SITES *Derived from HAZDAT 1992 FIGURE 5—2. FREQUENCY OF NPL SITES WITH DIELDRIN CONTAMINATION * aunsoaxa NVWflH 80:! 'lVliNElOd ‘9 £6 FREQUENCY EEEEB 1 TO 3 SITES m 4 To a SITES 12 T0 16 SITES _ a1 SITES *Derived from HAZDAT 1992 98 5. POTENTIAL FOR HUMAN EXPOSURE the groundwater samples taken from NFL sites at a mean concentration of 0.40 ppb in the positive samples (CLPSD 1989). Note that the information used from the CLPSD includes data from NFL sites only. Aldrin was identified in leachate from the Love Canal industrial landfill in Niagara Falls, New York, at a concentration of 0.023 mg/L (23 ppb) (data were gathered prior to 1982) (Brown and Donnelly 1988). In 1986, a waste site was identified in Clark County, Washington, that contained buried drums believed to have originally held chemicals used at a plywood manufacturing plant. Analysis of the soil and water contamination found aldrin to be present in groundwater samples taken from shallow wells on site at a maximum concentration of 2.12 pg/L (2.12 ppb) and in groundwater samples from nearby private wells at 0.79 pg/L (0.79 ppb) (EPA 1986i). A hazardous waste site in Gallaway, Tennessee, had received drums and bottles containing chemicals from a pesticide blending operation that had been emptied or discarded into a number of small ponds on the site. Dieldrin was present in sediment samples from on-site ponds at 1,400 ppb and in surface waters at 0.40-1.4 ppb; dieldrin was detected in one off-site sediment sample but was not detected in any off-site water samples (EPA 1987i). 5.2.3 Soil Possible releases of aldrin and dieldrin to soil may come from the improper disposal of old stocks at landfill sites and as a result of the historical use of these compounds as insecticides. Aldrin and dieldrin have been detected in 0.71% and 1.42% of the soil samples taken from the NFL sites included in the CLPSD, respectively, at mean concentrations of 19 ppb for aldrin and 57 ppb for dieldrin in the positive samples (CLPSD 1989). Note that the information used from the CLPSD includes data from NFL sites only. 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partltlonlng The leaching potential (concentration in soil water/concentration in soil) for aldrin in soil is 9.0x10'3, and the volatilization potential (concentration in soil air/concentration in soil) is 2.0x10'5, suggesting that aldrin is unlikely to leach appreciably from soil to water or volatilize from soil particles to the atmosphere (McLean et al. 1988). Volatilization of aldrin is more rapid when it is applied to the soil surface rather than incorporated into the soil. A loss of 50% from a surface application was estimated to occur within 1—2 weeks after application compared to 10—15 weeks for soil-incorporated aldrin. The relatively rapid loss of both aldrin and dieldrin from soil during the first few months after application has been attributed to loss by volatilization (Caro and Taylor 1971; Elgar 1975). The half-lives of aldrin applied to clay loam soil at a rate of 3, 9, and 15 kg per hectare in 1974 were 79.21, 97.09, and 88.53 days, respectively (Gupta et al. 1979). The half-lives of aldrin applied to sandy loam soil at a rate of 3, 9, and 15 kg/hectare were 41.69, 36.48, and 45 days, respectively. The loss of aldrin residues was more from sandy loam soil as compared to clay loam soil (Gupta et al. 1979). The volatilization potential of field-applied dieldrin (10 ppm) was studied for 5 months using three different soil moisture regimes (Willis et al. 1972). The three soil moisture regimes included: (1) flooded to a depth of 10 cm; (2) moist; and (3) nonflooded with no water added except for natural rainfall. The results showed that the soil moisture had an effect on the volatilization rate. About 18% of the applied dieldrin volatilized from a moist plot in 5 months, but only 2% and 7% volatilized from the flooded and nonflooded plots, respectively. Flooding retarded the volatilization potential of surface-applied dieldrin. Volatilization of dieldrin from the nonflooded plot tended to increase with increasing precipitation (Willis et al. 1972). 99 5. POTENTIAL FOR HUMAN EXPOSURE The logarithm of the n-octanol/water partition coefficient (log Kow) is a useful preliminary indicator of potential bioaccumulation of a compound. The log Kow value for aldrin ranges from 5.68 (McLean et al. 1988) to 7.4 (Briggs 1981), indicating a high potential for bioaccumulation. In modeling ecosystem tests, bioconcentration factors for aldrin of 3,140 in fish and 44,600 in snails have been reported (Metcalf et al. 1973). Experimental evidence indicates that aldrin is rapidly converted to dieldrin, which readily bioconcentrates and biomagnifies (Metcalf et al. 1973). Radiolabeled aldrin added to a model ecosystem was rapidly converted to dieldrin. Of the radiolabel stored in organisms, 95. 9% of the total stored in the fish _G_—ambusia affinis, 916% stored in the snails of the genus Physa, and 85. 7% stored in the algae Oedogonium cardiacum were in the form of dieldrin. Aldrin also bioconcentrates in terrestrial ecosystems. In a model ecosystem study, 2 weeks after corn planting, the concentration of aldrin residues was 27% greater in plants than in the preplanting soil. Approximately 78% of the plant residue was in the roots and was composed of 33% aldrin and 49% dieldrin. On day 15, a prairie vole (Microtus ochrogaster) was introduced to the model ecosystem. After 5 days, the concentration of residue in the vole was 70% greater than the initial soil concentration and consisted of 2% aldrin and 89% dieldrin (Cole et al. 1976). Biotransfer factors (BTFs) for beef and cow’s milk have been determined for aldrin. The concept of biotransfer is useful since it takes into account exposure through both food and water pathways. Biotransfer factors for beef and milk are defined as the concentration of a compound in beef or milk (mg/kg) divided by the daily intake of the compound by the animal (mg/day). The biotransfer values for beef and milk were estimated to be 0.085 and 0.023, respectively. Biotransfer factors for aldrin in beef and milk are directly proportional to octanol-water partition coefficients (Kow). In addition, a bioconcentration factor (BCF) for aldrin in vegetables was also determined. The bioconcentration factor was defined as the ratio of the concentration in aboveground parts (mg of compound/kg of dry plant) to the concentration in soil (mg of compound/kg of dry soil); the bioconcentration factor was estimated to be 0.021 (Travis and Arms 1988). The vegetation bioconcentration factor is inversely proportional to the square root of K0W The regression equations for beef, milk, and vegetation provide a technique for predicting a chemical’s BTF in beef and milk and BCF in vegetation. Consequently, regression analyses will be of value in more precisely quantifying human exposure to organics through the terrestrial food chains (Travis and Arms 1988). Dieldrin may be transported great distances in the atmosphere and be removed by wet or dry deposition (Baldwin et al. 1977). Snowpack samples were collected at 12 sites in the Northwest Territories, Canada, in the winter of 1985—1986; dieldrin was found in all 21 samples at a mean concentration of 0.75 ng/L (Gregor and Gummer 1989). There were no known local sources of dieldrin in the Canadian Arctic snow. Dieldrin has an estimated half-life of 723 days for evaporation at 25°C from a column of water of l-meter depth (Mackay and Leinonen 1975). Dieldrin has a low water solubility as well (186 pig/L at 25°C) (Sittig 1985). Dieldrin, when compared to other chlorinated hydrocarbons, has the longest evaporation half-life in water 1 meter in depth; it was estimated to be 72.3 days compared to 3.7 days for DDT (Mackay and Wolkoff 1973). Dieldrin is extremely nonpolar and, therefore, has a strong affinity for organic matter such as animal fat and plant waxes; it also sorbs tightly to soil particulates. Volatilization is the principal route of loss of dieldrin from soil; however, the process is relatively slow because of the low vapor pressure of dieldrin. 100 5. POTENTIAL FOR HUMAN EXPOSURE It may also be impeded by low soil moisture or incorporation of the compound into the soil (Cliath and Spencer 1971). Volatilization of dieldrin from soil is slower than aldrin (<10 g/hectare/day) based on its vapor pressure of 1.78x10'7 mmHg at 20°C (Sittig 1985). The volatilization rate decreases with time (Nash 1983) and increases with increasing temperature to a maximum at 25°C (Nash and Gish 1989). After 11 days in a microagroecosystem, 35% of the applied dieldrin had volatilized, while 73% remained on the soil surface (Nash 1983). Movement of dieldrin in solution through the soil is extremely slow, indicating little potential for groundwater contamination. Using a low pollution potential scenario (soil with a high organic content and a high average water content), it is estimated that it will take 2,594 years for dieldrin to travel to a depth of 3 meters. Even with a high pollution potential scenario (soil with a low organic content and a low water content), it would still take an estimated 270 years for dieldrin to reach a depth of 3 meters (Jury et al. 1987b). Dieldrin has been estimated to have a sorption coefficient on mixed-liquor solids (typical of municipal waste-water treatment plants) of 38.9 mg/g at an equilibrium concentration of 1.0 mg/L (Dobbs et al. 1989). Movement of dieldrin in waterborne sediment is a major pathway of loss from treated soil (Caro and Taylor 1971; Eye 1968; Hardee et al. 1964). Leaching is minimal. Like aldrin, dieldrin has a potential for high bioaccumulation as indicated by a log K0w value that ranges from 4.32 (Geyer et al. 1987) to 6.2 (Briggs 1981). Measured bioconcentration factors for dieldrin are 2,700 in fish and 61,657 in snails (Metcalf et al. 1973). A second study using the same model ecosystem found bioconcentration factors for dieldrin to be 6,145 in fish, 7,480 in algae, 247 in crabs (Uca minax), 1,015 in clams (Corbicula manilensis), 1,280 in the water plant Elodea, and 114,935 in snails (Sanborn and Yu 1973). A bioconcentration factor of 2,095 has been determined for the ciliate Tetrahymena pyriformis exposed to 1 pg/mL dieldrin for 12 hours (Bhatnagar et al. 1988). A biomagnification factor of 1.0 has been determined for dieldrin for rainbow trout on a lipid weight basis; the average wet weight bioconcentration factor is 2.3 (Connell 1989). Channel catfish, exposed to varying concentrations of dieldrin, were used to determine when equilibrium was reached between uptake of dieldrin and elimination from muscle tissue. At 13 ppt, equilibrium was reached after 56 days, whereas, at 49 ppt, equilibrium was not reached even after 70 days of exposure (Shannon 1977). Biotransfer factors for beef and cow milk and a bioconcentration factor for vegetables have been determined for dieldrin as well as aldrin. The biotransfer values for dieldrin in beef and milk were estimated to be 0.008 and 0.011, respectively, while the bioconcentration factor for vegetables was estimated to be 0.098 (Travis and Arms 1988). Data indicate that dieldrin is taken up by various crops (Beall and Nash 1969, 1971). To determine whether foliar contamination of soybean plants occurred via root sorption or vapor sorption, 20 ppm 14C-dieldrin was applied to surface or subsurface soil, and residue levels in soybean plants were determined (Beall and Nash 1971). The results indicated that foliar contamination by dieldrin occurred by both root sorption (10.8 ppm) and vapor sorption (8.5 ppm) (Beall and Nash 1971). In a greenhouse experiment, various crop seedlings took up dieldrin from soils treated with 0.5 or 5.0 ppm dieldrin (Beall and Nash 1969). Mean concentrations of dieldrin found in soybeans, wheat, corn, alfalfa, brome grass, and cucumber treated with 0.5 ppm dieldrin were 0.017, 0.147, 0.017, 0.031, 0.075, and 0.070 ppm (dry weight). Mean concentrations of dieldrin found in soybeans, wheat, corn, alfalfa, brome grass, and cucumber treated with 5.0 ppm dieldrin were 0.194, 1.385, 0.171, 0.350, 0.808, and 0.185 ppm (dry weight) (Beall and Nash 1969). 101 5. POTENTIAL FOR HUMAN EXPOSURE 5.3.2 Transformation and Degradation 5.3.2.1 Alr While the evidence supports the view that a considerable proportion of the aldrin and dieldrin used in agriculture reaches the atmosphere, it seems probable that atmospheric degradation prevents accumulation of aldrin. In laboratory studies, aldrin is photochemically isomerized and epoxidated by sunlight to photoaldrin, dieldrin, or photodieldrin (Glotfelty 1978). Irradiation of aldrin (5 mg) vapor with ultraviolet light for 45 hours resulted in the formation of photoaldrin (20-30 pg) and dieldrin (50—60 pg). Irradiation of either photoaldrin (2 mg) or dieldrin (0.5 mg) vapor for 65 hours and 91 minutes, respectively, resulted in a single photoproduct, photodieldrin (20-30 pg), which was resistant to further photolyses (Crosby and Moilanen 1974). Since photodieldrin no longer contains a chromophore, it is believed to be a stable photoproduct of aldrin (dieldrin) (Glotfelty 1978). However, results of a laboratory study showed that photolysis of photoaldrin and photodieldrin in the presence of triethylamine gave photometabolites arising from the loss of chlorine atoms (Dureja et al. 1986). Information regarding the persistence of photodieldrin in the atmosphere was not located; however, air samples taken in 1973 in Ireland contained dieldrin, but neither aldrin nor the photoproducts of aldrin or dieldrin were detected (Baldwin et al. 1977). The estimated lifetime of dieldrin in the atmosphere, based on reactions with atmospheric hydroxyl radicals, is approximately 1 day. However, dieldrin may be more stable than implied by this lifetime if it is associated with particulate matter in the atmosphere. Under these conditions, wet and dry deposition may be more important loss processes (Bidleman et al. 1990). 