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, ~w.Y| ,1 *3$*V,''* `< v.7>-; ***,*** '^-., ^-> *- `-i-MUTf", *''Vv J#''% u-^vn. ;j. --~r`-'f- ]^r 1 ^ 4 il*%f j^rv. t- i?i .! "Bte . _ .,, . __ -., .M`V C DE Draff for Public Comment Comment Period Ends: February 20,1996 U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES . /A .:,... Public Health Service ^ Agency for Toxic Substances and Disease Registry DRAFT TOXICOLOGICAL PROFILE FOR VINYL CHLORIDE Prepared by: Sciences International, Inc. Under Subcontract to: 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 August 1995 `"DRAFT FOR PUBLIC COMMENT*** FI&S 149008 VINYL CHLORIDE ii 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. R&S149009 "`DRAFT FOR PUBLIC COMMENT" VINYL CHLORIDE UPDATE STATEMENT A Toxicological Profile for Vinyl Chloride was released on April 1993. This edition supersedes any previously released draft or final profile. Toxicological profiles are revised and republished as necessary, but no less than once every three years. For information regarding the update status of previously released profiles, contact ATSDR at: Agency for Toxic Substances and Disease Registry Division of Toxicology/Toxicology Information Branch 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 --DRAFT FOR PUBLIC COMMENT*" V FOREWORD This toxicological profile is prepared in accordance with guidelines developed by ATSDR and EPA. The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature (that has been peer-reviewed) that describes a hazardous substance's toxicologic properties. Other pertinent literature is also presented, but described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. Each toxicological profile begins with a public health statement, that describes in nontechnical language, a substance's relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance's health effects is described in a health effects summary. Data needs that are of significance to protect public health will be identified by ATSDR and EPA. The focus of the profiles is on health and toxicologic information; therefore, we have included this information in the beginning of the document. Each profile must include the following: (A) The examination, summary, and interpretation of available toxicologic information and epidemiologic evaluations on a hazardous substance in order to ascertain the levels of 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. (C) Where appropriate, identification of toxicologic testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. The principal audiences for the toxicological profiles are health professionals at the federal, state, and local levels, interested private sector organizations and groups, and members of the public. We plan to revise these documents in response to public comments and as additional data become available. Therefore, we encourage comments that will make the toxicological profile series of the greatest use. Comments should be sent to: Agency for Toxic Substances and Disease Registry Division of Toxicology Mail Stop E-29 Atlanta, Georgia 30333 R&S149012 VI Foreword The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) which amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare toxicological profiles for hazardous substances most commonly found at facilities on the CERCLA National Priorities List and that pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA), The availability of the revised priority list of 275 hazardous substances was announced in the Federal Register on February 28, 1994 (59 FR 9486). For prior versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); October 20, 1988 (53 FR 41280); October 26. 1989 (54 FR 43619); October 17, 1990 (55 FR 42067); and October 17, 1991 (56 FR 52166); and October 28, 1992 (57 FR 48801). Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the list This profile reflects our assessment of all relevant toxicologic testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR, the Centers for Disease Control and Prevention (CDC), and other federal agencies. It has also been reviewed by a panel of nongovernment peer reviewers and is being made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. David Satcher, M.D., Ph.D. Administrator Agency for Toxic Substances and Disease Registry VINYL CHLORIDE VII CONTRIBUTORS CHEMICAL MANAGER(S)/AUTHOR(S): Michael Brown, M.P.H. ATSDR, Division of Toxicology, Atlanta, GA Patricia M. Bittner, M.S. Sciences International, Inc., Alexandria, VA THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 1. Green Border Review. Green Border review assures consistency with ATSDR policy. 2. Health Effects Review. The Health Effects Review Committee examines the health effects chapter of each profile for consistency and accuracy in interpreting health effects and classifying end points. 3. 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. R&S149014 '"DRAFT FOR PUBLIC COMMENT"* R&S149015 VINYL CHLORIDE IX PEER REVIEW A peer review panel was assembled for Vinyl Chloride. The panel consisted of the following members: 1. Dale Hattis, Ph.D., Research Associate Professor, Clark University, Worcester, MA 2. Martha Radike, Ph.D., Research Associate Professor, University of Cincinnati, Cincinnati, OH 3. Theodore R. Torkelson, Sc.D., Private Consultant, Midland, MI These experts collectively have knowledge of vinyl chloride'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. R&S149016 '"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE xii 2.2.3.2 Systemic Effects............................................ 