a- - ,. m '1’, xicological oflle ' {C V a fo r ‘ qQ‘VVdm i i CH-LORPYRIFOS .» f V ‘ f Draft for Public Comment Commeni Period Ends: February 20, 19% \ US. DEPARTMENT OF HEALTH & HUMAN SERVICES _ Public Health Service Agency for Toxic Substances and Disease Registry p‘usuc HEALTH mam ‘ ”muff , LIBRARY ’ UNIVERSITY©F H"- DRAFT TOXICOLOGICAL PROFILE FOR CH LORPYRIFOS Prepared by: Research Triangle Institute Under Contract No. 205-93-0606 Prepared for: US. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry August 1995 "*DRAFT FOR PUBLIC COMMENT'” (N L CHLORPYRIFOS m DISCLAIMER M; H mum 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. “"DRAFT FOR PUBLIC COMMENT‘“ CHLORPYRIFOS iii EA tam TM :z rams" Toxicological profiles are revised and republished as necessary, but no less than once every three {3 _‘ _ A 9 years. For information regarding the update status of previously released profiles, contact ATSDR at: l J“ ‘ UPDATE STATEMENT ' W" |. .T Agency for Toxic Substances and Disease Registry Division of Toxicology/'1‘ oxicology Information Branch 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 “"DRAFT FOR PUBLIC COMMENT’“ FOREWORD 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 succinctly characterizes the toxicologic 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 toxicologic 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, that 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 protect public health will be identified by ATSDR and EPA. The focus of the profiles is on health and toxicologic information; therefore, we have included this information in the beginning of the document. Each profile must include the following: (A) The examination, summary, and interpretation of available toxicologic information and epidemiologic evaluations on a hazardous substance in order to ascertain the levels of signifith 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 that present a significant risk to human health of acute, subacute, and chronic health effects. (C) Where appropriate, identification of toxicologic testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. The principal audiences for the toxicological profiles are health professionals at the federal, state, and local levels, interested private sector organizations and groups, and members of the public. We plan to revise these documents in response to public comments and as additional data become available. Therefore, we encourage comments that will make the toxicological profile series of the greatest use. Comments should be sent to: Agency for Toxic Substances and Disease Registry Division of Toxicology Mail Stop E—29 Atlanta, Georgia 30333 vi Foreword The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99—499) which 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 most commonly found at facilities on the CERCLA National Priorities List and that pose the most significant potential threat to human health. as determined by ATSDR and the Environmental Protection Agency (EPA). The availability of the revised priority list of 275 hazardous substances was announced in the Federal Register on February 28. 1994 (59 FR 9486). For prior versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); October 20, 1988 (53 FR 41280); October 26. 1989 (54 FR 43619); October 17, 1990 (55 FR 42067); and October 17. 1991 (56 FR 52166); and October 28, 1992 (57 FR 48801). Section 104(i)(3) of CERCLA, as amended. directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. This profile reflects our assessment of all relevant toxicologic 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. W David Satcher. M.D., Ph.D. Administrator Agency for Toxic Substances and Disease Registry CHLORPYRIFOS vii CONTRIBUTORS CHEMICAL MANAGER(S)/AUTHORS(S): John F. Risher, Ph.D. ATSDR, Division of Toxicology, Atlanta, GA Heman A. Navarro, PhD. Research Triangle Institute, Research Triangle Park, NC THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 1. 2. Green Border Review. Green Border review assures 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 end points. 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. "*DRAFT FOR PUBLIC COMMENT‘“ “35".” .rwawydrm .mmm» .. WM m. “WWW CHLORPYRIFOS ix PEER REVIEW A peer review panel was assembled for chlorpyrifos. The panel consisted of the following members: 1. Dr. William Buck, Professor of Toxicology, University of Illinois, Tolono, IL 61880; 2. Dr. Joel Coats, Professor, Department of Entomology, Iowa State University, Ames, IA 50011; and 3. Dr. Morris Cranmer, Private Consultant, Cranmer & Associates, Little Rock, AR 72212 These experts collectively have knowledge of chlorpyrifos’ physical and chemical properties, toxico— kinetics, 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. "’DRAFT FOR PUBLIC COMMENT*'* CHLORPYRIFOS Xi CONTENTS FOREWORD ............................................................ v CONTRIBUTORS ......................................................... vii PEER REVIEW .......................................................... ix LIST OF FIGURES ....................................................... xv LIST OF TABLES ....................................................... xvii -' 1. PUBLIC HEALTH STATEMENT ........................................... 1 1.1 WHATISCHLORPYRIFOS?................. ......................... 1 1.2 WHAT HAPPENS TO CHLORPYRIFOS WHEN IT ENTERS THE ENVIRONMENT? . 2 1.3 HOW MIGHT I BE EXPOSED TO CHLORPYRIFOS? ........................ 2 1.4 HOW CAN CHLORPYRIFOS ENTER AND LEAVE MY BODY? ............... 3 1.5 HOW CAN CHLORPYRIFOS AFFECT MY HEALTH? ....................... 3 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO CHLORPYRIFOS? ...................................... 4 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 ........................................... 9 2.2.1.1 Death .............................................. 9 2.2.1.2 Systemic Effects ...................................... 9 2.2.1.3 Immunological and Lymphoreticular Effects .................. 13 2.2.1.4 Neurological Effects .................................. 14 2.2.1.5 Reproductive Effects .................................. 15 2.2.1.6 Developmental Effects ................................. 16 2.2.1.7 Genotoxic Effects .................................... 16 2.2.1.8 Cancer ............................................ 16 2.2.2 Oral Exposure .............................................. 16 2.2.2.1 Death ............................................. 16 2.2.2.2 Systemic Effects ..................................... 17 2.2.2.3 Immunological and Lymphoreticular Effects .................. 24 2.2.2.4 Neurological Effects .................................. 24 2.2.2.5 Reproductive Effects .................................. 26 2.2.2.6 Developmental Effects ................................. 27 2.2.2.7 Genotoxic Effects .................................... 28 2.2.2.8 Cancer ............................................ 29 "‘DRAFT FOR PUBLIC COMMENT‘” CHLORPYRIFOS xii 2.2.3 Dermal Exposure ............................................ 25 2.2.3.1 Death ............................................. 25 2.2.3.2 Systemic Effects ..................................... 25 2.2.3.3 Immunological and Lymphoreticular Effects .................. 28 2.2.3.4 Neurological Effects .................................. 28 2.2.3.5 Reproductive Effects .................................. 28 2.2.3.6 Developmental Effects ................................. 29 2.2.3.7 Genotoxic Effects .................................... 29 2.2.3.8 Cancer ............................................ 30 2.3 TOXICOKINETICS .......................................... 30 2.3.1 Absorption ................................................ 30 2.3.1.1 Inhalation Exposure ................................... 30 2.3.1.2 Oral Exposure ....................................... 30 2.3.1.3 Dermal Exposure ..................................... 30 2.3.2 Distribution ................................................ 31 2.3.2.1 Inhalation Exposure ................................... 31 2.3.2.2 Oral Exposure ....................................... 31 2.3.2.3 Dermal Exposure ..................................... 31 2.3.3 Metabolism ................................................ 32 2.3.4 Elimination and Excretion ...................................... 32 2.3.4.1 Inhalation Exposure ................................... 32 2.3.4.2 Oral Exposure ....................................... 33 2.3.4.3 Dermal Exposure ..................................... 33 2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 33 2.4 MECHANISMS OF ACTION ......................................... 35 2.4.1 Pharmacokinetic Mechanisms ................................... 35 2.4.2 Mechanisms of Toxicity ....................................... 36 2.4.3 Animal—to—Human Extrapolations ................................. 37 2.5 RELEVANCE TO PUBLIC HEALTH ................................... 37 - 2.6 BIOMARKERS OF EXPOSURE AND EFFECT ............................ 45 2.6.1 Biomarkers Used to Identify or Quantify Exposure to Chlorpyrifos ......... 46 2.6.2 Biomarkers Used to Characterize Effects Caused by Chlorpyrifos .......... 47 2.7 INTERACTIONS WITH OTHER CHEMICALS ............................ 47 2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ................... 47 2.9 METHODS FOR REDUCING TOXIC EFFECTS ........................... 48 2.9.1 Reducing Peak Absorption Following Exposure ....................... 49 2.9.2 Reducing Body Burden ........................................ 49 2.9.3 Interfering with the Mechanism of Action for Toxic Effects .............. 49 2.10 ADEQUACY OF THE DATABASE .................................... 50 2.10.1 Existing Information on Health Effects of Chlorpyrifos ................... 50 2.10.2 Identification of Data Needs .................................... 51 2.10.3 Ongoing Studies ............................................ 53 3. CHEMICAL AND PHYSICAL INFORMATION ................................ 54 3.1 CHEMICAL IDENTITY ............................................. 54 3.2 PHYSICAL AND CHEMICAL PROPERTIES ............................. 54 *"DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS . xiii 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ....................... 73 4.1 PRODUCTION ................................................... 73 4.2 IMPORT/EXPORT ................................................. 73 4.3 USE ........................................................... 73 4.4 DISPOSAL ......... ' ............................................. 75 5. POTENTIAL FOR HUMAN EXPOSURE ..................................... 77 5.1 OVERVIEW ..................................................... 77 5.2 RELEASES TO THE ENVIRONMENT .................................. 79 5.2.1 Air ...................................................... 79 5.2.2 Water .................................................... 79 5.2.3 Soil ..................................................... 79 5.3 ENVIRONMENTAL FATE ........................................... 80 5.3.1 Transport and Partitioning ..................... ‘ ................. 80 5.3.2 Transformation and Degradation ................................. 83 5.3.2.1 Air ............................................... 83 5.3.2.2 Water ............................................. 84 5.3.2.3 Sediment and Soil .................................... 86 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............ 88 5.4.1 Air ...................................................... 88 5.4.2 Water .................................................... 89 5.4.3 Sediment and Soil ........................................... 90 5.4.4 Other Environmental Media .................................... 90 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ............... 91 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .................. 93 5.7 ADEQUACY OF THE DATABASE .................................... 94 5.7.1 Identification of Data Needs .................................... 94 5.7.2 Ongoing Studies ............................................ 97 ‘ 6. ANALYTICAL METHODS ............................................... 99 6.1 BIOLOGICAL SAMPLES ............................................ 99 6.2 ENVIRONMENTAL SAMPLES ....................................... 102 6.3 ADEQUACY OF THE DATABASE .................................... 112 6.3.1 Identification of Data Needs .................................... 113 6.3.2 Ongoing Studies ............................................ 114 _ 8. REFERENCES ........................................................ 119 9. GLOSSARY ......................................................... 139 APPENDICES A. MINIMAL RISK LEVEL (MRL) WORKSHEETS ........................... A-l B. USER’S GUIDE .................................................. B—l C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS ........................ C-l "*'DRAFT FOR PUBLIC COMMENT““ CHLORPYRIFOS xv 2-2 2-3 2—4 5—1 LIST OF FIGURES Levels of Significant Exposure to Chlorpyrifos - Oral ........................... 21 Proposed Metabolic Pathway for Chlorpyrifos ................................ 39 Conceptual Representation of a Physiologically Based Pharrnacokinetic (PBPK) Model for a Hypothetical Chemical Substance ...................................... 41 Existing Information on Health Effects of Chlorpyrifos .......................... 62 Frequency of NFL Sites With Chlorpyrifos Contamination ......................... 78 Environmental Degredation Pathways of Chlorpyrifos ............................ 85 “"DRAFT FOR PUBLIC COMMENT'" v 1.6.715 CHLORPYRIFOS 2-1 2-2 2-3 3—1 3-2 6—1 6-2 7-1 LIST OF TABLES Levels of Significant Exposure to Chlorpyrifos — Oral ........................... Genotoxicity of Chlorpyrifos in Vivo ....................................... Genotoxicity of Chlorpyrifos in Vitro ...................................... Chemical Identity of Chlorpyrifos .......................................... Physical and Chemical Properties of Chlorpyrifos .............................. Analytical Methods for Determining Chlorpyrifos and Metabolites in BiologicalSamples Analytical Methods for Determining Chlorpyrifos and Transformation Products in Environmental Samples ................................................ Regulations and Guidelines Applicable to Chlorpyrifos .......................... "*DRAFT FOR PUBLIC COMMENT” xvii 18 55 56 70 71 100 103 116 .» W1i.wm,..yq-...wn m a. pm, ., W . gammy“ ... CHLORPYRIFOS 1. PUBLIC HEALTH STATEMENT This public health statement tells you about Chlorpyrifos and the effects of exposure. The Environmental Protection Agency (EPA) has identified 1,416 hazardous waste sites as the most serious in the nation. These sites make up the National Priorities List (NPL) and are targeted for long- term federal clean-up. Chlorpyrifos has been found in at least 7 NPL sites. However, it’s unknown how many NPL sites have been evaluated for this substance. As EPA looks at more sites, the sites with Chlorpyrifos may increase. This is important because exposure to this substance may harm you and because these sites may be sources of exposure. When a substance 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. This release does not always lead to exposure. You can be exposed to a substance only when you come in contact with it by breathing, eating, touching, or drinking. If you are exposed to Chlorpyrifos, many factors determine whether you’ll be harmed. These factors include the dose (how much), the duration (how long), and how you come in contact with it. You must also consider the other chemicals you’re exposed to and your age, sex, diet, family traits, lifestyle, and state of health. 1.1 WHAT IS CHLORPYRIFOS? Chlorpyrifos is an organophosphorus pesticide that is widely used in the home and on the farm. In the home, Chlorpyrifos is used to control cockroaches, fleas, and termites; it is also found in some petflea and tick collars. On the farm, it is used as a dip or spray to control ticks on cattle and as a spray or dust to control crop pests. Chlorpyrifos is a white crystalline solid with a strong odor. It does not mix well with water, so it is usually mixed with oily liquids before it is applied to crops or animals. Chlorpyrifos is the active ingredient of various commercial insecticides including Dursban® and Lorsban®. "*"DRAFT FOR PUBLIC COMMENT*** CHLORPYRIFOS 1. PUBLIC HEALTH STATEMENT See Chapter 3 for more information on the chemical and physical properties of chlorpyrifos. See Chapter 4 for more information on the production and use of chlorpyrifos. 1.2 WHAT HAPPENS TO CHLORPYRIFOS WHEN IT ENTERS THE ENVIRONMENT? Chlorpyrifos intentionally enters the environment through direct application to crops, lawns, domesticated animals, and in the home and workplace. Chlorpyrifos enters the environment unintentionally through volatization, spills, and the disposal of chlorpyrifos waste. Chlorpyrifos that has been applied to the soil generally stays in the area where it has been applied because it sticks tightly to soil particles. Because of this, there is a low chance that chlorpyrifos will be washed off the soil and enter local water systems. Also, since it does not mix well with water, what little chlorpyrifos that does get into the natural waters remains on or near the surface and evaporates. Volatilization is the major way in which chlorpyrifos spreads after it has been applied. Once in the environment (soil, air, or water), chlorpyrifos is broken down by sunlight, bacteria, or other chemical processes. ‘ Please refer to Chapters 4 and 5 for more information. 1.3 HOW MIGHT I BE EXPOSED TO CHLORPYRIFOS? You can be exposed to chlorpyrifos in many places because of its wide range of uses. You can be exposed to chlorpyrifos in your home or office if it has recently been used to control household pests such as fleas or cockroaches. Exposure can also occur outside your home if chlorpyrifos has been applied to the ground around the foundation to control termites. However, possibly harmful levels may persist for long periods of time after it has been applied either inside or outside of the home. Opening windows and doors after chlorpyrifos has been sprayed rapidly lowers its levels in a house. You can also be exposed to chlorpyrifos on the farm. The greatest risk occurs soon after a crop has been sprayed or dusted, because there will be high levels of chlorpyrifos on plants and the ground. The EPA recommends that a 24-hour waiting period be observed before entering fields where chlorpyrifos has been applied. This chemical is also used as a dip or spray to control ticks and other *"DRAFT FOR PUBLIC COMMENT'" up“... CHLORPYRIFOS 3 1. PUBLIC HEALTH STATEMENT parasites on livestock, so exposure could occur during the treatment of the livestock. In addition, there is the risk of exposure to chlorpyrifos when it is being prepared for use. Chlorpyrifos can also be found at waste disposal sites, so exposure to high levels of the pesticide may also occur there. 1.4 HOW CAN CHLORPYRIFOS ENTER AND LEAVE MY BODY? Chlorpyrifos can enter your body through the mouth, lungs, and skin. After being eaten or drunk, chlorpyrifos quickly passes from the intestines to the rest of the body. It can also enter the body through the lungs by breathing chlorpyrifos sprays or dust. When chlorpyrifos enters the body this way, it also passes quickly into the blood. It may also enter the body through the skin, but the chances of being exposed to harmful levels of chlorpyrifos are very low because the amount that gets through the skin is small (about 3% of what was put on the skin). For more information, please refer to Chapter 2. 1.5 HOW CAN CHLORPYRIFOS AFFECT MY HEALTH? Short-term exposure (one day) to low (milligrams) to moderate (grams) levels of chlorpyrifos in people causes dizziness, confusion, salivation, tremors, rapid heart rate, paralysis, and loss of consciousness. Reports in people also show that short—term exposure to chlorpyrifos may cause muscle weakness weeks after the original symptoms have disappeared. This is known as organophosphate-induced distal neuropathy (OPIDN). OPIDN has also been seen in laboratory animals. However, permanent effects of short-term chlorpyrifos exposure in people have not been found. Infants and young children may be at greater risk to the effects of chlorpyrifos because more of it gets through the skin of children than adults, and children cannot get rid of it as fast. Also, women may be at generally higher risk than men because animal studies indicate that females eliminate chlorpyrifos 2—3 times more slowly than males. Work with cell cultures and insects indicates that short-term exposure to relatively high concentrations (micromolar range) of chlorpyrifos may damage DNA, but not enough information exists to say for certain. Also, little or no information exists on the health effects of prenatal, intermediate, and chronic exposure to chlorpyrifos to determine what might be the health risks due to exposure under those conditions. "'DRAFT FOR PUBLIC COMMENT'“ CHLORPYRIFOS 4 1. PUBLIC HEALTH STATEMENT For more information, please refer to Chapter 2. To protect the public from the harmful effects of toxic chemicals and to find ways to treat people who have been harmed, scientists use many tests. One way to see if a chemical will hurt people is to learn how the chemical is absorbed, used, and released by the body; for some chemicals, animal testing may be necessary. Animal testing may also be used to identify health effects such as cancer or birth defects. Without laboratory animals, scientists would lose a basic method to get information needed to make wise decisions to protect public health. Scientists have the responsibility to treat research animals with care and compassion. Laws today protect the welfare of research animals, and scientists must comply with strict animal care guidelines. 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO CHLORPYRIFOS? There is a general test that can be performed to determine if you have been exposed to carbamate or organophosphate pesticides. Those types of pesticides inhibit the activity of acetylcholinesterase, the enzyme responsible for inactivating acetylcholine, the compound ultimately responsible for most of the pesticide-related toxicity. The test measures the activity of the enzyme acetylcholinesterase in the blood or a similar enzyme pseudocholinesterase in the plasma, or both. If enzyme activity is inhibited, then exposure to an organophosphate or carbamate pesticide is suspected. There is also a biochemical test that can determine if you have been specifically exposed to chlorpyrifos. After chlorpyrifos enters the body, it is changed by the liver into other forms of the compound that may or may not be less toxic than the original material. The major nontoxic chlorpyrifos metabolic product formed by the liver is 3,5,6-trichloro-2—pyridinol or TCP. TCP is primarily eliminated from the body in the urine. Since TCP is only produced from chlorpyrifos, it is a unique marker for chlorpyrifos exposure. TCP can be detected in the urine using readily available laboratory equipment. The length of time after exposure that TCP can be detected in the urine depends on how big the exposure was. Typically, TCP can be found in the urine for several days after exposure to chlorpyrifos. For more information, please refer to Chapter 2. *“DRAFT FOR PUBLIC COMMENT" W. . 0.. 7m. WW, -.t,......w...»m CHLORF’YRIFOS 1. PUBLIC HEALTH STATEMENT 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The federal government develops regulations and recommendations to protect public health. Regulations Q11; be enforced by law. Federal agencies that develop regulations for toxic substances include the Environmental Protection Agency (EPA), the Occupational Safety and Health Administration (OSHA), and the Food and Drug Administration (FDA). Recommendations provide valuable guidelines to protect public health but m be enforced by law. Federal organizations that develop recommendations for toxic substances include the Agency for Toxic Substances and Disease Registry (ATSDR) and the National Institute for Occupational Safety and Health (NIOSH). Regulations and recommendations can be expressed in not-to-exceed levels in air, water, soil, or food that are usually based on levels that affect animals, then they are adjusted to help protect people. Sometimes these not—to—exceed levels differ among federal organizations because of different exposure times (an 8-hour workday or a 24-hour day), the use of different animal studies, or other factors. Recommendations and regulations are also periodically updated as more information becomes available. For the most current information, check with the federal agency or organization that provides it. Some regulations and recommendations for chlorpyrifos include the following: - Chlorpyrifos is one of a list of chemicals regulated under "The Emergency Planning and Community Right—to—Know Act of 1986" (EPCRA). This requires owners and operators of certain facilities that manufacture, import, process, or otherwise use the chemicals on this list to report annually their release of those chemicals to any environmental media. 0 Chlorpyrifos is designated a hazardous substance and subject to regulations in the Federal Water Pollution Act and the Clean Water Act. 0 EPA has established tolerances for chlorpyrifos in raw agricultural commodities, foods, and animal feeds. See Chapter 7 for specific regulatory values for chlorpyrifos. '"DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 1. PUBLIC HEALTH STATEMENT 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, Mailstop E-29 Atlanta, GA 30333 * Information line and technical assistance Phone: (404) 639-6000 Fax: (404) 639-6315 or 6324 ATSDR can also tell you the location of occupational and environmental health clinics. These clinics specialize in recognizing, evaluating, and treating illnesses resulting from exposure to hazardous substances. * To order toxicological profiles, contact: National Technical Information Service ' 5285 Port Royal Road Springfield, VA 2216] Phone: (800) 553-6847 or (703) 487—4650 "’DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 7 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 chlorpyrifos. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health guidance. A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals and others 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, reproductive, developmental, 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. "Serious" effects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a considerable amount of judgment may be required in establishing whether an end point should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be insufficient data to decide whether the effect is indicative of significant dysfunction. However, the Agency has established guidelines and policies that are used to classify these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt “*DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 8 2. HEALTH EFFECTS at distinguishing between "less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is considered to be important because it helps the users of the profiles to identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should also help in determining 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 Levels of Significant Exposure (LSE) tables and figures may differ depending on the user’s perspective. Public health officials and others 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 (NOAELs) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for chlorpyrifos. An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal exposure. Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), 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. A User’s Guide has been provided at the end of this profile (see Appendix B). This guide should aid in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. "*DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 9 2. HEALTH EFFECTS Chlorpyrifos (0,0-diethyl O-[3,5,6-trichloro-2-pyridyl] phosphorothioate) is a clear to white crystalline solid pesticide (EPA 1988b) with a strong mercaptan odor (Worthing 1987). Chlorpyrifos is widely used to control insects in the home, workplace, and in agriculture; it is also found in at least 7 hazardous waste sites that have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 1995). Thus, the potential for chlorpyrifos exposure is high. 2.2.1 Inhalation Exposure 2.2.1.1 Death No information was found concerning the potential for death in humans following acute-, intermediate-, or chronic-duration exposure. For animals, no data were located for death following intermediate or chronic exposure to chlorpyrifos, but limited LD50 (lethal dose, 50% kill) studies were available. The LD50 for acute inhalation exposure to chlorpyrifos aerosol was determined for mice and female rats (Berteau and Deen 1978). In mice, an LD50 of 94 mg/kg was determined after whole-body inhalation exposure to 6.7—7.9 mg/L chlorpyrifos in 65% xylene. In that study, the dose range was achieved by varying the length of exposure from 27 to 50 minutes. Virgin female Sprague-Dawley rats were similarly exposed to 5.9—7.5 mg/L chlorpyrifos in 65% xylene, and an acute exposure inhalation LD50 of 78 mg/kg was determined by varying the exposure duration from 48 to 61 minutes. 2.2.1.2 Systemic Effects Respiratory Effects. The effects of acute inhalation exposure to chlorpyrifos were reported for 11 persons exposed to chlorpyrifos primarily in the home or workplace following professional application of the pesticide (Thrasher et al. 1993). The approximate dose received and the length of time between exposure and the onset of symptoms was not known for any of the patients. The pesticide-exposed persons reported an increase in flu—like symptoms and upper and lower respiratory problems when compared to 60 (28 male and 32 female) control subjects—healthy home dwellers with or without exposure to formaldehyde. *"DRAFT FOR PUBLIC COMMENT"* CHLORPYRIFOS 10 2. HEALTH EFFECTS No information was located concerning the potential respiratory effects of inhaled chlorpyrifos in humans following intermediate- or chronic-duration exposure. The effects of intermediate-duration exposure to chlorpyrifos on lung histology were assessed in male and female rats (Corley et al. 1989). The rats were exposed nose-only to 0, 0.075, 0.148, or 0.295 mg/m3 chlorpyrifos for 6 hours per day, 5 days per week for 13 weeks. Histopathological evaluation of lungs from the control and 0.295 mg/m3 groups revealed normal lung histology. The exposure levels in this study did not inhibit erythrocyte or plasma cholinesterase activity. No data were located for respiratory effects in animals following acute or chronic exposure to chlorpyrifos. Cardiovascular Effects. No information was located concerning the potential cardiovascular effects of inhaled chlorpyrifos in humans or animals following acute—, intermediate-, or chronic- duration exposure. Gastrointestinal EffECts. Gastrointestinal effects following acute exposure to chlorpyrifos have been observed in humans (Kaplan et a1. 1993; Thrasher et al. 1993). A family became ill and complained of feeling nauseated after their house was sprayed with Dursban® (Kaplan et al. 1993). The time from exposure to the onset of symptoms was not reported. Nonspecific gastrointestinal disturbances were also reported by 11 individuals acutely exposed to unknown quantities of chlorpyrifos (Thrasher et al. 1993). Intermediate exposure to chlorpyrifos also causes gastrointestinal distress in humans. Diarrhea developed in a 40-year-old male exterminator who was repeatedly exposed to Dursban® in a closed environment over a 6—month interval (Kaplan et al. 1993). Erythrocyte cholinesterase levels determined at the onset of symptoms were initially low (value not given). The diarrhea probably resulted from a stimulation of parasympathetic nervous system- dependent physiological processes as a consequence of cholinesterase inhibition. Stimulation of the parasympathetic nervous system increases gastrointestinal motility, thereby decreasing food transit times. The net result is that there is less time for water to be absorbed by the colon and diarrhea results. No information was located concerning the potential gastrointestinal effects of inhaled chlorpyrifos in humans following chronic exposure. "*DRAFT FOR PUBLIC COMMENT"* CHLORPYRIFOS 11 2. HEALTH EFFECTS No data were located for gastrointestinal effects for animals following acute—, intermediate-, or chronic-duration inhalation exposure to chlorpyrifos. Hematological Effects. A 33-year-old man acutely exposed to an undetermined amount of chlorpyrifos after it was sprayed into the ventilation system of his place of work was examined 2 weeks later because of neurological problems (Kaplan et a1. 1993). Routine blood chemistry and hematological evaluations were performed and were found to be within normal limits. Similar tests performed on a 42-year-old woman exposed for 3 weeks to Dursban® sprayed in her basement were also negative. No information was located concerning the potential hematological effects of chronic exposure to inhaled chlorpyrifos in humans. No information was located concerning the potential hematological effects of inhaled chlorpyrifos after acute-, intermediate-, or chronic-duration exposure in animals. Musculoskeletal Effects. In humans, acute-duration exposure to undetermined amounts of chlorpyrifos was reported to produce unspecified muscle pain (Thrasher et a1. 1993) and muscle cramps (Kaplan et a1. 1993). Additionally, muscle twitching was reported by a 40—year-old exterminator exposed to unspecified amounts of chlorpyrifos over a 6-month period (Kaplan et a1. 1993). No information was located concerning musculoskeletal effects of inhaled chlorpyrifos in humans following chronic exposure. For animals, no data were located for musculoskeletal effects following acute—, intermediate-, or chronic-duration exposure to chlorpyrifos. Hepatic Effects. No information was located concerning hepatic effects of inhaled chlorpyrifos in humans following acute-, intermediate-, or chronic-duration exposure. The effect of intermediate—duration exposure to chlorpyrifos on liver histology was assessed in male and female rats (Corley et a1. 