TOXICOLOGICAL PROFILE FOR ALPHA-, BETA-, GAMMA-, and DELTA-HEXACHLOROCYCLOHEXANE Prepared by: Research Triangle Institute Under Contract No. 205-93-0606 Prepared for: U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry July 1999 or oil DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. HCH iii RAI242 UPDATE STATEMENT H “4d 495 A Toxicological Profile for hexachlorocyclohexane was released in May 1997. This edition supersedes any previously released draft or final profile. J q 7 o £ Toxicological profiles are revised and republished as necessary, but no less than once every three years. For information regarding the update status of previously released profiles, contact ATSDR at: F vy KL Agency for Toxic Substances and Disease Registry Division of Toxicology/Toxicology Information Branch 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 FOREWORD This toxicological profile is prepared in accordance with guidelines* developed by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (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 described therein. Each peer-reviewed profile identifies and reviews the key literature that describes a hazardous substance's toxicologic properties. Other pertinent literature is also presented, but is 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. The focus of the profiles is on health and toxicologic information; therefore, 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 protection of public health are identified by ATSDR and EPA. Each profile includes the following: (A) The examination, summary, and interpretation of available toxicologic information and epidemiologic evaluations on a hazardous substance to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects; (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure that present a significant risk to human health of acute, subacute, and chronic health effects; and (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. This profile reflects ATSDR ’s assessment of all relevant toxicologic testing and information that has been peer-reviewed. Staff of the Centers for Disease Control and Prevention and other Federal scientists have also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel and was made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. Jeffrey P. Koplan, M.D., M.P.H. Administrator Agency for Toxic Substances and Disease Registry vi *Legislative Background 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 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 EPA. The availability of the revised priority list of 275 hazardous substances was announced in the Federal Register on November 17, 1997 (62 FR 61332). For prior versions of the list of substances, see Federal Register notices dated April 29, 1996 (61 FR 18744); April 17, 1987 (52 FR 12866); October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17,1990 (55 FR 42067); October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); and February 28, 1994 (59 FR 9486). Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. HCH vii QUICK REFERENCE FOR HEALTH CARE PROVIDERS Toxicological Profiles are a unique compilation of toxicological information on a given hazardous substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation of available toxicologic and epidemiologic information on a substance. Health care providers treating patients potentially exposed to hazardous substances will find the following information helpful for fast answers to often-asked questions. Primary Chapters/Sections of Interest Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating patients about possible exposure to a hazardous substance. It explains a substance’s relevant toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of the general health effects observed following exposure. Chapter 2: Health Effects: Specific health effects of a given hazardous compound are reported by route of exposure, by type of health effect (death, systemic, immunologic, reproductive), and by length of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are reported in this section. NOTE: Not all health effects reported in this section are necessarily observed in the clinical setting. Please refer to the Public Health Statement to identify general health effects observed following exposure. Pediatrics: Four new sections have been added to each Toxicological Profile to address child health issues: Section 1.6 How Can (Chemical X) Affect Children? Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)? Section 2.6 ~~ Children’s Susceptibility Section 5.6 Exposures of Children Other Sections of Interest: : Section 2.7 Biomarkers of Exposure and Effect Section 2.10 Methods for Reducing Toxic Effects ATSDR Information Center Phone: 1-800-447-1544 (to be replaced by 1-888-42-ATSDR in 1999) or 404-639-6357 Fax: 404-639-6359 E-mail: atsdric@cdc.gov Internet: http://atsdrl.atsdr.cdc.gov:8080 The following additional material can be ordered through the ATSDR Information Center: Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an exposure history and how to conduct one are described, and an example of a thorough exposure history is provided. Other case studies of interest include Reproductive and Developmental Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide Toxicity; and numerous chemical-specific case studies. Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene (prehospital) and hospital medical management of patients exposed during a hazardous materials incident. Volumes I and II are planning guides to assist first responders and hospital emergency department personnel in planning for incidents that involve hazardous materials. Volume Ill—Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care professionals treating patients exposed to hazardous materials. Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. HCH viii Other Agencies and Organizations The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, injury, and disability related to the interactions between people and their environment outside the workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, GA 30341-3724 « Phone: 770-488-7000 « FAX: 770-488-7015. The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational diseases and injuries, responds to requests for assistance by investigating problems of health and safety in the workplace, recommends standards to the Occupational Safety and Health Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, SW, Washington, DC 20201 « Phone: 800-356-4674 or NIOSH Technical Information Branch, Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 « Phone: 800-35-NIOSH. The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for biomedical research on the effects of chemical, physical, and biologic environmental agents on human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, Research Triangle Park, NC 27709 « Phone: 919-541-3212. Referrals The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics in the United States to provide expertise in occupational and environmental issues. Contact: AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 * Phone: 202-347-4976 « FAX: 202- 347-4950 » e-mail: aoec @dgs.dgsys.com + AOEC Clinic Director: http://occ-env- med.mc.duke.edu/oem/aoec.htm. The American College of Occupational and Environmental Medicine (ACOEM) is an association of physicians and other health care providers specializing in the field of occupational and environmental medicine. Contact: ACOEM, 55 West Seegers Road, Arlington Heights, IL 60005 * Phone: 847- 228-6850 « FAX: 847-228-1856. HCH Ix CONTRIBUTORS CHEMICAL MANAGER(S)AUTHOR(S): Gangadhar Choudhary, Ph.D. ATSDR, Division of Toxicology, Atlanta, GA Diana Wong, Ph.D., DABT Sciences International Incorporated, Alexandria, VA Steve Donkin, Ph.D. Sciences International Incorporated, Alexandria, VA THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 1. Health Effects Review. The Health Effects Review Committee examines the health effects chapter of each profile for consistency and accuracy in interpreting health effects and classifying endpoints. 2. 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. 3. Data Needs Review. The Research Implementation Branch reviews data needs sections to assure consistency across profiles and adherence to instructions in the Guidance. HCH Xi PEER REVIEW A peer review panel was assembled for hexachlorocyclohexane. The panel consisted of the following members: 1. Dr. Carson Conaway, Research Scientist, American Health Foundation, Valhalla, New York 2. Dr. Arthur Gregory, Private Consultant, Luray, Virginia 3. Dr. Donald Morgan, Private Consultant, Cedar Rapids, Iowa 4. James E. Klaunig, Ph.D., Professor and Director of Toxicology, Department of Pharmacology and Toxicology, Indiana University College of Medicine 5. Christine Ecles, Ph.D., Associate Professor, University of Maryland, School of Pharmacy, Baltimore, Maryland These experts collectively have knowledge of hexachlorocyclohexane's physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers' comments and determined which comments will be included in the profile. A listing of the peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile's final content. The responsibility for the content of this profile lies with the ATSDR. HCH ili CONTENTS FOREWORD . Lee ee eee ete ee teeta aan v QUICK REFERENCE FOR HEALTH CAREPROVIDERS ..............0iiiiiiiiiiiiiinnnn. vii CONTRIBUTORS Loe eee eee ete eee eee eee ean ix PEER REVIEW Le eee ee tee ee teeta xi LIST OF FIGURES . . oe eee eee ee ee eee tee e ie ea xvii LIST OF TABLES ieee Xix 1. PUBLIC HEALTH STATEMENT ... iti ieee eee eas 1 1.1 WHAT IS HEXACHLOROCYCLOHEXANE? ...... oii iii 1 1.2 WHAT HAPPENS TO HEXACHLOROCYCLOHEXANE WHEN IT ENTERS THE ENVIRONMENT? eee teens 2 1.3 HOW MIGHT I BE EXPOSED TO HEXACHLOROCYCLOHEXANE? .................. 3 1.4 HOW CAN HEXACHLOROCYCLOHEXANE ENTER AND LEAVE MY BODY? ......... 3 1.5 HOW CAN HEXACHLOROCYCLOHEXANE AFFECT MY HEALTH? ................. 4 1.6 HOW CAN HEXACHLOROCYCLOHEXANE AFFECT CHILDREN? ................... 5 1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO HEXACHLOROCYCLOHEXANE? . otitis 6 1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO HEXACHLOROCYCLOHEXANE? . . ott iiiieeiiiaeeeiiaaean 7 1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? ..... ie ieee ieee ean 7 1.10 WHERE CAN I GET MORE INFORMATION? .......oiiiiiiiiiiii iia 8 2. HEALTH EFFECTS eee eee ein 11 2.1 INTRODUCTION . Ltt ee eee tetas 11 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTEOFEXPOSURE. ................... 11 2.2.1 Inhalation EXpOsSUre .............ciuuiiinnein eit 13 22.0.1 Death... 13 22.12 SystemicEffects ............couiiiiiii iii ee 18 2.2.1.3 Immunological and Lymphoreticular Effects ......................... 20 22.14 Neurological Effects .............ouiiniiiiiiiiii iii iin. 21 2.2.1.5 Reproductive Effects . ........ c.count 21 22.1.6 Developmental Effects ............. c.count. 22 22.1.7 Genotoxic Effects ........ c.count 22 22.018 CANCET ett tte eta 22 2.2.2 Oral EXpOSUIE . . oot eee ea 23 222.01 Death... eee 23 2222 SystemicEffects ...........coouiiiniiii iii ieee 54 2.2.2.3 Immunological and Lymphoreticular Effects ......................... 61 222.4 Neurological Effects .............ciiiiiiiiiiiiiiiiiiiiiiiinnn.. 62 222.5 Reproductive Effects ...........ooiiuiiiiiiiiiiiiii iii 65 HCH 2.3 2.4 2.5 2.6 2.7 2.8 2.9 2.10 2.11 xiv 2.22.6 Developmental Effects .................. iii 66 2.2277 GenotoxiC Effects ...........ooiiiiiiiii i 68 2.22.8 CANCEL «ttt t eee 68 2.2.3 Dermal EXPOSUIE ...... oii 71 223.1 Death .... oo 71 2.2.32 Systemic Effects ......... cco 72 2.2.3.3 Immunological and Lymphoreticular Effects ......................... 78 2.2.3.4 Neurological Effects ............... coi 78 2.23.5 Reproductive Effects. ..........c.. iii 79 2.2.3.6 Developmental Effects ............... coin. 79 2.23.7 GenotoxicEffects .......... ci 80 2.2.3.8 CANCE oti ttt ee 80 TOXICOKINETICS Li ie ict cians 80 2.3.1 ADSOIPHON Lotte ee 81 2.3.1.1 Inhalation EXPOSUIE ..........c.uuiiinininiinninnnennnnnnn. 81 2.3.1.2 Oral EXPOSUIE . . out tt tite ete eee eee eee eee ieee eas 81 2.3.1.3 Dermal EXPOSUIE .... oc. 82 2.32 DIStbUtiOn . . o.oo 83 2.3.2.1 Inhalation Exposure .................iiiiiiiiiii iii 84 2.3.22 Oral EXpOSUIE . . cuits 84 2.3.23 Dermal EXPOSUIE .... counties 85 2.3.3 Metabolism . «o.oo eee 87 2.3.4 Elimination and EXCretion .............. coitus 90 2.3.4.1 Inhalation EXpOSUIE ...........oiiuuiiiniiniii inna. 90 2.3.42 Oral EXPOSUIE . out tt te ee ieee eee eee ee eee eee 90 2.34.3 Dermal EXpOSUIe ..........iouniiniiiiiiiit iii, 91 2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models .... 92 2.3.5.1 Summary of PBPK Models. ............ciiiiiiiiii iii 93 MECHANISMS OF ACTION ott eee ee eee eee eae 97 24.1 Pharmacokinetic Mechanisms ............. coin... 97 2.4.2 Mechanisms of TOXICILY . . o.oo v vente eee eee ieee eee ieee 97 2.4.3 Animal-to-Human Extrapolations .............. c.count ininnnnnenenn. 99 RELEVANCE TO PUBLIC HEALTH ......couiii iii ein 99 CHILDREN’S SUSCEPTIBILITY .. octet ieee ieee 110 BIOMARKERS OF EXPOSURE AND EFFECT .......c.uiitiiii initia. 114 2.7.1 Biomarkers Used to Identify or Quantify Exposure to Hexachlorocyclohexane . . . . .. 115 2.7.2 Biomarkers Used to Characterize Effects Caused by Hexachlorocyclohexane . .. .... 116 INTERACTIONS WITH OTHER CHEMICALS .......... cian. 117 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ......................... 119 METHODS FOR REDUCING TOXIC EFFECTS ..... cities 120 2.10.1 Reducing Peak Absorption Following Exposure .............................. 120 2.10.2 Reducing Body Burden ............... iii 120 2.10.3 Interfering with the Mechanism of Action for Toxic Effects ..................... 121 ADEQUACY OF THE DATABASE . . oii eee ee ieee ein 121 2.11.1 Existing Information on Health Effects of Hexachlorocyclohexane ............... 122 2.11.2 Identification of Data Needs ........ cout, 124 2.11.3 Ongoing Studies . ...... oii eee 135 HCH XV 3. CHEMICAL AND PHYSICAL INFORMATION ........it iii iti ie iain, 137 3.1 CHEMICAL IDENTITY oie ee ee te eet eee teins 137 3.2 PHYSICAL AND CHEMICAL PROPERTIES ........ciii ieee ieee 137 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ....... cit iiiiiiiiiinnnnnn. 143 © 4.1 PRODUCTION titi eee eee eee eee eee 143 42 IMPORT/EXPORT . teeta 143 4.3 USE oii ee 145 4.4 DISPOSAL eee 146 5. POTENTIAL FOR HUMAN EXPOSURE . ....... ieee ieee eee 149 5.1 OVERVIEW ee ee ee 149 5.2 RELEASES TO THE ENVIRONMENT ........ iii iii ieee 149 5.2.1 AT © oe 155 52.2 Ya OT oti te 155 5.2.3 S00] i 156 5.3 ENVIRONMENTAL FATE ..... i eee ete e eit 157 5.3.1 Transport and Partitioning ................iiuiiniiniiniiiiiiiinnnenn.. 157 5.3.2 Transformation and Degradation .................. cco iiiiiiiiiiiiin... 161 5.3.2.0 AIT oe 161 5.3.2.2 Water. oii ee ea 161 5.323 Sedimentand Soil ......... ccc. ee 162 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT .................. 164 5.4.1 AT Lo ee 164 5.4.2 aT «Lo ee 165 54.3 Sediment and Soil .......... iii ee eee 166 54.4 Other Environmental Media ..............citininiint tint iinieinananan.. 167 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ..................... 168 5.6 EXPOSURES OF CHILDREN ....... citi eet tn ieee. 172 5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ........................ 175 5.8 ADEQUACY OF THE DATABASE . ... oii ett teeta 175 5.8.1 Identification of Data Needs . . ..........otiirt iit itt eii nein. 176 5.82 Ongoing StUAIES .....v'itit tte 180 6. ANALYTICAL METHODS . . i tet ee eteeee eeeteeeen 183 6.1 BIOLOGICAL SAMPLES . eee ee eee 183 6.2 ENVIRONMENTAL SAMPLES . ... iit ete ete e ieee 188 6.3 ADEQUACY OF THE DATABASE . .. oie eee eee 200 6.3.1 Identification of Data Needs .. ..........ottiriiei iii ieee ieienennenn. 200 6.3.2 Ongoing StUAIES .....otitttteeea 201 7. REGULATIONS AND ADVISORIES ...... itt ieee t teeta anenan, 203 8. REFERENCES . oii ee ee et eet eet ete ete 213 0. GLOSSARY oe 271 HCH APPENDICES A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS B. USERSGUIDE ................cciiiiiiiinnnn. C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS .... © ss ss ses ee ss es ses esse eee eee HCH 2-1 2-2 2-3 2-4 2-5 5-4 LIST OF FIGURES Levels of Significant Exposure to Gamma-Hexachlorocyclohexane—Inhalation ................ Levels of Significant Exposure to Gamma-Hexachlorocyclohexane—Oral ..................... Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane—Oral ............. intuit iii The Proposed Metabolism of Hexachlorocyclohexane ..................... iit. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance ............... cotinine, Structure of the PBPK Model forLindane .................. iii iii... Existing Information on the Health Effects of Hexachlorocyclohexane ....................... Frequency of NPL Sites with Gamma-Hexachlorocyclohexane Contamination ................ Frequency of NPL Sites with Alpha-Hexachlorocyclohexane Contamination .................. Frequency of NPL Sites with Beta-Hexachlorocyclohexane Contamination ................... Frequency of NPL Sites with Delta-Hexachlorocyclohexane Contamination .................. xvii HCH Xix LIST OF TABLES 2-1 Levels of Significant Exposure to Gamma-Hexachlorocyclohexane—Inhalation ................ 14 2-2 Levels of Significant Exposure to Gamma-Hexachlorocyclohexane—Oral . .................... 24 2-3 Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade . ................. 38 2-4 Levels of Significant Exposure to Gamma-Hexachlorocyclohexane—Dermal .................. 73 2-5 Levels of Significant Exposure to Technical-Grade Hexachlorocyclohexane—Dermal ........... 75 2-6 Parameters of a PBPK Model for LindaneinRats ...................... iii... 96 2-7 Genotoxicity of Hexachlorocyclohexane Isomers In Vivo ................. cocoa... 108 2-8 Genotoxicity of Hexachlorocyclohexane Isomers In Vitro ............... coin. 109 3-1 Chemical Identity of Hexachlorocyclohexane Isomers ..................... oii... 138 3-2 Chemical and Physical Properties of Hexachlorocyclohexane Isomers ....................... 141 4-1 Facilities that Manufacture or Process Lindane ................... . iii... 144 5-1 Releases to the Environment from Facilities that Manufacture or Process Lindane . ............. 154 6-1 Analytical Methods for Determining Hexachlorocyclohexane in Biological Samples ............ 184 6-2 Analytical Methods for Determining Hexachlorocyclohexane in Environmental Samples ........ 189 7-1 Regulations and Guidelines Applicable to Hexachlorocyclohexane . ......................... 204 HCH 1 1. PUBLIC HEALTH STATEMENT This public health statement tells you about hexachlorocyclohexane and the effects of exposure. The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the nation. These sites make up the National Priorities List (NPL) and are the sites targeted for long-term federal cleanup activities. Hexachlorocyclohexane has been found in at least 144 of the 1,467 current or former NPL sites. However, the total number of NPL sites evaluated for this substance is not known. As more sites are evaluated, the sites at which hexachlorocyclohexane is found may increase. This information 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 are exposed to a substance only when you come in contact with it. You may be exposed by breathing, eating, or drinking the substance or by skin contact. If you are exposed to hexachlorocyclohexane, 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 HEXACHLOROCYCLOHEXANE? Hexachlorocyclohexane (HCH), also known as benzene hexachloride (BHC), is a synthetic chemical that exists in eight chemical forms called isomers. The different isomers are named according to the position of the hydrogen atoms in the structure of the chemical. One of these forms, gamma-HCH (or Y-HCH, commonly called lindane), is produced and used as an insecticide on fruit, vegetables, and forest crops. It is also used in the United States and in many other countries as a topical treatment for head and body lice and scabies, a contagious skin HCH 2 1. PUBLIC HEALTH STATEMENT disease caused by mites. It is a white solid whose vapor may evaporate into the air. The vapor is colorless and has a slight musty odor when it is present at 12 or more parts HCH per million parts air (ppm). y-HCH has not been produced in the United States since 1976. However, imported y-HCH is available in the United States for insecticide use as a dust, powder, liquid, or concentrate. It is also available as a lotion, cream, or shampoo to control scabies and head lice. Technical-grade HCH, a mixture of several chemical forms of HCH, was also once used as an insecticide in the United States and typically contained about 10-15% y-HCH as well as the alpha (a), beta (B), delta (8), and epsilon (€) forms of HCH. Virtually all of the insecticidal properties reside in the gamma isomer. Technical-grade HCH has not been produced in the United States since 1983. In addition, isomers of HCH other than y-HCH may not be made or used commercially in the United States. The scope of this profile includes information on technical-grade HCH, as well as the alpha («), beta (3), gamma (y), and delta (8) isomers. Available information on the epsilon (€) isomer is limited and is not included in this profile. Chapter 3 contains more information on the chemical and physical properties of HCH. 1.2 WHAT HAPPENS TO HEXACHLOROCYCLOHEXANE WHEN IT ENTERS THE ENVIRONMENT? Although technical-grade HCH is no longer used as an insecticide in the United States, o-, B-, y-, and 8-HCH have been found in the soil and surface water at hazardous waste sites. In air, the different forms of HCH can be present as a vapor or attached to small particles such as soil and dust; the particles may be removed from the air by rain. y-HCH can remain in the air for as long as 17 weeks depending on moisture in the air and temperature. In soil, sediments, and water, it is broken down to less toxic substances by algae, fungi, and bacteria. In general, HCH isomers are broken down quickly in water; in natural water samples, Y-HCH does not remain for much longer than 30 days. y-HCH is not generally found in drinking water. The length of time that HCH isomers remain in soil is not known. Chapter 5 contains more information about the presence of HCH in the environment. HCH 3 1. PUBLIC HEALTH STATEMENT 1.3 HOW MIGHT | BE EXPOSED TO HEXACHLOROCYCLOHEXANE? Humans can be exposed to a-, B-, y-, and 8-HCH in workplace air; in the air surrounding factories where HCH is used; or by eating plants, meat, milk, or water that contain forms of HCH. According to the National Occupational Exposure Survey from 1981-1983, about 15,000 workers were exposed to HCH (NOES 1983). At spill and dump sites, HCH isomers can enter the air from contaminated soil and from plants grown in contaminated soil. They can also be washed from the soil and plants into surface water. Typically, people are not exposed to the «, B, and 6 forms of HCH separately, but to y-HCH only or to technical-grade HCH, which contains a mixture of the isomers. People are exposed to y-HCH when it is applied to the skin as a lotion or shampoo to control lice and scabies. The most severe exposures to lindane have occurred in workers who make lindane or in other workplaces such as fertilizer manufacturing sites. For more information on exposure to HCH, refer to Chapter 5. 1.4 HOW CAN HEXACHLOROCYCLOHEXANE ENTER AND LEAVE MY BODY? v-HCH and the other isomers of HCH can enter your body when you eat food or drink water contaminated with HCH. Inhaling air contaminated with Y-HCH or other isomers of HCH can also lead to entry of these chemicals into the lungs. y-HCH can be absorbed through the skin when it is used as a lotion to control scabies or body lice. In general, HCH isomers and the products formed from them in the body can be temporarily stored in body fat. Among the HCH isomers, 3-HCH leaves the body the most slowly. a-HCH, 6-HCH, and y-HCH, and the products formed from them in the body, are more rapidly excreted in the urine; small amounts leave in the feces and expired air. HCH breaks down in the body to many other substances; these include various chlorophenols, some of which have toxic properties. Chapter 2 gives more information on how HCH enters and leaves the body. HCH 4 1. PUBLIC HEALTH STATEMENT 1.5 HOW CAN HEXACHLOROCYCLOHEXANE AFFECT MY HEALTH? 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. In humans, the effects of breathing toxic amounts of Y-HCH and/or o-, B-, and 8-HCH can result in blood disorders, dizziness, headaches, and possible changes in the levels of sex hormones in the blood. These effects have occurred in workers exposed to HCH vapors during pesticide manufacturing. People who have swallowed large amounts have had seizures; some have died. A few people, who have used very large amounts of Y-HCH or used it frequently on their skin, have developed blood disorders or seizures. However, no cause-and-effect relationship between exposure to Y-HCH and blood disorders in humans has been established. Animals that have been fed y- and a-HCH have had convulsions, and animals fed f-HCH have become comatose. All isomers can produce liver and kidney effects. Reduced ability to fight infection was reported in animals fed Y-HCH, and injury to the ovaries and testes was reported in animals given y-HCH or B-HCH. HCH isomers are changed by the body into other chemical products, some of which may be responsible for the harmful effects. Long-term oral administration of a-HCH, 3-HCH, y-HCH, or technical-grade HCH to laboratory rodents has been reported to result in liver cancer. The Department of Health and Human Services (DHHS) has determined that HCH may reasonably be anticipated to cause cancer in humans. Chapter 2 gives more information about the health effects of HCH isomers. HCH 5 1. PUBLIC HEALTH STATEMENT 1.6 HOW CAN HEXACHLOROCYCLOHEXANE AFFECT CHILDREN? This section discusses potential health effects from exposures during the period from conception to maturity at 18 years of age in humans. The most likely source of exposure for children is from the use of shampoos and lotions containing HCH for the treatment of lice. HCH has also been found as a residue in food products; B-HCH isomer accumulates in animal tissue. In the body, a-, 8-, and Y-HCH are rapidly broken down and excreted. Although HCH is a restricted use pesticide in the U.S., children could be exposed from eating foods grown in areas where HCH is still used or misused as a pesticide. HCH has also been detected in breast milk and this is a possible exposure pathway for infants and children. Limited information is available on the specific health effects resulting from HCH exposure in children. Health effects observed in adults should also be of potential concern in children. Children can experience convulsions from exposure to Y-HCH. Accidentally eating enough y-HCH can kill a child. It is not known for sure whether children are more susceptible than adults to health effects from exposure Y-HCH. However, a study performed on rabbits showed that young animals had higher death rates and greater sensitivity than adults when y-HCH was applied to skin. We do not know whether HCH causes birth defects in humans. Technical grade and y-HCH do not cause significant birth defects in animals. Animals fed y-HCH during pregnancy had an increased number of fetuses with extra ribs, a normal variation. HCH has been shown to cross the placenta in pregnant women. HCH is likely to be stored in fat. It has been measured in skin lipids and breast milk. In studies on rats, HCH has been shown to pass from the mother to newborns in the dam’s milk and causes neurological and hormonal effects. The male offspring of female rats that had been fed HCH during lactation demonstrated a 50% reduction in testosterone levels and reduced testicular weight in adolescence and adulthood. HCH 6 1. PUBLIC HEALTH STATEMENT More information on how HCH can affect the health of children can be found in Sections 2.6 and 5.6. 1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO HEXACHLOROCYCLOHEXANE? If your doctor finds that you have been exposed to significant amounts of hexachlorocyclohexane, ask if children may also be exposed. When necessary your doctor may need to ask your state department of public health to investigate. There are two primary pathways through which families can be exposed to HCH. y-HCH, also known as lindane is used in shampoos and lotions for the treatment of lice. It is normally safe if used as directed, but is often misused. If you use shampoos or lotions containing Y-HCH, follow the directions carefully. Products containing yY-HCH (lindane) should never be used on infants. Shampoos or lotions that contain lindane should be stored out of the reach of young children to prevent accidental poisonings. You may expose your child to lindane if you use lindane to treat lice on your child’s head. There are alternatives that do not involve the use of lindane. y-HCH is a restricted use pesticide. Its allowed use around the home is limited to structural treatments, animal shampoos, and animal flea dusts. Your children may be exposed to HCH if an unqualified person applies pesticides containing it around your home. In some cases, the improper use of pesticides banned for use in homes has turned homes into hazardous waste sites. Make sure that any person you hire is licensed and certified to apply pesticides. Your state licenses each person who is qualified to apply pesticides according to EPA standards and further certifies each person who is qualified to apply “restricted use” pesticides. Ask to see the license and certification. Also ask for the brand name of the pesticide, a Material Safety Data Sheet (MSDS), the name of the product’s active ingredients, and the EPA registration number. This information can be important if you or your family react to the product. HCH 7 1. PUBLIC HEALTH STATEMENT 1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER | HAVE BEEN EXPOSED TO HEXACHLOROCYCLOHEXANE? HCH isomers can be measured in the blood, urine, and semen of exposed persons. Samples of these fluids can be collected in a doctor's office and sent to a laboratory that has the special equipment needed to measure the levels of HCH. Although the amount of HCH isomers in blood, urine, or semen can be measured, it is usually not possible to determine the environmental levels to which the person was exposed or to predict the health effects that are likely to occur from specific concentrations. The products of HCH that are formed in the body and then found in the urine have also been measured to find out whether a person was exposed to HCH. However, this method cannot yet be used to determine exposure to HCH alone because other environmental chemicals produce the same end products. Chapter 6 contains more information on ways to measure HCH in human blood and tissues. 1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The federal government develops regulations and recommendations to protect public health. Regulations can 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). Recom- mendations provide valuable guidelines to protect public health but cannot 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. HCH 8 1. PUBLIC HEALTH STATEMENT 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 HCH include the following: y-HCH is categorized by EPA as a restricted use pesticide. It can only be used by certified applicators. EPA has also recommended guidelines on how much HCH can be present in drinking water for specific periods of time without producing health effects. EPA advises that children should not have more than 1.2 milligrams per liter of water (mg/L) in 10 days or more than 0.033 mg/L per day for long-term (7 years) exposure. For long-term exposure in adults, EPA recommends that there should not be more than 0.12 mg/L in drinking water. The EPA has classified a-HCH and technical-grade HCH as probable human carcinogens. [3-HCH has been classified as a possible human carcinogen, while 8-HCH has been designated as not classifiable for human cancer. IARC has classified HCH as a possible human carcinogen. EPA has classified HCH as a hazardous waste that must meet certain disposal requirements. OSHA regulates levels of Y-HCH in the workplace. The maximum allowable amount in workroom air during an 8-hour workday in a 40-hour workweek is 0.5 mg per cubic meter of air. Chapter 7 contains more information about regulations and guidelines concerning HCH. 1.10 WHERE CAN | 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 HCH 1. PUBLIC HEALTH STATEMENT * Inf on I | technical assi Phone: 1-800-447-1544 Fax: (404) 639-6359 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 ord icological profil National Technical Information Service 5285 Port Royal Road Springfield, VA 22161 Phone: (800) 553-6847 or (703) 487-4650 HCH 11 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 hexachlorocyclohexane (HCH). 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. 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 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 NOAELSs should also help in HCH 12 2. HEALTH EFFECTS 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. Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of hexachlorocyclohexane are indicated in Tables 2-1 and 2-2 and Figures 2-1 and 2-2. Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for hexachlorocyclohexane. 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. HCH 13 2. HEALTH EFFECTS HCH exists as several isomers. The four major isomers discussed in this profile are alpha-HCH («-HCH), beta-HCH (B-HCH), gamma-HCH (y-HCH), and delta-HCH (8-HCH). y-HCH is also commonly known as lindane. Technical-grade HCH consists of at least 5 isomers (approximately 60-70% «-HCH, 5-12% B-HCH, 10-15% y-HCH, 6-10% &-HCH, and 3-4% e-HCH). The toxicity of the isomers varies. With respect to acute exposure, Y-HCH is the most toxic, followed by a-, 6-, and B-HCH. With chronic exposure, however, p-HCH is the most toxic followed by «-, y-, and 3-HCH. With chronic exposures, the increased toxicity of B-HCH is probably due to its longer biological half-life in the body and its accumulation in the body over time. 2.2.1 Inhalation Exposure Studies examining the inhalation toxicity of HCH in humans are limited. Most of the available information is from case reports of acute poisoning in the home following the use of y-HCH vaporizers, whereby y-HCH pellets are vaporized by electrical warming of a ceramic jacket, and from studies of workers engaged in the manufacture and formulation of pesticides and fertilizers. Limitations inherent in these reports or studies include unquantified exposure concentrations and concomitant exposure to HCH mixtures, pyrolysis products from vaporizers, and other pesticides and chemicals. Studies that provide levels of significant exposure for inhalation exposure to Y-HCH are shown in Table 2-1 and Figure 2-1. 2.2.1.1 Death y-HCH was once used in vaporizers, resulting in human exposure to unspecified levels via inhalation and dermal routes. Occasional deaths associated with the use of this product for several months or years have been reported, but in no case is it clear that y-HCH was responsible for the deaths (Loge 1965). No human deaths from inhalation exposure to other isomers have been reported. An acute study with rats exposed to nose-only inhalation of lindane aerosol for 4 hours, followed by a 22-day observation period, estimated the acute LCj, to be 1,560 mg/m? (Ullmann 1986b). Rats inhaling up to 603 mg/m? lindane aerosol for 4 hours in whole-body exposure chambers exhibited no mortality throughout the 14-day observation period (Oldiges et al. 1980). However, the particle sizes produced in aerosol studies are variable, and there is a potential for dermal and oral exposures since the animals could lick their fur. TABLE 2-1. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Inhalation S103443 H1V3H 2 a Exposure LOAEL Key to Species duration/ NOAEL Less serious Serious Reference figure (strain) frequency system (mg/m3) (mg/m3) (mg/m3) ACUTE EXPOSURE Death 1 Rat 4 hr 1560 (LCso) Ullmann 1986b (Wistar) 2 Mouse 1 wk 10 (16% mortality) Kionne and Kintigh (CD-1) 5 diwk } 1988 6 hr/d Systemic 3 Rat 4 hr Resp 603 Oldiges et al. 1980 (Wistar) Hepatic 603 Renal 603 Neurological 4 Rat 4 hr 101 (sedation) 642 (restlessness, excitation, Ullmann 1986b (Wistar) ataxia) INTERMEDIATE EXPOSURE Death 5 Mouse 14 wk 1.0 (2% mortality) Klonne and Kintigh (CD-1) 5 diwk 1988 6 hr/d HOH vi TABLE 2-1. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Inhalation (continued) a Exposure LOAEL Key to Species duration/ NOAEL Less serious Serious Reference figure (strain) frequency System (mg/m3) (mg/m3) (mg/m3) Systemic 6 Rat 90d Resp 5 Oldiges et al. 1983 (Wistar) 6 hr/d Hemato 5 Hepatic 5 Renal 5 Bd Wt 5 Neurological 7 Mouse 14 wk 5 Klonne and Kintigh (CD-1) 5 diwk 1988 6 hr/d *The number corresponds to entries in Figure 2-1. Bd Wt = body weight; d = day(s); Hemato = hematological; LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level, Resp = respiratory; wk = week(s). S103443 H1TV3H 2 HOH St Figure 2-1. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Inhalation Acute (<14 days) Systemic (mg/m?) Ss 5 5 % 8 3 & &* & & 10000 Q « z & 2 ir 1000 | " 3r 3r 3r 4r Oo Oo Oo o ar 100 0 2m 10 | ° 1} 01 0.01 } Key roa B® [C,, (animals) The number next to ch point 0.001 | m mouse @® LOAEL for serious effects (animals) Sametponds to Q LOAEL for less serious effects (animals) entries in Table 2-1. 0.0001 } O NOAEL (animals) 0.00001 S103443 HLTV3H 2 HOH 91 Figure 2-1. Levels of Significant Exposure to Intermediate (15-364 days) Gamma-Hexachlorocyclohexane (Lindane) - Inhalation (cont.) Systemic 3 - - ¢ > 5 3 8g 5 0 o S (mg/m?) Ss 5 g 5 » $ g 3 & > & & S & 10000 2 « z z « @ 2 1000 } 100 | 10 6r 6r 6r 6r er 7" Oo Oo Oo Oo Oo Oo 5m 1 2 01 roorat B® | C,, (animals) The number next to m mouse . . ch point 0.001 | @ LOAEL for serious effects (animals) Somosponds 10 Q LOAEL for less serious effects (animals) entries in Table 2-1. 0.0001 | O NOAEL (animals) 0.00001 S103443 H1TV3H 2 HOH Ll HCH 18 2. HEALTH EFFECTS Therefore, the estimated doses delivered to the animals cannot be precisely determined, and thus, the toxicity levels cited may be of questionable validity. In an intermediate-duration study with mice inhaling lindane dust aerosol in whole-body exposure chambers, 16% mortality was observed after 1 week of exposure to 10 mg/m’, while exposures of up to 14 weeks resulted in 22% mortality at 5 mg/m’, 2% mortality at 1 mg/m’, and no mortality at 0.3 mg/m® (Klonne and Kintigh 1988). 2.2.1.2 Systemic Effects Respiratory Effects. In humans, mucous membrane irritation of the nose and throat was observed after acute exposure to the HCH products dispensed by an overheated y-HCH vaporizer (Conley 1952). Exposure levels were not reported and dermal exposure may also have occurred, although the observed irritation was probably due to direct action upon the mucous membranes. No respiratory effects were observed in rats exposed to up to 603 mg/m? lindane aerosol for 4 hours (Oldiges et al. 1980). No respiratory effects were observed in rats exposed to lindane aerosol (up to 5 mg/m?) for 90 days (Oldiges et al. 1983) or in mice similarly exposed for 14 weeks (Klonne and Kintigh 1988). Cardiovascular Effects. Cardiovascular effects of HCH have been reported in humans exposed to HCH. Kashyap (1986) reported electrocardiogram (ECG) abnormalities in 15% of 45 factory workers involved in the production of technical-grade HCH; exposure concentrations were not reported and dermal exposure may have occurred. No studies were located regarding cardiovascular effects in animals following inhalation exposure to HCH. Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans or animals following inhalation exposure to HCH. Hematological Effects. Hematological effects have been reported in humans following acute or chronic inhalation exposure to Y-HCH; however, a causal relationship between exposure to y-HCH and hematological effects in humans has not been established. Hypochromic anemia was reported in a 2.5-year-old boy who was exposed to Y-HCH in a home in which a pesticide vaporizer was operated. Air y-HCH concentrations measured in the basement and living room of the house were 2.4-5.5 ug/m?; however, the actual concentration the child was exposed to and the duration of exposure were not determined (Morgan HCH 19 2. HEALTH EFFECTS et al. 1980). Aplastic anemia was reported in a boy exposed to y-HCH used as an insecticide in his home and in a man exposed at work (Rugman and Cosstick 1990). The anemia was reversible and was not present in other family members. The levels and routes of exposure are not known, although they are presumed to be inhalation and dermal. Other hematological abnormalities, including isolated instances of leukopenia, leukocytosis, granulocytopenia, granulocytosis, eosinophilia, monocytosis, and thrombocytopenia, have been reported following chronic human occupational exposure to Y-HCH (Brassow et al. 1981; Jedlicka et al. 1958). Exposure concentrations were not specified in these studies and concomitant dermal exposure probably occurred. Although Brassow et al. (1981) reported slight changes in clinical chemistry tests in 60 human workers, there were no cases of severe impairment of health. Granulocytopenia, aplastic anemia, paramyeloblastic leukemia, and pancytopenia have been reported in a number of case reports of individuals following exposure to Y-HCH and other pesticides such as DDT in the home, during the handling of the pesticide, or from a nearby formulating plant (Danopoulos et al. 1953; Friberg and Martensson 1953; Gewin 1939; Loge 1965; Mendeloff and Smith 1955). Exposure concentrations were not reported, dermal exposure was likely, and in many cases there was concomitant exposure to other pesticides; therefore, determination of a causal relationship between exposure and hematological effects cannot be made. No hematological effects were seen in rats exposed to lindane aerosol (up to 5 mg/m?) for 90 days (Oldiges et al. 1983). Hepatic Effects. In humans, statistically significant increases in the blood levels of the enzymes lactate dehydrogenase (33%), leucine aminopeptidase (45%), and y-glutamyl transpeptidase (174%) were reported in 19 individuals occupationally exposed to technical-grade HCH for over 10 years in an HCH-formulating plant (Kashyap 1986); the HCH isomer concentrations showed a 1-fold increase compared to the control group of workers. Both inhalation and dermal exposure probably occurred. The large standard deviation (SD) from the mean reported for y-glutamyl transpeptidase in exposed workers (mean+SD = 22.2+40.31 25 p/mL) suggests the increased level of this enzyme may not be related to HCH exposure or that individual responses may vary. No hepatic effects were observed in rats after acute exposure to 603 mg/m’ y-HCH (Oldiges et al. 1980). Rats exposed to lindane aerosol (5 mg/m?) exhibited increased hepatic cytochrome P-450 concentration after 90 days, but this level returned to control values after a 4-week recovery period (Oldiges et al. 1983). HCH 20 2. HEALTH EFFECTS Renal Effects. No studies were located regarding renal effects in humans following inhalation exposure to HCH. No renal effects were seen in rats exposed to up to 603 mg/m’ lindane aerosol for 4 hours (Oldiges et al. 1980) or up to 5 mg/m? lindane aerosol for 90 days (Oldiges et al. 1983). Endocrine Effects. Serum luteinizing hormone levels which were reported to be statistically significant, increased in 54 men occupationally exposed to y-HCH for approximately 8 years in a Y-HCH producing factory (Tomczak et al. 1981). The mean serum concentration of follicle stimulating hormone was increased and testosterone was decreased; but these differences were not statistically significant (Tomczak et al. 1981). No studies were located regarding endocrine effects in animals following inhalation exposure to HCH. Dermal Effects. No studies were located regarding dermal effects in humans or animals following inhalation exposure to HCH. Ocular Effects. No studies were located regarding ocular effects in humans following inhalation exposure to HCH. Mice exposed to lindane aerosol (up to 5 mg/m?) for 14 weeks exhibited no ophthalmic effects (Klonne and Kintigh 1988). Body Weight Effects. No studies were located regarding body weight effects in humans following inhalation exposure to HCH. No body weight effects were seen in rats exposed to up to 5 mg/m’ lindane aerosol for 90 days (Oldiges et al. 1983). 2.2.1.3 Immunological and Lymphoreticular Effects A statistically significant increase (approximately 18%) in the level of immunoglobulin M (IgM) was noted in 19 workers occupationally exposed to technical-grade HCH during pesticide formulation as compared to 14 nonexposed workers (Kashyap 1986). The HCH isomer concentrations in serum showed a 10-fold HCH 21 2. HEALTH EFFECTS increase when compared to the control group. Both inhalation and dermal exposure probably occurred, and the measurement of IgM alone is not a reliable measure of immune function in adults. No studies were located regarding immunological or lymphoreticular effects in animals following inhalation exposure to HCH. 2.2.1.4 Neurological Effects Paresthesia of the face and extremities, headache, and vertigo have been reported in a group of 45 workers occupationally exposed during manufacture and formulation of technical-grade HCH for several years (Kashyap 1986); exposure concentrations were not reported. Both inhalation and dermal exposure probably occurred. Abnormal electroencephalographic (EEG) patterns (increased variation in the frequency and amplitude of wave pattern or more serious changes without specific EEG signs) have been reported in 16 of 37 workers following exposure to y-HCH for 0.5-2 years in a fertilizer plant (Czegledi-Janko and Avar 1970). Exposure concentrations were not reported; however, these EEG changes were found to correlate with blood levels of y-HCH. Weakness of the left and right limbs, dysarthria, and dysphagia were seen in an agricultural worker exposed by inhalation and dermal contact to unspecified levels of several organochlorine pesticides, including lindane (Fonseca et al. 1993). Rats exposed to various concentrations of 99.6% lindane aerosol via nose-only inhalation for 4 hours exhibited dose-related neurological effects when observed for up to 22 days after exposure (Ullmann 1986b). Slight-to-moderate sedation was observed after exposure to 101 mg/m’; slight-to-severe sedation was noted after exposure to 378 mg/m’; restlessness, excitation, and ataxia were seen after exposure to 642 and 2,104 mg/m?; and spasms were also noted at the highest concentration (2,104 mg/m®). Rats exposed to 0.02-5 mg/m? lindane aerosol for 90 days exhibited a "slightly disturbed general condition" beginning at day 15 (Oldiges et al. 1983). Mice were similarly exposed for 14 weeks and exhibited no clinical signs of neurotoxicity (Klonne and Kintigh 1988). 2.2.1.5 Reproductive Effects Statistically significant increases in the levels of serum luteinizing hormone were reported in a group of 54 men occupationally exposed to y-HCH for approximately 8 years in a y-HCH-producing factory (Tomczak et al. 1981). Although the mean serum concentration of follicle stimulating hormone was HCH 22 2. HEALTH EFFECTS increased and testosterone was decreased, these differences were not statistically significant. No causal relationship could be established because exposure levels were not reported. These hormonal changes may have resulted in diminished reproductive capability. No studies were located regarding reproductive effects in animals following inhalation exposure to HCH. 2.2.1.6 Developmental Effects No studies were located regarding developmental effects in humans or animals following inhalation exposure to HCH. 2.2.1.7 Genotoxic Effects No increase in the frequency of chromosome aberrations was observed in humans exposed primarily to y-HCH by inhalation in a pesticide production factory (Kiraly et al. 1979). These individuals had been exposed for 8 hours/day for at least 6 months. Other studies are available regarding genotoxic effects in humans exposed to a wide variety of pesticides, including lindane, when they were used on farms (Rupa et al. 1988, 1989a, 1989b, 1989c). The specific effects of HCH, apart from the effects due to the other exposures, are not known. No studies were located regarding genotoxic effects in animals following inhalation exposure to HCH. Other genotoxicity studies are discussed in Section 2.5. 2.2.1.8 Cancer Use of y-HCH pesticides by farmers in 4 western or midwestern states was associated with a 50% increased risk of having non-Hodgkin’s lymphoma (Blair et al. 1998). There was some evidence of a nonstatistically significant dose-response relationship because odds ratios (OR) were greater in farmers who used y-HCH pesticides >20 compared with <20 years prior to diagnosis (OR 1.7 compared with 1.3) and >5 compared with <5 times per year (OR 2.0 versus 1.6). However, use of certain insecticides such as 2,4-D and diazinon reduced odds ratios from 1.5 to 1.2 and 1.3, respectively. The authors concluded that y-HCH is not a major factor in the development of non-Hodgkin’s lymphoma but may play some role. HCH 23 2. HEALTH EFFECTS No studies were located regarding carcinogenic effects in animals following inhalation exposure to HCH. 2.2.2 Oral Exposure There are two tables and two figures for the Levels of Significant Exposure for oral exposure to the HCH isomers. Table 2-2 and Figure 2-2 are for y-HCH. Table 2-3 and Figure 2-3 are for a-, B-, and 8-HCH, and technical-grade HCH. 2.2.2.1 Death Occasional deaths of humans (usually children) have been reported following ingestion of y-HCH, often from the tablets intended for y-HCH vaporizers (Storen 1955). y-HCH has also been used for suicide (Sunder Ram Rao et al. 1988). The levels associated with death are not known. y-HCH has been shown to be lethal to animals following single gavage administration (Gaines 1960; Liu and Morgan 1986; Tusell et al. 1987). The LD, value for female rats is 91 mg/kg, and the LD, value for male rats is 88 mg/kg (Gaines 1960). One of 7 male Wistar rats died following a single oral administration of 60 mg/kg y-HCH (Martinez et al. 1991). DBA/2 strain mice, recognized as being "unresponsive" to microsomal enzyme induction, are more sensitive to the acute lethal effects of y-HCH than C57BL/6 strain mice when exposed to 20 mg/kg/day for 10 days (Liu and Morgan 1986). In a 15-week study, 2 of 12 F-344 rats treated with 20 mg/kg/day died (Chadwick et al. 1988). A 2-year study in rats fed lindane in their diets (32 mg/kg/day) also found a significantly increased mortality rate compared with controls (Amyes 1990). The oral LDj, for technical-grade HCH in CFT-Wistar rats treated once by gavage was 2,428 mg/kg (Joseph et al. 1992a). Exposure to 5 mg/kg/day of technical-grade HCH for 90 days resulted in the deaths of 6/12 male rats and 4/12 female rats (Dikshith et al. 1991b). Exposure to low levels (0.4 mg/kg/day) of technical-grade HCH in the diet for 360 days resulted in deaths of 4/20 rats (Dikshith et al. 1991a). However, the deaths occurred late in the study and were accompanied by other changes indicating that they were due to pathogenic infection rather than HCH exposure. The LDj, for rats and the LOAEL values from the intermediate-duration studies are recorded in Tables 2-2 and 2-3 and plotted in Figures 2-2 and 2-3. TABLE 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral EXposure a duration/ LOAEL Key to species frequency NOAEL Less serious Serious Reference figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) ACUTE EXPOSURE Death 1 Rat once 88 M (LDso) Gaines 1960 (Sherman) (GO) 91 F (LDso) 2 Rat once 60 M (1/7 deaths) Martinez et al. (Wistar) (GO) 1991 nN Systemic T g 3 Rat 2wks Hepatic 72 Altered activities of Srinivasan and i F SIUM Radhakrishnamurt m aminotransferases, y 1988 7 alkaline phosphatase, Q decreased soluble » enzymes and altered carbohydrate metabolism. 4 Rat 14d Renal 72 M (10% increase in kidney Srinivasan et al. (Wistar) ad libitum weight, altered excretion ~~ 1984 (F) patterns, distention of glomeruli, swelling of tubular epithelia) HOH ve TABLE 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (continued) S103443 H1TV3H ¢ EXposure a eaten LOAEL Keyto Species frequency NOAEL Less serious Serious Reference figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 5 Mouse 3d Resp 40M Hong and Boorman (B6C3F1) 1x/d 1993 (GO) Cardio 40M Gastro 40M Hemato 20M (Transient reduction in marrow progenitor cell number) Hepatic 40M Renal 40M Endocr 40M Bd Wt 40M 6 Mouse 10d Resp 20M Hong and Boorman (B6C3F1) 1 x/d 1993 (GO) Cardio 20M Gastro 20M Hemato 10M (Transient decrease in marrow progenitor cell numbers) Hepatic 20M Renal 20M Bd Wt 20M Immunological/Lymphoreticular 7 Mouse 10M (Dose-related decrease Hong and Boorman (B6C3F1) in thymus and spleen 1993 weights) 8 Mouse 3d 10M 20M Decreased thymus 40 M Atrophy of thymus cortex ~~ Hong and Boorman (B6C3F1) 1x/d (GO) transient weight 1993 HOH Ge TABLE 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (continued) EXpOSUTS LOAEL a duration/ Keyto Species frequency NOAEL Less serious Serious Reference figure (strain) (specific route) (mg/kg/day) (mg/kg/day) (mg/kg/day) Neurological 9 Rat 6d 3M (increased pineal Attia et al. 1991 (Sprague- 1x/d N-acetyltransferase, Dawley) (GO) decreased serotonin levels) 10 Rat once Barron et al. 1995a 1 12 13 14 15 (Wistar) (GO) Rat once (Long- Evans) (GO) Rat 4d (Sprague- 1x/d Dawley) (GO) Rat once (Wistar) (GO) Rat once (Wistar) (GO) Rat 3d (Wistar) 1x/d (GO) 5M (myoclonic jerks and single clonic seizure in kindled animals) 10M 3M (increased kindling acquisition) 5 (decreased myelin and 2',3'-cyclic nucleotide 3'-phosphodiesterase activity in brains) 30 M (convulsions, decreased calmodulin mRNA expression in the brain) 10 M (myoclonic jerks and single clonic seizures in naive animals) 10 M (seizures) 60 (convulsions) 60 M (tonic-clonic seizures) Gilbert and Mack 1995 Joy et al. 1982 Martinez and Martinez-Conde 1995 Martinez et al. 1991 Serrano et al. 1990a S103443 HLIV3H 2 HOH 92 TABLE 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (continued) EXposure HOH LOAEL a duration/ Keyto Species frequency NOAEL Less serious Serious Reference figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 16 Rat once 15M 20 M (convulsions) Vendrell et al. (Wistar) (GO) 1992a 17 Rat once 30 M (seizures) Wooley and Griffith (Sprague- (GO) 1989 Dawley) Reproductive 18 Rat 6 days, day 1M (reduced testosterone Dalsenter et al. 9-14 of level at puberty, relative 1997a lactation testes weight) 19 Rat once day 9 6M Reduced relative testical Dalsenter et al. or 14 of and epidymis weight 1997a lactation (~10%), spermatid and (GO) sperm counts (~8-10%), testosterone levels (~30-50%), Leydig cell numbers and spermatogenisis. 20 Rat 7d 40F Laws et al. 1994 (Long- Evans) 1x/d (GO) 21 Rat once 25 (increased length of Uphouse and (CDF-F344) estrous cycle) Williams 1989 S103443 H1TV3H 2 le TABLE 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (continued) EXposure a duration/ LOAEL Keyto Species frequency NOAEL Less serious Serious Reference figure (strain) (specific route) System Developmental 22 Rat single dose 30 (reduction of serum Dalsenter et al. (Wistar) day 15 of testosterone 1997b gestation concentration in adult (GO) offspring) 23 Rat Gd 6-15 25F Khera et al. 1979 (Wistar) 1x/d (GO) 24 Rat Gd 6-15 20F Palmer et al. 1978a (CFY) 1x/d G) 25 Rat once 20 (regional changes in Rivera et al. 1991 (Wistar) (GO) brain noradrenaline and serotonin levels in suckling rats) 26 Mouse Single oral 45 (decrease in fetal and Hassoun and DBAZ2J dose on day placental weight) Stohs, 1996a 12 of gestation Gl 27 Mouse Single oral 30 (decrease in fetal weight, Hassoun and C57BU6N dose on day fetal thymus weight) Stohs, 1996a 12 of gestation Gl S103443 H1TV3H 2 HOH 82 TABLE 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (continued) EXposure a duration/ LOABL. Keyto Species frequency NOAEL Less serious Serious Reference figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 28 Rabbit Gd 6-18 20F Palmer et al. 1978a (New 1x/d Zealand) (G) INTERMEDIATE EXPOSURE Death 29 Rat 15 wk 20 F (2/12 deaths) Chadwick et al. (Fischer- 1x/d 1988 344) (GO) Systemic 30 Rat 16d Hepatic 1.8 M Increases in lipid Barros et al. 1991 (Wistar) ad libitum peroxidation, level of (F) cytochrome P-450, and activities of superoxide dismutase. 31 Rat 30d Hepatic 1.8 M Increases in lipid Barros et al. 1991 (Wistar) ad libitum peroxidation, level of (F) cytochrome P-450, and activities of superoxide dismutase. 32 Rat 40d Hepatic 50 Desi 1974 (Wistar) (F) Renal 5 S103443 H1IV3H ¢ HOH 62 TABLE 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (continued) EXposure a duration/ LOAEL Key to species frequency NOAEL Less serious Serious Reference figure (strain) (specific route) System 33 Rat 7 and 15 Gastro 20 Reduction in jejunum Moreno et al. 1996 (Wistar) days maltase activity gavage (SC) 34 Rat 12 wk Hepatic 0.4 2 (centrilobular Suter 1983 (Wistar) ad libitum hypertrophy) (F) Renal 0.4 2 (ddtubular distension, basophilic tubules) Hemato 10 35 Mouse 24 wk Hepatic 90M (centrilobular Ito etal. 1973 (dd) ad libitum hypertrophy) (F) Immunological/Lymphoreticular 36 Mouse 24 wk (Swiss ad libitum albino) F Neurological 37 Rat 90d (Wistar) ad libitum (F) 38 Rat 30d (Long- Evans) {1x/d (GO) 0.012€¢ F (biphasic changes in cell- and humoral-mediated immune system) 1.2 F (necrosis of thymus) 90 M (tonic convulsions) Meera et al. 1992 Arisi et al. 1994 10 M (myoclonic jerks and clonic Gilbert 1995 seizures) S103443 H1TV3H 2 HOH oe TABLE 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (continued) EXposure a duration/ LOA Keyto Species frequency NOAEL Less serious Serious Reference figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 39 Rat 10 wk 10 M (myoclonic jerks and clonic Gilbert 1995 (Long- Evans) 3 d/wk seizures) (GO) 40 Rat 30d 2 (decreased dopamine Martinez and (Wistar) (GO) levels) Martinez-Conde 1995 41 Rat 30d 123M 25.4 M (reduced tail nerve Muller et al. 1981 (Wistar) ad libitum conduction velocity) (F) Reproductive 42 Rat 15 wk 5F 10F (disrupted ovarian Chadwick et al. (Fischer- 1x/d cycling, antiestrogenic 1988 344) (GO) effects) 43 Rabbit 12 wk 0.8F (reduced ovulation rate) Lindenau et al. (hybrid) 3 diwk 1994 (GO) 44 Rabbit 12-15 wk 08 F Seiler et al. 1994 (New 3 diwk Zealand) (GO) S103443 H1TV3H ¢ HOH LE TABLE 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (continued) EXposure . LOAEL a duration/ Keyto species frequency NOAEL Less serious Serious Reference figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Developmental 45 Rat 21 day GO 25 Increased liver weight Srinivasan et al. (Wistar) 21 GD and and decreased kidney 1991a 28 LD or 28 weight in pups exposed LD during gestatino and (F) lactation 46 Rabbit 12-15 wk 08F Seiler et al. 1994 (New 3 diwk Zealand) (GO) CHRONIC EXPOSURE Death 47 Rat up to 52 32 F (increased mortality rate) ~~ Amyes et al. 1990 (Wistar) weeks ad libitum (F) Systemic 48 Rat 5to 52 Hepatic 0.7 M 7 M (periacinar hepatocytic Amyes et al. 1990 (Wistar) weeks 08 F 8 F hypertrophy) ad libitum Renal 07M 7 M (male: pale kidneys, (F) 8F 28 F increased kidney weight, urinary volume, and protein, tubular necrosis. female: increase in urine specific gravity, urea, and creatinine and kidney weight ) S103443 H1IV3H 2 HOH [4% TABLE 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (continued) EXposure a duration/ LOAEL Keyto species frequency NOAEL Less serious Serious Reference figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) 49 Rat 109 weeks Hepatic 35M 7 M (focal necrosis, fatty Fitzhugh et al. 1950 (Wistar) (F) 40 F 8 F degeneration, 35% increase in liver weight) Renal 35M 7 M (focal nephritis) 4F 8F Bd Wt 56 M 112M (17% decrease in body weight gain) 64 F 128F (13 % decrease in body weight gain) Cancer > m > 50 Mouse 80 wk 13.6 M (CEL: hepatocellular NCI 1977 5 (B6C3F1) ad libitum carcinoma) - (F) on m Q =i n 51 Mouse 24 mo 27.2 F (CEL: hepatocellular Wolff et al. 1987 (F-1 hybrid) ad libitum carcinoma, lung tumors) (F) *The number corresponds to entries in Figure 2-2. ®Used to derive an acute-duration oral Minimal Risk Level (MRL) of 0.01 mg/kg/day for gamma-HCH; 1 mg/kg/day divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans, 10 for human variability) = 0.01 mg/kg/day. Used to derive an intermediate-duration oral Minimal Risk Level (MRL) of 0.00001 mg/kg/day for gamma-HCH; 0.012 mg/kg/day divided by an uncertainty factor of 1000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, 10 for human variability) = 0.00001 mg/kg/day. Bd Wt = body weight; CEL = cancer effect level; d = day(s); F = female; (F) = food; (G) = gavage; (GO) = gavage, oil; (GO) = gavage, water; Gd = gestation day(s), LD50 = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; mRNA = messenger ribonucleic acid; mo = month(s); NOAEL = no-observed-adverse-effect level; NS = not specified; wk = week(s); x = time(s); yr = year(s). HOH €e Figure 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral Acute (<14 days) Systemic ~ $ $ 3 $ § s & & o > o T -£ > § S S 3 9 £L 5 i ~ Ss iN (mg/kg/day) & S Sg & § 8 s 5 S Q oO oO Q 10000 z z x v 1000 1r 3r 4r 100 + un ® 5m 5m 5m EL @ 5m 5m 5m O 6m O 6m O em 5m O em O 6m ©) O em Oo Oo Oo Dem Oo Oo Oo 10 } 0 1} 01} Key ro rat B |D,, (animals) + Minimal risk m mouse . . level for effects 0.01 h rabbit @ LOAEL for serious effects (animals) ! other than ( LOAEL for less serious effects (animals) WW cancer ; The number next to ooot | O NOAEL (animals) each point : @ CEL: cancer effect level (animals) corresponds to entries in Table 2-2. 0.0001 | * 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. 0.00001 tL S103443 H1TV3H ‘2 HOH ve Figure 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (cont.) Acute (<14 days) Systemic SS = 8s 8 = @ 85 & S § 8 ° g 5 (mg/kg/day) 13 3 a $ 10000 = = z o 1000 100 f+ 13r 14r ® 10r o 17r 2 2r 3 a 27m 16 @ Oo 0 0 24r 25r () 28h 10 a 2 8m ° 12r oO i 15r 19r 8m or ap 12 0 ior 0 D 1m OD 12r 18r 1+ Oo 0 | | | 01 } Key | ! ro rat ® | D,, (animals) ' Minimal risk I , m mouse . . 1 level for effects 0.01 WV h rabbit @ LOAEL for serious effects (animals) I other than LOAEL for less serious effects (animals) cancer : The number next to 0.001 | O NOAEL (animals) each point @ CEL: cancer effect level (animals) corresponds to entries in Table 2-2. 0.0001 * 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. 0.00001 “ HOH S103443 H1TV3H 2 SE Figure 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (cont.) Intermediate (15-364 days) Systemic NAS -~ ~ -~ £ 3 33 ~ 0 Z % 5 = 8 = @ 2 o 32 S> o £ £ oS 0 es o 5 q Ss 9S © 5 - S§ oS o © megs) FF § 8 g ES 3 s 2 10000 « 38 O T T & s3 2 @ Q 1000 35m 37r 100 1 32r 0 ® 29r 33r o 41r 451 @ 0 34r 38r 39r oO 42r » 10 } Oo 32r LA 41r ? 30r 31r o> o> 36m o So . | > 0 43h 44h 46h 34r 34r o oO Oo Oo 0.1 Key 36m 0.01 | ro rat ® | Dy, (animals) + Minimal risk ? m mouse . . 1 level for effects , h rabbit @ LOAEL for serious effects (animals) I other than ' | Q LOAEL for less serious effects (animals) cancer : ’ O NOAEL (animals) The number next to | . each point : @ CEL: cancer effect level (animals) corresponds to ' 0.0001 } entries in Table 2-2. : * 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. Wu 0.00001 * HOH S103443 H1IV3H 2 9g Figure 2-2. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Oral (cont.) HOH Chronic (>365 days) Systemic ~ S$ o § s § 5 (mg/kg/day) 5 g g $ $ q I @ & J 10000 1000 49r 100 } 0 47r Oo 51m 49r 50m $ 10 } 48r 49r 48r 49r % 0 9 2 0 Oo Oo 49r 49r 1} 48r 48r oO 01 f Key ro rat ® | D,, (animals) ' Minimal risk m mouse . . 1 level for effects 0.01 } h rabbit @® LOAEL for serious effects (animals) | other than ( LOAEL for less serious effects (animals) cancer ; The number next to 0.001 | O NOAEL (animals) each point @ CEL: cancer effect level (animals) corresponds to entries in Table 2-2. 0.0001 + * 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. 0.00001 t S103443 H1TV3H 2 LE TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral Exposure a duration/ LOAEL Reference/ Keyto gpecies frequency NOAEL Less serious Serious Chemical figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Form ACUTE EXPOSURE Death 1 Rat once 2428 M (LDso) Joseph et al. 1992a (CFT-Wistar) (Go) technical Systemic 2 Rat once Metab 100F (increased Agrawal et al. 1995 (NS) (GO) phosphoinositide technical turnover in erythrocyte membranes) no 3 Rat 2 wk Hepatic 90M (increased triglycerides, Ikegami et al. o (Sprague- ad libitum phospholipids and 1991a q Dawley) (F) cholesterol, increased beta x cytochrome C reductase a and decreased 3 glutathione peroxidase) a 4 Rat 2 wk Hepatic 90M (increased relative liver Ikegami et al. (Sprague- ad libitum weight and cytochrome 1991b Dawley) F) P-450 levels and beta decreased hepatic vitamin A levels) 5 Rat 14d Renal 72 M (tubular degeneration, Srinivasan et al. (Wistar) ad libitum distention of glomeruli, 1984 (F) swelling of tubular epithelia, beta 22% increase in kidney weight, altered excretion patterns) HOH 8€ TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) Ex a dations LOAEL Reference/ Keyto species frequency NOAEL Less serious Serious Chemical figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Form 6 Mouse Gd9 Hepatic 5F (significantly decreased Dikshith et al. 1990 (Swiss once GOT, GPT, and lactate technical albino) (GO) dehydrogenase (LD) activities) 7 Mouse 1,5,15d Hepatic 50 (congestion of portal Philip et al. 1989 (NS) 1x/d vessels and central vein, technical (GO) fatty changes, granular degeneration) Renal 50 (congestion of portal vessels and glomeruli, fatty changes, interstitial ~ hemorrhaging) T m 8 Mouse 2 wk Hepatic 72M (226% increase in liver Ravinder et al. 2 (Swiss ad libitum weight, increased serum 1989 a» albino) (F) alanine and aspartate technical a aminotransferases and o ALP, increased hepatic a phosphatases and acid cathepsin) 9 Mouse 2 wk Hepatic 72M (cellular hypertrophy, Ravinder et al. (Swiss ad libitum centrilobular 1990 albino) (F) degeneration, focal technical necrosis) Neurological 10 Rat once 100M (decreased calmodulin Barron et al. 1995 (Wistar) (GO) mRNA expression in the delta brain) 11 Mouse 1 wk 19° F 57F (ataxia) 190 F (lateral recumbancy) Cornacoff et al. (B6C3F1) ad libitum 1988 beta (F) HOH 6€ TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) Exposure a duration/ LOAEL Reference/ Key to Species frequency NOAEL Less serious Serious Chemical figure (strain) (specific route) System (mglkg/day) (mg/kg/day) (mg/kg/day) Form Reproductive 12 Mouse Gdo 5F 25 F (increased fetal resorptions) Dikshith et al. 1990 (Swiss once technical albino) (GO) INTERMEDIATE EXPOSURE Death 13 Rat 360d 0.4 M (4/20 deaths) Dikshith et al. (NS) ad libitum 1991a (F) technical 14 Rat 90d 5 (6/12 M, 4/12 F died) Dikshith et al. (NS) 1x/d 1991b (GO) technical Systemic 15 Rat 3-6 mo Metab 5F (increased Agrawal et al. 1995 (NS) 5 diwk phosphoinositide technical (GO) turnover in erythrocyte membranes and cerebrum) 16 Rat 30d Hepatic 1.8 M (increased cytochrome Barros et al. 1991 (Wistar) ad libitum P-450 level, superoxide alpha (F) dismutase, catalase, NADPH-cytochrome P-450 reductase activities, and lipid peroxidation) S103443 H1TV3H 2 HOH ov TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) a Exposure LOAEL Reference/ Keyto species frequency NOAEL Less serious Serious Chemical figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Form 17 Rat 15d Hepatic 1.8M (increased cytochrome Barros et al. 1991 (Wistar) ad libitum P-450 level, superoxide alpha (F) dismutase, catalase, and lipid peroxidation activities) 18 Rat 30d Hemato 60 M Dikshith et al. (NS) 1x/d 1989a (GO) technical Hepatic 60M (decreased GOT and LDH activities, increased ALP activity, 65% ~o increase in liver weight) T Renal 60 M o 9 19 Rat 360d Hepatic 04M 2M (increased liver weight) 20 M (focal necrosis, Dikshith et al. I (NS) ad libitum enlargement of 1991a mo (F) hepatocytes, nuclear technical m pyknosis, vacuolation, a margination) Renal 2M 20 M (tubular necrosis, glomerular degeneration) 20 Rat 90d Hepatic 5M (decreased liver and Dikshith et al. (NS) 1x/d serum GOT and alkaline 1991b (GO) phosphatase activities) technical 21 Rat 180d Bd Wt 3M (17% decrease in body Gautam et al. 1989 (Charles 1x/d weight gain) technical Foster) (GO) HOH Iv TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) a Exposure LOAEL Reference/ Key to Species frequency NOAEL Less serious Serious Chemical figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Form 22 Rat 7 wk Hepatic 90M (decreased hepatic Joseph et al. 1992b (CFT-Wistar) ad libitum vitamin A content, GOT, technical (F) GPT ALP, and beta-GLR activities, 121% increase in liver weight) Bd Wt 90M (17% decrease in body weight gain) 23 Rat 7 wk Hemato 90M (decreased white blood Joseph et al. 1992¢c (CFT-Wistar) ad libitum cell counts) technical (F) 24 Rat 30d Hepatic 50M Khanna et al. 1990 ro (NS) 1x/d technical & (GO) Renal 50 M = 25 Rat 90d Bd Wt 20F (significantly decreased Nagaraja and on (Wistar) ad libitum body weight gain) Desiraju 1994 a (F) technical a 26 Rat 13 wk Hemato 45M 22.5 M (decreased red blood Van Velsen et al. (Wistar) ad libitum 5F 25F cell, leukocyte, and 1986 (F) hemoglobin beta concentrations) Hepatic 0.18¢ M (hyalinization of 4.5 M (hyalinization of 0.2 F centrilobular cells) 5 F centrilobular cells, focal cell necrosis, increased mitoses) Renal 45M 22.5M (calcinosis in males) Bd Wt 45M 22.5 M (15% decrease in body 5F 25F weight) 27 Mouse 32 wk Hepatic 18 M 54 M (nuclear irregularities in Hanada et al. 1973 (dd) ad libitum 20 F 60 F foci of enlarged beta (F) hepatocytes) HOH av TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) Exposure a duration/ LOAEL Reference/ Keyto species frequency NOAEL Less serious Serious Chemical figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Form 28 Mouse 24 wk Hepatic 18M (centrilobular Ito et al. 1973 (dd) ad libitum hypertrophy) alpha (F) 29 Mouse 24 wk Hepatic 45M (centrilobular Ito et al. 1973 (dd) ad libitum hypertrophy) beta (F) 30 Mouse 24 wk Hepatic 90M (centrilobular Ito et al. 1973 (dd) ad libitum hypertrophy) delta (F) 31 Mouse 2-8 mo Hepatic 90 (100% increase in liver Karnik et al. 1981 » (Swiss) ad libitum weight, decreased G6P technical a (F) and FDP activity, 7 glycogen accumulation, I smooth endoplasmic o reticulum proliferation) ® — 32 Mouse 50 wk Hepatic 90M (hyperplastic nodules) Tryphonas and @ (HPB) ad libitum Iverson 1983 F) alpha Immunological/Lymphoreticular 33 Rat 13 wk 22.5 M (cortical atrophy in thymus) Van Velsen et al. (Wistar) ad libitum 25 F 1986 (F) beta 34 Mouse 30d 20F 60F (decr. lymphoproliferative Cornacoff et al. (B6C3F1) ad libitum responses to T-cell 1988 beta (F) mitogens, decr. natural killer cytolytic activity) HOH TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) Exposure a duration/ LOAEL Reference/ Key to Species frequency NOAEL Less serious Serious Chemical figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Form Neurological 35 Rat 3 mo 50M (increased dopamine and Anand et al. 1991 (NS) 6 diwk decreased serotonin, technical 1x/d acetylcholine, (GO) norepinephrine in cerebral cortex, behavioral changes, increased brain wave frequency) 36 Rat 360d 0.04 M 0.4 M (convulsions, tremors, Dikshith et al. o (NS) 1x/d hindlimb paralysis, 1991a : (F) salivation) technical & 37 Rat 120d 50M (increased motor Gopal et al. 1992 5 (NS) 1x/d activity, decreased technical a (GO) resting stereotypic time) m 38 Rat 30d 106.2 M Muller et al. 1981 ® (Wistar) ad libitum alpha (F) 39 Rat 30d 66.3 M (reduced tail nerve Muller et al. 1981 (Wistar) ad libitum conduction velocity) beta (F) 40 Rat 90d 20F (increased GABA levels, Nagaraja and (Wistar) ad libitum increased GAD activity, Desiraju 1994 F decreased glutamate technical levels) 41 Rat 13 wk 45M 22.5 M (ataxia, coma) Van Velsen et al. (Wistar) ad libitum 5F 25 F 1986 (F) beta HOH TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) Exposure a duration/ LOAEL Reference/ Key to Species frequency NOAEL Less serious Serious Chemical figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Form Reproductive 42 Rat 360d 2M 20 M (testicular degeneration) ~~ Dikshith et al. (NS) 1x/d 1991a (F) technical 43 Rat 180d 3M (6% decrease in vas Gautam et al. 1989 (Charles 1x/d deferens weight, technical Fosten (GO) degeneration of inner muscle and cell layers) 44 Rat 7 wk 90 M (decreased testes, Pius et al. 1990 (CFT-Wistar) ad libitum epididymides, and seminal technical (F) vesicle weights, 30% decrease in sperm count) 45 Rat 180d 3M (decreased seminiferous 6 M (seminiferous tubular Roy Chowdhury (Charles 1x/d tubular and Leydig cell degeneration) and Gautam 1990 Foster) (GO) nuclear diameter) technical 46 Rat 13 wk 09M 4.5 M (decreased testes 22.5 M (atrophy of ovary and Van Velsen et al. (Wistar) ad libitum 02F 1.0 F weight) 25 F testes, hyperplastic and 1986 (F) (increased ovary vacuolized endometrium beta weights) epithelium in uterus) 47 Mouse 30d 60 F Cornacoff et al. (B6C3F1) ad libitum 1988 (F) beta 48 Mouse 3 mo 90 M (increased testis weight, Nigam et al. 1979 (Swiss) ad libitum degeneration of technical (F) seminiferous tubules, decreased spermatocytes) S103443 H1V3H 2 HOH Sv TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) Exposure a duration/ LOAEL Reference/ Keyto species frequency Less serious Serious Chemical figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) Form Developmental 49 Rat 60d 10F (alterations in levels of Nagaraja and (Wistar) ad libitum dopamine, serotonin, and Desiraju 1994 (G) noradrenaline in pup technical brains) 50 Rat 21GD, 28 (increased liver weight in 20 (increased pup mortaility) ~~ Srinivasan et al. (Wistar) LD, 28LD pups exposed during 1991a (F) gestation and lactation) beta Cancer nN 51 Rat 20 wk 2 F (CEL: increase in Schroter et al. 1987 T (Wistar) ad libitum preneoplastic hepatic foci) alpha n (F) E T 52 Rat 20 wk 3 F (CEL: increase in Schroter et al. 1987 on (Wistar) ad libitum preneoplastic hepatic foci) peta m (F) a 53 Mouse 32 wk 18 M (CEL: hepatoma) Hanada et al. 1973 (dd) ad libitum 60 F alpha (F) 54 Mouse 24 wk 45 M (CEL: hepatocellular Ito etal. 1973 (dd) ad libitum carcinoma) alpha (F) 55 Mouse 16-36 wk 90 M (CEL: hepatocellular Ito et al. 1976 (DDY) ad libitum carcinoma) alpha (F) 56 Mouse 2-4 mo Hepatic 90 (CEL: liver tumors) Karnik et al. 1981 (Swiss) ad libitum technical (F) HOH 9 TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) Exposure a duration/ LOAEL Reference/ Keyto species frequency NOAEL Less serious Serious Chemical figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Form 57 Mouse 24 wk 90 M (CEL: hepatocellular Nagasaki et al. (DDY, ICR, ad libitum 100 F carcinoma) 1975b DBA/2, (F) alpha C57BUS, C3H/He) 58 Mouse 2-8 mo 90 (CEL: hepatocellular Thakore et al. 1981 (Swiss) ad libitum carcinoma) technical (F) 59 Mouse 50 wk 90 M (CEL: hyperplastic nodules Tryphonas and (HPB) ad libitum and adenomas in liver) Iverson 1983 (F) alpha 60 Mouse 16-36 wk 90 M (CEL: hepatoma) Tsukada et al. 1979 (DD) ad libitum alpha (F) CHRONIC EXPOSURE Systemic 61 Rat 107 weeks Hepatic 07 M 3.5 M (focal necrosis, fatty Fitzhugh et al. 1950 (Wistar) ad libitum 084 F 4 F degeneration, 32% alpha (F) increase in liver weight) Renal 7M 56 M (focal nephritis) 8 F 64 F Bd Wt 7™ 56M (18% decrease in body weight gain) 8F 64F (13% decrease in body weight gain) S103443 H1TV3H 2 HOH Ly TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) Exposure a duration/ LOAEL Reference/ Key to Species frequency NOAEL Less serious Serious Chemical figure (strain) (specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Form 62 Rat 107 weeks Hepatic 0.7 M (focal necrosis, fatty Fitzhugh et al. 1950 (Wistar) ad libitum 0.8 F degeneration, 33% beta (F) increase in liver weight) Renal 7™ 56 M (focal nephritis) 8 F 64 F Bd Wt 56 M 08 F 8F (12% decrease in body weight gain) 63 Rat 107 weeks Hepatic 07M 3.5 M (very slight microscopic 7 M (focal necrosis, fatty Fitzhugh et al. 1950 (Wistar) ad libitum 08 F 4F damage) 8 F degeneration, 36% technical (F) increase in liver weight) ~o Renal 7M 56 M (focal nephritis) T 8 F 64 F £ Bd Wt 7M 56 M (decreased body weight 3 8 F 64 F gain) m Neurological : —4 64 Mouse 80 wk 17 (convulsions) Kashyap et al. 1979 @ (Swiss) ad libitum technical (F) 65 Mouse 80 wk 10 (convulsions) Kashyap et al. 1979 (Swiss) 1x/d technical (GO) Cancer 66 Rat 72 wk 50 (CEL: hepatocellular Ito et al. 1975 ad libitum carcinoma) alpha (F) 67 Mouse 80 wk 10 (CEL: hepatocellular Kashyap et al. 1979 (Swiss) 1x/d carcinoma) technical (GO) HOH 514 TABLE 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (continued) Exposure a duration/ Reference/ Keyto species frequency Less serious Serious Chemical figure (strain) (specific route) (mg/kg/day) Form 68 Mouse 80 wk 17 (CEL: hepatocellular Kashyap et al. 1979 (Swiss) ad libitum carcinoma) technical (F) 69 Mouse 20 mo 21.3 M (CEL: hepatocellular Munir et al. 1983 (Swiss) ad libitum carcinoma) technical (F) 70 Mouse 104 wk 34 (CEL:hepatocellular Thorpe and Walker (CF1) ad libitum carcinoma) 1973 (F) beta *The number corresponds to entries in Figure 2-3. ®Used to derive an acute-duration oral Minimal Risk Level (MRL) of 0.2 mg/kg/day for beta-HCH; 19 mg/kg/day divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans, 10 for human variability) = 0.19 mg/kg/day. Used to derive an intermediate-duration oral Minimal Risk Level (MRL) of 0.0006 mg/kg/day for beta-HCH; 0.18 mg/kg/day divided by an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for extrapolation from animals to humans, 10 for human variability) = 0.0006 mg/kg/day. Used to derive a chronic-duration oral Minimum Risk Level (MRL) of 0.008 mg/kg/day for alpha-HCH; 0.8 mg/kg/day divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans, 10 for human variability) = 0.008 mg/kg/day. S103d443 HLIV3H 2 ALP = alkaline phosphatase; Bd Wt = body weight; CEL = cancer effect level; d = day(s); F = female; FDP = fructose-1,6-diphosphatase; GABA = gamma-aminobutyric acid; GAD = glutamate decarboxylase; GLR = glucuronidase; GOT = glutamate oxaloacetate transaminase; G6P = glucose-6-phosphatase; GPT = glutamate pyruvate transaminase; Hemato = hematological; LD50 = lethal dose, 50% kill; LDH = lactate dehydrogenase; LOAEL = lowest-observed-adverse-effect level; M = male; Metab = metabolism; mo = month(s); NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respiratory; wk = week(s); x = time(s). HOH 6v Figure 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral Acute (<14 days) Systemic o 2 5 S S 5 = S Ss 3 (mgkg/day) 8 2 g 5 5 Q z « s 2 & 10000 r 1r =m 1000 | 11m 3r 4r 8m am 5 zr 10r o 100 0 0 7m 0 0 ® 7m 0 0 11m o o > 12m 11m ® Oo 10 6m . 12m 0 1 Oo | 1 1 1 | 1 Key YU 0.1 : . . [ r rat ® | D,, (animals) ! Minimal risk mouse . . 1 level for effects @® LOAEL for serious effects (animals) | other than 001 | LOAEL for less serious effects (animals) cancer O NOAEL (animals) The number next to . each point @ CEL: cancer effect level (animals) pL to 0.001 } entries in Table 2-3. * 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. 