2.2.3.3 Immunological and Lymphoreticular Effects 2.2.3.4 Neurological Effects.................................... 2.2.3.5 Reproductive Effects.................................... 2.2.3.6 Developmental Effects ............................... 2.23.1 Genotoxic Effects......................................... 2.2.3.8 Cancer .......................................................... TOXICOKINETICS................................................................. 2.3.1 Absorption .................................................................... 2.3.1.1 Inhalation Exposure .................................... 2.3.1.2 Oral Exposure .............................................. 2.3.1.3 Dermal Exposure ......................................... 2.3.2 Distribution.................................................................... 2.3.2.1 Inhalation Exposure .................................... 2.3.2.2 Oral Exposure .............................................. 2.3.2.3 Dermal Exposure ......................................... 2.3.3 Metabolism.................................................................... 2.3.3.1 Inhalation Exposure .................................... 2.3.3.2 Oral Exposure .............................................. 2.3.3.3 Dennal Exposure ......................................... 2.3.4 Elimination and Excretion . 2.3.4.1 Inhalation Exposure 2.3.4.2 Oral Exposure . 2.3.4.3 Dermal Exposure 2.3.4.4 Other Routes of Exposure 2.3.5 Physiologically based Phannacokinetic (PBPK)/Pharmacodynaime (PD) 4ode s 2.4 MECHANISMS OF ACTION............... 2.4.1 Phannacokinctic Mechanisms . . 2.4.2 Mechanisms of Toxicity............ 2.4.3 Animal-to-Human Extrapolations 2'.5 RELEVANCE TO PUBLIC HEALTH . 2.6 BIOMARKERS OF EXPOSURE AND EFFECT 2.6.1 Biomarkers Used to Identify or Quantify Exposure to Vinyl Chloride 2.6.2 Biomarkers Used to Characterize Effects Caused by Vinyl Chloride 2.7 INTERACTIONS WITH OTHER SUBSTANCES........................ 2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE . . . 2.9 METHODS FOR REDUCING TOXIC EFFECTS ........................ 2.9.1 Reducing Peak Absorption Following Exposure................. 2.9.2 Reducing Body Burden ........................................................ 2.9.3 Interfering with the Mechanism of Action lor Toxic Effects 2.10 ADEQUACY OF THE DATABASE .............................................. 2.10.1 Existing Infonnation on Health Effects of Vinyl Chloride . 2.10.2 Identification of Data Needs ................................................ 2.10.3 On-going Studies.................................................................... 64 64 65 65 65 65 65 65 67 67 68 69 69 69 71 71 72 72 75 76 76 76 77 78 78 79 85 85 85 87 87 104 105 107 109 111 113 113 114 114 117 117 119 130 3. CHEMICAL AND PHYSICAL INFORMATION........................................................................... 133 3.1 CHEMICAL IDENTITY........................................................................................................... 133 3.2 PHYSICAL AND CHEMICAL PROPERTIES .................................................................... 133 R&S149017 --DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 4. PRODUCTION, IMPORT, USE, AND DISPOSAL .............................................................................. 137 4.1 PRODUCTION ....................................................................................................................................... 137 4.2 IMPORT/EXPORT................................................................................................................................. 141 4.3 USE............................................................................................................................................................. 141 4.4 DISPOSAL ............................................................................................................................................... 142 5. POTENTIAL FOR HUMAN EXPOSURE ............................................................................................... 143 5.1 OVERVIEW ............................................................................................................................................ 143 5.2 RELEASES TO THE ENVIRONMENT.............................................................................. - ... 145 5.2.1 Air.................................................................................................................................................. 145 5.2.2 Water............................................................................................................................................ 145 5.2.3 Soil ............................................................................................................................................... 148 5.3 ENVIRONMENTAL FATE................................................................................................................. 148 5.3.1 Transport and Partitioning....................................................................................................... 148 5.3.2 Transformation and Degradation .......................................................................................... 150 5.3.2.1 Air............................................................................................................................... 150 5.3.2.2 Water ......................................................................................................................... 