1989). The rats were exposed nose-only to 0, 0.075, 0.148, or 0.295 mg/m3 chlorpyrifos for 6 hours per day, 5 days per week for 13 weeks. Histopathological evaluation of livers from the control and 0.295 mg/m‘3 groups revealed normal liver histology in the chlorpyrifos-treated rats. The exposure levels in this study were not sufficient to inhibit erythrocyte or "*DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 12 2. HEALTH EFFECTS plasma cholinesterase. No data were located for hepatic effects in animals following acute- or chronic- duration exposure to chlorpyrifos. Renal Effects. The acute-duration exposure of a 33-year-old male to an unspecified amount of chlorpyrifos that was sprayed into a workplace ventilation system caused an increase in urinary frequency (Kaplan et al. 1993). Intermediate (3 months) inhalation exposure to undetermined amounts of chlorpyrifos in humans was assessed in a survey of pesticide applicators working in a variety of settings (Ames et al. 1989). Those applicators reported an unspecified decrease in urinary frequency. No information concerning the potential renal effects of inhaled chlorpyrifos in humans following chronic exposure was located. In animals, the effects of intermediate exposure to chlorpyrifos on urine chemistry were assessed in male and female rats (Corley et al. 1989). The rats were exposed nose-only to 0, 0.075, 0.148, or 0.295 mg/m3 chlorpyrifos for 6 hours per day, 5 days per week for 13 weeks. Urinary chemistry in the treated groups was comparable to controls. The exposure levels in this study were not sufficient to inhibit erythrocyte or plasma cholinesterase. No data were located in animals for renal effects following acute- or chronic-duration exposure to chlorpyrifos. Dermal Effects. The intermediate inhalation exposure to undetermined amounts of chlorpyrifos in humans was assessed in a survey of pesticide applicators working in a variety of settings (Ames et al. 1989). Those applicators reported an unspecified increase in skin flushing. No information was located concerning the potential dermal effects of inhaled chlorpyrifos in humans following acute- or chronic-duration exposure. For animals, no data were located for dermal effects following acute-, intermediate-, or chronic- duration inhalation exposure to chlorpyrifos. Ocular Effects. The intermediate exposure to an undetermined amount of chlorpyrifos caused an unspecified increase in tearing in a 40-year-old male pesticide applicator repeatedly exposed to Dursban® over a 6-month period (Kaplan et al. 1993,). Additionally, intermediate (3 months) inhalation exposure to undetermined amounts of chlorpyrifos in humans was assessed in a survey of ""DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS , 13 2. HEALTH EFFECTS pesticide applicators working in a variety of settings (Ames et a1. 1989). Those applicators reported an unspecified increase in blurred vision. No information was located concerning potential ocular effects of inhaled chlorpyrifos in humans following acute— or chronic-duration exposure. For animals, no data were located for ocular effects following acute-, intermediate-, or chronic-duration exposure to chlorpyrifos. Body Weight Effects. No information was located concerning the effects on body weight of inhaled chlorpyrifos in humans following acute-, intermediate-, or chronic-duration exposure. The effects of intermediate-duration exposure to chlorpyrifos on body weight were assessed in male and female rats (Corley et a1. 1989). The rats were exposed nose-only to 0, 0.075, 0.148, or 0.295 mg/m3 chlorpyrifos for 6 hours per day, 5 days per week for 13 weeks. Body weight was not affected by any dose of chlorpyrifos. The exposure levels in this study were not sufficient to inhibit erythrocyte or plasma cholinesterase. No data were located for body weight effects following acute- or chronic-duration exposure to chlorpyrifos. 2.2.1.3 Immunological and Lymphoreticular Effects The effects of acute-duration inhalation exposure to chlorpyrifos were reported for 11 persons exposed to chlorpyrifos primarily in the home or work place following professional application of the pesticide (Thrasher et al. 1993). The approximate dose received and the length of time following exposure were not known for any of the patients. Examination of blood taken from the chlorpyrifos-exposed persons indicated that there were changes in some lymphocyte subtypes when compared to 60 (28 male and 32 female) control subjects, healthy home dwellers with or without exposure to formaldehyde. The presence of autoantibodies to smooth muscle, parietal cells, brush border, mitochondria, or nuclei was also determined. Analysis of the blood revealed a 300% increase in the mean absolute counts of CD26 cells and a decrease in the relative percentages of CD5 (11%) and CD4 (7%) lymphocytes. Additionally, 83% of the chlorpyrifos—exposed individuals had increased levels (300—1,200%) of circulating autoantibodies to at least one of the cell types or organelles (except mitochondria) listed above, and 25% of the chlorpyrifos-exposed patients had elevated autoantibodies to three or more of the cell types or "'DRAFT FOR PUBLIC COMMENT'“ CHLORPYRIFOS 14 2. HEALTH EFFECTS organelles, compared to 0—3.7% in the control group. The authors suggested that the increase in autoantibodies was due to chlorpyrifos-induced tissue damage. No information was located concerning potential immunological and lymphoreticular effects of inhaled chlorpyrifos in humans following intermediate- or chronic-duration exposure. No data were located for immunological and lymphoreticular effects in animals following acute-, intermediate-, or chronic-duration exposure to chlorpyrifos. 2.2.1.4 Neurological Effects The neurological symptoms associated with chlorpyrifos exposure result from its inhibition of acetyl- cholinesterase and the subsequent cholinergic overstimulation. In adults and children, acute-duration inhalation exposure to chlorpyrifos is associated with paresthesia, and lightheadedness (Kaplan et a1. 1993). Headache is also a common occurrence. Additionally, acute chlorpyrifos exposure may produce signs of neurological toxicity weeks or months after the initial symptoms have resolved. For example, a family which became ill after chlorpyrifos was applied in their home initially presented with headaches, nausea, and muscle cramps (Kaplan et al. 1993). However, numbness, paresthesia (most prominent in the legs), and memory impairment were reported by the family one month later. The children also showed a decline in scholastic performance that lasted for approximately six months. Neurological exams conducted six months post-exposure revealed mild short-term memory loss on all routine mental status testing of recall of multiple objects. Neuropsychological testing was declined although all other neurological exams were normal. Nerve conduction studies revealed low-amplitude sural nerve action potentials in all family members. Motor and upper-extremity sensory nerve action potential were normal. Sural nerve amplitudes in all but one family member had returned to normal six months later. The aforementioned symptoms might have been due to a multiple route exposure. Although inhalation was the most likely route, the family could also have been exposed dermally. Other patients in the Kaplan et a1. (1993) report presented with similar delayed neurotoxicity that resolved after a period of weeks or months. Intermediate-duration inhalation exposure to chlorpyrifos in humans may produce delayed neurotoxicity similar to that observed after acute-duration exposure (Kaplan et a1. 1993). For example, a neurological evaluation conducted 6 weeks after a man left the hospital for treatment of chlorpyrifos- *“DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 15 2. HEALTH EFFECTS related toxicity revealed sensory loss as well as mild distal weakness and areflexia in the lower extremities. Nerve conduction studies and quantitative sensory threshold studies revealed changes consistent with peripheral neuropathy of the distal axonopathy type._ However, follow-up one year later revealed normalization of the results of the neurological examination, nerve conduction studies, quantitative sensory threshold studies and remission of all symptoms. No information was located concerning potential neurological effects of inhaled chlorpyrifos in humans following chronic exposure. In female mice, acute—duration inhalation exposure to 95.6 mg/kg chlorpyrifos (total dose received during 5 hours of exposure) caused an approximately 90% decrease in plasma cholinesterase 3 days after exposure (Berteau and 'Deen 1978). Fourteen days after exposure, plasma cholinesterase returned to within 20% of predosing levels. The effects of intermediate-duration exposure to chlorpyrifos on brain weight and brain cholinesterase were assessed in male and female rats (Corley et al. 1989). The rats were exposed nose—only to 0, 0.075, 0.148, or 0.295 mg/m3 chlorpyrifos for 6 hours per day, 5 days per week for 13 weeks. Brain weight and cholinesterase levels were not affected by any dose of chlorpyrifos. The concentrations of chlorpyrifos used in this study were not sufficient to inhibit erythrocyte or plasma cholinesterase activity. No data were located for neurological effects in animals following chronic-duration exposure to chlorpyrifos. 2.2.1.5 Reproductive Effects No information was located concerning potential reproductive effects of inhaled chlorpyrifos in humans following acute-, intermediate-, or chronic-duration exposure. In animals, the effect of intermediate exposure to chlorpyrifos on testicular weight and histology was assessed in male rats (Corley et al. 1989). The rats were exposed nose-only to O, 0.075, 0.148, or 0.295 mg/m3 chlorpyrifos for 6 hours per day, 5 days per week for 13 weeks. No effects of treatment on testes weight or histology were detected. The air concentrations of chlorpyrifos used in this study were not sufficient to inhibit erythrocyte or plasma cholinesterase activity. No data were located for reproductive effects in animals following acute— or chronic-duration exposure to chlorpyrifos. ""DRAFT FOR PUBLIC COMMENT**' CHLORPYRIFOS 16 2. HEALTH EFFECTS 2.2.1.6 Developmental Effects No information was located concerning potential developmental effects of inhaled chlorpyrifos in humans or animals following acute-, intermediate—, or chronic-duration exposure. 2.2.1.7 Genotoxic Effects No information was located concerning potential genotoxic effects of inhaled chlorpyrifos in humans or animals following acute-, intermediate-, or chronic—duration exposure. Genotoxicity studies are also discussed in Section 2.5. 2.2.1.8 Cancer No information was located concerning the potential cancer risk of inhaled chlorpyrifos in humans or animals following acute—, intermediate-, or chronic-duration exposure. 2.2.2 Oral Exposure 2.2.2.1 Death No information was found concerning the potential for death in humans following acute-, intermediate-, or chronic—duration oral exposure. Acute oral LD50 has been assessed in rodents (El-Sebae et a1. 1978; Gaines 1969). In rats, chlorpyrifos appears to be more toxic to females than males. Gaines (1969) reported an LD50 of 82 mg/kg for female rats and an LD50 of 155 mg/kg for males. An LD50 of 60 mg/kg has been determined for mice (unspecified gender) (El-Sebae et al. 1978). In pregnant mice, 25 mg/kg/day chlorpyrifos administered from days 6 to 15 of gestation caused death in 4 of 47 of the treated mice (Deacon et al. 1980); no death was observed at 10 mg/kg/day chlorpyrifos. No data were located for death in animals following intermediate— or chronic-duration exposure to chlorpyrifos. "*DRAFT FOR PUBLIC COMMENT**' CHLORF’YRlFOS 17 2. HEALTH EFFECTS The gender-dependent toxicity of chlorpyrifos may be due to an increased rate of extrahepatic detoxification of the pesticide in males. A complete discussion of this phenomenon may be found in Section 2.3, Toxicokinetics, of this profile. The LOAEL and LD50 values for lethality in each reliable study for each species and duration category are shown in Table 2—1 and Figure 2—1. 2.2.2.2 Systemic Effects No studies were located concerning the potential gastrointestinal, hematological, renal, or dermal effects in humans or animals following acute-, intermediate-, or chronic-duration oral exposure to chlorpyrifos. The highest NOAEL value and all LOAEL values for systemic effects in each reliable study for each species and duration category are shown in Table 2—1 and Figure 2-1. Respiratory Effects. In humans, acute-duration oral exposure to chlorpyrifos has been shown to cause respiratory distress. A 3—year—old boy was taken to the hospital in respiratory distress following the ingestion of an unknown amount of chlorpyrifos (Aiuto et a1. 1993). He lapsed into a coma and was placed on a respirator. After three days, the endotracheal tube was removed, but the boy soon developed severe stridor and respiratory distress. Upper airway edema was also evident. It should be noted that stridor often develops in children after they are removed from artificial respirators. Stridor recurred, but responded well to aerosolized racemic epinephrine and cool mist. An acute episode of stridor that did not respond to the aforementioned treatment occurred on day 11 of hospitalization. The airway appeared normal after direct laryngoscopy and bronchoscopy. Bilateral vocal cord paralysis was noted. All respiratory symptoms had resolved by day 52 of hospitalization. Similar symptoms were reported in a 5-year—old girl who drank an undetermined amount of Rid A Bug®, a pesticide preparation containing chlorpyrifos. When she arrived at the hospital, she presented with slow and labored breathing, wheezing, and copious secretions in the nose and mouth that required frequent suctioning (Selden and Curry 1987). The symptoms resolved by day 6 of hospitalization. Respiratory distress was also observed in an adult following acute oral exposure to chlorpyrifos (Lotti et a1. 1986). No information was found concerning the potential for respiratory effects in humans following intermediate- or chronic—duration oral exposure. ”*DRAFT FOR PUBLIC COMMENT'“ ...J.N3WWOO OlWBfid 80:] .L-JVHC]... TABLE 2-1. Levels of Significant Exposure to Chlorpyrifos - Oral Exposure! LOAEL a Duratlonl Key to Specles/ Frequency NOAEL Less Serious Serlous “9“Ire (5mm) (Speclflc Route) 3’3““ (meme/day) (mg/kg/dav) (mg/kglday) Reference ACUTE EXPOSURE Death 1 Rat once 82 F (L050) Gaines 1969 (Sherman) (GO) 155 M (”350) 2 Mouse Gd 6-15 25 F (4/47 died) Deacon etal. 1980 (CF-1) 1x/d (GO) Systemic 3 Mouse Gd 6-15 Hepatic 25 F Deacon et al. 1980 (CF-1) 1x/d (GO) Bd Wt 25 F (14% mean body weight gain decrease Gd 6-17) 4 Mouse Gd 6-15 Hepatic 10 F Deacon et al. 1980 (CF-1) 1x/d (GO) Bd Wt 10 F Neurological 5 Human 9 d 0.03b M 0.1 M (runny nose; blurred vision, Coulston etal. (C) with 65% decreased plasma 1972 cholinesterase activity) 6 Mouse Gd 6-15 1 F 25 F (symptoms of severe ChE Deacon et al. 1980 (CF-1) 1x/d inhibition in 32/47 mice) (GO) 7 M0039 Gd 6-15 10 F Deacon et al. 1980 (CF-1) 1x/d (GO) 3103333 Hl'IVEH ’3 SOdIHAdHOWHO 8i ...J.N3WWOO Ol'lflfld 80:! JJVUO... Exposure! TABLE 2-1. Levels of Significant Exposure to Chlorpyrifos - Oral (continued) LOAEL . Duration] 'jiey to 8;”ch Frequency NOAEL Less Serious Serious gure ( "I I1) (Speclflc Route) System (mg/kgldtly) (mglkg/day) (mg/kgday) Reference 8 Mouse Gd 6, 6-10, 10 F (40-43% decreased Deacon et al. 1980 (CF-1) or 6-15 erythrocyte ChE all time 1x/d points; 95-97% (Go) decreased plasma ChE all time points) 9 Mouse Gd 6, 6-10, 0.1 F 1 F (25-29% decreased Deacon et al. 1980 (CF-1) or 6-15 erythrocyte ChE Gds 1x/d 6-10 and 6-15; 41-75% ((30) decreased plasma ChE all days) 10 Cat once 40 M (hypersalivation, muscular Hooser et al. 1988 (Domestic (90) tremors, ataxia) Short-hair) 11 Cat once 40 M (hypersalivation, tremors, Hooser et al. 1988 (Domestic ((30) 71% decreased plasma Short-halr) ChE actwtty) Reproductive 12 Mouse Gd 6-15 10 F Deacon et al. 1980 (CF-1) 1x/d (GO) _ 13 Mouse Gd 6-15 25 F Deacon etal. 1980 (CF-1) 1x/d (GO) Developmental 14 Mouse Gd 6-15 10 (35% decreased fetal Deacon el al. 1980 (CF-1) 1x/d homogenate ChE (Go) activity) $103333 HJJVBH 'Z SOdIHAdUOWHO 6L ....LN3WWOO onand 80d .ldVHCl... TABLE 2-1. Levels of Significant Exposure to Chlorpyrifos - Oral (continued) Exposure] a Duration! LOAEL Key ‘0 599d”, FTOQWPCY NOAEL Less Serious Serious ""9“re (5mm) (Specific Route) SW9") (mglkg/day) (mg/kg/day) (mg/kglday) "mm“ INTERMEDIATE EXPOSURE Neurological y 15 Human 20 d 0.03 0 M (C) 16 Hen 90 d (Leghorn) 1X/d (C) 10 F (extreme debilitation. weakness and lethargy 35-60 days postdosing) Coulston et al. 1 972 Francis et al. 1985 aThe number corresponds to entries in Figure 2-1. bUsed to derive an acute oral minimal risk level (MRL) of 0.003 mg/kg/day; dose divided by an uncertainty factor of 10 for human variability. cUsed to derive an intermediate oral MFiL of 0.003 mg/kg/day; dose divided by an uncertainty factor of 10 for human variability. Bd Wt = body weight; (C) = capsule; ChE = cholinesterase; d = day(s); F = female; Gd = gestational day; (GO) = gavage in oil; LD50 = lethal dose. 50% kill; LOAEL = lowest-observable-adverse-effect level; M = male; NOAEL = no—observable-adverse-efiect level; NS = not specified; x = times $103533 HJJVBH 'Z SOdIUAdUO'lHO OZ ...J.N3WWOO Ql'lafld 80:! ldVHCl... Figure 2-1. List of Significant Exposures to Chlorpyrifos - Oral Acute (s 14 days) SOdIUAdHOWHO 8133353 Hl’lVBH '3 S stemic \ y t \ Q, 63’ o 0 0°-’ 6° 0Q ® \\ & o - e} /k /d 0” «790 05\ 6" e9" 6“ (mg 9 ay) 0 ‘3‘ q; es Q— 0 100 _ I 10c 11c 1r 3m 3m 6m . . 13m 2 0 4m 04m . 7m 8m 12m 0 14m 10 —~ m 0 O O O O 0 6m 1 — O 5 9m Ke 0.1 —— A O y 5 I LD50 r = Rat . , A m = Mouse . LOAEL for serious effects (animals) : C = Cat 0 LOAEL for less serious effects (animals) 0‘01 I x = Chicken 0 NOAEL (animals) : A LOAEL for serious effects (human) V A NOAEL (humans) 0.001 — ' . , . ‘ Minimal risk level for effects The number next to each point Q/ other than cancer corresponds to entries in Table 2-2‘ 0.0001 ”— L3 ....LN3WWOO onend 80:! LdVHCl... Figure 2-1. List of Significant Exposures to Chlorpyrifos - Oral (continued) Intemiediate (1 5-364 days) (mg/kg/day) 100 10 0.1 0.01 0.001 0.0001 (-——-i>a Key r = Rat I LD50 : Minimal risk level for effects th th . m = Mouse . LOAEL for serious effects (animals) Q1 0 er a" cancer c = Cat 0 LOAEL for less serious effects (animals) X = Chicken 0 NOAEL (animals) The number next to each ' t d t A LOAEL for serious effects (human) gifbfififig 2:; A. NOAEL (humans) $103553 Hl'IVBH 'Z SOleAdHO'lHO 33 CHLORPYRIFOS 23 2. HEALTH EFFECTS No data were located for respiratory effects in animals following acute-, intermediate-, or chronic- duration oral exposure to chlorpyrifos. Cardiovascular Effects. Acute oral exposure to chlorpyrifos in humans has been shown to cause tachycardia (Aiuto et al. 1993; Selden and Curry 1987). Although these studies only found tachycardia, the initial response after exposure to an acetylcholinesterase inhibitor is likely to be bradycardia because of stimulation of muscarinic receptors in the heart. No information was found concerning the potential for cardiovascular effects in humans following intermediate- or chronic— duration oral exposure to chlorpyrifos. No data were located for cardiovascular effects in animals following acute-, intermediate-, or chronic- duration oral exposure to chlorpyrifos. Musculoskeletal Effects. Acute oral exposure to an undetermined amount of chlorpyrifos caused increased muscle tone in a 23-year-old woman (Joubert et al. 1984), fasciculations in an 42—year-old male, and vocal chord paralysis in a 3-year—old boy who swallowed an undetermined amount of chlorpyrifos (Aiuto et al. 1993). No information was found concerning the potential for musculoskeletal effects in humans following intermediate- or chronic—duration oral exposure to chlorpyrifos. No data were located for musculoskeletal effects in animals following acute-, intermediate—, or chronic— duration oral exposure to chlorpyrifos. Hepatic Effects. No information was found concerning the potential for hepatic effects in humans following acute-, intermediate-, or chronic-duration oral exposure to chlorpyrifos. The effects on liver weight and relative liver weight (liver weight/body weight) were assessed in pregnant mice following acute oral exposure to doses as high as 25 mg/kg chlorpyrifos from gestational days 6—15 (Deacon et a1. 1980). Liver weight and relative liver weight determined on gestational day 18 were comparable to controls in all treatment groups. No data were located for hepatic effects in animals following intermediate or chronic oral exposure to chlorpyrifos. "*DRAFT FOR PUBLIC COMMENT**‘ CHLORPYRIFOS 24 2. HEALTH EFFECTS Body Weight Effects. No information was found concerning the potential for effects on body weight in humans following acute—, intermediate—, or chronic-duration oral exposure to chlorpyrifos. The effects on body weight and body weight gain were assessed in pregnant mice following acute oral exposure to doses as high as 25 mg/kg chlorpyrifos from gestational days 6—15 (Deacon et a1. 1980). A statistically significant decrease in mean body weight gain for gestation days 10—15 (33.3%) and overall (gestational days 6-17; 14%) was observed in animals exposed to 25 mg/kg chlorpyrifos. The body weight gain of dams exposed to 1 or 10 mg/kg chlorpyrifos was comparable to controls. Additionally, body weights determined on gestational day 18 for all the treatment groups were similar to control values. No data were located for body weight effects in animals following intermediate- or chronic—duration oral exposure to chlorpyrifos. Ocular Effects. No information was found concerning the potential for ocular effects in humans following intermediate- or chronic-duration oral exposure to chlorpyrifos. Acute-duration exposure in children (Aiuto et al. 1993; Selden and Curry 1987) and adults (Joubert et al. 1984; Lotti et a1. 1986) causes miosis. No data were located for ocular effects in animals following acute-, intermediate-, or chronic-duration oral exposure to chlorpyrifos. 2.2.2.3 Immunological and Lymphoreticular Effects No information was located concerning the potential immunological and lymphoreticular effects of chlorpyrifos in humans or animals following acute-, intermediate-, or chronic-duration oral exposure. 2.2.2.4 Neurological Effects In humans, acute oral exposure to 0.10 mg/kg/day of chlorpyrifos for 9 days has been reported to inhibit plasma cholinesterase activity 66% (Coulston et al. 1972). Additionally, acute oral exposure to undetermined amounts of chlorpyrifos has been reported to inhibit both erythrocyte and plasma cholinesterase activity 78—95% (Joubert et a1. 1984; Selden and Curry 1987). This level of inhibition was sufficient to cause life-threatening cholinergic symptoms requiring hospitalization. Acute oral "‘DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 25 2. HEALTH EFFECTS exposure to undetermined amounts of chlorpyrifos caused stupor in a 23—year-old woman (Joubert et a1. 1984), seizure-like motor activity in a 5-year—old girl (Selden and Curry 1987), and coma in a 42—year-old man (Lotti et al. 1986) and a 3—year-old boy (Aiuto et a1. 1993). Additionally, a variety of other symptoms is associated with acute chlorpyrifos exposure. For example, miosis, muscle twitching and fasciculations, hyper- or hyporeflexia, lacrimation, salivation, sweating, bronchorrhea, diaphoresis, and coreo-athetotic motions have all been observed following acute chlorpyrifos exposure (Aiuto et al. 1993; Joubert et al. 1984; Selden and Curry 1987). Similar chlorpyrifos-related effects have been observed for mice at 25 mg/kg, but not at 10 mg/kg chlorpyrifos (Deacon et a1. 1980); in cats at 40 mg/kg (Hooser et al. 1988); and in hens at 90 mg/kg (Capodicasa et al. 1991). Plasma and erythrocyte cholinesterase activity in humans following intermediate oral exposure to doses up to 0.03 mg/kg/day chlorpyrifos for 20 days were unaffected (Coulston et a1. 1972). No information was found concerning the potential for neurological effects in humans following chronic-duration oral exposure to chlorpyrifos. In cats, 40 mg/kg chlorpyrifos caused a 43—57% decrease in whole blood acetylcholinesterase activity and a 71% decreased plasma cholinesterase activity (Hooser et al. 1988). Female CF—l mice were exposed by gavage to 1, 10, or 25 mg/kg/day Dursban P® (96.8% chlorpyrifos) as a solution in cottonseed oil on day 6, days 6—10, or days 6—15 of gestation (Deacon et al. 1980). Controls received cottonseed oil alone. Five hours after the final dosing (days 6, 10, or 15 of gestation), blood was obtained via cardiac puncture, and plasma and erythrocyte cholinesterase activities determined. Plasma and erythrocyte cholinesterase levels were significantly decreased from control values among mice given 10 or 25 mg/kg chlorpyrifos on day 6 (plasma: 95 and 97% decrease, respectively; erythrocyte: 40 and 20%, respectively) and, days 6—10 (plasma: 97 and 99%, respectively; erythrocyte: 43 and 71%, respectively), or days 6—15 of gestation (plasma: 96 and 98%, respectively; erythrocyte: 43 and 57%, respectively). Plasma cholinesterase levels were significantly reduced among mice given 1 mg/kg chlorpyrifos during the same time intervals (69, 78, and 85%, respectively). Erythrocyte cholinesterase levels were also reduced (43%) after 1 mg/kg chlorpyrifos, but only after exposure on gestational days 6—10 (Deacon et al. 1980). In a concurrent study of cholinesterase inhibition using dosages of 0.1, 1.0, and 10.0 mg/kg/day, Deacon et al. (1980) determined a no effect level for cholinesterase inhibition to be 0.1 mg/kg/day. In humans, acute oral exposure to undetermined amounts of chlorpyrifos has been shown to cause transient distal polyneuropathies that eventually resolve after termination of the exposure (Aiuto et a1. "‘"DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 26 2. HEALTH EFFECTS 1993; Lotti et al. 1986). Acute oral exposure to undetermined amounts of chlorpyrifos has also been reported to cause transient (Aiuto et al. 1993) and persistent delayed neurotoxicity in humans (Lotti et al. 1986). In the hen, the species of choice for the evaluation of the organophosphate-induced delayed neuropathy (OPIDN) (Johnson 1982), acute oral exposure to 150 mg/kg chlorpyrifos caused a >80% inhibition of neurotoxic esterase (NTE) 4 days after exposure (Capodicasa et al. 1991). NTE inhibition is believed by some to be directly related to the onset of OPIDN (Johnson 1982). In a study to examine the potential for intermediate-duration chlorpyrifos exposure to produce OPIDN (Francis et al. 1985), 2 hens were exposed to 10 mg/kg chlorpyrifos for 90 days. Physical deterioration began 30 days after exposure, and extreme debilitation, weakness, and lethargy occurred between 35 and 60 days after dosing. The report indicates that both hens recovered from the chlorpyrifos-induced neurotoxicity after 1 the cessation of dosing, but the time to recovery was not given. The time-course of toxicity and the eventual resolution of neurological symptoms following the exposure indicate that chlorpyrifos did not cause the classic OPIDN in this study. No data were located for neurological effects in animals following chronic-duration oral exposure to chlorpyrifos. The highest NOAEL value and all LOAEL values for neurological effects in each reliable study for each species and duration category are shown in Table 2—1 and Figure 2-1. 2.2.2.5 Reproductive Effects No information was found concerning the potential for reproductive effects in humans following oral acute-, intermediate-, or chronic-duration exposure to chlorpyrifos. Pregnant mice were exposed on gestational day 6, or on gestational days 6—10 or 6—15, to 0, l, 10, or 25 mg/kg/day chlorpyrifos (Deacon et al. 1980). Four of 47 dams exposed to 25 mg/kg chlorpyrifos died. There was also a small reduction in body weight gain for gestational days 6—17, but no effect on overall body weight was seen at that dose. Thirty-two of 47 mice exposed to 25 mg/kg/day chlorpyrifos exhibited symptoms (excessive salivation, tremors, urine-soaked coat, ataxia, and lethargy) of cholinergic overstimulation; similar clinical signs were seen in 5 of 44 dams dosed with 10 mg/kg/day chlorpyrifos. Additionally, food and water intake were significantly decreased in mice exposed to 25 mg/kg/day chlorpyrifos. No overt neurological symptoms were observed at the "*DRAFT FOR PUBLIC COMMENT"" CHLORPYRIFOS 27 2. HEALTH EFFECTS 1 mg/kg/day dose. In a concurrent study, pregnant mice were dosed with 0, 0.1, 1.0, or 10 mg/kg/day chlorpyrifos. No significant clinical signs of maternal toxicity were noted at any dose of chlorpyrifos. Despite the maternal toxicity, chlorpyrifos did not affect the ability of the surviving dams to maintain pregnancy at any close. No data were located for reproductive effects in animals following intermediate or chronic oral exposure to chlorpyrifos. The highest NOAEL values for reproductive effects in each reliable study for each species and duration category are shown in Table 2—1 and Figure 2—1. 2.2.2.6 Developmental Effects No information was found concerning the potential for developmental effects in humans following oral acute-, intermediate—, or chronic—duration exposure to chlorpyrifos. The potential for chlorpyrifos to cause developmental toxicity was assessed in mice exposed to 0, 1, 10, or 25 mg/kg/day chlorpyrifos on gestational days 6—15 (Deacon et al. 1980). On gestational day 18, all fetuses were weighed, sexed, examined for external malformations and cleft palate, and had their crown-rump length determined. One-third of the fetuses of each litter were also examined for evidence of soft-tissue alterations. There was no biologically significant effect of treatment on the number of live fetuses per litter, the number of dead fetuses per litter, the number of resorptions per litter, the average fetal body weight, or average crown-rump length. However, significant increases in skeletal variations were observed in litters exposed to 25 mg/kg chlorpyrifos. Increases were seen for the number of fetuses with delayed ossification of the skull bones (6.8-fold increase), delayed ossification of the stemebrae (2.1—fold increase), and unfused stemebrae (4-fold increase). In the same study, 10 and 25 mg/kg/day significantly decreased whole fetal homogenate cholinesterase activity by 35% and 65%, respectively. No data were located for developmental effects in animals following intermediate or chronic oral exposure to chlorpyrifos. The LOAEL values for developmental effects in each reliable study for each species and duration category are shown in Table 2-1 and Figure 2-1. "*DRAFT FOR PUBLIC COMMENT'” CHLORPYRIFOS ' 28 2. HEALTH EFFECTS 2.2.2.7 Genotoxic Effects No information was found concerning the potential genotoxic effects in humans following oral acute-, intermediate-, or chronic-duration exposure to Chlorpyrifos. Chlorpyrifos was tested for its ability to induce complete and partial chromosome losses in D. melanogaster males (Woodruff et a1. 1983). Initial attempts were made to identify an approximate LD3o (lethal dose, 30% kill) dose prior to treatment, with toxicity defined as the number of dead flies out of the total number treated over a 3-day period. Mortality was recorded at 24, 48, and 72 hours. At 72 hours, males were removed and mated with mus-302 repair-defective females, and F1 male progeny were screened for complete and. partial chromosome loss. Treated and control males that contained a ring-X chromosome and a doubly-marked Y chromosome were used in a screen for ring chromosome loss and for loss of Y-chromosome markers. Chlorpyrifos induced a significant increase in complete chromosome loss, but had no effect on partial chromosome loss. The mutagenic potential of Durmet® (20% Chlorpyrifos) was assessed using the Drosophila wing mosaic and sex-linked recessive lethal tests (Patnaik and Tripathy 1992). In the wing mosaic test, second- and third-instar larvae that were transheterozygous for the recessive marker mutations multiple wing hair (mwh) and flare-3 (flr3) were obtained from a cross of mwh females and flr3/TM3 Ser males. They were exposed to various concentrations of Durrnet® and the frequency of the mutant mosaic spot induction on the wings noted. The Basc technique was used to evaluate the induction of sex-linked lethals. Because of an increase in the frequency of induction of mosaic wing spots and sex- linked recessive lethals, Durmet® was considered to be genotoxic to Drosophila somatic and germ cells. Intermediate oral exposure to Chlorpyrifos (as Dursban®) has been shown to increase the incidence of erythroblast chromosomal aberrations (Amer and Fahmy 1982). In that study, mice received rat chow containing either 0, 80, or 240 ppm Dursban® for 24 hours, 7 days, 14 days, or 14 days with a 7-day recovery period. Doses of 1.39 or 4.18 mg/kg/day Dursban® were estimated from those concentrations. Dursban®at 4.18 mg/kg/day caused a statistically significant increase in the percentage of polychromatic erythrocytes (PE) and PE with micronuclei after 24 hours (70% and 176% increases, respectively) and 7 days (25% and 257% increases, respectively) of exposure. PE with micronuclei were also significantly increased 14 days post-treatment with 4.18 mg/kg/day (458% increase). These ***DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 29 2. HEALTH EFFECTS increases were transient, and percentages of PE and PE with micronuclei were normal seven days after the end of the dosing period. These results indicate that during exposure, chlorpyrifos increased the incidence of erythroblast chromosomal aberrations. Similar transient increases in PE and PE with micronuclei were found after mice were dose-fed 2.09 mg/kg/day Dursban® for 10 weeks (Amer and Fahmy 1982). No data were located for genotoxic effects in animals following chronic oral exposure to chlorpyrifos. Genotoxicity studies are also discussed in Section 2.5. 2.2.2.8 Cancer No information was located concerning the potential cancer effects of chlorpyrifos in humans or animals following oral acute-, intermediate—, or chronic-duration exposure. 2.2.3 Dermal Exposure 2.2.3.1 Death No information was found concerning the potential for death in humans following acute-, intermediate-, or chronic-duration dermal exposure to chlorpyrifos. Acute-duration dermal exposure LD50 for chlorpyrifos was determined to be 202 mg/kg in rats (Gaines 1969). Acute-duration dermal exposure of 185 young (9—52 months of age) bulls to an undetermined . dose of chlorpyrifos to control lice killed 7 of the animals (Everett 1982). Additionally, age-related death was observed in piglets sprayed with an undetermined amount of chlorpyrifos at various times after birth (Long et a1. 