5.3.2.2 Water The resistance of aldrin and dieldrin to soil leaching generally precludes their appearance in groundwater. The general absence of aldrin and dieldrin from groundwater samples supports this conclusion (Richard et al. 1975; Spalding et al. 1980). The potential for surface runoff of aldrin and dieldrin in soils is supported by reports of findings of small amounts of dieldrin in surface waters (Hindin et al. 1964; Richard et al. 1975). Aldrin, irradiated with ultraviolet light in an oxygenated aqueous solution, underwent little change except in the presence of amino acids and humic acids present in natural waters (Ross and Crosby 1975, 1985). In filtered natural field water, aldrin was photooxidized by 75% to dieldrin after 48 hours of irradiation at 238 nm (Ross and Crosby 1985). More than 80% of the initial dieldrin added to natural water (from a drainage canal in an agricultural area) was present after 16 weeks of incubation in the dark (Sharon et al. 1980). Dieldrin exposed to sunlight is converted to photodieldrin, a stereoisomer of dieldrin. It is unlikely that photodieldrin occurs widely in the environment. Microorganisms isolated from lake water and lake-bottom sediments may convert dieldrin to photodieldrin under anaerobic conditions (Fries 1972). Aldrin was degraded under anaerobic conditions in biologically active wastewater sludge (pH 7-8, 35°C) with a half-life of less than 1 week (Hill and McCarty 1967). Dieldrin does not undergo any significant degradation in biologically active wastewater sludge or by sewage sludge microorganisms under anaerobic conditions (Battersby and Wilson 1988; Hill and McCarty 1967). After 48 hours of continuous anaerobic digestion with primary sludge, dieldrin was degraded by only 11% (Buisson et al. 1990). Likewise, when incubated for 32 days with anaerobic sludge, only 24% of the dieldrin was removed (Kirk and Lester 1988). In contrast, aerobic incubation with activated sludge removed 55% of the dieldrin in 9 days (Kirk and Lester 1988). A mixed, anaerobic microbial enrichment culture was able to degrade 10 pg/mL dieldrin by 50% in 30 days. Syn-monodechlorodieldrin and anti-monodechlorodieldrin, both of which are resistant to 102 5. POTENTIAL FOR HUMAN EXPOSURE microbial degradation, were identified as the initial degradation products (Maule et al. 1987). In another study, dieldrin was degraded by 30—60% using activated sludge treatment, with the most effective removal by activated sludge aged 4 days as opposed to sludge aged 6 and 9 days (Buisson et al. 1988). Dieldrin has been found to undergo minor degradation to photodieldrin in marine environments. The marine algae of the genus Dunaliella had the maximum degradation activity, degrading 23% of aldrin to dieldrin and 8.5% of dieldrin to photodieldrin (Patil et al. 1972). 5.3.2.3 Soil Aldrin in the soil is converted to dieldrin by epoxidation (Gannon and Bigger 1958). Aldrin epoxidation occurs in all aerobic and biologically active soils, with 50—75% of the end-season residues detected as dieldrin. The transformation of aldrin to aldrin acid also occurs in soils. The half-life of aldrin in soil is estimated to be 53 days. Mathematical modeling estimates that aldrin, applied to soil up to 15 cm in depth, will degrade to dieldrin by 69% after 81 days. At a typical soil application rate of 1.1-3.4 kg/hectare the half-life of aldrin was estimated to be 0.3 years with a 95% disappearance in 3 years (Freedman 1989). Loam soils treated with aldrin at 25 pounds per 5-inch acre over the 5-year period of 1958 through 1962 contained in the fall of 1968, 4-5% of the applied dosages mainly in the form of dieldrin. Aldrin treated soils also contained photodieldrin, which amounted to 1.5% of the recovered dieldrin (Lichtenstein et al. 1970). The degradation of aldrin and dieldrin was studied under upland and flooded soil conditions (Castro and Yoshida 1971). For the upland soil condition, water was added to give 80% of the maximum water-holding capacity of the soil. For the flooded soil condition, the water level was maintained 5 cm above the soil surface. This represents an anaerobic environment. Results showed that aldrin was more persistent in flooded than in upland soil. After 2 months incubation under upland conditions, 33-58% of added aldrin remained in the soil. Under flooded conditions, 64-81% remained in the soil (Castro and Yoshida 1971). Dieldrin is much more resistant to biodegradation than aldrin (Castro and Yoshida 1971; Gannon and Bigger 1958; Jagnow and Haider 1972; Willis et al. 1972). Based on the Henry’s law constant and the organic carbon partition coefficient (Koc), the half-life of dieldrin in soil is estimated to be 868 days (Jury et al. 1987b). Of 20 soil microbes that were able to degrade dieldrin, only 13 of them could also degrade aldrin to dieldrin (Patil et al. 1970). The bacteria Aerobacter aerogenes aerobically degraded approximately 12% of dieldrin to aldrin diol within 5 days, but no further degradation was detected with increased incubation periods (Wedemeyer 1968). Dieldrin residues in soil plots that were treated for 15 years with dieldrin were approximately the same 4 years after treatment was stopped (average 0.42 ppm) as at the time of the last treatment (average 0.37 ppm). At a soil application rate of 1.1—3.4 kg/hectare, dieldrin was estimated to have a half-life of 2.5 years and a 95% disappearance from soil in 8 years (Freedman 1989), although other studies indicate that dieldrin loses between 75% and 100% of its biological activity in 3 years (Jury et al. 1987). After 6 months, dieldrin persisted in moist, flooded, and nonflooded soils, indicating that these three soil moisture conditions had no effect on the degradation of soil-incorporated dieldrin (Willis et al. 1972). The roots of grass grown on the plots contained 11.6 ppm dieldrin while the aerial grass parts contained only 0.05 ppm (Voerman and Besemer 1975). Twenty-one years after the application of dieldrin to the foundation of a house at an application rate commonly used for termite control, 10% of the original dieldrin remained, primarily in the upper 6 inches of soil (Bennett et al. 1974). Aldrin and dieldrin applied to soil may also undergo degradation by ultraviolet light to form photodieldrin; this reaction may occur as a result of microbial action as well (Matsumura et al. 1970; Suzuki et a1. 1974). After ultraviolet irradiation for 168 hours, dieldrin applied to various environmental media was found to be photodecomposed by 9.6% on loam soil, 1.2% on clay soil, and 44% on activated 103 5. POTENTIAL FOR HUMAN EXPOSURE charcoal; the degradation products were photodieldrin and an unknown compound (Elbeit et al. 1983). Residues in soil samples found after application of dieldrin to soil (0.83 kg/hectare in soil that already contained 0.521 ppm dieldrin) consisted largely of unchanged dieldrin (2.581 ppm) and photodieldrin (0.029 PW“)- 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT Aldrin is readily converted to dieldrin in the environment. Dieldrin is subject to atmospheric transport, and, as a result, is ubiquitous in the environment. Dieldrin persists because it is relatively resistant to biotransformation and abiotic degradation. Thus, it is found in low levels in all media (air, water, and soil). 5.4.1 Air Aldrin and dieldrin enter the atmosphere through various mechanisms such as spray drift during application of the compounds as insecticides, water evaporation, and suspension of particulates to which the compounds are absorbed. The analysis of 2,479 air sam les from 16 states from 1970 to 1972 revealed the following ambient concentrations: aldrin, mean 0.4 ng/m‘ (3x10'5 ppb), 13.5% of samples positive; dieldrin, mean 1.6 ng/m3 (1x10'4 ppb), 94% of samples positive (Kutz et al. 1976). More recent data on the atmospheric concentrations of aldrin and dieldrin were gathered in 1986, approximately 10 years after the use of aldrin and dieldrin was restricted in the Great Lakes Basin (Chan and Perkins 1989). It was found that aldrin was present in wet precipitation at three of four sampling sites located around the basin, but in only 5 of the 75 samples collected at these sites at a mean concentration of 0.01 ng/L (1x10‘5 ppb) at two sites and 0.24 ng/L (2.4x10'4 ppb) at the third site. Dieldrin was detected at all four sites and in more than 60% of the samples at mean concentrations ranging from 0.41 to 1.81 ng/L (4.1x10'4-1.8x10'3 ppb). The highest concentrations of both aldrin and dieldrin were found in samples collected at Pelee Island at the western end of Lake Erie (maximum concentrations of 3.4 ng/L (3.4x10'3 ppb) and 5.9 ng/L (5.9x10'3 ppb), respectively). In 1979—1980, dieldrin was detected in the ambient air and rainfall over College Station, Texas, at average concentrations of 0.08 ng/m3 (5.1x10‘6 ppb) and 0.80 ng/L (8x10'4 ppb), respectively (Atlas and Giam 1987). The washout ratio (concentration in rain/concentration in air) for dieldrin was calculated to be 8.9. Dieldrin was present in rainfall measured at three points in Canada during 1984, at mean concentrations of 0.78 ng/L (7.8x10'4 ppb) over Lake Superior, 0.27 ng/L in New Brunswick, and 0.38 ng/L (3.8x10’4 ppb) over northern Saskatchewan (Strachan 1988). Dieldrin has been detected in indoor air in homes that have been treated for termites. Measurements of air concentrations were taken in homes 1-10 years after treatment. Dieldrin was found at concentrations ranging from 0.03-2.7 ug/m3 (0002—017 ppb) in roof voids, 0.01-0.51 pig/m3 (00006—003 ppb) in living rooms and bedrooms and all interior areas other than roof voids (Dobbs and Williams 1983). 5.4.2 Water A comprehensive study of US. drinking water samples (1975) revealed that less than 17% of the samples contained dieldrin, with 78% of the positive samples containing concentrations between 4 and 10 ng of dieldrin per liter of water (0.004—0.01 ppb) (EPA 1980a). There are no current monitoring studies on levels of these compounds in drinking water. In early studies, dieldrin was found more often than any other pesticide in water samples collected from all major river basins (mean concentration, 7.5 ng/L (0.0075 ppb)) in the United States (Weaver et al. 104 5. POTENTIAL FOR HUMAN EXPOSURE 1965). In 1976, dieldrin was reported in many fresh surface waters of the United States with mean concentrations ranging from 5 to 395 ng/L (0005—0395 ppb) (EPA 19803). Data maintained in the STORET database for 1980—1982 included aldrin and dieldrin concentrations in industrial effluent, ambient water, sediments, and biota. Median values from all STORET stations were as follows (Staples et al. 1985): Aldrin Dieldrin Median Number Percentage Median Number Percentage Media (ppb) of samples detectable (ppb) of samples detectable Effluent <0.01 677 3.1 <0.01 676 3.7 Water 0.001 7,891 40.0 0.001 7,609 40.0 Sediment 0.1 2,048 33.0 0.8 1,812 33.0 Biota <0.1 211 0 0.03 530 41 In 1980, aldrin and dieldrin were detected in water samples taken from the Inner Harbor Navigation Canal of Lake Pontchartrain (New Orleans, Louisiana) on the ebb and flood tides at a depth of 1.5 meters; respective concentrations were 0.3 ng/L (0.0003 ppb) and 5.6 ng/L (0.0056 ppb) for aldrin and 0.6 ng/L (0.0006 ppb) and 5.9 ng/L (0.0059 ppb) for dieldrin (McFall et al. 1985). In 1987, dieldrin was detected in seawater samples taken from the Gulf of Mexico at concentrations ranging from 0.009 to 0.02 ng/L (9x10‘6-2x10'5 ppb) and from seawater off the southeastern United States at 0.007—0.01 ng/L (7x10'6—1x10'5 ppm); aldrin was also detected in the southeastern U.S. coastal waters at concentrations of 031-15 ng/L (0.0003-0.001 ppb) (Sauer et al. 1989). Aldrin and dieldrin were detected in water and sediment samples taken between 1975 and 1980 at 160—180 stations on major rivers of the United States as part of the National Pesticide Monitoring Program. Aldrin and dieldrin were both detected in 0.2% of the 2,946 water samples and in 0.6% and 12% of the approximately 1,016 sediment samples, respectively (Gilliom et al. 1985). In 1988, dieldrin was detected in 9% of 422 groundwater samples taken from a sandy, alluvial aquifer in Illinois at a median concentration of 0.01 pg/L (0.00001 ppb), and in 4% of groundwater well samples taken in the vicinity of an agrichemical dealer facility, at a mean concentration of 0.03 pig/L (0.00003 ppb) (Hallberg 1989). A monitoring survey of 17 wetland areas in the north central United States, found dieldrin to be present in only one Iowa sediment sample at 170 ng/g (170 ppb) dry weight (Martin and Hartman 1985). Analysis of urban stormwater runoff collected between 1979 and 1983 in the Canadian Great Lakes Basin found dieldrin to be ‘present in approximately 32 of 124 water samples at a mean concentration of 5.1x10'4 pg/L (5.1x10' ppb) and in approximately 17 of 110 runoff sediment samples at a mean concentration of 4.4x10' mg/kg (4.4 ppb). Aldrin was found in approximately 13 of 129 runoff sediment samples at a mean concentration of 1.2x10’3 mg/kg (1.2 ppb) but was not detected in any water samples (Marsalek and Schroeter 1988). These concentrations resulted in mean annual loadings to the Canadian Great Lakes Basin of 0.2 kg/year for aldrin and 0.6 kg/year for dieldrin. In 1982, water samples taken from 19 U.S. cities for the National Urban Runoff Program, found aldrin to be present only in samples taken from Washington, DC, at a concentration of 0.1 pg/L (0.1 ppb) (6% of samples), and dieldrin was detected only in water from Bellevue, Washington, at 0008-01 pg/L (0.008—0.1 ppb) (2% of samples) (Cole et al. 1984). Water sampling conducted during the 1986 spring isothermal period in the Great Lakes did not detect aldrin in any samples. However, dieldrin was present in all samples at mean concentrations ranging from 0.300 ng/L (0.0003 ppb) for Lake Superior to 0.402 ng/L (4.2x10‘4 ppb) in Lake Erie (Stevens and Neilson 1989). 105 5. POTENTIAL FOR HUMAN EXPOSURE Sediment samples taken from two lakes near the US. Army Rocky Mountain Arsenal, Colorado, in 1983, indicated that aldrin and dieldrin persisted in the sediments long after deposition ceased at concentrations up to 2,050 ppb for aldrin and 100 ppb for dieldrin at a core depth of approximately 21 cm for one lake. The second lake also had elevated levels of aldrin and dieldrin contamination, but at lower concentrations (approximately 250 ppb for aldrin and 40 ppb for dieldrin) and at a lower core depth, indicating that most of the deposition had occurred at an earlier date (Bergersen 1987). 