0.0001 * S103443 HLV3H 2 HOH 0S Figure 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (cont.) Intermediate (15-364 days) Systemic 8 - S S 5 o o s > S = 3 S £ [1] © 3, Q (mghkg/day) & 2 a s 5 3 10000 1 —2 < @ Q s 1000 8 23r 22r 30m 31m 32m 29r 100 + "0 18r D 24 27m om @ OO 18r sar Oo 0 0 Oo Oo 53 19r 27m 28m 19r 26r 25r 26 ® oO 0 ® 2? 0 0r ° 26r 20r 26r 26r 26¢ 15r 21r © 16r 17r 19r 19r Oo 0 Oo (0 JING) 0 Oo 1 13r 19r ® o 26r Key a 01 f : ro rat B® | D,, (animals) ' Minimal risk 1 m mouse . . @® LOAEL for serious effects (animals) level for effects . . Ww ! ® LOAEL for less serious effects (animals cancer 0.01 1 . O NOAEL (animals) The number next to . each poin © CEL: cancer effect level (animals) pl © | . . entries in Table 2-3. 0.001 + , . vv 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. 0.0001 S103443 H1TV3H 2 HOH 1S Figure 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (cont.) Intermediate (15-364 days) Systemic a ® SE $ S £ g 8 2° 3 3 oO * 8 8 $ 3 5 8 (mahkg/day) £ £ 3 g 3 8 § ~~ 10000 ¢ Zz x Q I oO 1000 + » 38r 44r 48m 56m 55m 57m 58m 59m 60m 100 > 35r an © > ® oe ® sm © © © @ 33 34m 2 40r 41 ar 46r 50r 53m * o oO 0 ® & o 49r o ® 10 } “tr ase i 0 43r & 0 0 52r 2) 0 Str o 451 46r * Tr 36r Oo & Key 01 } - & r rat B® | D,, (animals) !" Minimal risk m mouse . . 1 level for effects @ LOAEL for serious effects (animals) | other than 0.01 ( LOAEL for less serious effects (animals) cancer O NOAEL (animals) The number next to . ea on @ CEL: cancer effect level (animals) ones to 0.001 entries in Table 2-3. * 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. 0.0001 + HOH S103443 HLV3H ¢ 2s Figure 2-3. Levels of Significant Exposure to Alpha-, Beta-, Delta-, and Technical-Grade Hexachlorocyclohexane - Oral (cont.) Chronic (>365 days) HOH Systemic Q s S * hd -— Oo (mg/kg/day) 8 g 8 s § @ 10000 z x Z S 1000 } 100 } 6ir 62r 63r 61r 62r 63r 66r o a 0 0 0 Oo 0 m i. + wn 65m 67m 10 } 63r 61r 62r 63r 61r 63r ® ® $ * 61r @® Oo Oo Oo Oo Oo 2 a 63r 61r 62r 63r 1} © oo o 1 1 | Key 01 | } ! r rat ky LD, (animals) 1 Minimal risk m mouse . . | @® LOAEL for serious effects (animals) level for effects ! . . Ww 0.01 W ( LOAEL for less serious effects (animals) cancer O NOAEL (animals) The number next to . each poin @ CEL: cancer effect level (animals) corresponds to 0.001 entries in Table 2-3. * 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. 0.0001 S103443 H1V3H 2 £5 HCH 54 2. HEALTH EFFECTS 2.2.2.2 Systemic Effects No studies were located regarding respiratory, dermal, or ocular effects in humans or animals following oral exposure to HCH. The animal studies in which systemic effects of HCH were examined, in most cases, used isomers of >99% purity. The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each species and duration category are recorded in Tables 2-2 and 2-3 and plotted in Figures 2-2 and 2-3. Cardiovascular Effects. There are no reports of cardiovascular damage from y-HCH or any other HCH isomer. Gastrointestinal Effects. Decreased appetite, vomiting, nausea, and diarrhea have been observed in humans following ingestion of y-HCH in contaminated food; exposure levels were not reported, but exposure was inferred from levels of y-HCH measured in urine (Nantel et al. 1977). Vomiting and nausea are usual manifestations of lindane ingestion (Sunder Ram Rao et al. 1988). The activities of the digestive enzyme maltase on brush border membrane of rat jejunum are reported to be inhibited by oral treatment with 20 mg/kg y-HCH over 7 and 15 days (Moreno et al. 1996). In addition, y-HCH has been shown to have an effect on intestinal functions such as uptake of glucose, glycine, and calcium in rats (Labana et al. 1997), and the effect depends on the nutritional status of the animals. Hematological Effects. A woman who committed suicide by drinking y-HCH was found to have disseminated intravascular coagulation during the period when serum y-HCH levels were elevated (Sunder Ram Rao et al. 1988). No other reports were found on the possible effect of Y-HCH on blood-clotting factors in humans. No hematological effects were noted in beagle dogs exposed to 12.5 mg y-HCH/kg/day in the diet for 32 weeks or to 2.9 mg y-HCH/kg/day in the diet for 104 weeks (Rivett et al. 1978). Twelve-week studies in rats, using lower doses (10 mg/kg/day), support this finding (Suter 1983). However, exposure to 22.5 mg B-HCH/kg/day in the diet for 13 weeks in rats was found to be more toxic, resulting in a statistically significant decrease in numbers of red blood cells and white blood cells and reduced hemoglobin and packed cell volume values (Van Velsen et al. 1986). Significant decreases in total white blood cell counts and HCH 55 2. HEALTH EFFECTS clotting time were reported in rats fed vitamin A-free diets containing technical-grade HCH at a dose level of 90 mg/kg/day for 7 weeks (Joseph et al. 1992c). In rats fed a vitamin A-supplemented diet containing the same dose level of technical-grade HCH, a significant reduction in total white blood cell count, but not red blood cell count, was observed (Joseph et al. 1992c). Significant suppression in bone marrow cellularity, erythrocyte precursors, and granulocyte-macrophage progenitor cells, and residual progenitor cell damage were reported in male B6C3F, mice given 20 or 40 mg y-HCH/kg/day by gavage in corn oil for 3 days (Hong and Boorman 1993). Following 10 days of exposure to 10 or 20 mg y-HCH/kg/day, dose-dependent decreases in bone marrow cellularity, granulocyte-macrophage progenitor cells, and pluripotent bone marrow stem cells were noted (Hong and Boorman 1993). No hematological effects were seen in rats following oral exposure to 60 mg/kg/day technical-grade HCH for 30 days (Dikshith et al. 1989a). Musculoskeletal Effects. In humans, ingestion of a single dose of approximately 15-30 mL y-HCH powder was associated with seizures and limb muscle weakness and necrosis (Munk and Nantel 1977); a muscle biopsy was conducted on day 15 after ingestion and showed no evidence of denervation or neuropathy. Widespread striatal muscle necrosis was seen in a woman who died 11 days after intentionally ingesting 8 ounces of a 20% lindane solution (Sunder Ram Rao et al. 1988). Decreased cross-sectional bone area was found in young rats treated with 20 mg/kg/day of y-HCH by gavage for 10 weeks (Andrews and Gray 1990). Myelotoxicity, manifested as significant, dose-dependent decrease in marrow progenitor numbers, was seen in mice exposed to 10 or 20 mg/kg/day lindane for 10 days (Hong and Boorman 1993). Hepatic Effects. No studies were located regarding hepatic effects in humans following oral exposure to HCH. Significantly increased liver microsomal 7-ethoxycoumarin-o-dealkylase activity was found in Osborne-Mendel rats exposed to 11.2 mg y-HCH/kg/day and in CF, and B6C3F, strain mice exposed to 23.6 and 50.5 mg/kg/day in the diet for 3 days (Oesch et al. 1982). No adverse effects were noted in rats exposed to 10 mg/kg/day for a minimum of 4 days (Joy et al. 1982). No significant increase in liver weight was reported, but no histopathological examinations were performed to confirm the presence or absence of toxicity. Hepatocellular damage as indicated by elevation in serum aminotransferases and decrease in hepatic HCH 56 2. HEALTH EFFECTS soluble enzymes was found in rats given 72 mg/kg/day y-HCH for 2 weeks (Srinivasan and Radhakrish- namurty 1988). Significant increases in hepatic microsomal cytochrome P-450 levels and increases in hepatic microsomal superoxide anion production and cytoplasmic superoxide dismutase activity and lipid peroxidation were found in Wistar rats fed diets containing 1.8 mg/kg/day y-HCH for 15 or 30 days (Barros et al. 1991). Male Wistar rats fed 13.5 mg lindane/kg/day in their diet for 12 days exhibited decreased activities of liver lipogenic enzymes and increased levels of serum triglycerides (Boll et al. 1995). Focal degeneration of hepatocytes was noted in rabbits given y-HCH at a dose of 7 mg/kg/day by gavage for 4 weeks (Grabarczyk et al. 1990; Kopec-Szlezak et al. 1989). Rabbits treated with 4.21 mg lindane/kg/day by gavage for 28 days exhibited a significant increase of plasma alkaline phosphatase and alanine aminotransferase activities immediately following initiation of dosing; these activities returned to control levels by day 14 (Cerén et al. 1995). Activity of aspartate aminotransferase also increased immediately following dosing and remained elevated up to 7 days postexposure (day 35). Lindane residues were detected in the blood. Exposure for 3 months (12 weeks) resulted in increases in liver microsomal mixed-function oxidase activity in rats and mice and a significant increase in absolute and relative liver weights in female rats fed 10.6 and 32.3 mg/kg/day and male and female CF, mice fed 21.1 mg/kg/day; histopathological examinations were not performed (Oesch et al. 1982). Liver centrilobular hypertrophy increased in a dose-dependent manner beginning at a dose of 0.4 mg lindane/kg/day in Wistar rats exposed in their diet for 12 weeks (Suter 1983). Liver cell lipospheres were reported in rats fed 2.5 mg y-HCH/kg/day in the diet for 32 weeks (Ortega et al. 1957). In mice, administration of 90 mg y-HCH/kg/day in the diet for 24 weeks was reported to result in centrilobular hypertrophy (Ito et al. 1973). Hanada et al. (1973) reported liver cancer in mice fed 78 mg/kg/day in the diet for 32 weeks. Other studies of intermediate-duration exposure (3—48 weeks) have reported slight liver effects or increased liver weight in mice exposed to 18 mg/kg/day of a-HCH, 45 mg/kg/day of B-HCH, and 90 mg/kg/day for -HCH and y-HCH. (Ito et al. 1975). These studies were limited by either a small sample size or lack of statistical analysis. Chronic exposure of rats to 7-8 mg/kg/day y-HCH in the diet for 38-70 weeks was reported to result in liver necrosis and fatty degeneration (Fitzhugh et al. 1950). A dose-related increase in periacinal hepatocytic hypertrophy was seen in Wistar rats given 7-8 mg lindane/kg/day in the diet for 104 weeks (Amyes 1990). No liver effects were reported in dogs exposed to 2.9 mg/kg/day for 104 weeks (Rivett et al. 1978). In mice, chronic administration of 13.6-27.2 mg y-HCH/kg/day in the diet was associated with an increased incidence of liver cancer (NCI 1977; Wolff et al. 1987) (see Section 2.2.2.8). HCH 57 2. HEALTH EFFECTS Similar liver effects were reported in animals following intermediate- or chronic-duration exposure to a-HCH in the diet. Administration of 1.8 mg/kg/day a:-HCH in the diet to rats for 15 or 30 days resulted in increases in hepatic cytochrome P-450 content, hepatic lipid peroxidation, and hepatic microsomal superoxide production (Barros et al. 1991). Ito et al. (1975) reported liver cell hypertrophy and hyperplasia in rats exposed to 45 mg/kg/day a-HCH for 24-48 weeks. Hypertrophied liver cells were reported in mice fed 18 mg/kg/day «-HCH and 45 mg/kg/day B-HCH for 24 weeks (Ito et al. 1973), and hepatomegaly was reported in mice exposed to 90 mg/kg/day in the diet for 50 weeks (Tryphonas and Iverson 1983). Liver cancer has also been reported in mice given 18-90 mg a-HCH/kg/day for 16-36 weeks (Hanada et al. 1973; Ito et al. 1973, 1976; Nagasaki et al. 1975; Tsukada et al. 1979) (see Section 2.2.2.8). Long-term exposure to lower doses of a-HCH was reported to result in fatty degeneration and focal necrosis in rats exposed to 3.5-4.0 mg/kg/day for 36-56 weeks (Fitzhugh et al. 1950), and liver cancer was reported in rats administered 50 mg/kg/day in the diet for 72 weeks (Ito et al. 1975). Significant increases in liver weight and in the levels of hepatic cytochrome P-450, triglycerides, phospholipids, and cholesterol were observed in rats administered 90 mg/kg/day B-HCH in the diet for 2 weeks (Ikegami et al. 1991a, 1991b); decreases in cytochrome c reductase activity were also reported. Intermediate and chronic exposure to B-HCH in the diet is also associated with liver effects in animals. A dose-dependent increase in liver weight was noted in rats exposed for 13 weeks to 0.18-4.5 mg B-HCH/kg/day; the increase was significant at doses of >1 mg/kg/day (Van Velsen et al. 1986). Liver cell hypertrophy was reported in rats fed 25 or 50 mg/kg/day in the diet for 24 or 48 weeks (Ito et al. 1975). In mice, exposure to 45 mg/kg/day for 24 weeks resulted in liver cell hypertrophy (Ito et al. 1973), and exposure to 54-57 mg/kg/day for 32 weeks resulted in hepatic foci of degeneration (Hanada et al. 1973). B-HCH was not found to be carcinogenic in rats or mice exposed for 24-48 weeks (Hanada et al. 1973; Ito et al. 1975). Chronic exposure to lower doses of 3-HCH resulted in fatty degeneration and necrosis in the liver of mice fed 3.5-4 mg/kg/day for 36-56 weeks (Fitzhugh et al. 1950), and Thorpe and Walker (1973) reported liver cancer in mice fed 34 mg/kg/day for 26 months. Liver hypertrophy was observed in rats fed with 45 mg/kg/day of «-, B-, or 5-HCH in the diet for 24 or 48 weeks (Ito et al. 1975) and in mice fed 18 mg/kg/day e-HCH in the diet for 24 weeks (Ito et al. 1973). The toxicity of ingested 8-HCH has not been investigated following chronic exposure. Technical-grade HCH was reported to cause increases in liver weight and enzymatic activity (e.g., alkaline phosphatase, aminotransferases) in male Swiss mice given 72 mg/kg in the diet for 2 weeks (Ravinder et al. HCH 58 2. HEALTH EFFECTS 1989). The same dosing regime also caused significantly increased serum triglycerides, phospholipids, and cholesterol, as well as hypertrophy of hepatocytes with enlargement of nuclei, centrilobular degeneration, and focal necrosis (Ravinder et al. 1990). Statistically significant decreases in the liver activity of glutamic oxaloacetate transaminase (GOT) and lactate dehydrogenase (LD) were observed in pregnant mice administered a single dose of technical-grade HCH (5 mg/kg) on gestation day 9 (Dikshith et al. 1990). Pregnant mice dosed with 25 mg/kg technical-grade HCH experienced a statistically significant decrease in glutamic pyruvic transaminase(GPT) and alkaline phosphatase (AP) activity. Virgin mice administered a single dose of 5-200 mg/kg technical-grade HCH had statistically significant decreases in liver activity of GOT and GPT. Statistically significant increases in liver AP activity were observed in the virgin mice administered 25-200 mg/kg technical-grade HCH. However, with the exception of GOT activity in pregnant mice, the dose response relationships were questionable (Dikshith et al. 1990). There were also no corresponding pathological changes in the liver. Similar effects were seen in male, but not female, rats given 5 or 25 mg/kg/day by gavage for 90 days (Dikshith et al. 1991b). A 65% decrease in liver weight, decreased liver aspartate aminotransferase and lactate dehydrogenase activities, and increased alkaline phosphatase activity were noted in male rats given 60 mg/kg by gavage for 30 days, but animals had normal liver histology (Dikshith et al. 1989a). However, enlargement of hepatocytes, nuclear pyknosis, margination, and vacuolation were observed in rats fed 20 mg/kg/day technical-grade HCH in the diet for 360 days (Dikshith et al. 1991a). No adverse hepatic effects were seen in rats treated with 50 mg/kg/day technical-grade HCH for 30 days (Khanna et al. 1990). Technical-grade HCH was reported to deplete the hepatic vitamin A content, decrease enzyme activities, and increase liver weight in male rats fed a vitamin A-free diet containing 90 mg/kg/day HCH for 7 weeks (Joseph et al. 1992b). Fatty degeneration and necrosis of the liver were found in rats exposed to 7-8 mg/kg/day of technical-grade HCH for 33-61 weeks (Fitzhugh et al. 1950); these effects were more pronounced at 56-64 mg/kg/day. Mice treated daily with 50 mg/kg/day technical-grade HCH for 1, 5, or 15 days by oil gavage exhibited congestion of hepatic portal vessels and central vein, swollen hepatic cells with vacuolar or parenchymatous degeneration, and fatty changes in periportal and centrilobular cells (Philip et al. 1989). Mice fed diets containing 90 mg/kg/day of HCH for 8 months exhibited increased liver weight, glycogen accumulation, and decreased glucose-6-phosphatase and fructose-1,6-diphosphatase activities (Karnik et al. 1981). Technical-grade HCH was also reported to cause liver cancer in mice following exposure to 90 mg/kg/day in the diet for 2-8 months (Karnik et al. 1981; Thakore et al. 1981) or exposure to 10-50 mg/kg/day for 80-88 weeks (Kashyap et al. 1979; Munir et al. 1983) (see Section 2.2.2.8). HCH 59 2. HEALTH EFFECTS Based on the occurrence of hepatic effects in rats and mice exposed to f-HCH, an intermediate MRL of 0.0006 mg/kg/day has been calculated from the LOAEL of 0.18 mg B-HCH/kg/day (Van Velsen et al. 1986), as described in the footnote in Table 2-3. An MRL of 0.01 mg/kg/day has been derived for intermediate-duration oral exposure to a-HCH, based on a NOAEL of 1.0 mg/kg/day for hepatic effects in male and female rats (Fitzhugh et al. 1950). Renal Effects. Progressive renal failure was seen in a woman who died 11 days after intentionally ingesting 8 ounces of a 20% lindane solution (Sunder Ram Rao et al. 1988). The myoglobin release resulting from muscle lysis in this case led to kidney shutdown which was the ultimate cause of death. Male Fischer-344 rats receiving gavage doses of 10 mg/kg/day of y-HCH for 4 days showed a-2u-globulin staining in the kidney cortex. Histopathological changes in the proximal tubule epithelial cells included accumulation of protein droplets, hypertrophy and necrosis, pyknotic nuclei, cellular exfoliation, and regenerative epithelium (Dietrich and Swenberg 1990, 1991). These effects did not occur or were seen to a very slight extent in Fischer-344 male controls, Fischer-344 female exposed rats, or exposed NBR rats (a strain that does not synthesize a-2p-globulin). These results indicate that damage to male rat kidneys by y-HCH may be caused by «-2u-globulin, a protein that is not present in humans. Thus, it is unlikely that humans are at risk for developing this type of pathology from y-HCH (EPA 1991a). Other biochemical changes indicative of kidney injury, such as significantly increased excretion of glucose in urine, and histological changes, such as hypertrophy and degeneration of the renal tubular epithelia, were observed in Wistar rats exposed to 72 mg/kg/day of y-HCH for up to 2 weeks (Srinivasan and Radhakrishnamurty 1988; Srinivasan et al. 1984). However, no renal effects other than significantly increased kidney weight were observed in rats exposed to up to 5-50 mg y-HCH/kg/day in the diet for up to 40 days (Desi 1974); histological examination of the kidney did not reveal any changes. Slight kidney damage (calcified tubular casts) was reported in rats exposed to 9-10 mg y-HCH/kg/day for an average of 39.7 weeks (Fitzhugh et al. 1950); the results of this study are limited by poor survival in control and treated animals at all doses. Male rats exposed for 2 years to lindane in their diet exhibited hyaline droplets in the renal proximal tubules at 0.07 mg/kg/day, and pale kidneys, increased kidney weights and urine volumes, and higher urinary protein excretions and tubular necrosis at 7 mg/kg/day (Amyes 1990). Hyaline droplet formation also occurred in a dose-dependent manner in rats treated with 0.02—-10 mg lindane/kg/day in their diets for 12 weeks (Suter 1983). Dose-dependent HCH 60 2. HEALTH EFFECTS incidents of renal tubular distension and degeneration were seen in this study beginning at a dose of 2 mg lindane/kg/day. Fitzhugh et al. (1950) reported kidney damage (nephritis and basal vacuolation) in rats fed 72-80 mg a-HCH/kg/day for an average of 35.9 weeks; no such effects were observed in rats fed 5 mg/kg/day. Poor survival was noted in both control and treated animals. Renal effects have also been noted in rats exposed to p-HCH in the diet. Srinivasan et al. (1984) reported significantly increased excretion of glucose in urine and increased excretion of creatinine and urea as well as hypertrophy and degeneration of the renal tubular epithelia in rats exposed to 72 mg B-HCH/kg/day for up to 2 weeks. Van Velsen et al. (1986) reported significantly increased kidney weights in female rats exposed to 0.18 mg B-HCH/kg/day for 13 weeks; males did not show a significant increase until they were exposed to a dose of 4.5 mg/kg/day. At 22.5 mg/kg/day, both males and females exhibited renal calcinosis in the outer medulla; however, the female controls also exhibited calcinosis. The study authors noted that renal calcinosis is common in female rats but that this finding was of significance in males (Van Velsen et al. 1986). Fitzhugh et al. (1950) also examined the renal effects of exposure to B-HCH in rats that died after an average of 4.4 weeks and found nephritis and basal vacuolation similar to that described in rats exposed to a-HCH; poor survival due to unspecified causes was reported in both control and treated animals. Nephritis, pigmentation, and basal vacuolation were also observed in rats fed 56-64 mg technical-grade HCH/kg/day (64% «-HCH, 10% B-HCH, 13% y-HCH, 9% &-HCH, and 1.3% e-HCH) in the diet for an average of 32.9-64.6 weeks (Fitzhugh et al. 1950); poor survival (for which there was no explanation) was noted in both control and treated animals. Tubular necrosis and glomerular degeneration was seen in animals exposed for 360 days to 20 mg/kg/day of technical-grade HCH (Dikshith et al. 1991a), but no renal effects were seen in rats exposed to 60 mg/kg/day technical-grade HCH for 30 days by oil gavage (Dikshith et al. 1989a). Mice treated daily with 50 mg/kg/day technical-grade HCH for 1, 5, or 15 days by oil gavage exhibited congestion of blood vessels and glomerular tufts, swollen tubules with hyaline casts, cystic dilation, fatty changes, some interstitial hemorrhaging in the medulla, and epithelial cell vacuolation (Philip et al. 1989). No adverse effects were seen in rats treated with 50 mg/kg/day technical-grade HCH for 30 days (Khanna et al. 1990). HCH 61 2. HEALTH EFFECTS Endocrine Effects. No studies were located regarding endocrine effects in humans or animals following oral exposure to HCH. Body Weight Effects. No studies were located regarding body weight effects in humans following oral exposure to HCH. Significantly decreased body weight gain has been seen in rats treated orally with 800 ppm a- (Fitzhugh et al. 1950), 250 mg/kg feed B- (Fitzhugh et al. 1950; Van Velsen et al. 1986), 40 mg/kg/day y- (Fitzhugh et al. 1950; Laws et al. 1994), and 10 or 20 mg/kg/day technical-grade HCH (Gautam et al. 1989; Joseph et al. 1992b; Nagaraja and Desiraju 1994). Metabolic Effects. No studies were located regarding metabolic effects in humans following oral exposure to HCH. Increased phosphoinositide turnover and generation of second messengers from phosphoinositides were seen in erythrocyte membranes from female rats treated by gavage with a single dose of 100 mg/kg technical-grade HCH, or with doses of 5 mg/kg/day technical-grade HCH for 3-6 months, 5 days/week (Agrawal et al. 1995). The latter exposure regime also resulted in a significant decrease in phosphatidylinositol, phosphatidylinositol 4-phosphate, and phosphatidylinositol 4,5-bisphosphate in erythrocyte membrane and cerebrum; the levels decreased with increased time of treatment (3—6 months). 2.2.2.3 Immunological and Lymphoreticular Effects No studies were located regarding immunological or lymphoreticular effects in humans following oral exposure to HCH. Some evidence of possible immunotoxic effects of y-HCH is available from animal studies. Immuno- suppression, as measured by decreased agglutinin titers against typhoid vaccine and Salmonella vaccine, was reported in rats exposed by gavage to 6.25 and 25 mg y-HCH/kg/day for 5 weeks (Dewan et al. 1980) and in rabbits exposed by capsules 5 times each week to 1.5, 6, and 12 mg/kg/day for 5-6 weeks (Desi et al. 1978). Dose related decreases in thymus and spleen weights were observed in mice gavaged with 10-20 mg/kg/day y-HCH for 10 days and decreased thymus weight was observed in mice gavaged with 20-40 mg/kg/day y-HCH for 3 days (Hong and Boorman 1993). The primary antibody response to sheep red blood cells was HCH 62 2. HEALTH EFFECTS suppressed in albino mice after exposure to 9 mg/kg/day y-HCH in their diet for 12 weeks (Banerjee et al. 1996). Suppression of secondary antibody response was also observed after 3 weeks exposure to 9 mg/kg/day y-HCH and after 12 weeks of 5.4 mg/kg/day lindane exposure. Decreased lymphoproliferative responses to mitogens were seen in mice exposed to 60 mg/kg/day B-HCH in the diet for 30 days (Cornacoff et al. 1988). There were no associated changes in immunoglobulins, red blood cell counts, or histology of the thymus, spleen, or lymph nodes. Cortical atrophy of the thymus was observed in rats fed 22.5-25 mg/kg/day B-HCH (Van Velsen et al. 1986). A biphasic dose-dependent immunological effect of y-HCH on components of cell- and humoral-mediated immunity, characterized by initial stimulation followed by immunosuppression, was reported in mice fed 0.012, 0.12, or 1.2 mg y-HCH/kg/day for 24 weeks (Meera et al. 1992). In addition, histological examinations revealed decreased lymphocyte populations in the thymus and lymph nodes and a reduction in overall cellularity in the spleen and necrosis of the thymus at 1.2 mg/kg/day. The LOAEL values for immunological effects are recorded in Tables 2-2 and 2-3 and plotted in Figures 2-2 and 2-3. Based on immunological effects of y-HCH on components of cell- and humoral-mediated immunity in mice, an intermediate MRL of 1x10 mg/kg/day has been calculated from the LOAEL of 0.012 mg y-HCH/kg/day (Meera et al. 1992), as described in the footnote in Table 2-2. 2.2.2.4 Neurological Effects In humans, the most commonly reported effects associated with oral exposure to y-HCH are neurological. Most of the information is from case reports of acute Y-HCH poisoning. No studies were located regarding neurological effects in humans following long-term ingestion of «-, B-, y-, or 8-HCH. Seizures and convulsions have been observed in individuals who have accidentally or intentionally ingested y-HCH in insecticide pellets, liquid scabicide, or contaminated food (Davies et al. 1983; Harris et al. 1969; Munk and Nantel 1977; Powell 1980; Starr and Clifford 1972; Storen 1955). In most cases, exposure to y-HCH was inferred from the presence of y-HCH in the urine or blood. Also, the actual amount of y-HCH ingested could not be determined because the Y-HCH was present in solution or in pellets in which other substances were present. Liquid scabicide has been reported to contain approximately 1% y-HCH (Davies et al. 1983; Powell 1980). Neurotoxic effects have been reported in several species of animals exposed to Y-HCH. The most serious effects were seizures following a single intragastric administration of approximately 15-60 mg/kg in rats HCH 63 2. HEALTH EFFECTS (Martinez and Martinez-Conde 1995; Martinez et al. 1991; Tilson et al. 1987; Tusell et al. 1987; Vendrell et al. 1992a, 1992b; Woolley and Griffith 1989). Treatment of rats with a single dose of 30 mg lindane/kg by gavage resulted in convulsions 10-30 minutes later, with molecular analysis revealing the repression of calmodulin (CAM) genes, in particular, decreased levels of mRNA from the CAM II gene (Barrén et al. 1995a). Less-serious effects in rats included increased anxiety following a single gavage dose of 20 mg/kg (Llorens et al. 1990b) and increased spontaneous motor behavior observed at 10 mg/kg (Llorens et al. 1989). Kindling, the induction of seizures with repeated application of subthreshold electrical or chemical stimuli, has been used as a method of investigating neurological response to HCH poisoning. A single oral dose of 5-20 mg lindane/kg to rats previously kindled by electrical stimulus produced incidences of myoclonic jerks and clonic seizures which increased in a dose-dependent manner (Gilbert and Mack 1995). Nonkindled animals displayed these symptoms at a dose of 10 mg lindane/kg. Enhanced susceptibility to kindled seizures brought on by electrical stimulation was seen in rats exposed for 10 weeks to 10 mg lindane/kg/day, 3 days/week (Gilbert 1995). Increased rates of acquisition of kindled seizures were observed following dosing of rats with 3-10 mg lindane/kg/day for 4 days (Joy et al. 1982). An MRL of 0.01 mg/kg/day has been derived for acute-duration oral exposure to Y-HCH, based on a NOAEL of 1 mg/kg/day for increased kindling acquisition (Joy et al. 1982). Eleptiform seizures have been reported in male rats fed milk, from dams that were gavaged with 20 mg y-HCH/kg, on postnatal days 3—15 (Albertson et al. 1985). These data suggest that y-HCH can be transferred in the dam’s milk and elicit neurological effects in offspring. It is not possible to determine the doses received by the pups. Avoidance response latency was statistically increased in rats administered a single dose of 15 mg/kg by gavage (Tilson et al. 1987). No clinical signs of behavioral effects were seen in suckling Wistar rats treated once with 20 mg/kg lindane by gavage at postnatal days 8, 15, 22, or 29, although regional changes in brain noradrenaline and serotonin were seen, with differential effects depending on age at the time of exposure (Rivera et al. 1991). Changes in levels of brain norepinephrine (Rivera et al. 1991) and serotonin (Attia et al. 1991; Rivera et al. 1991) have also been reported in rats administered acute oral doses of Y-HCH. Decreased dopamine levels were seen in rats treated by gavage with 10 doses totaling 60 mg lindane/kg (half the LCs) over a period of 30 days (Martinez and Martinez-Conde 1995). Increase in the levels of brain catecholamines, particularly norepinephrine and dopamine, and associated signs of toxicity such as mild tremor, lacrimation, salivation, and dysnea were observed in female rats given oral doses of 100 mg/kg/day of technical-grade HCH for HCH 64 2. HEALTH EFFECTS 7 days (Raizada et al. 1993). The activity of monoamine oxidase (MAO) in the cerebrum showed a marginal decrease; while the cerebellum and spinal cord indicated a significant increase and decrease in MAO, respectively. Rats treated with 20 mg technical-grade HCH/kg/day in food for 90 days exhibited increased y- aminobutyric acid (GABA) levels, increased glutamate decarboxylase (GAD) activity, and decreased glutamate levels in the brain (Nagaraja and Desiraju 1994). No significant changes were seen in lipid peroxidation in brain tissue from rats treated for 90 days with 90 mg lindane/kg/day in food, indicating that the tonic convulsions observed throughout the exposure period were probably not brought on by oxidative stress in the brain (Arisi et al. 1994). Decreased myelin basic protein was observed in rats exposed to 5 mg/kg/day by gavage for 3 days (Serrano et al. 1990a). Longer exposures to lower doses of y-HCH were reported to result in significantly altered Skinner box behavior (operant conditioning) in a small number of rats exposed to 2.5 mg/kg/day for 40 days (Desi 1974), and significantly decreased nerve conduction velocity in rats exposed to 25.4 mg/kg/day for 30 days (Muller et al. 1981). The latter study did not examine any behavioral parameters. Similar neurological effects have not been reported in animals treated with ¢-HCH. Muller et al. (1981) reported no delay in tail nerve conduction velocity in rats fed 5.1, 54.2, or 106.2 mg «-HCH/kg/day for 30 days. However, neurological effects have been reported in rats exposed to B-HCH. Mice treated with 57 or 190 mg/kg/day B-HCH for 30 days developed ataxia within 1 week of treatment (Cornacoff et al 1988). An acute-oral MRL of 0.2 mg/kg/day was derived based on a NOAEL of 19 mg/kg/day for ataxia. The study was limited by small sample size (6 per group) and lack of quantificative and dose-response information. Muller et al. (1981) reported a significant delay in tail nerve conduction velocity in rats fed 66.3 mg B-HCH/kg/day for 30 days. Van Velsen et al. (1986) reported ataxia and coma in rats exposed to 22.5-25 mg B-HCH/kg/day for 13 weeks. Rats treated once with 100 mg 3-HCH/kg by gavage exhibited no convulsions, although molecular analysis revealed a significant decrease in mRNA expression from brain calmodulin (CAM) genes (Barrén et al. 1995). Seizures were noted in mice exposed to technical-grade HCH through feed or gavage at levels of 10-17 mg/kg/day in the feed for 80 weeks (Kashyap et al. 1979). A significant increase in motor activity was noted in rats exposed to technical-grade HCH at a level of 50 mg/kg/day for 120 days (Gopal et al. 1992); a significant decrease in rearing (sitting back on haunches) was seen in rats exposed to 50 mg/kg/day technical-grade HCH and fed a protein-deficient diet. Alterations in neurotransmitter levels, increased brain wave frequency, and behavioral changes were reported in male rats administered 50 mg/kg/day technical-grade HCH by gavage for 1 or 3 months (Anand et al. 1991). Exposure to 0.4 mg/kg/day technical-grade HCH for 360 days resulted in convulsions, tremors, and paralysis in male HCH 65 2. HEALTH EFFECTS rats after 270 days, although the number of animals affected or the severity of the symptoms were not reported (Dikshith et al. 1991a). This study also found degeneration of the cerebellum and cerebellar cortex in animals sacrificed after a one-year exposure to 20 mg/kg/day. 2.2.2.5 Reproductive Effects No studies were located regarding reproductive effects in humans following oral exposure to HCH. Increased length of estrous cycle and decreased sexual receptivity were found in female rats treated with a single dose of Y-HCH (25 mg/kg) given by gavage (Uphouse and Williams 1989). Inhibition of the formation of estradiol-receptor complex in the rat uterus cytosol was reported in female rats administered 30 mg y-HCH/kg/day by oral intubation for 7 days (Tezak et al. 1992). Female mink treated with 1 mg/kg/day y-HCH in their diet from 6 weeks before mating until weaning showed a decrease in receptivity to a second mating and a decrease in whelping rate, although litter size was not affected (Beard et al. 1997). This decreased fertility effect was primarily a result of embryo mortality after implantation. Mouse dams treated with y-HCH (6.2 mg/kg) during gestation period days 6-12 had increased numbers of resorbed fetuses (Sircar and Lahiri 1989). A lack of implantation sites and pups death were observed following treatment with 10.8 mg/kg/day on gestation days 1-4 and 3.6 mg/kg/day on gestation days 14-19, respectively. Statistically significant increases in the glycogen content of the uterus, cervix, and vagina (but no increase in organ weight) were reported in female rats exposed to 20 mg y-HCH/kg/day in the diet for 30 days (Raizada et al. 1980). Antiestrogenic properties were found in female rats given oral gavage doses of 10 mg/kg/day y-HCH for 15 weeks (Chadwick et al. 1988). These responses were not seen at 5 mg/kg/day. Ovariectomized rats exposed for 5 days and sexually immature female rats exposed for 7 days to 40 mg lindane/kg/day showed no effects on the number of estrogen and estrogen-dependent progesterone receptors (Laws et al. 1994). Thus, lindane's antiestrogenic effects in reproductive tissue do not appear to be due to direct action on estrogen receptors or its induction of progesterone receptors. Female rabbits exposed to 0.8 mg y-HCH/kg/day, 3 days/week for 12 weeks, had a reduced ovulation rate (Lindenau et al. 1994). However, rabbits given the same treatment regime followed by artificial insemination exhibited no effects on the fertilization rate or on pre- or postimplantation losses (Seiler et al. 1994). In male rats, oral administration of 6 mg/kg for 5 days or a single dose of 30 mg/kg of y-HCH resulted in a reduction in the number of testicular spermatids and epididymal sperms of both treated groups 2 weeks after treatment (Dalsenter et al. 1996). y-HCH was detected in the testes of both groups 24 hours and 2 weeks after the last treatment. Histological examination by electron microscopy revealed ballooning of the Sertoli cells with HCH 66 2. HEALTH EFFECTS fragmentation or loss of organelles. Similarly, Shivanandappa and Krishnakumari (1983) reported testicular atrophy, degeneration of seminiferous tubules, and disruption of spermatogenesis in male rats fed 75 mg v-HCH/kg/day for 90 days. Significant reductions in the relative weight of testicles and epididymis, spermatid and sperm counts, and testosterone levels were observed in pubescent or adult rats fed milk as neonates from dams gavaged with 6 mg/kg y-HCH on lactation day 9 or 14 or 1 mg/kg y-HCH on lactation days 9-14 (Dalsenter 1997). Histopathological observations included a reduction in Leydig cell numbers and spermatogenesis. However, fertility, measured by impregnation of female rats, was unaffected. Rats exposed to approximately 10 mg/kg/day for 4 generations showed no adverse reproductive effects (Palmer et al. 1978b). Oral exposure to 60 mg 3-HCH/kg for 30 days resulted in normal uteri and reproductive cycling in female mice (Cornacoff et al. 1988). Atrophy of the ovaries and testes, hyperplastic and vacuolized endometrial epithelium, degeneration of the seminiferous tubules, and disruption of spermatogenesis were seen in rats exposed to 22.5-25 mg B-HCH/kg/day in their diet for 13 weeks (Van Velsen et al. 1986). Technical-grade HCH caused transient changes in testes’ weights and decreased sperm counts in a 7-week study (Pius et al. 1990), degeneration of seminiferous tubules and Leydig cells (Roy Chowdhury and Gautam 1990), and changes in the muscle layer of the seminiferous tubules (Gautam et al. 1989). None of these studies provide adequate evidence for the effects of technical-grade HCH on sperm function in animals or humans. In mice, exposure to 90 mg technical-grade HCH/kg/day (isomer composition unknown) for 3 months led to increased testicular weight and degeneration of seminiferous tubules (Nigam et al. 1979). Testicular degeneration was reported in male rats exposed to 20 mg/kg/day technical-grade HCH in the diet for 360 days (Dikshith et al. 1991a). A dose-related increase in fetal resorptions was seen in pregnant female mice treated once with 25-200 mg/kg technical-grade HCH by gavage on the ninth gestation day (Dikshith et al. 1990). 