1986). Mortality was 4 of 4 in piglets treated 0—3 hours after birth, 3 of 3 in piglets treated 1—3 hours after birth, 3 of 5 in piglets treated 24—30 hours after birth, and 0 of 3 in piglets treated 30—36 hours after birth. The results indicate that newborn piglets are more susceptible to the chlorpyrifos toxicity. In hens, intermediate-duration dermal exposure to 20 mg/kg/day killed 2 of 3 hens after 30 or 38 days of exposure (Francis et al. 1985). No data were located for death in animals following chronic—duration dermal exposure to chlorpyrifos. Two of 4 bulls treated with 1 gram testosterone for 86 days, then exposed to chlorpyrifos 28 and 58 days after the start of the testosterone treatment, had to be killed because of severe diarrhea (Haas et al. 1983). "*DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 30 2. HEALTH EFFECTS 2.2.3.2 Systemic Effects No studies were located concerning the potential cardiovascular, hematological, musculoskeletal, or hepatic effects of chlorpyrifos in humans or animals following acute-, intermediate-, or chronic- duration dermal exposure to chlorpyrifos. Respiratory Effects. No information was found concerning the potential for respiratory effects in humans following acute-, intermediate-, or chronic-duration dermal exposure to chlorpyrifos. Piglets acutely exposed to an undetermined amount of chlorpyrifos at 0—3, 1—3, 24—30, or 30—36 hours after birth were observed for clinical signs of toxicity, and various tissues were taken for histopathological evaluations (Long et al. 1986). Mortality was 4 of 4 in piglets treated 0—3 hours after birth, 3 of 3 in piglets treated l—3 hours after birth, 3 of 5 in piglets treated 24-30 hours after birth, and O of 3 in piglets treated 30—36 hours after birth. Dyspnea, resulting from cholinergic over— stimulation, was observed in the pigs that eventually died. However, microscopic evaluation of the lung tissues from the treated piglets did not reveal any abnormalities. No data were located for . respiratory effects in animals following intermediate- or chronic-duration dermal exposure to chlorpyrifos. Gastrointestinal Effects. No information was found concerning the potential for gastrointestinal effects in humans following acute-, intermediate-, or chronic-duration dermal exposure to chlorpyrifos. Piglets acutely exposed to an undetermined amount of chlorpyrifos at 0—3, 1—3, 24—30, or 30—36 hours after birth were observed for clinical signs of toxicosis, and various tissues were taken for histopathological evaluations (Long et al. 1986). Mortality was 4 of 4 in piglets treated 0—3 hours after birth, 3 of 3 in piglets treated 1—3 hours after birth, 3 of 5 in piglets treated 24—30 hours after birth, and 0 of 3 in piglets treated 30—36 hours after birth. Diarrhea, resulting from cholinergic over- stimulation, was observed in the pigs that eventually died. Necropsy of the piglets revealed increased fluid in the intestines, but only in those piglets exposed 1—3 hours after birth. No data were located for gastrointestinal effects in animals following intermediate or chronic dermal exposure to chlorpyrifos. *"DRAFI' FOR PUBLIC COMMENT*”"’ CHLORPYRIFOS 31 2. HEALTH EFFECTS Renal Effects. No information was found concerning the potential for renal effects in humans following acute- or chronic-duration dermal exposure to chlorpyrifos. The effects of intermediate exposure to undetermined amounts of chlorpyrifos in humans were assessed in a survey of pesticide applicators working in a variety of settings (Ames et a1. 1989). Those applicators reported an unspecified decrease in urinary frequency. This information is also present in Section 2.2.1 of this profile because the route of exposure is not specified in the Ames et a1. (1989) report, and it is probable that exposure occurred by multiple routes. No data were located for renal effects in animals following acute-, intermediate-, or chronic-duration dermal exposure to chlorpyrifos. Dermal Effects. No information was found concerning the potential for dermal effects in humans following acute-duration dermal exposure to chlorpyrifos. The effects of intermediate exposure to undetermined amounts of chlorpyrifos in humans were assessed in a survey of pesticide applicators working in a variety of settings (Ames et a1. 1989). Those applicators reported an unspecified increase in skin flushing. This information is also present in Section 2.2.1 of this profile because the route of exposure is not specified in the Ames et a1. (1989) report, and it is probable that exposure occurred by multiple routes. Additionally, prolonged dermal contact with chlorpyrifos may produce irritation and slight burns; dermal sensitization may also occur (HSDB 1995). In adult mice, the dermal application of chlorpyrifos dissolved in acetone caused dose—dependent dermal irritation (Shah et a1. 1987). In that study, approximately 99% of a single 21.03 mg/kg dose was absorbed, compared with 46% of a 4.21 mg/kg dose. However, considerably more irritation and blistering accompanied the high dose, compromising the integrity of the skin and increasing the possibility of absorption. Thus, the dose-dependent absorption of chlorpyrifos may have been, at least in part, an artifact resulting from the destruction of the epidermis. No data were located for dermal effects in animals following intermediate- or chronic-duration dermal exposure to chlorpyrifos. "*DRAFT FOR PUBLIC COMMENT‘“ CHLORPYRIFOS 32 2. HEALTH EFFECTS Ocular Effects. No information was found concerning the potential for ocular effects in humans following chronic-duration dermal exposure to chlorpyrifos. Acute dermal exposure to an undetermined amount of chlorpyrifos in a 42—year—old woman caused unilateral miosis (Flach and Donahue 1994). The effects of intermediate—duration exposure to undetermined amounts of chlorpyrifos in humans were assessed in a survey of pesticide applicators working in a variety of settings (Ames et a1. 1989). Those applicators reported an unspecified increase in blurred vision. This information is also present in Section 2.2.1 of this profile because the route of exposure is not specified in the Ames et a1. (1989) report, and it is probable that exposure occurred by multiple routes. No data were located for ocular effects in animals following acute-, intermediate—, or chronic-duration dermal exposure to chlorpyrifos. 2.2.3.3 Immunological and Lymphoreticular Effects No information was located concerning the potential immunological and lymphoreticular effects of chlorpyrifos in humans or animals following acute-, intermediate-, or chronic-duration dermal exposure. 2.2.3.4 Neurological Effects The accidental application of chlorpyrifos into the eye of a 42-year-old woman caused unilateral miosis presenting as anisocoria (Flach and Donahue 1994). No information was found concerning the potential for neurological effects in humans following intermediate- or Chronic-duration dermal exposure to chlorpyrifos. Piglets acutely exposed to an undetermined amount of chlorpyrifos at 0—3, 1—3, 24—30, or 30—36 hours after birth were observed for clinical signs of toxicity (Long et a1. 1986). Mortality was 4 of 4 in piglets treated 0~3 hours after birth, 3 of 3 in piglets treated 1—3 hours after birth, 3 of 5 in piglets treated 24—30 hours after birth, and 0 of 3 in piglets treated 30—36 hours after birth. Weakness, trembling, ataxia, miosis, and lateral recumbency were observed in the piglets that eventually died. Additionally, determinations of brain cholinesterase activity in piglets exposed 1—3 hours after births ""DRAFT FOR PUBLIC COMMENT"" CHLORPYRIFOS ' I 33 2. HEALTH EFFECTS showed a 55—67% inhibition in activity. Blood acetylcholinesterase activity determined in piglets 12—17 hours after exposure displayed 81—99% decreases in activity. Intermediate-duration dermal exposure to 20 mg/kg/day chlorpyrifos applied to the ventral wing surface at the humerus for at least 28 days produced debilitation and paralysis after 20—28 days of closing in 2 of 3 exposed hens (Francis et a1. 1985). No data were located for neurological effects in animals following chronic dermal exposure to chlorpyrifos. 2.2.3.5 Reproductive Effects No information was found concerning the potential for reproductive effects in humans following acute—, intermediate-, or chronic-duration dermal exposure to chlorpyrifos. Dursban 44® was applied once to 185 young bulls (9—52 months of age) for lice control. Semen output was analyzed from historical samples collected from 583 control animals to establish normal production (Everett 1982). Following exposure, semen production and sperm viability were determined in frozen samples. The bulls were divided into 2 post-exposure groups (6-month and 7—12-month) in order to assess the short— and long-term effects of the treatment, respectively. Six months post-exposure, the treated bulls were reported to have an unspecified increase in nonmotile sperm upon thawing of samples. Sperm motility and ejaculate volume were decreased, and the number of post-thaw nonmotile sperm increased in those bulls that became ill after treatment and required veterinary interventions. No adverse effects on bull sperm were observed 7—12 months postexposure. No data were located for reproductive effects in animals following intermediate- or chronic—duration dermal exposure to chlorpyrifos. 2.2.3.6 Developmental Effects No information was located concerning the potential developmental effects of chlorpyrifos in humans or animals following acute-, intermediate-, or chronic-duration dermal exposure. 2.2.3.7 Genotoxic Effects No information was located concerning the potential genotoxic effects of chlorpyrifos in humans following acute, intermediate, or chronic dermal exposure. “*DRAFT FOR PUBLlC COMMENT” CHLORPYRIFOS 34 2. HEALTH EFFECTS The effect of intermediate exposure to chlorpyrifos was assessed in mice (Amer and Fahmy 1982). Dursban® (99 mg/kg) was applied as a solution in 0.1 mL dimethyl sulfoxide (DMSO) to the backs of mice for 24 hours, 7 days, or 14 days, and the percentage of polychromatic erythrocytes (PE) determined. The applications were performed twice weekly for the 7- and 14-day exposures. Additionally, some animals exposed for 14 days were allowed to recover 1 or 2 weeks before having the percentage of PE determined. Controls received DMSO only. After 1 and 14 days of exposure, the percentage of PE increased 17% and 82%, respectively. However, no effect on PE was observed for the 7—day exposure group. As a result, the authors concluded that the effect seen after one day of exposure was probably spurious. The percentage of PE was still elevated in the 14-day exposure group 7 days post—exposure. However, normal percentages of PE were found in the 14—day exposure group allowed to recoverfor 14 days. Additionally, there was no induction of micronuclei in any of the treatment groups. The results indicate that chlorpyrifos has the potential to cause transient increases in the incidence of erythroblast chromosomal aberrations. No data were located for genotoxic effects in animals following acute or chronic dermal exposure to chlorpyrifos. Other genotoxicity studies are discussed in Section 2.5. 2.2.3.8 Cancer No information was located concerning the potential cancer effects of chlorpyrifos in humans or animals following acute-, intermediate-, or chronic-duration dermal exposure. 2.3 TOXICOKINETICS Most of the toxicokinetic data on chlorpyrifos were collected following oral or dermal administration. Limited inhalation exposure data are available. Studies in humans and other animals indicate that orally administered chlorpyrifos is well absorbed with 70—90% of the administered dose being absorbed within 48 hours after exposure. In humans, the skin greatly attenuates chlorpyrifos absorption with only 3% of the dermally applied dose being absorbed. In animals, the amount of chlorpyrifos absorbed following dermal application is comparable to oral administration. However, those studies are confounded by the fact that dermal irritation accompanied the dermal dosing, which may have decreased skin integrity, increasing absorption. Animal studies indicate that orally and dermally administered chlorpyrifos rapidly distributes to all the major organs. Chlorpyrifos metabolism is similar in both humans and other animals. Chlorpyrifos is bioactivated to chlorpyrifos "'DRAFT FOR PUBLIC COMMENT“* CHLORPYRIFOS 35 2. HEALTH EFFECTS oxon in the liver via cytochrome P—450—dependent desulfuration. The oxon is hydrolyzed by A-esterase to TCP, the major metabolite detected in humans and other animals. The tissue elimination of chlorpyrifos is organ-dependent, with the slowest elimination occurring from fat (half—life = 62 hours). Chlorpyrifos is primarily excreted in the urine in the form of TCP conjugates. 2.3.1 Absorption 2.3.1.1 Inhalation Exposure No toxicokinetic infomiation was located concerning the absorption of chlorpyrifos following inhalation exposure in humans or animals. 2.3.1.2 Oral Exposure The absorption of chlorpyrifos following acute oral exposure has been investigated in humans and other animals. In humans, determination of chlorpyrifos metabolites in the urine from six adult males orally exposed to chlorpyrifos indicated that an average of 70% of the administered dose was absorbed within 48 hours (Nolan et al. 1984). In rats (Bakke et al. 1976; Smith et al. 1967) and mice (Ahdaya et al. 1981), nearly 90% of the administered dose of l4C-labeled chlorpyrifos in an acute oral exposure was absorbed, as assessed by the amount of radioactivity recovered in the feces and urine. 2.3.1.3 Dermal Exposure The absorption of chlorpyrifos following dermal exposure has been investigated in humans and other animals. In humans, determination of chlorpyrifos metabolites in the urine from six adult males dermally exposed to chlorpyrifos indicated that an average of 3% of a dose administered in dipropylene methylether was absorbed within 48 hours, compared to 70% of an oral dose (Nolan et al. 1984). In goats, 80—96% of a 22 mg/kg dermal dose (vehicle not specified) was absorbed 12—16 hours after dosing (Cheng et a1. 1989). In adult mice, the percentage of chlorpyrifos dissolved in acetone absorbed through the skin during a 72—hour period was dose-dependent, with relatively more absorption occurring at higher doses (Shah et a1. 1987). In that study, approximately 99% of a 21.03 mg/kg dose was absorbed, compared with 46% of a 4.21 mg/kg dose. However, considerably more irritation and blistering accompanied the high dose, compromising the integrity of the skin and "*DRAFT FOR PUBLIC COMMENT"" CHLORPYRIFOS 36 2. HEALTH EFFECTS increasing the possibility of absorption. Thus, the dose-dependent absorption of chlorpyrifos may have been, at least in part, an artifact resulting from the destruction of the epidermis. In that same study, Shah et a1. (1987) also assessed the effect of age on dermal penetration of chlorpyrifos. On average, 23% more chlorpyrifos was absorbed by young (33-day—old) mice than by adults (82~day-old). The possible age-dependence of the dermal absorption of chlorpyrifos was also investigated in a study in which piglets of varying ages were sprayed with a solution containing an unspecified concentration of chlorpyrifos (Long et a1. 1986). In that study, the toxicity of chlorpyrifos decreased with increasing time following birth. 2.3.2 Distribution 2.3.2.1 Inhalation Exposure No toxicokinetic information was located concerning the distribution of chlorpyrifos following inhalation exposure in humans or animals. 2.3.2.2 Oral Exposure The distribution of 14C-labeled chlorpyrifos following oral exposure has been investigated using rats (Smith et al. 1967). The results of that study indicate that chlorpyrifos readily distributes to all organs of the body. 2.3.2.3 Dermal Exposure The distribution of dermally applied MC—labeled chlorpyrifos has been investigated using goats (Cheng et a1. 1989) and mice (Shah et a1. 1981). The results from those studies indicate that chlorpyrifos readily distributes to all organs of the body, with relatively higher concentrations being found in the blood, liver, and fat than in other organs (e.g., heart, gastrointestinal tract, skeletal muscle). 2.3.3 Metabolism An adaptation of the scheme for organophosphorus compounds analyzed in serum and urine of persons poisoned by chlorpyrifos (Drevenkar et a1. 1993) is presented in Figure 2-2. "*DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 37 2. HEALTH EFFECTS Figure 2-2. Proposed Metabolic Pathway for Chlorpyrifos CHLORPYRIFOS CHLORPYRIFOS OXON O s H «mom-120143)2 || Cl O—P(OCHZCH3)2 Cl N o \ \ l ———> I / c. / Cl CI CI H H 0 17“” I DETP DEP Source: Drevenkar et al. 1993 "'DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 38 2. HEALTH EFFECTS In the rat and mouse, chlorpyrifos is bioactivated in the liver to chlorpyrifos oxon via cytochrome P-450-dependent desulfuration (Ma and Chambers 1994; Sultatos and Murphy 1983a). The oxon is rapidly hydrolyzed to TCP, probably by A-esterase, since the reaction is calcium-dependent (Sultatos and Murphy 1983a, 1983b). Studies using liver perfusion have shown that both bioactivation and detoxification of chlorpyrifos occur very rapidly, since only TCP can be detected in the hepatic effluent once steady-state conditions are reached (Sultatos and Murphy 1983a, 1983b). Another possible route for detoxification of chlorpyrifos involves the hepatic phosphorylation of aliesterase by chlorpyrifos (Chambers et al. 1990). Hydrolysis of the chlorpyrifos oxon by A-esterase is probably the more common route of detoxification, since TCP or a conjugate of TCP is the major metabolite of chlorpyrifos in humans (Nolan et al. 1984) and rodents (Bakke et al. 1976; Smith et al. 1967; Sultatos and Murphy 1983a, 1983b; Sultatos et al. 1985). The relative rates of desulfuration and detoxification are gender-dependent and may account for the increased toxicity of chlorpyrifos in female rats (Chambers and Chambers 1989; Sultatos 1991). The results of the above studies indicate that although the rates of bioactivation (desulfuration) and detoxification (dearylation) are higher in males than females, the ratio of the rates of bioactivation to detoxification is 2—3—fold higher for females. Those studies suggest that females may be at increased risk to chlorpyrifos—induced toxicity. However, bulls with high levels of testosterone were more sensitive than steers (castrated bulls) to the toxic effects of chlorpyrifos (Haas et al. 1983). Although no metabolism data were present in that study, it suggests that for bovines, the male may be more susceptible than the female. 2.3.4 Elimination and Excretion 2.3.4.1 Inhalation Exposure Examination of urine samples from pesticide applicators presumably exposed to chlorpyrifos by inhalation revealed the presence of TCP (J itsunari et al. 1989). 2.3.4.2 Oral Exposure Male rats exposed to 14C-labeled chlorpyrifos had their urine and feces collected every 12 hours for 48 hours (Bakke et al. 1976). The combined urine from all 4 samples contained approximately 88% "'DRAFT FOR PUBLIC COMMENT’“ CHLORPYRIFOS 39 2. HEALTH EFFECTS of the recovered radiolabel, and it separated into at least 6 Chlorpyrifos metabolites. Three of these ' metabolites were identified as the glucuronide of TCP, a glycoside of 3,5,6-trichloro—pyridinol, and TCP, comprising 80%, 4%, and 12% of the total metabolites, respectively. In a similar study, 90% of the radiolabel was found in the urine, and 10% was recovered in the feces (Smith et a1. 1967). Additionally, the elimination half-life was estimated for several compartments. Chlorpyrifos was eliminated slowly from fat (half—life = 62 hours) and relatively rapidly from liver, heart, and kidney (half-life = 10—16 hours) (Smith et a1. 1967). In humans, an elimination half-life of 27 hours has been estimated for humans following oral or dermal exposure (Nolan et a1. 1984). 2.3.4.3 Dermal Exposure A half-life of 21 hours has been estimated for the urinary elimination and fecal excretion of Ichlorpyrifos following dermal exposure in mice (Shah et a1. 1981). For humans, an elimination half- life of 27 hours has been estimated following oral or dermal exposure (Nolan et a1. 1984). As with oral exposure, the majority of dermally absorbed Chlorpyrifos is eliminated in the urine (Shah et a1. 1981). 2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and disposition of chemical substances to quantitatively describe the relationships among critical biological processes (Krishnan et a1. 1994). PBPK models are also called biologically based tissue dosimetry models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of potentially toxic moieties of a chemical that will be delivered to any given target tissue following various combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to quantitatively describe the relationship between target tissue dose and toxic end points. PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate and characterize the relationships between: (1) the external/exposure concentration and target tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et a1. 1987; Andersen and Krishnan 1994). These models are biologically and mechanistically based and *"DRAFT FOR PUBLIC COMMENT"" CHLORPYRIFOS 40 2. HEALTH EFFECTS can be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between species, and between subpopulations within a species. The biological basis of PBPK models results in more meaningful extrapolations than those generated with the more conventional use of uncertainty factors. The PBPK model for a chemical substance is developed in four interconnected steps: '(1) model representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and Andersen 1994). In the early 19905, validated PBPK models were developed for a number of toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substance-specific physicochemical parameters, and species-specific physiological and biological parameters. The numerical estimates of these model parameters are incorporated within a set of differential and algebraic equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations provides the predictions of tissue dose. Computers then provide process simulations based on these solutions. The structure and mathematical expressions used in PBPK models significantly simplify the true complexities of biological systems. If the uptake and disposition of the chemical substance(s) is adequately described, however, this simplification is desirable because data are often unavailable for many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The adequacy of the model is, therefore, of great importance, and model validation is essential to the use of PBPK models in risk assessment. PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies where doses were higher or were administered in different species. Figure 2-3 shows a conceptualized representation of a PBPK model. If PBPK models for chlorpyrifos exist, the overall results and individual models are discussed in this section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations. “"DRAFT FOR PUBLIC COMMENT'“ CHLORPYRIFOS Figure 2-3. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance 2. HEALTH EFFECTS Inhaled chemical """ - I I I V ‘ ' ‘ ' * Exhaled chemical UOOrm CDCOZITl< Ingesfion Fat Tract Skwfly penused fissues Richly perfused tissues ll Kidney Urine Skin r>—mmdm> UOOI'CD Source: adapted from Krisnan et al. 1992 L I I I - - - -Chemical in air contacting skin 41 Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation. "‘DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 42 2. HEALTH EFFECTS No PBPK information was found for chlorpyrifos. 2.4 MECHANISMS OF ACTION 2.4.1 Pharmacokinetic Mechanisms Chlorpyrifos is well absorbed through the gut and lungs, but dermal absorption is considerably less effective. The skin presents a reasonably effective barrier to penetration, unless the pesticide is mixed with a carrier or the skin is compromised. However, since all commercial chlorpyrifos products, with the exception of granular forms, contain solvents or emulsifiers, human exposure to chlorpyrifos that is not mixed with a carrier is unlikely. Nevertheless, human skin may be an effective barrier to chlorpyrifos penetration. Oral and dermal absorption of chlorpyrifos was assessed in six adult male humans (Nolan et a1. 1984). On average, 70% of the oral dose was absorbed, compared to only 3% of the dermal dose. Once chlorpyrifos has been absorbed, it rapidly distributes to all organs (Shah et a1. 1981; Smith et al. 1967). The half-life for elimination of chlorpyrifos from the various organs in rats is comparable (10—16 hours), except for elimination from fat, which was estimated to be 62 hours (Smith et a1. 1967). The elimination half—life in humans has been estimated to be 27 hours (Nolan et a1. 1984). The major site of chlorpyrifos metabolism is the liver, where it is rapidly bioactivated (desulfurated) by a P-450—dependent monooxygenase to chlorpyrifos oxon (Ma and Chambers 1994; Sultatos and Murphy 1983a). The oxon is a 300—400 times more potent inhibitor of acetylcholinesterase than the parent compound (Sultatos and Murphy 1983a, 1983b). The rate of detoxification of the oxon is also rapid (Sultatos and Murphy 1983a, 1983b). Thus, it is rare to find either the parent compound or the oxon in body fluid samples (Nolan et al. 1984; Sultatos and Murphy 1983a), except in very high exposures. What is found in the general circulation is the major oxon metabolite TCP (Bakke et al. 1976; Nolan et al. 1984; Smith et a1. 1967). TCP is a unique metabolite of chlorpyrifos, and it (or one of its conjugates) is almost exclusively (90%) excreted in the urine (Bakke et a1. 1976; Smith et al. 1967). Kinetic studies using rats indicate that following a single-dose exposure, most (>90%) of the chlorpyrifos is eliminated within 48 hours (Bakke et a1. 1976; Smith et a1. 1967). Thus, urine TCP can be used as a qualitative biomarker for chlorpyrifos exposure, provided the testing is performed within 48 hours after exposure. It should be noted that the relative rate of detoxification of chlorpyrifos is lower in female rats (i.e., ratio of bioactivation to detoxification), and it is postulated *“DRAFT FOR PUBLIC COMMENT"“ CHLORPYRIFOS 43 2. HEALTH EFFECTS that this may account for the increased toxicity of chlorpyrifos in those animals (Chambers and Chambers 1989; Chambers et al. 1994; Sultatos 1991). The dose of chlorpyrifos is important in predicting the potential toxicity. Further, factors such as age, health, and possibly gender may significantly lower the threshold for toxic effects. While acute high dose intoxication has been demonstrated in a variety of species, including humans, the effects of longer-term, low—level exposure are less clear. Small-scale attempts to qualify chlorpyrifos-related toxicity in pesticide applicators suggest that intermediate exposure to low levels of chlorpyrifos may adversely affect health (Ames et al. 1989); but whether the effects may be related to cumulative direct target insult or simply to cholinesterase inhibition is less clear. Low levels of exposure are assumed for that study because pesticide applicators are usually presumed to wear protective clothing and respirators when spraying the pesticide. However, neither the dose nor the length of exposure could be estimated. 2.4.2 Mechanisms of Toxicity Chlorpyrifos-induced toxicity results almost entirely from inhibition of acetylcholinesterase by chlorpyrifos and its bioactivation product, chlorpyrifos oxon (Namba et al. 1971). Acetylcholinesterase (true cholinesterase) belongs to a class of choline ester hydrolases which includes butyryl— cholinesterase, or pseudocholinesterase (Ballantyne and Marrs 1992). Acetylcholinesterase is found postsynaptically in central and peripheral cholinergic synapses, including the preganglionic autonomic synapses and postganglionic parasympathetic synapses (Palmer 1980). It is also found at the motor end plate in the neuromuscular junction and is further associated with erythrocytes (red blood cells) (Ballantyne and Marrs 1992). Butyrylcholinesterase can be found in the plasma, and also in non- neuronal tissues such as the liver and fat (Ballantyne and Marrs 1992). Butyrylcholinesterase levels can be affected by health, age, genetic factors, and gender (Ballantyne and Marrs 1992). Inhibition of butyrylcholinesterase can be used as an indicator of exposure to cholinesterase—inhibiting substances, but is not, in and of itself, considered to constitute an adverse health effect. Organophosphorus insecticides, such as chlorpyrifos and its oxon, may cause irreversible cholinesterase inhibition by forming a stable covalent bond at the active site (Goodman et a1. 1990). Stability of the bond is.further enhanced by a process called aging, which occurs when one of the alkyl groups of the enzyme is lost (Goodman et a1. 1990). Aging of the enzyme is an important factor in determining the "*DRAFT FOR PUBLIC COMMENT"" CHLORPYRIFOS 44 2. HEALTH EFFECTS effectiveness of oximes, such as pyridine-Z-aldoxime methyl chloride (2—PAM or pralidoxime), to reactivate the enzyme through nucleophilic attack on the phosphorus. Once aging has occurred, 2-PAM can no longer reactivate the enzyme. Without the use of oximes, enzyme activity can only return after hours or days; thus, recovery often depends heavily on the synthesis of new cholinesterases. The result of cholinesterase inhibition is cholinergic overstimulation. 2.4.3 Animal-to-Human Extrapolations Extrapolating from laboratory animals to humans may be done in the case of chlorpyrifos because the mechanism of action of the pesticide is the same in all species examined, and the metabolism and excretion of the pesticide are similar, if not identical, in humans and common laboratory animals. The area of lesser certainty is whether or not the gender-dependent differences in chlorpyrifos metabolism exist for humans. Research indicates that the effects of chlorpyrifos may be gender-specific. In rats, females are more susceptible to chlorpyrifos—induced toxicity due to a decreased ability to break down the chlorpyrifos oxon (see Section 2.3.3, Metabolism), but in bovines, experimental evidence suggests that bulls may be more sensitive to chlorpyrifos toxicity (Haas et al. 1983). Clearly, more information on the possibility of gender-dependent chlorpyrifos toxicity is needed. 2.5 RELEVANCE TO PUBLIC HEALTH Overview The most likely mode of exposure to chlorpyrifos at a hazardous waste site is through the skin. The most significant effect of acute exposure to chlorpyrifos is cholinergic over-stimulation resulting from cholinesterase inhibition. Clinical signs associated with parasympathetic stimulation include headache, diaphoresis, nausea, vomiting, diarrhea, epigastric cramping, bradycardia, blurred vision, miosis, bronchoconstriction and excess mucous secretions, pulmonary edema, dyspnea, muscle fasciculations, salivation, lacrimation, and urination (Ballantyne and Marrs 1992). Exposure to high doses can also produce a profound tachycardia, pulmonary edema, loss of bowel control, convulsions, coma, and death. The actual symptoms seen in patients poisoned with cholinesterase-inhibiting pesticides result from actions at both nerve synapses and neuromuscular junctions. Cholinesterase inhibition in skeletal *"DRAFT FOR PUBLIC COMMENT’" CHLORPYRIFOS 45 2. HEALTH EFFECTS muscle can cause muscle weakness, fasciculations, and tremors. Central nervous system effects may include anxiety, headaches, drowsiness, confusion, tremor, ataxia, abnormal gait, hypotension, respiratory depression, convulsions, and coma (Ballantyne and Marrs 1992). Peripheral neuropathies and polyneuritis have also been observed in humans and other animals following acute, high-dose exposures. Transient memory impairment following acute-duration exposure to chlorpyrifos has been observed in humans. Acute chlorpyrifos exposure in laboratory animals has also been shown to cause transient memory impairment, as well as long-term down-regulation of central muscarinic receptors (Bushnell et a1. 1993). Chlorpyrifos has not been shown to affect reproduction in laboratory animals, but sperm production was decreased in bulls dermally exposed to chlorpyrifos. Limited information for rodents suggests that in utero exposure to chlorpyrifos may increase the incidence of skeletal variations and be developmentally neurotoxic to offspring. Additionally, data collected from mice and Drosophila indicate that chlorpyrifos may be genotoxic. Following acute exposure in humans or animals, chlorpyrifos is rapidly eliminated from the body; only trace amounts of chlorpyrifos metabolites can usually be found in the blood or urine 48 hours after a single exposure. However, in humans (Lotti et a1. 1986), bulls (Haas et a1. 