150 5.3.2.3 Sediment and Soil ................................................................................................. 151 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT .............................. 152 5.4.1 Air.................................................................................................................................................. 152 5.4.2 Water............................................................................................................................................ 152 5.4.3 Sediment and Soil .................................................................................................................... 153 5.4.4 Other Environmental Media ................................................................................................. 153 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ...................................... 154 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES.............................................. 155 5.7 ADEQUACY OF THE DATABASE ............................................................................................... 155 5.7.1 Identification of Data Needs ................................................................................................. 156 5.7.2 On-going Studies....................................................................................................................... 158 6. ANALYTICAL METHODS............................................................................................................................ 161 6.1 BIOLOGICAL MATERIALS ............................................................................................................ 161 6.2 ENVIRONMENTAL SAMPLES ....................................................................................................... 164 6.3 ADEQUACY OF THE DATABASE ............................................................................................... 171 6.3.1 Identification of Data Needs .................................................................................................. 172 6.3.2 On-going Studies .7.................................................................................................................. 173 7. REGULATIONS AND ADVISORIES ....................................................................................................... 175 8. REFERENCES..................................................................................................................................................... 183 9. GLOSSARY ...........................................................................................................................................................223 APPENDICES A. MINIMAL RISK LEVEL WORKSHEETS ..........................................................................................A-l B. USER'S GUIDE............................................................................................................................................. B-l C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS....................................................................... C-l "'DRAFT FOR PUBLIC COMMENT*" R&S149018 R&S149019 VINYL CHLORIDE xvn LIST OF TABLES 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation.................................................... 13 2-2. Levels of Significant Exposure to Vinyl Chloride - Oral ........................................................... 58 2-3. Vinyl Chloride Partition Coefficients............................................................................................ 70 2-4. Physiological Parameters Used to Estimate Parameters from Vinyl Chloride Gas Uptake Experiments......................................................................................................................... 83 2-5. Estimates of Metabolic Parameters Obtained from Vinyl Chloride Gas Uptake Experiments . 84 2-6. Genotoxicity of Vinyl Chloride In Vivo .......................................................................... 101 2-7. Genotoxicity of Vinyl Chloride In Vitro....................................................................................... 102 2- 8. On-going Studies on Vinyl Chloride ............................................................................................... 131 3- 1. Chemical Identity of Vinyl Chloride ............................................................................................... 134 3- 2. Physical and Chemical Properties ofVinyl Chloride .................................................................... 135 4- 1. Facilities That Manufacture or Process Vinyl Chloride.............................................................. 138 5- 1. Releases to the Environment from Facilities That Manufacture or Process Vinyl Chloride .. 146 6- 1. Analytical Methods for Determining Vinyl Chloride in BiologicalMaterials.................................162 6- 2. Analytical Methods for Determining Vinyl Chloride in EnvironmentalSamples ......................... 166 7- 1. Regulations and Guidelines Applicable to Vinyl Chloride......................................................... 