5.4.3 Soil As a result of the rapid conversion of aldrin to dieldrin, soil residues of dieldrin are found in higher concentration and with greater frequency than residues of aldrin, even though aldrin is applied more frequently to the soil. An analysis of sediment samples taken from Lake Ontario in 1981 showed that dieldrin levels had increased from approximately 26 ng/g (26 ppb) in 1970 to 48 ng/g (48 ppb) in 1980, although the use of dieldrin was banned in much of the Great Lakes Basin in the early 19705 (Eisenreich et al. 1989). The National Soils Monitoring Program (Kutz et al. 1976) detected dieldrin in soils at varying concentrations and areas throughout 24 states; the mean concentration ranged from 1 to 49 ppb. 5.4.4 Other Environmental Media The persistence of dieldrin in the environment is demonstrated by a monitoring survey conducted in and around cotton fields in four counties in Alabama between 1972 and 1974. Although cotton farmers had not used aldrin or dieldrin "for several years," dieldrin was found to be present at 7—40 ppb in 50% of the soil samples; at less than 100 ppb in 50% of forage samples with levels declining over time; at an average of 1,490 ppb in 11 of 19 rat tissue samples with number of positive samples increasing between 1973 and 1974; at low levels in some quail tissue samples (maximum level = 790 ppb); at levels declining from 302 to 70 ppb between 1972 and 1974 for mockingbird tissue samples; and at less than 30 ppb in most of the 25% positive fish tissue samples taken from farm ponds (Elliott 1975). Aldrin was estimated to have a half-life of 1.7 days on crops with the half-life of dieldrin ranging from 2.7 to 6.8 days depending on the crop (Willis and McDowell 1987). In 1985, fish samples taken from the lower Savannah River in Georgia and South Carolina were found to occasionally contain dieldrin but at concentrations of less than 0.01 pg/g (10 ppb) (Winger et al. 1990); common carp and white bass samples from a lake in Kansas located in an agricultural area had mean concentrations of 0.069 ppb and 0.058 ppb, respectively (Arruda et al. 1988). Fish samples taken from tributary rivers around the Great Lakes in 1980-1981 had dieldrin levels up to 0.15 mg/kg (150 ppb) (average concentration = 0.03 mg/kg (30 ppb)) (DeVault 1985). Fish taken from Lake Huron between 1970 and 1980 had mean dieldrin levels ranging from 0.01 to 0.50 mg/kg (IO—500 ppb) (EPA 1985c); however, by 1984, mean concentrations of dieldrin in Lake Michigan coho salmon had dropped to 0.01 pg/g (10 ppb) from 0.06 pg/g (60 ppb) in 1980 (DeVault et al. 1988). An analysis of 315 composite samples of whole fish collected from 107 sites nationwide in 1980-1981 as part of the National Pesticide Monitoring Program found that the mean concentrations of dieldrin were essentially unchanged since 1978—1979. In 1978, dieldrin was detected in 81% of the samples, and in 1980, in 75% of the samples at mean concentrations of 0.05 pg/g (50 ppb) wet weight and 0.04 pg/g (40 ppb), respectively (Schmitt et al. 1985). Three of eight samples of bluegill (Lepomis macrochrius) collected from the San Joaquin Valley in July 1981 contained dieldrin at concentrations ranging from 0.005 to 0.008 mg/kg (5-8 ppb) wet weight; four of the eight common carp (gflprinus carpio) obtained from the same sites contained dieldrin at concentrations ranging from 0.015 to 0.067 mg/kg (15-67 ppb) wet weight (Saiki and Schmitt 1986). Dieldrin was also detected in a variety of fish taken from a section of Lake Oconee in Georgia that 106 5. POTENTIAL FOR HUMAN EXPOSURE received storm runoff from insecticide-treated areas between 1981 and 1982. Dieldrin concentrations ranged from <10 to 200 pg/kg (10—200 ppb). Dieldrin was not detected in fish taken from the lake after 1982 (Bush et al. 1986). A survey of 17 wetland areas in the north central United States found dieldrin in two fish samples taken from Kansas and Iowa at concentrations of 6 ng/g (6 ppb) and 9 ng/g (9 ppb), respectively (Martin and Hartman 1985). Dieldrin was found in S of 20 raw bluefish fillets collected in Massachusetts waters in 1986, at concentrations of 0.02-0.04 ppm (20-40 ppb); after cooking, dieldrin was still detected in the fillets, indicating that heating does not degrade the pesticide in foods (Trotter et al. 1989). Aldrin and dieldrin were detected in shrimp (Penaeus setiferus and Penaeus aztecus) collected from the Calcasieu River Basin in an industrial area of Louisiana in 1985-1986. Aldrin was present in shrimp taken from 7 of 30 stations at concentrations ranging from 0.01 to 0.12 pg/g (IO-120 ppb), and dieldrin was present in 21 of 30 samples at concentrations of 0.05—9.47 ug/g (SO—9,470 ppb) (average concentration 1.57 pig/g (1,570 ppb)) (Murray and Beck 1990). Between October 1981 and September 1986, over 12,044 imported and 6,391 domestic commodities were sampled for pesticide residues. Dieldrin was detected in 420 imported and 44 domestic products; however, the tolerance (the maximum amount of a residue expected in a food when a pesticide is used according to label directions, provided that the level does not present an unacceptable health risk) for dieldrin was exceeded in only 8 imported products and 1 domestic product, indicating that most agricultural products do not contain harmful levels of dieldrin (Hundley et al. 1988). 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE Use of aldrin and dieldrin for pest control on crops such as cotton, corn, and citrus products was canceled by EPA in 1974 (EPA 1974a), and use for extermination of termites was voluntarily canceled by the manufacturer in 1987 (EPA 1990b). However, during the period of widespread use and production of aldrin and dieldrin, intake by workers who manufactured these compounds was estimated to range from 0.72 to 1.10 mg/person/day with a good correlation between levels in tissue (fat, serum, and urine) and total length of exposure or intensity of exposure (Hayes and Curley 1968). The National Occupational Exposure Survey, conducted by NIOSH between 1980 and 1983, estimated that 647 employees were exposed to aldrin and 760 employees were exposed to dieldrin in the workplace (NOES 1990). One pest control operator was found to have 0.5 and 0.3 pg dieldrin on his left and right hands, respectively, more than 2 years after his last exposure to aldrin; serum blood levels taken at the same time showed 10 ppb dieldrin. A further analysis of individuals exposed to dieldrin found no correlation between the pesticide levels on their hands and in their sera (Kazen et al. 1974). A 1981 survey of Florida citrus field workers found dieldrin to be present in more than 3% of the 567 serum samples, at a mean concentration of 1.8 ppm (1,800 ppb) (Griffith and Duncan 1985). Workers cleaning up hazardous waste sites may also be exposed, but no information on monitored levels of exposure was found. The National Health and Nutrition Examination Survey (NHANES II) conducted between 1976 and 1980, found that an estimated 10.6% of the population aged 12—74 years old, were exposed to dieldrin based on an analysis of blood serum and urine specimens (Stehr-Green 1989). When specimens from populations in the northeast, midwest and south regions of the United States were examined almost 20% of the adults aged 45—74 years had quantifiable levels of dieldrin (mean concentration 1.4 ppb), while only 1.5% of the adults aged 12—24 years had quantifiable levels (mean concentration 1.4 ppb) (Murphy and Harvey 1985; Stehr-Green 1989). Dieldrin was found in 14 of 46 adipose tissue samples taken from cadavers and surgical patients during the 1982 Human Adipose Tissue Survey conducted by EPA on a nationwide basis. Concentrations of dieldrin in wet tissue were in trace amounts ranging from 0.053 to 3.84 pg/g (53—3,840 ppb) (mean concentration, 0.458 pg/g or 458 ppb). Aldrin was not present in any of the samples; the detection level was 0.010 pg/g (10 ppb) for a 20-g tissue sample (EPA 1986a). In 1976 and 107 5. POTENTIAL FOR HUMAN EXPOSURE 1984, human adipose tissue samples were taken from cadavers of Canadians from the Great Lakes region and examined for the presence of a variety of compounds. Dieldrin was found in 100% of the tissue samples taken each year at a mean concentration of 0.049 pg/g (49 ppb) wet weight in 1976 (Mes et al. 1982) and 0.047 ug/g (47 ppb) wet weight in 1984 (Williams et al. 1988). Based on a study with 12 male volunteers who ingested up to 225 pg dieldrin per day for up to 2 years, a wet weight BCF of 30 was calculated, although the BCF for the lipid fraction of body weight was 45. Other studies have found wet weight BCFs ranging from 38 to 77 (mean, 48.7) and lipid basis BCFs ranging from 55 to 115 (mean, 70.9) (Geyer et al. 1986, 1987). Blood samples taken from residents of El Paso, Texas, during 1982—1983, showed aldrin to be present in 39 of 112 samples (34%) at a mean concentration of 4.6 ppb (Mossing et al. 1985). Individuals living in homes contaminated by past termiticide treatment constitute a significant group exposed to aldrin and dieldrin in indoor air. Measurements of air concentrations in homes 1-10 years after termiticide treatment showed dieldrin levels ranging from 0.0006 to 0.03 ppb in living rooms and bedrooms and all interior areas (Dobbs and Williams 1983). A pilot study of nonoccupational general population exposure to pesticides in ambient air inside and outside the home was conducted in nine homes in Florida in August 1985. Air was monitored for 24 hours outside the house and inside the house, and personal air monitors were worn by one occupant of each house. Aldrin and dieldrin were detected in indoor air at six and five of the nine households, respectively; outdoors at four of the nine households each; and by personal monitors for three and five of the nine individuals, respectively. In one designated high-pesticide-use household, aldrin and dieldrin were detected in the indoor air at average concentrations of 0.058 /,tg/m3 (0.004 ppb) and 0.038 pg/m3 (0.002 ppb), respectively. Neither compound was detected in the outdoor air immediately adjacent to the home, and concentrations detected with personal air monitors were half (aldrin) to one-third (dieldrin) the concentrations for ambient indoor air (Lewis et al. 1988). A composite sample of the dust from four Seattle homes collected in 1988—1989 showed dieldrin to be present at 1.1 ppm, although none of the homeowners could remember using the pesticide. It was suggested that the source of the dieldrin was soil surrounding the homes; however, since the use of dieldrin is restricted to termite control, and Seattle has few termites, the source of the contaminated soil is unknown (Roberts and Camann 1989). Atmospheric sampling of aldrin and dieldrin conducted from 1970 to 1972 indicated that aldrin and dieldrin were present at mean concentrations of 0.4 ng/m3 (2.7x10'5 ppb) and 1.6 ng/m3 (1.02x10'4 ppb), respectively (Kutz et al. 1976). Combining these figures and assuming that 20 m3 of air are inspired each day, average daily intake of aldrin plus dieldrin from the atmosphere would be 0.57 ng/kg body weight. However, the recent restrictions on the use of these compounds and declining stockpiles suggests that current inhalation intake will be much less. Guicherit and Schulting (1985) used data on air samples collected in the western part of the Netherlands in 1979-1981 and calculated the average daily intake by inhalation to be 0.02 ng dieldrin/kg body weight and 0.01 ng aldrin/kg body weight. A significant source of general population exposure to dieldrin is through diet. In the absence of occupational or domestic use as a pesticide, food is probably the primary source of dieldrin residues in human adipose tissues (Ackerman 1980). Because of the rapid epoxidation of aldrin in the environment, it is not considered to be an important human dietary contaminant, with an average intake of less than 0.001 pg/kg/day. Dieldrin, however, may be ingested as a result of eating contaminated fish, milk, and other foods with a high fat content including meat. EPA established tolerances for aldrin and dieldrin in or on raw agricultural commodities at maximums of 0.0—0.1 ppm, depending on the crop (Sittig 1980). Although there are no published data on present residue levels of dieldrin in dietary component in the 108 5. POTENTIAL FOR HUMAN EXPOSURE United States, Table 5-1 is a summary of dieldrin residues in dietary components analyzed in 1981-1982. A 1985 Canadian survey of foods found that although aldrin was not detected in any of the food samples analyzed, dieldrin was detected in all food composites at 0.00011 pg/g in fruit; 0.0019 rig/g in milk; 0.0031 pg/g in leafy vegetables, eggs, and meat; and at 0.023 pg/g in root vegetables (Davies 1988). Dieldrin residues may persist in foods such as milk butterfat and subcutaneous fat in cattle with an estimated half-life in butterfat of 9 weeks (Dingle et al. 1989). Samples of ultra-pasteurized heavy cream and cow’s milk purchased in Binghamton, New York, in 1986 had dieldrin levels of 0.006 and 0.003 ppm, respectively (Schecter et al. 1989a). During the period of 1965—1970, total US. dietary intake was reported to be 0.05—0.08 pg dieldrin/kg/day and 0.0001-0.04 pg aldrin/kg/day (IARC 1974b). Since that time, the use of aldrin and dieldrin has been severely restricted, and dietary intake decreased. An FDA Total Diet Study, conducted between 1982 and 1984, found that aldrin intake was less than 0.001 pg/kg/day for all age and sex groups and that toddlers (2 years old) had the highest intake levels for dieldrin (0.016 pg/kg/day), followed by infants with 0.010 pg/kg/day. Adults had dieldrin intake of 0.007 pg/kg/day (25—30-year-old males) and adolescent males (14-16-year-olds) had an intake of 0.08 pg/kg/day (Gunderson 1988; Lombardo 1986). Dieldrin was found in 15% of the food samples analyzed. These values represent a decrease from the 1980 Total Diet Study. Between 1980 and 1982-1984, daily intakes of dieldrin