2.2.2.6 Developmental Effects No studies were located regarding developmental effects in humans following oral exposure to any of the HCH isomers. A single oral dose of 25 mg/kg technical-grade HCH caused increased resorptions of the fetus in female mice, but fetal development was normal (Dikshith et al. 1990). Srivastava and Raizada (1993) further studied the HCH 67 2. HEALTH EFFECTS prenatal effect of orally administered technical-grade HCH. While mice exposed to HCH during the preimplantation period (day 2—6 of gestation) did not show fetolethality, exposure during the postimplantation period (day 6-12 of gestation) to 25 and 50 mg/kg/day HCH produced significant increases in resorption of fetuses, inhibition of maternal serum progesterone levels, and higher levels of HCH in fetal tissues. Oral exposure to Benesan (a pesticidal formulation containing 50% y-HCH) given at doses of 6.25, 12.5, or 25 mg/kg/day by gavage on days 6-15 of gestation failed to produce teratogenic effects in rats (Khera et al. 1979). When minks were treated with 1 mg/kg/day y-HCH in their diet (Beard et al. 1997), the proportion of embryos lost after implantation was increased. In another study, y-HCH was administered to pregnant mice by gastric intubation on day 12 of gestation. At doses of 30 and 45 mg/kg body weight in C57BL/6] mice, significant decreases in fetal weight, fetal thymic weight, and placental weight were observed (Hassoun and Stohs 1996a). When given to DBA/2J mice at a dose of 45 mg/kg body weight, y-HCH caused significant reduction in fetal and placental weight. No malformations in the fetuses of both strains of mice were observed, even though the administered doses caused maternal deaths. Increases in the production of lipid metabolites in maternal sera and the amniotic fluids were found to parallel the observed fetotoxicities (Hassoun et al. 1996). Superoxide production, lipid peroxidation and DNA-single strand breaks were increased in fetal and placental tissues 48 hours after administration of single dose of 30 mg/kg y-HCH to pregnant mice on day 12 of gestation (Hassoun and Stohs 1996b). Significant increases in lipid peroxidation also occurred in fetal livers collected on day 18 of gestation. Thus, it was suggested that fetotoxic effects of y-HCH may be due to induced oxidative stress, enhanced lipid peroxidation, and DNA- single strand breaks in the fetal and placental tissues of mice. In another study, y-HCH given to rat dams during gestation and lactation did not cause developmental effects in the pups, but B-HCH (20 mg/kg/day during gestation) caused increased fetal deaths within 5 days of birth and exposure to 5 mg/kg/day during gestation and lactation resulted in increased liver weights of pups (Srinivasan et al. 1991a). When lactating female rats were treated orally with a single dose of 6 mg/kg of y-HCH on day 9 or 14, or 1 mg/kg on days 9-14 of lactation; the testosterone level of the male offspring was reduced 50% at puberty (day 60) when compared to the control group (Dalsenter et al. 1997a). When the offspring reached adulthood (day 140 postnatal), the relative testicular weight was significantly lower (Dalsenter et al. 1997). The number of sperm and spermatids was also significantly reduced. A dose-related increase in the incidence of fetuses with an extra 14th rib was reported in CFY rats exposed to 5, 10, or 20 mg/kg y-HCH by gavage during gestation days 6-15; statistical significance was attained only at 20 mg/kg (Palmer et al. 1978a). The incidence of fetuses with an extra 13th rib was statistically increased in rabbits exposed to 20 mg/kg y-HCH by gavage during gestation days 6-18 (Palmer et al. 1978a). In both rats and rabbits, the incidences of extra ribs were within or just greater than the ranges recorded for the control groups, and therefore, may not be sufficient HCH 68 2. HEALTH EFFECTS evidence of teratogenicity caused by exposure to y-HCH. No effects on embryonic development were seen in rabbits treated by oral gavage with 0.8 mg lindane/kg, 3 times per week for 12-15 weeks before artificial insemination and throughout gestation (Seiler et al. 1994). Regional changes in brain noradrenaline, serotonin and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) levels were noted in suckling rats treated with 20 mg/kg/day y-HCH, as a single dose (Rivera et al. 1991). Alterations in levels of brain dopamine, serotonin, gamma-aminobutyric acid (GABA), glutamate, glutamate decarboxylase, and noradrenaline were seen in various areas of the brains of female rat pups treated with 10 mg technical-grade HCH/kg/day for 60 days (Nagaraja and Desiraju 1994). 2.2.2.7 Genotoxic Effects No studies were located regarding genetic effects in humans following oral exposure to HCH. In animals, ingestion of technical-grade HCH was reported to induce dominant lethal mutations in mice (Lakkad et al. 1982). Oral exposure to a-HCH was reported to result in mitotic disturbances including an increased mitotic rate and an increased frequency of polyploid hepatic cells in rats (Hitachi et al. 1975). Incidence of chromosome clastogeny in bone marrow cells was increased in mice exposed for 7 days to 1.6 mg y-HCH/kg/day (Kumar et al. 1995). Other genotoxicity studies are discussed in Section 2.5. 2.2.2.8 Cancer No studies were located regarding the carcinogenicity of the individual isomers of HCH or technical-grade HCH following ingestion by humans. «-HCH, B-HCH, y-HCH, and technical-grade HCH have been shown to be liver carcinogens in rats and mice; however, in some studies the liver was the only organ examined. Ito et al. (1973) examined the carcinogenicity of HCH isomers in dd mice exposed to 45 mg/kg/day of each isomer (total dosage was 90 mg/kg/day) for 24 weeks. Exposure to B-, y-, or 8-HCH alone did not result in hepatocellular carcinoma. However, when these isomers were mixed with «-HCH, hepatocellular carcinoma was observed. These results suggest that «-HCH is itself a hepatocellular carcinogen or acts synergistically with the other isomers. HCH 69 2. HEALTH EFFECTS In Wistar rats, exposure to 25 mg y-HCH/kg/day in the diet for 24 or 48 weeks did not result in any identifiable carcinogenic effect (Ito et al. 1975); however, high mortality in the control and treatment groups precludes determination that y-HCH is not carcinogenic to rats under this experimental protocol. Mice (dd strain) exposed to as much as 90 mg y-HCH/kg/day in the diet for 24 weeks did not exhibit any carcinogenic effects (Ito et al. 1973). Although an increased incidence of malignant hepatomas was reported in male dd mice exposed to 108-120 mg/kg/day in the diet for 32 weeks (Hanada et al. 1973), this dose level may have exceeded the maximum tolerated dose (MTD), based on effects of y-HCH on survival. Liver nodules developed in mice receiving 39 mg/kg/day of y-HCH, although the number of animals tested was small, the study was limited by the lack of statistical analysis. Information concerning the cancer effects of y-HCH following chronic-feeding exposure is equivocal. No statistically significant increases in endocrine, thyroid, pituitary, adrenal gland, liver, or ovary tumors were observed in male and female Osborne-Mendel rats fed 10.8—-33 mg/kg/day in the diet for 80 weeks (NCI 1977) and in Wistar rats fed 0.07-32 mg y-HCH/kg/day in the diet for 104 weeks (Amyes 1990); however, poor survival rates limit the significance of these results. On the other hand, hepatocellular carcinomas have been reported in CF, and B6C3F, mice exposed to 13.6-27.2 mg/kg/day in the diet for 80 or 104 weeks, respectively (NCI 1977; Wolff et al. 1987). In addition, hepatocellular carcinomas have been reported in yellow (YS/UY)F-1 mice exposed to 27.2 mg/kg/day in the diet for 96 weeks (Wolff et al. 1987); this strain of mouse has a dominant mutation at the agouti locus (A") that results in an increased susceptibility to formation of strain-specific neoplasms. The human oral carcinogenicity assessment for y-HCH is currently under review (IRIS 1998). No evidence of liver carcinogenicity was reported in Wistar rats exposed to 45 or 90 mg «-HCH/kg/day in the diet for 24 or 48 weeks (Ito et al. 1975; Nagasaki et al. 1975); high mortality was observed in both the treated and control groups. However, a-HCH appears to be carcinogenic in mice following intermediate- duration exposure. Hepatomas and hepatocellular carcinomas have been reported in a number of strains of mice exposed to 13-95 mg/kg/day for 16-36 weeks (Hanada et al. 1973; Ito et al. 1973, 1976; Nagasaki et al. 1975; Tsukada et al. 1979). Tryphonas and Iverson (1983), however, reported no evidence of a carcino- genic effect in male mice exposed to 90 mg a.-HCH/kg/day in the diet for 50 weeks. Ito et al. (1975) reported an increased incidence of hepatocellular carcinoma in male rats exposed to 50 and 75 mg a-HCH/kg/day in the diet for 72 weeks, suggesting that «-HCH may be carcinogenic in rats after long-term exposure. A study of enzyme-altered liver foci in rats treated first with the tumor initiator N-nitrosomorpholine, and then 20 mg a-HCH/kg/day in food for 49 weeks, found that the tumor promoter activity of HCH is apparently due to HCH 70 2. HEALTH EFFECTS increased cell proliferation caused by a lowering of the cell death (apoptosis) rate (Luebeck et al. 1995). In another study in rats, additional administration of 35 mg/kg/day of a-HCH in the diet for 65 weeks inhibited the induction of liver tumors by 0.07 mg/kg/day of aflatoxin B, (Angsubhakorn et al. 1981). IRIS (1998) lists «-HCH as a probable human carcinogen and estimated an oral cancer potency factor for «-HCH of 6.3 (mg/kg/day)! based on the incidence of hepatic nodules and hepatocellular carcinomas observed in male mice administered o-HCH in the diet (Ito et al. 1973). The oral cancer potency factor is a plausible upper-bound estimate of the lifetime probability of an individual developing cancer as a result of oral exposure per unit intake of the chemical. B-HCH has not been found to be carcinogenic in Wistar rats exposed to 25 or 50 mg/kg/day in the diet for 24 or 48 weeks (Ito et al. 1975) or in dd mice exposed to 18-120 mg/kg/day in the diet for 24 or 32 weeks (Hanada et al. 1973; Ito et al. 1973). However, Thorpe and Walker (1973) reported an increased incidence of hepatocellular carcinomas in CF1 mice exposed to 26 mg/kg/day in the diet for 104 weeks. The studies with negative results were, in general, of short duration, used a small number of animals, or failed to examine all of the animals. IRIS (1998) lists B-HCH as a possible human carcinogen and estimated an oral cancer potency factor for ingested B-HCH of 1.8 (mg/kg/day)! based on the incidence of hepatic nodules and hepatocellular carcinomas observed in male mice administered f-HCH at a single dose level in the diet (Thorpe and Walker 1973). This is the only chronic study from which to estimate cancer risk from exposure to f-HCH. The study is limited by the use of only one nonzero dose group. Also, the use of incidence of liver tumors alone in mice to predict a compound’s carcinogenicity in humans may be equivocal (Vesselinovitch and Negri 1988). Diversity of factors has been shown to influence the development of liver cell tumors in mice, such as the strain of the mice (Nagasaki et al. 1975b), the protein or calorific value of the diet (Tannenbaum and Silverstone 1949), and the microbial flora of the animals (Roe and Grant 1970). 8-HCH has not been found to be carcinogenic in male Wistar rats exposed to 45 or 90 mg/kg/day in the diet for 24 or 48 weeks (Ito et al. 1975) or in male dd mice exposed to 18-90 mg/kg/day in the diet for 24 weeks (Ito et al. 1973). However, these studies were of relatively short-exposure duration. 8-HCH is structurally related to carcinogenic HCH isomers, but it is currently listed as not classifiable for human carcinogenicity (IRIS 1998). Increased incidence of carcinoma was reported in Swiss mice following exposure to 90 mg technical-grade HCH/kg/day in the diet for 8-32 weeks (Thakore et al. 1981). Increased incidences of hepatocellular carcinoma were also reported in Swiss mice exposed to 21.3-85 mg/kg/day in the diet for 20 months (Munir HCH 71 2. HEALTH EFFECTS et al. 1983) and in Swiss mice exposed to 10 or 17 mg/kg/day through gavage or the diet, respectively, for 80 weeks (Kashyap et al. 1979). 2.2.3 Dermal Exposure Studies examining the dermal toxicity of HCH in humans are limited. Most of the available information is obtained from cases in which y-HCH was dermally applied as a scabicide. y-HCH in topical creams and lotions is efficiently absorbed through the skin (Ginsburg et al. 1977). Although it has been reported that these lotions contain 1% y-HCH, it is not possible to quantify the amount of y-HCH to which these individuals were exposed, because of the different areas of skin treated. 2.2.3.1 Death No studies were located regarding lethal effects in humans following dermal exposure to a-, B-, or -HCH. An acute whole-body dermal application of 1% y-HCH lotion to a 2-month-old infant for the treatment of scabies was reported to result in death (Davies et al. 1983), and a concentration of 110 ppb y-HCH was identified in the brain. In general, most humans dermally poisoned with y-HCH have recovered with no apparent adverse effects (Fagan 1981). In animals, acute dermal exposure to high doses of y-HCH were reported to result in death. The dermal LD, for y-HCH is 900 mg/kg in female rats and 1,000 mg/kg in male rats (Gaines 1960). Rats exposed to moistened lindane for 24 hours exhibited no mortality at 250 mg/kg, 20% mortality at 600 mg/kg, 40% mortality at 1,000 mg/kg, and 30% mortality at 2,000 mg/kg (Ullmann 1986a). Significant lethality (47%) was seen in female rats, but not male rats, exposed dermally to 400 mg y-HCH/kg/day for 13 weeks, 5 days/week, 6 hours/day (Brown 1988). Calves dermally exposed to 33.3 mg/kg y-HCH died within 5 months (Venant et al. 1991). Dikshith et al. (1978) reported that guinea pigs dermally exposed to 200 mg technical-grade HCH/kg died within 5-12 days. Four of 20 rats died from exposure to technical-grade HCH at 100 mg/kg/day for 15-30 days (Dikshith et al. 1991c). Weanling rabbits were more sensitive to y-HCH treatment than young adults, as seen by increased mortality rates accompanied by excitement and convulsions after a single whole-body treatment with a 1% solution at a dose of 60 mg y-HCH/kg (Hanig et al. 1976). This suggests that children might be at a greater risk than adults for toxic responses to dermal absorption of HCH. Rabbits treated with 25 mg/kg/day technical-grade HCH for 30 days by skin painting on shaved dorsal, ventral, or thigh areas exhibited no deaths in the group exposed by dorsal application, but 2 of HCH 72 2. HEALTH EFFECTS 8 rabbits died in the group exposed by ventral application, and 4 of 8 died in the group exposed by thigh application (Dikshith et al. 1989b). These and other values are in Tables 2-4 and 2-5. 2.2.3.2 Systemic Effects Reliable LOAELS for respiratory, hepatic, and renal effects in animals after acute and intermediate exposure to y-HCH are shown in Table 2-4. Reliable LOAELSs for hepatic, renal, and dermal effects in animals after intermediate exposure to technical-grade HCH are shown in Table 2-5. Respiratory Effects. An acute dermal poisoning of a 2-month-old infant exposed to a whole body application of 1% y-HCH lotion resulted in death. The autopsy revealed pulmonary petechiae (tiny reddish spots that contain blood) (Davies et al. 1983). Slight dyspnea was observed in rats exposed dermally for 24 hours to 1,000 or 2,000 mg y-HCH/kg on a shaved patch of dorsal skin (Ullmann 1986a). The dyspnea was severe in one female administered the high dose. Rapid respiration or wheezing was noted in rats exposed dermally to 10 mg y-HCH/kg/day for 13 weeks (Brown 1988). Cardiovascular Effects. An acute dermal poisoning of a 2-month-old infant exposed to a whole-body application of 1% y-HCH lotion resulted in death. The autopsy findings were minimal but revealed epicardial petechiae (Davies et al. 1983). No studies were located regarding cardiovascular effects in animals following dermal exposure to HCH. Gastrointestinal Effects. Vomiting and diarrhea occurred in a child who had 1% y-HCH applied to the skin to treat a rash (Ramchander et al. 1991). No studies were located regarding gastrointestinal effects in animals following dermal exposure to HCH. Hematological Effects. Aplastic anemia was documented in a man who applied y-HCH to his skin for 3 weeks for treatment of scabies (Rauch et al. 1990). Excessive dermal exposure to HCH was reported to result in aplastic anemia and bone marrow hyperplasia in a woman who bathed her dog once a week for 2 years in a preparation that reportedly contained 2% HCH (Woodliff et al. 1966). Reduced hemoglobin and hematocrit values and a nearly complete absence of red blood cell precursors in bone marrow were reported in TABLE 24. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Dermal S I Exposure LOAEL Species duration/ NOAEL Less serious Serious Reference (strain) frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) ACUTE EXPOSURE Death Rat 10d 1,000 M (LDso) Gaines 1960 (Sherman) once 900 F (LDso) Rat 24 hr 1,000 (LDso) Ullmann 1986a (Wistar) once Systemic Rat 24 hr Resp 600 1,000 (dyspnea) Ullmann 1986a n (Wistar) once & > Rabbit once Ocular 40 (mild eye irratation) Ullmann 1986¢ d (New m Zealand) 1 3 Rabbit 4 hr Dermal 200 Ullmann 1986d a (New once Zealand) Neurological Rat 24 hr 600 1,000 (slight sedation) 2,000 F (severe spasms) Ulimann 1986a (Wistar) once INTERMEDIATE EXPOSURE Death Rat 13 wk 60 F 400 F (23 deaths out of 49) Brown 1988 (Cri:(WIBR) 5 diwk 6 hr/d €L TABLE 2-4. Levels of Significant Exposure to Gamma-Hexachlorocyclohexane (Lindane) - Dermal (continued) Exposure LOAEL Species duration/ NOAEL Less serious Serious Reference (strain) frequency system (mg/kg/day) (mg/kg/day) (mg/kg/day) Systemic Rat 13 wk Resp 10 (rapid respiration or Brown 1988 (Cri:(WIBR) 5 diwk wheezing) 6 hr/d Hepatic 10 60 (centrilobular hypertrophy) Renal 10M (hyaline droplet formation Renal 10F 60F (basophilic tubules) Rat once for 25 180F (mild dermatitis) Dikshith et al. 1973 days Neurological Rat 13 wk 10 (hyperactivity) 60 F (ataxia, tremors, Brown 1988 (Cr:(WI)BR) 5 d/wk convulsions) 6 hr/d d = day(s); F = female; hr = hour(s); LD50 = lethal dose, 50% kill, LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s). S103443 H1V3H 2 HOH vL TABLE 2-5. Levels of Significant Exposure to Technical - Grade Hexachlorocyclohexane - Dermal Exposure LOAEL Reference/ Species duration/ NOAEL Less serious Serious Chemical (strain) frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Form ACUTE EXPOSURE Death Gn pig 5-12d 200 M (24/24 deaths) Dikshith et al. 1978 (NS) 1x/d technical INTERMEDIATE EXPOSURE Death Rat 15d 100 F (2/10 deaths) Dikshith et al. (Wistar) 1x/d 1991c technical Rabbit 30d 25 M (6/24 deaths) Dikshith et al. (NS) 1x/d 1989b technical Systemic Rat 30d Hepatic 100 F (hypertrophy, fatty Dikshith et al. (Wistar) 1x/d degeneration, nuclear 1991c pyknosis of hepatocytes, technical diffuse and focal liver necrosis) Renal 100 F (tubular necrosis) Dermal 100F (hyperkeratosis, epidermal cell vacuolization, thickening of collagen fibers) S103443 H1TV3H 2 HOH SL TABLE 2-5. Levels of Significant Exposure to Technical - Grade Hexachlorocyclohexane - Dermal (continued) } Exposure LOAEL Reference/ Species duration/ NOAEL Less serious Serious Chemical (strain) frequency System (mg/kg/day) (mg/kg/day) (mglkg/day) Form Rabbit 30d Hepatic 25M (hepatocyte Dikshith et al. (NS) 1x/d degeneration, pycnotic 1989b nuclei, enlarged liver, technical altered GOT, GPT, LDH, and ALP activities) Renal 25 M (altered epithelial lining of proximal convoluted tubules, loss of brush borders of tubules, atrophy of glomerular capsules) Dermal 25M (thickened epidermis, hyperkeratinization, and n infiltration of I mononuclear cells) g — Gn pig 30d Hepatic 100M (38% increase in liver Dikshith et al. 1978 o (NS) 1x/d weight, hepatic technical a hypertrophy, pycnotic a nuclei in cytoplasm, a focal fatty inclusions, increased GOT and ALP activity) Renal 100 M CHRONIC EXPOSURE Cancer Mouse 80 wk 2.4 (CEL: liver tumors) Kashyap et al. 1979 (Swiss) 2 diwk technical ALP = alkaline phosphatase; CEL = cancer effect level; d = day(s); F = female; Gn pig = guinea pig; GOT = glutamate oxaloacetate transaminase; GPT = glutamate pyruvate transaminase; LDH = lactate dehydrogenase; LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; NS = not specified; wk = week(s); x = time(s). HOH 9L HCH 77 2. HEALTH EFFECTS a 2-year-old boy exposed to a family dog that was dipped regularly in mange treatment containing 12% v-HCH (Vodopick 1975). No studies were located regarding hematological effects in animals following dermal exposure to any of the HCH isomers. Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans or animals following dermal exposure to HCH. Hepatic Effects. No studies were located regarding hepatic effects in humans following dermal exposure to HCH. Liver pathology, including dilation of sinusoids, focal fatty inclusions, hypertrophy of hepatocytes, thickened blood vessels, swelling, and proliferation of epithelial cells of bile ducts, was observed in guinea pigs treated with 100 mg technical-grade HCH/kg/day for 30 days (Dikshith et al. 1978). The patch of the abdomen on which the HCH was applied was not covered to prevent licking, so oral exposure may also have occurred. In rabbits exposed to 25 mg technical-grade HCH/kg/day for 30 days, there were degenerative changes in hepatocytes along with increased liver and serum GPT and alkaline phosphatase (Dikshith et al. 1989b). Liver cell hypertrophy, fatty degeneration, nuclear pyknosis, and focal and diffuse necrosis were found in female rats treated with 100 mg/kg/day technical-grade HCH for 7-30 days, but the time that it took for these lesions to occur, the severity, and the number of animals affected were not reported (Dikshith et al. 1991c). Centrilobular hypertrophy was reported in male and female rats exposed dermally to 60 mg lindane/kg/day for 13 weeks, 5 days/week, 6 hours/day (Brown 1988). Renal Effects. No studies were located regarding renal effects in humans following dermal exposure to HCH. Female rats treated with 100 mg/kg/day of technical-grade HCH for 7, 15, or 30 days had necrosis and atrophy of the renal tubules and glomeruli, although the number of animals affected and the severity of the lesions were not reported (Dikshith et al. 1991c). Similar effects were noted in male rabbits treated with 25 mg/kg/day technical-grade HCH (Dikshith et al. 1989b). Male rats treated dermally with 10 mg/kg/day lindane for 13 weeks exhibited hyaline droplet formation, and urinalysis showed increased cast formation and HCH 78 2. HEALTH EFFECTS positive scores for protein, blood, and turbidity in treated males (Brown 1988). Females in the same study exhibited a slight increase in the incidence of tubular basophilia at 60 mg/kg/day. Dermal Effects. Rashes were observed in a boy following treatment with shampoo containing y-HCH (Fagan 1981). No exposure level was reported, but the shampoo was rinsed over the boy's entire body. Mild dermatitis was observed in rats after 15 skin paintings with 180 mg/kg/day y-HCH/kg for 25 days (Dikshith et al. 1973). Rabbits exposed to 132 mg/kg moistened lindane for 4 hours showed no primary skin irritation or other toxic symptoms (Ullmann 1986d). Rabbits exposed to technical-grade HCH (25 mg/kg/day for 30 days) had hyperkeratinization of the epidermal layer and swollen collagen fibers in the dermis, but no scoring level was provided (Dikshith et al. 1989b). Dermal treatment of rats with 100 mg/kg/day technical-grade HCH for 7-30 days resulted in hyperkeratosis, epidermal cell vacuolization, and thickening of collagen fibers (Dikshith et al. 1991c). Ocular Effects. No studies were located regarding ocular effects in humans following dermal exposure to HCH. Mild eye irritation was seen in rabbits exposed to 26 mg/kg lindane in the conjunctival sac for up to 72 hours, giving a primary irritation score of 0.6 out of a maximum possible cumulative score of 16 (Ullmann 1986c¢). 2.2.3.3 Immunological and Lymphoreticular Effects No studies were located regarding immunological or lymphoreticular effects in humans or animals following dermal exposure to HCH. 2.2.3.4 Neurological Effects There have been several reports of human intoxication involving convulsions in children after excessive topical application of y-HCH (Lee and Groth 1977; Matsuoka 1981; Ramchander et al. 1991; Telch and Jarvis 1982; Tenenbein 1991); exposure levels were not reported. Heiberg and Wright (1955) reported convulsions in a woman who had treated calves with an insecticide containing 11% y-HCH and 16% other HCH isomers. Weakness of the left and right limbs, dysarthria, and dysphagia were seen in an agricultural worker exposed by inhalation and dermal contact to unspecified levels of several organochlorine pesticides, HCH 79 2. HEALTH EFFECTS including lindane (Fonseca et al. 1993). A man with human immunodeficiency virus (HIV) exhibited generalized tonic-clonic seizure activity after a single topical application of a 1% lindane lotion to treat scabies (Solomon et al. 1995). Studies in animals have substantiated the neurological symptoms resulting from y-HCH application. Manifestations such as excitability, seizures, and convulsions have been observed in rabbits following a single topical application of 60 mg lindane/kg in a 1% solution (Hanig et al. 1976); young rabbits were more susceptible than older rabbits. Slight sedation was observed in rats exposed once for 24 hours to 1,000 mg/kg lindane through shaved dorsal skin (Ullmann 1986a). Sedation was severe in one female receiving the highest dose (2,000 mg/kg). This female also showed severe spasms. Damage to Purkinje cells in the cerebellum and tremors were found in female Wistar rats treated with 100 mg/kg/day technical-grade HCH for 7-30 days (Dikshith et al. 1991c). Aggressiveness or hyperactivity was noted in female rats exposed dermally for 13 weeks to 10 mg lindane/kg/day, while ataxia and tremors were seen at 60 mg/kg/day (Brown 1988). 2.2.3.5 Reproductive Effects No studies were located regarding reproductive effects in humans following dermal exposure to HCH. Dikshith et al. (1978) reported testicular hypertrophy and atrophy and complete inhibition of spermatogenesis in guinea pigs dermally treated with technical-grade HCH for 7, 15, or 30 days at doses as low as 100 mg/kg/day. The patch of the abdomen on which the HCH was applied was not covered to prevent licking, so oral exposure more than likely occurred. In a similar study, the backs of male rats were sprayed with 50 or 100 mg/kg/day technical-grade HCH for 120 days and the rats were housed in separate cages to prevent licking (Prasad et al. 1995). Depletion of germ cells and impaired function of Leydig and Sertoli cells was suggested by significant dose-related changes in activities of testicular enzymes such as sorbitol dehydrogenase, glucose-6-P-dehydrogenase, y-glutamyl transpeptidase, and -glucoronidase. Significant reductions in sperm count and motility and increased percentages of abnormal sperm were also observed in both groups. A significant reduction in testosterone level was observed in the high dose group. 2.2.3.6 Developmental Effects No studies were located regarding developmental effects in humans or animals following dermal exposure to HCH. HCH 80 2. HEALTH EFFECTS 2.2.3.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans or animals following dermal exposure to HCH. Genotoxicity studies are discussed in Section 2.5. 2.2.3.8 Cancer A case-control study surveying childhood brain cancer cases among Missouri residents found that the odds ratios for the use of Kwell, a shampoo containing lindane for lice control, were slightly elevated during the first 7 months of age to diagnosis (Davis et al. 1993). Thus, Kwell use was significantly associated with childhood brain cancer compared to controls. However, this study was limited by small sample sizes, potential recall bias in questionnaires, multiple comparisons, and the lack of detailed exposure information. In mice, dermal exposure to a 0.5% solution of y-HCH in acetone applied twice a day for 60 days was reported to result in no treatment-related tumors (Orr 1948). Increases that were not statistically significant were reported in the incidences of hyperplastic and preneoplastic areas in the liver and hepatic tumors in Swiss mice exposed to 2.4 mg technical-grade HCH/kg/day for 80 weeks (Kashyap et al. 1979). Limitations of these studies, including less-than-lifetime exposure and study duration, the testing of only one dose, and the potential for ingestion of some of the compound from the skin, preclude determination that dermally applied HCH is noncarcinogenic in mice. 2.3 TOXICOKINETICS Absorption of the various HCH isomers following inhalation, oral, or dermal exposure has been inferred from humans who have become ill or who had increased serum levels of the various isomers following exposure by these routes. No animal data are available from the inhalation route to quantify the extent or rate of absorp- tion. Technical-grade HCH has been shown to be well absorbed from the gastrointestinal tract of animals (Albro and Thomas 1974). The distribution of HCH isomers in humans and animals is primarily to the adipose tissue but also to the brain, kidney, muscle, blood, and other tissues (Siddiqui et al. 1981a; Baumann et al. 1980). B-HCH accumulates to a much greater extent than y-HCH. The excretion of HCH isomer metabolites is primarily through the urine. The isomers have also been detected in breast milk (Ejobi et al. HCH 81 2. HEALTH EFFECTS 1996; Schoula et al. 1996) and semen (Szymczynski et al. 1981) . The primary urinary metabolites are chlorophenols and an epoxide. The conversion occurs mainly by the action of hepatic enzymes. 2.3.1 Absorption 2.3.1.1 Inhalation Exposure Evidence exists that humans absorb y-HCH vapor or dusts via inhalation. This can be inferred from occupational studies in which adverse health effects, including hematological abnormalities and neurological effects, have been reported in workers exposed to y-HCH in workplace air (Brassow et al. 1981; Czegledi-Janko and Avar 1970; Kashyap 1986; Samuels and Milby 1971). In addition, «-, B-, y-, and 8-HCH have been detected in the blood serum, adipose tissue, and semen of occupationally and environmentally exposed individuals indicating that absorption does take place (Baumann et al. 1980; Czegledi-Janko and Avar 1970; Kashyap 1986; Nigam et al. 1986; Saxena et al. 1980, 1981a, 1981b). There are no specific studies that have quantified the rate or extent of absorption of the HCH isomers following inhalation exposure. No information is available on the absorption of «-, B-, y-, and 8-HCH following inhalation exposure in experimental animals. 2.3.1.2 Oral Exposure In humans, HCH is absorbed following oral exposure. Many accidental poisonings have occurred in humans as a result of y-HCH ingestion, and high blood concentrations have been demonstrated in a number of acute poisoning cases (Berry et al. 1987; Harris et al. 1969; Khare et al. 1977; Munk and Nantel 1977; Nantel et al. 1977; Powell 1980; Starr and Clifford 1972). HCH is similarly absorbed following oral exposure in animals. Information concerning the rate of absorption from the gastrointestinal tract can be inferred from studies conducted in mice and rats. These studies indicated that y-HCH is readily absorbed from the gastrointestinal tract (Ahdaya et al. 1981; Turner and Shanks 1980). Ahdaya et al. (1981) demonstrated that half of the administered dose was absorbed from the gastrointestinal tract of fasting mice approximately 14 minutes after administration of radiolabelled y-HCH by stomach tube. Although this study demonstrates the rapid absorption of y-HCH from the gastrointestinal tract, the use of fasted animals prevents an assessment of the effect of stomach contents on the rate of absorption. Turner and Shanks (1980) studied the rate of absorption of y-HCH from the gastrointestinal HCH 82 2. HEALTH EFFECTS tract and intestinal lymphatic system using rat intestinal loop. preparations. Prepared loops were injected with y-HCH, and the blood and lymph were sampled for 30 minutes. y-HCH was readily absorbed from the intestine into the blood; however, only a small amount of Y-HCH entered the lymphatic system from the intestine. Absorption of technical-grade HCH following oral exposure has been quantified in rats. The extent of absorption of technical-grade HCH has been estimated to be 95.8% in rats within 4 days following the oral administration of single doses of the substance (Albro and Thomas 1974). Variation of the dosages from 30 to 125 mg/kg had no effect on the percentage of absorption. The overall degree of absorption of technical-grade HCH administered in the feed for 14 days was similar (94.9%), but the average absorption values of «-, B-, y-, and 6-HCH were 97.4%, 90.7%, 99.4%, and 91.9%, respectively (Albro and Thomas 1974). 2.3.1.3 Dermal Exposure The ready absorption of y-HCH across human skin, due to its lipid solubility, has been demonstrated in several studies that examined the absorption of y-HCH from an antiscabies lotion (Feldmann and Maibach 1974; Lange et al. 1981; Franz et al. 1996). Maximum serum levels in healthy volunteers and scabies patients were reported within 4-6 hours following whole-body application (Lange et al. 1981). However, the maximum serum levels of y-HCH in scabies patients were greater than those reported for normal volunteers. Studies involving a single topical application of y-HCH to the forearm, which was left for 24 hours before washing, indicate that at least 9% of the applied dose was absorbed; maximum absorption occurred during the first 12 hours after application of y-HCH to the skin, but absorption continued for at least 5 days (Feldmann and Maibach 1974). The absorption of y-HCH through the skin was studied following application of 2 different preparations to the forearm of human volunteers (Dick et al. 1997a). One with 120 mg y-HCH/ml in acetone as the vehicle and the other, a commercial product, consisted of 3 mg y-HCH/mI formulation which primarily contained white spirit as the solvent base. The proportion of the applied dose absorbed into the systemic circulation in 6 hours was 5% for the dose applied in acetone and 60% of the applied dose in white spirit-based formulation. Thus, the white spirit enhanced the absorption of y-HCH relative to acetone as the vehicle. The absorption of y-HCH through human skin was also assessed in an in vitro study (Dick et al. 1997b). y-HCH absorption was reported to be 15-25% in 24 hours for the 2 formulations that contained white spirit as the HCH 83 2. HEALTH EFFECTS predominant solvent, 3% in 24 hours from an aqueous spray dilution, and <1% in 24 hours for the acetone preparation. y-HCH is similarly absorbed through the skin of animals. Toxicity was observed in guinea pigs and rabbits following dermal exposure to y-HCH and following dermal exposure to technical-grade HCH (Dikshith et al. 1978; Hanig et al. 1976). Male rats treated dermally with radiolabelled lindane (20% emulsifiable concentrate) on a 4.9 cm” shaved dorsal area exhibited absorption of radiolabel which increased with time of exposure (Bosch 1987a). After 4 hours, 10.1%, 5.3%, and 2.0% were absorbed from doses of 0.06, 0.6, and 6 mg/cm?/kg, respectively. After 24 hours, 27.7%, 20.9%, and 5.1% were absorbed from doses of 0.06, 0.6, and 6 mg/cm?/kg, respectively. Male rabbits treated dermally with radiolabelled lindane (20% emulsifiable concentrate) in a 28.3-cm?® shaved dorsal area absorbed, after 4 hours, 29.6%, 18.3%, and 7.3% radiolabel from doses of 0.005, 0.05, and 0.5 mg/cm?/kg, respectively, and, after 24 hours, 55.7%, 40.0%, and 16.6% from the same respective doses (Bosch 1987b). The absorption of y-HCH in infants and children who had received dermal treatment with 1% lindane(y-HCH) lotion was investigated in one study (Ginsburg et al. 1977). Maximum blood concentrations were observed in 6 hours, and averaged at 0.028 pg/ml for the group infected with scabies and 0.024 pg/ml for the noninfected group. 2.3.2 Distribution Placental transfer of HCH in humans has been well documented (Saxena et al. 1981a). The levels of HCH and other organochlorine insecticides were found to be higher in the maternal blood, placenta, and umbilical- cord blood of stillborn cases than those of live-born cases (Saxena and Siddiqui 1983). HCH has been shown to accumulate in amniotic fluid, placenta and fetal tissues after oral treatment of pregnant mice (Srivastava and Raizada 1993) and can be related to fetolethality. HCH isomers have been detected in human breast- milk, particularly in developing countries that still use HCH as a pesticide. Detected concentrations in these studies are discussed in Section 5.6. In a study on rats, y-HCH has been reported to be transferred in the breastmilk and to elicit neurological effects in neonates. Epileptiform seizures have been reported in male rats fed maternal milk for 12 days beginning on the third day after birth, from dams exposed daily to 20 mg y-HCH/kg by gavage (Albertson et al. 1985). In another study, lactating females were treated orally with a single dose of 6 mg/kg of y-HCH on day 9 to 14 of lactation, the testosterone level of the male offspring was reduced 50% when puberty was reached (day 60) when compared to the control group (Dalsenter et al. 1997). HCH 84 2. HEALTH EFFECTS When the offspring reached adulthood (day 140 postnatal), the relative testicular weight was significantly lower (Dalsenter et al. 1997). The number of sperm and spermatids was also significantly reduced. «-, pB-, and y-HCH have been found to be bioconcentrated and excreted in women’s breast milk who have been exposed to technical-grade HCH in pesticide residues (Nair et al. 1996). 2.3.2.1 Inhalation Exposure Information on the distribution of the HCH isomers, following inhalation by humans, comes from studies of humans exposed to HCH in the workplace. Air concentrations of «-HCH (0.002-1.99 mg/m?), B-HCH (0.001-0.38 mg/m®), and y-HCH (0.004-0.15 mg/m’) were associated with concurrent mean blood serum levels in workers of 69.6, 190.3, and 36.9 pg/L, respectively (Baumann et al. 1980). Serum levels of total HCH of 0.14-0.60 ppm were found in workers with unknown levels of exposure to technical-grade HCH (Nigam et al. 1986). HCH isomers have also been detected in the adipose tissues of workers occupationally exposed and individuals exposed via the ambient environment (Baumann et al. 1980; Siddiqui et al. 1981a). Accumulation of B-HCH has been shown to increase approximately linearly with time of exposure (Baumann et al. 1980). Siddiqui et al. (1981a) found adipose levels of 0.1-1.5, 0.06-0.9, 0.7-3.0, and 0.97-5.8 ppm of «-, B-, Y-, and total HCH, respectively, in the tissues collected during an autopsy case study conducted in India. In a study with Wistar rats exposed to air concentrations of 0.02—5 mg/m’ lindane for 90 days, male rats exhibited higher serum lindane levels than females, but females had higher liver, brain, and fat levels (Oldiges et al. 1983). The organ levels of lindane were dose-dependent but had returned to baseline levels after a 4- week recovery period. 2.3.2.2 Oral Exposure Information on the distribution of the HCH isomers following ingestion by humans comes from case reports. A fatal poisoning case confirmed that y-HCH is, in part, distributed to the central nervous system. y-HCH was detected in the cerebrospinal fluid of a young boy following ingestion of an unknown quantity of y-HCH (Davies et al. 1983). More detailed information on the distribution of HCH or its isomers is available from studies in which laboratory animals were exposed by ingestion (Chand and Ramachandran 1980; Eichler et al. 1983; HCH 85 2. HEALTH EFFECTS Srinivasan and Radhakrishnamurty 1983b). These studies examined the overall distribution pattern of HCH isomers. y-HCH and B-HCH are primarily stored in the fat of rats acutely exposed for 5, 10, or 15 days (Srinivasan and Radhakrishnamurty 1983b). The overall distribution of y-HCH was greatest in fat, followed by brain, kidney, muscle, lungs, heart, spleen, liver, and blood. More recently, y-HCH has also been found in the adrenal glands of rats (Lahiri et al. 1990; Sulik et al. 1988). In an experiment lasting 12 days, the accumulation of y-HCH in the brain of rats gavaged with 5 or 12 mg/kg/day began to decline after 8 days. This reduction was not observed in rats gavaged with 20 mg/kg/day (Tusell et al. 1988). In rats gavaged with y-HCH on lactation day 9 or 14, y-HCH levels were higher in their milk than plasma (Dalsenter et al. 1997). Levels of y-HCH in the offspring of those rats were approximately twice as high in kidneys and liver than in brain and testes. In the brain of rats, a-HCH has been found to accumulate preferentially in the white matter, an area containing lipid-rich myelin, as opposed to gray matter (Portig et al. 1989). However, the same brain distribution pattern was not noted for y-HCH in mice, despite the fact that it is equally lipophilic. Differences in distribution of y-HCH and «-HCH are most likely due to stereospecific forces. The distribution pattern for B-HCH was found to be in the following order: fat > kidney > lungs > liver > muscle > heart > spleen > brain > blood. For y-HCH, the distribution pattern was as follows: fat > brain > kidney > muscle > lungs > heart > spleen > liver > blood. B-HCH accumulates in tissues to a greater degree than y-HCH except in the brain, where the Y-HCH accumulates at a higher concentration (Srinivasan and Radhakrishnamurty 1983b). This accumulation increases with increasing dose and treatment period for B-HCH more so than for y-HCH. The greater accumulation of B-HCH in tissues is expected since this isomer is known to be metabolized more slowly. In addition, y-HCH is known to induce the liver mixed- function oxygenase system, and thus. self-induced metabolism is an important factor that minimizes the accumulation of y-HCH residues in animal tissues. The preferential accumulation of HCH in fatty tissues is also observed following intermediate-duration exposure of rats to HCH (isomer unspecified) in the diet (overall distribution: fat > liver > serum) (Chand and Ramachandran 1980) or exposure to a- or y-HCH by gavage (overall distribution: fat > kidney > liver > brain > blood) (Eichler et al. 1983). 