1983), and cats (Jaggy and Oliver 1992), clinical signs of toxicity may be evident for weeks following exposure, long after the chlorpyrifos should have been eliminated. There is no evidence to suggest that chlorpyrifos is bioaccumulated. Little information is available concerning the effects of intermediate-duration exposure in humans or animals to chlorpyrifos, and no information was located regarding the effects of chronic-duration exposure. Measurement of erythrocyte and plasma cholinesterase activity is usually performed if organophosphate poisoning is suspected. However, erythrocyte cholinesterase inhibition by itself is not always associated with the presence of cholinergic symptoms, and plasma (pseudo-) cholinesterase is generally considered only an index of exposure. Brain acetylcholinesterase inhibition, where available, and erythrocyte acetylcholinesterase inhibition are commonly used to correlate cholinesterase inhibition with a threshold for toxic manifestations associated with inhibition of the cholinesterase enzyme. In the case of chlorpyrifos, this particular insecticide is considered a selective pseudo— cholinesterase inhibitor (HSDB 1995). The course of inhibition of the respective acetyl— and butyryl- cholinesterase enzymes have different times of onset after a single exposure, with acetylcholinesterase *"DRAFT FOR PUBLIC COMMENT’" CHLORPYRIFOS 46 2. HEALTH EFFECTS inhibition following the drop in butyrylcholinestrerase activity (Ballantyne and Marrs 1992). Thus, both plasma and erythrocyte cholinesterase activities should be measured if chlorpyrifos exposure is suspected. It should be noted that the degree of erythrocyte cholinesterase inhibition does not always correlate with toxicity; this is especially true in children. In some cases, children have been highly symptomatic after chlorpyrifos exposure at a time when only plasma cholinesterase levels have been reduced, or when all cholinesterase levels were within normal ranges. Thus, measuring cholinesterase activity in children may have little practical value except to confirm exposure to chlorpyrifos. There are many populations at potentially greater risk to chlorpyrifos—induced toxicity. Populations at risk include the elderly, persons with pre—existing medical conditions, infants and children, and women (especially pregnant women). The elderly are considered at risk for increased toxicity because of the general decline in health that accompanies aging. Persons with chronic respiratory ailments such as asthma, emphysema, and bronchitis would be at greater risk for respiratory distress following chlorpyrifos exposure. Additionally, approximately 5% of the population are succinylcholine (diacetylcholine) sensitive and would be at greater risk following chlorpyrifos exposure because they have a genetically controlled deficiency in pseudocholinesterase. Research using rats indicates that females are more susceptible to the toxic effects of chlorpyrifos, possibly because they detoxify chlorpyrifos at a lower rate than males. However, in bovines, bulls have been shown to be at increased risk to chlorpyrifos toxicosis. It is not known if gender differences in chlorpyrifos metabolism or susceptibility exist in humans. Additionally, the doses of chlorpyrifos needed to cause death in pregnant mice are approximately six times lower than those need to cause death in nonpregnant mice, suggesting that pregnancy may increase the risk of chlorpyrifos-induced toxicity. Infants and children may also be at increased risk for toxicity. Results from animal studies suggest that chlorpyrifos more easily penetrates the skin of young animals compared to adults. Very young children and infants also have a decreased metabolic capacity to eliminate toxicants and are more susceptible to central nervous system toxicants, thus lowering the exposure levels needed to cause chlorpyrifos toxicity in that population. Chlorpyrifos may also be developmentally toxic. Studies in pregnant rats suggest that low levels of chlorpyrifos exposure during gestation have the potential to increase offspring mortality, reduce birth weight, and alter offspring behavior. “"DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 47 2. HEALTH EFFECTS Minimal Risk Levels for Chlorpyrifos Inhalation MRLs No MRLs have been derived for this route of exposure because of the lack of suitable information for all exposure durations. Oral MRLs No MRLs have been derived for chronic-duration exposure to Chlorpyrifos because of the lack of adequate quantitative data. 0 An MRL of 0.003 mg/kg/day has been derived for both acute (14 days or less) and intermediate (15—364 days) oral exposure to Chlorpyrifos. The combination of the length of exposure period and the critical effect in this study enable it to be used for the derivation of both acute- and intermediate-duration oral exposure MRLs. These MRLs are based upon a study by Coulston et a1. (1972) in which 16 human adult male volunteers (4 per dose group) were administered Chlorpyrifos in doses of 0, 0.014, 0.03, or 0.1 mg/kg body weight once daily in a tablet with breakfast for up to 28 days. The low and mid-dose groups were dosed for 28 and 21 days, respectively, but the high-dose treatment was discontinued after 9 days due to one individual in this group experiencing a runny nose, blurred vision, and a feeling of faintness. Twice each week, blood samples were obtained from each volunteer for determination of cholinesterase activity. Mean plasma and red blood cell (RBC) cholinesterase levels were ascertained for all groups and compared with pretreatment values, and comparison was also made between treated and control groups. At weekly intervals, additional blood samples were obtained for hematology and routine serum chemistry determinations. Urinalyses were also performed on a weekly basis. Throughout the course of the experiment, no treatment—related effects were found among any of the parameters examined in the urinalyses, hematological, or serum chemistry tests. In the high-dose group, mean plasma cholinesterase (ChE) was depressed by 66% of average baseline levels after 9 days of treatment. In the group receiving 0.03 mg/kg/day, plasma ChE levels were reduced by an average of 30% from baseline levels; however, when compared with control group levels on a day-to- day basis, plasma ChE was reduced by only 13% of concurrent control values. Statistical analysis of ”*DRAFT FOR PUBLIC COMMENT‘“ CHLORF’VRIFOS 48 2. HEALTH EFFECTS the differences in this treatment group revealed no statistical significance. There was no statistically significant effect on plasma ChE activity during the four-week experiment in the low—dose group. No effect on RBC ChE activity was apparent at any dose, and the plasma ChE levels in all high—dose volunteers had returned to baseline levels within four weeks. Although the authors of the Coulston et a1. (1972) study indicated that the individual with the runny nose, blurred vision, and fath feeling was treated for a cold and was asymptomatic by the end of the day (day 9), they neither provided further comment indicating that the symptoms were unrelated to treatment nor explained why the high-dose treatments were discontinued after 9 days. Therefore, the highest dose that can be unequivocally stated to be a no—observed-adverse-effect—level (NOAEL) in this study is the 0.03 mg/kg.day dosage. While plasma cholinesterase activity was depressed by approximately 65% in the high—dose group, plasma (pseudo-) cholinesterase activity is considered by ATSDR to be only an indicator of exposure to a cholinesterase-inhibition substance or substances, and does not, in and of itself, constitute an adverse health effect. The MRLs derived from the Coulston et al. (1972) study are closely supported by the Deacon et a1. (1980) study, in which pregnant adult CF-l mice (40—47 per group) were bred and administered daily gavage chlorpyrifos dosages of l, 10, or 25 mg/kg in cottonseed oil on days 6—15 of gestation. A group of 51 female control animals was given an equivalent volume of cottonseed oil without the test material. (Since the high dose resulted in severe maternal toxicity, additional mice (35—41 per dosage group) were bred and administered chlorpyrifos at doses of 0.1, 1.0, or 10 mg/kg/day on gestation days 6—15, inclusively to further evaluate the teratogenic potential of chlorpyrifos. Animals were observed daily (from day 6 on) for signs of toxicity. Maternal body weights were recorded for days 6—15 of gestation. Maternal body weight, liver weight, and weight of the gravid uterus (including ovaries) were recorded at the time of cesarean section on day 18 of gestation. After sacrifice (with C02) the number and position of live, dead, or resorbed fetuses were noted. Fetuses were weighed, their crown-rump length measure, and then examined for external alterations and cleft palate. In addition, 1 in 3 of the fetuses from each litter were examined for evidence of soft-tissue alterations by dissections under a stereomicroscope. To determine the degree of plasma and erythrocyte cholinesterase depression, groups of 4—10 bred mice were given 0, 1, 10, or 25 mg/kg/day on day 6, days 6—10, or days 6—15 of gestation. Subsequently, groups of 5—15 mice were given 0.1, 1.0, or 10 mg/kg/day of chlorpyrifos concurrently with the animals for the teratologic study on days 6, days 6—10, or days 6—15 of gestation. Five hours after the final dosing for each period, blood was obtained ’“DRAFT FOR PUBLIC COMMENT‘" CHLORF’YRIFOS 49 2. HEALTH EFFECTS by cardiac puncture. A homogenate of fetuses from the litters of mice sacrificed on day 15 of gestation was prepared to measure total fetal cholinesterase levels. In the 25 mg/kg group, severe maternal toxicity (4 deaths; clinical symptoms indicating "severe cholinesterase inhibition") was observed in 32 of 47 mice. Cholinergic symptoms included excessive salivation, tremors, urine—soaked coat, ataxia, and lethargy. Mean body weight was significantly decreased in this group on day 16, and the mean value for total body weight gain was also significantly decreased, as was food and water consumption at this dosage. Plasma and RBC ChE levels were significantly decreased from controls at day 6, days 6—10, and days 6—15 of gestation, and fetal homogenate ChE levels were also significantly decreased. While there was no significant effect ' on the incidence of pregnancy, average number of implantations, live fetuses, or resorptions (at this or any experimental dosage), there was a significant decrease in fetal body weight and crown-rump length at the high dose. There were also significant increases in the occurrence of several minor skeletal variants, including delayed ossification of the skull bones, delayed ossification of the stemebrae, and unfused stemebrae at 25 mg/kg/day. By contrast, the 10 mg/kg groups showed only occasional mild to moderate symptoms of ChE inhibition in 9 of 44 treated animals, with both plasma and RBC ChE levels significantly decreased from controls at day 6, days 6—10, and days 6—15 of gestation; fetal ChE levels significantly decreased in this group as well. In the 1 mg/kg groups, only a single animal showedany cholinergic symptom (excess salivation on day 7). In the two 1 mg/kg treatment groups, plasma (but not RBC) levels were significantly reduced from controls at day 6 and days 6—15 of gestation; both plasma and RBC levels were significantly "reduced in mice treated from day 6 through day 10 of gestation in the primary study; and both plasma and RBC ChE levels were significantly decreased on days 6—10 and 6—15 in the second (concurrent) phase of this study. There was also a significantly increased incidence of exencephaly at this dosage, but this effect was not seen at either of the higher dosages making this finding questionable and of indeterminable significance. An increase in the incidence of unfused stemebrae and an decreased incidence of fused stemebrae were also observed at this treatment level. The 0.1 mg/kg dosage was found to be the NOAEL for both fetotoxicity and acetylcholinesterase inhibition in this study. With the application of appropriate uncertainty factors to account for extrapolation of animal experimental data to humans and for intraspecies variability (100 total uncertainty factor), an acute MRL of 0.001 mg/kg/day could be calculated from this study alone. However, the human data from the Coulston et a1. (1972) study is considered to be more appropriate for use in MRL derivation, and ***DRAFT FOR PUBLIC COMMENT'_M CHLORPYRIFOS 50 2. HEALTH EFFECTS the calculated MRL of 0.003 mg/kg/day is considered adequate to afford protection from all adverse health effects that have been associated experimentally as well as clinically with chlorpyrifos. Death. The LD50 for acute inhalation exposure to chlorpyrifos was determined for mice and female rats (Berteau and Deen 1978). In mice, an LD50 of 94 mg/kg was determined after whole-body inhalation exposure to 6.7—7.9 mg/L chlorpyrifos in 65% xylene. In that study, the dose range was achieved by varying the length of exposure from 27 to 50 minutes. Virgin female Sprague-Dawley rats were similarly exposed to 5.9—7.5 ug/L chlorpyrifos in 65% xylene, and an acute exposure inhalation LD50 of 78 mg/kg was determined by varying the exposure duration from 48 to 61 minutes. Systemic Effects Respiratory Effects. Acute-duration exposure to chlorpyrifos in humans has been shown to cause respiratory distress, probably due to acetylcholinesterase inhibition (Aiuto et al. 1993; Lotti et a1. 1986; Selden and Curry 1987). In piglets, acute-duration dermal exposure to chlorpyrifos causes dyspnea, also a result of acetylcholinesterase inhibition (Long et al. 1986). Cardiovascular Effects. In humans, acute-duration oral exposure to chlorpyrifos initially causes bradycardia, then tachycardia (Aiuto et a1. 1993; Selden and Curry 1987). However, the progression to tachycardia is a dose-dependent effect. Gastrointestinal Effects. Gastrointestinal distress, including nausea and diarrhea, have been observed in humans following acute- (Kaplan et al. 1993; Thrasher et al. 1993) or intermediate—duration (Kaplan et al. 1993) inhalation exposure to chlorpyrifos. In bulls, acute dermal exposure caused severe diarrhea and rumen atony (Haas et al. 1983). Hematological Effects. Acute-duration inhalation exposure to chlorpyrifos in humans has not been shown to affect blood chemistry (Kaplan et al. 1993). Musculoskeletal Effects. In humans, muscle pain (Thrasher et al. 1993) and muscle cramps (Kaplan et a1. 1993) have been reported following acute—duration inhalation exposure to chlorpyrifos. Increased muscle tone (Joubert et al. 1984) and vocal chord paralysis (Aiuto et al. 1993) were observed in humans following acute—duration oral exposure. Muscle twitching and fasciculations, hyper- or ""DRAFT FOR PUBLIC COMMENT*** CHLORPYRIFOS 51 2. HEALTH EFFECTS hyporeflexia, and coreo-athetotic motions have also been observed following acute chlorpyrifos exposure (Aiuto et al. 1993; Joubert et al. 1984; Lotti et al. 1986; Selden and Curry 1987). Hepatic Effects. In pregnant mice, acute-duration oral exposure to 25 mg/kg/day chlorpyrifos did not affect absolute or relative liver weight (Deacon et al. 1980). Endocrine Effects. No information was found associating endocrine effects with chlorpyrifos exposure in humans or animals. Renal Effects. Acute—duration inhalation exposure to chlorpyrifos caused increased urinary frequency in an adult male humans (Kaplan et a1. 1993). However, intermediate-duration human exposure to undetermined amounts of chlorpyrifos resulted in an unspecified decrease in urinary frequency (Ames et al. 1989). Dermal Effects. In humans, intermediate—duration (3 months) exposure to undetermined amounts of chlorpyrifos resulted in an unspecified increase in skin flushing (Ames et al. 1989). Ocular Effects. Acute-duration exposure in children (Aiuto et al. 1993; Selden and Curry 1987) and adults (Joubert et al. 1984) causes miosis. In humans, intermediate (3 months) exposure to undetermined amounts of chlorpyrifos resulted in an unspecified increase in blurred vision (Ames et al. 1989). Body Weight Effects. The effects of Dursban® on body weight and body weight gain were assessed in pregnant mice following acute oral exposure to doses as high as 25 mg/kg chlorpyrifos from gestational days 6—15 (Deacon et al. 1980). A statistically significant decrease in mean body weight gain for gestation days 10—15 (33.3%) and overall (gestational days 6—17; 14%) was observed in animals exposed to 25 mg/kg chlorpyrifos. In the same study, the body weight gains of dams exposed to 1 or 10 mg/kg chlorpyrifos in the same study were comparable to controls. Additionally, body weights determined on gestational day 18 for all the treatment groups were similar to control values. Immunological and Lymphoreticular Effects. The effects of acute inhalation exposure to chlorpyrifos were reported for 11 persons exposed to chlorpyrifos primarily in the home or workplace following professional application of the pesticide (Thrasher et a1. 1993). The approximate dose “*DRAFT FOR PUBLIC COMMENT*"‘ CHLORPYRIFOS 52 2. HEALTH EFFECTS received and the length of time following exposure were not known for any of the patients. Examination of blood taken from the chlorpyrifos-exposed persons indicated that there were changes in some lymphocyte subtypes when compared to 60 (28 male and 32 female) control subjects, healthy home-dwellers with or without exposure to formaldehyde. Analysis of the blood revealed a 300% increase in the mean absolute counts of CD26 cells and a decrease in the relative percentages of CD5 (11%) and CD4 (7%) lymphocytes. Additionally, 83% of the chlorpyrifos-exposed individuals had increased levels (300—1,200%) of circulating autoantibodies to at least one of the following cell types or organelles: smooth muscle, parietal cells, brush boarder, and nuclei. Twenty-five percent of the chlorpyrifos-exposed patients had elevated autoantibodies to 3 or more of the cell types or organelles compared to O—3.7% in the control group. The authors suggested that the increase in autoantibodies was due to chlorpyrifos-induced tissue damage. Neurological Effects. The most common effect in humans and other animals following acute chlorpyrifos exposure is inhibition of cholinesterase activity (Berteau and Deen_1978; Deacon et a1. 1980; Hooser et a1. 1988; Joubert et a1. 1984; Kaplan et a1. 1993; Long et a1. 1986; Selden and Curry 1987). In humans, acute exposure to chlorpyrifos is associated with a variety of symptoms, including headache, excessive salivation and lacrimation, diaphoresis, bradycardia, tachycardia, excessive respiratory tract secretions, bronchoconstriction, paresthesia, lightheadedness, memory impairment, stupor (Joubert et a1. 1984), seizure—like motor activity, and coma (Aiuto et a1. 1993; Kaplan et al. 1993; Lotti et a1. 1986; Selden and Curry 1987). Motor symptoms such as muscle twitching, fasciculations, and coreo—athetotic movements have also been observed following acute oral exposure to chlorpyrifos (Aiuto et a1. 1993; Joubert et al. 1984; Lotti et al. 1986; Selden and Curry 1987). Transient, delayed polyneuropathy has been noted in humans following acute (Aiuto et a1. 1993; Lotti et al. 1986) or intermediate (Kaplan et al. 1993) exposure to chlorpyrifos. Neurotoxic effects similar to the ones described above have also been observed in laboratory animals following acute exposure (Capodicasa et a1. 1991; Deacon et a1. 1980; Hooser et al. 1988). In the Deacon et a1. (1980) study, erythrocyte acetylcholinesterase activity was significantly inhibited at dosages of 10 and 1 mg/kg/day, but not at 0.1 mg/kg/day. Muscle weakness and abnormal gait were observed in hens orally dosed for 90 days with 10 mg/kg/day chlorpyrifos. The symptoms subsided by 60 days after the end of the dosing period (Francis et a1. 1985). "*DRAFT FOR PUBLIC COMMENT*" CHLORPYRIFOS 53 2. HEALTH EFFECTS Reproductive Effects. No effects on reproduction were observed in mice following acute- duration oral exposure to chlorpyrifos during pregnancy (Deacon et a1. 1980). However, decreased sperm production was observed in bulls to which an undetermined amount of chlorpyrifos had been dermally applied (Everett 1982). Developmental. The potential for chlorpyrifos to be developmentally toxic was assessed in mice exposed to 0, 1, 10, or 25 mg/kg/day chlorpyrifos on gestational days 6—15 (Deacon et a1. 1980). On gestational day 18, all fetuses were weighed, sexed, examined for external malformations and cleft palate, and had their crown—rump length determined. One-third of the fetuses of each litter were also examined for evidence of soft-tissue alterations. There was no biologically significant effect of treatment on the number of live fetuses per litter, the number of dead fetuses per litter, the number of resorptions per litter, the average fetal body weight, or average crown-rump length. However, significant increases in skeletal variations were observed in litters exposed to 25 mg/kg chlorpyrifos, a level also causing significant maternal toxicity. Increases were seen for the number of fetus with delayed ossification of the skull bones (68—fold increase), delayed ossification of the stemebrae (2.1-fold increase), and unfused stemebrae (4-fold increase) at the same dosage. In the same study, total fetal homogenate cholinesterase levels were decreased by 19, 35, and 65% in the litters of mice given 1, 10, or 25 mg/kg chlorpyrifos, respectively, on gestation days 6—15 (Deacon et a1. 1980). The decreases in cholinesterase activity were significantly different from controls at the 10 and 25 mg/kg doses. The intraperitoneal injection of 0.03 mg/kg chlorpyrifos to pregnant rats on gestational days 0—7 resulted in a 77% increase in fetal mortality, an unspecified body weight decrease in 15% of the litters, and an 11% increase in falls from a rotorod (Muto et a1. 1992). The results of that study provide further support that acute low-level exposure to chlorpyrifos may be fetotoxic; however, the route of administration renders this study inappropriate for MRL derivation. Genotoxic Effects. Results of studies conducted with rodent and insect cell lines suggest that chlorpyrifos may be genotoxic (Amer and Fahmy 1982; Patnaik and Tripathy 1992; Sobti et al. 1982; Woodruff et a1. 1983). A dose response effect of chlorpyrifos on the induction of micronuclei in bone marrow has been observed (Amer and Fahmy 1982). A dose response of cytotoxic cytogenetic effects in human lymphoid cells has also been demonstrated. Chlorpyrifos has been shown to produce significant increases in sister chromatid exchanges with the percentage of M3 metaphases showing a ”*DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 54 2. HEALTH EFFECTS dose response decrease (Sobti et a1. 1982). It has also been reported that chlorpyrifos causes X chromosome loss (Woodruff et a1. 1983). Spindle poisoning and induction of micronuclei and polyploidy have also been reported following chlorpyrifos exposure (Rao et al. 1988). Sex—linked recessive lethals have also been produced by chlorpyrifos exposure, indicating that chlorpyrifos is genotoxic in somatic and germ cells (Patnaik and Tripathy 1992). Finally, chlorpyrifos at concentrations of 0.05 ug/mL caused induction of chromosomal aberrations and sister chromatid exchanges in spleen cells. Chromosomal aberrations included chromatic and chromosomal gaps, and fragments. Additionally, some polyploid metaphases were observed (Amer and Aly 1992). The results of these studies are summarized in Tables 2-2 and 2-3. 2.6 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators signaling events in biological systems or samples. They have been classified as markers of exposure, markers of effect and markers of susceptibility (NAS/NRC 1989). Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers as tools of exposure in the general population is very limited. 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 molecule(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 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 chlorpyrifos are discussed in Section 2.6.1. “*DRAFT FOR PUBLIC COMMENT’" ....LN3W|NOO Ol‘lafid HOd 1.:IVHG... Table 2-2. Genotoxicity of Chlorpyrifos In Vivo Species (test system) End point Results Reference Fly (Drosophila melanogaster) Complete chromosome loss + Woodruff et al. 1983 germ cells ‘ Fly (Drosophila melanogaster) Partial chromosome loss — Woodrufl et al. 1983 germ cells Fly (Drosophila) somatic and germ cells Induction of mosaic wing spots + Patnaik and Tripathy 1992 Fly (Drosophila) somatic and germ cells Induction of sex-linked recessive + Patnaik and Tripathy 1992 lethals Mouse (Swiss) bone marrow Polychromatic erythrocytes (PE) + Amer and Fahmy 1982 and PE with micronuclei - = negative; + = positive $103553 H11V3H 'Z SOleAdHO'lHO SS ...J.N3WWOO OlWGfld HOd HVHG." Table 2-3. Genotoxicity of Chlorpyrifos In Vitro Result Species (test system) End point With activation Without Reference activation Human peripheral blood Sister chromatid exchange - Nelson et al. 1990 Mouse (Swiss) bone marrow Poiychromatic erythrocytes (PE) + Amer and Fahmy 1982 Mouse (Swiss) bone marrow Induction of micronuclei — Amer and Fahmy 1982 Mouse (Swiss) spleen cells Cytotoxicity + Amer and Aly 1992 Mouse (Swiss) spleen cells Chromosomal aberrations + Amer and Aly 1992 — = negative results; + = positive 8103533 Hl‘IVEH 'Z SOdiBAdUOTHO 99 CHLORPYRIFOS 57 2. HEALTH EFFECTS 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. Note that these markers are not often substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by chlorpyrifos are discussed in Section 2.6.2. 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, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.8, Populations That Are Unusually Susceptible. 2.6.1 Biomarkers Used to Identify or Quantify Exposure to Chlorpyrifos Measurement of erythrocyte or plasma cholinesterase activity is usually performed if organophosphate poisoning is suspected. Erythrocyte cholinesterase activity may be used as both an index of exposure and as a harbinger of potential toxicity. Butyrylcholinesterase activity may also be used as an indicator of exposure to a cholinesterase—inhibiting agent, but due to its lack of substrate specificity, it may not, by itself, be used as a reliable index of toxicity. In the case of chlorpyrifos, this insecticide inhibits acetylcholinesterase activity, but the degree of inhibition does not correlate well with the onset of toxicity or the amount of exposure. Moreover, acetylcholinesterase inhibition may occur after exposure to a wide variety of organophosphate and carbamate pesticides. Thus, acetylcholinesterase activity is not a specific marker for chlorpyrifos exposure. However, unlike many pesticides, chlorpyrifos metabolism yields some unique compounds. The major and unique metabolite of chlorpyrifos is TCP. TCP can be found in the general circulation and in the urine, its principal route of excretion. Moreover, TCP levels correlate well with the degree of exposure to chlorpyrifos, and current analytic methods can detect TCP in the nanomolar range. The results of metabolism studies conducted in animals indicate that >90% of absorbed chlorpyrifos is eliminated from the body within 48 hours. Therefore, urine TCP can be used as a qualitative *"DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 58 2. HEALTH EFFECTS biomarker for Chlorpyrifos exposure, providing the testing is performed within 48 hours after exposure. It should be noted that clinical signs of Chlorpyrifos-induced toxicity may persist for several weeks after exposure, or longer in the case of extremely high exposures. 2.6.2 Biomarkers Used to Characterize Effects Caused by Chlorpyrifos There are no specific biomarkers that may be used to characterize the effects caused by Chlorpyrifos. All the signs and symptoms of Chlorpyrifos exposure relate directly to its inhibition of acetyl- cholinesterase, which may be caused by any organophosphate or carbamate insecticide. For more information on biomarkers for renal and hepatic effects of chemicals, see ATSDR/CDC Subcommittee Report on Biological Indicators of Organ Damage (1990) and for information on biomarkers for neurological effects, see OTA (1990). 2.7 INTERACTIONS WITH OTHER CHEMICALS The primary risk of interaction is with other compounds that also inhibit acetylcholinesterase. In those cases, the dose needed to produce Chlorpyrifos-induced toxicity would be correspondingly lower. Additionally, it would be expected that concurrent exposure to other central nervous system toxicants such as solvents may exacerbate the Chlorpyrifos-induced neurotoxicity or confound the diagnosis, depending on whether the toxicant has excitatory or depressant neurological effects. Additionally, Chlorpyrifos toxicity in bovines appears to correlate with high circulating levels of testosterone, indicating that sex steroids may lower the threshold for toxicity. 2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A susceptible population will exhibit a different or enhanced response to Chlorpyrifos than will most persons exposed to the same level of Chlorpyrifos in the environment. Reasons may include genetic makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These parameters may result in reduced detoxification or excretion of Chlorpyrifos, or compromised function of target organs affected by Chlorpyrifos. Populations who are at greater risk due to their unusually high exposure to Chlorpyrifos are discussed in Section 5.6, Populations With Potentially High Exposure. "*DRAFT FOR PUBLIC COMMENT*" CHLORPYRIFOS 59 2. HEALTH EFFECTS There are many populations at potentially greater risk to chlorpyrifos-induced toxicity. Populations at risk include the elderly, persons with pre- existing medical conditions, infants and children, and pregnant and nonpregnant women The elderly are considered at risk for increased toxicity because of the general decline in health that accompanies aging. Persons with chronic respiratory ailments such as asthma, emphysema, and bronchitis would be at greater risk for respiratory distress following chlorpyrifos exposure. Persons suffering from heart disease may also represent a group at particular risk. Research using rats indicates that females are more susceptible to the toxic effects of chlorpyrifos, possibly because they detoxify chlorpyrifos at a lower rate than males. However, in bovines, bulls have been shown to be at increased risk to chlorpyrifos toxicity. It is not known if gender differences in chlorpyrifos metabolism or susceptibility exist in humans. Additionally, the doses of chlorpyrifos needed to cause death in pregnant mice are approximately six times lower than those need to cause death in nonpregnant mice, suggesting that pregnancy may increase the risk of chlorpyrifos—induced toxicity. Infants and children may also be at increased risk for toxicity. Results from animal studies suggest that chlorpyrifos more easily penetrates the skin of young animals compared to adults. Children also have a decreased metabolic capacity to eliminate toxicants and are more susceptible to central nervous system toxicants, thus lowering the exposure levels considered protective against the potential toxicity of chlorpyrifos in that population. Chlorpyrifos may also be developmentally toxic. Studies in pregnant rats suggest that low levels of chlorpyrifos exposure during gestation have the potential to increase offspring mortality, reduce birth weight, and alter offspring behavior. 2.9 METHODS FOR REDUCING TOXIC EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to chlorpyrifos. 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 chlorpyrifos. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. The following texts provide specific information about treatment following exposures to chlorpyrifos: "Cholinesterase Inhibitor Insecticides" in Harrison’s Principals of Internal Medicine, 1983, McGraw-Hill, Inc., (city not specified); B. Ballantyne and TC. Marrs. 1992. Clinical and Experimental Toxicology of Organophosphates and Carbamates, Butterworth-Heinemann, '“DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 60 2. HEALTH EFFECTS Ltd., Linacre House, Jordan Hill, Oxford; Goodman et al. 1990. The Pharmacological Basis of Therapeutics. 2.9.1 Reducing Peak Absorption Following Exposure Gastric lavage may be used to reduce peak absorption following oral exposure to chlorpyrifos (Aiuto et al. 1993; Namba et a1. 1971). Additionally, the oral administration of activated charcoal with a saline cathartic given repeatedly interrupts the enterohepatic circulation of chlorpyrifos and its metabolites. For dermal exposure, gently washing the exposed area with soap and water would be recommended; however, rough cleansing may damage the skin, leading to increased absorption of the pesticide. 2.9.2 Reducing Body Burden Repeated oral administration of activated charcoal interrupts enterohepatic circulation and reduces body burden via hepatic excretion. 2.9.3 Interfering with the Mechanism of Action for Toxic Effects There are two commonly used procedures (antidotes) to interfere with the mechanism of chlorpyrifos. One is to administer pralidoxime (2—PAM, 1 gram) intravenously to displace the chlorpyrifos or its oxon from the acetylcholinesterase enzyme and restore its activity (Namba et al. 1971). Since 2—PAM is itself a potent inhibitor of acetylcholinesterase, care should be taken not to use it in cases of concurrent exposure to carbamate insecticides, since this may exacerbate the toxicity of that group of pesticides. Additionally, 2—PAM cannot displace chlorpyrifos or its oxon from the aged form of the cholinesterase enzyme. However, 2-PAM may be given if clinical signs of toxicity are still observable. Since the percentage of aged acetylcholinesterase increases with time after exposure, 2-PAM treatment should be given as soon as chlorpyrifos exposure has been determined. Chlorpyrifos toxicosis can also be reduced using muscarinic cholinergic receptor blockers such as atropine. Atropine blocks the predominantly parasympathetic effects caused by chlorpyrifos (Aiuto et a1. 1993; Goodman et a1. 1990; Namba et a1. 1971). Atropine and 2-PAM are toxic and should be used with care. In addition to the above treatments, diazepam may be used to reduce muscle fasciculations and seizure activity (Ballantyne and Marrs 1992). "*DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 61 2. HEALTH EFFECTS 2.10 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, 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 chlorpyrifos 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 chlorpyrifos. 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 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. 2.10.1 Existing Information on Health Effects of Chlorpyrifos The existing data on health effects of inhalation, oral, and dermal exposure of humans and other animals to chlorpyrifos are summarized in Figure 2-4. The purpose of this figure is to illustrate the existing information concerning the health effects of chlorpyrifos. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not necessarily imply anything about the quality of the study or studies, nor should missing information in this figure be interpreted as a "data need." A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from the scientific literature. 2.10.2 Identification of Data Needs Acute-Duration Exposure. In general, acute—duration toxicity of chlorpyrifos has been well characterized in humans and other animals. The most common effect in humans and other animals following acute chlorpyrifos exposure is inhibition of cholinesterase activity (Berteau and Deen 1978', Deacon et al. 1980; Hooser et al. 1988; Joubert et a1. 1984; Kaplan et al. 1993; Long et al. 1986; *"DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 62 2. HEALTH EFFECTS FIGURE 2-4.1 Existing Information on Health Effects of Chlorpyrifos {$0 . K Systemic 9° «32 \fi \ .\ Q, Q: 0 -Q 0 \0 0° \° 5 \0Q \°+ ‘ (8&0 $0 «’60 ‘00 6‘0 0‘0 QQKO 0% <9 900 0"” v" 0 0“ \6‘ e Q~ 0 C9“ 0’0 Inhalation . . . . Oral . . Dermal . . Human '0 . «0“ Systemic Q90 96‘ a \Q; Q0 $40 Q0 6‘” \° $0 0" 6‘ '\° 6 o 0 \0 6 oQ 6“ x v 6‘ 0‘ 0° 0 0 e) \ 0 o“ v \0 0“ 6‘ e <2~ <> 0 0” inhalation . . . . . . Oral O O O O O Dermal . . . . . Animal 0 Existing Studies "'DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 63 2. HEALTH EFFECTS Selden and Curry 1987). In humans, acute exposure to chlorpyrifos is associated with a variety of symptoms, including headache, excessive salivation and lacrimation, diaphoresis, bradycardia, tachycardia, excessive respiratory tract secretions, bronchoconstriction, paresthesia, lightheadedness, memory impairment, stupor (J oubert et a1. 1984), seizure-like motor activity, and coma (Aiuto et a1. 1993; Kaplan et a1. 1993', Lotti et a1. 1986', Selden and Curry 1987). Motor symptoms such as muscle twitching, fasciculations, and coreo-athetotic movements have also been observed following acute oral exposure to chlorpyrifos (Aiuto et a1. 1993; Joubert et a1. 1984', Lotti et a1. 1986; Selden and Curry 1987). Transient, delayed polyneuropathy has been noted in humans following acute (Aiuto et al. 1993', Lotti et al. 1986) or intermediate (Kaplan et a1. 1993) exposure to chlorpyrifos. Neurotoxic effects similar to the ones described above have also been observed in laboratory animals following acute exposure (Capodicasa et a1. 1991', Deacon et a1. 1980', Hooser et a1. 1988). These data indicate that the database is adequate for this exposure duration and sufficient to derive an acute exposure MRL. However, acute exposure toxicity in bovines appears to be associated with high levels of testosterone. The nature of the chlorpyrifos/testosterone interaction needs to be evaluated to determine if gender-related susceptibility to chlorpyrifos toxicity exists. Intermediate-Duration Exposure. The toxic effects of chlorpyrifos following intermediate- duration exposure are expected to be similar to the cholinergic effects seen after acute-duration exposure. For example, blurred vision and skin flushing have been reported following occupational exposure to chlorpyrifos by multiple routes (Ames et al. 1989). Sufficient oral exposure data exist to calculate an MRL for this exposure route. However, toxicological data for dermal and inhalation exposure are sparse. Since chlorpyrifos is rapidly absorbed through the lungs, inhalation exposure may represent a significant health risk. Small-scale attempts to qualify chlorpyrifos-related toxicity in pesticide applicators suggest that intermediate exposure to low levels of chlorpyrifos may adversely affect health (Ames et a1. 