decreased from 33 ng/kg/day to 10 pg/kg/day for infants, from 46 ng/kg/day to 16 ng/kg/day for toddlers, and from 22 ng/kg/day to 7—8 ng/kg/day for adults (Gunderson 1988). Recently a Total Diet Study conducted by FDA, found dieldrin in only 6% of the food items analyzed from 1990 (FDA 1991). Daily intakes of 0.0014, 0.0016, and 0.0016 pg/kg body weight were estimated for an infant 6—11 months old, a 14—16-year-old male, and a 60-65-year-old female, respectively (FDA 1991). Assuming 2 liters of water are ingested each day, the average drinking water contribution of dieldrin may range from 0.1 to 0.29 ng/kg/day for a 70-kg adult. These levels are well below the Acceptable Daily Intake (ADI) of 0.1 pg/kg/day recommended by the World Health Organization (WHO) for dieldrin (Geyer et al. 1986). The FDA Total Diet studies are based on levels found in representative commercially available food products. However, many infants receive human breast milk as a major dietary component rather than milk purchased in grocery stores. Therefore, the daily intake of infants may be more closely related to concentrations of dieldrin found in mother’s milk. Current levels of dieldrin found in human breast milk were not located. However, dieldrin was found in the breast milk of 80.8% of 1,436 nursing women sampled in 1980, with the greatest percentage (88.9%) in samples collected in the southeastern United States and the lowest percentage from samples collected in the northeast (63.9%) (Savage et al. 1981). The mean fat-adjusted residue level of these samples was 164 ppb. Assuming that milk fat accounts for approximately 3% of whole milk, this would correspond to approximately 5 ppb in whole milk. Of 54 nursing mothers studied in Hawaii (1979—1980), 94% had dieldrin in their milk (Takei et al. 1983). The mean concentration in milk fat was 42 ppb, which would correspond to a concentration of 1.3 ppb in whole milk. Of 57 nursing women sampled in 1973-1974 in Arkansas and Mississippi, 28% had a dieldrin residue level of 4 ppb in their milk (Strassman and Kutz 1977). A level of 0.5 ppb was found in a national survey of the general Canadian population (Davies and Mes 1987). Several factors may influence the levels of dieldrin found in breast milk. For example, a highly significant (p<0.001) association was reported in women with low levels of dieldrin in breast milk and a history of breast-feeding several children (Ackerman 1980). In addition, women who consume foods lower on the food chain, i.e., vegetarians, had dieldrin levels in their breast milk that were only 1—2% as high as the average levels in the United States (Hergenrather et al. 1981). Also, a mother’s total body weight may influence the concentration of dieldrin found in breast milk. In a study of Israeli women conducted in 109 5. POTENTIAL FOR HUMAN EXPOSURE guOOHOfi d0: H 92 «82 .3 .0 =2§o 5.5 BER... 92 DZ 8w£o>om DZ DZ Swam 88.9 N86 8 85h. «5 25 EC 886 «86 ES» 23 £830 886 Sad 33.”— muood Sod 9 82. 3:5 5an DZ OZ 8:531— 886 N86 9 82% 8350»? use: 386 wood 9 88% 8380a? 80% good N86 9 82h. 8950.— 285 v8.9 9 82p. 32: 5:5; .fiE 88.: «.85 8 829 ES 9335 A59: 95% coal act—228:8 onio>< 09.8 oazuém L32.82. 3:28.58 535 .33 c. 3:28: 5.205 .E 39:. 110 5. POTENTIAL FOR HUMAN EXPOSURE 1975, those weighing over 72 kg had significantly lower levels of dieldrin in their breast milk (6 ppb) than those weighing under 63 kg (8.7 ppb) (Polishuk et al. 1977a). This difference was observed despite similar plasma levels of dieldrin in the two groups. A Swedish study found that dieldrin levels in mother’s milk decreased from 0.044 pg/g (44 ppb) to 0.010 ng/g (10 ppb) between 1972 and 1984-1985; the use of dieldrin in Sweden was prohibited in 1970 (Noren 1988). A survey of 14 human milk donors whose homes in western Australia had been treated yearly with various pesticides for termite control found dieldrin residues in the milk ranging from 2 to 35 ng/g (2—35 ppb) (mean of 13 ng/g (13 ppb)) (Stacey and Tatum 1985). Milk levels of dieldrin peaked at 7—8 months after house treatment. Three of the 14 houses had recently been treated with aldrin, and the houses of the 11 other donors had been treated with aldrin previously. Dietary intake may have contributed partially to the milk levels since there was not a good correlation between dieldrin and the most recent use of aldrin. Studies show that transplacental transfer of aldrin and dieldrin occurs. A study of organochlorine compounds in mothers and fetuses during labor found that dieldrin concentrations in extracted lipids of fetal blood (1.22 ppm) and placenta (0.80 ppm) greatly exceeded those in maternal blood (0.53 ppm) and uterine muscle (0.54 ppm) (Polishuk et al. 1977b). A study of four Iraqi women with no known exposure to organochlorine pesticides found dieldrin levels in the placenta to range from 0.006 to 0.020 mg/kg total tissue weight and average dieldrin levels in their milk to range from 0.007 to 0.023 mg/kg whole milk. However, there was no correlation between the level of dieldrin in the placenta and the level in milk for each individual (Al-Omar et al. 1986). 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES Infants and toddlers are possibly exposed to higher levels of aldrin or dieldrin in the diet than are adults. Table 5-2 is a listing of calculated daily dietary intakes of dieldrin for adults, toddlers, and infants. Infant and toddler dietary intakes decreased significantly from 1978 to 1982; however, they remained elevated when compared with adult dietary intake. Higher exposure rates can be expected for large segments of the population residing in homes treated with aldrin or dieldrin for termite control. Measurements of air concentrations in homes 1—10 years after pesticide treatment showed dieldrin concentrations ranging from 0.002 to 0.17 ppb in roof voids and from 0.0006 to 0.03 ppb in living rooms and bedrooms and all interior areas (Dobbs and Williams 1983). An assessment of the environmental contamination of a residential community built on a thick layer of harbor sludge in the Netherlands, found that the maximal combined daily intake of aldrin, dieldrin, isodrin, and telodrin (the authors referred to these four compounds collectively as "drins") by soil ingestion, inhalation of contaminated indoor air, and diet exceeded the ADI by a factor of three (Van Wijnen and Stijkel 1988). The concentrations of the drins were highest in soil samples taken from the top 40 cm. Indoor air concentrations of drins in the living rooms of homes built on contaminated soil were 10 times higher than outdoor air levels (9.9 ng/m3 versus 0.8 ng/m3); levels in the crawl spaces of these homes were 100 times higher (88.7 ng/m3) than outdoor levels although no explanation was given for these elevated levels. Dieldrin concentrations were also elevated in vegetables grown in the soil (up to 40 mg/kg fresh weight) and resulted in a recommendation against the consumption of home-grown vegetables. Drin concentrations were not elevated in drinking water samples in any of the homes tested. Persons with chronic skin disease may be at increased risk from occupational exposure to pesticides. A formulator with scleroderma had higher blood and tissue levels of dieldrin than did his associates with similar exposures (Hayes 1982). 111 5. POTENTIAL FOR HUMAN EXPOSURE TABLE 5-2. Calculated Dietary Intakes of Dieldrin for Three Population Groupsa Dieldrin intake (pg/kg/day) Group 1981-1982 1980 1979 1978 Adults 0.016 0.022 0.016 0.017 Infants 0.020 0.033 0.048 0.045 Toddlers 0.023 0.046 0.036 0.039 'Derived from Gartrell et al. 1986a, 1986b 112 5. POTENTIAL FOR HUMAN EXPOSURE Residents who live near hazardous waste sites that contain aldrin or dieldrin may also have greater exposure to these compounds as a result of contact with contaminated environmental media. Although aldrin is unlikely to persist, dieldrin may enter surface water as a result of surface runoff of contaminated soil. Only limited information in available regarding the extent of contamination at hazardous waste sites and the levels to which individuals may be exposed. 5.7 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of aldrin or dieldrin is available. Where adequate information is not available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of aldrin or dieldrin. - The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce or eliminate the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 5.7.1 Identification of Data Needs Physical and Chemical Properties. The physical and chemical properties of aldrin and dieldrin are sufficiently well defined to allow assessments of the environmental fate of the compounds to be made (CHEMFATE 19853, 1985b; EPA 1987a; Hayes 1982; HSDB 1990a, 1990b; OHM/TADS 1985a, 1985b; Verschueren 1983). No additional information is needed. Production, Import/Export, Use, and Release and Disposal. The risk for exposure of the general population to substantial levels of aldrin or dieldrin is quite low. Aldrin and dieldrin have not been produced in the United States since 1974, nor is there any indication that US. production of either of these two chemicals will resume (EPA 1990b). Aldrin has not been imported into the United States since 1985 (EPA 1986d). No information was available regarding exports of aldrin or dieldrin, nor was information available regarding the amount of these insecticides currently stockpiled in the United States. More information would be useful on current stockpile levels. Currently, all uses of aldrin and dieldrin have been canceled (EPA 1990b). However, due to the persistence of these insecticides in the environment, the likelihood of their bioconcentration, and their former widespread use, these agents are still found at low levels in foods such as root crops and meat and dairy products. The soil around dwellings that have been treated with termiticides containing aldrin and dieldrin is the environmental media most likely to be contaminated with significant quantities of aldrin and dieldrin. The air within treated homes may also contain elevated levels of these agents. According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit chemical release and off-site transfer information to the EPA. 113 5. POTENTIAL FOR HUMAN EXPOSURE The Toxic Chemical Release Inventory (TRI), which contains this information for 1988, became available in May of 1990. This database will be updated yearly and should provide a list of industrial production facilities and emissions. However, for aldrin and dieldrin, there are no TRI data, indicating that no industrial releases of either of these chemicals were reported for 1988. Incineration and activated-carbon adsorption have greater than 99% efficiencies as methods for disposing of aldrin or dieldrin (HSDB 1990a, 1990b). However, no information is available regarding the amounts of aldrin or dieldrin disposed of by each method. Additional information on current disposal patterns would be useful. Envlronmental Fate. Aldrin released to surface and shallow subsurface soils partitions to the atmosphere where it is transported (Caro and Taylor 1971; Elgar 1975; McLean et al. 1988). In deeper subsurface soils, aldrin generally is sorbed to soil particulates (McLean et al. 1988); the compound should not leach to groundwater (McLean et al. 1988). Aldrin is biotransformed to dieldrin in aerobic soils (Gannon and Bigger 1958). Additional information is needed on the transformations of the compound in anaerobic soils and sediments. This information will be helpful in identifying the most important pathways of human exposure to the compound. Dieldrin sorbs to soils and sediments (Cliath and Spencer 1971). The compound also partitions to biota and slowly volatilizes from soils to the atmosphere (Nash 1983). Dieldrin is transported in the particulate phase of surface water runoff (Caro and Taylor 1971; Eye 1968; Hardee et al. 1964) and in the atmosphere (Baldwin et al. 1977). In deep subsurface soils, dieldrin is sorbed to particulates and does not leach to groundwater (Dobbs et al. 1989). The compound is persistent in environmental media, being resistant to biodegradation and abiotic transformation (Gannon and Bigger 1958; Jagnow and Haider 1972). Additional information is needed on the atmospheric transformation of the compound. This information would be useful in identifying the most important pathways of human exposure. Bioavallablllty from Environmental Media. Limited available pharmacokinetic data indicate that the compounds are absorbed by humans following inhalation of contaminated air (Stacey and Tatum 1985). Absorption also occurs following oral and dermal exposures (Feldmann and Maibach 1974; Heath and Vandekar 1964; Hunter and Robinson 1967; Hunter et al. 1969; Iatropoulos et al. 1975). Additional information is needed on the absorption of the compounds following ingestion of contaminated drinking water and soils. This information would be useful in evaluating the importance of various routes of exposure to populations living in the vicinity of hazardous waste sites. Food Chain Bloaccumulation. Aldrin and dieldrin are bioconcentrated by plants, animals, and aquatic organisms and biomagnified in aquatic and terrestrial food chains (Bhatnagar et al. 1988; Cole et al. 1976; Connell 1989; Metcalf et al. 1973; Sanborn and Yu 1973; Shannon 1977; Travis and Arms 1988). Food chain bioaccumulation appears to be a more important fate process for dieldrin, which is persistent, than for aldrin, which is rapidly converted to dieldrin (Metcalf et al. 1973). No additional information is necessary. Exposure Levels In Environmental Media. Aldrin and dieldrin have historically been detected in ambient air (Kutz et al. 1976), surface water (EPA 1980a; Weaver et al. 1965), drinking water (EPA 1980a), soils (Eisenreich et al. 1989; Kutz et al. 1976), sediments (Bergersen 1987; Staples et al. 1985), and foods (EPA 1985e; Hundley et al. 1988). However, limited current monitoring data were found (Chan and Perkins 1989; Hallberg 1989). The available data probably overestimate current background concentrations in these media since most of these monitoring studies were conducted before the use of the compounds 114 5. POTENTIAL FOR HUMAN EXPOSURE had been canceled. Dieldrin has been detected at low concentrations in soil samples collected at a limited number of hazardous waste sites (CLPSD 1989). Aldrin has been detected in waste site groundwater samples (CLPSD 1989). Recent estimates of dietary intake, which is believed to be the most important source of exposure for most members of the general population, are also available (FDA 1989). Additional information on hazardous waste site media concentrations is needed. This information will be helpful in identifying the most important exposure pathways for populations living near these sites. Exposure Levels In Humans. The presence of dieldrin in human blood and adipose tissue has been used as an indicator of exposure to aldrin and dieldrin (Hunter and Robinson 1967). The compounds have also been widely detected in human breast milk (Davies and Mes 1987; Savage et al. 1981; Strassman and Kutz 1977; Takei et al. 1983). Additional information on the concentration of these compounds in the biological tissue and fluids of populations living in the vicinity of NFL sites would be helpful in assessing the extent to which these populations have been exposed to these compounds. Exposure Registrles. No exposure registries for aldrin and dieldrin were located. These compounds are not currently among the compounds for which a subregistry has been established in the National Exposure Registry. The compounds will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be related to the exposure to these compounds. 