2.3.2.3 Dermal Exposure HCH 86 2. HEALTH EFFECTS Information on the distribution of the HCH isomers in exposed humans comes from case reports. A fatal poisoning case indicated that y-HCH is, in part, distributed to the brain following topical application. The isomer was detected in brain tissue (110 ppb) and heart blood (33.3 ppb) collected during the autopsy of an infant who was treated with a whole-body application of a 1% y-HCH lotion after a hot bath (Davies et al. 1983). In another study, blood levels of y-HCH peaked 6 hours following topical application of a 1% solution to 20 children (12 infected with scabies, 8 noninfected) (Ginsburg et al. 1977). Mean concentrations did not differ statistically between the two groups at 6 hours and were 0.024 pg/ml in healthy children and 0.028 pg/ml in infected children. The half-life in blood was 17.9 hours and 21.4 hours in infected and healthy children respectively. Differences in dosage between the two groups of children were considered marginally significant (p=0.11). However, the infected children were younger. The mean age for the infected and noninfected group were 32.5 months and 64.3 months, respectively. The distribution of y-HCH through the skin was studied following application of 2 different preparations to the forearm of human volunteers (Dick et al. 1997a). The mean peak plasma concentrations of y-HCH following exposure to the acetone and white-spirit based applications were 0.91 and 0.47 ng/mL, respectively; although the preparation in acetone contained a 40-fold higher concentration of y-HCH. About 30% of the applied dose for the white-spirit based formulation was observed in the stratum corneum at 6 hours exposure and decreased by 90% at 24 hours. Fifteen percent of the applied dose for the acetone-based application was located in the stratum corneum. Some information on the distribution of y-HCH is available from studies in which laboratory animals were exposed by dermal application (Bosch 1987a, 1987b; Hanig et al. 1976; Solomon et al. 1977a, 1977b). A study on the distribution of y-HCH in guinea pigs following acute dermal exposure indicates that accumulation of y-HCH in the brain is greater than in the blood after single and multiple topical applications (Solomon et al. 1977a, 1977b); the levels in both tissues increased with the number of applications. Experiments with radiolabeled lindane in dermally treated rats (Bosch 1987a) and rabbits (Bosch 1987b) found that absorption of radiolabel increased with time of exposure, with greater absorption and subsequent excretion in the urine occurring at the lower treatment doses. In weanling rabbits, which appear to be more sensitive to lindane toxicity from dermal exposure than young adults, levels of lindane in the blood after a single application of a 1% solution (60 mg lindane/kg) were 1.67 and 2.48 pg/mL in 2 individuals that had been shaved and depilated, then stripped to remove the keratin layer (Hanig et al. 1976). In contrast, a blood level of only 0.67 pg/mL was seen in an individual that had only been shaved and depilated, indicating that absorption increases with loss of skin integrity. HCH 87 2. HEALTH EFFECTS Following dermal treatment of rats with 50 or 100 mg/kg/day technical-grade HCH for 120 days, «-, B-, y-, and 8-HCH were accumulated in testicular tissue and sperm in a dose-related manner (Prasad et al. 1995). B-HCH was present at the highest concentration in testicular tissue and sperm. 2.3.3 Metabolism The metabolism of y-HCH is illustrated in Figure 2-4. Angerer et al. (1983) determined that chlorophenols were the primary urinary metabolites of Y-HCH excreted by workers involved in y-HCH production. In the study, glucuronides and sulfates of chlorophenols were cleaved by acidic hydrolysis of urine samples. The metabolites 2,3,5-, 2,4,6-, and 2,4,5-trichlorophenol accounted for almost 57.7% of the y-HCH metabolites identified in the urine collected during the last 2 hours of the workers’ shifts. Other urinary metabolites identified included other trichlorophenols, dichlorophenols, tetrachlorophenols, and dihydroxychloro- benzenes. Pentachlorophenol has also been identified as a urinary metabolite in humans following occupational exposure (Engst et al. 1979). In vitro investigations indicate that human liver microsomes convert Y-HCH by dechlorination, dehydrogenation, dehydrochlorination, and hydroxylation to 5 primary metabolites: 3,6/4,5-hexachlorocyclohexene, pentachlorocyclohexene, 2,4,6-trichlorophenol, 2,3,4,6-tetra- chlorophenol, and pentachlorobenzene (Fitzloff et al. 1982). Similar in vitro studies have demonstrated that an epoxide forms during the metabolism of pentachlorocyclohexene. This stable halogenated hydrocarbon epoxide metabolite may be responsible for the mutagenic and carcinogenic effects of y-HCH (Fitzloff and Pan 1984). In animals, Y-HCH appears to be transformed by hepatic enzymes to form chlorophenols, chlorobenzene, chlorocyclohexanes, chlorocyclohexanols, and conjugates of mercapturic acid, glucuronide, and sulfate (Chadwick and Freal 1972a; Chadwick et al. 1978a; Engst et al. 1979; Kujawa et al. 1977). These metabolites have been identified in various tissues and in the urine of laboratory animals. Metabolites found in the liver of rats following intermediate exposure to y-HCH via gavage or diet include di-, tri-, tetra-, and pentachlorobenzenes; pentachlorocyclohexenes; and pentachloro-2-cyclohexen-1-ol (Chadwick and Freal 1972a; Kujawa et al. 1977). Metabolites identified in the blood of these rats include di-, tri-, tetra-, and pentachlorophenols and pentachloro-2-cyclohexen-1-ol (Kujawa et al. 1977). Di-, tri-, and tetrachlorophenols; pentachlorocyclohexenes; and pentachloro-2-cyclohexen-1-ol have been identified in samples of kidney, spleen, heart, and brain tissue from rats fed y-HCH (Kujawa et al. 1977). Metabolites found in the urine include tri-, tetra-, and pentachlorophenol; pentachloro-2-cyclohexen-1-ol; and isomers of tetrachloro-2-cyclohexen-1-ol (Chadwick and Freal 1972a; Chadwick et al. 1978c; Kujawa et al. 1977). The metabolism of y-HCH in the intestine was reported to be very minor, or the metabolites were completely Figure 2-4. The Proposed Metabolism of Hexachlorocyclohexane* Nroapturie Acid Conjugates “ 2,4,56-TCCOL LN 2,4,56-TCCOL 34 mi A 2.34-TTCB 3,4,6,5-PCCH 3,4,6,5-TCCH J \ 3,6/4, 1. HCB OH OH OH *.. LY 0) femme ccc eee 1 Pp 4,6-TCCOL DN , cis B-PCCH 1,24- Bc 24-TCB J "T HCCHD HO x - 1 1 v 2487C8 2,3,5-TCB . 248-7CP J 345TICP 2345TTCP PCB Seee ll Sa PCCHA 1 eT = A v &° Glucuronide & Sulfate es Abreviations: PCCHA: Pentachlorocyclohexane TTCP: Tetrachlorophenol HCCH: Hexachlorocyclohexene PCCOL: Pentachlorocyclohexenol TCB: Trichlorobenzene HCB: Hexachlorobenzene PCCH: Pentachlorocyclohexene TCP: Trichlorophenol HCCHD: Hexachlorocyclohexadiene PCB: Pentachlorobenzene 3,6/4 5-HCCH: 3,6/4,5-Hexachlorocyclohexene HCCOL: Hexachlorocyclohexenol HCH: Hexachlorocyclohexane TCCH: Tetrachlorobenzene TCCOL: Tetrachlorocylcohexenol *Adapted from Chadwick et al. 1979, 1985; Fitzlof and Pan 1984; Fitzloff et al. 1982 S$103443 H1V3H 2 HOH 88 HCH 89 2. HEALTH EFFECTS absorbed. No metabolites were detected in the feces or in the adrenal gland (Kujawa et al. 1977). In vitro preparations using rat liver slices have also found that y-HCH is converted to hexachlorobenzene (Gopalaswamy and Aiyar 1984). However, these findings have not yet been confirmed in in vivo experiments. The major urinary metabolites formed in rats, following intermediate oral exposure to &- or 3-HCH, were identified as tri- and tetrachlorophenols; pentachlorocyclohexene was also identified as a metabolite of y-HCH in kidney tissue (Macholz et al. 1982a, 1982b). The detoxification of y-HCH appears to be dependent on the P-450 oxidative system. Intermediate exposure to lindane resulted in greater toxicity in DBA/2 (D2) mice than in C57BL/6 (B6) mice; the former are unresponsive to microsomal enzyme induction by lindane (Liu and Morgan 1986). Increased toxicity was associated with higher blood and brain concentrations in D2 mice than in B6 mice at the time of sacrifice. In addition, D2 mice were found to have more 2,4,6-trichlorophenol in the liver, kidney, and spleen than the less-susceptible B6 mice. The inability of D2 mice to undergo enzyme induction to increase the rate of detoxification led to Y-HCH's enhanced toxicity in this strain. Other investigators have demonstrated the importance of the hepatic microsomal enzymes in the detoxification of y-HCH (Baker et al. 1985; Chadwick and Freal 1972a; Chand and Ramachandran 1980; Chadwick et al. 1981; Tanaka et al. 1979). Chadwick et al. (1981) demonstrated that pretreatment of rats with inducers of hepatic enzymes significantly influenced the metabolism and excretion of y-HCH and its metabolites by altering specific metabolic pathways; excretion of y-HCH metabolites in the urine increased nearly 4-fold following pretreatment with Aroclor 1254 or phenobarbitol. Following pretreatment with Aroclor 1254, a 7-fold increase in expired metabolites was observed. Naphthoflavon had no effect on excretion rate. Metabolism of HCH has not been studied in children. However, although it is unknown whether the ability to metabolize HCH specifically differs between children and adults, some enzymes which belong to the enzyme superfamilies involved in phase I HCH metabolism are developmentally regulated in humans. The development of UDP-glucuronosyltransferase (responsible for glucuronide conjugation) depends on the enzyme isoform but in general adult activity is attained by 6-18 months of age (Leeder and Kearns 1997). Development of sulfotransferase (responsible for sulfate conjugates) activity is also substrate specific and is usually earlier than UDP-glucuronosyltransferase. In fact, levels of some sulfotransferases may be greater during infancy and early childhood than during adulthood (Leeder and Kearns 1997). A series of enzymes are involved in the production of mercapturic acid conjugates: y-glutamyltranspeptidase, glutathione HCH 90 2. HEALTH EFFECTS S-transferase, cysteinyl glycinase, and N-acetyl transferase (Sipes and Gandolfi 1991). There are 2 superfamilies of N-acetyltransferases, and one—the N-acetyltransferase 2 superfamily—has members that are developmentally regulated in humans. There is some N-acetyltransferase 2 activity in fetuses by 16 weeks of gestation. Infants up to 2 months of age have the slow metabolizer phenotype (there is a genetic polymorphism in this enzyme in adults). The adult distribution of slow and fast metabolizer phenotypes is reached by 4-6 months of age and full adult activity is achieved at 1-3 years of age (Leeder and Kearns 1997). 2.3.4 Elimination and Excretion Excretion of hexachlorocyclohexane has not been studied in children. 2.3.4.1 Inhalation Exposure Humans excrete Y-HCH and its metabolites in urine, milk, and semen (Angerer et al. 1981). Chromatographic analysis of urine from humans occupationally exposed to HCH showed the presence of chlorinated phenols and all isomers of di-, tri-, and tetrachlorophenol (Angerer et al. 1981). In another study, the elimination of B-HCH was investigated in a group of 40 former workers of a y-HCH-producing plant by analyzing at least 2 blood specimens from different time points between 1952 and 1980. The median half-life of B-HCH was 7.2 years, calculated by concentrations in whole blood, and 7.6 years, calculated by concentrations in extractable lipids (Jung et al. 1997), assuming first order kinetics for excretion. HCH is commonly detected in low concentrations (0.015 mg/kg fat) in the breastmilk of women exposed to HCH in the environment (Fytianos et al. 1985). All five of the HCH isomers discussed in this profile have been detected in human semen following environmental exposure, suggesting another route of elimination (Szymczynski and Waliszewski 1981). No animal studies using the inhalation route of exposure were located. 2.3.4.2 Oral Exposure Excretion of y-HCH and its metabolites in laboratory animals has been well documented. Data indicate that its major route of elimination is via the urine following intermediate and chronic oral feeding in mice (Chadwick et al. 1985). Very little is eliminated in exhaled air (Ahdaya et al. 1981; Chadwick et al. 1985) or HCH 91 2. HEALTH EFFECTS feces (Chadwick et al. 1985) following acute, intermediate, and chronic oral administration in rodents. Because of its high lipid solubility, y-HCH is excreted through the dam’s milk (Dalsenter et al. 1997). Very little y-HCH is excreted unaltered. Various phenylmercapturic acid derivatives have been detected in the urine of rats, formed by the conjugation of y-HCH metabolites with glutathione subsequent to dechlorinations and dehydrochlorinations (Allsup and Walsh 1982; Kurihara et al. 1979). In vitro investigations using rat liver cells indicate that 3-HCH seems to resist, to some extent, conversion to the glutathione derivative; Y-HCH and a-HCH are readily conjugated (Fitzloff and Pan 1984; Fitzloff et al. 1982). y-HCH derivatives are not only excreted in the form of phenylmercapturic acids; there is ample evidence that they are also excreted in the form of glucuronides and sulfate conjugates (Chadwick et al. 1978a). 2.3.4.3 Dermal Exposure Nonmetabolized y-HCH was excreted in the urine and feces of healthy volunteers and scabies patients acutely exposed to a 0.3% y-HCH emulsion by whole-body application. The cumulative excretion of nonmetabolized y-HCH was almost the same in the healthy volunteers and the scabies patients (Zesch et al. 1982). The elimination of y-HCH was studied following application of two different preparations to the forearm of human volunteers (Dick et al. 1997a). The elimination half-life was between 50-111 hours for the acetone-based application, and 25-58 hours for the white-spirit based formulation. Absorbed y-HCH was excreted in the urine as conjugates of 2,4,6-; 2,3,5-; and 2,4,5-trichlorophenol. Only 0.01-0.15% of the dose was excreted in the urine in 72 hours following dermal exposure for 6 hours. In a study in which children infected with scabies and their noninfected siblings were treated dermally with 1% lindane lotion, the blood level was found to diminish rapidly after application, with a half-life of 17.9 hours in infected children and 21.4 hours in noninfected children. In male rats treated dermally with radiolabeled lindane, 0.28, 0.08, and 0.02% radiolabel were excreted in urine 4 hours after doses of 0.06, 0.6, and 6 mg/cm?/kg, respectively (Bosch 1987a). After 24 hours, 4.4, 3.2, and 0.6% radiolabel were excreted in urine from the same respective doses. In a similar study with male rabbits, 3.8, 2.6, and 1.3% radiolabel were excreted in urine 4 hours after doses of 0.005, 0.05, and HCH 92 2. HEALTH EFFECTS 0.5 mg/cm?/kg, respectively (Bosch 1987b). After 24 hours, 25.5, 11.6, and 6.8% radiolabel were excreted in urine from the same respective doses. 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 al. 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 al. 1987; Andersen and Krishnan 1994). These models are biologically and mechanistically based and 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 1990s, 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. HCH 93 2. HEALTH EFFECTS 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 2-5 shows a conceptualized representation of a PBPK model. If PBPK models for hexachlorocyclohexane 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. An existing PBPK model for hexachlorocyclohexane is discussed below. 2.3.5.1 Summary of PBPK Models. DeJongh and Blaauboer (1997) simulated the kinetics of lindane in rats with a PBPK model. A five compartment model for the rat as presented in Figure 2-6 was constructed, including (1) the liver, serving as the metabolizing organ; (2) blood; (3) fat; (4) brain; and (5) a lumped compartment representing all other tissues, consisting mainly of muscle tissue. Values for the physiological parameters, tissue-blood partition coefficients, were obtained from the literature and are presented in Table 2-6. The model was calibrated on a dataset from the literature on the disposition of lindane from blood in vivo after single oral dosage and first order biotransformation and gastrointestinal absorption constants for lindane were obtained. The model was validated by simulating the disposition of lindane in vivo after single intraperitoneal and chronic oral dosage and comparing simulated with experimental results. Simulated lindane concentrations in blood, brain, muscle, and fat after single intraperitoneal and chronic oral dosage compared adequately well with experimental results. HCH 2. HEALTH EFFECTS Figure 2-5. Conceptual Representation of a Physiologically-Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance Inhaled chemical ~~ Exhaled chemical r>—20mM4 30> OO0OO0Orw v v Ingestion — Lungs — r—— Liver mi mm— | ' Vv Vmax Kn Gl E Tract N NH BHP Fat «| Oo uU S +«— 1 Slowly perfused tissues | +— B L . . 0 +«— 1 Richly perfused tissues | «—— Oo D ERR PF Kidney — Urine Skin 4 Note: This is a conceptual representation of a physiologically -based pharmacokinetic (PBPK) model for a hypothetical The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, chemical substance. metabolized in the liver, and excreted in the urine or by exhalation. Chemical in air contacting skin HCH 2. HEALTH EFFECTS Figure 2-6. PBPK Model for Gamma-Hexachlorocyclohexane blood ac < fat af other tissue (SPT) Qs brain Qb , Ql liver biotransformation oral or i.p. uptake Qc = movement from blood to other tissues Qf = uptake to fat Qs = uptake to other tissues Qb = uptake to brain Ql = uptake to liver HCH 2. HEALTH EFFECTS 96 Table 2-6. Parameters for a PBPK Model for y-Hexachlorocyclohexane in Rats Parameter Value Scaling factor Body weight (kg) 0.135-0.313 — BE 11-15 16-20 *Derived from HAZDAT 1998 FHNSOdX3 NVWNH HO4 TVILNILOd 'S HOH 0st Figure 5-2. Frequency of NPL Sites with Alpha-HCH Contamination Sea * Derived from HAZDAT 1998 HOH 3HNSOdX3 NYWNH HOH TVILN3LOd 'S NPL Sites 1-3 EX 4-6 BEd 7-9 ml 1-14 LSE Figure 5-3. Frequency of NPL Sites with Beta-HCH Contamination ok : NPL Sites ! oS _ Ni 1-3 Te oD = 3 4-6 > EE 7-9 mm 10-13 *Derived from HAZDAT 1998 FHNSOdX3 NYWNH HOH TVILNILOd 'S HOH est Figure 5-4. Frequency of NPL Sites with Delta-HCH Contamination . NPL Sites : a NS 1-2 on oe Bi ; EK 3-5 P EE 6-8 9-1 1 *Derived from HAZDAT 1998 FHNSOdX3 NYWNH HOA TVILN3LOd 'S HOH £51 Table 5-1. Releases to the Environment from Facilities that Manufacture or Process Hexachlorocyclohexane Total of reported amounts in pounds per year Underground POTW Off-Site Total State® City Facility Air Water Land Injection Transfer Waste Transfer Environment? GA Cordele Drexel Chemical Co. 10 5 250 0 0 0 265 ID Marsing Gustafson Inc. 0 0 0 0 0 414 414 KY Buckner Rigo Co. 0 0 0 0 0 250 250 NE Fremont Platte Chemical Co. 500 0 0 0 0 1,000 1,500 TOTALS 510 5 250 0 0 1,664 2,429 Source: TRI9% 1998 *Data in TRI are maximum amounts released by each facility *Post office state abbreviations used “The sum of fugitive and stack releases are included in releases to air by a given facility “The sum of all releases of the chemical to air, land, and water, and underground injection well; and transfers off-site by a given facility POTW = publicly owned treatment works 3JHNSOdX3 NVWNH HOH TVILN3LOd 'S HOH vst HCH 155 5. POTENTIAL FOR HUMAN EXPOSURE 5.2.1 Air According to the Toxic Chemical Release Inventory, in 1996, releases of lindane to the air from four large processing facilities were 510 kg (1,133 pounds) (TRI96 1998). Table 5-1 lists amounts released from these facilities. The TRI data should be used with caution because only certain types of facilities are required to report. This is not an exhaustive list. Historically, the largest source of y-HCH releases to the air resulted from agricultural application of the pesticide lindane. Other air releases occurred during the manufacture of the pesticide. Aerial applications of y-HCH are now prohibited in the United States as its use as a pesticide was restricted (EPA 1985b), and atmospheric releases from these sources are not expected. «-HCH and y-HCH were detected in 60-90% of the air samples collected in the vicinity of formulation plants in Arkansas and Tennessee in 1971 at mean levels of 1.0 and 1.3 mg/m’, respectively (Lewis and Lee 1976). Quantitative estimates of the total quantities of y-HCH released to the air from these sources were not located. In addition to releases from industrial facilities, y-HCH is present in the environment as a result of its use or disposal. For example, wind erosion of contaminated soil may distribute pesticides into the atmosphere. y-HCH can also be released to the atmosphere via volatilization from treated agricultural soils and plant foliage (Lewis and Lee 1976). Evaporative loss of y-HCH from water is not considered a significant source of atmospheric y-HCH because of its relatively high water solubility (Mackay and Leinonen 1975). Quantitative estimates of the amount of y-HCH released from these sources were not located in the literature. Atmospheric release of Y-HCH from disposal sites or hazardous waste sites has not been documented but is likely, considering the physical and chemical properties of y-HCH. a, B, vy, and 8-HCH have been detected in air samples collected at 5, 3, 6, and 3 of the 1,467 current or former EPA NPL hazardous waste sites, respectively (HazDat 1998). 5.2.2 Water According to the Toxic Chemical Release Inventory, in 1996, releases of lindane to the water from four large processing facilities were 5 kg (11 pounds) (TRI96 1998). Table 5-1 lists amounts released from these HCH 156 5. POTENTIAL FOR HUMAN EXPOSURE facilities. The TRI data should be used with caution because only certain types of facilities are required to report. This is not an exhaustive list. y-HCH can be released to surface water via surface runoff (as the dissolved chemical or adsorbed to particulates) or via wet deposition of rain and snow (Tanabe et al. 1982; Wheatly and Hardman 1965). For example, Lake Ontario received 7 kg/year of «-HCH and <2 kg/year of y-HCH because of suspended sediment loading from the Niagara River between 1979 and 1981 (Kuntz and Warry 1983). The Great Lakes in general receive from 0.77 to 3.3 metric tons/year of ¢-HCH and from 3.7 to 15.9 metric tons/year of y-HCH because of atmospheric deposition of these contaminants (Eisenreich et al. 1981). In 1982, a-HCH and y-HCH were detected in samples of urban stormwater runoff from Denver, Colorado, and Washington, DC, at 0.0027-0.1 and 0.052-0.1 pg/L in 20% and 11%, respectively, of the 86 samples collected; 3-HCH was detected in runoff from Washington, DC, only, in 5% of the samples at a concentration of 0.1 pg/L (Cole et al. 1984). Y-HCH can be released to groundwater via soil leachate. Although available adsorption data indicate that y-HCH has a low mobility in soils, the results of monitoring studies suggest that y-HCH does migrate to groundwater (Page 1981; Sandhu et al. 1978) (see Section 5.4.2). In water tested from 1,076 wells throughout New Jersey, Y-HCH was not detected in at least half of the samples, but a maximum concentration of 0.9 ppb y-HCH was detected (Page 1981). «, B, y, and 8-HCH have been detected in groundwater samples collected at 61, 60, 77, and 58 of the 1,467 current or former EPA NPL sites, respectively (HazDat 1998). «, B, y, and 8-HCH have been detected in surface water samples collected at 26, 16, 30, and 10 of the 1,467 current or former EPA NPL sites, respectively (HazDat 1998). 5.2.3 Soil According to the Toxic Chemical Release Inventory, in 1996, releases of lindane to the soil from eight large processing facilities were 250 kg (556 pounds) (TRI96 1998). Table 5-1 lists amounts released from these facilities. The TRI data should be used with caution because only certain types of facilities are required to report. This is not an exhaustive list. HCH 157 5. POTENTIAL FOR HUMAN EXPOSURE y-HCH can be released to the soil by direct application of the pesticide to soil or by direct or indirect releases during formulation, storage, and/or disposal. Hazardous waste sites where Y-HCH has been disposed of in the past are sources of y-HCH in soils (HAZDAT 1992). However, the application of lindane (purity unspecified) to laboratory refuse columns simulating municipal landfills indicated that lindane did not volatilize or leach from the refuse surface, and movement through the column was slight, suggesting that codisposal of lindane with municipal refuse will result in minimal releases (Reinhart and Pohland 1991; Reinhart et al. 1991). «, B, vy, and 8-HCH have been detected in sediment samples collected at 13, 16, 30, and 20 of the 1,467 current or former EPA NPL sites, respectively (HazDat 1998). «, 3, y, and 8-HCH have been detected in soil samples collected at 51, 64, 77, and 50 of the 1,467 current or former EPA NPL sites, respectively (HazDat 1998). Also, c, B, ¥, and 8-HCH have been detected in leachate collected at 7, 8, 12, and 9 of the 1,467 current or former EPA NPL sites, respectively (HazDat 1998). 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partitioning y-HCH present in soil can leach to groundwater, sorb to soil particulates, or volatilize to the atmosphere. In general, the leaching of organic chemicals through soil is governed by the water solubility of the chemicals and their propensity to bind to soil. Based on the results of a number of laboratory soil column leaching studies that used soils of both high and low organic carbon content as well as municipal refuse, y-HCH is generally immobile in soils (Hollifield 1979; Melancon et al. 1986; Rao and Davidson 1982; Reinhart et al. 1991). Adsorption of Y-HCH to soil particulates is generally a more important partitioning process than leaching to groundwater. However, groundwater sediments, which have low organic carbon content, are not sufficient to adsorb y-HCH to the extent that groundwater contamination is prevented (Nordmeyer et al. 1992). In a study involving a laboratory sediment/water system, «- and Y-HCH isomers were highly adsorbed on sediments under both aerobic and anaerobic conditions (Wu et al. 1997). ¥-HCH sorbed to the soil can partition to the atmosphere by wind erosion of surface soil particulates (Stanley et al. 1971) and via volatilization from treated agricultural soils and plant foliage (Lewis and Lee 1976). In tests conducted in a model laboratory system at 10°C and 20°C, volatilization half-lives of y-HCH from soil and oat plant surfaces of 2.3-24.8 days and 0.29-0.73 days, respectively, were reported (Dorfler et al. HCH 158 5. POTENTIAL FOR HUMAN EXPOSURE 1991a); half-lives were greater on dry, sandy soils versus peat soils;. however, when moisture was added to the soils, the half-life was greater for the peat soil, while the warmer temperature decreased the half-life under all soil and moisture conditions (Dorfler et al. 1991b). In tests performed with a wind tunnel, a volatilization rate of >20% for lindane from soil surfaces within a 24-hour period was determined (Riidel 1997). The volatilization rate from plant surfaces was 55% for lindane. Application of Y-HCH to fields of sunflowers and sugarbeets resulted in a 54% evaporative loss of the pesticide within 24 hours (Neururer and Womastek 1991). An analysis of the concentrations of «-HCH to y-HCH in air over southern Ontario suggested that high levels of y-HCH were indicative of recent lindane usage (Hoff et al. 1992a). The levels of a-HCH were less variable throughout the year, ranging from 77-260 pg/m®. During the winter, higher ratios of ¢-HCH to y-HCH reflect the movement of air containing the more persistent ¢-HCH isomer from the colder Arctic regions to the south, while the lower ratios in the summer reflect both increased lindane usage in the region and the lack of movement of Arctic air (Hoff et al. 1992a). y-HCH is also seen to move with warm air during the summer months from the lower United States (or areas even further to the south) to the Great Lakes region, although a similar trajectory cannot be identified for the more ubiquitous ¢-HCH. Levels of a-HCH in air are not dominated by volatilization or partitioning to surfaces but are dependent on local temperature changes (Hoff et al. 1992b). a-HCH appears to have a long residence time in the atmosphere and is controlled primarily by transport. yY-HCH in the atmosphere is likely to be subject to rain-out and dry deposition. y-HCH removal rates by rainfall and dry deposition were 2.5%/week and 3.3 %/week, respectively, and the estimated residence time of y-HCH in the atmosphere was 17 weeks in a study by Atkins and Eggleton (1971). Rain-out and dry deposition of atmospheric y-HCH results in the contamination of surface soil and water in areas not directly exposed via pesticide application. y-HCH concentrations were positively correlated with ambient air temperature although concentrations of ¢-HCH were not. In surface waters, y-HCH has a tendency to dissolve and remain in the water column. Although y-HCH has a relatively high vapor pressure compared with many other organochlorine insecticides, evaporative loss of y-HCH from water is not considered to be significant. Mackay and Leinonen (1975) calculated theoretical losses of several pesticides from saturated water solutions and predicted a volatilization half-life of 191 days for y-HCH. HCH 159 5. POTENTIAL FOR HUMAN EXPOSURE y-HCH released to water may undergo adsorption/desorption with sediments and other materials in the water. Adsorption and desorption studies of y-HCH in natural water-sediment systems performed by Saleh et al. (1982) indicate that a diversity of the natural water-sediment characteristics may affect the sorption-desorption behavior of y-HCH in addition to the organic carbon content of the sediments. Lindane is sorbed to silt solutions with a slow desorption rate, indicating that transport through the environment is most likely to be particle mediated (Noegrohati and Hammers 1992c). Biosorption of lindane was seen for the fungus Rhizopus arrhizus and activated sludge, with equilibrium being reached within 1 and 4 hours, respectively. Death of the sludge biomass resulted in rapid desorption with zero-order kinetics, suggesting that adsorbed lindane can be released back into the environment (Tsezos and Wang 1991a). The sorption of lindane from water using wood charcoal has been described (Keerthinarayana and Bandyopadhyay 1998); it was found to be a good sorbent for the sorption of lindane from water. Lindane which is adsorbed to sediments may be recycled to the atmosphere as gas bubbles are formed in the sediment by the methanogenesis and denitrification processes of bacteria. It is estimated that in one case studied 85% of the lindane associated with the sediment gas bubbles will be released to the atmosphere, with the remaining 15% being dissolved in the water column as the bubble rises toward the surface (Fendinger et al. 1992). y-HCH is bioconcentrated to high levels following uptake from surface waters by a number of aquatic organisms. However, uptake from soils and bioconcentration by plants and terrestrial organisms appears to be limited. For example, bioconcentration factors (BCFs) for y-HCH from surface waters include 183 in brine shrimp (Matsumura and Benezet 1973), 319 in rainbow trout fry (Ramamoorthy 1985), 84 in pink shrimp, 218 in pinfish, 63 in grass shrimp, and 490 in sheepshead minnows (Schimmel et al. 1977). Introduction of y-HCH onto sand resulted in a BCF of 95 in brine shrimp and 1,613 in northern brook silverside fish (Matsumura and Benezet 1973). A BCF of 1,273 (lipid basis) in prawns (crustacean) was seen to be 0.58 times the Y-HCH concentration in the underlying sediment, indicating that although aquatic organisms may accumulate Y-HCH from the water column, uptake from contaminated sediment alone may not be extensive (Just et al. 1990). BCFs for the isomers of HCH, using zebra-fish under steady-state conditions, were 1,100 for «-HCH, 1,460 for B-HCH, 850 for y-HCH, and 1,770 for -HCH; BCFs determined by uptake and clearance rate constants were slightly lower (Butte et al. 1991). BCFs on a wet weight basis for y-HCH in different fish species were positively correlated with their lipid content (Geyer et al. 1997). The bioaccumulation of lindane by tubificide oligochaetes from a static system consisting of sediment and water has been reported (Egeler et al. 1997). HCH 160 5. POTENTIAL FOR HUMAN EXPOSURE v-HCH applied to an aquatic mesocosm (i.e., a small, artificial ecosystem) at 61.3 ug/L was reduced by 50% at 24 hours postapplication, while at 19 weeks postapplication the concentration in the water was only 0.2%, and no y-HCH was detected at 21 weeks. The biological half-life was estimated to be 16.7 days. Movement through the water column was shown by increasing sediment concentrations up to a maximum of 75.4 pg/kg at 96 hours postapplication; however, sediment concentrations decreased to below the detection limit at 23 weeks to give a half-life in sediment of 48.1 days. Rooted aquatic macrophytes have a BCF of 56 at a maximum concentration of 1.7 mg/kg at 24 hours postapplication; however, at 14 weeks all residues were below the detection limit for a half-disappearance time of 18 days. Gastropods in the system had a maximum y-HCH concentration of 7.2 mg/kg at 24 hours posttreatment, yielding a BCF of 232.4 and a half- disappearance time of 13.7 days with all residues eliminated by 13 weeks (Caquet et al. 1992). In tests with radiolabeled y-HCH, grain, maize, and rice plants accumulated 0.95%, 0.11%, and 0.04%, respectively, of the amount of bound residues following 14-20 days growth in a sandy loam soil. Bioconcentration increased by 4-10 times when the plants were grown in test soils containing both bound and extractable residues of y-HCH (Verma and Pilli 1991). Plants and grains grown on soil treated with y-HCH showed a-HCH as the predominant isomer although all isomers were found to some extent; amounts decreased with increasing time after application (Singh et al. 1991). Uptake of y-HCH by earthworms from a treated humus soil has also been reported. Following exposure to 5 ppm of the compound for up to 8 weeks, the test organisms bioconcentrated y-HCH by a factor of 2.5. The earthworms biotransformed more than 50% of the accumulated y-HCH; the main degradation product was y-2,3,4,5,6-pentachlorocyclohex-1-ene (Viswanathan et al. 1988). y-HCH and the other isomers of HCH do not appear to undergo biomagnification in terrestrial food chains to a great extent, although there is a moderate potential for transfer of y-HCH to animal tissue as a result of soil ingestion or ingestion of contaminated foliage (Wild and Jones 1992). Clark et al. (1974) found that y-HCH levels in the adipose tissue of cattle were 10 times higher than in the feed (0.002 mg/kg). Szokolay et al. (1977) examined relative accumulation of HCH isomers including y-HCH and various components in the food chain in Czechoslovakia. Lower y-HCH residues were found in tissues of animals (chickens, sheep, pigeons) feeding entirely on plant material whereas carnivores had higher concentrations. The effect of soil loading (the amount of soil deposited per unit area of skin) on the dermal bioavailability of y-HCH from contaminated soils has been examined (Duff and Kissel 1996). A static in vitro diffusion HCH 161 5. POTENTIAL FOR HUMAN EXPOSURE apparatus and abdominal skin from human cadavers were used. Results indicated that the dermal absorption of y-HCH from soil is dependent on soil loading and was estimated to be 0.45-2.35%. Dermal absorption of y-HCH increased significantly with decreases in soil loading providing monolayer or greater coverage of the skin is maintained. 5.3.2 Transformation and Degradation 5.3.2.1 Air As mentioned earlier, Y-HCH can be present in the air as vapor or sorbed to particulate matter. The widespread global distribution of HCH isomers is indicative of the persistence of y-HCH in the air. It appears that photodegradation or other degradation processes are not significant in the removal of y-HCH from air, as compared to rain-out or dry deposition. However, Hamada et al. (1981) found that y-HCH underwent photodegradation to form two isomers of tetrachlorohexene and pentachlorohexene in propanol solution when irradiated with ultraviolet light produced by a low-pressure mercury lamp. Similar transformation of y-HCH and other isomers may occur, to some extent, in the atmosphere. 5.3.2.2 Water Biodegradation is believed to be the dominant degradative process for y-HCH in aquatic systems, although hydrolysis and photolysis do occur. Sharom et al. (1980) found that <30% of the applied Y-HCH remained in unsterilized natural waters in capped bottles after 16 weeks. Biodegradation was concluded to be responsible for these results, although it was unclear to what extent hydrolysis or adsorption to the glass bottles may have contributed to the results. Zoetemann et al. (1980) estimated river, lake, and groundwater half-lives for y-HCH from degradation data in these environments to be 3-30 days, 30-300 days, and >300 days, respec- tively. In natural lake water with a pH of 9.0 and a hardness of greater than 600 mg calcium carbonate/liter, the half-life of y-HCH was estimated to be 65 hours (Ferrando et al. 1992). Lindane, applied at concentra- tions of 50 or 500 pg/L to aerobic batch cultures of microorganisms with sodium acetate as a carbon source, was initially removed by adsorption and followed by desorption onto the biomass with subsequent decompo- sition (McTernan and Pereira 1991). Approximately 56-62% of the lindane was removed from the water column in 23 days, with 26% removal by adsorption onto the biological solids produced in these batch reactors. Microbial growth, using y-HCH in the absence of sodium acetate, increased as the microorganisms HCH 162 5. POTENTIAL FOR HUMAN EXPOSURE became acclimated, the pesticide still showed toxic properties, as evidenced by a concurrent increase in microbial death rates. It has been shown that y-HCH is degraded by nitrogen-fixing blue-green algae. These algae reduce the toxic effects of y-HCH following repeated inoculations (Kar and Singh 1979b). The degradation of y-HCH became more efficient with time, thus reducing the pesticide's toxicity in cultures of nitrogen-fixing blue- green algae. Dechlorination of y-HCH to y-pentachlorocyclo-hexene was also shown to occur with fungi in aqueous suspensions (Machholz and Kujawa 1985) and in algal cultures (Sweeney 1969). Hydrolysis is not considered an important degradation process for y-HCH in aquatic environments under neutral pH conditions. However, under alkaline conditions, y-HCH is hydrolyzed fairly rapidly. Saleh et al. (1982) tested rates of hydrolysis of y-HCH in sterilized natural waters at 25°C and found that hydrolysis of y-HCH followed first-order kinetics with half-lives of 92 hours at pH 9.3, 648 hours at pH 7.8, and 771 hours at pH 7.3. Somewhat conflicting information is available on the rate of photolysis of y-HCH in water. In the study by Saleh et al. (1982) discussed above, the authors also reported y-HCH first-order photolysis half-lives of 169, 1,791, and 1,540 hours at pH 9.3, 7.3, and 7.8, respectively. The adjusted midwinter half-life of y-HCH in pure water was reported to be 1,560 hours. However, in another study, y-HCH rapidly disappeared from a sterile aqueous solution when exposed to ultraviolet radiation in atmospheric nitrogen; less than 1% of the original amount was left in solution after 30 hours of exposure (Malaiyandi et al. 1982). Photolysis of lindane in aqueous solution in the presence of polyoxomethallate and ultraviolet light has been demonstrated (Hiskia et al. 1997). 