1989); but whether the effects may be related to cumulative direct target insult or simply to cholinesterase inhibition is less clear. Low level inhalation or dermal exposures are assumed for that study because pesticide applicators are usually presumed to wear protective clothing and respirators when spraying the pesticide. However, neither the dose nor the length of exposure could be estimated. Thus, toxicological information is needed following inhalation and dermal exposure to chlorpyrifos. Based on the Ames et a1. (1989) study, it would particularly relevant to assess the toxic effects of low—level intermediate exposure on human health. Intermediate-duration exposure neurotoxicity studies conducted .in animals are recommended. Better quantification of the "*DRAFT FOR PUBLIC COMMENT**' CHLORPYRIFOS ’ 64 2. HEALTH EFFECTS toxicity caused by intermediate-duration occupational exposure would help in assessing the health risks posed by chlorpyrifos. Chronic-Duration Exposure and Cancer. Information concerning potential toxic and carcinogenic effects of chronic, low-level exposure to chlorpyrifos is needed. Of particular concern are the potential systemic effects of chronic exposure to low levels of the pesticide, particularly by the oral, dermal, and inhalation routes, because of its widespread use in industry, the home, and agriculture. Genotoxicity. Results of studies conducted with rodent and insect cell lines indicate that chlorpyrifos may be genotoxic (Amer and Fahmy 1982; Patnaik and Tripathy 1992; Sobti et al. 1982; Woodruff et al. 1983). A dose response effect of chlorpyrifos on the induction of micronuclei in bone marrow has been observed (Amer and Fahmy 1982). A dose response of cytotoxic cytogenetic effects in human lymphoid cells has also been demonstrated. Chlorpyrifos has been shown to produce significant increases in sister chromatid exchanges with the percentage of M3 metaphases showing a dose response decrease (Sobti et al. 1982). It has also been reported that chlorpyrifos causes X chromosome loss (Woodruff et al. 1983). Spindle poisoning and induction of micronuclei and polyploidy have also been reported following chlorpyrifos exposure (Rao et al. 1988). Sex—linked recessive lethals have also been produced by chlorpyrifos exposure, indicating that chlorpyrifos is genotoxic in somatic and germ cells (Patnaik and Tripathy 1992). Finally, chlorpyrifos at concentrations of 0.05 ug/mL caused induction of chromosomal aberrations and sister chromatic exchanges in spleen cells. Chromosomal aberrations included chromatic and chromosomal gaps, and fragments. Additionally, some polyploid metaphases were observed (Amer and Aly 1992). Thus, sufficient data exist to identify chlorpyrifos as genotoxic. Epidemiological studies are recommend to determine if the human data agrees with the in vitro information. Reproductive Toxicity. Chlorpyrifos administered orally from gestational days 6—15 caused severe maternal toxicity at 25 mg/kg/day (Deacon et al. 1980). The toxicity was characterized by symptoms of cholinergic stimulation and death. Despite the maternal toxicity, the surviving dams gave birth to normal numbers of offspring. No effects on reproduction were observed in mice receiving lower doses of chlorpyrifos. Decreased sperm production was observed in bulls to which an undetermined amount of chlorpyrifos had been derrnally applied (Everett 1982). The data are not sufficient to evaluate the reproductive health risk of chlorpyrifos, especially in light of its genotoxic *"DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 65 2. HEALTH EFFECTS potential. Since chlorpyrifos may affect sperm production and viability, and because the effects of intermediate or long-term exposure are not know, a two-generation reproductive toxicity assessment is recommended. This type of study would be useful because it would address the effects of chlorpyrifos on both male and female reproduction. Developmental Toxicity. The intraperitoneal injection of 0.03 mg/kg chlorpyrifos to pregnant rats on gestational days 0-7 resulted in a 77% increase in fetal mortality, an unspecified body weight decrease in 15% of the litters, and an 11% increase in falls from a rotorod (Muto et a1. 1992). The acute oral administration of 25 mg/kg/day chlorpyrifos from gestational days 6—15 decreased average fetal weight and crown—rump length (Deacon et a1. 1980). Chlorpyrifos also inhibits fetal cholinesterase activity (Deacon et al. 1980). However, the fetal effects in that study occurred in tandem with severe maternal toxicity. Thus, it is not certain if the reduction in fetal growth were secondary to maternal toxicity. More information is needed in this area, especially as it relates to the effect of chlorpyrifos on the developing nervous system because of the potential for chlorpyrifos to affect cholinergic systems. Developmental toxicity and neurotoxicity toxicity studies are recommended. Dosing in the neurotoxicity studies should extend from gestation through weaning in order to expose brain regions that develop primarily postnatally. Immunotoxicity. Preliminary data in humans suggest that chlorpyrifos may adversely affect the immune system. The effects of acute inhalation exposure to chlorpyrifos were reported for 11 persons exposed to chlorpyrifos primarily in the home or workplace following professional application of the pesticide (Thrasher et a1. 1993). The approximate-dose received and the length of time following exposure were not known for any of the patients. Examination of blood taken from the chlorpyrifos— exposed persons indicated that there were changes in some lymphocyte subtypes when compared to 60 (28 male and 32 female) control subjects, healthy home-dwellers with or without exposure to formaldehyde. Analysis of the blood revealed a 300% increase in the mean absolute counts of CD26 cells and a decrease in the relative percentages of CD5 (11%) and CD4 (7%) lymphocytes. Additionally, 83% of the chlorpyrifos—exposed individuals had increased levels (300—1,200%) of circulating autoantibodies to at least one of the following cell types or organelles: smooth muscle, parietal cells, brush boarder, and 25% of the chlorpyrifos-exposed patients had elevated autoantibodies to 3 or more of the cell types or organelles compared to 0—3.7% in the control group. The authors suggested that the increase in autoantibodies was due to chlorpyrifos-induced tissue damage. However, these data do not rule out a direct effect of the pesticide on immune function. Thus, data *“DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 65 2. HEALTH EFFECTS are insufficient to estimate the immunological toxicity potential of chlorpyrifos. An immunological test battery following intennediate- and chronic-duration exposure to low levels of chlorpyrifos is recommended. Neurotoxicity. Acute exposure to chlorpyrifos has been shown to cause transient delayed peripheral neuropathy in humans and hens. Limited epidemiological studies in humans failed to reveal motor effects of intermediate chlorpyrifos exposure. However, acute oral exposure to chlorpyrifos in humans and other animals has been reported to cause transient memory impairment. Information is lacking regarding the potential for inhaled or dermally abSorbed chlorpyrifos to cause similar cognitive deficits. Thus, data are needed regarding the potential neuropathy and neurobehavioral toxicity associated with intermediate— or chronic-duration oral, inhalation, and dermal exposure to chlorpyrifos. Epidemiological research is also needed to identify levels of cholinergic inhibition associated with the onset of cholinergic symptoms in people exposed to chlorpyrifos, and to determine if susceptible or sensitized individuals can be identified. Epidemiological and Human Dosimetry Studies. Epidemiological/ occupational studies are needed because of the large population that is potentially at risk to chlorpyrifos exposure both in the work place and the home. Biomarkers of Exposure and Effect. No additional information is needed in this area. Chlorpyrifos has a unique metabolite, TCP, that has been well characterized and for which sensitive analytic methods exist. Exposure. Although chlorpyrifos inhibits acetylcholinesterase, the degree of inhibition does not correlate well with toxicity or the amount of exposure. Moreover, acetylcholinesterase inhibition may occur after exposure to a wide variety of organophosphate and carbamate pesticides. Thus, acetyl- cholinesterase activity is not a specific marker for chlorpyrifos exposure, though total blood cholinesterase is a good indicator in animals. However, unlike many pesticides, chlorpyrifos metabolism yields some unique compounds. The major and unique metabolite of chlorpyrifos is TCP. TCP can be found in the general circulation and in the urine, its principal route of excretion. Moreover, TCP levels correlate well with the degree of exposure to chlorpyrifos, and analytic methods “*DRAFT FOR PUBLIC COMMENT*** CHLORPYRIFOS 67 2. HEALTH EFFECTS can detect TCP in the nanomolar range. Thus, TCP is a specific and sensitive marker for chlorpyrifos exposure. Effect. There are no specific biomarkers that may be used to characterize the effects caused by chlorpyrifos. All clinical signs and symptoms of chlorpyrifos exposure relate directly to its inhibition of acetylcholinesterase, which may be caused by any organophosphate or carbamate insecticide. Absorption, Distribution, Metabolism, and Excretion. In general, the absorption, distribution, metabolism, and excretion of chlorpyrifos have been well characterized in humans and other animals. However, female rats and bulls with high circulating testosterone levels appear to more susceptible to chlorpyrifos toxicity. Thus, toxicokinetic data is needed in rats and bovines to determine whether there are gender—related differences in chlorpyrifos metabolism which could be used to identify a specific population at risk. Additionally, clinical signs of chlorpyrifos toxicity may persist long after it has been eliminated form the body. Information is needed to determine if this is due to a metabolite or to long-term changes in organ responsiveness resulting from the exposure. Comparative Toxicokinetics. Adequate data exist for this area. Methods for Reducing Toxic Effects. The method for reducing the toxic effects of chlorpyrifos are well established. 2.10.3 Ongoing Studies A project currently funded by the Research Triangle Institute is investigating the effects of prenatal exposure to chlorpyrifos on offspring neurochemical and behavioral development. ”*DRAFT FOR PUBLIC COMMENT’” CHLORPYRIFOS 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Information regardin g the chemical identity of chlorpyrifos is located in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Information regardin g the physical and chemical properties of chlorpyrifos is located in Table 3-2. m'DFIAFT FOR PUBLIC COMMENT‘" 69 CHLORPYRIFOS 70 3. CHEMICAL AND PHYSICAL INFORMATION Table 3-1. Chemical Identity of Chlorpyrifos Characteristic Information Reference Chemical name 0,0-diethyl O-(3,5,6-trichloro-2-pyridyl) Worthing 1987 phosphorothioate Synonym(s) Phosphorothioic acid 0,0-diethyl Merck 1989 O-(3,5,6-trichloro-2-pyridinyl) ester; chlorpyrifos-ethyl; chlorpyriphos Registered trade name(s) Dowco 179; ENT 27311; Dursban; Merck 1989 Lorsban; Pyrinex; DMS-0971 Chemical formula C9H11CI3N03PS Merck 1989 Chemical structure Cl CH CH O N Merck 1989 3 2 \H / \ P—O Cl CH30H20/ — Cl Identification numbers: CAS Registry 2921—88-2 Merck 1989 NIOSH RTECS TF6300000 HSDB 1994 EPA Hazardous Waste 059101 HSDB 1994 OHM/T ADS 7800025 HSDB 1994 DOT/UN/NA/lMCO NA 2783 Chlorpyrifos HSDB 1994 HSDB 389 HSDB 1994 NCI No data 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 Substance Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; OHM/T ADS = Oil and Hazardous Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances "'DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 3. CHEMICAL AND PHYSICAL INFORMATION 71 TABLE 3-2. Physical and Chemical Properties of Chlorpyrifos Property Information Reference Molecular weight 350.57 Merck 1989 Color White granular crystals Merck 1989 White to tan EPA 1988b Physical state Melting point Boiling point Density at 43.5 °C Odor Odor threshold: Water Air Solubility: Water at 20 °C Water at 25 ”0 Water at 23 °C Organic solvent(s) Partition coefficients: Log KOW Log K0c Vapor pressure at 20 °C Vapor pressure at 25 °C Henry’s law constant: at 25 °C Autoignition temperature Flashpoint Flammability limits at 25 “’0 Conversion factors (25 °C) Explosive limits Amber solid cake with amber oil Colorless crystals Crystalline solid 41—42 °C 42-435 °C Decomposes at approximately 160 °C 1.398 g/cm3 Mild mercaptan No data No data 0.73 mg/L 2 mg/L 0.4 mg/mL 79% w/w in isooctane 43% w/w in methanol Readily soluble in other organic solvents 5.11 4.96 3.73 4.13 1.87x10'5 mm Hg 1.87x10'5 mm Hg 1.23x10’5 atm-ms/mol 1.73 x10'5atm-m3/moi No data None No data 1 ppm=14.3 mg/m3 1 mg/m3=0.070 ppm No data Verschueren 1983 Worthing 1987 EPA 1988b Merck 1989 Worthing 1987 Verschueren 1983 Verschueren 1983 EPA 1988b; Worthing 1987 Bowman and Sans 1985 Merck 1989 Verschueren 1983 Merck 1989 Verschueren 1983 Bowman and Sans 1983 McCall et al. 1980 Kenaga 1980 Verschueren 1983 Merck 1989 HSDB 1994 Domine et al. 1992 EPA 1988b Calculated Calculated 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 Substance Data Bank; iNCI = National Cancer Institute; NlOSH = National Institut e for Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances "'DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 73 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 4.1 PRODUCTION Chlorpyrifos is prepared commercially by several methods (Rigterink 1966). In a preferred method, the final step in the synthesis is reacting TCP and 0,0—diethylphosphorochloridothioate under basic conditions in dimethylformamide (Sittig 1985). It was introduced in 1965 by Dow Chemical Company under the protection of US. Patent 3,244,586. Producers in the United States are DowElanco in Midland, Michigan, and SureCo, Inc. in Fort Valley, Georgia (Dursban®, Empire®, Equity®, Lentrek®, Lock-On®, Lorsban®, Pageant®) (SRI 1994). Production volumes have not been located. No information is available in the Toxics Release Inventory (TRI) database on total environmental releases of Chlorpyrifos from production facilities, because Chlorpyrifos is not included under SARA, Title III, and, therefore, is not one of the chemicals that facilities are required to report (EPA 19930). 4.2 IMPORT/EXPORT Information on import/export volumes was not located. 4.3 USE Chlorpyrifos is a broad spectrum organophosphate insecticide/acaricide which is used to control a variety of harmful insects. First introduced into the non—crop specialty market, it was marketed in the late 19605 to control pests in turfgrass and ornamentals, and to control indoor pests. Chlorpyrifos was first registered for termiticide use in the United States in 1980 (Racke 1993). Products are available both for professional pest control workers and homeowners. Agricultural commercial products were introduced in the mid-19708. As a foliar pesticide for alfalfa and cotton, it is used to control aphids, armyworms, pillbugs, chinch bugs, common stalk borers, corn borers, corn earworm, corn rootworm adults, cutworms, flea beetle adults, grasshoppers, and lesser comstalk borers. It also controls peach tree borer and overwinter scale on dormant fruit trees and is used as a slurry seed treatment for seed corn maggot. It has additional uses as a foliar and soil applicant on sorghum, soybeans, sugarbeets, and sunflowers and as a soil applicant for peanuts. Dursban® is used to control fire ants, ornamental *"DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 74 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL plant insects, stored product insects, and turf— and wood-destroying insects. Lorsban® is used as a soil insecticide for pillbugs, corn rootworms, cutworms, flea beetle larvae, grubs, lesser comstalk borer, V seed' corn beetle, seed corn maggot, symphylan, and wireworm on corn (Farm Chemicals Handbook 1994). At one time, it was used to kill mosquitoes in the immature, larval stage of development, a use that involved application of formulated product directly to bodies of water, but Chlorpyrifos is no longer registered for this purpose (EPA 1986). Other discontinued uses are spray-dip or pour-on applications of Chlorpyrifos for cattle and sheep (Racke 1993). Formulations for Chlorpyrifos include emulsifiable concentrate, dust, flowable, granular wettable powder, microcapsule, pellet, and spray. Chlorpyrifos acts on pests primarily as a contact poison, with some action as a stomach poison. It is a nonsystemic contact chemical, meaning that it acts only where it comes into direct contact with plant tissues, and is not transported to other plant parts. It interferes with the activities of acetyl- cholinesterase, an enzyme that is essential for the proper working of the nervous systems of both humans and insects. There is currently no federal requirement to report sales or use of pesticides; consequently, the only figures available are estimates (Felsot 1991). From data collected from usage surveys conducted by USDA, EPA, and the Department of Food and Agriculture of the State of California, the usage of Chlorpyrifos is estimated to be 7,023,190 pounds active ingredient per year (Gianessi 1986). Agricultural uses account for most of its applications. In 1982, total agricultural use of Chlorpyrifos was estimated at 2.2—3.2 million kg (4.8—7.0 million pounds), and industrial uses ranged between 0.68 and 1.04 million kg (1.5—2.3 million pounds) (EPA 1982). The State of Ohio Agricultural Extension Service estimates that 36.33 metric tons (80,093 pounds) of Chlorpyrifos were used in the Lake Erie Basin in 1986 (Baker and Richards 1988). In 1984, about 0.15 million kg (0.33 million pounds) of Chlorpyrifos was applied to about 600,000 hectares (1.48 million acres) of wetlands in the United States for mosquito control (Odenkirchen and Eisler 1988), a use which has since been discontinued. Chlorpyrifos is used significantly in urban settings. Based on former chlordane use, the annual application of Chlorpyrifos for termite control is estimated at approximately 1.7 million pounds of active ingredient (Cink and Coats 1993). Each year, the pesticides used to control structural pests account for about 15% of California’s nonagricultural use of conventional pesticides. Structural pest control encompasses treatment of private residences, office buildings, schools, hotels, hospitals, restaurants, public transportation, and other publicly used buildings. In 1990, 604,713 pounds of “*DRAFT FOR PUBLIC COMMENT**‘ CHLORPYRIFOS 75 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL chlorpyrifos were used as structural pesticides in California, and 693,354 pounds were used in 1991 (Robinson et a1. 1994). Pesticides for commercial landscape maintenance account for about 2% of nonagricultural use in California. The landscaping use figures for chlorpyrifos in 1990 and 1991 were 45,267 pounds and 32,118 pounds, respectively. Nationally, chlorpyrifos is ranked twelfth in frequency of indoor pesticide applications and fifth in frequency of outdoor pesticide applications (Robinson et al. 1994). 4.4 DISPOSAL The recommended treatment and disposal methods for chlorpyrifos are incineration, adsorption, and landfilling (IRPTC 1989). For small amounts, the recommended disposal is absorption with materials such as sand and burying in locations away from domestic water supplies. For the decontamination of containers, the triple rinse and drain procedure is recommended. The use of a caustic soda-methanol or caustic soda-detergent rinse solution is also effective in decontaminating the container, but the rinse solutions must be disposed of either by incineration or burial in an area away from water supplies (IRPTC 1989). Small-scale farm operators have a pressing need for methods to dispose of unused concentrated and dilute formulated chlorpyrifos suspensions or solutions such as rinsate. The use of solid state fermentation (SSF) techniques to dispose of pesticide waste may be a viable alternative to other disposal methods that are either too expensive or technically too sophisticated. Chlorpyrifos was evaluated in bioreactors by Berry et al. (1993), who reported that chlorpyrifos levels were reduced to 0.6% (by solvent extraction) in 290 days in wheat straw/horse manure reactors, and that leachability studies showed that of the 28 pg chlorpyrifos in the soil column, only 72 ng leached. While not strictly a disposal method, it is worth pointing out that NaOH-methanol and sodium hypochlorite can be used to degrade (but not necessarily detoxify) chlorpyrifos. For example, on exposed surfaces, the use of caustic soda-methanol or caustic soda—detergent rinse solution can also be effective in decontaminating containers used to store chlorpyrifos, but these rinse solutions must be disposed of either by incineration or proper burial (Dillon 1981). A full discussion of regulations regarding disposal of chlorpyrifos is given in Chapter 7. ***DRAFT FOR PUBLIC COMMENT*" CHLORPYRIFOS 77 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW Chlorpyrifos enters the environment as the result of its use as a broad spectrum insecticide/acaricide for treatment of crops, lawns, ornamental plants, domestic animals, and a variety of building structures. Unintentional releases to the environment include improper indoor application, redeposition of air residues, spills, and the disposal of chlorpyrifos wastes. The important physical and chemical characteristics which influence the fate and transport of chlorpyrifos in the environment are its low solubility, volatility, and strong affinity for colloidal matter. Abiotic hydrolysis, photodegradation, and biodegradation are all important processes for the transformation and degradation of chlorpyrifos. Chlorpyrifos bioconcentrates to only a limited extent, and has little mobility in most soils. Chlorpyrifos exists in the atmosphere primarily in the vapor phase, but can partition to particulates. Chlorpyrifos is not persistent in water, due to volatilization and strong adsorption to particulate matter. Indoor air, food, and soil are the environmental media with the highest degree of chlorpyrifos contamination; ambient air, and ground and surface water have lesser degrees of contamination. Although a large amount of chlorpyrifos is used in various environments (see Chapter 4), levels of general exposure are mediated by its limited mobility and persistence, and by environmental degradation processes. Several subpopulations are at higher risk of exposure: workers in industries that manufacture and formulate chlorpyrifos, those whd apply the insecticide, and farm workers who enter treated fields after the insecticide has been applied. Among the general population, people who use the insecticide in homes and gardens and people who ingest food exposed to chlorpyrifos are at higher risks of exposure. Chlorpyrifos has been identified in at least 7 of the 1,416 hazardous waste sites that have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 1995). However, the number of sites evaluated for chlorpyrifos is not known. The frequency of these sites within the United States can be seen in Figure 5-1. "*DRAFT FOR PUBLIC COMMENT‘" ....LN3WWOO OHQnd 80:! LdVHG... FIGURE 5—1. FREQUENCY OF NPL SITES WITH CHLORPYRIFOS CONTAMINATION * FREQUENCY [BE 1 SITE m 3 SITES *Derived from HazDat 1995 BHQSOdXS NVWOH 80:! WVILNBLOd '5 SOSIHAdHO‘IHO 8L CHLORPYRIFOS 79 5. POTENTIAL FOR HUMAN EXPOSURE 5.2 RELEASES TO THE ENVIRONMENT 5.2.1 Air Chlorpyrifos enters the atmosphere as a result of its use as an insecticide/acaricide. Chlorpyrifos is released to the atmosphere by volatilization during foliage or soil application by ground or air broadcast equipment (Racke 1993). Air emissions from chlorpyrifos production have been reported to be 0.5 kg per 1,000 kg (one metric ton) produced (Sittig 1980). The Toxic Chemical Release Inventory in 1992 did not require reporting of chlorpyrifos releases to air (EPA 1993c). No information was found on detections of chlorpyrifos in air at NPL hazardous waste sites (HazDat 1995). 5.2.2 Water Chlorpyrifos is released to water during foliage or soil application as an insecticide/acaricide by ground or air broadcast equipment and during subsequent runoff or leaching (Racke 1993). Leaching and runoff from treated fields, pesticide disposal pits, or hazardous waste sites may inadvertently contaminate both groundwater and surface water with chlorpyrifos. Entry into water can also occur from accidental spills, redeposition of atmospheric chlorpyrifos, and discharge of waste water from chlorpyrifos manufacturing, formulation, and packaging facilities (HSDB 1994; Racke 1993). In the past, chlorpyrifos was aerially applied to water over swamps for mosquito abatement; however, it is no longer registered for this use. No other uses are known which result in direct application to water (EPA 1986). The Toxics Release Inventory in 1992 did not require reporting of chlorpyrifos releases to water (EPA 1993c). Chlorpyrifos has been detected in surface water samples collected at one of the 7 NPL sites where chlorpyrifos has been detected in some environmental media (HazDat 1995). The HazDat information used includes data from NPL sites only. 5.2.3 Soil Chlorpyrifos is released in agricultural, home, and garden soil during direct soil or foliar treatment, and from disposal of chlorpyrifos-containing wastes in hazardous waste sites (HSDB 1994). Much of the chlorpyrifos (or its metabolites) applied to foliage eventually reaches soil (Racke 1993). Soil in waste disposal sites may include manufacturing wastes containing chlorpyrifos. A primary method for *"DRAFT FOR PUBLIC COMMENT*“ CHLORPYRIFOS ‘ 80 5. POTENTIAL FOR HUMAN EXPOSURE disposing of liquid pesticide wastes has been the dumping of liquid materials into soil evaporation pits, ditches, and ponds. Topsoil from such discharge areas is expected to be contaminated with pesticides; the soil from one such discharge pit contained chlorpyrifos at concentrations between 1,012 and 3,193 mg/L in the top 7.5 cm. (Winterlin et al. 1989). Soil from tail water pits used for collecting irrigation runoff may also be a source of chlorpyrifos if the soil is treated with this insecticide (Kadoum and Mock 1978). Chlorpyrifos may also enter soil by redeposition of atmospheric chlorpyrifos (Racke 1992). Entry may also occur from spills during storage, transport, or equipment loading and cleaning, although the sophistication of contemporary management practices limits this amount. The Toxics Release Inventory in 1992 did not require reporting of chlorpyrifos releases to soils (EPA 1993c). Chlorpyrifos has been detected in soil samples collected at one of the 7 NFL sites where chlorpyrifos has been detected in some environmental media (HazDat 1995). The HazDat information used includes data from NFL sites only. 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partitioning The vapor pressure of chlorpyrifos is 1.9x10'5 mm Hg at 25 °C (2.5x10'8 atm) (Racke 1993). This suggests that while chlorpyrifos is in the atmosphere it will exist primarily in the vapor phase, but will also partition to available airborne particulate (Eisenreich et al. 1981). Experimental evidence during fog events (Glotfelty et al. 1990) supports this hypothesis. The removal rate by dry deposition is low for such compounds (Schroeder and Lane 1988); therefore, depending on its reactivity characteristics and the amount of available airborne particulate, chlorpyrifos may travel long distances in the air. The low solubility of chlorpyrifos at 1.12 mg/L at 24 °C (Felsot and Dahm 1979) indicates that dry deposition is a more important process than wet deposition. The transport of chlorpyrifos from water to air can occur due to volatilization. Compounds with a Henry’s law constant (H) of <10'5 atm-m3/mol may volatilize slowly from water (Lyman et al. 1990). Chlorpyrifos, with an H value of 6.6x10'6 atm-m3/mol at 25 °C (Downey 1987) may therefore volatilize slowly from water. The dimensionless Henry’s law constant (H’) or air/water partition coefficient for chlorpyrifos, as calculated from vapor pressure and solubility data, has been reported to be 5.0x10‘4 (Glotfelty et al. 1987), 7.3x10'4 (Suntio et a1. 1987), and 1.7 :0.3x10'4 (Fendinger and ""DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 81 5. POTENTIAL FOR HUMAN EXPOSURE Glotfelty 1990). Using these data, the estimated volatilization half—life from a river 1 meter deep flowing 1 m/sec with a wind velocity of 3 m/sec is estimated to be 9 days (Lyman et al. 1982). The amount of Chlorpyrifos available to be volatilized from surface water is reduced by sediment adsorption. Chlorpyrifos has a strong affinity for soil colloids, as evidenced by its measured range of organic carbon-adjusted soil sorption coefficient (K06) of 973—31,000 (Felsot and Dahm 1979; Kenaga 1980; McCall et a1. 1980', Racke 1993). This suggests that Chlorpyrifos in natural water ecosystems adsorbs strongly to suspended solids and sediments, and that this process may transport considerable amounts of Chlorpyrifos from water to particulate matter. Several studies have reported very low concentrations of Chlorpyrifos in surface waters (see Section 5.4.2). Aquatic bioconcentration factors (BCF) ranging from 1 to 5,100 for Chlorpyrifos and metabolites have been determined extensively from laboratory and field studies (Odenkirchen and Eisler 1988; Macek et al. 1972; Mulla et al. 1973; Racke 1993). These studies suggest that Chlorpyrifos bioconcentrates to varying degrees in different organisms, and with different doses and durations of exposure. It has been suggested (Racke 1993) that the BCF values determined during short duration single-dose exposure studies may not be indicative of long-term exposure due to nonattainment of equilibrium conditions. Five to nine days have been observed to be necessary for steady-state conditions (Hedlund 1973; Welling and deVries 1992). The transport processes that may move Chlorpyrifos from soil to other media are volatilization, leaching, runoff, and biotransfer by plants. Post-application volatilization of Chlorpyrifos applied as an agricultural insecticide and subsequent atmospheric transport is thought to be a primary means by which Chlorpyrifos is dispersed throughout the environment. Volatilization is affected by soil cultivation practices. Cumulative losses of Chlorpyrifos by volatilization from no till (NT) and from conventionally tilled (CT) plots were measured by Whang et a1. (1993). The NT/CT flux ratio increased from a factor of about 3 on days 1 and 2 to a factor of 12 by day 26. Soil dryness did not often limit volatilization, and differences in soil moisture resulting from different tillage practices were not usually a major reason for differences between fluxes. Volatilization rates, which result from the complex interplay between Chlorpyrifos sorbed to soil, dissolved in the soil pore water, and present in the soil air spaces, can be quite variable. Chlorpyrifos (applied to the soil at 11 ug/cmz) was captured from three moist soils (0.3 bar soil moisture tension, *"DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 82 5. POTENTIAL FOR HUMAN EXPOSURE 25 °C) by blowing an airstream of 1 km/hour over the soils. The calculated flux rate ranged from 80—290 g/hectare/day during the first 3 days, with 62—89% of applied chlorpyrifos remaining after 36 hours (McCall et al. 1985). Racke et al. (1991) observed significantly less volatility over a longer exposure period with ranges of 3—39 g/hectare/day, with >90% of the applied chlorpyrifos remaining after 30 days. When applied as a foliar spray, the volatilization of chlorpyrifos from corn leaves is rapid. In the laboratory, 80% volatilized within 48 hours at 30 °C with a simulated wind speed of 0.8 km/hour (McCall et al. 1985). A field study confirmed the fairly rapid rate of volatilization, with an observed half-life of about 1.5 days on corn and soybean foliage (McCall et al. 1984). Leaching studies have shown chlorpyrifos to have little mobility in soil. Laboratory leaching studies revealed that all the surface-applied residues of chlorpyrifos were confined to the upper 5 cm of several soils after elution with 20 cm of water (Harris et al. 1988; McCall et a1. 1985). Field studies have confirmed this lack of mobility, with chlorpyrifos residues being confined to the upper 12 inches of soils in several trials (Oliver et al. 1987; Fontaine and Teeter 1987). The leaching and dissipation of the applied l4C-chlorpyrifos in sandy soil under simulated field precipitation, drainage and temperature was less than 0.2% (Fermanich and Daniel 1991). Amounts of chlorpyrifos lethal to termites moved to a depth of at least 30 cm in decomposed granite soil from the Santa Ana River bed in Colton, California, after having been applied at 500 ppm to the top 7.62 cm of soil in a long column of 34 mm diameter and 2130 mL of water dripped through (Smith and Rust 1992). Studies indicate that runoff of chlorpyrifos is of minor environmental significance. In a study conducted in an Iowa cornfield, approximately 0.003% of three applications of chlorpyrifos was transported via runoff to a pond within the watershed (McCall et a1. 1984). Information from irrigated environments such as turf indicates that because of the lack of erosion of soil particles, strongly sorbed chlorpyrifos is not transported via runoff (Watschke and Mumma 1989). Even during a simulated 100-year rainfall event (13.6 cm) occurring less than a week after application, only between 0.10 and 0.29% of the applied chlorpyrifos was present in runoff. In another study of runoff from turfgrass treated at 1.12 kg/hectare with irrigation applied at 150 mm/hour, no residue of chlorpyrifos was detected at 5 pg/L (minimum detection level) (Harrison et a]. 1992). The movement of chlorpyrifos was studied from 1985 to 1987 in a small agricultural Saskatchewan watershed (Waite et al. 1992). In 1985—86, 3—4 million hectares of farmland were treated with insecticides at application rates as high as 1 kg/hectare to control grasshopper infestations. The frequency of occurrence and concentrations of chlorpyrifos in groundwater, surface water and runoff from spring snow melt were measured. No "’DRAFT FOR PUBLIC COMMENT”; CHLORPYRIFOS 83 5. POTENTIAL FOR HUMAN EXPOSURE chlorpyrifos was found in any of the samples at a detection limit of 1.0 ppb in 1985 and 0.1 ppb in 1986. Spills are an important way that chlorpyrifos enters surface waters. A spill of chlorpyrifos into a marine bay resulted in initial water concentrations of up to 300 ug/L, but because of sediment sorption, dissipation, and dilution, the concentration had dropped to below detectable levels within 17 days (Cowgill et a1. 1991). Some research has shown that only very small levels of chlorpyrifos are taken up by roots, translocated, or metabolized by plant tissues (Kenaga et al. 1965; Smith et a1. 1967). Cranberry bean plants were hydroponically grown in nutrient solutions containing 50 ppm of chlorpyrifos emulsifiable concentration. After 72 hours, only 0.07—0.10% of the radioactivity present, composed of TCP and other degradation products, had been translocated to the plant tops. In another experiment (Smith et a1. 1967), one leaf of the cranberry bean plant was treated foliarly with 1 mg of chlorpyrifos. After 7 days, <1% of the chlorpyrifos applied was found in nontreated areas of the plant. Other researchers have found that soil-applied doses of chlorpyrifos are transported to foliage (Rouchaud et al. 1991). Cauliflower and brussels sprouts were treated with chlorpyrifos by pouring it onto soil around the stem of the plant for protection against the root fly. During plant growth chlorpyrifos and its soil metabolites were transported from soil into the plant foliage, were it could give a secondary plant protection against the foliage insects. The foliage concentrations of the nonsystemic chlorpyrifos was 21 mg/kg fresh weight during a period of about 44 days after soil treatment in brussels sprouts crops and a period of 35 days in cauliflower crops. 5.3.2 Transformation and Degradation 5.3.2.1 Air Both chlorpyrifos and its degradation product, TCP, have ultraviolet (UV) absorbencies above 295 nm, indicating their susceptibility to photodegradation by sunlight. The photodegradation half-life of chlorpyrifos in the laboratory is approximately 2.6 days (Fontaine and Teeter 1987). While in the atmosphere, chlorpyrifos will react with photochemically induced hydroxyl radicals. Its estimated half- ***DRAFT FOR PUBLIC COMMENT’" CHLORPYRIFOS 84 5. POTENTIAL FOR HUMAN EXPOSURE life is 6.34 hours (Atkinson 1987). Figure 5-2 shows environmental degradation pathways of chlorpyrifos. 