5.7.2 On-golng Studies A pilot project is under way in South Dakota to identify types and levels of pesticide residues in breast milk of South Dakota residents and to evaluate the effect of diet and maternal weight change on proximate composition and pesticide excretion levels in milk. The project will also estimate pesticide loading in breast-fed and non-breast-fed infants. To date, trace amounts of dieldrin (>0.001 ppm) have been detected in human milk samples. Levels of dieldrin appear to decrease from week 1 to week 7 postpartum. Remedial investigations and feasibility studies conducted at the NFL sites contaminated with aldrin and dieldrin will add to the available database on exposure levels in environmental media and in humans and will contribute information for exposure registries. Investigations at the sites will also increase the current knowledge regarding the transport and transformation of aldrin and dieldrin at hazardous sites. No other long-term research studies regarding the environment fate and transport of aldrin and dieldrin or the occupational and general population exposure to these compounds were identified. 115 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting and/or measuring and monitoring aldrin or dieldrin in environmental media and in biological samples. The intent is not to provide an exhaustive list of analytical methods that could be used to detect and quantify aldrin or dieldrin. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used to detect aldrin or dieldrin in environmental samples are the methods approved by federal organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included that refine previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. 6.1 BIOLOGICAL MATERIALS Analytical methods exist for measuring aldrin, dieldrin, and their metabolites in blood, body tissues, breast milk, urine, and feces. The primary method used is gas chromatography (GC) coupled with electron capture detection (ECD). Since aldrin is converted so rapidly to dieldrin, exposure to aldrin or dieldrin is measured exclusively by determining levels of dieldrin in blood. Exposure is also measured by determining the levels of dieldrin in fat since it is rapidly distributed to adipose tissue. Metabolites of aldrin and dieldrin have been measured in feces and urine; however, they are not routinely used to quantify exposure to aldrin or dieldrin (Klein et al. 1968; Walker et al. 1969). A summary of the methods for various biological media is presented in Table 6-1. Dieldrin is determined in blood and fat using GC/ECD. TWO commonly used preparation methods for determining levels of dieldrin in blood are the acetone extraction procedure and the hexane extraction procedure (Robinson et al. 1967). The difference between the two is in the initial step where dieldrin is extracted from blood with either acetone or hexane. Both preparation methods are followed by concentration and extraction with hexane. A comparison of the two methods showed that the concentration of dieldrin in the blood with the hexane extraction method is only 65-70% of the concentration of dieldrin in blood using the acetone extraction method. The authors suggest that the relationship may indicate a partitioning of dieldrin between hexane and whole blood (Robinson et al. 1967). The reproducibility of the acetone technique is better than that of hexane. The preparation method used for measuring levels of dieldrin in fat includes extraction with hexane/acetone solution, partitioning between hexane and dimethylformamide (DMF), clean-up, and elution in hexane. Recovery and sensitivity of this technique are good. Precision was not reported (Walker et al. 1969). Aldrin and dieldrin have also been measured in samples of milk using GC/ECD (Barcarolo et al. 1988; Stacey and Tatum 1985; Takei et al. 1983). Sample preparation steps for milk involve homogenization, lipid extraction with hexane and acetone, residue extraction with acetonitrile, and partitioning into hexane. Recovery was adequate for dieldrin and good for aldrin. Precision was good. Sensitivity was not reported (Barcarolo et al. 1988). 6.2 ENVIRONMENTAL SAMPLES Methods exist for determining aldrin and dieldrin in air, water, and soil. The most common methods involve separation by GC coupled with ECD, electrolytic conductivity detector, or mass spectrometry (MS). GC has also been used with Fourier transform infrared spectroscopy (FTIR). Table 6-2 summarizes the methods that have been used to analyze for aldrin and dieldrin in environmental samples. TABLE 6-1. Analytical Methods for Determining Aldrin/Dieldrin In Biological Materials Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Blood Hexane extraction. GC/ECD 1 ng/mL 100 MacCuaig 1976 (dieldrin) Serum Denature with methanol, GC/ECD NR 70-75 Burse et a1. 1983 (dieldrin) mixed solvent extraction with hexane/ethylether, elute from activated silica gel. Milk Milk sample homogenized, GC/ECD NR NR Stacey and Tatum (aldrin and at extraction. Florisil 1985 dieldrin) clean-up, elution with hexane and acetonitrile. Milk Homogenize milk. GC/ECD NR 99 (aldrin); Barmrolo et a1. Multiresidue extraction 70 (dieldrin) 1988 through microcartridge. Elution with hexane and methanol. Feces Feces homogenized and GC/ECD NR NR Richardson and (9-hydroxy- extracted with acetone, then GC/MS Robinson 1971 dieldrin) hexane. Florisil clean-up. Elute with acetone and hexane. SGOHEW 'IVOLM'IVNV '9 9H TABLE 6-1 (Continued) Sample matrix Preparation method Analytical method Urine (urinary metabolites of aldrin and dieldrin) Fat, liver, brain (dieldrin) Urine mixed with ethyl ether and petroleum ether. Dried over anhydrous sulfate, concentrated. Florisilclean-up. Elution with ethyl ether/petroleum ether to remove aldrin and ethyl ether/acetone to remove dieldrin. Tissues extracted with hexane/acetone solution. Fats partitioned between hexane and dimethyl formamide. Florisil clean- up. Elution with 10% ether in hexane. GC/ECD GC/ECD Sample detection Percent limit recovery Reference NR NR Klein et al. 1968 0.5 ng 95 Walker et al. 1969 (dieldrin) GC/ECD = gas chromatography/electron capture detector; GC/MS = gas chromatography/mass spectrometry; ng = nanogram; NR = not reported SGOHJSW ‘IVOIM'IVNV '9 Lu TABLE 6-2. Analytical Methods for Determining Aldrin/Dieldrin in Environmental Samples Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Air (aldrin) Adsorption on TenaxO-GC, GC/ECD 0.003 ppb 76-110 Wallace and Sherren elution with acetone/petroleum 1986 spirit. Air (aldrin) Collection on glass fiber filter; GC/ 2.2 ppm 103 NIOSH 1984 extract in isooctane glass electrolytic blubbler. conductivity detector Water Samples extracted with methylene. GC/ECD 0.004 ppb 81 (aldrin); EPA 1986j chloride. Solvent exchange to (method 8080) (aldrin); 90 (dieldrin) hexane prior to GC analysis. 0.002 ppb (dieldrin) Water Samples extracted with methylene GC/MS 1 ppb 83—96 (aldrin), Alford-Stephens chloride, dried and concentrated. (aldrin and reagent water; et al. 1986 Solvent exchange to hexane. dieldrin) 94 (aldrin), river water 97—106 (dieldrin), reagent water; 90 (dieldrin), river water SCIOHJSW TVOIM'WNV '9 8H TABLE 6-2 (Continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Soil Samples extracted with acetone. GC/MS 5 ng (aldrin 76-102 (aldrin); Kobayashi et a1. Solvent exchange to hexane, dried and 84—101 1983 over sodium sulfate; acetone dieldrin) (dieldrin) added. Soil Soil mixed with acetone, filtered GC/MS 5 ng 90 (aldrin); Kobayashi et a1. dried, extracted with hexane. 94 (dieldrin) 1983 EPA = Environmental Protection Agency; GC/ECD = gas chromatography/electron capture detector; GC/MS = gas chromatography/mass spectrometry; ng = nanogram SCIOHJSW "IVOIM'IVNV '9 SH 120 6. ANALYTICAL METHODS The primary methods used for analyzing aldrin and dieldrin in air are GC/ECD and GC/electrolytic conductivity detector. The preparation method recommended by NIOSH for analysis of aldrin in air samples involves trapping the air on a glass fiber filter and extraction in an isooctane gas bubbler (NIOSH 1984). An alternative procedure to this method is the replacement of the gas bubbler with a stainless steel trapping tube packed with Tenax®GC (Wallace and Sherren 1986). TenaxG’GC is an efficient absorbent for aldrin. The solvent trapping efficiency for the isooctane procedure ranges from 83% to 94% while the trapping efficiency for Tenax®GC is >99%. Also, use of Tenax®GC does not require frequent replenishment of the volatile solvent needed for the isooctane bubbler, and the Tenax®GC trapping tube can be transported easily from sampling sites to the laboratory (Wallace and Sherren 1986). The sensitivity of these methods is in the low- to sub-ppb range. Precision is good. Recoveries for these methods are generally good but can range from 76% to 110%, depending on the series of solvents used in the preparation method. The methods most frequently used to analyze water samples containing aldrin and dieldrin are GC/ECD and GC/MS. Interferences by phthalate esters can pose a problem in pesticide determinations when using the ECD. (Interferences from phthalates can best be minimized by avoiding contact with any plastic materials.) The contamination from phthalate esters can be completely eliminated with an electrolytic conductivity detector (EPA 1986j). Aldrin and dieldrin are isolated from aqueous media by extraction in methylene chloride followed by drying with sodium sulfate, concentration, and solvent exchange to hexane (Alford-Stevens et al. 1986; EPA 1986j; Marsden et al. 1986). The limit of detection for both aldrin and dieldrin is in the low- to sub-ppb range for GC/ECD and GC/MS, respectively. Accuracy is generally good with the percent recoveries for dieldrin (90—106%) being higher that those for aldrin (81—96%). The precision obtained using GC/MS was better than that obtained using GC/ECD. The majority of analytical laboratories continue to rely on ECD for determination of aldrin and dieldrin. The main reason is that ECD provides a greater degree of sensitivity than MS. The difference in sensitivity has been reported to be as much as 2—3 orders of magnitude. The sensitivity of this method, however, depends on the level of interferences. Samples may require cleanup with a Florisil® column. The ECDs, however, do not provide the molecular structure information that is obtained with an MS detector. The structural information increases the level of confidence that the compound being measured has been correctly identified (Alford-Stevens et al. 1986). GC/FTIR has also been used to measure aldrin and dieldrin in water. However, this is not the recommended method because chlorinated pesticides are weak infrared absorbers (Gomez-Taylor et al. 1978). Solid samples such as soil and sediment are detected and quantified mainly by GC/ECD and GC/MS (EPA 1986j; Kobayashi et al. 1983; Marsden et al. 1986). The soil or sediment samples are prepared for analysis by extraction with a mixture of methylene chloride and acetone, followed by drying with sodium sulfate, and solvent exchange to hexane. Recoveries are generally good, and detection limits are in the low- to sub-ppb range for GC/MS and GC/ECD, respectively. While GC/ECD is highly sensitive, this method requires a complicated clean-up procedure to remove interferences in the sample that produce peaks having the same retention times. The MS detector is a simple, rapid, and selective method for the determination of aldrin and dieldrin in soil and is free from sample-related interferences (Kobayashi et al. 1983). Aldrin ‘ and dieldrin have been measured in fruits and vegetables using GC/ECD. Sample preparation involves boiling in water with a cyclic steam distillation unit with 2,2,4-trimethylpentane in the solvent trap. Variations in recoveries were reported. Sensitivity and precision were not reported (Santa Maria et al. 1986). 121 6. ANALYTICAL METHODS 6.3 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of aldrin or dieldrin is available. Where adequate information is not available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of aldrin or dieldrin. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce or eliminate the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance—specific research agenda will be proposed. 6.3.1 Identification of Data Needs Methods for Determlnlng Biomarkers of Exposure and Effect. Methods exist for determining aldrin and dieldrin in blood (Burse et al. 1983; MacCuaig 1976; Robinson et al. 1967), milk (Barcarolo et al. 1988; Stacey and Tatum 1985; Takei et a1. 1983), body tissues (Walker et a1. 