5.3.2.3 Sediment and Soil y-HCH in soil or sediment is degraded primarily by biotransformation; however, the major removal mechanism for y-HCH from soils, at least in warm climates, is the volatilization of the compound from soil surfaces. A 6-fold increase in Y-HCH volatilization from soil was seen when the temperature increased from 15°C to 45°C; flooding the soil also increased the volatilization (Samuel and Pillai 1990). Tu (1976) reported that 71 of 147 microorganisms isolated from a loamy sand soil were able to utilize a y-HCH solution as the sole carbon source. White rot fungus degraded radiolabeled y-HCH in aerobic pure culture laboratory tests. In a silt loam soil/corncob test matrix, 34.7% of the compound was degraded over a 60-day HCH 163 5. POTENTIAL FOR HUMAN EXPOSURE test period, whereas 53.5% degradation was observed in liquid cultures over a 30-day test period (Kennedy et al. 1990). The results of this study have been confirmed by more recent studies (Mougin et al. 1996; Mougin et al. 1997). The isolation of y-HCH-degrading bacteria, classified as Sphingomonas paucimobilis, from contaminated soils has been reported (Thomas et al. 1996). A Pseudomonas species has also been isolated from pretreated soil that is able to degrade y-HCH and a-HCH, but not B-HCH, within 10-20 days under both flooded (anaerobic) and unflooded (aerobic) conditions; greater degradation rates were observed under aerobic conditions (Sahu et al. 1993). However, the concentrations and persistence of y-HCH in soil are dependent on soil types. An analysis of two soil types, loamy sand (approximately 1-2% organic matter) and muck (approximately 27-56% organic matter), for y-HCH residues showed that mean residues in the loamy sand soil had decreased from 95 ppb dry weight in 1971 to below the detection limit of 10 ppb in 1989; however, in muck, residues had decreased from 426 ppb in 1971 to 168 ppb in 1989 (Szeto and Price 1991). The presence of crops on the soils also affects the persistence of HCH residues, with half-lives of 58.8 days and 83.8 days for cropped and uncropped plots, respectively. 3-HCH was the most persistent isomer with half-lives of 184 and 100 days, respectively, on cropped and uncropped plots; y-HCH was next at 107 and 62.1 days, followed by a-HCH at 54.4 days and 56.1 days, and finally, -HCH at 33.9 and 23.4 days. Only trace amounts of the isomers were found to leach below 20 cm soil depth (Singh et al. 1991). The B-HCH isomer comprised 80—100% of the total HCH residues found in soil or vegetation on land surrounding an industrial landfill in Germany 10 years after the final HCH input (Heinisch et al. 1993). Most available information suggests that y-HCH transformation is favored in biologically rich, anaerobic environments (Callahan et al. 1979; Haider 1979; Kalsch et al. 1998). In bench-scale anaerobic digestion tests designed to assess the fate of semivolatile organic pollutants in primary and secondary sludges, Y-HCH was found to undergo 98% degradation at 120 days. Sorption of the compound to the digester solids accounted for 2% of the initial feed; none of the compound was lost by volatilization. The digesters were operated at 35°C with a 30-day solids retention time (Govind et al. 1991). Similar results were seen with live activated sludge where initially reversible biosorption dominates the removal process followed by an increased aerobic biodegradation after approximately 10 hours of acclimation. The biodegradation process includes hydrolytic dechlorination with subsequent ring cleavage and finally, partial or total mineralization (Tsezos and Wang 1991b). Adaptation of sewage sludge is slow and may take 1-2 months; however, once acclimation occurs, 70-80% biodegradation of y-HCH may occur, with the percentage of degradation decreasing with increasing sludge age (Nyholm et al. 1992). Co-oxidation or reductive dechlorination are the probable degradation mechanisms (Jacobsen et al. 1991; Nyholm et al. 1992). HCH 164 5. POTENTIAL FOR HUMAN EXPOSURE Numerous diverse studies on biological degradation have shown that y-HCH was transformed to tetrachloro- hexene; tri-, tetra-, and pentachlorinated benzenes; penta- and tetra cyclohexanes; other isomers of HCH; and other related chemicals. The products varied depending on what organisms were present, what products were sought, and when the sample was analyzed (Callahan et al. 1979). Laboratory studies have demonstrated the bioisomerization of y-HCH to «-, B-, and 8-HCH but bioisomerization in the environment was considered to be nonsignificant by an investigator who conducted a field study (Waliszewski 1993). Levels of individual isomers were approximately 0.1-1.4% and 0.8-4.0% of the y-HCH concentrations at 3-31 weeks and 34-46 weeks, respectively, following y-HCH treatment of soil. An inability to control all environmental conditions in the laboratory was discussed as a possible reason for differences in results between laboratory and field studies. Abiotic transformation and degradation processes of Y-HCH in soil/sediment are not thought to be significant pathways. As discussed earlier for water, photolysis or hydrolysis are not considered important degradation pathways of y-HCH and other isomers. 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT Reliable evaluation of the potential for human exposure to hexachlorocyclohexane depends in part on the reliability of supporting analytical data from environmental samples and biological specimens. In reviewing data on hexachlorocyclohexane levels monitored or estimated in the environment, it should also be noted that the amount of chemical identified analytically is not necessarily equivalent to the amount that is bioavailable. 5.4.1 Air y-HCH was detected in ground level ambient air samples collected in College Station, Texas, in 1979-1980 at a mean concentration of 0.23 ng/m’ (range, 0.01-1.60 ng/m®) (Atlas and Giam 1988). The compound has also been detected in troposphere air samples collected over the Adirondack Mountains in New York state in 1985 at a mean concentration of 0.509 ng/m?® and over Newport News, Virginia, in 1988 at a mean concentration of 0.021 ng/m® (Knap and Binkley 1991). Air monitoring over southern Ontario, Canada, from July 1988 to July 1989 showed annual mean air concentrations of «-, B-, and y-isomers to be 0.145, 0.0018, and 0.06 ng/m® with a total HCH annual mean concentration of 0.21 ng/m® and with the greatest total HCH concentrations during the summer months (Hoff et al. 1992a). HCH 165 5. POTENTIAL FOR HUMAN EXPOSURE In a study of global distribution and atmospheric transport of chlorinated hydrocarbons in the West Pacific, Eastern Indian, and Antarctic Oceans, Tanabe et al. (1982) confirmed the widespread distribution of HCH isomers. HCH residues were detected in all 79 air and water samples collected. The concentrations ranged from 1.1 to 2.0 ng/m’ in air and from 3.1 to 7.3 ng/L in water. Other monitoring studies include the detection of y-HCH in the lower troposphere over the Southern Indian Ocean in 1986 at a mean concentration of 0.406 ng/m* (Wittinger and Ballschmiter 1990), in the lower troposphere over Bermuda in 1988 at a mean concentration of 0.012 ng/m® (Knap and Binkley 1991), and in ambient air samples collected at Axel Hieberg Island in the Canadian arctic at 0.017-0.07 ng/m® (Hargrave et al. 1988). y-HCH has also been detected in rainfall samples collected in College Station, Texas, in 1979-1980 at a weighted mean concentration of 2.81 ng/L (range, 0.30-7.8 ng/L) (Atlas and Giam 1988) and in Bermuda in 1983-1984 at a mean concentration of 0.126 ng/L (range, 0.001-0.936 ng/L) (Knap et al. 1988). In rainfall samples collected at four sites in Canada in 1984, y-HCH concentrations ranged from 0.46 to 34 ng/L (Strachan 1988). The mean concentration in rainfall samples collected at Lake Superior during the 1984 wetfall season was 3.0 ng/L, with an annual loading of 2.0 pg/m* year (Strachan 1988). These values were less than those determined in the years 1977, 1981, and 1983 (Strachan 1988). y-HCH has been detected in rain and snow water in Portland, Oregon in 1982 at mean concentrations ranging from 0.45 to 11 ng/L (Pankow et al. 1984). Rainwater collected in Hawaii in 1970-1971 had a mean y-HCH concentration of 5 ng/L, with concentrations ranging from 1 to 19 ng/L (Bevenue et al. 1972). Snow and ice samples collected at Axel Hiberg Island in the Canadian Arctic in 1986 contained y-HCH at concentrations of 0.211-0.644 ng/L and 0.186 ng/L, respectively (Hargrave et al. 1988). Rain samples collected in Germany between June 1990 and August 1991 contained y-HCH at a mean concentration of 0.208 pg/L (range, 0.020-0.833 pg/L; detection limit, 0.5 pg) in 39 of 41 samples (Scharf et al. 1992). 5.4.2 Water Surface water concentrations of y-HCH have been measured in many areas across the United States. Reported concentrations ranged from 10 to 319 parts per ton (ppt) (mean concentration of 147 ppt) in Hampton County, South Carolina (Sandhu et al. 1978), to much higher concentrations of 0.052-0.1 parts per billion (ppb) in Washington, DC, and Denver (Cole et al. 1984). The majority of the available monitoring studies were conducted in the early to mid 1970s. The most recent monitoring study was conducted in 1980-1981 in the Niagara River near its entry into Lake Ontario. In that study, y-HCH was detected in 99% of all samples at a mean concentration of 2.1 ppt (Kuntz and Warry 1983). y-HCH concentration in Lake HCH 166 5. POTENTIAL FOR HUMAN EXPOSURE Michigan tributary streams ranged from undetected to 0.15 ppb (Schacht et al. 1974). According to EPA's STORET database, y-HCH was detected in 27% of 4,505 surface water samples collected in the United States at a median concentration of 0.020 pg/L (Staples et al. 1985). y-HCH concentrations in groundwater samples were greatest in the West South Central region (Phillips and Birchard 1991). The compound was also found in water samples collected in Lake Ontario in 1983 at 0.806-1.85 ng/L concentration (Biberhofer and Stevens 1987). y-HCH has been detected in more than 10% of urban stormwater runoff samples in two U.S. cities at concentrations between 0.052 and 0.1 ppt (Cole et al. 1984). In urban runoff samples collected in the Canadian Great Lakes Basin, y-HCH was detected at mean concentrations of 0.0065 pg/L and 0.0035 mg/kg in the aqueous and sediment portions, respectively; the mean annual loading of the compound in runoff in the basin was reported to be 4.1 kg/year (Marsalek and Schroeter 1988). y-HCH has been detected in groundwater at a median concentration of 16 ppt in Chesterfield County, South Carolina, and 163 ppt in Hampton, South Carolina (Sandhu et al. 1978). A concentration range of undetected to 0.9 ppt was reported for groundwater samples from New Jersey. y-HCH has also been detected in drinking water from Cincinnati, Ohio (Keith et al. 1976); Hampton, South Carolina (Sandhu et al. 1978); and Oahu, Hawaii (Bevenue et al. 1972), at mean concentrations of 0.01 ppt, 10 ppt, and 0.2 ppt, respectively. In a study of a-HCH and y-HCH in Saskatchewan, Canada, these HCH isomers were not detected frequently in surface waters that originate from ground water (Donald et al. 1997). 5.4.3 Sediment and Soil According to EPA's STORET database, y-HCH was detected in 0.5% of 596 sediment samples collected throughout the United States at a median concentration of <2.0 pg/kg (Staples et al. 1985). According to data collected in STORET between 1978 and 1987, y-HCH was found in the greatest concentration in sediment from the West North Central census region of the United States, followed by the Mountain region and the East South Central region (Phillips and Birchard 1991). y-HCH was detected in 33% of suspended sediment samples collected from the Niagara River; the average concentration was 2 ppb (Kuntz and Warry 1983). The average y-HCH concentration in settling particulates from Lake Ontario was 2.4 ppb in 1982 (Oliver and Charlton 1984). Sediment samples from Lake St. Francis on the St. Lawrence River contained a mean total HCH concentration of 0.6 ng/g dry weight (range, <0.1-2.0 ng/g), suggesting that deposition of contaminated materials from Lake Ontario was of less importance than local inputs of HCH (Sloterdijk HCH 167 5. POTENTIAL FOR HUMAN EXPOSURE 1991). y-HCH concentrations in creek sediments collected in 1976 near the James River in Virginia ranged from 7.3 to 8.5 ppb (Saleh et al. 1978). y-HCH was included in the analytes monitored in the National Oceanic and Atmospheric Administration's (NOAA) Status and Trends Mussel Watch Program conducted in the Gulf of Mexico. The compound was detected in 19% of the sediment samples collected in 1987 at a mean concentration of 0.07 ng/g (median, <0.02 ng/g; range, <0.02-1.74 ng/g) (Sericano et al 1990). Sediment samples collected around the Great Lakes in May 1989, contained y-HCH concentrations ranging from below the detection limit (0.10 pg/kg) to 0.99 pg/kg (wet weight) (Verbrugge et al. 1991). Thirty-three sediment samples from 11 impoundments along the Indian River Lagoon in Florida contained y-HCH at concentrations ranging from 34.4 ng/g in the top layer of sediment at one impoundment to 9.4 ng/g in the bottom layer at the same site (Wang et al. 1992). The pesticide lindane had been used for mosquito control in the area from the late 1950s to the mid 1960s. Interstitial water samples from the impoundment sites did not contain detectable levels of the pesticide. 5.4.4 Other Environmental Media y-HCH residues were detected in fat samples of domestic farm animals collected in Ontario, Canada, in 1986-1988. Mean concentrations in fat from chickens, turkeys, beef, lamb, and pork ranged from 0.012 to 0.032 mg/kg; the mean concentration in hen eggs was 0.008 mg/kg (Frank et al. 1990b). Residues of y-HCH on tomatoes decreased by 23.9%, 15 days after application of the pesticide (from 195.6 ng/kg to 148.8 ng/kg). Processing the tomatoes (e.g., pureeing, making tomato juice) reduced the residue levels by 100% after the waiting period; however, washing the tomatoes reduced the residues by up to 55.9% (Bessar et al. 1991). A pesticide residue screening program carried out by the H.E.B. Food Stores of San Antonio between 1989 and 1991 detected y-HCH in 4 of 429 onion samples (detection limit, 0.02 ppm); however, none of the positive samples exceeded the action level for this commodity (Schattenberg and Hsu 1992). As part of NOAA's Status and Trends Mussel Watch Program conducted in the Gulf of Mexico, y-HCH was detected in 80% of the oyster samples collected in 1987 at a mean concentration of 1.74 ng/g (median, 1.20 ng/g; range, <0.25-9.06 ng/g) (Sericano et al. 1990). Samples taken in 1992 from Mexico's Palizada River, located in a major agricultural area with substantial pesticide use, contained an average y-HCH concentration of 0.08 ng/g in shrimp but no detectable levels in oysters or mussels (Gold-Bouchot et al. 1995). Combined concentrations of other HCH isomers were found to be 1.18 ng/g in shrimp, 1.04-1.97 ng/g in oysters, and HCH 168 5. POTENTIAL FOR HUMAN EXPOSURE 1.68 ng/g in mussels. Schmitt et al. (1985) reported the results of a monitoring study of fish tissues from 107 freshwater stations in the United States. A decline in tissue occurrence of detectable «- and y-HCH residues was observed from 1976 to 1981. During 1980-1981, whole body residues of y-HCH exceeded 0.01 ppb at only one station, where levels were 0.02-0.03 ppb. Tissue concentrations of a-HCH were higher than y-HCH. The highest concentrations for a-HCH were 0.03—0.04 ppb and were found in fish from the southwestern and midwestern United States. An analysis of fish from the Upper Steele Bayou in Mississippi in 1988 indicated that 3-HCH concentrations ranged from undetected to 0.02 mg/kg wet weight in fish; no B-HCH was detected in snakes or sediments taken from the same area (Ford and Hill 1991). Atlantic cod taken from relatively isolated stock in the southern Gulf of St. Lawrence showed declining tissue concentrations of a-HCH between 1977 (1.865 pg/kg) and 1985 (1.792 pg/kg). An analysis of pesticide residues in green coffee and after roasting indicated that technical-grade HCH was found in green coffee at concentrations ranging from <0.005 ppm to 0.204 ppm. However, storage and roasting reduced the pesticide residues by 60-67% and up to 98%, respectively, with darker roasting resulting in the greatest reduction (McCarthy et al. 1992). 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE Human exposures to y-HCH can result from the ingestion of plants, animals, animal products, milk, and water containing the pesticide. Farm animals may be exposed to the compound through feed, air, or water or cutaneous application for protection from ectoparasites. Lipophilic pesticides such as y-HCH accumulate in adipose tissue. Clark et al. (1974) found that y-HCH levels in the adipose tissue of cattle were 10 times higher than in the feed (0.002 mg/kg). An analysis of data from 238 families in Missouri between June 1989 and March 1990, indicated that 9.2% of the families reported using Kwell shampoo (contains y-HCH) for lice control on children (Davis et al. 1992). The most likely route of nonmedicinal human exposure to y-HCH is ingestion of food containing the pesticide. A smaller degree of exposure may result from ingestion of drinking water containing y-HCH. For example, Y-HCH was detected in 6% of the foods collected in eight market basket surveys from different regions of the United States during the period of April 1982 to April 1984 (Gunderson 1988). Foods representative of eight infant and adult population groups were prepared for consumption prior to analysis in a revision to FDA's Total Diet Studies methodology. The estimated mean daily intakes (ng/kg body weight/day) of y-HCH for these groups in 1982-1984 were as follows: (1) 6—11-month-old infants, 1.9; HCH 169 5. POTENTIAL FOR HUMAN EXPOSURE (2) 2-year-old toddlers, 7.9; (3) 14-16-year-old females, 3.1; (4) 14—16-year-old males, 3.4; (5) 25-30-year-old females, 2.0; (6) 25-30-year-old males, 2.5; (7) 60-65-year-old females, 1.6; and (8) 60-65-year-old males, 1.8. y-HCH intakes (ng/kg body weight/day) for three of these groups in 1988 were estimated in the FDA's Total Diet Analyses to be as follows: (1) 6—11-month-old infants, 0.8; (2) 14-16-year-old males, 1.4; and (3) 60-65-year-old females, 0.9 (FDA 1989b). HCH isomers have been detected in the following feed types formulated for infants and toddlers: whole milk and other dairy products; meat, fish, and poultry; oils and fats; vegetables; and sugars and adjuncts (Gartrell et al. 1986a). HCH isomers were also detected in adult diet foodstuffs, including dairy products; meat, fish, and poultry; garden fruits; oils and fats; leafy and root vegetables; and sugar and adjuncts (Gartrell et al. 1986b). Daily intake values of HCH isomers in adult diets in 1981-1982 were reported to be 0.010 pg/kg/day for total HCH; 0.008 pg/kg/day for a-HCH; <0.001 pg/kg/day for f-HCH and 8-HCH; and 0.002 pg/kg/day for y-HCH. In the Total Diet Study conducted by FDA in 1990 on 936 food items, Y-HCH was detected in 23 items, while ¢-HCH and B-HCH (combined) were detected in 11 items. Information on the amount of levels found were not provided (Yess 1991). The average concentration of lindane in 234 ready-to-eat foods was 0.0012 pg/g (KAN-DO Office and Pesticides Team 1995). Studies in which soils containing 10 ppm radiolabeled y-HCH were added to human skin samples at a quantity that exceeded complete coverage (5 mg soil / cm? skin) demonstrated mean y-HCH absorptions of 1.04% from sandy soils and 1.64% from silt soils (Duff and Kissel 1996). However, data from soil absorption studies can vary due to factors such as the amount of soil added to skin, the exposure time, and possible evaporation of the contaminant. The results of biomonitoring studies can be used as indicators of human exposures to HCH. The National Human Adipose Tissue Survey (NHATS) conducted in 1982 showed that B-HCH (the most prevalent HCH isomer in fatty tissue) was detected in 87% of 46 composite samples at <19-570 ng/g (ppb) concentrations (Stanley 1986). It was detected most often in postmortem samples collected from individuals from the southern United States. In another survey conducted in 1970-1975, B-HCH was detected in more than 90% of the postmortem human adipose tissue samples at an average level of 300 ppb (Kutz et al. 1979). Ina review of the NHATS data available from 1970 to 1983, Mack and Mohadjer (1985) reported that the estimated 1983 national median level of B-HCH was 80 ppb, in comparison to the historic level of 140 ppb. The median level has decreased over time, but the compound has continued to be detected in nearly 100% of the population surveyed. Median levels are highest in the South census region and tend to increase with age HCH 170 5. POTENTIAL FOR HUMAN EXPOSURE but have not been found to differ across the sexes or racial groups. A further analysis of the NHATS data indicated that average B-HCH concentrations in fat had decreased from 0.45 ppm in 1970 to approximately 0.16 ppm since 1981 (Kutz et al. 1991). A comparison of the levels of a-HCH and B-HCH in the whole blood and biopsy fat of 25 patients showed median levels of 0.04 ng/g (maximum, <0.04 ng/g) and 0.13 ng/g (maximum, 2.60 ng/g) for the blood and 1.1 ng/g (maximum, 9.6 ng/g) and 18.0 ng/g (maximum, 748.6 ng/g) for the fat tissue, respectively (Mes 1992). A further comparison of B-HCH levels in breastmilk and adipose tissue samples was made for populations living near the Great Lakes (Canada only) and in other Canadian regions. Mean B-HCH levels in breast milk (0.6 ng/g) and adipose tissue (23.4 ng/g) were lower near the Great Lakes than in other parts of Canada (0.8 ng/g and 30.8 ng/g, respectively) (Mes and Malcolm 1992). Levels of HCHs in the adipose tissue of Japanese males increased from the late 1940s to 1966, coinciding with an increased annual production of HCH (Loganathan et al. 1993). Levels have been dropping since HCHs were banned in 1971, from a maximum level of 28 ug/g to present levels of less than 1 pg/g. Since 1974, only the more persistent [B-HCH isomer has been found (Loganathan et al. 1993). y-HCH was one of the most frequently detected pesticides in the blood of Virginia residents, although the number of individuals sampled was not identified (Griffith and Blanke 1975). y-HCH blood concentrations were the highest in residents of the middle age group (41-60 years). Some of the frequency of y-HCH occurrence in the state was attributed to its common use in commercial vaporizers and its presence in cigarette smoke (Griffith and Blanke 1975). The National Health and Nutrition Examination Survey (NHANES) analyzed blood and urine specimens for the presence of HCH isomers. B-HCH was detected in approximately 13.9% of the U.S. population (12-74 years) in the Northeast, Midwest, and South. The median level for the 91% quantifiable positive results was 1.7 ppb (Murphy and Harvey 1985). Factors such as age, dietary habits, and residence can influence the body burden of y-HCH in exposed individuals. In one study, it was shown that women between the ages of 26 and 34 years who lived in a rural area of India and were nonvegetarians tended to show higher body levels of Y-HCH than other Indian women who lived in an urban area or who were vegetarians (Saxena et al. 1981a). The higher levels of y-HCH in women at an older child-bearing age suggest that a longer life span may cause a greater accumulation of pesticide in the body. Higher pesticide levels are found in mutton, eggs, and chicken which are common in nonvegetarian meals; therefore, there tends to be a higher level of y-HCH in the bodies of nonvegetarians. Individuals living in rural areas are more likely to be exposed to y-HCH because agricultural fields are the HCH 171 5. POTENTIAL FOR HUMAN EXPOSURE primary site of application of pesticides. In addition, studies indicate that y-HCH is also present in breast- milk at an average level of 0.006 ppm in Alberta, Canada (Currie et al. 1979). In a study of 50 donors of breastmilk in Oahu, Hawaii, Takahashi et al. (1981) demonstrated HCH in 82% of the samples at a mean level of 81 ppb within a range of 0—480 ppb, expressed in terms of extractable lipid. A study conducted in Colorado indicated, in general, that no quantitative relationships were demonstrated between pesticide levels in household dust and pesticide levels in blood. However, Y-HCH levels in blood sera in a pesticide formulator (16.8 ppb) and his wife (5 ppb) were found to be elevated in a household in which dust levels measured 5.85 ppb (Starr et al. 1974). It is possible that the y-HCH found in the wife's blood and in the household came from the clothes and person of the pesticide formulator. The Nonoccupational Pesticide Exposure Study (NOPES) conducted by EPA was based on the Total Exposure Assessment Methodology (TEAM) approach to exposure estimation. NOPES was designed to provide estimates of nonoccupational exposure to 32 household pesticides in the United States. Samples were collected at two locations: (1) Jacksonville, Florida, an area representative of high pesticide usage; and (2) Springfield/Chicopee, Massachusetts, an area of low-to-moderate pesticide usage. Detectable levels of y-HCH were found in the personal air samples of 32-70% of the Jacksonville sample population; the range of mean concentrations in the air samples was 7-22 ng/m®. For the Springfield population, detectable levels of y-HCH were found in personal air samples collected from 8% to 10% of the population, with mean concentrations of 0.7-5 ng/m? (EPA 1990c). A study on occupational pesticide exposure of commercial seed-treating applicators was conducted in Montana (Grey et al. 1983). No exposure was detectable on the chest and arm pads, but y-HCH was detected on the hands and on the respirator pads. Workers involved with y-HCH application complained of nasal irritation if they did not wear a respirator or mask. The «-, B-, Y-, and 8-isomers of HCH have been detected in the blood serum and adipose tissue of individuals occupationally exposed to HCH in pesticide formulation. Serum levels of <0.5 ppb-1 ppm «-HCH, <0.9 ppb-0.72 ppm B-HCH, <0.7 ppb—0.17 ppm y-HCH, and 0.002-0.16 ppm 8-HCH have been detected in exposed workers (Baumann et al. 1980; Kashyap 1986; Morgan and Lin 1978; Nigam et al. 1986). Mean adipose tissue levels of 5.8 mg «-HCH/kg, 45.6 mg B-HCH/kg, and 3.1 mg y-HCH/kg have also been reported in exposed workers (Baumann et al. 1980). In general, accidental or intentional ingestion would lead to the highest exposures. Worker exposure constitutes the next highest exposure population although worker exposure is decreasing in both the number HCH 172 5. POTENTIAL FOR HUMAN EXPOSURE of workers exposed and the levels of exposure. Lastly, the general population receives the lowest levels, which occur mainly from ingestion of foods and water with y-HCH residues. Living near a waste disposal site contaminated with y-HCH will also increase the likelihood of exposure. 5.6 EXPOSURES OF CHILDREN This section focuses on exposures from conception to maturity at 18 years in humans and briefly considers potential pre-conception exposure to germ cells. Differences from adults in susceptibility to hazardous substances are discussed in 2.6 Children's Susceptibility. Children are not small adults. A child's exposure may differ from an adult's exposure in many ways. Children drink more fluids, eat more food, and breathe more air per kilogram of body weight, and have a larger skin surface in proportion to their body volume. A child's diet often differs from that of adults. The developing human's source of nutrition changes with age: from placental nourishment to breast milk or formula to the diet of older children who eat more of certain types of foods than adults. A child's behavior and lifestyle also influence exposure. Children crawl on the floor, they put things in their mouths, they may ingest inappropriate things such as dirt or paint chips, they spend more time outdoors. Children also are closer to the ground, and they do not have the judgement of adults in avoiding hazards (NRC 1993). Prenatal exposure of children to HCH can occur. 3- HCH and y-HCH have been found in samples of human maternal adipose tissue, maternal blood, cord blood, and breastmilk in women who were exposed to unknown levels of various organochlorine pesticides in Kenya (Kanja et al. 1992). Placental transfer of HCH in humans has been well documented (Saxena et al. 1981). Higher levels of total HCH and lindane were found in specimens of maternal blood, placenta, and umbilical-cord blood from women experiencing premature labor, spontaneous abortions, and stillbirths when compared to matched controls (Saxena et al. 1980; Saxena and Siddiqui 1983). Saxena et al. (1980) reported HCH levels of 69.3-550.4 ppb and y-HCH levels of 30.8-113.6 ppb in the blood of women in India who had experienced spontaneous abortions or premature labor compared with blood HCH levels of 22.2-85.5 ppb and y-HCH levels of 7.1-32.5 ppb in women who had undergone full-term pregnancy. Serum levels of a number of other pesticides including aldrin, DDE, DDT, and DDD were also found to be higher in cases of premature labor and spontaneous abortions. It was, therefore, not possible to establish a causal relationship between the serum HCH levels and these adverse effects. However, HCH has been shown to accumulate in amniotic fluid, placenta, and fetal tissues after treatment of pregnant mice (Srivastava and Raizada 1993) and can be related to fetolethality. HCH 173 5. POTENTIAL FOR HUMAN EXPOSURE HCH is commonly detected in low concentrations (0.015 mg/kg fat) in the breastmilk of women exposed to HCH in the environment (Fytianos et al. 1985). Levels of HCH isomers in breastmilk have been reported, particularly in developing countries that still use HCH as a pesticide. Studies indicate the y-HCH is present in breastmilk at an average level of 6 ppb in Alberta, Canada (Currie et al. 1979). In a study of 50 donors of breastmilk in Oahu, Hawaii, Takahashi et al. (1981) demonstrated HCH in 82% of the samples at a mean level of 81 ppb within a range of 0-480 ppb, expressed in terms of extractable lipids. Breastmilk concentra- tions of «-, B -, y-, and 8-HCH were determined from samples obtained from two areas of India that were under malaria control (Dua et al. 1997). The mean concentrations of «-, y-, B-, and 8-HCH in one area were 0.002, 0.002, 0.022, and 0.001 (mg/kg) , while in the second area concentrations were 0.003, 0.006, 0.078, and 0.002, respectively. Another study performed in a different region of India also demonstrated the presence of HCH isomers in breastmilk (Nair et al. 1996). Mean breastmilk concentrations of «-, B-, and y-HCH were 0.045, 0.198 and 0.084 (mg/L), respectively. 8-HCH was not detected in the breastmilk samples. In a study designed to quantify the levels of organochlorine residues in the breastmilk of mothers in Uganda, Africa, the milk fat concentrations of «- HCH, B-HCH and y-HCH ranged from 0.006-0.46, 0.005-0.25 and 0.01-0.87 mg/kg, respectively (Ejobi et al. 1996). The concentration of f-HCH in breastmilk samples from 3 regions in the Czech Republic ranged from 71 to 80 ng/g (Schoular et al. 1996). A comparison of B-HCH levels in breastmilk and adipose tissue samples was made for populations living near the Great Lakes (Canada only) and the rest of Canada. Mean 3-HCH levels in breastmilk (0.6 ng/g) and adipose tissue (23.4 ng/g) were lower near the Great Lakes than in other parts of Canada (0.8 ng/g and 30.8 ng/g, respectively) (Mes and Malcolm 1992). As mentioned previously, exposures to HCH can result from the ingestion of plants, animals, animal products, milk, and water containing the pesticide. A smaller degree of exposure may result from ingestion of drinking water containing HCH. There is also the possibility of exposure to y-HCH from medical usage (e.g., shampoos for control of lice and lotion for treatment of scabies). Numerous studies have documented the effects in humans overexposed to y-HCH through misuse or accidental ingestion of products used to treat head lice (Davies et al. 1983; Jaeger et al. 1984; Lee and Groth 1977). Although some controversy exists as to whether y-HCH is a safe therapeutic agent when used in accordance with the manufacturers’ guidelines, it is clear that most exposures occur through misuse of products (Rasmussen 1980, 1981, 1987). Besides medical usage, children are likely to be exposed to HCH from the ingestion of food containing the pesticide. Based on FDA's Total Diet Analyses, Y-HCH intakes (body weight/day) are 0.8 pg/kg for 6-11-month-old infants, 7.9 pg/kg for 2-year-old toddlers, and 1.4 and 3.1 pg/kg for 14-16-year-old males and females, respectively (FDA 1989b). HCH isomers have been detected in the following food types formulated for HCH 174 5. POTENTIAL FOR HUMAN EXPOSURE infants and toddlers: whole milk and other dairy products; meat, fish, and poultry; oils and fats; vegetables; and sugars and adjuncts (Gartrell et al. 1986a). HCH isomers have also been detected in cow’s milk in those countries that still use the chemical as a pesticide. In a study performed in Uganda, Africa, the concentrations of ¢- HCH, B-HCH and lindane in cow’s milk were 0.002-0.014, 0.003-0.018, and 0.006-0.036 mg/kg milkfat, respectively (Ejobi et al. 1996). Mean levels of HCH isomers analyzed in cow’s milk samples from 2 separate areas in India were 0.0045 and 0.012 mg/kg a-HCH, 0.002 and 0.015 mg/kg y-HCH, 0.0105 and 0.028 mg/kg B-HCH and 0.002 and 0.003 mg/kg 8-HCH (Dua et al. 1997). A monitoring study of 192 samples of cow’s milk from Mexico revealed 0.001-0.201 mg/kg e.-HCH, 0.008-0.253 mg/kg B-HCH and 0.002-0.187 mg/kg y-HCH (Waliszewski et al. 1996). HCH isomers have also been detected in buttermilk and butter prepared from cow’s milk contaminated with these isomers (Sreenivas et al. 1983). HCH is bioavailable from soil and can be absorbed both orally and dermally (Duff and Kissel 1996). y-HCH exhibited mean 24-hour dermal absorption values from 0.45 to 2.35% varying with different soil types and soil loadings of 1, 5, and 10 mg/cm®. Some children intentionally eat dirt and most inadvertently ingest dirt by putting fingers or other objects in their mouths while playing outdoors. Thus, they are more likely than adults to be exposed to HCH via ingestion or direct contact of soil contaminated with HCH. Children may also be exposed to a significant amount of HCH from household dust; parents’ work clothes, skin, hair, tools, and other objects removed from the workplace are a likely source of exposure to children. An analysis of environmental contribution to pesticide body burden indicated household dust can be a major source of environmental HCH exposure (Starr et al. 1974), as indicated by elevated y-HCH levels in blood sera in a pesticide formulator (16.8 ppb) and his wife (5 ppb) in a household in which dust levels measured 5.85 ppb. It is possible that the y-HCH found in the wife’s blood and in the household came from the clothes and person of the pesticide formulator. y-HCH is a restricted use pesticide. Its registered use around the home is limited to structural treatment, dog shampoo, and dog dust for fleas and ticks. Children can be exposed at home because of its potential use on pets and improper or illegal pesticide application. Analyses of blood samples of 186 children living in an area contaminated with HCH, which was used as an insecticide in Brazil, revealed the presence of «-, y-, and B-, HCH isomers (Brilhante and Oliveira 1996). HCH 175 5. POTENTIAL FOR HUMAN EXPOSURE The authors reported that 24% of the children showed 0.89 ppb average concentrations of 3-HCH in the blood. «- and y-isomers were detected in only 3 and 1 children, respectively, at a mean concentration of 1.8 ppb and 0.95 ppb, respectively. 5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES The populations with the most potential for chronic exposure to HCH are workers who either manufacture or routinely use these isomers. Exposure of the general population to Y-HCH tends to be low because federal regulations limiting its use have taken effect. However, y-HCH is available in some consumer products (e.g., shampoos, food) and medications, and the possibility of exposure from these products is a source of concern. Individuals living near hazardous waste sites contaminated with y-HCH may also be exposed to the compound. Numerous studies have documented the effects in humans overexposed to y-HCH through misuse or accidental ingestion of products used to treat scabies and head lice (Davies et al. 1983; Jaeger et al. 1984; Lee and Groth 1977). Although some controversy exists as to whether y-HCH is a safe therapeutic agent when used in accordance with the manufacturers’ guidelines, it is clear that most exposures occur through misuse of products (Rasmussen 1980, 1981, 1987). In addition, other studies have described cases in which patients have shown neurotoxic effects following excess exposure or ingestion of pesticides (Harris et al. 1969; Hayes 1976; West 1967). Exposure to the other isomers of HCH (as in the technical-grade HCH) is limited in the United States as a result of regulations restricting their use. However, persons traveling or living in areas where the use of HCH is legal (e.g., South America, Eastern Europe, and Asia) should be wary of exposure to isomers of HCH through food and drinking water sources (Krauthacker et al. 1986; Radomski et al. 1971a; Saxena et al. 1980, 1981a, 1981Db). 5.8 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 hexachlorocyclohexane 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 HCH 176 5. POTENTIAL FOR HUMAN EXPOSURE designed to determine the health effects (and techniques for developing methods to determine such health effects) of hexachlorocyclohexane. 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. 