5.3.2.2 Water The processes primarily responsible for the transformation and degradation of chlorpyrifos in water are abiotic hydrolysis and photosensitized oxidation. Neutral hydrolysis is favored below pH 9, whereas alkaline hydrolysis dominates above pH 9 (Macalady and Wolfe 1983). Thus, both the disappearance half-life and the products are pH-dependent. Neutral hydrolysis yields O-ethyl-O—3,5,6-trichloro- 2-pyridy1 phosphorothioate, while alkaline hydrolysis occurs by base-catalyzed cleavage at the phosphate ester linkage to produce TCP and phosphorthioic acid. Neutral hydrolysis is pseudo-first- order, while alkaline hydrolysis is second order (Wolfe 1988). Keeping the temperature at 25 °C, at pH 1, the half—life 0f chlorpyrifos in distilled water was 89.14 days, and at pH 12.9, it was 0.01 days (Macalady and Wolfe 1983). At 20 °C, it has a half-life of 120 days at pH 6.1 and 53 days at pH 7.4 (Freed et a1. 1979). The activation energy for the hydrolysis of chlorpyrifos at a pH of 7.4 is 14 kcal/mol indicating its sensitivity to temperature change. Laboratory studies on the interaction of chlorpyrifos with Cu2+ have demonstrated metal-catalyzed hydrolysis and have provided rate constants for this pathway (Blanchet and St. George 1982). Photodegradation in water is possible since chlorpyrifos absorbs in the UV region at >295 nm; however, its relative importance as a dissipative force in the environment is unclear. Laboratory studies from artificial light sources may not be very useful for predicting environmental photodegradation kinetics (Miller and Zepp 1983). For example, chlorpyrifos in natural waters is usually very strongly sorbed to suspended particulate and bottom sediment, and thus less readily available to photolytic forces than chlorpyrifos in clear distilled water in the laboratory. Under field conditions, chlorpyrifos exhibits very short persistence in the water compartment of aquatic ecosystems, and half-lives as short as several hours have been observed. This is due both to its considerable volatility from water (arising from low solubility and moderate vapor pressure) and its high association with sediment. The rate of disappearance of chlorpyrifos from river and well waters in a pH range of 8.0—8.5 was studied in the laboratory at a range of temperatures and under conditions of light and dark (Frank et a1. 1991). The half—life for the disappearance of chlorpyrifos at 21 °C was 4.8 days and at 4 °C was 27 days, indicating that temperature plays a major role in the degradation of *“DRAFT FOR PUBLIC COMMENT‘“ .ulNHWWOO OlWSfid 80$ L'IVHG... Figure 5-2. Environmental Degradation Pathways of Chlorpyrifos Cl Cl Cl CI Cl \ \ C' \ / / / Cl N 0 —fi’ —~ (OCZH5)2 Cl N OH Cl N OCH3 S CHLORPYRIFOS (0.0-diethyl-O-(3.5,6-trichloro- 3,5,6-trichloro-2-pyridinol (TCP) 3,5,6-trichloro-2-methoxy- 2-pyridyl)phosphorothioate) pyridine . CO H20 [0] / N 2 Organic Acids Conjugates , Cl CI CI CI \ \ | OH I / l / Cl N 0— p—- OCZH5 0| N 0— III)— (002H5)2 H S O O-ethyl-O—(a,5,6-trichloro- 2-pyn’dyl) phosphorothioate ("desethyl chlorpyflfos') 0,0-diethyl-O-(3,5,6-trichloro- 2-pyridyl)phosphate ('chlorpyrifos oxon') H20 Cl Cl TCP \ | OH / I Cl N 0—P— OCZHS H o O-ethyI-O-(S,5,6-trichloro- 2-pvn‘dvl) phosphate EHflSOdXB NVWflH 80:! 'lVliNalOd '9 SOdIUAdHO'IHO 98 CHLORPYRIFOS 86 5. POTENTIAL FOR HUMAN EXPOSURE chlorpyrifos in water. The half-life for disappearance of chlorpyrifos in the dark was 56 days and in the light was 46 days at 21 °C, indicating that in water sunlight photolysis is not a major route of chlorpyrifos degradation. The persistence of chlorpyrifos in surface water was studied (Hughes et a1. 1980) by application of 10 ppb to polyethylene-lined ponds and a single natural pond inoculated with leaf litter. In early post— treatment, there was rapid partitioning to adsorption on bottom sediments and polyethylene; 30—60% disappeared from the water within 24 hours. The time for the concentration of chlorpyrifos to decline to 0.01 ppb in the polyethylene-lined pond was estimated to be 40 to >200 days compared to 18 days for the natural pond. The desorption from sediments was considerably slower from organic matter than from polyethylene. Desorption from the polyethylene contributed to residual concentrations in the water of artificial ponds for up to 18 months. Similar results were noted in an artificial lake treated with chlorpyrifos: lake water concentrations peaked 1 day after treatment at 0.9 ug/L and leveled near 0.2 ug/L after 3 weeks (Mulla et al. 1973). First—order degradation rate constants of chlorpyrifos were determined in estuarine water and sediment/water slurry systems (Walker et a1. 1988). Half-lives of chlorpyrifos in sediment/slurry systems calculated from these rate constants ranged from. 12 to 30 days for the non-sterile system, and 16—51 days for the sterile system. Half-lives for the seawater-only systems ranged from 13 to 41 days for the non—sterile systems and 3.5—24 days for the sterile systems. The half-life of chlorpyrifos in seawater was 24 days in a sediment-seawater slurry (Schimmel et a1. 1983). These data indicate that abiotic processes predominate in estuarine systems. 5.3.2.3 Sediment and Soil Chlorpyrifos may undergo degradation on the surface of soils by photo-induced reactions. Laboratory photodegradation of chlorpyrifos on soil surfaces with UV light (254 nm from mercury lamps) demonstrated that three different photochemical processes (hydrolysis, dechlorination, and oxidation) take place simultaneously (Walia et a1. 1988). The oxidative and dehalogenated products formed during photo—irradiation of soil undergo further photolysis to form chloropyridinols and 0,0—diethyl phosphorothioic acid. The oxon is unstable; it tends to hydrolyze more rapidly than chlorpyrifos and does not accumulate in the soil. With the passage of time, the percentage of chlorinated pyridinols also decreased, suggesting that these products are mineralized in the soil under UV-photo-irradiation "*DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 87 5. POTENTIAL FOR HUMAN EXPOSURE conditions. Under simulated sunlight conditions, the rate of photodegradation of chlorpyrifos on a leaf surface was slow. Chlorpyrifos was stable up to 10 days; then the oxon (1.5%) and the hydrolytic product, TCP (2.5%), were detected. Dehalogenated analogs of chlorpyrifos could be detected only after 15 days of constant irradiation. Under these conditions, the photo-oxidation process was more predominant than the photohydrolytic or dehalogenation process. Formation of such photoproducts on an irradiated soil surface was very fast, but the rates in the laboratory will differ from those found under environmental conditions. Chlorpyrifos undergoes transformation in soil by the processes of abiotic hydrolysis and microbial degradation. A few studies have attempted to separate abiotic chemical hydrolysis from microbial processes and to determine their relative importance (Miles et al. 1979, 1983). The half-lives of chlorpyrifos in muck (48% organic matter [OM]) and loam (2.7% OM) were determined in sterilized and natural soils at 3 temperatures (3, 15, and 28 °C). The results indicate that in sterile soils, chlorpyrifos is progressively more degraded by abiotic hydrolysis as the temperature increases, and that it degrades faster in sandy loam than in muck (after 24 weeks, 38% versus 68% remaining at the highest temperature). An explanation for the soil difference may lie in the pH. The sterile loam had a pH of 6.5, whereas the sterile muck had a pH of 5.9, indicating that increasing pH increases degradation. The degradation study of chlorpyrifos in natural soil gave the same progression for increasing temperature, and it continued to degrade faster in the loam than in the muck (half-lives of 16, 6, and 2.5 weeks versus >24, 15, and 6 weeks at the respective temperatures). All half-lives were shorter in the natural soils as opposed to the sterile soils, however, indicating microbial degradation in addition to abiotic chemical hydrolysis. Some researchers have concluded that chlorpyrifos is not catabolized (Racke and Coats 1988, 1990) because it is resistant to enhanced degradation by microbes. When chlorpyrifos is applied to fields with a soil history of chlorpyrifos use, the breakdown of chlorpyrifos is not enhanced, and is often delayed (Racke and Coats 1988; Somasundaram et al. 1989). The biotic process at work is probably co-metabolism. Patterns of persistence were observed in a variety of agricultural soils after treatment with l4C-chlorpyrifos and its hydrolysis product, TCP (Racke et al. 1988). In soils with no previous history of chlorpyrifos use, significant quantities of TCP and soil—bound residues were produced, but little l4C02. In soils with a history of chlorpyrifos use, neither TCP nor soil-bound residues accumulated, but large quantities of 14CO2 were produced. Direct treatment of fresh samples of each of these soils with l4C-TCP resulted in rapid mineralization of TCP to 14C02 only in those soils with ""DRAFT FOR PUBLIC COMMENT*** CHLORPYRIFOS 88 5. POTENTIAL FOR HUMAN EXPOSURE a history of prior chlorpyrifos use. The rapid mineralization of TCP in these soils was microbially mediated. It is unclear if catabolic or co-metabolic processes are predominant (Racke and Robbins 1990) in the degradation of TCP. TCP exhibited sorption (Kd) coefficients of between 0.3 and 20.3 mL/g (mean of 3.1) and calculated mean K0C coefficients for the neutral and anionic forms of 3,344 and 54 mL/g, respectively. In a study of persistence of chlorpyrifos in a silt loam soil, the disappearance rate was fast in the first 15 days, but slowed after that. The pseudo- first- order rate constants were 0.041 day'1 and 0 044 day"1 , for the band treatment at seeding, and 0 040 day"1 for the drench at seeding. The calculated half— lives ranged from 15.8 to 17.3 days (Szeto et a1. 1988). 5.4 LEVELS MONITORED 0R ESTIMATED IN THE ENVIRONMENT 5.4.1 Air Chlorpyrifos has been detected in both outdoor and indoor air; of special concern are levels in fogwater and environments receiving broadcast pesticide application, and in selected indoor environments such as poorly ventilated and artificially lit environments and the infant breathing zone (25 cm above the carpet). Selected studies documenting chlorpyrifos concentration and persistence in these environments include Anderson and Hites (1988); Fenske et a1. (1990); Jackson and Lewis (1981); Leidy et a1. (1992); Lewis et al. (1988); Moye and Malagodi (1987); Vaccarro (1993); and Wright et al. (1991, 1994). Special issues in these environments are discussed below. Substantially higher chlorpyrifos concentrations were measured in the infant breathing zone than in the adult breathing zone, implying a vertical gradient with the treated carpet serving as a source of volatilized chlorpyrifos (Fenske et a1. 1990). All concentrations in the infant breathing zone exceeded the National Academy of Sciences interim guideline of 10 ug/m3. This study also indicated that broadcast applications appear to produce average levels 5—10 times higher and peak levels 1—2 orders of magnitude greater than other application procedures, with peak concentrations occurring 3—7 hours after application. Significantly more chlorpyrifos was present in the air of houses built over sand than in the air of houses built over clay soils following treatment in the crawl spaces. However, no differences were found between rooms or construction types (slab, crawl, crawl-slab) (Wright et al. 1988). The air of storage rooms in commercial pest control buildings was found to have a higher "‘DRAFI' FOR PUBLIC COMMENT’" CHLORPYRIFOS 89 5. POTENTIAL FOR HUMAN EXPOSURE concentration (220 ng/m3) of chlorpyrifos than office rooms (126 ng/m3). The same study detected levels of chlorpyrifos from 20 to 1,488 ng/m3 in the air of six food preparation serving areas following application of a 0.5% emulsion spray into cracks and crevices, although concentrations dropped considerably over 24 hours in all areas. Chlorpyrifos was detected in homes and pest control offices and vehicles, with residues ranging from 0.1 pg/m3 to 5.0 ug/m3 (Leidy et a1. 1992). Air concentrations in commercial pest control vehicles ranged from 9 to 221 ng/m3 (Wright and Leidy 1980). High fogwater concentrations (320—6,500 ng/L) were reported at Parlier, Corcoran, and Lodi, California, relative to air concentrations (0.6-14.7 ng/L), with enrichment factors of 160—260 (Plimmer 1992). Other researchers have found similar enrichment factors (Glotfelty et al. 1987, 1990). Enrichment was attributed to the effect of temperature correction, colloidal organic matter, and adsorption. The enrichment factor has also been correlated to hydrophobicity, as indicated by KOW (Valsaraj et al. 1993). There is less evidence of general contamination of ambient air, although residues have been detected. Ambient air monitoring at 10 US. locations in 1980 resulted in 14 detections from 123 samples, with a maximum of 100 ng/m3 and an arithmetic mean of 2.1 ng/m3 (Carey and Kutz 1985). This same study reported 2 detections of chlorpyrifos from 11 air samples in Pekin, Illinois, in 1980. Ambient air and wet deposition monitoring of chlorpyrifos in California indicated that atmospheric transport is occurring from the Central Valley, where chlorpyrifos is used agronomically, to the Sierra Nevada Mountains; concentrations decrease with distance from the source area and elevation (Zabik and Seiber 1993). A maximum concentration of 6.5 ng/m3 was recorded in the valley; the maximum value mid- slope was 0.083 ng/m3. A loading rate of 0.8 ug/m2 to Sierra National Park was calculated. 5.4.2 Water Chlorpyrifos has been detected in ground and surface waters, but only rarely, and generally well below levels of concern. Hallberg (1989) reported that chlorpyrifos was detected (concentrations unspecified) in 0.2% of 334 samples from groundwater used for public drinking water supply in Illinois, but was not detected in 15 Iowa samples. This same study detected chlorpyrifos in 45% of the wells in the vicinity of agrochemical dealers, and in 1.4% of farm water supply wells. In a survey of surface waters in southern Ontario from 1975—1977, chlorpyrifos was detected in 3 of 949 samples from “"DRAFT FOR PUBLIC COMMENT”“’ CHLORPYRIFOS 90 5. POTENTIAL FOR HUMAN EXPOSURE 11 agricultural watersheds (Braun and Frank 1980). Krill and Sonzogni (1986) reported no detections of chlorpyrifos in groundwater sampling of 358 wells in Wisconsin. In a study of 54 wells in California, Maddy et al. (1982) found no detectable levels of chlorpyrifos. Pionke et al. (1988) and Pionke and Glotfelty (1989) found no detectable levels of chlorpyrifos in a study of 21 wells and 2 springs (detection limit of 4 ng/L) in Pennsylvania. Maddy et al. ( 1982) found no detectable levels of chlorpyrifos in a study of 53 wells in California. In an intensive monitoring effort, Richards and Baker (1993) detected chlorpyrifos in 0.0—1.06% of 750 samples for each of 7 tributaries to Lake Erie from 1983—1991. A maximum chlorpyrifos concentration of 480 ug/kg in runoff from irrigated cropland in California was reported by Leonard (1990). Total seasonal losses as a percentage of application were 0.02—0.24, and were attributed to aerial application during irrigation. Chlorpyrifos detections were not reported as part of the national surface water monitoring program for 1976—1980 (Carey and Kutz 1985). 5.4.3 Sediment and Soil Limited data on chlorpyrifos residues in soils or sediments were located. At a detection limit of 0.01 mg/kg, chlorpyrifos was not detected in sediment samples collected from Lakes Superior and Huron, including Georgian Bay, in 1974 (Gloschenko et al. 1976). Chlorpyrifos detections were not reported in sediments as part of the national surface water monitoring program for 1976—1980 (Carey and Kutz 1985). Soil evaporation pits, ditches, and ponds have been used to dispose of liquid pesticide wastes in California (Winterlin et al. 1989). A core soil sample taken from one such pit in northern California contained detectable levels of chlorpyrifos to a depth of 67.5 cm (Winterlin et al. 1989). 5.4.4 Other Environmental Media The Food and Drug Administration (FDA) identified chlorpyrifos in four grain samples and in four samples of animal feed in 1975 (Duggan et al. 1983). The FDA’s pesticide residue monitoring program for domestic and imported food commodities detected chlorpyrifos 33 times from 1,044 samples in unspecified foods at unspecified concentrations during fiscal years 1978—1982 and 295 times from 3,744 samples during fiscal years 1982—86 (Yess et al. 1991a, 1991b). From October 1, 1981, to September 30, 1986, the FDA Los Angeles District Laboratory detected chlorpyrifos in 1,969 of 19,851 samples of domestic and imported food and feed commodities (Luke et al. 1988). Chlorpyrifos was detected in 440 of 4,916 samples analyzed as part of the FDA Total Diet "*DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 91 5. POTENTIAL FOR HUMAN EXPOSURE Study between 1986 and 1991. As part of the FDA’s Pesticide Monitoring Program for domestic and imported foods, chlorpyrifos residues have been detected during 1988—1989, 1989—1990, 1990—1991, and 1991—92 (FDA 1990, 1991, 1992, 1993). Chlorpyrifos was detected in domestic feed, lavender, lettuce, cantaloupe, peanuts, bell peppers, summer squash, and cherry tomatoes, and in imported apples, green beans, cabbage, coriander, cucumbers, eggplant, feijoa, kiwi, green leaf lettuce, cantaloupe, honeydew, nectarine, Chinese peas, peaches, peppers, spinach, squash, tomatillos, and tomatoes (Hundley et al. 1988). Gartrell et al. (1986) found chlorpyrifos in meat, fish and poultry, grain and cereal products, garden fruits, oils and fats, and sugar. Chlorpyrifos was detected in 121 different domestic foods (0.9% of samples) in 1988 and 128 domestic foods (1.0% of samples) in 1989 by state regulatory monitoring (Minyard et a1. 1991). In a pesticide residue screening program conducted in 1989—91 in San Antonio Texas on 6,970 produce samples, chlorpyrifos was detected in 41 produce samples (lemons, oranges, peppers, turnips), with a detection limit of 0.25 ppm (Schattenburg and Hsu 1992). In a study of pesticide residue contamination of processed milk—based and soy-based infant formula, chlorpyrifos was not detected (Gelardi and Mountford 1993). However, in a study of pesticide residues in composited milk, chlorpyrifos was found in 23 of 806 composite samples (Trotter and Dickerson 1992). The EPA Office of Water has recommended that chlorpyrifos residues be monitored by states in their fish and shellfish contaminant monitoring programs in watersheds where this pesticide has been or is currently used extensively in agriculture (EPA 1993c). While no fish or shellfish consumption advisories are currently in effect for chlorpyrifos, this contaminant has not been widely monitored in State fish contaminant monitoring programs or the US Fish and Wildlife Service National Contaminant Biomonitoring Program (EPA 1993c). In a national study, EPA (1992a) did detect chlorpyrifos in fish in 26% of 362 sites with mean and maximum concentrations of 4.09 ng/g and 344 ng/g, respectively. 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE The general population is exposed to chlorpyrifos primarily by inhaling indoor air and ingesting food containing chlorpyrifos, and through skin contact during or after pesticide application. Chlorpyrifos has been very infrequently detected in ambient air, and only at very low concentrations (see Section 5.4.1). It is not anticipated that the general population would experience substantial levels of exposure by inhaling ambient air. Chlorpyrifos has rarely been detected in drinking water (see Section 5.4.2), ***DRAFT FOR PUBLIC COMMENT**" CHLORPYRIFOS 92 5. POTENTIAL FOR HUMAN EXPOSURE and consumption of chlorpyrifos-contaminated drinking water is not considered a significant exposure route for the general population. Chlorpyrifos has been detected in some foods (see Section 5.4.4), so ingestion may be a route of exposure for the general population. The FDA has estimated daily food intakes of chlorpyrifos for different age/sex groups in the United States. The FDA estimated the dietary intake of chlorpyrifos for a 14—16-year-old male in the United States to be 3.4 ng/kg body weight/day, which is much lower than the Food and Agricultural Organization of the United Nations/World Health Organization’s (FAO/WHO) acceptable daily intake (ADI) of 10 ug/kg body weight/day and ATSDR’s intermediate oral MRL and EPA’s RfD of 3 ug/kg body weight/day, (FDA 1992; IRIS 1994). Other than during home and garden insecticide application, exposure of the general public to chlorpyrifos through skin contact is not expected, because chlorpyrifos has not been identified in any consumer. products. The Non—Occupational Exposure Survey (NOES) conducted by NIOSH from 1981 to 1983 on the number of workers and the number of facilities where workers could be potentially exposed to chlorpyrifos in the United States estimated that 911 janitors and cleaners in meat packing plants, and bread, cake, and related product industries; 10,452 pest control workers; and 41 groundskeepers and gardeners in the medical industry were potentially exposed (NOES 1994). The American Conference of Governmental Industrial Hygienists (ACGIH) (1993—94) recommends that workplace air levels of chlorpyrifos not exceed 0.2 mg/m3 as a time-weighted average (TWA) for an 8-hour workday, 40-hour workweek and not exceed a 0.6 mg/m3 short-term exposure limit (STEL). The STEL is a 15-minute TWA exposure which should not be exceeded during a workday, even if the 8-hour TWA is within the threshold limit value (TLV)-TWA; also exposure should not be >15 minutes and should occur not more than 4 times per day. Workers involved in the manufacture, formulation, handling, or application of chlorpyrifos, or those involved in the disposal of chlorpyrifos-contaminated wastes are likely to be exposed to higher concentrations by dermal contact and inhalation than the general population. A study of pet handlers responsible for flea control in California in 1987 indicated that chlorpyrifos was associated with increased frequency of blurred vision, flushing of skin, and a decrease in urination (Ames et a1. 1989). In a study of airborne and surface concentrations of chlorpyrifos after application in offices, Currie et "*DRAFT FOR PUBLIC COMMENT*** CHLORPYRIFOS 93 5. POTENTIAL FOR HUMAN EXPOSURE al. (1990) found airborne concentrations peaked 4 hours after application at 27 ug/m3, and surface residue concentrations peaked at 5.9 ng/cm2 48 hours after application. Airborne levels were found to be lower in furnished offices than unfurnished offices. When granular chlorpyrifos at 0.75 active ingredient per acre was applied to a field by air, the estimated inhalation exposure to chlorpyrifos was 0.02 mg per 8—hour day for the pilot and 0.03 mg per 8-hour day for the ground staff (Myram and Forrest 1969). The estimated inhalation exposure to chlorpyrifos for workers using ground machines was 0.33 mg per 8—hour day (Myram and Forrest 1969). Hodgson et a1. (1986) reported symptoms of organophosphate intoxication among five office workers after chlorpyrifos treatment for termites. The duration of symptoms and erythrocyte cholinesterase levels over time suggested redistribution of the active ingredient after absorption to a second body compartment, with subsequent slow release into the bloodstream. Estimated potential dermal exposure (i.e., unprotected by clothing) of three greenhouse workers in Florida ranged from 17,500—24,000 ug/hour (Stamper et a1. 1989), with highest exposure to applicators’ legs. Tyvek® protective clothing afforded 89%, i 5% protection. In a study of termiticide applicator exposure in eight North Carolina homes, exposures of 01—98 rig/m3 were reported. Exposure levels in crawl-space constructed houses were higher. Values were all lower than the National Academy of Sciences Threshold Limit Value of 200 ug/m3 (Wright et a1. 1988). The NOES reported detectable levels of chlorpyrifos in indoor, outdoor, and personal air in Jacksonville, Florida, and in Springfield/Chicopee, Massachusetts (Whitmore et a1. 1994). Concentrations tended to be highest in summer, lower in spring, and lowest in winter. Indoor and personal air concentrations were generally higher than outdoor concentrations. Of 11 carpets sampled in the study, all had detectable levels of chlorpyrifos in carpet dust, with a mean concentration of 5.8 ug/g, suggesting that infants and toddlers may be at higher risk of exposure. 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES Workers in industries that manufacture and formulate chlorpyrifos and, particularly, applicators of the insecticide are at higher risk than the general population for chlorpyrifos exposure. Farm workers who enter treated fields after insecticide application may also be exposed to chlorpyrifos at higher levels than the general population. Those who use the insecticide for homes and gardens are also at higher risk of exposure to chlorpyrifos. Although no investigative evidence from the hazardous waste sites "'DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 94 5. POTENTIAL FOR HUMAN EXPOSURE was located, it is likely that people who live near hazardous waste sites containing chlorpyrifos wastes are at higher risk of exposure to chlorpyrifos. 5.7 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, 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 chlorpyrifos is available. Where adequate information is not available, ATSDR, in conjunction with the 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 chlorpyrifos. 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 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. As seen in Table 3-2, the relevant physical and chemical properties of chlorpyrifos are known (HSDB 1994; Sanbom et a1. 1977) and it is possible to predict the environmental fate and transport of chlorpyrifos based on Kow, K00, and H. Therefore, further data acquisition and research are not recommended as a high-priority activity. Production, Import/Export, Use, Release, and Disposal. Knowledge of production and use data for a chemical is important in predicting its potential for environmental contamination and human exposure. Since chlorpyrifos is produced by two manufacturers (SRI 1994), to maintain confidentiality, its recent production volume is not known. Similarly, data concerning the import and export volumes for chlorpyrifos in recent years have not been located. There is currently no federal requirement to report the use of chlorpyrifos. The most recent estimates of its yearly use in the United States are available (Gianessi 1986). Therefore, more current estimates of use and projected trends are needed. No information in the available literature was located that indicates the use of chlorpyrifos in “*DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 95 5. POTENTIAL FOR HUMAN EXPOSURE any consumer products other than edible crops and vegetables during and after their planting. Although some information regarding the disposal of wastes containing chlorpyrifos is available, more detailed and recent information would be helpful. The standards promulgated by the EPA for the disposal of wastes containing chlorpyrifos are available (Berlow and Cunningham 1989). 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. The Toxics Release Inventory (TRI), which contains this information for 1992, became available in May of 1994. This database will be updated yearly and should provide a list of industrial facilities and emissions. However, no TRI data were located for chlorpyrifos because this chemical is not required to be reported. As with most pesticide agents, it is virtually impossible to make decent quantitative estimates of the amounts of chlorpyrifos produced, used, disposed, imported and exported. This presents some fundamental problems in making more than the most general sorts of risk assessments. Improved information for any of these categories is considered a major data need. Environmental Fate. Information regarding the fate of chlorpyrifos in air was limited in the literature. Although the available data indicate that the concentration of chlorpyrifos in air will be low (Carey and Kutz 1985), more information would help predict the residence time and distance of its aerial transport. Knowledge about the fate of chlorpyrifos in water is also limited. Although it has been estimated that sorption onto particulates and settling into the sediment are important for chlorpyrifos in water, more information regarding the relative importance of sorption for removal of chlorpyrifos from water to sediment would be helpful. There is some evidence in the literature regarding the mobility of chlorpyrifos in soil. Additional information on the degradation of chlorpyrifos in water and air and the fate of the degradation products in soil would be helpful. Bioavailability from Environmental Media. Available information regarding the rate of chlorpyrifos absorption following inhalation, oral, or dermal contact has been discussed in the Toxicokinetics section (see Section 2.3). Although no data on the bioavailability of chlorpyrifos from contaminated air are available, the bioavailability from inhalation exposure is expected to be high because chlorpyrifos is likely to be present in the vapor phase and not in the particulate phase in the adsorbed state. Similarly, no data on the bioavailability of chlorpyrifos from water and soil or plant material are available; however, chlorpyrifos is adsorbed rather strongly to soil. Since the part that remains adsorbed to soil or sediments may be, at most, partially bioavailable, chlorpyrifos is expected ”*DRAFT FOR PUBLIC COMMENT*** CHLORPYRIFOS . 95 5. POTENTIAL FOR HUMAN EXPOSURE to have reduced bioavailability from soil and water. Data on the bioavailability of chlorpyrifos from actual environmental media and the difference in bioavailability for different media need further development. Food Chain Bioaccumulation. Measured BCF values for chlorpyrifos are available for a large number of aquatic invertebrate and fish species (Odenkirchen and Eisler 1988; Racke 1993). Research on accumulation of chlorpyrifos applied to soils in the roots, stems, and leaves of plants has also been undertaken (Rouchaud et a1. 1991). Exposure Levels in Environmental Media. A number of studies have been conducted dealing with chlorpyrifos concentrations in indoor air. Although some data on the levels of chlorpyrifos in ambient air are available (Carey and Kutz 1985), these data are neither current nor general enough to estimate inhalation exposure to chlorpyrifos for the general population in the United States. Limited data on the level of chlorpyrifos in drinking water were located in the literature. More recent data regarding the levels of chlorpyrifos in ambient air, drinking water, and soil are needed. Data on chlorpyrifos levels in food and recent estimates of the human intake of chlorpyrifos from foods are available (Duggan et a1. 1983; FDA 1990, 1991, 1992, 1993: Gelardi and Mountford 1993; Gunderson 1988; Luke et al. 1988; Schattenburg and Hsu 1992; Yess et al. 1991a, 1991b). Reliable monitoring data for the levels of chlorpyrifos in contaminated media at hazardous waste sites are needed so that the information obtained on levels of chlorpyrifos in the environment can be used in combination with the known body burden of chlorpyrifos to assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. Exposure Levels in Humans. No data on chlorpyrifos levels in human tissues and body fluids, for example, for a control population, populations near hazardous waste sites, or occupationally exposed groups were located. Data on the levels of chlorpyrifos and its metabolites in body tissues and fluids in symptomatic, exposed individuals, as well as red blood cell and plasma ChE activity levels in these persons, are needed to correlate exposure levels with adverse symptoms and to identify levels of ChE inhibition associated with the onset of toxic manifestations. One potential source of this information is the American Association of National Poison Control Centers. "‘DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS 97 5. POTENTIAL FOR HUMAN EXPOSURE Exposure Registries. No exposure registries for chlorpyrifos were located. This substance is not currently one of the compounds for which a subregistry has been established in the National Exposure Registry. The substance will be considered in the future when chemical selection is made for subregistries establishment. 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 exposure to a substance. 5.7.2 Ongoing Studies As part of the National Pesticide Impact Assessment Program, research is in progress at North Carolina State University (Leidy) to study the movement of herbicides into poorly drained soils of the Tidewater region of North Carolina and to determine the dislodgeable residue of chlorpyrifos from carpet samples. Research is in progress at the University of Florida, Belle Glade (Snyder) to quantify organophosphate losses in percolate, retention in soil and thatch, and removal in grass clippings. Research is in progress at the University of Florida, Gainesville (Moye and Wheeler), Texas A&M (Plapp), and Clemson (Camper) to determine the metabolic fate of chlorpyrifos in different media. Researchers at the University of Puerto Rico (Singmaster and Acin-Diaz) are determining the dissipation and persistence of chlorpyrifos in surface and vadose—zone soils and water. The USDA Agricultural Research Service (ARS) (Wauchope) is determining chlorpyrifos residues for 22 minor food crops at Tifton, Georgia, 7 crops at Yakima, Washington (Toba), and chlorpyrifos residues in coffee in Puerto Rico (Acin—Diaz, Liu, Armstrong). The USDA-ARS in Riverside, California (Spencer and Yates) is studying water and pesticide management systems for minimizing groundwater and air contamination, as well as the persistence (fate and transport) of chlorpyrifos (Gaston). The USDA- ARS in Beltsville, Maryland (Wright and Hapeman) are quantifying chlorpyrifos volatilization, transport, partitioning, and deposition. The National Taiwan University (Hsu and Epstein), with funding from the USDA, is investigating the effects of different processing/cooking variables on chlorpyrifos residues in meat and poultry products. Research is in progress at the University of Nebraska (Shea) to determine the mobility and bioavailability of chlorpyrifos in soil and at Iowa State University to compare degradation kinetics at high as oppposed to low concentrations, persistence of TCP, and effect of temperature and moisture on degradation of chlorpyrifos (coats). Argonne National Laboratory (Kakar) is studying the biodegradability/bioremediation of chlorpyrifos with white rot fungus. "*DRAFT FOR PUBLIC COMMENT*‘* CHLORPYRIFOS 99 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or measuring, and/or monitoring chlorpyrifos, its metabolites, and other biomarkers of exposure and effect to chlorpyrifos. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used for environmental samples are the methods approved by federal agencies and 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 modify previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. 6.1 BIOLOGICAL SAMPLES Methods for the determination of Chlorpyrifos and its metabolites are shown in Table 6-1. Chlorpyrifos has been measured in human whole blood, plasma, and urine at concentrations as low as 10 ppb (Drevenkar et al. 1994; Jitsunari et al. 1989; Nolan et al. 1984). The Chlorpyrifos oxygen analog (oxon) has been reported to be recoverable from serum and urine by hexane extraction, but no limit of detection or recovery was reported (Drevenkar et al. 1993). The Chlorpyrifos metabolite TCP has been measured at concentrations as low as 0.5 ng/mL weight per volume (0.5 ppb, w/v) in human blood and urine (Bartels and Kastl 1992; Jitsunari et al. 1989; Nolan et al. 1984). The hydrolysis product diethyl phosphate (DEP) has been measured in urine and plasma (Drevenkar et al. 1994; Takamiya 1994) and the hydrolysis product diethylthiophosphate (DETP) has been measured in plasma (Drevenkar et al. 1994) with limits of detection of approximately 50 ppb. Chlorpyrifos and its oxon can be extracted directly into organic solvent while TCP, DEP, and DETP can be isolated after acid hydrolysis of the conjugated forms. Chlorpyrifos and its oxon can be determined directly using gas chromatography (GC) and selective detection methods (see below). The metabolites TCP, DEP, and DETP are typically derivatized to improve the chromatography and, hence, detectability. No methods were found for Chlorpyrifos and its metabolites in human tissue, but methods have been reported for animal tissue (see Table 6-2) (Brown et a1. 1987; Claborn et al. 1968; Dishburger et a1. ”*DRAFT FOR PUBLIC COMMENT*" ...J.N3WWOO OHGfld HOd .L-lVHCl... TABLE 6-1. Analytical Methods for Determining Chlorpyrifos and Metabolites in Biological Samples Sample . detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Blood. urine Blood: Chlorpyrifos extraction with Chlorpyrifos: Chlorpyrifos: Chlorpyrifos: Jitsunari et al. (chlorpyrifos and TCP) acetone and solvent exchanged to GC/FPD; No data; No data; 1989; hexane. Water was removed from TCP: GC/ECD TOP: 10 ng/mL TCP: 91.5% Nolan et al. the extract followed by clean-up (10 ppb, w/v) (4% RSD) at 1984 using silica gel. TCP was 0.1 ug/mL (0.1 recovered via SPE from separate ppm, w/v) aliquot of acidified blood. TCP elution'from SPE with methanol then extraction into benzene and derivatization with NO- bis(trimethylsilyl)acetamide. ‘ Urine: Chlorpyrifos extraction with hexane. Hydrolysis of conjugates of TCP with H2804 at 90 °C for 1 hour. TCP isolation via SPE. extraction into benzene, and derivatization as for blood. Urine (TCP) TCP isolation from urine by acid GC/NClMS 0.5 ng/mL (0.5 Relative Bartels and hydrolysis of urine aliquots followed ppb, w/v) recoveries Kastl 1992 by extraction with diethyl ether. 80.6 to 89.9% Residues dissolved in o-xylene over followed by derivatization with N- concentration (ten-butyldimethylsilyl)-N- range of 4.1 methyltrifluoroacetamide. to 411 ng/mL of urine Urine (DEP) Inorganic phosphate removal by GC/FPD No data 149% (9% Takamiya 1994 addition of Ca(OH)2. DEP isolation RSD) at 0.50 using ion exchange and ppm derivatization to pentafluorobenzyl derivative. SOOHLBW TVOIMTVNV '9 SOleAdHOTHO OOl .uiNEWWOO Ol'lflfld 80:1 HVUG... TABLE 6-1. Analytical Methods for Determining Chlorpyrifos and Metabolites in Biological Samples (continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Plasma (Chlorpyrifos, Chlorpyrifos extraction into hexane. Chlorpyrifos: 50 ng/mL (50 DEP: 97% Drevenkar et DEP, DETP) DEP and DETP were recovered GC/ECD; ppb, w/v) (3% RSD) at al. 1994 from hexane-extracted plasma as DEP, DETP: concentrations follows: plasma saturationwith NaCl, GC/AFID 2 2 ug/mL; acidification with 6N HCI, and DETP: 97% extraction with diethyl ether. DEP (11% R30) at and DETP methylation using concentrations diazomethane. ranging from 0.1 to 2.8 11me Serum and urine Chlorpyrifos and its oxon recovered GC/MS No data No data Drevenkar et (Chlorpyrifos, chorpyrifos oxon. DEP. DETP) via extraction with hexane. Extracted sample was acidified and saturated with NaCl folowed by extraction with diethyl ether. DEP and DETP derivatization with diazomethane. al. 1993 AFID = alkali flame ionization detector; DEP = diethyl phosphate; DETP = diethyl thiophosphate; GC = gas chromatography; ECD = electron capture detector; FPD = flame photometric detector; M8 = mass spectrometry; NCIMS = negative ion chemical ionization mass spectrometry; TCP = 3,5,6-trichloro—2—pyridinol SGOHLEW 'lVOiLA'lVNV i9 somexauowo LOL CHLORPYRIFOS 102 6. ANALYTICAL METHODS 1977; Ivey and Clabom 1968; Lino and Noronha da Silveira 1994) and could most likely be applied to human tissues. 6.2 ENVIRONMENTAL SAMPLES Methods for the determination of chlorpyrifos and environmental transformation products are shown in Table 6-2. The analytical methods for chlorpyrifos in air are based on GC with some form of selective detection. For air matrices, collection methods rely on the entrapment of chlorpyrifos onto a polymeric material, such as XAD or polyurethane foam, as the air is pulled through the sorbent (EPA 1988c; Fenske et al. 1990; OSHA 1986). The analyte is subsequently recovered from the sorbent through solvent extraction. Losses of chlorpyrifos can occur during Soxhlet extraction or extract concentration using Kudema-Danish devices as a result of the boiling chips used (Hsu et al. 1988). Thus, it is very important that the performance of any method be verified prior to its application in a study. The proper use of field control samples is also very important. Reported limits of detection were as low as sub parts per trillion (EPA 1988c). Although chlorpyrifos can be converted to its oxygen analog (thiophosphate to phosphate) under normal environmental conditions (see Chapter 5), none of the methods surveyed indicated that this conversion was problematic for the determination of chlorpyrifos in air. In the case of water, soils, and wastes, sample preparation is based on liquid/liquid extractions (EPA 1986c, 1986d, 1992b, 19920; Sherma and Slobodien 1984), solid phase extraction (SPE) (Bogus et al. 1991; Johnson et al. 1991; Lacorte et al. 1993; Mattem et al. 199]), or Soxhlet extractions (EPA 1986c, 1986d). Humic material in natural waters can reduce recoveries of chlorpyrifos in SPE—based sample preparation (Johnson et al. 1991). The decreased recovery is hypothesized to be the result of inefficient trapping of the chlorpyrifos/humic material complex. EPA Method 507 for the determination of nitrogen- and phosphorus-containing pesticides in drinking water (EPA 1991) should be applicable to chlorpyrifos but has not been validated for this compound. Soxhlet extractions are commonly employed in methods used to study chlorpyrifos residues in carpet dust and on surfaces sampled using wiping approaches (Fenske et a1. 1990; Lewis et al. 1994). Supercritical fluid extraction has shown promise for the recovery of chlorpyrifos from environmental solids (Lopez—Avila et al. 1991; Miles and Randall 1992). Chlorpyrifos in sample extracts is typically determined using *“DRAFT FOR PUBLIC COMMENT*"” ...J_N3WWOO Ol'lafld HOd JJVUG... Table 6-2. Analytical Methods for Determining Chlorpyritos and Transformation Products in Environmental Samples Sample detection Percent Sample matrixa Preparation method Analytical method limit recovery Reference Air Known volumes of air drawn through GC/FPD (OSHA 0.23 ppb 96.6 (5.3% OSHA 1986 XAD-2 adsorbent. Desorption with Method 62) (mole/mole); standard error at toluene. 0.003 mg/m3 0.014 ppm) Air Known volumes of air drawn through GC/ECD (EPA Approximately 87 (20% RSD) EPA 19880 polyurethane foam (PUF). Desorption Method TO-10) 0.01 pg/m3 (0.7 for 10—1,000 via Soxhlet extraction using 5% diethyi May also use ppt, mole/mole) rig/ma ether in hexane. Extract volume GC/FPD, GC/NPD. This limit depends concentration reduction and further clean-up using GC/MS on the sampling and 24 h Florisil if needed. volume sampling Air, surfaces Air: Known volume of air pulled through GC/ECD Air: 83 rig/m3 (5.8 Air: 85 (80:6); Fenske et al. ORBO-44 tubes (Supelpak 20) and ppt, mole/mole) Wipes: 84 1990 elution with toluene. Surfaces: wiping Surface wipes: (80:10) with surgical gauze moistened with 0.6 ng/cm2 distilled water. Gauze extraction with toluene. Drinking Water Chlorpyrifos: Water extraction with TLC <2 ng/L or <2 ppb Chloropyrifos: 87 Sherma and (chlorpyrifos and hexane. Water removal from extract (w/v) for (8% R80) at Slobodien 1984 TCP) followed by volume reduction. TCP: chlorpyrifos; <1 5 ppb; TOP: 84 Water acidification. NaCl addition, and ng/L or <1 ppb (5% RSD) at extraction with benzene. Water (w/v) for TOP 5 ppb removal from extract followed by volume reduction. Well water Direct injection of 20 uL onto 60 GC/ECD <0.9 ppb (WM 95 (16% RSD) at Gerhart and (drinking water) retention gap. 0.9 ppb Cortes 1990 SGOHLEIN 'lVOlLA'lVNV '9 SOleAdHOWHO 60L ....LN3WWOO OHSnd UOd J.:lVHO... Table 6-2. Analytical Methods for Determining Chlorpyrifos and Transformation Products in Environmental Samples (continued) Sample matrixa River water, fish Surface water Surface water Waste water Groundwater, soil, sludges, wastes Preparation method , Water: Water passage through C‘8 SPE cartridge and analyte elution with ethyl acetate. Solvent removal and redissolution in ethyl acetate. Fish: Sample lyophilization and Soxhlet extraction with ethyl acetate. Extract clean-up using SPE and GPC. Water passage through XAD-2 and XAD—7 resins and analyte elution with methylene chloride. Internal standard addition, water removal and extract concentration. Water passage through C8 SPE cartridge and elution of analytes with methanol. Extraction using methylene chloride. Water removal, solvent exchange to hexane and extract volume reduction. Aqueous samples: Extraction using methylene chloride; water removal and extract volume reduction. Soils, sludges. wastes: Extraction (sonication or Soxhlet) using methylene chloride after mixing sample with sodium sulfate. Additional clean-up using Florisil if needed. Analytical method GC/NPD. GC/MS, GC/NCIMS GC/lon Trap MS HPLC/UV GC/NPD or GC/FPD (P mode) (EPA Method 622) GC/NPD or GC/FPD (EPA Method 8140); GC/MS (EPA Method 8270) Sample detection limit Water: 0.1 (lg/L (0.1 ppb, w/v) NPD; 0.02 ug/L (0.02 ppb, w/v) NClMS. Fish: 2 ng/g (2 ppt, w/w) NClMS 0.005 ppb (w/v) or 5 ng/L 5.0 ppb (w/v) or 5 H9"— 0.3 ug/L (0.3 ppb, w/v) 3 119"— (3 ppb. w/v) for groundwater; 3 mg/kg (3 Ppm. w/w) for high level soil and sludges Percent recovery . Water: 94 (4% RSD) at 10—15 ug/L. Fish: 92-136 at 0-1 119/9 86.7 (17% RSD) 93 (14% RSD) 98 (5.5% RSD over concentration range 1—50 ug/L) 98 (5.5% RSD) Reference Lacorte et al. 1993 Mattern et al. 1991 Bogus et al. 1990 EPA 19920 EPA 1986c (Method 8140); EPA 1986d (Method 8270). soomaw ‘IVOIUCIVNV ‘9 SOleAdUOWHO VOL .uLNEWWOO Ol’lafld 80:! ldVBG... Table 6-2. Analytical Methods for Determining Chlorpyrifos and Transformation Products in Environmental Samples (continued) Sample detection Percent Sample matrix‘ Preparation method Analytical method limit recovery Reference Groundwater, Extraction of aqeous samples at neutral GC/NPD or 0.7 ug/L (0.7 89:67:. from EPA 1992b soil, wastes pH using methylene chloride, water GC/FPD (EPA ppm, w/v) for water at 1.56 removal, and volume reduction. Method 8141A) groundwater; 5 ug/L; 79:7% Extraction of solid samples with mg/kg (5 ppm, from soil at 52 methylene chloride/acetone. Additional w/w) for water- pg/kg clean-up using Florisil if needed. immiscible wastes Pesticide Liquids: Weighing sufficent sample to HPLC/UV No data No data Helrich 1990a formulations contain ca. 80 mg into vial and addition (chlorpyrifos, of 25 mL of acetonitrile containing 1,4- TCP) dibromonaphthalene (internal standard). Solids: As for liquids with added filtration step before analysis. Turkey and Extraction of 250 mg of ground sample GC/ECD 0.05 ppm (w/w) 79-99 (at 0.05 Hunt et al. chicken ground with petroleum ether. Water and 0.10 ppm, 1969 (muscle, skin, removal using sodium sulfate followed w/w) heart, gizzard, by centrifugation. brain, liver, fat) Fatty and non— Homogenization of sample with acetone GC/FPD 5.2 ppb (w/w) 80 at 0.03 ppm Leoni et al. fatty foods (water addition needed for certain spike 1992 (eggs, pasta) foods) and extraction with methylene chloride/acetone after NaCl addition. Water removal using sodium sulfate and extraction twice with methylene chloride. Water removal from extract and solvent evaporation. Further ~ extract clean-up using carbon/Celite, Extrelut-3, or Cm-SPE. Solvent evaporation and redissolution in benzene. SCIOHJBW 'lVOlLA'lVNV '9 SOleAdHOTHO 90L .uiNEWWOO Ol'lfind UOd .L-iVHO... Table 6-2. Analytical Methods for Determining Chlorpyrifos and Transformation Products in Environmental Samples (continued) Sample detection Percent Sample matrix‘ Preparation method Analytical method limit recovery Reference Beef fat Tissue extraction sweep oo-distillation GC/ECD No data 83.5% (5.3% Luke and to isolate analytes. RSD) at 0.16 Richards 1984 mg/kg (0.16 ppm, w/w) Rumen content, liver Fats and oils Peppermint oil (ch Iorpyrifos, TC P) Homogenization of 5 9 sample with methanolzmethylene chloride (1 :9, v/v). Water removal from extract followed by volume reduction prior to clean-up using GPC and silica SPE. Sample mixing with light petroleum and extraction five times with light petroleum-saturated acetonitrile. Chlorpyrifos isolation using C“, SPE followed by solvent exchange to acetone for analysis. Chlorpyrifos: Oil application to silica gel column and elution with 3% water- saturated diethyl ether in hexane followed by volume adjustment. TCP: Oil dissolution in benzenezpentane (2:3) and extraction with 0.5% sodium carbonate. Aqueous phase washing with chloroform, acidification and extraction with chloroform. Further extract purification via acidic alumina column chromatography. Trimethysilyl derivative formation. GC/FPD GC/FPD GC/FPD (ch lorpyrifos); GC/ECD (TCP) 0.01 to 0.05 ug/g (ppm. w/w) was “9/9 (0.08 ppm. w/W) 0-1 ppm (lug/g, w/w) for chlorpyrifos; 0.5 ppm for TCP Rumen content: 99 (3% RSD) at 0.1 ug/g. Liver: 105 (2% R80) at 0.05 ug/g 85—97 at 0.16—0.5 ug/g (ppm. w/W) 73—104 for chlorpyrifos over concentration range 0.11—10 ppm; 70 to 101% at 0.5—1.0 ppm Holstege et al. 1991 Gillespie and Walters 1991 lnman et al. 1981 SOOHLEW WVOIMTVNV '9 SOdIHAdHOWHO 90l ....LN3WWOO onend HOd JJVHG... Table 6-2. Analytical Methods for Determining Chlorpyrifos and Transformation Products in Environmental Samples (continued) Sample detection Percent Sample matrix" Preparation method Analytical method limit recovery Reference Chicken muscle, Homogenization of weighed tissue once GC/NPD 2.5 ug/kg (ppb Muscle: 91.9 at Lino and skin with acetonitrile and twice with 70% w/w) for muscle; 6.6 ug/kg Noronha da acetonitrile/water followed by filtration. 2.2 ug/kg (ppb, (6.6 ppb, w/w) Silveira 1994 Filtrate extraction with zinc w/w) for skin Skin: 105 at acetate/water, filtration and filtrate 19 ug/kg (ppb, extraction with dichloromethane. w/w) Solvent exchange to hexane and Florisil clean—up. Bovine milk, Fat: Sample dissolution in hexane, GC/ECD 0.002 ppm (w/w) Tissue: 75-100 Clabom et al. tissues (muscle, water removal and extraction with for tissues and at 0.012 ppm; 1968 liver, heart, acetonitrile. Extract volume reduction, 0.005 ppm (w/v) Milk: 84 at kidney, brain, dilution with aqeous sodium sulfate and for milk 0.05 ppm spleen, omental fat) back-extraction with hexane. Water removal from extract, concentration and clean-up using silicic acid column chromatography. Tissue: Sample blending with Celite and acetone. Acetone removal and aqueous phase extraction with hexane; clean-up as for fat. Milk: Milk combined with activated Florisil. Application of mixture to Florisil column and elution with 10% (v/v) methylene chloride in hexane. SOOHJEW ~IVOLLA'WNV ‘9 SOdlUAdHOTHO LOL ...J.N3WWOO Ol‘iBfld 60:! JJVHG... Table 6-2. Analytical Methods for Determining Chlorpyrifos and Transformation Products in Environmental Samples (continued) Sample detection Percent Sample matrix‘ Preparation method Analytical method limit recovery Reference Bovine milk, Fat: Sample dissolution in hexane, GC/ECD 0.1 ppm (w/w) for 70 and 92 for Ivey and tissues (muscle, water removal and extraction with fat and muscle; muscle and fat, Clabom 1968 liver, heart, acetonitrile. Extract volume reduction, 0.025 ppm (w/v) respectively. at kidney, brain, dilution with aqeous sodium sulfate and for milk 0.1 ppm; 80 from spleen, omental back-extraction with hexane. Water milk at fat); chlorpyritos removal from extract, concentration and 0.025 ppm oxygen analog clean-up using silicic acid column chromatography. Tissue: Sample blending with Celite and acetone. Acetone removal and aqueous phase extraction with hexane; clean-up as for fat. Milk: Milk combined with silicic acid followed by water removal and elution . with hexane. Application of mixture to silicic acid column and elution with water-saturated methylene chloride. Bovine tissue Tissue homogenization with methanol, GC/ECD <0.05 ppm (WM) 81—89 without Dishburger et (muscle, liver, filtration and mixing with acidifed water hydrolysis; al. 1977 kidney, fat); containing NaCl. TCP extraction with 86—101 with TCP benzene. TCP isolation using alumina hydrolysis column chromatography and derivatization to trimethylsilyl derivative. Total TCP (free plus conjugated) also examined after alkaline hydrolysis (any chlorpyrifos also converted to TCP). Bovine fat Tissue extraction and sweep co— GC/NPD No data 92 (5% BSD) at Brown et al. distillation to isolate analytes. Extract clean-up using activated Florisil followed by extract volume reduction. 0.4 mg/kg (ppm, 1987 MW) SOOHLEW WVOILA'IVNV ‘9 SOdIHAdHO'lHO 801 ...1N3WWOO OHEDd 80:! .LdVHO... Table 6-2. Analytical Methods for Determining Chlorpyrifos and Transformation Products in Environmental Samples (continued) Sample matrixa Preparation method Analytical method Sample detection limit Percent recovery Reference Butter fat, potatoes Lettuce, strawberries, and tomatoes Cucumbers, lettuce, radishes, strawberries, tomatoes, witloof chicory Dispersion of homogenized sample with GC/NPD pelletized diatomaceous earth (Hydromatrix), packing into high pressure extraction cell, and extraction with supercritical carbon dioxide. Collection of extracts from fatty samples into a flask and clean-up using GPC and Florisil adsorption chromatography. Extracts from non—fatty samples trapped onto a Florisil column. Chlorpyrifos elution with acetone. GC/NPD (AOAC Method 985.22) Sample homogenization with acetone followed by filtration; pesticide extraction into organic phase by shaking with petroleum ether and methylene chloride. Water removal from extract and organic phase volume reduction in presence of petroleum ether and then acetone to remove methlene chloride. Extraction of homogenized sample with acetone. Analytes recovered via back extraction with methylene chloride followed by water removal and clean-up using activated carbon-silica gel. GC/NPD (German Pesticides Commission Method 88) <0.06 ppm (w/w) No data 0.05 mg/kg (0.05 ppm, MW) at 0.5 mg/kg Butter fat: 90 (006—06 ppm) potatoes: 97 at 0.120 ppm No data >70 Hopper and King 1991 Helrich 1990b Thier and Zeumer 1987a SGOHJBW WVOILAWVNV '9 SOAIHAdHO'lHO 60l .ulNBWWOO Ghana 80:! .L-iVHO... Table 6-2. Analytical Methods for Determining Chlorpyrifos and Transformation Products in Environmental Samples (continued) Sample detection Percent Sample matrix“ Preparation method Analytical method limit recovery Reference Potatoes, Extraction of homogenized plant GC/FPD (German No data >70 Thier and lettuce, citrus material with acetone and saturation of Pesticided Zeumer 1987b fruit this extract with NaCl and dilution with Commission methylene chloride. Clean-up of Method 819) organic phase using GPC and silica gel column chromatography. Non-fatty foods Sample homogenization with acetone GC/FPD, Approximately 20 >80 FDA 1994a (chlorpyrifos and followed by filtration. Residues GC/HECD, ppb (w/w, pig/kg) chlorpyrifos partitioned into methylene chloride and GC/NPD (US FDA depending on oxygen analog.) petroleum ether after addition of NaCl. PAMl Method 302) analytical system Alternatively, acetone solution passage used through Hydromatrix (diatomaceous earth) and residue elution with methylene chloride. Dates Extraction of homogenized sample with GC/NPD 0.01 ppm (WM, 93 for Mansour 1985 (chlorpyrifos and benzene. Application of extract to silica mg/kg) for chlorpyrifos and oxygen analog) gel column and elution with benzene to chlorpyrifos; 0.05 84 for oxygen collect chlorpyrifos and then with ppm for oxygen analog over acetone to recover the oxygen analog. analog concentration range 0.01-2.0 PPm ‘ Unless otherwise specified, method is for chlorpyrifos. If method was applied to transformation products, these are indicated in parentheses with the matrix studied. AOAC = Association of Official Analytical Chemists; ECD = electron capture detector; EPA = Environmental Protection Agency; FPD = Flame photometric detector; 60 = gas chromatography; GPC = gel permeation chromatography; HPLC = high performance liquid chromatography; MS = mass spectrometry; NCIMS = negative ion chemical ionization mass spectrometry; NPD = nitrogen phosphorus detector (thermionic); OSHA = Occupational Safety and Health Administration; RSD = relative standard deviation; SD = standard deviation; SPE = solid phase extraction; TCP = 3,5,6—trichloropyridinol; TLC = thin layer chromatography; UV = ultraviolet absorbance detection; WV 2 volume/volume; w/v = weight/volume SGOHLBW ‘IVOILAWVNV '9 SOdIHAdHO'lHO 0H CHLORPYRIFOS 111 6. ANALYTICAL METHODS GC, although thin-layer chromatography (TLC) and high-performance liquid chromatography (HFLC) have also been employed (Bogus et a1. 1990; Sherma and Slobodien 1984). Sherma and Slobodien (1984) also used TLC to quantify the chlorpyrifos transformation product TCP in drinking water. Gerhart and Cortes (1990) have reported a method for chlorpyrifos that used direct injection of well water into a GC retention gap. Reported lower limits of detection for chlorpyrifos ranged from 5 ppt (w/v) for surface water (Mattem et a1. 1991) to 3 ppm (w/w) for soils and sludges (EPA 1986c). The determination of chlorpyrifos and its transformation products, especially chlorpyrifos oxygen analog and TCP in foods has received considerable attention. Foods are generally divided into fatty (animal products, oils) and non-fatty types (produce). Chlorpyrifos is fairly non-polar and thus tends to partition into fat. This dictates that slightly different methods be used for the extraction of fatty and non-fatty samples. In general, chlorpyrifos, chlorpyrifos oxygen analog, and TCP are extracted from fatty foods using petroleum ether (Hunt et a1. 1969), methylene chloride/acetone (Leoni et a1. 1992), methanol/methylene chloride (Holstege et al. 1991), acetonitrile (Claborn et a1. 1968), or methanol (Dishburger et al. 1977). The sample or initial extracts are usually acidified followed by additional extraction steps to recover TCP (Dishburger et a1. 1977; Inman et a1. 1981). Non—fatty samples are most often extracted with acetone (FDA 1994a; Helrich 1990b; Thier and Zeumer 1987a, 1987b), although the use of benzene has also been reported (Mansour 1985). Supercritical fluid extraction (SFE) has been successfully used to recover chlorpyrifos from potatoes and butter fat (Hopper and King 1991) and grass (Cortes et al. 1991). The determinative step for chlorpyrifos, chlorpyrifos oxygen analog, and TCP is usually GC in conjunction with selective detection such as flame photometric detection (FPD), nitrogen phosphorus thermionic detection (NPD), or electron capture detection (ECD). Depending on the original sample matrix, additional clean-up can be required to remove fats or other material that can interfere with the chromatography (Walters 1990) or with detection (FDA 1994a). In addition, natural sample constituents, such as large amounts of sulfur-containing compounds in cauliflower, onions and broccoli, can increase the FPD background detector signal and make the method less sensitive (Lee and Wylie 1991). Common approaches to further extract purification include SPE (Gillespie and Walters 1991; Leoni et al. 1992; Thier and Zeumer 1987a, 1987b), gel permeation chromatography (GPC) (FDA 1994a; Holstege et a1. 1991; Thier and Zeumer 1987b), Florisil column chromatography (Brown et a1. 1987; Clabom et a1. 1968; FDA 1994a; Hopper and King 1991; Leoni et a1. 1992), sweep co—distillation (Luke and Richards 1984) and HPLC (Gillespie and Walters 1986, 1989). The *"DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 112 6. ANALYTICAL METHODS adequate recovery of the desired compound must be validated for the fractionation technique to be used. For example, SPE cartridges from different vendors or production lots have been shown to affect retention and recovery (Gillespie and Walters 1991). Chlorpyrifos oxygen analog has been found to be hydrolyzed by activated silica (Braun 1974). Florisil can also give rise to poor recoveries of Chlorpyrifos oxygen analog (FDA 1994a, 1994b; Leoni et a1. 1992). The FDA method for fatty foods or composited food (Method 304) can be applied with limited success to Chlorpyrifos (variable recovery) but not at all to the oxygen analog (FDA 1994b). TLC has been used to separate Chlorpyrifos and TCP (Judge et a1. 1993) and to screen for 170 commonly used pesticides, including Chlorpyrifos (Erdmann et a1. 1990). Additional analytical techniques that have been applied to Chlorpyrifos include GC with atomic emission detection (Lee and Wylie 1991), GC with pulsed positive ion/negative ion chemical ionization mass spectrometry (Stan and Kellner 1989), simultaneous analysis on two GC columns with both ECD and electrolytic conductivity detectors (Hopper 1991), and two-dimensional GC with simultaneous detection by ECD, NPD, and FPD (Stan and Heil 1991). 6.3 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, 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 Chlorpyrifos is available. Where adequate information is not available, ATSDR, in conjunction with the 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 Chlorpyrifos. 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 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. "“DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 113 6. ANALYTICAL METHODS 6.3.1 Identification of Data Needs Methods for Determining Biomarkers of Exposure and Effect. Chlorpyrifos and TCP can serve as biomarkers of exposure. TCP will be present at much greater concentrations relative to chlorpyrifos, so it is a better and more sensitive marker of exposure (He 1993; WHO 1975). The method for TCP in urine published by Bartels and Kastl (1992) should be adequately sensitive to study background concentrations in the general population because they measured low concentrations in control urine from presumably unexposed individuals. A limit of detection of 0.5 ng/mL (0.5 ppb, w/v) for TCP in urine was stated. The methods of Nolan et a1. (1989) and Jitsunari et a1. (1989) for TCP in blood and urine claim an LCD of 10 ppb with a reproducibility of 4% at 100 ppb. Chlorpyrifos oxon was not detected in serum and urine of poisoned persons, presumably because of the rapid rate of hydrolysis of the oxon relative to its rate of formation from chlorpyrifos (Drevenkar et a1. 1993). The metabolites DEP and DETP can serve as markers of exposure to chlorpyrifos but can also be present as a result of exposure to organophosphorus compounds that have the same phosphate moiety. Thus, they are not specific. Exposure to organophosphorus pesticides also results in decreases in whole blood and erythrocyte acetylcholinesterase activities (Drevenkar et al. 1993; He 1993) and are not specific to exposure to chlorpyrifos. The best marker of exposure to chlorpyrifos appears to be TCP, for which there are adequate methods; therefore, no new methods for TCP are needed. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Methods are available for the determination of chlorpyrifos in air at sub—ppb concentrations (OSHA 1986; EPA 1988c; Fenske et al. 1990) and are adequate to estimate potential exposures of the general population. No methods were found for chlorpyrifos oxon in air. It has been reported that the oxon is more toxic than the parent compound (Drevenkar et a1. 1993) but it does not persist (Walia et a1. 1988). No additional methods are needed. The predominant route of exposure to chlorpyrifos will be through contact with contaminated environmental matrices such as food and water. Methods for the determination of chlorpyrifos in water, wastes, soils, and foods are available that have limits of detection in the ppb and sub-ppb range (e.g., EPA 1992c; FDA 1994a; Gerhart and Cortes 1990; Gillespie and Walters 1991; Mansour 1985; Mattem et a1. 1991). Assuming an oral MRL of 0.003 mg/kg/day (Chapter 2), 2 L/day water consumption and a 70—kg person, this converts to a needed method LOD of 0.105 ppm (w/v) in *"DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS 114 6. ANALYTICAL METHODS drinking water. Reported LODs in water are 2 ppb (Sherma and Slobodien 1984), 0.9 ppb (Gerhart and Cortes 1990), 0.1 ppb (Lacorte et a1. 1993), 0.005 ppb (Mattem et al. 1991), and 5 ppb (Bogus et a1. 1990). These methods are sufficiently sensitive to detect concentrations at or below the MRL. Method reproducibilities range from 4 to 16% and will be adequate for most measurements. If 2 kg/day food consumption is assumed, method LODs of 0.105 ppm or 105 ppb (w/w) are needed. The methods of Hunt et al. (1969), Leoni et a1. (1992), Lino and Noronha da Silveira (1994), Clabom et a1. (1968), Ivey and Clabom (1968), Dishburger et a1. (1977),'Hopper and King (1991), Thier and Zeumer (1987a), FDA (1994a), and Mansour (1985) claim method LODs that range from 2 to 100 ppb and are sufficiently sensitive to detect concentrations at or below the MRL. No reproducibility information was available. No additional methods for chlorpyrifos in foods are needed. Methods are also available for the determination of the oxon in some foods (tissue and produce) (FDA 1994a; Ivey and Clabom 1968; Mansour 1985) at the sub-ppm level. Chlorpyrifos and its oxon are quickly hydrolyzed to TCP; some methods exist for the determination of TCP in drinking water (Sherma and Slobodien 1984), peppermint oil (Gillespie and Walters 1991), and bovine tissue (Dishburger et a1. 1977). 6.3.2 Ongoing Studies Researchers at North Dakota State University (Fargo) and at the University of Maine, Department of Food Science, have been working on immunochemical—based methods for the determination of chlorpyrifos. Researchers at the US. Department of Agriculture in Beltsville, Maryland; at the University of Florida (Gainesville) Department of Food Science and Nutrition; and at the University of Puerto Rico (Mayaguez), Crop Protection, are working on fate and transport of chlorpyrifos in the environment and will be developing methods as needed to define the processes and to develop models to predict fate and transport. Researchers at National Taiwan University (Taipei) are studying the degradation of chlorpyrifos residues in meat and poultry as a function of cooking methods for modeling purposes and might need to develop some methods. *“DRAFT FOR PUBLIC COMMENT*" CHLORPYRIFOS , 115 7. REGULATIONS AND ADVISORIES The international, national, and state regulations and guidelines regarding chlorpyrifos in air, water, and other media are summarized in Table 7-1. ATSDR has derived an MRL of 0.003 mg/kg/day for both acute (14 days or less) and intermediate ' (15—364 days) oral exposure to chlorpyrifos, based on a NOAEL of 0.03 mg/kg/day observed in human adult males exposed orally to chlorpyrifos (Coulston et a1. 1972). The US. EPA oral reference dose for chlorpyrifos is 3x10'3 mg/kg/day (IRIS 1994). No inhalation reference concentration exists for this compound. Chlorpyrifos is one of the chemicals regulated under "The Emergency Planning and Community Right- to—Know Act of 1986" (EPCRA) (EPA 1988a). Section 313 of Title III of EPCRA requires owners and operators of certain facilities that manufacture, import, process, or otherwise use the chemicals on this list to report annually their release of those chemicals to any environmental media. An Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) for chlorpyrifos has not been set. Chlorpyrifos is designated a hazardous substance and subject to regulations implementing Section 311 of the Federal Water Pollution Act (EPA 1978b) and Section 311 of the Clean Water Act (EPA 1986b). A maximum contaminant level in (MCL) drinking water does not exist. Tolerances for chlorpyrifos in raw agricultural commodities, foods, and animal feeds have been established by EPA (EPA 1987, 1982, 1979) ranging from 0.05 to 25 ppm. ""DRAFT FOR PUBLIC COMMENT‘“ CHLORPYRIFOS 7. REGULATIONS AND ADVISOHIES 116 Table 7-1. Regulations and Guidelines Applicable to Chiorpyrifos Agency Description information References iNTERNATiONAL Limits in Workplace Air (mg/m3) TWA STEL Sittig 1994 Australia 0.2 0.6 Belgium 0.2 0.6 Switzeriand 0.2 — Denmark 0.2 - Finland 0.2 0.6 France 0.2 — United Kingdom 0.2 0.6 lsraei 0.2 — Limits in Water (3ng Domestic/ Drinking Fishery Canada 90 — Mexico — 3 (salt) NATIONAL Regulations: a. Water EPA OW Designation of Hazardous Substances Yes 40 CFR 116.4 EPA 1978a Reportable Quantities oi Hazardous 1 lbs. 40 CFR 117.3 Substances Pursuant to the Clean Water Act EPA 1986a National Pollutant Discharge Elimination Yes 40 CFR 122, App. D System (NPDES) -- List of Toxic Pollutants EPA 1993a and Hazardous Substances instructions -- Form 2c. NPDES Criteria and Yes 40 CFR 125 Standards EPA 1984 Proposed Rule: Water Quality Guidance for Yes 58 FR 20802 the Great Lakes System EPA 1993b b. Food: . EPA OPTS Tolerances for Related Pesticide Chemicals Yes 40 CFR 180.3 EPA 1976b Tolerance Range for Agriculture Products ODS—15.0 ppm 40 CFR 180.342 EPA 1987 Listing of Pesticide Chemicals Yes 40 CFR 180 EPA 1976a Tolerance in Food: Yes 40 CFR 185.1000 Citrus Oil 25 ppm EPA 1982a Corn Oil 3.0 ppm Mint Oil 10.0 ppm Peanut Oil 1.5 ppm "'DRAF'T FOR PUBLIC COMMENT'“ CHLORPYRIFOS 7. REGULATIONS AND ADVISORIES 117 Table 7-1. Regulations and Guidelines Applicable to Chlorpyrifos (continued) Agency Description Information References NATIONAL (cont) Tolerance Range in Animal Feeds O.5-15.0 ppm 40 CFR 186.1000 EPA 1979 c. Other EPA OERR Reportable Quantity 1 lb. 40 CFR 302.4 EPA 1989 Guidelines: 090 mg/m3 (skin) ACGIH 1994 a. Air: ACGIH Threshold Limit Value for Occupational Exposure (T LV-TWA) NIOSH Recommended Exposure Limit for 0.2 mg/m3 NIOSH 1992 Occupational Exposure (TWA) Recommended Exposure Limit for 0.6 mg/m3 NIOSH 1992 Occupational Exposure (STEL) b. Water: EPA ow 1-d Health Advisory 0.03 mg/L (child) EPA 1994 10-d Health Advisory 0.03 mg/L (child) EPA 1994 Lifetime Health Advisory 0.02 mg/L EPA 1994 Longer-term Health 0.03 mg/L (child EPA 1994 0.1 mg/L (adult) c. Other EPA RfD 3x103 mg/kg/day lRlS 1994 STATE Regulations and Guidelines: a. Air: Average Acceptable Ambient Air NATICH 1992 CELDs 1994 Concentrations CT 8-hour 4.00 ug/m3 FL-Pinella 8-hour 2.00 ug/m3 24-hour 0.48 ug/m3 ND 8~hour 0.002 mg/m3 1-hour 0.006 mg/m3 NV 8-hour 0.005 mg/rn3 TX 30-minutes 2.00 ug/m3 Annual 0.20 rig/m3 VA Annual 3.30 [lg/m3 WA-SWEST 24-hour 0.70 ug/m3 b. Water: Water Qualiy: Human Health FSTRAC 1990 VT Drinking Water Standard 21 ug/L "'DFiAFT FOR PUBLIC COMMENT‘" CHLORPYRlFOS 118 7. REGULATIONS AND ADVISORIES Table 7-1. Regulations and Guidelines Applicable to Chlorpyrifos (continued) Agency Description information References STATE (Cont) Water Quality Criteria: Human Health CELDs 1994 AR Toxic Substances - Chronic Toxicity 4-day avg 0.041 pg/L Toxic Substances - Acute Toxicity - 1-hr avg 0.083 ug/L HI Toxic Substances Applicable to All Waters Fresh water acute 0.083 pg/L Fresh water chronic 0.041 ug/L Saltwater acute 0.011 pg/L Saltwater chronic 0.0056 pg/L Fish consumption NS Water Quality Criteria: Aquatic Life CELDs 1994 CO Aquatic Life Segments Organic Compounds to Second Power Standard acute 0.083 pg/L Standard chronic 0.041 pg/L PR Maximum Allowable Gone. for Organothiophosphorus and Other Non- Persistent Pesticides Coastal estuaries 0.0056 pg/L Surface waters 0.41 pg/L Groundwaters 0.041 ug/L OK Numeric Criteria for Toxic Substances to Protect Fish and Wildlife Acute .083 pg/L Chronic .041 pg/L VT WQ Criteria for Protection of Aquatic - Biota Acute .083 ug/L Chronic .041 pg/L Restricted Pesticides CELDs 1994 NJ All conc. above 15% ACGIH = American Conference of Governmental Industrial Hygienists; CELDs = Conputer-assisted Environmental Legislative Database; EPA = Environmental Protection Agency; FSTRAC = Federal State Toxicology and Regulatory Alliance Committee; IRIS = Integrated Risk Information System; NIOSH = National Institute of Occupational Safety and Health; NPDES = National Pollutant Discharge Elimination System; RfD = Reference Dose; STEL = Short-term Exposure Limit; TLV = Threshold Limit Value; TWA = Time Weighted Average "'DRAFT FOR PUBLIC COMMENT'“ 00\IO\LII4>-UJN-—e 4:..pAAA#mwwwmwwwwWNNNNNNNNNNt—‘t—bv—I—tw—n—HH—i M4>WNt—‘owmflamtht—‘OQ‘OOQOUI#UJNb—‘OCOONOUIAWNHCO CHLORPYRIFOS 119 8. 