1969), feces (Richardson and Robinson 1971), and urine (Klein et al. 1968). These methods are sensitive for measuring levels at which health effects might occur, as well as background levels in the population. Methods for determining dieldrin in blood are relatively precise; however, improvements in recovery of dieldrin are needed. These improvements would allow for better evaluation of exposure to aldrin or dieldrin. Sensitive techniques exist for measuring dieldrin in tissues; however, precision data are lacking. Data on the determination of dieldrin or its metabolites in milk, urine, and feces are limited. More information on the sensitivity and recovery obtained for these methods is needed to evaluate the value of using levels of dieldrin or its metabolites as an indicator of exposure. The methods for determining biomarkers of effect are the same as those for exposure, and are subject to the same limitations. Improved methods could allow a better assessment of the relationship between levels of dieldrin in blood, body tissues, and fluids and the known health effects associated with these chemicals. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Methods for determining levels of aldrin and dieldrin in air (NIOSH 1984; Wallace and Sherren 1986), water (Alford-Stevens et al. 1986; EPA 1986j), and soil (EPA 1986j; Kobayashi et al. 1983; Marsden et al. 1986) are sensitive enough to measure background levels in the environment, as well as levels at which health effects might occur. Limited data regarding the analysis of aldrin and dieldrin in foods were located (Santa Maria et al. 1986). Additional data on analytical methods for food are needed to better assess the risk of exposure for this media. Research investigating the relationship between levels measured in air, water, soil, and foods and observed health effects could increase our confidence in existing methods and/or indicate where improvements are needed. 6.3.2 On-going Studies An on-going study regarding analytical methods for determining aldrin and dieldrin in food was reported in the CRIS/USDA (1990a) database. S.L. Melton at the University of Tennessee in Knoxville is examining 122 6. ANALYTICAL METHODS pesticide residues and their degradation products in raw and processed foods. His objective is to improve existing methodology for multiple pesticide residues and to develop new methodology for short-life pesticide residues in food. The pesticides will be analyzed using capillary column GC coupled with an ECD. 123 7. REGULATIONS AND ADVISORIES The international, national, and state regulations and guidelines regarding aldrin and dieldrin in air, water, and other media are summarized in Tables 7-1 and 7-2, respectively. ATSDR has developed two MRL values for aldrin. An acute-duration oral MRL of 2x10‘3 mg/kg/day was derived for aldrin based on its ability to produce decreased pup body weight and increased electroconvulsive shock threshold in offspring of maternal mice exposed during gestation (Al-Hachim 1971). A chronic- duration oral MRL for aldrin was derived based on hepatocellular enlargement and eosinophilia with possible vacuolation and bile duct proliferation in rats (Fitzhugh et al. 1964). ATSDR has also derived two MRL values for dieldrin. An acute-duration oral MRL of 7x10'5 mg/kg/day was derived for dieldrin based on its ability to impair antigen processing by macrophages (Loose et al. 1981). A chronic-duration oral MRL of 5x10'5 mg/kg/day was derived for dieldrin based on a NOAEL for increased serum alkaline phosphatase levels and decreased serum proteins in dogs (Walker et al. 1969). EPA (IRIS 1990) has derived an oral reference dose (RfD) for aldrin of 3.0x10'5 mg/kg/day with an uncertainty factor of 1,000, based on liver toxicity in rats (Fitzhugh et al. 1964). EPA (IRIS 1990) assigned dieldrin an oral RfD of 5.0x10‘5 mg/kg/day with an uncertainty factor of 100, based on liver lesions in rats (Walker et al. 1969). No inhalation reference concentration (RfC) data are available for either chemical. Aldrin and dieldrin are on the list of chemicals appearing in "Toxic Chemicals Subject to Section 313 of the Emergency Planning and Community Right-to-Know Act of 1986" (EPA 1987j, 1988d). All uses of aldrin and dieldrin were canceled in 1974, except for subsurface ground insertion for termite control, dipping of nonfood roots and tops, and moth-proofing by manufacturing processes in a closed system (EPA 1974a). In 1987, these final three uses were voluntarily canceled by the sole manufacturer (EPA 1989a). FDA has determined action levels for the sum of aldrin and dieldrin residues for the following foods (meats and milk determined on a fat basis): 0.3 ppm for fat, meat, and meat byproducts of cattle, goats, horses, sheep, swine, poultry, and rabbits, and milk; 0.1 ppm for sugar beet pulp; 0.05 ppm for artichokes, figs, and small fruits and berries; and 0.03 ppm for eggs and hay (EPA 1986f). EPA recommended replacement action levels for the sum of aldrin and dieldrin residues after revoking the previous tolerances (EPA 1986f). These replacement action levels are summarized in Table 7-3. 124 7. REGULATIONS AND ADVISOFIIES TABLE 7-1. Regulatlons and Guldellnes Appllcable' to Aldrln Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 3" IARC 1987 WHO Acceptable daily intake 0.1 ug/kg WHO 1975 (body weight) NATIONAL Regulations: 3. Air: OSHA PEL TWA 0.25 mg/m3; OSHA 1989a (29 (skin designation) CFR 1910.1000); OSHA 198% b. Water. EPA OWRS Pesticides regulated by Yes EPA 1985c (40 CFR NSPS, PSES, and PSNS when 455); EPA l985d formulated and packaged Toxic Pollutant Effluent Standards Prohibited EPA 1977b (40 CFR 129.100); EPA 1977c Ambient water criterion in 0.003 [Lg/L EPA 1977b (40 CFR navigable waters 129.100); EPA 1977c d. Other: EPA OERR Reportable quantity 1 pound EPA 1986b (40 CFR 117.3); EPA 1986c Extremely Hazardous Substance TPQ 500 pounds EPA 1987c (40 CFR 355, Appendix A); EPA 1987d EPA OSW Designated as a Hazardous Substance under Yes EPA 1978a (40 CFR Section 311(b)(_2)(A) of the Federal 116.4); EPA 1978b Water Pollution Control Act Designated as a Toxic Pollutant under Yes EPA 1979b (40 CFR Section 307(a)(1) of the Federal 401.15); EPA 1979a Water Pollution Control Act and is subject to effluent limitations Listing as hazardous waste: Discarded Yes EPA 1980b (40 CFR commercial chemical products off- 261.33); EPA 1980c specification species, container residues, and spill residues thereof Listing as a Hazardous Waste Constituent Yes EPA 1981a (40 CFR 261, Appendix VIII); EPA 1988a Groundwater Monitoring Requirement Yes EPA 1987c (40 CFR 264, Appendix IX); EPA 1987b EPA OTS Toxic Chemical Release Reporting; Yes EPA 1988d (40 CFR Community Right-to-Know 372); EPA 1987j 125 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Contlnued) Agency Description Information References National (Cont.) Guidelines: a. Air: ACGIH TLV TWA (skin) 0.25 tug/m3 ACGlH 1990 EPA RfC (Inhalation) Not available lRlS 1990 NlOSH REL TWA (skin) Ca”; 0.25 mg/m3 NlOSH 1992 b. Water: EPA OWRS Health Advisories None IRIS 1990 Ambient Water Quality Criteria for EPA 1980d Protection of Human Healthc lngesting water and organisms: 10-5 0.74 rig/L 10* 0.074 ng/L 10-7 0.0074 ng/L lngesting organism only. 10-5 0.79 ng/L 10" 0.079 ng/L 10'7 0.0079 ng/L Water Quality Standards for Aquatic Life» EPA 1980d Concentration should never uceed: Saltwater (acute) 1.3 ug/L Freshwater (acute) 3.0 ug/L c. Other: EPA RfD (oral) 3.00x10-s mg/kg/day ms 190 Sui. 1,000) Carcinogen Classification 32 lRlS 1990 Unit risk (air) 4.9x10-3 [Lg/m3 lRlS 1990 Unit risk (water) 4.9><104 ml. IRIS 1990 STATE Regulations and Guidelines: a. Air: Acceptable Ambient Air Concentrations NATICH 1990 Connecticut (8-hour) 1.50 [Lg/m3 Kansas (Annual) 0.595 [Lg/m3 Kansas-KC (Annual) 0.0217 [Lg/m3 Massachusetts (24 hour) 1.74 [kg/m3 Maryland 0.00 North Dakota (8-hour) 0.0025 mg/m3 Nevada (8-hour) 0.006 hug/in3 Pennsylvania-Phil. (l-year) 0.035 [lg/m3 Pennsylvania-Phil. (Annual) 0.035 lIg/m3 Texas (30-minutes) 2.50 1;me Texas (Annual) 0.25 ll.g/m3 Virginia (24-hour) 4.20 [Lg/m3 126 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Contlnued) Agency Description Information References State (Cont) Kentucky Significant Emission Levels of 6.379><10'4 NREPC 1986' (401 Toxic Air Pollutants pounds/hour KAR 63:022) Wisconsin Hazardous Air Contaminants with WAC 1988 Acceptable Ambient Concentrations Emission points <25 feet 0.020880 pounds/hour Emission points :25 feet 0.086400 pounds/hour Wisconsin Hazardous Air Contaminants with WAC 1988 Acceptable Ambient Concentrations Emission points <25 feet 0.020880 pounds/hour Emission points :25 feet 0.086400 pounds/hour b. Water: Drinking water quality guidelines FSTRAC 1988 and standards California 0.7 ug/L Illinois 1.0 [Lg/L Kansas 0.013 ug/L Minnesota 0.03 [Lg/L Alabama Toxic Pollutant Criteria for Aquatic Life CELDS 1990c Freshwater (acute) 3.0 ug/L Marine (acute) 1.3 ug/L Anzona Surface Water Standards 0.003 ug/L CELDS 19908 Arkansas Surface Water Quality Standards CELDS 1990a Acute 3.0 ug/L Chronic (24-hour) none California Applied Action Level 0.05 ppb EPA 1987k Indiana Water Quality Criteria Acute aquatic maximum 1.5 mg/L CELDS 1990c lndiana Continuous Criterion Concentration for CELDS 1990c Human Health (4-day average): Outside the mixing zone 0.00079 mg/L Point of water intake 0.00074 mg/L Maryland Water Quality Criteria for 0.003 ug/L CELDS 1990a Class I Waterse Nevada Water Quality Criteria: CELDS 1990c Irrigation 0.00 Watering of Livestock <0 003 mg/L Aquatic Use <0.003 mg/L Propagation of Wildlife 0.00 Municipal or Domestic Water Supply 0.00 127 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Contlnued) Agency Description Information References m (Conn) New York Effluent standards: Maximum allowable Not detectable CELDS 1990b concentrations into saturated or unsaturated zones Allowable concentration limits for Not detectable CELDS 1990c Class GA waters North Carolina Water Quality Standards for Freshwater 0.002 mg/L CELDS 1990a North Dakota Water Quality Standards for Class [ streamse CELDS 1990a Acute 3.0 ug/L Chronic None Virginia Groundwater Monitoring Parameter Yes CELDS 19900 Virginia Chronic Criteria for Protection CELDS 1990a of Aquatic Life: Freshwater 0.03 ug/L Saltwater 0.003 ug/L Washington DC. Water Quality Standards CELDS 1990b Class C waters protected for 0.4 mg/L aquatic life, waterfowl, shore birds, and water-oriented wildlife Class D waters protected for use 0.00007 mg/Lr as a raw water source for public water supply Wisconsin Human Cancer Criteria DNR 1987 Public Water Supply: Warm water sport fish communities 0.54 ng/L Cold water communities 0.17 ng/L Great Lakes communities 0.17 ng/L Non-Water Supply: Warm water sport fish communities 0.57 ng/L Cold water communities 0.17 ng/L Warm water forage and limited forage 6.1 ng/L fish wmmunities and limited aquatic life c. Food: Illinois FDA Action Level 0.3 ppm IEPA 1988 Public and Food Processing 0.001 mg/L CELDS 1990a Water Supply Standards 128 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Continued) Agency Description Information References State (Cont.) d. Other: (‘alifomia Designated a restricted pesticide Yes CELDS 1990c Toxic materials limitations objectives 0.022 ng/L CELDS 1990c for protection of human health (30-day average): Florida Persistent pesticides may not be applied Yes CELDS 1990a in a broadcast manner Kentucky Defined as Hazardous Waste Yes NREPC 1988 Wisconsin Defined as a Limited Use Pesticide; Yes WAC 1988 permit required for use Designated as a Toxic Pollutant Yes CELDS 1990a “Group 3: Not classifiable as to the carcinogenicity to humans bAgent recommended by NIOSH to be treated as a potential occupational carcinogen cBecause of its carcinogenic potential, the EPA-recommended concentration for aldrin inambient water is zero. However, because attainment of this level may not be possible, levels which correspond to upper bound incremental lifetime cancer risks of 10-5, 10", and 10‘7 are estimated. dGroup BZ: Probable human carcinogen cClass l waters include water contact recreation and aquatic life. fA risk factor of 10'6 is associated with the criterion; the preferred level is zero. ACGIH = American Conference of Governmental Industrial Hygienists; EPA = Environmental Protection Agency; FDA = Food and Drug Administration; GA = New York classification for fresh water, [ARC = International Agency for Research on Cancer; ng = nanograms; NlOSH = National institute for Occupational Safety and Health; NSPS = New Source Performance Standards; OERR = Office of Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Wastes; OTS = Office of Toxic Substances; OWRS = Office of Water Regulations and Standards; PEL = Permissible Exposure Limit; PSES = Pretreatment Standards for Existing Sources; PSNS = Pretreatment Standards for New Sources; REL = Recommended Exposure Limit; RfC = Reference Concentration; RfD = Reference Dose; TLV = Threshold Limit Value; 'I'PQ = Threshold Planning Quantity; TWA = Time-Weighted Average; u.f = uncertainty factor, WHO = World Health Organimtion 129 7. REGULATIONS AND ADVISORIES TABLE 7-2. Regulations and Guidelines Applicable to Dieldrin Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 3“ IARC 1987 WHO Acceptable daily intake 0.1 ug/kg WHO 1975 (body weight) NATIONAL Regulations: a. Air: OSHA PEL TWA 0.25 mg/m3; OSHA 1989a (29 (skin designation) CFR 1910.1000); OSHA 1989b b. Water: EPA OWRS Pesticides regulated by Yes EPA 1985c (40 CFR NSPS, PSES, and PSNS when 455); EPA 1985d formulated and packaged Toxic Pollutant Effluent Standards Prohibited EPA 1977b (40 CFR 129.100) EPA 1977c Ambient water criterion in 0.003 ug/L EPA 1977b (40 CFR navigable waters 129.100); EPA 1977c c. Other: EPA OERR Reportable quantity 1 pound EPA 1986b (40 CFR 117.3); EPA 1986c EPA OSW Designated as a Hazardous Substance under Yes EPA 1978a (40 CFR Section 311(b)(2)(A) of the Federal 116.4); EPA 1978b Water Pollution Control Act . Designated as a Toxic Pollutant under Yes EPA 1979b (40 CFR Section 307(a)(1) of the Federal 401.15); EPA 1979a Water Pollution Control Act and is subject to effluent limitations Listing as hazardous waste: Discarded Yes EPA 1980b (40 CFR commercial chemical products off- 261.33); EPA 1980c specification species. container residues. and spill residues thereof Listing as a Hazardous Waste Constituent Yes EPA 1981a (40 CFR 261, Appendix Vili); EPA 1988a Groundwater Moniton’ng Requirement Yes EPA l987e (40 CFR 264, Appendix D(); EPA 1987h Guidelines: a. Air: ACGIH TLV TWA (skin) 0.25 mg/m3 ACGIH 1990 130 7. REGULATIONS AND ADVISORIES TABLE 7-2 (Contlnued) Agency Description Information References National (Cont.) EPA RfC (Inhalation) Not available IRIS 1990 NlOSH REL TWA Ga”; 0.25 mg/m’; NIOSH 1992 (skin) b. Water. HEW Recommended Drinking Water Standard 17 ppb NAS 1977 EPA OWRS Health Advisories EPA 1988b 1-day (proposed)(child) 0.0005 lug/1..c 10-day (child) 0.0005 tug/1..c Longer-term (child) 0.0005 mg/Lc Lifetime Not recommended“ DWEL 2 ug/L Ambient Water Quality Criteria for EPA 1980d Protection of Human Healthe lngesting water and organisms: 10‘5 0.7 ng/L 10*5 0.071 ng/L 10'7 0.0071 ng/L Ingesting organisms only: 10‘5 0.76 rig/L 10*5 0.076 ng/L 10'7 0.0076 ng/L Water Quality Standards for Aquatic Life EPA 1980d Concentration should never exceed: Saltwater 0.71 rig/L Freshwater 2.5 [Lg/L 24-hour average: Saltwater 0.0019 [Lg/L Freshwater 0.0019 ug/L c. Other: EPA RfD (oral) 5.50x10-5 mg/lrg/day lRIS 1990 (of. 100) Carcinogen Classification BZ IRIS 1990 Unit risk (air) 4.6x10'3 [Lg/m3 IRIS 1990 Unit risk (water) 4.6x10'4 [Lg/L IRIS 1990 STATE Regulations and Guidelines: a. Air: Acceptable Ambient Air Concentrations NATICH 1990 Connecticut (8-hour) 5.00 [Lg/n13 Kansas (Annual) 0595 [Lg/m3 Kansas-Kansas City (Annual) 0.000175 [Lg/m3 Maryland 0.00 North Dakota (8-hour) 0.0025 mg/m3 131 7. REGULATIONS AND ADVISORIES TABLE 7-2 (Contlnued) Class 1 Waters8 Agency Description Information References State (Cont) Nevada (8-hour) 0.0060 mg/m3 Pennsylvania- (l-year) 0.0350 ug/m3 Philadelphia Pennsylvania- (Annual) 0.0350 [Lg/m3 Philadelphia Texas (30-minutes) 1.50 u.g/m3 Texas (Annual) 0.150 [Lg/m3 Virginia (24-hour) 4.10 [Lg/r113 Kentucky Significant Emission Levels of 6.379x10'5 NREPC 1986 (401 Toxic Air Pollutants pounds/hour KAR 63:022) Wisconsin Hazardous Air Contaminants with WAC 1988 Acceptable Ambient Concentrations Emission points <25 feet 0.020880 pounds/hour Emission points 225 feet 0.086400 pounds/hour b. Water: Drinking water quality guidelines and standards Kansas 0.019 [Lg/L FSTRAC 1988 Minnesota 0.01 [Lg/L FSTRAC 1988 Puerto Rico 0.003 ppb CELDS 1990b Alabama Toxic Pollutant Criteria for Aquatic Life CELDS 1990c Freshwater Acute 2.5 [Lg/L Chronic 0.0019 [Lg/L Marine Acute 0.71 ug/L Chronic 0.0019 [Lg/L Arizona Surface Water Standards 0.003 [Lg/L CELDS 1990a California Applied Action Level 0.05 ppb EPA 1987K Arkansas Surface Water Quality Standards CELDS 1990a Acute 2.5 [Lg/L Chronic (24-hour) 0.0019 [Lg/L Indiana Water Quality Criteria CELDS 1990c Acute aquatic maximum 1.3 mg/L Continuous Criterion Concentratiqs 0.0019 mg/L (4-day average) Indiana Continuous Criterion Concentration for CELDS 1990c Human Health (4-day average): Outside the mixing zone 0.00076 mg/L Point of water intake 0.00071 mg/L Maryland Water Quality Criteria for 0.003 [Lg/L CELDS 1990a 132 7. REGULATIONS AND ADVISORIES TABLE 7-2 (Continued) Agency Description Information References State (Cont) Nevada Water Quality Criteria: CELDS 1990c Irrigation 0.00 Watering of Livestock <0.0025 mg/L Aquatic Use <0.0025 myl. 24-hour average <0.0000019 mg/L Propagation of Wildlife 0.00 Municipal or Domestic Water Supply 0.00 New York Effluent standards: Maximum allowable Not detectable CELDS 1990b concentrations into saturated or unsaturated zones Allowable concentration limits for Not detectable CELDS 1990c Class GA waters North Carolina Water Quality Standards for Freshwater 0.002 mg/L CELDS 1990a North Dakota Water Quality Standards for Class 1 streamss CELDS 1990a Acute 2.5 ug/L Chronic 0.002 ug/L Virginia Groundwater Monitoring Parameter Yes CELDS 1990c Virginia Chronic Criteria for Protection 0.0019 ug/L CELDS 1990a of Aquatic Life (all waters) Washington DC. Water Quality Standards CELDS 1990c Class C waters protected for 0.0019 mg/L aquatic life, waterfowl, shore birds, and Water-oriented wildlife Class D waters protected for use 0.00007 mg/Lh as a raw water source for public water supply Wisconsin Human Cancer Criteria DNR 1987 Public Water Supply. Warm water sport fish communities 0.54 ng/L Cold water communities 0.17 ng/L Great Lakes communities 0.17 nyl. Non-Water Supply: Warm water sport fish communities 0.57 ng/L Cold water communities 0.17 ng/L Warm water forage and limited forage 2,300 ng/L fish communities and limited aquatic life Wisconsin Wisconsin Division of Health Standards 0.3 ppm WAC 1988 for contaminants commonly found in sport fish 133 7. REGULATIONS AND ADVISORIES TABLE 7-2 (Continued) Agency Description Information References State (Cont) c. Food: Illinois FDA Action Level 0.3 ppm [EPA 1988 Public and Food Processing 0.001 mg/L CELDS 1990a Water Supply Standards d. Other: California Designated a restricted pesticide Yes CELDS 1990c Toxic materials limitations objectives 0.040 ng/L ‘ CELDS 1990c for protection of human health: Florida Persistent pesticides may not be applied Yes CELDS 1990a in a broadcast manner Kentucky Defined as Hazardous Waste Yes NREPC 1988 Wisconsin Defined as a Limited Use Pesticide; Yes WAC 1988 permit required for use Designated as a Toxic Pollutant Yes CELDS 1990a 3Group 3: not classifiable as to its carcinogenicity to humans I’Agent recommended by NIOSH to be treated as a potential occupational carcinogen °Because suitable data for derivation of health advisories were not found, a modified DWEL for a 10-kg child is recommended. dBecause dieldrin is a 32 carcinogen, a lifetime HA is not recommended. eBecause of its carcinogenic potential, the EPA-recommended concentration for dieldrin in ambient water is zero. However, because attainment of this level may not be possible, levels that correspond to upper-bound incremental lifetime cancer risks of 10‘s, 10", and 10'7 are estimated. rGroup 32:. probable human carcinogen gClass l waters include water contact recreation and aquatic life. hA risk factor of 10" is associated with the criterion; the preferred level is zero. ACGIH = American Conference of Governmental Industrial Hygienists; DWEL = Drinking Water Equivalent Level; EPA = Environmental Protection Agency; FDA = Food and Drug Administration; GA = New York classification for fresh water; HEW = US. Department of Health, Education, and Welfare; lARC = lntemational Agency for Research on Cancer; ng = nanograms; NlOSH = National Institute for Occupational Safety and Health; NSPS = New Source Performance Standards; OERR = Office of Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Wastes; ()WRS = Office of Water Regulations and Standards; PEL = Permissible Exposure Limit; PSES = Pretreatment Standards for Existing Sources; PSNS = Pretreatment Standards for New Sources; REL = Recommended Exposure Limit; RfC = Reference Concentration; RfD i Reference Dose; 'I‘LV = Threshold Limit me; TWA = Time-Weighted Average; u.f. ‘= uncertainty factor; WHO = World Health Organization 134 7. REGULATIONS AND ADVISORIES Table 7-3. Recommended Action Levels for Total Residues of Aldrin and Dieldrin‘ Commodities Recommended action levels (ppm) Peanuts Garden and sugar beets, carrots, cucumbers, garlic, horseradish, leeks, melons, onions, parsnips, potatoes, pumpkins, radishes, rutabagas, salsify roots, shallots, summer and winter squash, and turnips Beans, garden and sugar beet tops, blackeyed peas, collards, cowpeas, cranberries, eggplant, endive, grapes, kale, kohlrabi, mustard greens, peas, pimentos, salsify tops, soybeans, spinach, strawberries, Swiss chard, tomatoes, and turnip tops Alfalfa, apples, apricots, asparagus, barley (straw), broccoli, brussel sprouts, cabbage, cauliflower, celery, cherries, clover, corn (forage), cowpeas (hay), grain sorghum (forage), lespedeza, lettuce, mangoes, nectarines, oats (straw), peanuts (hay), pears, peas (hay), pineapples, plums, fresh prunes, quinces, radish tops, rice (straw), rye (straw), soybeans (hay), and wheat (straw) Bananas, barley (grain), com (grain), grain (sorghum), grapefruit, lemons, limes, oats (grain), oranges, peaches, popcorn, rice (grain), rye (grain), tangerines, and wheat (grain) 0.5 0.1 0.05 0.03 0.02 flDerived from EPA 1986g 135 8. 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The pesticide manual: A world compendium, 7th ed. Suffolk, Great Britain: The Lavenham Press Limited, 6, 191. Wright AS, Akintonwa DAA, Woodner MF. 1977. Studies on the interaction of dieldrin with mammalian liver cells at the subcellular level. Ecotoxicol Environ Safety 1:7-16. *Wright AS, Donninger C, Greenland RD, et al. 1978. The effects of prolonged ingestion of dieldrin on the livers of male rhesus monkeys. Ecotoxicol Environ Safety 1:477-502. *Wright AS, Potter D, Wooder MF, et al. 1972. The effects of dieldrin on the subcellular structure and function of mammalian liver cells. Food Cosmet Toxicol 10:311-332. Zanoni AE. 1987. Characteristics and treatability of urban runoff residuals. Water Res 20:651-660. Zepp RG, Schlotzhauer PF. 1983. Influence of Algae of photolysis rates of chemicals in water. Environ Sci Technol 17:462-4683 *Zhong-Xiang L, Kavanagh T, Trosko JE, et al. 1986. Inhibition of gap junctional intercellular communication in human teratocarcinoma cells by organochlorine pesticides. Toxicol Appl Pharmacol 83:10-19. 181 9. GLOSSARY Acceptable Daily Intake (ADI) -- Defined as the daily exposure level which, during the lifetime of man, appears to be without appreciable risk. Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical adsorbed per unit weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or sediment. Bioconcentration Factor (BCF) -- The quotient of the concentration of a chemical in aquatic organisms at a specific time or during a discrete time period of exposure divided by the concentration in the surrounding water at the same time or during the same period. Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control. Carcinogen -- A chemical capable of inducing cancer. Ceiling Value -- A concentration of a substance that should not be exceeded, even instantaneously. Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified in the Toxicological Profiles. Developmental Toxicity -- The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death. EPA Health Advisory -- An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. 182 9. GLOSSARY Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days, as specified in the Toxicological Profiles. Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. In Vitro -- Isolated from the living organism and artificially maintained, as in a test tube. In Vivo -- Occurring within the living organism. Lethal Concentrationam (LCm) -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration(50) (Lcso) -- A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. Lethal Dose(Do (LDLO) -- The lowest dose of a chemical introduced by a route other than inhalation that is expected to ave caused death in humans or animals. Lethal Dose(50) (Lnso) -- The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time(50) (LT50) -- A calculated period of time within which a specific concentration of a chemical is expected to cause death in 50% of a defined experimental animal population. Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations -- Permanent structural changes that may adversely affect survival, development, or function. Minimal Risk Level -- An estimate of daily human exposure to a dose of a chemical that is likely to be without an appreciable risk of adverse noncanoerous effects over a specified duration of exposure. Mutagen -- A substance that causes mutations. A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. Neurotoxicity -- The occurrence of adverse effects on the nervous system following exposure to chemical. No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which there were no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. Octanol-Water Partition Coefficient (Kow) n-octanol and water, in dilute solution. -- The equilibrium ratio of the concentrations of a chemical in 183 9. GLOSSARY Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace air averaged over an 8-hour shift. q1* -- The upper- -bound estimate of the low-dose slope of the dose- -response curve as determined by the multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and pg/m3 for air). Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate Rst and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The Rst are not applicable to nonthreshold effects such as cancer. Reportable Quantity (RQ) -- The quantity of a hazardous substance that is considered reportable under CERCLA. Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are measured over a 24-hour period. Reproductive Toxicity -- The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Target Organ Toxicity -- This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical. Teratogen -- A chemical that causes structural defects that affect the development of an organism. Threshold Limit Value (TLV) -- A concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. Time-Weighted Average (TWA) -- An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek. Toxic Dose (TDso) '- A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 184 9. GLOSSARY Uncertainty Factor (UF) -- A factor used in operationally deriving the RD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. A-1 APPENDIX A USER‘S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in nontechnical language. lts intended audience is the general public especially people living in the vicinity of a hazardous waste site or substance release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the substance. The major headings in the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic. Chapter 2 Tables and Figures for Levels of Significant Exposure (LSE) Tables (2-1. 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects by duration of exposure and endpoint and to illustrate graphically levels of exposure associated with those effects. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs), Lowest-Observed- Adverse-Effect Levels (LOAELS) for Less Serious and Serious health effects. or Cancer Effect Levels (CELs). In addition, these tables and figures illustrate differences in response by species, Minimal Risk Levels (MRLs) to humans for noncancer end points, and EPA’s estimated range associated with an upper-bound individual lifetime cancer risk of 1 in 10.000 to 1 in 10,000,000. The LSE tables and figures can be used for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. The legends presented below demonstrate the application of these tables and figures. A representative example of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure. LEGEND See LSE Table 2-1 (1). Route of Exposure One of the first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exist, three LSE tables and two LSE figures are presented in the document. The three LSE tables present data on the three principal routes of exposure, i.e.. inhalation. oral, and dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) and oral (LSE Figure 2-2) routes. (2). Exmsure Duration Three exposure periods: acute (14 days or less); intermediate (15 to 364 days); and chronic (365 days or more) are presented within each route of exposure. In this example, an inhalation study of intermediate duration exposure is reported. (3). (4). (5). (6). (7). (8). (9). (10). (11). (12). A-2 APPENDIX A Health Effect The major categories of health effects included in LSE tables and figures are death. systemic. immunological. neurological, developmental. reproductive. zuid cancer. NOAELs and LOAELs can he reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table. Key to Figure Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example. the study represented by key number 18 has been used to define a NOAEL and a Less Serious LOAEL (also see the two "l8r" data points in Figure 2-1). Smcies The test species, whether animal or human. are identified in this column. Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELS from different studies. In this case (key number 18). rats were exposed to [substance x] via inhalation for 13 weeks. 5 days per week, for 6 hours per day. System This column further defines the systemic effects. These systems include: respiratory. cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic. renal, and dennal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18. one systemic effect (respiratory) was investigated in this study. NOAEL A No—Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see footnote "b"). LOAEL A Lowest—Observed-Adverse-Effect Level (LOAEL) is the lowest exposure level used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific end point used to quantify the adverse effect accompanies the LOAEL. The "Less Serious" respiratory effect reported in key number 18 (hyperplasia) occurred at a LOAEL of 10 ppm. Reference The complete reference citation is given in Chapter 8 of the profile. % A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiological studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses which did not cause a measurable increase in cancer. Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in the footnotes. Footnote "b" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm. A-3 APPENDIX A LEGEND See LSE Figure 2-1 LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure levels for particular exposure duration. (13). (14). (15). (16). (17). (18). (19). Expgsure Duration The same exposure periods appear as in the LSE table. In this example, health effects observed within the intermediate and chronic exposure periods are illustrated. Health Effect These are the categories of health effects for which reliable quantitative data exist. The same health effects appear in the LSE table. Levels of Exposure Exposure levels for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure levels are reported on the log scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in mg/kg/day. NOAEL In this example, 18r NOAEL is the critical end point for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates a NOAEL for the test species (rat). The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the lvfllL of 0.005 ppm (see footnote "b" in the LSE table). CEL Key number 38r is one of three studies for which Cancer Effect Levels (CELs) were derived. The diamond symbol refers to a CEL for the test species (rat). The number 38 corresponds to the entry in the LSE table. Estimated Uppgr-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of l in 10,000 to 1 in 10,000,000. These risk levels are derived from EPA’s Human Health Assessment Group’s upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q,'). Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. p.000-0000'00w000000000 .a u o . o o. O O O . . . . . . . .0.0.0.093).0.Ofofofofafofefafofo’a'o'afaf [3f — mm 24. Level. of simific-It Em to run-scat x] - Inhalation Exposure LOAEL (effect) Key to frequency] NOAEL Less serious Serious figurea Species duration System (ppm) (ppll) (ppm) Reference '33—. INTERMEDIATE exposure [3... 18 m 13 ak Resp 3" 10 (hyperplasio) Nitschke et al. 5dluk 1981 6hr/d CHRONIC EXPOSURE Cancer [Til % 3 38 Rat 18 mo 20 (CEL, multiple Nona et al. 1982 g 5d/uk organs) : 7hr/d 39 Rat 89-10b wk 10 (CEL, ling tumors, NIP 1982 Still“! nasal tunors) 6hr/d (.0 House 79-103 HI: 10 (CEL, lung tuuors, MP 1982 Sdluk hemangiosarcomaa) 6hr/d a The nulber corresponds to entries in Figure 2-1. E—0 b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 10.3 ppm; dose adjusted for intermittent exposure and divided by an mcertainty factor of 100 (10 for extrapolation from animal to hunans, 10 for hunn variability). CEL I cancer effect level; d - day(a); hr I hour“); LOAEL I louest-observed-adverae-effect level; so = ninth“); NOAEL = no- observed-adverse-effect level; Resp = respiratory; wk 3 ueek(s) OO0.......uv..............¢ 10" IO -7 MOI-— GUI-M [g ——————. "newsman (mason-m patio-g» 1351-»;2 I 1Jx__./ E.|.:p I.” .. ~ d3.“ 0- 0- e— o:- o» o-- 0:- Our [El—~— —--———-~ 9-0- ' : I .0 . O : a on! J, 5!! ' W O tutu-cunt.“ ' m" I “II-‘- 0 lflllhI-Iee-ede-m : nun-un- ‘ at“ .mu-h-o J, chance-u.- not» : m Cfl-Cmnll-alnd mmnubmmmwnmhl‘ou ’0... u Jfima _ “dune-“'6‘ “ “ ‘7 FIGURE 2-1 . Levels of significant Exposure to [Che-10.1 XJ-Inheletion V XIONdeV 9" A‘s APPENDIX A Chapter 2 (Section 2.4) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicological, epidemiological, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions. 1. What effects are known to occur in humans? 2. What effects observed in animals are likely to be of concern to humans? 3. What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites? The section discusses health effects by end point. Human data are presented first. then animal data. Both are organized by route of exposure (inhalation, oral. and dermal) and by duration (acute, intermediate, and chronic). I_n m data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included. The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data ATSDR does not currently assess cancer potency or perform cancer risk assessments. MRLs for noncancer end points if derived, and the end points from which they were derived are indicated and discussed in the appropriate section(s). Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Identification of Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information was available, MRLs were derived. MRLs are specific for route (inhalation or oral) and duration (acute, intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral - acute, -intermediate, - chronic). These MRLs are not meant to support regulatory action, but to aquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a substance emission, given the concentration of a contaminant in air or the estimated daily dose received via food or water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. MRL users should be familiar with the toxicological information on which the number is based. Section 2.4, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.6, "Interactions with Other Chemicals" and 2.7. "Populations that are Unusually Susceptible" provide important supplemental information. MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology used by the Environmental Protection Agency (EPA) (Barnes and Dourson. 1988; EPA 1989a) to derive reference doses (Rst) for lifetime exposure. A-7 APPENDIX A To derive an MRL, ATSDR generally selects the end point which, in its best judgement. represents the most sensitive human health effect for a given exposure route and duralion. ATSDR cannot make this judgement or derive zm MRL unless infonnation (quzutlitative or qualitative) is available for all potential effects (e.g.. systemic, neurological. and developmental). In order to compare NOAELs and LOAELs for specific end points. all inhalation exposure levels are adjusted for 24hr exposures and all intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted for continous exposure (i.e., 7 days/week). If the information and reliable quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is not available. 21 Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor (UF) of 10 is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors of 10 each are used for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) zmd for interspecies variability (extrapolation from animals to humans). In deriving an MRL. these individual uncertainty factors are multiplied together. The product is then divided into the adjusted inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables. ACGIH ADME atm ATSDR BCF BSC C CDC CEL CERCLA CFR CLP cm CNS d DHEW DHHS DOL ECG EEG EPA EKG F F1 FAO FEMA FIFRA fpm ft FR g GC gen HPLC hr IDLH IARC ILO kkg APPENDIX B ACRONYMS, ABBREVIATIONS, AND SYMBOLS American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion atmosphere Agency for Toxic Substances and Disease Registry bioconcentration factor Board of Scientific Counselors Centigrade Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations Contract Laboratory Program centimeter central nervous system day Department of Health, Education, and Welfare Department of Health and Human Services Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECG Fahrenheit first filial generation Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act feet per minute foot Federal Register gram gas chromatography generation high-performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio kilogram metric ton organic carbon partition coefficient octanol-water partition coefficient liter LC LCLO LC50 LDLo LDso LOAEL LSE m mg min mL mm mmHg mmol mo mppcf MRL MS NIEI—IS NIOSH NIOSHTIC ng nm NHAN ES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL Pg pmol PHS PMR PPb PPm PPt REL RfD RTECS sec SCE SIC SMR B-2 APPENDIX 8 liquid chromatography lethal concentration, low lethal concentration, 50% kill lethal dose, low lethal dose, 50% kill lowest-observed-adverse-effect level Levels of Significant Exposure meter milligram minute milliliter millimeter millimeters of mercury millimole month millions of particles per cubic foot Minimal Risk Level mass spectrometry National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH’s Computerized Information Retrieval System nanogram nanometer National Health and Nutrition Examination Survey nanomole no-observed-adverse-effect level National Occupational Exposure Survey National Occupational Hazard Survey National Priorities List National Research Council National Technical Information Service National Toxicology Program Occupational Safety and Health Administration permissible exposure limit picogram picomole Public Health Service proportionate mortality ratio parts per billion parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification standard mortality ratio STEL STORET TLV TSCA TRI TWA U.S. UF yr WHO wk QquQQIAAIIIVV :1: “B 3-3 APPENDIX B short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average United States uncertainty factor year World Health Organization week greater than greater than or equal to equal to less than less than or equal to percent alpha beta delta gamma micron microgram APPENDIX C PEER REVIEW A peer review panel was assembled for aldrin/dieldrin. The panel consisted of the following members: Dr. William B. Buck, Private Consultant, Consul-Tex, Inc., Tolono, Illinois; Dr. Samuel Epstein, Professor of Environmental and Occupational Medicine, School of Public Health, University of Illinois Medical Center, Chicago, Illinois; Dr. Alan Hall, Private Consultant, Evergreen, Colorado; Dr. Peter Lacouture, Associate Director, Clinical Research, The Purdue Frederick Company; Norwalk, Connecticut; Dr. Fumio Matsumura, Assistant Director, Toxic Substances Program, LEHR Facility, University of California, Davis, California; Dr. Edward Morgan, Assistant Professor, Department of Pharmacology, Emory University, Atlanta, Georgia; and Dr. Raghubir Prasad Sharma, Professor, Chair of the Toxicology Program, Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah. These experts collectively have knowledge of aldrin/dieldrin’s physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and- animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(i)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers’ comments and determined which comments will be included in the profile. A listing of the peer reviewers’ comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile’s final content. The responsibility for the content of this profile lies with the ATSDR. if? US. GOVERNMENT PRINTING OFFICE: 1993 738-201 Wrfléfl’fi‘w E vs? RETURN PUBLI C HEALTH LIBRARY TO —> 42 Warren Hall 642—2511 LOAN PERIOD 1 SEMESTER 2 3 4 5 6 ALL BOOKS MAY BE RECALLED AFTER 7 DAY ALL JOURNALS ARE NON-RENEWABLE Return To desk from which borrowed DUE AS STAMPED BELOW SEMESTER LOAN WAN m2 31993 QI In 'ch TO RECAL! ‘ 1:70 RECAI‘ "613 NHL on 31 REG'DPUBL JAN 03 ' ‘ SEMESTER LOAN AUG 1 9 1995 SUBJECT TO REC/"d-L /,2// 4/ 4'9 FORM NO. DD26-7, 9m, UNIVERSITY OF CAUFORNIA, L 11/94 BERKELEY, CA 94720 PUBLIC HEALTH LiBRARY JAN 0 3 1994 U C. BERKELEY LIBRARIES e «Hummmmnw CUHHBSHBEE