5.8.1 Identification of Data Needs Physical and Chemical Properties. Sufficient information is available on the physical and chemical properties of Y-HCH and the other HCH isomers (see Chapter 3) to permit an assessment of the environmental fate of these compounds. No additional studies are required at this time. Production, Import/Export, Use, Release, and Disposal. Production methods for HCH are well described in the literature (IARC 1979). y-HCH is used as an insecticide and as a therapeutic scabicide and pediculicide for treatment of ectoparasite in humans and animals (Budvari et al. 1989). The production and use of y-HCH as a pesticide has been restricted in the United States, and the use of technical-grade HCH was voluntarily canceled in 1976 (EPA 1978). There is no current information on the import of y-HCH, and there is no information on the import of other HCH isomers. This information will be helpful for estimating human exposure particularly of populations living near industrial and hazardous waste sites. Release of y-HCH to environmental media has been primarily from its use as a pesticide. Wastes containing y-HCH must be contained, incinerated, and disposed of in landfills (EPA 1991g). Carbon absorption or flocculation are useful treatment methods for the removal of HCH from aqueous effluent streams, except when methanol is also contained in the effluents (HSDB 1993). Disposal methods are currently subject to revision under EPA guidance. 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 1994, became available in HCH 177 5. POTENTIAL FOR HUMAN EXPOSURE May of 1996. This database will be updated yearly and should provide a list of industrial production facilities and emissions. Environmental Fate. y-HCH released to the environment partitions to the atmosphere, soils, and sediments (Atkins and Eggleton 1971; Lewis and Lee 1976; Melancon et al. 1986; Saleh et al. 1982; Stanley et al. 1971). The compound is transported in the atmosphere, surface water, and groundwater (Mackay and Leinonen 1975; Nordmeyer et al. 1992; Stanley et al. 1971). y-HCH is transformed via biodegradation in soils and surface waters (Govind et al. 1991; Kar and Singh 1979b; Kennedy et al. 1990; Macholz and Kujawa 1985; Sharom et al. 1980; Tu 1976). Available data indicate that photodegradation or other degradation processes are not significant processes in the removal of y-HCH from air, as compared to rain- out and dry deposition (Atkins and Eggleton 1971; Hamada et al. 1981). Additional information on the transport, transformation, and persistence of the compound in soils and groundwater, particularly at hazardous waste sites, would be useful in identifying the most important routes of human exposure to y-HCH. There is information regarding the half-lives for y-HCH in water (3-30 days, 30-300 days, and >300 days for river, lake, and groundwater, respectively [Zoetemann et al. 1980]), but not in air or soil. There is no information about the half-lives for the other HCH isomers in any environmental media. Environmental fate data on HCH isomers other than y-HCH are scant. Additional data on the half-lives for y-HCH in air and soil, and further environmental fate data for the other HCH isomers, would be helpful. These data could be used to estimate exposure to HCH under various conditions of environmental release for purposes of planning and conducting meaningful follow-up exposure and health studies. Bioavailability from Environmental Media. Evidence of absorption following inhalation and dermal exposure is available for workers involved in the formulation of pesticide products containing HCH isomers and in the use of y-HCH (Baumann et al. 1980; Grey et al. 1983). Dietary intake is a major route of expo- sure for the general population (Gunderson 1988). Additional information on the absorption of y-HCH, following ingestion of foods containing residues of the compound, would be helpful. As mentioned in Section 5.3.1, Duff and Kissel (1996) showed that bioavailability of y-HCH via dermal exposure depended upon levels of soil loading. Dermal absorption ranged from 0.45 to 2.35%. For populations living in the vicinity of hazardous waste sites, additional information on absorption following dermal contact with, or ingestion of, contaminated soil would also be helpful, given the expected strong sorption of the compound to soil particulates. Besides y-HCH, other isomers of HCH have been detected in adult diet foodstuffs (Gartrell et al. 1986b). Additional information on the absorption of these other HCH isomers following ingestion of foods containing residues of these isomers would be helpful. Because of the potential of HCH to contaminate HCH 178 5. POTENTIAL FOR HUMAN EXPOSURE air, drinking water, and soil, further information on the bioavailability of the HCH isomers from these environmental media would be useful for assessing possible health concerns for humans. Food Chain Bioaccumulation. y-HCH in surface waters and soils is taken up and bioconcentrated by terrestrial and aquatic organisms (Just et al. 1990; Matsumura and Benezet 1973; Ramamoorthy 1985; Verma and Pillai 1991; Viswanathan et al. 1988). y-HCH is bioconcentrated to high levels following uptake from surface waters by a number of aquatic organisms (Matsumura and Benezet 1973; Ramamoorthy 1985; Schimmel et al. 1977). Uptake from soils and bioconcentration by plants and terrestrial organisms appears to be limited (Verma and Pillai 1991; Wild and Jones 1992). Limited information suggests that the compound is not biomagnified in terrestrial food chains because of its metabolism by terrestrial organisms (Schmitt et al. 1985). Bioconcentration values in zebra-fish for «-HCH and B-HCH are reported (Butte et al. 1991). Among the HCH isomers, 3-HCH accumulates the most in the food chain (Szokolay 1977). Additional information on the potential bioaccumulation of «-, B-, and 8-HCH isomers in terrestrial and aquatic food chains would be helpful. Exposure Levels in Environmental Media. Environmental monitoring data are available predominantly for y-HCH in air (Atlas and Giam 1988; Knap and Binkley 1991), surface water (Sandhu et al. 1978; Staples et al. 1985), groundwater (Sandhu et al. 1978), soil (Carey et al. 1978; Staples et al. 1985), and foods (FDA 1989b; Gunderson 1988; Kutz et al. 1976). y-HCH has been detected in air, surface water and groundwater, and sediment and soil. The widespread distribution of HCH isomers in air has been confirmed (Tanabe et al. 1982). Although the use of y-HCH has been restricted and the use of technical-grade HCH was voluntarily canceled in 1976 (EPA 1978), it is not likely that new environmental measurements will show considerably lower levels of y-HCH in these media since there are remaining impacts from importing and processing HCH. Therefore, additional information on the levels of y-HCH and a-, B-, and 8-HCH isomers is needed to assess the current potential human exposure to the chemicals from environmental media, particularly near hazardous waste sites. Reliable monitoring data for the levels of hexachlorocyclohexane in contaminated media at hazardous waste sites are needed so that the information obtained on levels of hexachlorocyclohexane in the environment can be used in combination with the known body burdens of hexachlorocyclohexane to assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. HCH 179 5. POTENTIAL FOR HUMAN EXPOSURE Exposure Levels in Humans. HCH can be detected in the blood (Baumann et al. 1980; Griffith and Blanke 1975; Murphy and Harvey 1985), urine (Murphy and Harvey 1985), adipose tissue (Baumann et al. 1980; Stanley 1986), breastmilk (Takahasi et al. 1981), and semen (Stachel et al. 1989) of exposed individuals. Most of the data on the body burden of HCH are from adipose tissue and blood serum analyses conducted postmortem or on occupationally exposed individuals. The disadvantage of using postmortem blood is that the HCH concentration may change after death. The occupational studies often do not report environmental levels; therefore, it is not possible to correlate body HCH levels with environmental levels. The results of the National Human Adipose Tissue Survey (NHATS) conducted in 1982 showed that 3-HCH, the most prevalent isomer in fatty tissue, was detected most often in postmortem samples collected from individuals from the southern U.S. Additional information is needed on exposure to y-HCH and «-, B-, and 0-HCH isomers in populations living in the vicinity of hazardous waste sites. This information is necessary for assessing the need to conduct health studies on these populations. Exposures of Children. The different pathways for exposure of children to HCH have been discussed in Section 5.6. Prenatal exposure of children to HCH has been demonstrated; it is well documented that placental transfer of HCH occurs, and HCH levels have been measured in placenta and cord blood in humans (Saxena et al. 1981; Nair 1996) and in amniotic fluid and fetal tissues in mice (Srivastava and Raijada 1993). Infants may also be exposed via ingestion of breastmilk and cow’s milk. Exposure may also occur via ingestion of water containing HCH, food and animal products, and possibly through incidental ingestion of household dust. It has been demonstrated that household dust can be an important source of environmental HCH (Starr et al. 1974). This occurs especially if the parents work in facilities that process or use HCH and can bring home residues of HCH via their work clothes, skin, hair, tools, or other objects removed from the workplace. A take-home exposure study on pesticide applicators might be useful if such occupational exposure settings occur. Limited studies conducted on exposure of infants and children to y-HCH from application of 1% y-HCH lotion as scabicide indicated dermal absorption occurred (Ginsberg et al. 1977). Adipose tissue is a major storage depot for HCH. Although data from a national human adipose tissue survey exist (Stanley 1984), no quantitative data are currently available on the body burden of HCH in children. These studies are needed because unique exposure pathways for children exist, and children may be different from adults in their weight-adjusted intake of HCH because of their higher surface area to volume ratio and higher ingestion rate of household dust. HCH 180 5. POTENTIAL FOR HUMAN EXPOSURE Exposure Registries. No exposure registries for hexachlorocyclohexane 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 to be established. The information that is amassed in the National Exposure Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be related to exposure to this substance. 5.8.2 Ongoing Studies As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental Health Laboratory Sciences Division of the National Center for Environmental Health, Centers for Disease Control and Prevention, will be analyzing human blood samples for hexachlorocyclohexane and other volatile organic compounds. These data will give an indication of the frequency of occurrence and background levels of these compounds in the general population. Biodegradability of HCH isomers and engineering applicability are being investigated in the Netherlands. Also, remedial investigations and feasibility studies at the NPL sites known to have y-HCH contamination should add to the available database for environmental levels, environmental fate, and human exposure. Ongoing studies concerning the environmental fate of HCH isomers have been identified as follows: C.A. Reddy (Michigan State University) is currently examining a lignin-degrading filamentous fungus (Phanerochaete chrysosporium) to isolate, characterize, and develop expression/secretion systems for ligninases. These ligninases play a key role in lignin degradation and are also believed to be involved in the detoxification of y-HCH. Similar studies on the biodegradation of y-HCH by the white rot fungus are also being conducted by S.D. Aust at Utah State University. W.F. Spencer (Agricultural Research Service, Riverside, California) is conducting studies in the laboratory and field to quantify the physical, chemical, and biological parameters related to rates of volatilization, degradation, and transport of y-HCH and other chemicals into the atmosphere. HCH 181 5. POTENTIAL FOR HUMAN EXPOSURE The effects of y-HCH and 14 other insecticides on transformations of urea nitrogen (urea hydrolysis and nitrification) in 2 coarse-textured and 2 fine-textured soils are currently being examined by J.M. Brenner (Iowa State University). M. Speedie and B. Pogell (University of Maryland) are investigating the metabolism of y-HCH by streptomycetes. They have found degradative detoxification of 80% of y-HCH added within 5 days; 60% is degraded by the end of the first 24 hours. The investigators assume that degradation occurs via a lignin peroxidase-mediated reaction. R.W. Coble of the U.S. Geological Survey is conducting a study of the hydrology of an area containing six pesticide disposal sites near Aberdeen, Maryland. y-HCH has been identified in water samples collected from several municipal wells in the area. HCH 183 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 hexachlorocyclohexane, its metabolites, and other biomarkers of exposure and effect to hexachlorocyclohexane. 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 The -, B-, Y-, and d-isomers of HCH, and/or their phenolic metabolites have been measured in biological samples such as adipose tissue, serum, urine, milk, semen, and the brain by gas chromatographic methods listed in Table 6-1. The most commonly used methods for measuring «-, B-, Y-, and 8-HCH in serum, semen, adipose tissue, and milk are gas chromatography (GC) or high-resolution gas chromatography (HRGC) combined with electron capture detection (ECD) and mass spectrometry (GC/MS) (Barquet et al. 1981; Burse et al. 1990; Butte and Fooken 1990; EPA 1980c; Gupta et al. 1978; LeBel and Williams 1986; Liao et al. 1988; Prapamontol and Stevenson 1991; Saady and Poklis 1990; Stachel et al. 1989; Waliszewski and Szymczynski 1983; Williams et al. 1988). The EPA GC/ECD method is capable of detecting Y-HCH and other HCH isomers in blood serum at the ppb level (EPA 1980c). Using HRGC, method detection limits for measuring HCH isomers in serum and milk are in the sub-ppm to low-ppb range (Butte and Fooken 1990; Prapamontol and Stevenson 1991; Saady and Poklis 1990); recovery and precision are acceptable (Butte and Fooken 1990; Prapamontol and Stevenson 1991; Saady and Poklis 1990). The use of capillary (high-resolution) GC enhances chromatographic separation of compounds with similar retention characteristics (Saady and Poklis 1990). Although GC has also been used in measuring the isomers in blood serum, recovery problems (i.e., low recoveries) have been encountered because of the volatility of the HCH isomers (Burse et al. 1990); sensitivity and precision data were not reported (Burse et al. 1990). GC/ECD combined with identification Table 6-1. Analytical Methods for Determining Hexachlorocyclohexane in Biological Materials Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Urine Hydrolyze sample; acidify; GC/ECD, Phenolic 1 ppb 95% Balikova et al. 1988 extract with hexane; TLC metabolites of (GC/ECD); NR derivatize for GC/ECD or y-HCH 1 ppm (TLC) evaporate to a small volume for TLC. Urine Hydrolyze acidified GC/ECD 49-18.6 ppb 87-119% Angerer et al. 1981 sample; extract with diethyl ether; concentrate phenol conjugates Serum Extract and concentrate HRGC/ECD a-HCH 0.18 ppm 70-75% Saady and Poklis 1990 serum using solid-phase y-HCH 0.33 ppm extraction; elute with isooctane; inject Serum Extract serum with organic GC/ECD B-HCH NR 57.2-58.2% Burse et al. 1990 solvents; sample and acid y-HCH NR 47.7-50.4% cleanup on Florisil column; sample cleanup using silica gel chromatography Serum Extract with hexane GC/ECD a-HCH 1 ppb NR EPA 1980a B-HCH 1 ppb NR y-HCH 1 ppb NR Serum Separate plasma from blood =~ GC/ECD B-HCH 0.8 ppb 85% Barquet et al. 1981 containing anticoagulant Serum Hexane or hexane-acetone GC/ECD a-HCH NR 82-83% Gupta et al. 1978 extraction B-HCH 73-77% y-HCH 90-96% SAOHL3IW TVOILATVYNY 9 HOH v8L Biological Materials (continued) Table 6-1. Analytical Methods for Determining Hexachlorocyclohexane in Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Semen Liquid-liquid extraction; GC/ECD a-BHC 0.02 ppb 72.5% Stachel et al. 1989 cleanup with Florisil GC/MS(NCI) B-BHC 0.32 ppb 94.7% Semen Extract with acetic acid; GC/ECD a-BHC NR 86.3% Waliszewski and cleanup with Florisil; elute B-BHC 101.3% Szymczynski 1983 with petroleum-diethyl y-BHC 951.0% ether 8-BHC 101.6% Adipose Extract with organic sol- GC/MS a-BHC 5-50 ppb >100% Liao et al. 1988 tissue vents; reextract lipids on B-BHC 80-100% Florisil column; elute with hexane and concentrate Adipose Extract fat from tissue with HRGC/ECD a-BHC 1.2 ppb >89% LeBel and Williams tissue acetone-hexane; fractionate GC/MS y-BHC 1.4 ppb >88% 1986 from fat by gel permeation B-BHC 3.0 ppb >91% chromatography with methylene chloride- cyclohexane; cleanup on Florisil column; inject Adipose Grind sample; isolate fat, GC/ECD a-HCH 10 ppb NR EPA 1980a tissue extract residue in petroluem B-HCH 20 ppb NR ether y-HCH 20 ppb NR Grind tissue; extract GC/ECD B-HCH 80 ppb 98% Barquet et al. 1981 with acetonitrile and acetone; evaporate; extract with hexane SAOHL3W TVOILATVNY ‘9 HOH sgl Biological Materials (continued) Table 6-1. Analytical Methods for Determining Hexachlorocyclohexane in Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Milk Solvent extract with HRGC/ECD a-HCH 0.5 ppb 83-105% Prapamontol and ethylacetate-methanol- B-HCH 1 ppb 91-119% Stevenson 1991 acetone; cleanup and y-HCH 0.5 ppb 80-96% concentrate using solid- phase extraction; elute with isooctane Milk Homogenize sample; HRGC/ECD a-HCH 0.002 ppm 125% Butte and Fooken 1990 extract and cleanup using B-HCH 0.009 ppm 114% silica gel; elute with ¥-HCH 0.004 ppm 125% hexane/dichloromethane; concentrate; inject Brain Homogenize sample in GC/MS (NCI) y-HCH and 3 pg/L NR Artigas et al. 1988b hexane; centrifuge; inject metabolites a-BHC = alpha-hexachlorocyclohexane; B-BHC = beta-hexachlorocyclohexane; y-BHC = gamma-hexachlorocyclohexane; 8-BHC = delta-hexachlorocyclohexane; ECD = electron capture detection; GC = gas chromatography; a-HCH = alpha-hexachlorocyclohexane; B-HCH = beta-hexachlorocyclohexane; y-HCH = gamma-hexachlorocyclohexane; 8-HCH = delta-hexachlorocyclohexane; HRGC = high-resolution gas chromatography; MS = mass spectrometry; NCI = negative chemical ionization; NR = not reported; TLC = thin-layer chromatography SAOHL3INW TVOILATVYNY “9 HOH 981 HCH 187 6. ANALYTICAL METHODS by GC/MS is a reliable method for quantitation and identification of HCH isomers in semen (Stachel et al. 1989); sensitivity of GC/ECD is in the sub-ppb range with acceptable recoveries (Stachel et al. 1989). HRGC/ECD and GC/MS have also been used for detection and identification of HCH isomers in adipose tissue (LeBel and Williams 1986; Liao et al. 1988). During sample preparation, the use of gel permeation chromatography is effective for separation of the isomers from adipose tissue (LeBel and Williams 1986). This method is sensitive (low- to sub-ppb range) and has good recoveries (>88%) and precision (<0.12% RSD). Although sensitivity is not quite as good as that of GC/ECD, GC/MS is more specific. GC/MS is usually used as a confirmatory method, but it can be reliably used alone and produces excellent recoveries and good precision (Liao et al. 1988). y-HCH and its metabolites have also been detected in brain tissue using GC/MS in the chemical ionization mode (Artigas et al. 1988a). The use of GC/MS with negative ion chemical ionization (NICI) is preferred over electron impact mass spectrometry (EIMS) because the sensitivity using NICI is orders of magnitude better than with EIMS. GC/MS with NICI is also more selective than GC/MS with EI or GC/ECD (Artigas et al. 1988a). Another advantage of GC/MS with NICI is that identification and quantitation are performed without any purification or extraction procedures (Artigas et al. 1988a). The phenolic metabolites of y-HCH and the other HCH isomers have been measured in urine samples using GC/ECD (Angerer et al. 1981; Balikova et al. 1988). Sensitivity for this method is in the low-ppb range and recovery is excellent (95%); however, precision was not reported (Balikova et al. 1988). Thin layer chromatography (TLC) has also been used in conjunction with GC/ECD for identification of HCH isomers (Balikova et al. 1988). Although TLC does not achieve the same sensitivity (ppm range) as GC/ECD, sensitivity can be increased by extraction of a larger volume of urine. The combination of GC and TLC was reported to be a reliable confirmation tool for identifying compounds (Balikova et al. 1988). Angerer et al. (1981) developed a sensitive and specific gas chromatographic method for the simultaneous detection of 10 chlorinated phenols that appear in the urine of individuals exposed to y-HCH. However, the study authors noted that both HCH and chlorobenzene compounds are commonly used as pesticides and that both are metabolized to chlorophenols. This suggests that detection of these metabolites does not distinguish between HCH, chlorobenzene, or pentachlorophenol (PCP) exposure. Edgerton et al. (1979) detected chlorinated phenol metabolites of HCH and PCP in the urine of experimental animals and exposed individuals by using GC/ECD. Discrimination between HCH and PCP exposure was possible through comparisons of metabolite profiles. However, detection of PCP in the urine may also be an indication of exposure to PCP or other compounds similar to HCH. HCH 188 6. ANALYTICAL METHODS 6.2 ENVIRONMENTAL SAMPLES HCH residues are present in the environment because y-HCH is used as an insecticide on a wide variety of vegetables, fruits, field crops, and on uncultivated land. The most commonly used methods for measuring HCH isomers in environmental samples is GC or HRGC combined with ECD or MS. Table 6-2 presents details on selected analytical methods. HCH isomers have been measured in air using GC/ECD, HRGC/ECD, or GC with dual detection by ECD and electrolytic conductivity detection (ELCD) (Durell and Sauer 1990; Kurtz and Atlas 1990; NIOSH 1984; Stein et al. 1987; Zaranski et al. 1991). Polyurethane foam or Florisil adsorbent tubes are suitable for collecting air samples. The use of a simultaneous dual-column, dual-detector method (ECD and ELCD) was found to reduce the risk of false positive identifications without increasing the cost or time of analysis (Durell and Sauer 1990). Both columns were able to separate a large number of analytes with good reproducibility. Although ECD is more sensitive for halogenated compounds and has a lower detection limit (sub-ppb to low-ppm) than ELCD (low ppb), ELCD can greatly reduce matrix interferences. Precision and recovery were not reported for either detector (Durell and Sauer 1990; Kurtz and Atlas 1990). The most commonly used methods for detecting HCH isomers in water (e.g., surface water, drinking water, sea water, groundwater, waste water, and rain) include GC or HRGC combined with ECD or MS (Allchin 1991; Barquet et al. 1981; Durell and Sauer 1990; EPA 1984, 1986a; Goosens et al. 1990; Kurtz and Atlas 1990; Lopez-Avila et al. 1989a, 1990b; Reding 1987; van der Hoff et al. 1991). To improve sample extraction and cleanup, the most current EPA method (Method 8120) used commercially available disposable Florisil cartridges instead of conventional Florisil cleanup (Lopez-Avila et al. 1989a). The disposable Florisil cartridges were simpler to use, shortened the analysis time, and reduced the overall cost of the analysis. The excellent precision, accuracy, and sensitivity (ppt range) of the results indicated that the revised method is reliable (Lopez-Avila et al. 1989a). Automated solid-phase extraction cartridges filled with silica and coupled on-line to GC/ECD have been effectively used to measure HCH isomers in water at low levels (ppt) (van der Hoff et al. 1991). This method is efficient and reproducible, with good recovery (>95%) and precision (<12% coefficient of variance (CV)) (van der Hoff et al. 1991). On-line liquid-liquid extraction coupled with HRGC/ECD is also a sensitive (ppb level) and reliable method (Goosens et al. 1990). A method validation study, conducted on EPA Method 508, for determining HCH isomers in finished drinking water using GC/ECD indicated the method was reliable, repeatable, and reproducible (Lopez-Avila et al. 1990b). Precision was good; recovery (>90%) was excellent. Sensitivity was in the ppb range (Lopez-Avila Table 6-2. Analytical Methods for Determining Hexachlorocyclohexane in Environmental Samples Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Air Collect air using filters HRGC/ECD 0.9 pg/puL NR Durell and Sauer 1990 and polyurethane foam; HRGC/ELCD 15.3 pg/puL NR Soxhlet extraction; column cleanup and isolation; concentration; dual column detection Air Collect sample in Florisil HRGC/ECD low pg/m’ NR Kurtz and Atlas 1990 adsorbent tubes; elute with methylene chloride in pentane; concentrate in Kudemna-Danish evapora- tive concentrator; solvent exchange to hexane Air Trap in isooctane GC/ECD 3 pg/sample NR NIOSH 1984 (Method 5502) Air Adsorb air sample on GC/ECD a-BHC 0.25 pg/m’ 83% Stein et al. 1987 florisil; elute with 10% B-BHC 88% 2-propanol in hexane y-BHC 81% 5-BHC 87% Surface Extract with hexane; GC/ECD «-HCH 7 ppt 95.6% van der Hoff et al. 1991 water concentrate; cleanup using B-HCH 10 ppt 98.2% automated solid-phase y-HCH 7 ppt 95.6% extraction technique 6-HCH 6 ppt 95.9% SAOHL3IN TVYOILLATVYNY 9 HOH 681 Table 6-2. Analytical Methods for Determining Hexachlorocyclohexane in Environmental Samples (continued) Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Water Extract twice with GC/ECD a-HCH 11 ppt 96% Lopez-Avila et al. methylene chloride; dry B-HCH 31 ppt 103% 1989a (Modified EPA with anhydrous sodium y-HCH 23 ppt 96% Method 8120) sulfate; concentrate; add 8-HCH 20 ppt 103% hexane and concentrate by evaporation; cleanup on disposable Florisil cartridge and elute with hexane- acetone Drinking Extract with methylene GC/ECD «-HCH 0.025 ppb 94.6% Lopez-Avila et al. water chloride; solvent exchange B-HCH 0.010 ppb 93.4% 1990b (EPA Method to methyl ter-butyl ether; y-HCH 0.010 ppb 94.2% 508) concentrate 8-HCH 0.015 ppb 92.0% Drinking Stripping for water with an HRGC/ECD 0.003 ppb 93-130% Reding 1987 (EPA water inert gas-helium (Method 505); Methods 505, 508) 0.006 ppb Method 508) Drinking Separation with Na,SO,; GC/ECD B-HCH 0.025 ppb 88% Barquet et al. 1981 water extraction with CH,Cl, Water and Extraction with methylene GC/ECD a-HCH 0.003 ppb NR EPA 1984 (Method waste water chloride B-HCH 0.006 ppb NR 608) y-HCH 0.004 ppb NR 8-HCH 0.009 ppb NR SAOHL3IW TVOILATVNY ‘9 HOH 061 Environmental Samples (continued) Table 6-2. Analytical Methods for Determining Hexachlorocyclohexane in Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Water and Extraction with methylene GC/MS B-HCH 4.2 ppb NR EPA 1984 (Method waste water chloride 6-HCH 3.1 ppb NR 625) Water and Extraction with methylene GC/ECD a-HCH 0.003 ppb NR EPA 1986e (Method waste water chloride B-HCH 0.006 ppb NR 8080) y-HCH 0.004 ppb NR 6-HCH 0.009 ppb NR Sea water Extract twice with hexane; GC/ECD a-HCH, 1 ppt >85% Allchin 1991 dry over anhydrous sodium y-HCH sulfate; concentrate; cleanup using column chromatography with 5% deactivated alumina; concentrate Ground- On-line liquid-liquid HRGC/ECD «-HCH 0.1 ppb 112% Goosens et al. 1990 water extraction of sample with 5-HCH 119% isooctane and separation of aqueous and organic phases by a sandwich phase separator Sea water, Liquid-liquid extraction; HRGC/ECD 0.9 ppb NR Durrell and Sauer 1990 rain column cleanup and HRGC/ELCD 15.3 ppb NR (lindane) isolation; concentration SAOHL3W TVOILATVYNY 9 HOH 164 Table 6-2. Analytical Methods for Determining Hexachlorocyclohexane in Environmental Samples (continued) Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Sea water Extract with methylene HRGC/ECD a-HCH, low pg/L NR Kurtz and Atlas 1990 chloride; solvent exchange y-HCH to hexane; cleanup on Florisil Soil Extract with supercritical GC/ECD a-BHC NR 77.43-93.6% Lopez-Avila et al. 1990 carbon dioxide or carbon GC/MS B-BHC 79.28-93.6% dioxide modified with 10% y-BHC 80.63-121% methanol 8-BHC 72.4-103% Soil Dry sample with anhydrous ~~ GC/ECD a-HCH <40 ng/L 96% Lopez-Avila et al. sodium sulfate; extract B-HCH 103% 1989b (Modified EPA twice with methylene y-HCH 96% Method 8120) chloride-acetone by 6-HCH 103% sonication; filter; dry; concentrate; cleanup on disposable Florisil cartridge and elute with hexane- acetone Soil (lindane) Equilibrate with water; extract GC 5 ppm 108% Noegrohati and (lindane) with acetone and hexane (1:1); Hammers 1992 wash with water and sodium chloride desiccate with anhy- drous sodium sulfate; concen- trate; add hexane; cleanup with SPE Florisil cartridge. SAOHL3W TVOILATVYNY “9 HOH 261 Table 6-2. Analytical Methods for Determining Hexachlorocyclohexane in Environmental Samples (continued) Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Soil, Extract sample with HRGC/ECD, y-BHC NR 83-91% Czuczwa and Alford- sediment, methylene chloride-acetone = HRGC/MS Stevens 1989 waste sludge by sonication; clean up using gel permeation chromatography processing of extracts dissolved in 1+1 butyl chloride-methylene chloride or 100% methylene chloride Soil Hexane-acetone extraction GC/ECD NR NR AOAC 1984 (Method 29.013) Soil Extraction with methylene GC/ECD, a-HCH 3.0 ppm NR EPA 1986e (Method chloride followed by clean- HSD B-HCH 6.0 ppm NR 8080) up on Florisil column 5-HCH 4.0 ppm NR 8-HCH 9.0 ppm NR Sediment Extract using vapor phase GC/ECD a-HCH 2.42 ppb 76% Schuphan et al. 1990 distillation technique; dry y-HCH 4.98 ppb 40% isooctane extract; concentrate Milk Selective extraction of GC/ECD a-HCH NR 94% DiMuccio et al. 1988 HCH isomers on solid- y-HCH 105% matrix disposable column B-HCH 113% by means of acetonitrile- saturated light petroleum; concentrate; cleanup extract on Florisil minicolumn SAOHL3N TVOILATYNY 9 HOH £61 Table 6-2. Analytical Methods for Determining Hexachlorocyclohexane in Environmental Samples (continued) Sample matrix Analytical Preparation method method Isomer Sample detection limit Percent recovery Reference Milk Soil, water, wheat, rice, beans Mussels (lindane) Fish (lindane) Extract fortified milk GC/ECD samples with acetone and n-hexane; centrifuge; evaporate organic phase; dissolve residues in ether Extract BHC from sample Spectrophoto- by activated charcoal, metry dechlorination of BHC to benzene; nitration of benzene to m-dinitro- benzene; reduction to m-phenylene diamine; diazotization and coupling to form azo dye Extract with acetonitrile; GC/ECD separate from coextractives by liquid-liquid partition between acetonitrile and water/hexane; cleanup on Sep-Pak Florisil cartridge; elute in second eluate with 15% ethyl ether in hexane Extract residue using one- GC/ECD step matrix solid phase dispersion combined with Florisil column cleanup; inject into GC a-HCH B-HCH y-HCH 8-HCH y-HCH NR NR 0.02 pg/kg 10 ng/g 95.7% Kapoor et al. 1981 99.9% 83.4% 89.7% >89% Raju and Gupta 1988 92-102% Muino et al. 1991 82% Long etal. 1991a SAOHL3IN TVOILATVYNY "9 HOH v6l Table 6-2. Analytical Methods for Determining Hexachlorocyclohexane in Environmental Samples (continued) Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Fish Petroleum ether extraction GC/ECD NR NR AOAC 1984 (Method 20.029) Fish Combine with anhydrous GC/MS (NCI) 1.6 ppb 115% Schmidt and (lindane) Na,SO,; extract with Hesselberg 1992 petroleum ether/ethyl acetate; separate lipids with GPC; solvent exchange to iso-octane; add dry N, gas Fruits and Extract samples with ace- HRGC/MS a-BHC 0.05 pg/g (all 88% Liao et al. 1991 vegetables tonitrile; partition with B-BHC isomers) 93% sodium chloride saturated y-BHC 93% aqueous solution; 8-BHC 112% concentrate Vegetables Extract with methanol; GC ppb range 87-137% Noegrohati and (lindane) and partition with sodium Hammers 1992 chloride and hexane; wash hexane layer with sodium chloride solution; desiccate with anhydrous sodium sulfate; concentrate; cleanup on SPE Sil-Florisil cartridge SAOHL3N TVOILATVYNY 9 HOH S61 Table 6-2. Analytical Methods for Determining Hexachlorocyclohexane in Environmental Samples (continued) Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Beef fat Extract residue using one- GC/ECD low ppb 85% Long etal. 1991b (lindane) step matrix solid phase dispersion combined with Florisil column cleanup; inject into GC Animal fat For dairy products, extract GC/ECD BHC low to sub ppm 82% Venant et al. 1989 and dairy fat with hexane; for animal products fat, melt sample and remove fat; cleanup with gel permeation chromatography; further cleanup with Florisil if necessary; inject Root Extract with CO, collect GC/ECD a-HCH NR 10-100% Bernal et al. 1992 vegetables with n-hexane; evaporate; y-HCH NR 12-98% and dairy add n-hexane; load on products Florisil column; elute with 1:1 (v/v) n- hexane/dichlo- romethane; evaporate; dissolve in n-hexane Beef Extract with acetone- GC/ECD B-BHC sub ppm 78.1-88.3% Tonogai et al. 1989 hexane; cleanup on Florisil column; inject SAOHLIN TVOILATYNY 9 HOH 961 Table 6-2. Analytical Methods for Determining Hexachlorocyclohexane in Environmental Samples (continued) Sample Analytical detection Percent Sample matrix Preparation method method Isomer limit recovery Reference Tobacco Soak in acetonitrile water GC/ECD a-HCH 1.0 ppm 98.2% Waliszewksi and mixture, extract with B-HCH 2.0 ppm 92.9% Szymczynski 1986 petroleum ether; shake with y-HCH 2.0 ppm 96.2% H,SO, 8-HCH 2.0 ppm 88.2% Wood Extract with toluene; sonify ~~ GC-MS 10 ppb NR Butte and Walker 1992 (rasped) and centrifuge; inject «-BHC = alpha-hexachlorocyclohexane; B-BHC = beta-hexachlorocyclohexane; y-BHC = gamma-hexachlorocyclohexane; 8-BHC = delta-hexachlorocyclo- hexane; CH,Cl, = methylene chloride; ECD = electron capture detection; ELCD = electrolytic conductivity detector; GC = gas chromatography; GPC = gas permeation chromatography; a-HCH = alpha-hexachlorocyclohexane; B-HCH = beta-hexachlorocyclohexane; y-HCH = gamma-hexachlorocyclohexane; 8-HCH = delta-hexachlorocyclohexane; H,SO, = sulfuric acid; HRGC = high-resolution gas chromatography; HSD = halogen specific detector; MS = mass spectrometry; Na,SO, = sodium sulfate; NCI = negative chemical ionization; NR = not reported; SPE = solid phase extraction SAOHL3INW TVOILATVYNY 9 HOH 61 HCH 198 6. ANALYTICAL METHODS et al. 1990b). The EPA-established analytical test procedures to analyze water, waste water, and drinking water samples use GC coupled with MS. EPA methods 608 and 625 are recommended to detect y-HCH and other HCH isomers in surface water and municipal and industrial discharges (EPA 1984). GC/ECD, HRGC/ECD, and HRGC/MS are the most commonly used methods to measure HCH isomers in soil, sediments, and solid wastes (AOAC 1984; Czuczwa and Alford-Stevens 1989; EPA 1986b; Lopez-Avila et al. 1989b, 1990a; Noegrohati and Hammers 1992b; Schuphan et al. 1990). More efficient extraction of the isomers from soil was obtained using a disposable Florisil cartridge (modified EPA Method 8120) prior to detection by GC/ECD (Lopez-Avila et al. 1989b). The method yielded excellent recoveries (>95%), and sensitivity was in the ppt range. Sample cleanup using a disposable solid phase extraction (SPE) cartridge with detection by GC yielded a higher recovery (108%) with excellent precision (4% CV). Although sample detection limits were not reported, sensitivity was in the ppm range (Noegrohati and Hammers 1992b). Sample cleanup using gel permeation chromatography and detection and identification by HRGC/ECD and HRGC/MS resulted in good recoveries (83-91%) and good precision (<5.1% relative standard deviation [RSD]) (Czuczwa and Alford-Stevens 1989); sensitivity was not reported (Czuczwa and Alford-Stevens 1989). A new technique, supercritical fluid extraction (SFE), has been applied to the analysis of soil samples (Lopez-Avila et al. 1990a). Recovery (>75%) and precision (<26% CV) are adequate. Because this is a relatively new method, the cost is higher than other accepted techniques. The vapor phase extraction technique has also been applied to the analysis of trace residues of HCH in sediments (Schuphan et al. 1990). The efficiency of this method was compared with conventional Soxhlet extraction and Florisil cleanup procedures. The results showed that recovery using the Soxhlet extraction method (73-81%) was better than with vapor-phase extraction (40-76%). The low recovery of y-HCH (40%) was due to sample loss during concentration of the iso-octane extract (Schuphan et al. 1990); sensitivity was in the low-ppb range; precision was excellent (0.01-0.03% coefficient of variation). GC/ECD and HRGC/ECD are the most commonly used methods for measuring HCH isomers in milk (DiMuccio et al. 1988; Kapoor et al. 1981), dairy products (Bernal et al. 1992; Venant et al. 1989), seafood (mussels and fish) (AOAC 1984; Long et al. 1991a; Muino et al. 1991; Schmidt and Hesselberg 1992), fruits and vegetables (Liao et al. 1991; Noegrohati and Hammers 1992), beef (Tonogai et al. 1989), and beef fat (Long et al. 1991b). Gel permeation chromatography is a suitable method for the cleanup of HCH residues in animal fats and dairy products (Venant et al. 1989); recoveries are good (82%). Although specific detection limits were not reported, sensitivity is in the low-to-sub-ppm range. Additional cleanup with Florisil is needed when residue levels are below 0.1 ppm; precision was not reported. High-pressure soxhlet extraction HCH 199 6. ANALYTICAL METHODS coupled with Florisil column cleanup yielded recoveries up to 100% for «-HCH and y-HCH in butter, if pressure, time, and sample volume in the extractor were optimized; detection limits and precision values were not reported. This method has also been used to detect y-HCH residues in potatoes with similar recoveries (Bernal et al. 1992). A reliable and reproducible method has been developed to determine HCH residues in milk (DiMuccio et al. 1988). The procedure involves a single-step, selective extraction of residues from milk on a solid-matrix disposable column, clean-up with Florisil, and detection by GC/ECD. Although specific detection limits were not reported, sensitivity is in the low-ppb range. With this extraction procedure, the HCH residues are more readily extracted than milk lipids, and the addition of a small amount of acetonitrile to the milk significantly improved recoveries without increasing the amount of fat in the extracts (diMuccio et al. 1988). A reliable, rapid screening technique for extraction of residues from a complex biological matrix such as fat uses matrix solid-phase dispersion (MSPD) extraction, Florisil column cleanup, and detection by GC/ECD (Long et. al. 1991a, 1991b). This method has been used to measure HCH residues in beef fat and fish. Recovery (82-85%) is good; sensitivity is in the low-ppb range. The MSPD method overcomes many of the complications associated with traditional pesticide isolation techniques because it uses small sample volumes and involves few steps (Long et al. 1991a, 1991b). GC/MS with negative ion chemical ionization (NCI) with GPC cleanup is a rapid, accurate, and simple method to quantify y-HCH in fish. Recoveries were excellent (115%) with good precision (8.9% RSD), and a detection limit of 1.6 ppb (Schmidt and Hesselberg 1992). An HRGC/MS screening method has been developed for the determination of pesticide residues in a variety of crop samples (fruits and vegetables) (Liao et al. 1991). This technique is a useful tool because it offers simultaneous detection and confirmation, which are not provided by ECD. This method, however, lacks the sensitivity achieved by ECD. Spectrophotometry has been used to measure HCH isomers in cereals (e.g., wheat, rice, and beans) with good recoveries (>89%) (Raju and Gupta 1988). This technique has also been used for other matrices such as soil and water (Raju and Gupta 1988). An accurate and simple extraction and cleanup method has been developed for capillary GC analysis of y-HCH in vegetables. The sample was extracted with methanol and cleanup was executed on disposable SPE cartridges. Recoveries ranged from 87% to 137% (average 100%) with good precision (CV < 5%). Although no specific detection limits were reported, sensitivity is expected to be in the ppb range (Noegrohati and Hammers 1992). HCH residues have also been detected in tobacco using GC/ECD (Waliszewski and Szymczynski 1986). Sensitivity is in the low-ppm range and recovery is excellent (88-98%) (Waliszewski and Szymczynski 1986). HCH 200 6. ANALYTICAL METHODS GC/MS has been used to determine y-HCH residues in wood preserving fluids on the surface of wood; the detection limit is 10 ppb. No recovery or precision values were reported (Butte and Walker 1992). 