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A comparison of oral and inhalation toxicities of four insecticides to mice and rats. Bull Environ Contam Toxicol 19(1):]13-20. *Blanchet DF, St. George A. 1982. Kinetics of chemical degradation of organophosphorus pesticides; hydrolysis of chlorpyrifos and chlorpyrifos-methyl in the presence of copper(II). Pestic Sci 13:85-91. *Bogus ER, Watschke TL, Mumma R0. 1990. Utilization of solid-phase extraction and reversed-phase and ion-pair chromatography in the analysis of seven agrochemicals in water. J Agric Food Chem 38(1):l42-144. *Bowman BT, Sans WW. 1983. Determination of octanol-water partitioning coefficients (Kow) of 61 organophosphorus and carbamate insecticides and their relationship to respective water solubility (S) values. J Environ Sci Health B18(6):667-683. *Bowman BT, Sans WW. 1985. Effect of temperature on the water solubility of insecticides. J Environ Sci Health B20(6):625-631. *Braun HE. 1974. 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Dow Elanco, Indianapolis, IN. [unpublished study] *Drevenkar V, Stengl B, Froebe Z. 1994. Microanalysis of dialkylphosphorus metabolites of organophosphorus pesticides in human blood by capillary gas chromatography and by phosphorus-selective and ion trap detection. Anal Chim Acta 290(3):277-286. *Drevenkar V, Vasilic Z, Stengl B, et al. 1993. Chlorpyrifos metabolites in serum and urine of poisoned persons. Chem Biol Interact 87(1-3):315-322. *Duggan RE, Comeliussen PE, Duggan MB, et al. 1983. Pesticide residue levels in foods in the United States from July 1, 1969 to June 30, 1976. In: Residue monitoring data. Published jointly by Food and Drug Administration and Association of Official Analytical Chemists. Washington, DC. 15-33. Ehrich M, Correll L, Veronesi B. 1994. Neuropathy target esterase inhibition by organophosphorus esters in human neuroblastoma cells. Neurotoxicology 15(2):309-314. *Eisenreich SJ, Looney BB, Thornton JD. 1981. Airborne organic contaminants in the Great Lakes ecosystem. Environ Sci Technol 15:30-38. *El-Sebae AH, Ahmed NS, Soliman SA. 1978. Effect of pre-exposure on acute toxicity of organophosphorus insecticides to white mice. J Environ Sci Health B13(1):11-24. El-Sebae AH, Soliman SA, Elamayem MA, et a1. 1977. Neurotoxicity of organophosphorus insecticides Leptophos and EPN. J Environ Sci Health B12(4):269-287. *“DRAFT FOR PUBLIC COMMENT'" ooqoxm-bwmi— ##4>A-D-AAAAUJUJUJWWUJWUJUJWNNNNNNNNNNH~HHHH~#HH OO\I0&1!thv-‘OOOO\IOVJIJRWN—‘OOOO\lO‘xLII-JkUJNv-‘OOOOQONLIIAWNr—OO CHLORPYRIFOS 123 8. REFERENCES Enan EE, El-Sebae AH, Enan OH, et al. 1982. In—vivo interaction of some organophosphorus insecticides with different biochemical targets in white rats. J Environ Sci Health B17(5):549-570. *EPA. 1976a. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 180. *EPA. 1976b. Environmental Protection Agency. Code of Federal Regulations. 40 CFR 180.3. *EPA. 1978a. 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Richardson R], Moore TB, Kayyali US, et al. 1993. Inhibition of hen brain acetylcholinesterase and neurotoxic esterase by chlorpyrifos in vivo and kinetics of inhibition by chlorpyrifos oxon in vitro: Application to assessment of neuropathic risk. Fundam Appl Toxicol 20(3):273-279. *Rigterink RH. 1966. O-pyridyl phosphates and phosphorothioates. US. Patent No. 3,244,586. *Robinson JC, Pease WS, Albright DS, et a1. 1994. Pesticides in the home and community: Health risks and policy alternatives. California Policy Seminar Report, Center for Occupational and Environmental Health, School of Public Health, University of California, Berkeley. *Rouchaud J, Gustin F, Van de Steene F. 1991. Transport of the insecticides chlorpyrifos, chlorfenvinphos, carbonfuran, carbonsulfan, and furathiocarb from soil into the foliage of cauliflower and brussel sprouts plants grown in the field. Toxic Environ Chem 30(‘/z):79. *Schattenberg HJ 111, Hsu JP. 1992. Pesticide residue survey of produce from 1989 to 1991. J Assoc off Anal Chem Int 75(5):925-933. *Schimmel SC, Gamas RL, Patrick JM Jr., et al. 1983. Acute toxicity, bioconcentration, and persistence of AC 222,705, benthiocarb, chlorpyrifos, fenvalerate, methyl parathion, and permethrin in the estuarine environment. J Agric Food Chem 31(1):104-113. “*VDRAFT FOR PUBLIC COMMENT’" mflom-RWNH Abb-bhbh-fiwwwwwwUJUJUJUJNNNNNNNNNNu—t—I>—-.—‘p—-v-—>—-.—-._i._. \IOM-bWNv—‘OOOOQO'JIAWNI—ONDOOQChU'l-bMNv—‘OKOOOQQUIAWN—OO CHLORPYRIFOS 135 8. REFERENCES *Schroeder WH, Lane DA. 1988. The fate of toxic airborne pollutants. Environ Sci Technol 22:240-246. *Selden BS, Curry SC. 1987. Prolonged succinylcholine—induced paralysis in organophosphate insecticide poisoning. Ann Emerg Med 16(2):215-217. *Shah PV, Fisher HL, Sumler MR, et a1. 1987. Comparison of the penetration of 14 pesticides through the skin of young and adult rats. J Toxicol Environ Health 21(3):353—366. *Shah PV, Monroe RJ, Guthrie FE. 1981. Comparative rates of dermal penetration of insecticides in mice. Toxicol Appl Pharmacol 59(3):414—423. *Sherma J, Slobodien R. 1984. Determination of chlorpyrifos and its metabolite 3,5,6-trichloro-2—pyridinol in tap water and bananas by quantitative TLC on preadsorbent silica gel. J Liq Chromatogr 7(14):2735-2742. *Sittig M, ed. 1980. Pesticide manufacturing and toxic materials control encyclopedia. Park Ridge, NJ: Noyes Data Corporation, 199-202. *Sittig M, ed. 1985. Handbook of toxic and hazardous chemicals and carcinogens. Park Ridge, NJ: Noyes Data Corporation. *Sittig M, ed. 1994. World-wide limits for toxic and hazardous chemicals in air, water and soil. Park Ridge, NJ : Noyes Data Corporation. *Smith GN, Watson BS, Fischer FS. 1967. Investigations on dursban insecticide. Metabolism of (”CD 0,0—diethyl-O- 3,5,6-trichloro—2-pyridyl phosphorothioate in rats. J Agric Food Chem 15, 132-138. *Smith JL, Rust MK. 1992. Activity and water-induced movement of termiticides in soil. J Econ Entomol 85(2):430-434. *Sobti RC, Krishan A, Pfaffenberger CD. 1982. Cytokinetic and cytogenetic effects of some agricultural chemicals on human lymphoid cells in vitro: organophosphates. Mutat Res 102(1):89—102. *Somasundaram L, Coats JR, Racke KD. 1989. Degradation of pesticides in soil as influenced by the presence of hydrolysis metabolites. J Environ Sci Health B24(5):457-478. *SRI. 1994. 1994 Directory of Chemical Producers, United States of America. SRI International. 801. ‘ *Stamper JH, Nigg HN, Mahon WD, et a1. 1989. Pesticide exposure to greenhouse handgunners. Arch Environ Contam Toxicol 18(4):515-529. *Stan H—J, Heil S. 1991. Two-dimensional capillary gas chromatography with three selective detectors as a valuable tool in residue analysis: State-of—the-art. Fresenius’ J Anal Chem 339(1):34-39. *"DRAFT FOR PUBLIC COMMENT**‘ WQOMAWN— AhhAAphhhmwwmwwmwwwwmmwmNNNNN.—_._._._i._._i.__._ OO\]O\UIJ>LANF—OOOOQOUI#UJN—OCOOQONLA-bWNt—‘ODOOQONUIAUJN—‘OO CHLORPYRIFOS 136 8. REFERENCES *Stan, H—J, Kellner G. 1989. Confirmation of organophosphorus pesticide residues in food applying gas chromatography-mass spectrometry with chemical ionization and pulsed positive negative detection. Biomed Environ Mass Spectrom l8(9):645-651. *Stanton ME, Mundy WR, Ward T, et al. 1994. Time-dependent effects of acute chlorpyrifos administration on spatial delayed alternation and cholinergic neurochemistry in weanling rats Neurotoxicology 15(1):201-208. Sultatos LG. 1988. Factors affecting the hepatic biotransformation of the phosphorothioate pesticide chlorpyrifos. Toxicology 51:191-200. *Sultatos LG. 1991. Metabolic activation of the organophosphorus insecticides chlorpyrifos and fenitrothion by perfused rat liver. Toxicology 68(1):l-9. *Sultatos LG, Costa LG, Murphy SD. 1982. Factors involved in the differential acute toxicity of the insecticides chlorpyrifos and methyl chlorpyrifos in mice. Toxicol Appl Pharmacol 65(1):l44-152. *Sultatos LG, Minor LD, Murphy SD. 1985. Metabolic activation of phosphorothioate pesticides: role of the liver. J Pharmacol Exp Ther 232(3):624-628. *Sultatos LG, Murphy SD. 1983. Hepatic microsomal detoxification of the organophosphates paraoxon and chlorpyrifos oxon in the mouse. Drug Metab Dispos Biol Fate Chem ll(3):232-238. *Sultatos LG, Murphy SD. 1983. Kinetic analyses of the microsomal biotransformation of the phosphorothioate insecticides chlorpyrifos and parathion. Fundam Appl Toxicol 3(1):l6-21. *Suntio LR, Shiu WY, Mackay D, et al. 1987. A critical review of Henry’s constants for pesticides. Rev Environ Contam Toxicol 10321-59. *Szeto SY, MacKemzie JR, Vernon RS. 1988. Comparative persistence of chlorpyrifos in a mineral soil after granular and drench applications. J Environ Sci Health B23(6):54l-558. *Takamiya K. 1994. Monitoring of urinary alkyl phosphates in pest control operators exposed to various organophosphorus Insecticides. Bull Environ Contam Toxicol 52(2):190-195. *Thier H-P, Zeumer H. 1987a. Method SS, Organochlorine, organophosphorus and triazine compounds. In: Manual of pesticide residue analysis, vol. 1. New York, NY: VCH Publishers, Inc. *Thier H-P, Zeumer H. 1987b. Method 819, Organochlorine, organophosphorus, nitrogen-containing and other compounds. In: Manual of pesticide residue analysis, vol. 1. New York, NY: VCH Publishers, Inc. *Thrasher JD, Madison R, Broughton A. 1993. Immunologic abnormalities in humans exposed to chlorpyrifos: preliminary observations. Arch Environ Health 48(2):89-93. *Trotter WJ, Dickerson R. 1993. Pesticide Residues in Composited Milk Collected Through the US. Pasteurized Milk Network. J Assoc Off Anal Chem Int 76(6)11229-1225. "*DRAFT FOR PUBLIC COMMENT'" OO\]O\UI-¥>UJN’—‘ «5-543-5-5##fibbwwmwwwwmeNNNNNNNNNN—‘Ht—‘v—‘P‘t—‘t—‘v—‘t—‘r— \OOO\]O\U\#WNHOOOOQOUI-PUJN—‘OOOONGUIJ>WNHONDOOQONUI-PWN—OC CHLORPYRIFOS 137 8. REFERENCES *Vaccaro JR. 1993. Risks associated with exposure to chlorpyrifos and chloropyrifos formulation components. In: K.D. Racke and AR. Leslie, eds. Pesticides in urban environments: fate and significance. ACS symposium series,522. American Chemica. *Valsaraj KT, Thoma GJ, Reible DD, et al. 1993. On the enrichment of hydrophobic organic compounds in fog droplets. Atmos Environ, Part A- Gen Top 27(2):203-210. *van Beelen P, Fleuren-Kemila AK. 1993. Toxic effects of pentachlorophenol and other pollutants on the mineralization of acetate in several soils. Ecotoxicol Environ Saf 26(1):]0-17. *van Beelen P, van Vlaardingen PLA, Fleuren-Kemila AK. 1994. Toxic effects of pollutants on the mineralization of chloroform in river sediments. Ecotox Environ Saf 27(2):]58—167. *Vasilic Z, Drevenkar V, Rumenjak V, et al. 1992. Urinary excretion of diethylphosphorus metabolites in persons poisoned by quinalphos or chlorpyrifos. Arch Environ Contam Toxicol 22(4):351-357. *Verschueren K. 1983. Chlorfpyrifos. In: Handbook of Environmental Data on Organic Chemicals. Second edition. K. Verschueren, editor. Van Nostrand Reinhold Co. New York, NY. Vodela JK, Patil RD, Whittiker MB, et al. 1994. Comparative toxicity of chlorpyrifos in rats and chickens. FASEB J 8(4-5):A407. *Waite DT, Grover R, Westcott ND, et al. 1992. Pesticides in ground water, surface water and spring runoff in a small Saskatchewan watershed. Environ Toxicol Chem 11(6):741-748. *Walia S, Dureja P, Mukerjee SK. 1988. New photodegradation products of chlorpyrifos and their detection on glass, soil, and leaf surfaces. Arch Environ Contam Toxicol 17(2):183-188. *Walker WW, Cripe CR, Pritchard PH, et al. 1988. Biological and abiotic degradation of xenobiotic compounds in in-vitro estuarine water and sediment-water systems. Chemosphere 17(12):2255-2270. *Walters SM. 1990. Clean-up techniques for pesticides in fatty foods. Anal Chim Acta 236(1):77-82. *Watschke TL, Mumma R0. 1989. The effect of nutrients and pesticides applied to turf on the quality of runoff and percolating water. Environmental Resources Research Institute report ER 8904, Pennsylvania State University, University Park, Pa. *Welling W, de Vries JW. 1992. Bioconcentration kinetics of the organophosphorus insecticide chlorpyrifos in guppies (Poecilies reticulate). Ecotoxicol Environ Saf 23:64-75. *Whang JM, Schomburg CJ, Glotfelty DE, et al. 1993. Volatilization of fonofos, chlorpyrifos, and atrazine from conventional and no—till surface soils in the field. J Environ Qual 22(1):]73-180. *Whitmore RW, Immerrnan FW, Camann DE, et al. 1994. Non—occupational exposures to pesticides for residents of two US. cities. Arch Environ Contam Toxicol 26(1):47-59. "'DRAFT FOR PUBLIC COMMENT‘“ OO\IO\&JIAUJI\J_ b4;L-bhwwwmwwwwwwNNNNNNNNNNHHH..._._.._.._..._.,_ AWN—‘OOOOQONKIIAWN—OKOOONONUIme—OOOONOKUI-wa—‘OO CHLORPYRIFOS 138 8. REFERENCES *WHO. 1975. Chemical and biochemical methodology for the assessment of hazards of pesticides for man. Report of a WHO scientific group. WHO technical report series no.560. Geneva, Switzerland: World Health Organization. ‘ *Winterlin W, Seiber JN, Craigmill A, et a1. 1989. Degradation of pesticide waste taken from a highly contaminated soil evaporation pit in California USA. Arch Environ Contam Toxicol 18(5):734-747. *Wolfe NL. 1988. Abiotic transformations of toxic organic chemicals in the liquid phase and sediments. In: Z. Gerstl, ed. Toxic organic chemicals in porous media. Ecological studies, vol. 73. Berlin, West Germany: Springer-Verlag. *Woodruff RC, Phillips JP, Irwin D. 1983. Pesticide-induced complete and partial chromosome loss in screens with repair-defective females of Drosophila melanogaster. Environ Mutagen 5(6):835-846. *Worthing CR, ed. 1987. The pesticide manual. A world compendium. Seventh edition. The British Crop Protection Council. 3050. *Wright CG, Leidy RB. 1980. Insecticide residues in the air of buildings and pest control vehicles. Bull Environ Contam Toxicol 24(4):582-589. *Wright CG, Leidy RB, Dupree HE. 1991. Chlorpyrifos in the air and soil of houses four years after its application for termite control. Bull Environ Contam Toxicol 46:686-689. (as cited in Racke 1993) *Wright CG, Leidy RB, Dupree HE, Jr. 1988. Chlorpyrifos in the ambient air of houses treated for termites. Bull Environ Contam Toxicol 40(4):561-568. *Wright CG, Leidy RB, Dupree HE, Jr. 1994. Chlorpyrifos in the air and soil of houses eight years after its application of termite control. Bull Environ Contam Toxicol 52(1):131-134. *Yamano T, Morita S. 1993. Effects of pesticides on isolated rat hepatocytes, mitochondria, and microsomes. Arch Environ Contam Toxicol 25(2):271-278. *Yess NJ, Houston MG, Gunderson EL. 1991a. Food and Drug Administration Pesticide Residue Monitoring of Foods: 1978-1982. J Off Anal Chem 74(2):265-272. *Yess NJ, Houston MG, Gunderson EL. 1991b. Food and Drug Administration Pesticide Residue Monitoring of Foods: 1983—1986. J Off Anal Chem 74(2):273-280. *Zabik JM, Seiber JN. 1993. Atmospheric transport of organophosphate pesticides from Califomia’s Central Valley to the Sierra Nevada mountains. J Environ Qual 22(1):80—90. “*DRAFT FOR PUBLIC COMMENT" WQOMAWN'd NNNNN_.—.—..—_.—a.—-.—.—.— kWNi—OOOOQONMhWNHOO % % m m w w m n n M 5 w m m w m m m B M a a M w w CHLORPYRIFOS 139 & GLOSSARY 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. Intermediate Exposure—Exposure to a chemical for a duration of 15—364 days, as specified in the Toxicological Profiles. ""DRAFT FOR PUBLIC COMMENT'" OWOONOUIAUJNh—I A«AAA-PAAAA-kwwwwwwwwwwNNNNNNNNNNt—‘HHt—tt-dr—At—At—At—tH \OOONGNU!AWN—‘00OOQONUI#WNHOOOONOUIAUJNHOWOOQGMAWNH CHLORPYRIFOS 140 9. GLOSSARY 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 Viva—Occurring within the living organism. Lethal Concentrationao) (LCLo)—The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentrationwo) (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 Dosemo) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Doseao) (LD50)—The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Timem) (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 noncancerous 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)_The equilibrium ratio of the concentrations of a chemical in n—octanol and water, in dilute solution. Permissible Exposure Limit (PEL)—An allowable exposure level in workplace air averaged over an 8-hour shift. ***DRAFT FOR PUBLIC COMMENT'“ \OOO\10'\UI4>UJN-- CHLORPYRIFOS 141 9. GLOSSARY 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 ug/L for water, mg/kg/day for food, and ug/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 (TD50)—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. Uncertainty Factor (UF)—A factor used in operationally deriving the RfD 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. "*DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS A-1 APPENDIX A MINIMAL RISK LEVEL (MRL) WORKSHEETS Chemical name: Chlorpyrifos CAS number: 50815-00—4 Date: July 17, 1995 Profile status: 4th Draft Route: [ ] Inhalation [X] Oral Duration: [X] Acute [ ] Intermediate [ ] Chronic Key to figure: 5 Species: Human MRL: 0.003 [X] mg/kg/day [ ] ppm [ ] mg/m3 Reference: Coulston et a1. (1972L Experimental design: 16 adult human male volunteers (4 per dose group) were treated with 0, 0.014, 0.03, or 0.10 mg/kg/day chlorpyrifos by capsule. Those subjects receiving 0.014 and 0.03 mg/kg/day were exposed for 20 days; those receiving 0.10 mg/kg/day were exposed for only 9 days. Effects noted in study and corresponding doses: Those subjects receiving 0.10 mg/kg/day were exposed for only 9 days because of blurred vision and a runny nose in one of the subjects. Plasma cholinesterase was decreased approximately 65% compared to controls in that group. No effect on plasma cholinesterase was seen at the lower doses and erythrocyte cholinesterase was unaffected by any of the chlorpyrifos doses. Thus, the NOAEL for chlorpyrifos plasma cholinesterase inhibition was 0.03 mg/kg/day. Based on this NOAEL, an MRL of 0.003 mg/kg was calculated: 0.03 mg/kg x an uncertainty factor of 1/ 10 for human variability. Please note that the combination of length of exposure period and the critical effect in this study enable it to be used for the derivation of both acute- and intermediate-duration oral exposure MRLs. MRL = Human dose x Uncertainty factor 0.03 mg/kg x 1 10 0.003 mg/kg Dose endpoint used for MRL derivation: Plasma cholinesterase inhibition [X] NOAEL [ ] LOAEL ""DRAFT FOR PUBLIC COMMENT*" CHLORPYRIFOS . A-2 APPENDIX A Uncertainty factors used in MRL derivation: []1 []3 [] 10(foruseofaLOAEL) [ ] l [ ] 3 [ ] 10 (for extrapolation from animals to humans) [ ] l [ ] 3 [X] 10 (for human variability) Was a conversion factor used from ppm in food or water to a mg/body weight dose? NO. If so, explain: If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Was a conversion used from intermittent to continuous exposure? NO. If so, explain: Other additional studies or pertinent information that lend support to this MRL: Deacon et a1. (1980) Embryotoxicity and Fetotoxicity of Orally Administered Chlorpyrifos in Mice. Toxicology and Applied Pharmacology. 54, 31—40. The MRL study is further supported by a study by Deacon et al. (1980). Female CF—l mice were exposed by gavage to l, 10, or 2 mg/kg/day Dursban F® (96.8% chlorpyrifos) as a solution in cottonseed oil on days 6, days 6—10, or days 6—15 of gestation. Controls received cottonseed oil alone. Five hours after the final dosing (days 6, 10, or 15 of gestation), blood was obtained via cardiac puncture and plasma and erythrocyte cholinesterase activities determined. Plasma and erythrocyte cholinesterase levels were significantly decreased from control values among mice given 10 or 25 mg/kg chlorpyrifos on day 6 (plasma, 95 and 97%, respectively; erythrocyte, 40 and 20%, respectively) and, days 6—10 (plasma, 97 and 99%, respectively; erythrocyte, 43 and 71%, respectively), or days 6—15 of gestation (plasma, 96 and 98%, respectively; erythrocyte, 43 and 57%, respectively). Plasma cholinesterase levels were significantly reduced among mice given 1 mg/kg chlorpyrifos during the same time intervals (69, 78, and 85%, respectively). Erythrocyte cholinesterase levels were also reduced (43%) after 1 mg/kg chlorpyrifos, but only after exposure on gestational days 6—10. In a concurrent study, no effects on plasma or erythrocyte cholinesterase activity were observed at 0.1 mg/kg chlorpyrifos. Agency Contact (Chemical Manager): John F. Risher, Ph.D. Agency Review Date: lst review: 2nd review: "‘DRAFT FOR PUBLIC COMMENT*" CHLORPYRIFOS A.3 APPENDIX A MINIMAL RISK LEVEL WORKSHEET Chemical name: Chlorpyrifos CAS number: 50815—00—4 Date: July 17, 1995 Profile status: 4th Draft Route: [ ] Inhalation [X] Oral Duration: [ ] Acute [X] Intermediate [ ] Chronic Key to figure: 15 Species: Human MRL: 0.003 [X] mg/kg/day [ ] ppm [ ] mg/m3 Reference: Coulston et a1. 1972. Experimental design: 16 adult human male volunteers (4 per dose group) were treated with 0, 0.014,- 0.03, or 0.10 mg/kg/day chlorpyrifos by capsule. Those subjects receiving 0.014 and 0.03 mg/kg/day were exposed for 20 days; those receiving 0.10 mg/kg/day were exposed for only 9 days. Effects noted in study and corresponding doses: Those subjects receiving 0.10 mg/kg/day were exposed for only 9 days because of blurred vision and a runny nose in one of the subjects. Plasma cholinesterase was decreased approximately 65% compared to controls in that group. No effect on plasma cholinesterase was seen at the lower doses and erythrocyte cholinesterase was unaffected by any of the chlorpyrifos doses. Thus, the NOAEL for chlorpyrifos plasma cholinesterase inhibition was 0.03 mg/kg/day. Based on this NOAEL, an MRL of 0.003 mg/kg was calculated: 0.03 mg/kg x an uncertainty factor of 1/ 10 for human variability. Please note that the combination of length of exposure period and the critical effect in this study enable it to be used for the derivation of both acute- and intermediate-duration oral exposure MRLs. MRL = Human close x Uncertainty factor 0.03 mg/kg x 1 10 0.003 mg/kg ll Dose endpoint used for MRL derivation: Plasma cholinesterase inhibition [X] NOAEL [ ] LOAEL "*DRAFT FOR PUBLIC COMMENT*" CHLORPYRIFOS A-4 APPENDIX A Uncertainty factors used in MRL derivation: ]1 []3 [] 10 (for use ofaLOAEL) ] 1 [ ] 3 [ ] 10 (for extrapolation from animals to humans) ] 1 [ ] 3 [X] 10 (for human variability) r—!r—!F—| Was a conversion factor used from ppm in food or water to a mg/body weight dose? NO. If so, explain: If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Was a conversion used from intermittent to continuous exposure? NO. If so, explain: Other additional studies or pertinent information that lend support to this MRL: Deacon et al. (1980) Embryotoxicity and Fetotoxicity of Orally Administered Chlorpyrifos in Mice. Toxicology and Applied Pharmacology. 54, 31—40. The MRL study is further supported by a study by Deacon et a1. (1980). Female CF—l mice were exposed by gavage to 1, 10, or 2 mg/kg/day Dursban F® (96.8% Chlorpyrifos) as a solution in . cottonseed oil on days 6, days 6—10, or days 6—15 of gestation. Controls received cottonseed oil alone. Five hours after the final dosing (days 6, 10, or 15 of gestation), blood was obtained via cardiac puncture and plasma and erythrocyte cholinesterase activities determined. Plasma and erythrocyte cholinesterase levels were significantly decreased from control values among mice given 10 or 25 mg/kg Chlorpyrifos on day 6 (plasma, 95 and 97%, respectively; erythrocyte, 40 and 20%, respectively) and, days 6—10 (plasma, 97 and 99%, respectively; erythrocyte, 43 and 71%, respectively), or days 6—15 of gestation (plasma, 96 and 98%, respectively; erythrocyte, 43 and 57%, respectively). Plasma cholinesterase levels were significantly reduced among mice given 1 mg/kg Chlorpyrifos during the same time intervals (69, 78, and 85%,. respectively). Erythrocyte cholinesterase levels were also reduced (43%) after 1 mg/kg Chlorpyrifos, but only after exposure on gestational days 6—10. In a concurrent study, no effects on plasma or erythrocyte cholinesterase activity were observed at 0.1 mg/kg Chlorpyrifos. Agency Contact (Chemical Manager): John F. Risher, Ph.D. Agency Review Date: lst review: 2nd review: "*DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS ‘ B-1 APPENDIX B USER’S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in non-technical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or chemical 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 chemical. 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 and illustrate graphically levels of exposure associated with those effects. These levels cover health effects observed at increasing dose concentrations and durations, 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. Use the LSE tables and figures 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. 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), or Cancer Effect Levels (CELs). The legends presented below demonstrate the application of these tables and figures. Representative examples 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 exists, 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. Not all substances will have data on each route of exposure and will not therefore have all five of the tables and figures. ""DRAFT FOR PUBLIC COMMENT‘” CHLORPYRIFOS B—2 (2) (3) (4) (5) (6) (7) (8) (9) APPENDIX B EXposure Period Three exposure periods — acute (less than 15 days), intermediate (15—364 days), and chronic (365 days or“ more) are presented within each relevant route of exposure. In this example, an inhalation study of intermediate exposure duration is reported. For quick reference to health effects occurring from a known length of exposure, locate the applicable exposure period within the LSE table and figure. Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table (see key number 18). 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 derive a NOAEL and a Less Serious LOAEL (also see the 2 "18r" data points in Figure 2-1). Species The test species, whether animal or human, are identified in this column. Section 2.5, "Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 2.3, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent human doses to derive an MRL. 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 l,l,2,2-tetrachloroethane via inhalation for 6 hours per day, 5 days per week, for 3 weeks. For a more complete review of the dosing regimen refer to the appropriate sections of the text or the original reference paper, i.e., Nitschke et al. 1981. System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/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, 1 systemic effect (respiratory) was investigated. 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 dose 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 endpoint used to quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10 ppm. MRLs are not derived from Serious LOAELs. (10) Reference The complete reference citation is given in chapter 8 of the profile. *"DRAFT FOR PUBLIC COMMENT'" CHLORPYRIFOS B-3 APPENDIX B (11) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses not causing measurable cancer increases. (12) 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. LEGEND See 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 concentrations for particular exposure periods. ' (13) Exposure Period 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. (14) Health Effect These are the categories of health effects for which reliable quantitative data exists. The same health effects appear in the LSE table. (15) Levels of Exposure concentrations or doses for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log scale y axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in mg/kg/day. (16) NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates to 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 MRL of 0.005 ppm (see footnote "b" in the LSE table). (17) CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond symbol refers to a Cancer Effect Level for the test species—mouse. The number 38 corresponds to the entry in the LSE table. (18) Estimated Upper—Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from the EPA’s Human Health Assessment Group’s upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q1*). (19) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. "'DRAFT FOR PUBLIC COMMENT‘“ .ulNEIWWOO onand HOd .l_-lVHCl.u SOdIHAdHOWHO TABLE 2-1. Levels of Significant Exposure to [Chemical x] — Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL _ . figurea Species duration System (ppm) Less serious (ppm) Serious (ppm) Reference lNTERMEDlATE EXPOSURE Systemic i ~L 18 Rat 13 wk Resp 3b 10 (hyperplasia) Nitschke et al. 5d/wk 1981 6hfld > 1] ______________________________________________________________________________________________ PR. CHRONIC EXPOSURE g Q 03 Cancer 38 Rat 18 mo - 20 (CEL, multiple Wong et al. 1982 5d/wk organs) 7hfld 39 Rat 89—104 wk 10 (CEL, lung tumors, NTP 1982 5d/wk nasal tumors) 6hr/d 40 Mouse 79—103 wk 10 (CEL, lung tumors, NTP 1982 5d/wk hemangiosarcomas) 6hr/d a The number corresponds to entries in Figure 2-1. 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 uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). CEL = cancer effect level; d = days(s); hr = hour(s); LOAEL = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no- observed-adverse-effect level; Resp = respiratory; wk = week(s) 7'8 .mLNEIWWOO OHGfld 80:! ldVHGu. Acute Intermediate (314 days) (15-364 days) Systemic Systemic \ \ ______, \o’z’ $6” ‘8‘?) {5‘0 \0\0 ‘éo \0\0 \CJ 600 o ‘\ ‘0 ‘x o \ 0 G ’—> (ppm) 0"} 0‘9 e63, 255‘ seq 6° 09% 29‘ 790 0 <2~ ~2~ O <2~ ~2‘ ~2~ <2~ O 1 0000 1 000 O . 37m 0 O O O 0 am 0 100 1.6 17r 2C: 0 o ZOmQ 020m 31r 0 35m 33 O r 9 18r 229 21 r 0 28m 0 29r 27r 1 Sr 33 22m 34r 18r l 1 i . 10'4 — l O .1 ¢ 1 0-5 0.0 1 Key 1 0-6 0-001 r Rat . LOAEL for serious effects (animals) ' Minimal risk level for effects 10-7 - | m Mouse 0 LOAEL for less serious effects (animals) I otherthan cancer 0'0001 h Rabbit O NOAEL (animals) 9 Guinea Pig CEL - Cancer Effect Level The number next to each point 0.00001 k Monkey . corresponds to entries in the accompanying table. 0.000001 _ . . “ Doses represent the lowest dose tested per study that produced a tumorigenic response and do not Imply the existence of a threshold for the cancer end point. 0.0000001 Estimated (__ Upper Bound Human Cancer Risk Levels 8 XlCINEddV SOdIHAdUO'IHO 9'8 CHLORPYRIFOS 3.6 APPENDIX B Chapter 2 (Section 2.5) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicologic, epidemiologic, 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 covers end points in the same order they appear within the Discussion of Health Effects by Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro 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. Minimal risk levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed. Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not meant to support regulatory action; but to acquaint 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 chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2.5, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.7, "Interactions with Other Substances,” and 2.8, "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 the Environmental Protection Agency (EPA) provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (Rst). *"DRAFT FOR PUBLIC COMMENT“" CHLORPYRIFOS B-7 APPENDIX B To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential systemic, neurological, and developmental effects. If this information and reliable quantitative data on the chosen endpoint 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. When a NOAEL is not available, a lowest-observed- adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and 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 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. *"DRAFT FOR PUBLIC COMMENT*“ CHLORPYRIFOS ' c-1 APPENDIX C ACRONYMS, ABBREVIATIONS, AND SYMBOLS ACGIH American Conference of Governmental Industrial Hygienists ADME Absorption, Distribution, Metabolism, and Excretion atm atmosphere ATSDR Agency for Toxic Substances and Disease Registry BCF bioconcentration factor BSC Board of Scientific Counselors C Centigrade CDC Centers for Disease Control CEL Cancer Effect Level CERCLA Comprehensive Environmental Response, Compensation, and Liability Act CFR Code of Federal Regulations ‘ CLP Contract Laboratory Program cm centimeter ' CNS central nervous system d day DHEW Department of Health, Education, and Welfare DHHS Department of Health and Human Services DOL Department of Labor ECG electrocardiogram EEG electroencephalogram EPA Environmental Protection Agency EKG see ECG F Fahrenheit F1 first filial generation FAO Food and Agricultural Organization of the United Nations FEMA Federal Emergency Management Agency FIFRA Federal Insecticide, Fungicide, and Rodenticide Act fpm feet per minute ft foot FR Federal Register g gram GC gas chromatography gen generation HPLC high-performance liquid Chromatography hr hour IDLH Immediately Dangerous to Life and Health IARC International Agency for Research on Cancer ILO International Labor Organization in inch Kd adsorption ratio kg kilogram kkg metric ton ~ KQC organic carbon partition coefficient KOW octanol-water partition coefficient "*DRAFT FOR PUBLIC COMMENT*** CHLORPYRIFOS L LC LCLo LCso LDLo LDso LOAEL LSE m mg min mL mm mm Hg mmol mo mppcf MRL MS NIEHS NIOSH NIOSHTIC ng nm NHANES nmol NOAEL NOES N OHS NPL NRC N TIS N TP OSHA PEL Pg pmol PHS PMR ppb PPm PPt REL RfD RTECS sec SCE SIC SMR APPENDIX C liter 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 ""DRAFT FOR PUBLIC COMMENT‘" CHLORPYRIFOS STEL STORET TLV TSCA TRI TWA U .S . UF yr WHO wk