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 hexachlorocyclohexane 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 hexachlorocyclohexane. 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. 6.3.1 Identification of Data Needs Methods for Determining Biomarkers of Exposure and Effect. Methods are available for measuring HCH residues and/or their metabolites in blood serum (Barquet et al. 1981; Burse et al. 1990; Gupta et al. 1978; EPA 1980c; Saady and Poklis 1990), urine (Angerer et al. 1981; Balikova et al. 1988), semen (Stachel et al. 1989; Waliszewski and Szymczynski 1983), adipose tissue (EPA 1980c; Barquet et al. 1981; LeBel and Williams 1986; Liao et al. 1988), breastmilk (Butte and Fooken 1990; Prapamontol and Stevenson 1991), and brain tissue (Artigas et al. 1988a). However, examination of blood and urine is most frequently conducted to determine exposure because of the ease of sample collection with these media. The available methods are accurate and reliable for most of the media. However, sensitivity and precision data for measuring HCH residues in serum are needed. Although available methods can detect and quantify background levels of HCH in the population, there is no information to quantitatively correlate levels in these fluids with exposure levels. Additional quantitative information regarding the relationship between body and environmental levels of HCH might allow investigators to predict environmental exposure levels from measured body levels. HCH 201 6. ANALYTICAL METHODS Methods are available to detect the chlorinated phenol metabolites present in the urine as a result of exposure to HCH (Angerer et al. 1981; Balikova et al. 1988). However, similar metabolites are detected following exposure to other pesticides. The identification of a specific urinary metabolite of HCH alone (e.g., chlorophenol) would not allow investigators to determine whether an individual has been exposed to HCH. The individual isomers of HCH can be detected in serum, urine, adipose tissue, and semen of exposed individuals as indicated above in Section 2.7.1 Biomarkers of Exposure and Effect. Since no quantitative correlation has been made between body levels of HCH and adverse health effects based on existing data, we do not know if the methods are sensitive enough to measure levels at which biological effects occur. Further studies need to be undertaken to quantitatively correlate body levels resulting from HCH exposure and the occurrence of specific adverse health effects. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Methods are available to detect HCH in air (Durell and Sauer 1990; Kurtz and Atlas 1990; NIOSH 1984; Stein et al. 1987; Zaranski et al. 1991), water (Allchin 1991; Barquet et al. 1981; Durell and Sauer 1990; EPA 1984, 1986a; Goosens et al. 1990; Kurtz and Atlas; Lopez-Avila et al. 1989a, 1990b; Reding 1987; van der Hoff et al. 1991), soil (AOAC 1984; Czuczwa and Alford-Stevens 1989; EPA 1986b; Lopez-Avila et al. 1989a, 1990b; Noegrohati and Hammers 1992; Schuphan et al. 1990), food (AOAC 1984; Bernal et al. 1992; Liao et al. 1991; Long et al. 1991a, 1991b; Muino et al. 1991; Noegrohati and Hammers 1992; Schmidt and Hesselberg 1992; Tonogai et al. 1989; Venant et al. 1989), milk (DiMuccio et al. 1988; Kapoor et al. 1981), tobacco (Waliszewski and Szymczynski 1986), and wood preserving fluid (Butte and Walker 1992). These methods are sensitive enough to measure background levels in environmental media. The precision, accuracy, reliability, and specificity of these methods are sufficiently documented. Research investigating the relationship between levels measured in air, water, soil, and food and observed health effects could increase our confidence in existing methods and/or indicate where improvements are needed. 6.3.2 Ongoing Studies New methodology for improving multiple pesticide analyses of short-life residues in processed foods is being developed at the University of Tennessee, in Knoxville (L. Melton, investigator). HCH 203 7. REGULATIONS AND ADVISORIES The international, national, and state regulations and guidelines regarding «-, B-, y-, and 8-HCH in air, water, and other media are summarized in Table 7-1. Unless otherwise specified, the regulations in the table refer to HCH in general (all isomers). EPA (IRIS 1998) assigned y-HCH an oral reference dose (RfD) of 3.00x10* mg/kg/day with an uncertainty factor of 1,000 based on liver and kidney toxicity in rats (Zoecon Corporation 1983). EPA (IRIS 1998) has assigned the following weight-of-evidence classifications: «-HCH is assigned a classification of B2 (probable human carcinogen); B-HCH is assigned a classification of C (possible human carcinogen); Y-HCH is among those substances being evaluated by the EPA for evidence of human carcinogenicity; and 8-HCH is assigned a classification of D (not classifiable as to human carcinogenicity). EPA estimates that concentrations of a-HCH in water of 0.6, 0.06, and 0.006 pg/L are associated in humans with excess lifetime cancer risks of 104, 10%, and 10°, respectively, and that concentrations of -HCH in water of 2, 0.2, and 0.02, ug/L are associated in humans with excess lifetime cancer risks of 10+, 10%, and 10°, respectively (IRIS 1998). y-HCH is on the list of chemicals appearing in "Toxic Chemicals Subject to Section 313 of the Emergency Planning and Right-to-Know Act of 1986" (EPA 1991h, 1988f). Tolerances are established for Y-HCH in or on raw agricultural commodities as follows: 7 ppm in or on the fat of meat from cattle, goats, horses, and sheep; 4 ppm in or on the fat of meat from hogs; 3 ppm in or on cucumbers, lettuce, melons, pumpkin, squash, summer squash, and tomatoes; and 1 ppm in or on apples and apricots (EPA 1974a, 1974b). The use of Y-HCH has been restricted by EPA since 1977 and is to be applied only by a certified applicator (EPA 1985b). HCH 7. REGULATIONS AND ADVISORIES 204 TABLE 7-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane Agency Description Information References INTERNATIONAL FAO/WHO ADI 0.0-0.1 mg/kg WHO 1976; FAO/ WHO 1978 body weight Allowable tolerances (y-HCH) WHO 1976 Potatoes 0.05 mg/kg Lettuce 2.0 mg/kg IARC Carcinogenic classification Group 2B* IARC 1987 WHO Guidelines for drinking water 0.003 mg/L WHO 1984 NATIONAL Regulations: a. Air: OSHA PEL TWA (skin designation)(y-HCH) 0.5 mg/m’ OSHA 1998 (29 CFR 1910.1000); OSHA 1989b Meets criteria for OSHA medical Yes OSHA 1987 (29 CFR records rule (a-HCH, y-HCH) 1910.20); OSHA 1988 b. Water: EPA ODW Regulated under the SDWA of 1986; 4 ng/L FSTRAC 1990 drinking water quality standard (Y-HCH) EPA OWRS General pretreatment regulations for Yes EPA 1988b (40 CFR existing and new sources of 403, Appendix B); pollution EPA 1988c c. Food: FDA Permissible levels in bottled water 0.004 mg/L FDA 1989a (21 CFR 103.35); FDA 1982b EPA Tolerance for residues (yY-HCH): EPA 1998 (40 CFR in or on the fat of meat from 7 mg/kg 180.133) cattle, goats, horses,and sheep in or on the fat of meat from hogs 4 mg/kg in or on cucumbers, lettuce, melons, 3 mg/kg mushrooms, pumpkin, squash, summer squash, and tomatoes in or on apples, apricots, asparagus, 1 mg/kg avocados, broccoli, brussel sprouts, cabbage, cauliflower, celery, cherries, collards, eggplants, grapes, gauvas, kale, kohlrabi, mangoes, mustard greens, nectarines, okra, onions (dry bulb only), peaches, pears, peppers, pineapples, plums (fresh prunes), quinces, spinach, strawberries, and Swiss chard in or on pecans 0.01 mg/kg d. Other: DOT Hazardous Material Transportation Act: Yes DOT 1989a (49 CFR y-HCH is designated as a hazardous materials which is subject to requirements for packaging, shipping and transporting. 172.101, Appendix A), DOT 198%b HCH 205 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane (continued) Agency Description Information References NATIONAL (Cont.) EPA OERR Reportable quantity (y-HCH) 1 pound EPA 1996a (40 CFR 302.4); EPA 1998 EPA OSW 302.4); EPA 1998 264.94); EPA 1987f VIII); EPA 1998 EPA OTS Guidelines: a. Air: ACGIH NIOSH b. Water: EPA ODW Extremely hazardous substances Threshold Planning Quantity (Y-HCH) Designated as a hazardous substance (y-HCH) Designated as a hazardous pollutant under section 311(b)(2)(A) of the Federal Water Pollution Control Act (y-HCH) Designated as a toxic pollutant under Section 307(a)(1) of the Federal Water Pollution Act (Y-HCH) Groundwater monitoring requirement (y-HCH)/Maximum concentration Listing as a hazardous waste; discarded commercial chemical products, manufacturing chemical intermediates, or off-specification commercial chemical products (Y-HCH) Listing as a hazardous constituent (y-HCH) Maximum concentration of contaminants for the toxicity characteristic (y-HCH) Toxic release reporting; Community Right-to-Know (y-HCH) TLV TWA (skin designation) (Y-HCH) REL TWA (skin designation) (y-HCH) MCL in drinking water (Y-HCH) MCLG in drinking water (Y-HCH) Health advisories (Y-HCH) 1-day 10-day Longer term (child) Longer term (adult) 1,000/10,000 pounds Yes Yes Yes/0.004 mg/L No Yes 0.4 mg/L Yes 0.5 mg/m’ 0.5 mg/m’ 0.0002 mg/L 0.0002 mg/L 1.0 mg/L 1.0 mg/L 0.03 mg/L 0.1 mg/L EPA 1996b (40 CFR 355, Appendix A); EPA 1998 EPA 1996¢ (40 CFR EPA 1996d (40 CFR 116.4); EPA 1998 EPA 1996e (40 CFR 401.15); EPA 1979 EPA 1987e (40 CFR EPA 1996f (40 CFR 261.33); EPA 1998 EPA 1998(40 CFR 261, Appendix EPA 1998(40 CFR 261.24); EPA 1990d EPA 1998 (40 CFR 372) ACGIH 1998 NIOSH 1998 EPA 1996 HCH 206 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane (continued) Agency Description Information References NATIONAL (Cont.) Lifetime 0.2x10* mg/L RfD 3.0x10* mg/L DWEL 0.01 mg/L EPA OWRS Ambient water quality criteria EPA 1996j (40 CFR for protection of human health: 130) Ingesting water and organisms a-HCH 3.9x10° pg/L B-HCH 1.4x10? pg/L y-HCH 1.9x107 pg/L Ingesting of organisms only a-HCH 1.3x10? pg/L B-HCH 4.6x10? pg/L y-HCH 6.3x10? pg/L Ambient water quality criteria for protection of aquatic life: freshwater ( y-HCH) acute 2.0 pg/L chronic 8.0x107 pg/L saltwater ( y-HCH) acute 1.6x10" pg/L NAS SNARL (y-HCH) NAS 1982 7 day 0.5 mg/L 24 hours 3.5mg/L c. Other EPA IRIS 1998 a-HCH Carcinogenic classification Group B2® Unit risk (air) 1.8x10 (ug/m’)"! Unit risk (water) 1.8x10* (pg/L) B-HCH Carcinogenic classification Group C Unit risk (air) 5.3x10™ (ug/m’)"! Unit risk (water) 5.3x10° (ug/L)! 6-HCH Carcinogenic classification Group D* y-HCH RfD (oral) 3.00x10* (mg/kg/day) Carcinogenic classification Under review Technical-HCH Carcinogenic classification B2® Unit risk (air) 5.1x10™ (ug/m’)"! Unit risk (water) 5.1x10” (ug/L)! NTP a-HCH, B-HCH, y-HCH, technical grade Reasonably anticipated NTP 1991 to be carcinogens HCH 207 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane (continued) Agency Description Information References STATE Regulations and Guidelines: a. Air: Acceptable ambient air concentrations NATICH 1996 a-HCH Arizona (1 hour) 1.10 pg/m® Arizona (24 hours) 3.00x10" pg/m3 Arizona (Annual) 8.10x10* pg/m’ Florida-Tampa (8 hours) 5.00x10” mg/m’ Florida- Fort Lauderdale (8 hours) 5.00x10” mg/m’ Florida-Pinellas (Annual) 5.60x10* pg/m’ New York (Annual) 1.67 pg/m’ Pennsylvania- Philadelphia (Annual) 1.20 pg/m’ f-HCH Arizona (1 hour) 1.10 pg/m’ Arizona (24 hours) 3.00x10" pg/m’ Arizona (Annual) 8.10x10* pg/m’ Florida-Pinellas (Annual) 1.90x10° pg/m’ y-HCH Arizona (1 hour) 1.10 pg/m’ Arizona (24 hours) 3.00x10" pg/m’ Arizona (Annual) 8.10x10™ pg/m’ Connecticut (8 hours) 5.00 pg/m’ Florida-Tampa (8 hours) 5.00x10”* mg/m’ Florida- Fort Lauderdale (8 hours) 5.00x10’mg/m’ Florida-Pinellas (8 hours) 5.00 pg/m’ Florida-Pinellas (24 hours) 1.20 pg/m’ Kansas (Annual) 3.33x10° pg/m’ Massachusetts (24 hours) 1.40x10" pg/m’ Massachusetts (Annual) 3.00x10° pg/m’ Nevada (8 hours) 1.20x10? mg/m’ North Dakota (8 hours) 5.00x10"* mg/m’ New York (Annual) 1.67 pg/m’ Oklahoma (24 hours) 5.00 pg/m’ Pennsylvania- Philadelphia (Annual) 1.20 pg/m’ South Carolina (24 hours) 5.00 pg/m’ Texas (30 minutes) 5.00 ug/m’ Texas (Annual) 5.00x10" pg/m’ Virginia (24 hour) 8.30 pg/m’ Washington-Southwest (24-hour) 1.60 pg/m’ technical-HCH Arizona (1 hour) 1.10 pg/m’ Arizona (24 hours) 3.00x10" pg/m’ Arizona (Annual) 8.10x10* pg/m’ Kentucky Significant emission levels of toxic 1.276x10* pounds NREPC 1986 air pollutants per hour (401 KAR 63.022) HCH 208 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane (continued) Agency Description Information References STATE (Cont.) Wisconsin Hazardous air contaminant without 25 pounds/year’ WAC 1988 acceptable ambient concentrations; lowest achievable emission rate b. Water: Drinking water quality criteria 0.0002 mg/L Alabama AL DEM 1998 Colorado CO DHWQD 1998 Connecticut CT DEP 1998 Delaware DE NREC 1998 Florida FL DEP 1998 Georgia GA DNR 1998 Idaho ID DHW 1998 Illinois IL EPA 1998 Indiana IN OWM 1998 Iowa IA DNR 1998 Kansas KS DHE 1998 Kentucky KY EPD 1998 Maine ME DEP 1998 Maryland MD DNR 1998 Massachusetts MA DEP 1998 Michigan MI DNR 1998 Minnesota MN PCA 1998 Missouri MO DNR 1998 Montana MT DHES 1998 Nebraska NE DEQ 1998 New Hampshire NH DES 1998 New Mexico NM ED 1998 Oklahoma OK WRB 1998 Oregon OR DEQ 1998 Rhode Island RI DEM 1998 South Carolina SC DHEC 1998 South Dakota SD DENR 1998 Texas TX NR 1998 Washington WA DE 1998 West Virginia WYV DEP 1998 Wyoming WY DEQ 1998 0.004 mg/L New York NY DEC 1998 North Dakota ND DH 1998 Surface water quality standards; aquatic life habitat Delaware Acute 2.0 pg/L DE NREC 1998 Delaware Chronic 0.08 pg/L Hawaii Acute 2.0 pg/L HI CWB 1998 Hawaii Chronic 0.08 pg/L Kentucky Acute 2.0 ug/L KY EPD 1998 Kentucky Chronic 0.08 pg/L Louisiana Acute 2.00 pg/L LA DEQ 1998 Louisiana Chronic 0.08 pg/L Maryland Acute 2.0 ug/L MD DNR 1998 HCH 209 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane (continued) Agency Description Information References STATE (Cont.) Maryland Chronic 0.08 pg/L Nevada 0.002 mg/L NV DCNR 1998 New Jersey Acute 2.0 ug/L NJ DEP 1998 Chronic 0.08 pg/L North Carolina 0.01 pg/L NC DEHNR 1998 South Dakota Acute 2.0 pg/L SD DENR 1998 South Dakota Chronic 0.08 pg/L Vermont Acute 2.0 pg/L VT ANR 1998 Vermont Chronic 0.08 pg/L Wisconsin Human threshold criteria WDNR 1987 a-HCH Public water supply: Warm water sport fish communities 0.07 pg/L Cold water communities 0.033 pg/L Great Lakes communities 0.034 pg/L Non-water supply: Warm water sport fish communities 0.15 pg/L Cold water communities 0.045 pg/L Warm water forage and limited 26 ug/L forage fish communities and limited aquatic life B-HCH Public water supply: Warm water sport fish communities 0.12 pg/L Cold water communities 0.059 pg/L Great Lakes communities 0.06 pg/L Non-water supply: Warm water sport fish communities 0.027 pg/L Cold water communities 0.079 pg/L Warm water forage and limited 46 pg/L forage fish communities and limited aquatic life y-HCH Public water supply: Warm water sport fish communities 0.14 pg/L Cold water communities 0.067 pg/L Great Lakes communities 0.068 pg/L Non-water supply: Warm water sport fish communities 0.03 pg/L Cold water communities 0.09 pg/L Warm water forage and limited 53 pg/L forage fish communities and limited aquatic life HCH-technical grade Public water supply: Warm water sport fish communities 0.094 pg/L Cold water communities 0.044 pg/L Great Lakes communities 0.045 pg/L Non-water supply: Warm water sport fish communities 0.02 pg/L Cold water communities 0.06 pg/L HCH 210 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane (continued) Agency Description Information References STATE (Cont.) Wisconsin Warm water forage and limited 35 pg/L forage fish communities and limited aquatic life c. Other Restricted use of pesticide. Special CELDS 1993 requirements on registration, permits, labeling, application, storage, disposal record keeping and/or reporting. Alabama Arkansas Arizona California Colorado Connecticut Delaware Florida Georgia Hawaii Kansas Kentucky Illinois Iowa Maine Maryland Massachusetts Michigan Minnesota Missouri Montana Nevada New Hampshire New Jersey New Mexico New York North Carolina North Dakota Ohio Oklahoma Oregon Pennsylvania South Carolina South Dakota Utah Vermont Virginia Washington Wisconsin Wyoming Groundwater protection; hazardous CELDS 1993 waste discharge Alabama 0.004 pg/L 7. REGULATIONS AND ADVISORIES 211 TABLE 7-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane (continued) West Virginia Agency Description Information References STATE (Cont.) California 0.004 pg/L CELDS 1993 Colorado Not specified Delaware Not specified Kentucky 0.004 pg/L Louisiana Not specified Massachusetts 0.004 pg/L Minnesota Not specified Nebraska 0.004 pg/L New Jersey 0.004 pg/L New York Not detectable North Carolina 0.004 pg/L North Dakota Not specified Oregon 0.004 pg/L South Carolina 0.004 pg/L Tennessee 0.004 pg/L Texas 0.004 pg/L Utah 0.004 pg/L Wisconsin 0.001 mg/L Groundwater protection; EP toxicity 0.4 mg/L CELDS 1993 Alabama Nebraska North Carolina Tennessee Vermont Virginia Water quality criteria for agricultural use, CELDS 1993 recreation, wildlife and/or fish Arizona Florida Missouri Nebraska Nevada Ohio Utah Hazardous waste criteria for lindane CELDS 1993 Colorado Illinois Louisiana Massachusetts Minnesota North Dakota Vermont HCH 212 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hexachlorocyclohexane (continued) Agency Description Information References Wisconsin ‘Group 2B: Possible human carcinogen Group B2: Probable human carcinogen “Group C: Possible human carcinogen ‘Group D: Not classifiable as to human carcinogenicity ACGIH = American Conference of Governmental Industrial Hygienists; ADI = Acceptable Daily Intake; DOT = Department of Transportation; EPA = Environmental Protection Agency; FAO = Food and Agriculture Organization; FDA = Food and Drug Administration; HCH = Hexachlorocyclohexane; IARC = International Agency for Research on Cancer; MCL = Maximum Contaminant Level; MCLG = Maximum Contaminant Level Goal; NAS = National Academy of Science; ND = Not Determined; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; ODW = Office of Drinking Water; OERR = Office of Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Wastes; OTS = Office of Toxic Substances; OWRS = Office of Water Regulations and Standards; PEL = Permissible Exposure Limit; REL = Recommended Exposure Limit; RfD = Reference dose; SDWA = Safe Drinking Water Act; SNARL = Suggested No Adverse Response Effect Level; TLV = Threshold Limit Value; TWA = Time Weighted Average; WHO = World Health Organization HCH 213 8. 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Formation of polychlorinated biphenyls from the pyrolysis of hexachlorocyclohexane in the presence of Fe,0,. Bull Environ Contam Toxicol 59:83-89. Zisterer DM, Moynaugh PN, Williams DC. 1996. Hexachlorocyclohexanes inhibit steroidogenesis in Y1 cells. Biochem Pharmacol 51:1303-1308. *Zoetemann BCJ, Harmsen K, Linders JBHJ, et al. 1980. Persistent organic pollutants in river water and ground water of the Netherlands. Chemosphere 9:231-249. HCH 271 9. GLOSSARY Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption Coefficient (K )—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—EXxposure 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. HCH 272 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—TIsolated from the living organism and artificially maintained, as in a test tube. In Vivo—Occurring within the living organism. Lethal Concentration ,, (LC, ,)—The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentrations, (L.Cy,)—A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. Lethal Dose ¢, (LD; ,)—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 Dose, (LD;,)—The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time, (LTs))—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 (K,,)—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. HCH 273 9. GLOSSARY q,*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q,* can be used to calculate an estimate of carcinogenic potency, the incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and pg/m?® 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 RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs 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 (TDyy)—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. HCH A-1 APPENDIX A ATSDR MINIMAL RISK LEVELS AND WORKSHEETS The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99-499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological profiles for each substance included on the priority list of hazardous substances; and assure the initiation of a research program to fill identified data needs associated with the substances. The toxicological profiles include an examination, summary, and interpretation of available toxicological information and epidemiologic evaluations of a hazardous substance. During the development of toxicological profiles, Minimal Risk Levels (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 for a given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are used by ATSDR health assessors to identify contaminants and potential health effects that may be of concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or action levels. MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor approach. They are below levels that might cause adverse health effects in the people most sensitive to such chemical-induced effects. MRLs are derived for acute (1-14 days), intermediate (15-364 days), and chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not mean that adverse health effects will occur. HCH A-2 APPENDIX A MRLs are intended only to serve as a screening tool to help public health professionals decide where to look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health principle of prevention. Although human data are preferred, MRLs often must be based on animal studies because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes that humans are more sensitive to the effects of hazardous substance than animals and that certain persons may be particularly sensitive. Thus, the resulting MRL may be as much as a hundredfold below levels that have been shown to be nontoxic in laboratory animals. Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews, with participation from other federal agencies and comments from the public. They are subject to change as new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. For additional information regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333. HCH A-3 APPENDIX A MINIMAL RISK LEVEL (MRL) WORKSHEET Chemical Name: y-HCH CAS Number: 58-89-9 Date: January 15, 1999 Profile Status: Draft 3, Post-public Route: [ ] Inhalation [X] Oral Duration: [X] Acute [] Intermediate [] Chronic Graph Key: 9 Species: Rat Minimal Risk Level: 0.01 [X] mg/kg/day [] ppm Reference: Joy et al. 1982 Experimental design: (human study details or strain, number of animals per exposure/control groups, sex, dose administration details): Groups of 7-14 male Sprague-Dawley rats were exposed by gavage to 0, 1, 3, or 10 mg/kg/day lindane in corn oil for up to 23 days. Kindling (development of seizures with repeated application of initially subthreshold electrical stimuli) was performed. Effects noted in study and corresponding doses: Electronic amygdaloid stimulation to induce epileptic-like seizures had a significant effect on number of rats with electrical after discharges exhibiting behavioral responses given the 3 mg/kg/day dose for 4 days. Significant changes in most indices (number of stimulations required to give a behavioral response, number of stimulations evoking an afterdischarge until subjects showed first generalized epileptic response) were seen at 3 mg/kg/day after 23 days. Calculations: 1 mg/kg/day X 1/100UF = 0.01 mg/kg/day. Dose and endpoin d for L derivation: [X] NOAEL []LOAEL Uncertainty Factors used in MRL derivation: [1 foruseof a LOAEL [X] 10 for extrapolation from animals to humans [X] 10 for human variability Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: No ther additional studies or pertinent information whi Rats exposed by gavage to 2.97 mg/kg/day lindane for 6 days exhibited increased pineal N-acetyl-transferase and decreased serotonin levels (Attia et al. 1991). Serrano et al. (1990a) exposed rats to 5 mg/kg/day y-HCH by oil gavage for 3 days, resulting in decreased myelin and 2',3'-cyclic nucleotide 43'-phosphodiesterase activity in the brain. Seizures and convulsions have been reported in humans following ingestion of y-HCH HCH A-4 APPENDIX A (Davies et al. 1983; Harris et al. 1969; Munk and Nantel 1977; Powell 1980; Starr and Clifford 1972; Storen 1955). HCH A-5 APPENDIX A MINIMAL RISK LEVEL (MRL) WORKSHEET Chemical Name: B-HCH CAS Number: 319-85-7 Date: January 15, 1999 Profile Status: Draft 3, Post-public Route: [ ] Inhalation [X] Oral Duration: [X] Acute [ ] Intermediate [] Chronic Graph Key: 9 Species: Mouse Minimal Risk Level: 0.2 [X] mg/kg/day [] ppm Reference: Cornacoff et al. 1988 Experimental design (human study details or strain, num f ani I eX dose administration details): Groups of 6 female B6C3F1 mice were treated with 0, 100, 300, or 1000 ppm beta-HCH in the diet for 30 days (0, 19, 57, or 190 mg/kg/day). Effects noted in study and corresponding doses: Mice receiving 57 or 190 mg/kg/day exhibited ataxia within 1 week. The signs were resolved in a few days in the 57 mg/kg/day group, but 80% of mice in the 190 mg/kg/day group became laterally recumbant and were euthanized. No ataxia was seen at 19 mg/kg/day. Dose and endpoint used for MRL derivation: 19 mg/kg/day (100 ppm); ataxia. Calculations: 19 mg/kg/day X 1/100UF = 0.19 mg/kg/day. [X] NOAEL []LOAEL Uncertainty Factors used in MRL derivation: [1 10 for use of a LOAEL [X] 10 for extrapolation from animals to humans [X] 10 for human variability Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: Yes. A food factor of 0.19 kg feed/kg body weight/day for female B6C3F, mice was used to convert dose from mg/kg (ppm) food to mg/kg body weight as follows: 100 ppm X 0.19 (mouse food factor) = 19 mg/kg/d; 300 ppm = 57 mg/kg/d; 1000 ppm = 190 mg/kg/day. If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: Other additional studies or pertinent inform whi A study by Hulth et al. (1978) in which female NMRI mice were exposed once ovally to alpha-HCH also found neurological effects in the form of increased convulsive threshold and increased brain GABA levels at 150 mg/kg/day. A significant reduction in motor conduction velocity in tail nerve was seen in Wistar rats exposed orally to 66 mg/kg/day beta-HCH for 30 days (Muller et al. 1981). Rats treated with 12.5 mg/kg/day beta-HCH in food for 13 weeks underwent early autopsy due to progressive clinical signs (e.g., ataxia followed by coma) (Van Velsen et al. 1986). HCH A-6 APPENDIX A MINIMAL RISK LEVEL (MRL) WORKSHEET Chemical Name: a-HCH CAS Number: 319-84-6 Date: January 15, 1999 Profile Status: Draft 3, Post-public Route: [ ] Inhalation [X] Oral Duration: [ ] Acute [ ] Intermediate [ X ] Chronic Graph Key: 61 Species: Rat Minimal Risk Level: _0.008 [X] mg/kg/day [ ] ppm Reference: Fitzhugh et al. 1950 (Table 2 of the article). Experimental design (human study details or strain, number of animals per exposure/control groups, sex, dose administration details): Groups of 10 male and 10 female Wistar rats were treated with 0, 10, 50, 100, or 800 ppm alpha-HCH in food (0.8, 4, 8, or 64 mg/kg/day) for the lifespan. The mean age at death of the 10 ppm group (NOAEL) was 54.6 weeks and of the control group was 58.3 weeks. The lifetime of the animals sacrificed at the end of the experiment was taken as 107 weeks. Body weight, organ weight, and histopathological changes were monitored. Effects noted in study and corresponding doses: Body weight decreased significantly compared to controls in males (18%) and females (13%) at 800 ppm (64 mg/kg/day). A significant decrease (38%) in age at death was seen at 80 mg/kg/day. A significant increase in relative liver weight (36%) was seen at 50 ppm (4 mg/kg/day). Slight microscopic liver damage (diffuse cell enlargement, focal necrosis, fatty degeneration) was seen at 50 ppm (4 mg/kg/day), and slight kidney damage (focal nephritis) was seen at 800 ppm (64 mg/kg/day). Dose and endpoint used for MRL derivation: 0.8 mg/kg/day (10 ppm); no hepatic effects. Calculations: 0.8 mg/kg/day x 1/100UF = 0.008 mg/kg/day. [X] NOAEL [] LOAEL Uncertainty Factors used in MRL derivation: [1] 10 for use of a LOAEL [X] 10 for extrapolation from animals to humans [X] 10 for human variability Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: Yes. A food factor of 0.08 kg feed/kg body weight/day for female Wistar rats was used to convert dose from ppm food to mg/kg body weight as follows: 10 ppm x 0.08 (rat food factor) = 0.8 mg/kg/day; 50 ppm = 4 mg/kg/day; 100 ppm = 8 mg/kg/day; 800 ppm = 64 mg/kg/day. If an inhalation study in animals, list the conversion factors used in determinin ivalen HCH A-7 APPENDIX A Other additional studies or pertinent information which lend support to this MRL:Other studies have observed various hepatic effects after chronic-duration oral exposure to alpha and other HCH isomers (Amyes et al. 1990; NCI 1977; Wolff et al. 1987; Ito et al. 1975; Thorpe and Walker 1973; Munir et al. 1983; Kashyap et al. 1979). Amyes et al. observed periacinar hypertrophy in male and female Wistar rats treated with 8 mg/kg/day y-HCH in their diet for up to 52 weeks. The NOAEL was determined to be 0.8 mg/kg/day. Hepatocellular carcinoma was observed in rats fed 50 mg/kg/day a-HCH in their diet for 72 week (Ito et al. 1975). Hepatocellular carcinoma was also reported in mice treated with 34 mg/kg/day B-HCH in their diet for 104 weeks (Thorpe and Walker 1973). HCH A-8 APPENDIX A MINIMAL RISK LEVEL (MRL) WORKSHEET Chemical Name: B-HCH CAS Number: 319-85-7 Date: January 15, 1999 Profile Status: Draft 3, Post-public Route: [ ] Inhalation [X] Oral Duration: [ ] Acute [X ] Intermediate [] Chronic Graph Key: 22 Species: Rat Minimal Risk Level: _0.0006 _ [X] mg/kg/day [ ] ppm Reference: Van Velsen et al. 1986 Experimental design (human study details or strain, number of animals per exposure/control grou X dose administration details): Groups of 10 male and 10 female Wistar rats were treated with 0, 2, 10, 50. or 250 ppm beta-HCH in food for 13 weeks (0, 0.18, 0.9, 4.5, or 22.5 mg/kg/day), then sacrificed. Effects noted in study and corresponding doses: Hyalinization of centrilobular cells, indicating the initiation of hepatic effects, was observed at the low dose (2 ppm or 0.18 mg/kg/day). An increase in cellular hypertrophy and number of eosinophils was seen at 2 ppm (0.18 mg/kg/day). Centrilobular hepatocytic hypertrophy and proliferation of smooth endoplasmic reticulum were seen at the high dose in 8/9 animals. A dose-dependent increase in liver weight was seen at 10 ppm (0.9 mg/kg/day) and above. Dose and endpoint used for MRL derivation: 0.18 mg/kg/day; hyalinization of centrilobular cells. Calculations: 0.18 mg/kg/day X 1/300UF = 0.0006 mg/kg/day. [INOAEL [X]LOAEL Uncertainty Factors used in MRL derivation: [X] 3 for use of a minimal LOAEL [X] 10 for extrapolation from animals to humans [X] 10 for human variability Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: Yes. A food factor of 0.09 kg feed/kg body weight/day for male Wistar rats was used to convert from ppm in food to mg/kg as follows: 2 ppm X 0.09 (rat food factor) = 0.18 mg/kg/day; 10 ppm = 0.9 mg/kg/day; 50 ppm = 4.5 mg/kg/day; 250 ppm = 22.5 mg/kg/day. If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: Other additional studies or pertinent information which lend support to this MRL: Significant increases in liver weight and the levels of hepatic cytochrome P-450, triglycerides, phospholipids, and cholesterol were seen in rats fed 50 mg/kg/day B-HCH for 2 weeks (Ikegami et al. 1991a, 1991b). Liver hypertrophy was seen in rats fed 25 mg/kg/day for 24 weeks (Ito et al. 1975), and in mice fed 32.5 mg/kg/day for 24 weeks (Tto et al. 1973). Fatty degeneration and necrosis were seen in liver of mice fed 0.5-40 mg/kg/day for up to HCH APPENDIX A 53 weeks (Fitzhugh et al. 1950). Schéter et al. (1987) also observed an increase in hepatic foci in rats exposed to 3 mg/kg/day in the diet for 20 weeks. A-9 HCH A-11 APPENDIX A MINIMAL RISK LEVEL (MRL) WORKSHEET Chemical Name: y-HCH CAS Number: 58-89-9 Date: January 15, 1999 Profile Status: Draft 3, Post-public Route: [ ] Inhalation [X] Oral Duration: [|] Acute [X ] Intermediate [ ] Chronic Graph Key: 29 Species: Mouse Minimal Risk Level: _0.00001 [X] mg/kg/day [] ppm Reference: Meera et al. 1992 Experimental design (human study details or strain, number of animals per exposure/control groups, sex, dose administration details): Groups of 6 female Swiss mice were exposed in the diet to 0, 0.012, 0.12, or 1.2 mg/kg/day y-HCH for up to 24 weeks. Effects noted in study and corresponding doses: A dose-dependent biphasic response (stimulation followed by suppression) in cell-mediated and humoral components of the immunological profile was seen. In vitro splenic lymphocyte transformation in response to the mitogen Con A showed a faster onset of proliferative response (4 weeks) at doses 0.12 and 1.2 mg/kg, with an onset of 8 weeks at 0.12 mg/kg. Dose-dependent increase in size of thymus medulla, and decrease in cellular population of cortex was also seen. Dose and endpoint used for MRL derivation: 0.012 mg/kg/day; reduced activity of lymphoid follicles with prominent megakaryocytes and delayed hypersensitivity to immune challenge. Calculations: 0.012 mg/kg/day X 1/1000UF = 0.00001 mg/kg/day. [ INOAEL [X]LOAEL Uncertainty Factors used in MRL derivation: [X] 10 for use of a LOAEL [X] 10 for extrapolation from animals to humans [X] 10 for human variability Was a conversion used from ppm in food or water to a mg/body weight dose? If so, explain: Yes. Conversions performed by authors of the study—details not provided. If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: Other additional studies or pertinent information which lend support to this MRL: Immunosuppression in the form of reduced antibody response to Salmonella challenge was seen in rats exposed to 6.25 mg/kg/day gamma-HCH for up to 5 weeks (Dewan et al. 1980). Acute oral exposures of mice to 10 mg/kg/day gamma-HCH for 10 days resulted in residual bone marrow damage and suppressed granulocyte-macrophage progenitor cells, while at 3-day exposures to 40 mg/kg/day, thymus cortex atrophy was also seen (Hong and Boorman 1993). HCH 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 (NOAELSs), Lowest-Observed-Adverse-Effect Levels (LOAELSs), or Cancer Effect Levels (CELSs). 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. (2) 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 HCH (3) “4 4) (6) (7 (®) ® (10) at) B-2 APPENDIX B 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. NOAELSs and LOAEL:s 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 LOAELSs 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 NOAELSs and LOAELSs from different studies. In this case (key number 18), rats were exposed to 1,1,2,2-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. LOAELSs 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 LOAELSs. Reference The complete reference citation is given in chapter 8 of the profile. CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELSs are always considered serious effects. HCH B-3 APPENDIX B 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/m?® 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 38ris 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 I evels 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 (q,*). (19) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. 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? HCH B-4 APPENDIX B 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. TABLE 2-1. Levels of Significant Exposure to [Chemical x] — Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL i figure® Species duration System (ppm) Less serious (ppm) Reference INTERMEDIATE EXPOSURE Systemic | | | ! | l 18 Rat 13 wk Resp 3 ® 10 (hyperplasia) Nitschke et al. 5d/wk 1981 6hr/d CHRONIC EXPOSURE Cancer | 38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982 5d/wk organs) 7hr/d 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 2 The number corresponds to entries in Figure 2-1. b an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 9 XION3ddVY HOH S-9 Acute Intermediate (14 days) (15-364 days) Systemic Systemic N N cr Rs < Oo RN) SP © sg gs & sf FF LS & & & > & & K &® 3 Q <& OS Q <& NS NS <& oO 10000 1000 o ® O oO e% ro 30r 100 ® Dd, 20m® Boom air 0 @ 3mm XL 0 ®*e 4918r;g 22g21r O 28m® 29r 27c 40mg 10 > 33r 22m 34r >Q er 1 I | 104 — 0.1 | 10-5 Estimated — v Upper Bound 0.01 § | Human Cancer Key 10 Risk Levels 0.001 r Rat @ LOAEL for serious effects (animals) | Minimal risk level for effects 1077 m Mouse (DP LOAEL for less serious effects (animals) | other than cancer 0.0001 h Rabbit (OO NOAEL (animals) g Guinea Pig CEL - Cancer Effect Level The number next to each point 0.00001 Dn * corresponds o entries in he 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 a XION3ddY HOH 9-9 HCH B-7 APPENDIX B Chapter 2 (Section 2.5) Relevance to Public Health 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 2.8, "Interactions with Other Substances,” and 2.9, "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 (RfDs). 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. HCH ACGIH ADME atm ATSDR BCF BSC C CDC CEL CERCLA CFR CLP cm CNS d DHEW DHHS DOL ECG EEG EPA EKG F F, FAO FEMA FIFRA fpm ft FR g GC gen HPLC hr IDLH IARC ILO in Kd kkg K,. Kow C-1 APPENDIX C ACRONYMS, ABBREVIATIONS, AND SYMBOLS American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion atmosphere Agency for Toxic Substances and Disease Registry bioconcentration factor Board of Scientific Counselors Centigrade Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations Contract Laboratory Program centimeter central nervous system day Department of Health, Education, and Welfare Department of Health and Human Services Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECG Fahrenheit first filial generation Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act feet per minute foot Federal Register gram gas chromatography generation high-performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio kilogram metric ton organic carbon partition coefficient octanol-water partition coefficient HCH mmHg mmol mo mppcf MRL MS NIEHS NIOSH NIOSHTIC ng nm NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP 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 HCH STEL STORET TLV TSCA = OR QM AI V tT ”@ 3 APPENDIX C short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average United States uncertainty factor year World Health Organization week greater than greater than or equal to equal to less than less than or equal to percent alpha beta delta gamma micrometer microgram US. GOVERNMENT PRINTING OFFICE: 1999-737-478 C-3 U.C. BERKELEY LIBRARIES c095491580