176 R&S149020 --DRAFT FOR PUBLIC COMMENT-- VINYL CHLORIDE 1. PUBLIC HEALTH STATEMENT 1 This public health statement tells you about vinyl chloride and the effects of exposure. The Environmental Protection Agency (EPA) has identified 1,416 hazardous waste sites as the most serious in the nation. These sites make up the National Priorities List (NPL) and are targeted for long term federal clean-up. Vinyl chloride has been found in at least 493 NPL sites. However, it's unknown how many NPL sites have been evaluated for these substances. As EPA looks at more sites, the sites with vinyl chloride may increase. This is important because exposure to this substance may harm you and because these sites may be sources of exposure. When a substance is released from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment. This release does not always lead to exposure. You are exposed to a substance only when you come in contact with it by breathing, eating, touching, or drinking. If you are exposed to vinyl chloride, many factors will 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 VINYL CHLORIDE? Vinyl chloride is a colorless gas at normal temperatures. It is also known as chloroethene, chloroethylene, ethylene monochloride, or monochloroethylene. It is flammable (easily capable of burning) as a gas and is not stable at high temperatures or pressure. Vinyl chloride will exist in liquid form if it is kept under high pressure. Vinyl chloride has a mild, sweet odor. Most people begin to smell vinyl chloride in the air at 3,000 pails vinyl chloride per million parts (ppm) of air. Most people begin to taste vinyl chloride in water at 3.4 ppm. All vinyl chloride is manmade or results from the breakdown of other manmade substances, such as trichloroethylene, trichloroethane. and tetrachloroethylene. Production of vinyl chloride in the United R & S 149022 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 1.0 PUBLIC HEALTH STATEMENT 2 States has grown at an average rate of 7% from the early 1980s to the early 1990s, with an additional increase of approximately 22% between the years 1992 and 1993. Most of the vinyl chloride produced in the United States is used to make polyvinyl chloride (PVC). PVC is used to make a variety of plastic products including pipes, wire and cable coatings, and packaging materials. Other uses include furniture and automobile upholstery, wall coverings, housewares, and automotive parts. At one time, vinyl chloride was also used as a coolant, as a propellant in spray cans, and in some cosmetics. Since the mid 1970s, it has not been used for these purposes. Please refer to Chapter 3 for more information on the chemical and physical properties of vinyl chloride. For more information on the production and use of vinyl chloride, see Chapter 4. 1.2 WHAT HAPPENS TO VINYL CHLORIDE WHEN IT ENTERS THE ENVIRONMENT? Most of the vinyl chloride that enters the environment comes from the plastics industries, which release it into the air or into waste water. EPA limits the amount that industries may release. Vinyl chloride is a breakdown product of other manmade chemicals in the environment. Vinyl chloride has entered the environment at hazardous waste sites as a result of its improper disposal or leakage from storage containers or from spills. Vinyl chloride has been found in tobacco smoke, perhaps as a result of the manufacturing process. Liquid vinyl chloride evaporates easily into the air. Vinyl chloride in water or soil evaporates rapidly if it is near the surface. Vinyl chloride in the air breaks down in a few days. When vinyl chloride breaks down in air, it can form other harmful chemicals. A limited amount of vinyl chloride can dissolve in water. It can enter groundwater and can also be found in groundwater from the breakdown of other chemicals. It is unlikely that vinyl chloride will build up in plants or animals that you might eat. For more information on what happens to vinyl chloride in the environment, please see Chapters 4 and 5. 1.3 HOW MIGHT I BE EXPOSED TO VINYL CHLORIDE? Since vinyl chloride commonly exists in a gaseous state, you are most likely to be exposed to it by breathing it in. Vinyl chloride is not normally found in urban, suburban, or rural air in amounts that R&S149023 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 1.0 PUBLIC HEALTH STATEMENT 3 are detectable by the usual methods of analysis. However, vinyl chloride has been found in the air near plastics industries, hazardous waste sites, and landfills. The amount of vinyl chloride in the air near these places ranges from trace amounts to 0.041 ppm of air, but may exceed 1 ppm. Levels as high as 44 ppm have been found at some landfills. One can also be exposed to vinyl chloride in the air through tobacco smoke from cigarettes or cigars. You may also be exposed to vinyl chloride by drinking water from contaminated wells but how often this occurs is not known. Most drinking water supplies do not contain vinyl chloride. In a 1982 survey, vinyl chloride was found in less than 1% of the 945 groundwater supplies tested in the United States. The concentrations found in groundwater were up to 0.008 ppm, with a detection limit of 0.001 ppm. Other studies have reported groundwater vinyl chloride concentrations at or below 0.38 ppm. At one time, the flow of water through PVC pipes added very low amounts of vinyl chloride to water. For example, in one study of newly installed pipes, the drinking water had 0.001 ppm of vinyl chloride. No current information on the amount of vinyl chloride released from PVC pipes into water is available. In the past, vinyl chloride could get into food that was stored in materials that contained PVC. Now the U.S. government regulates the amount of vinyl chloride in food packaging materials. A model of food systems shows that when levels less than 1 ppm of vinyl chloride monomer are used in PVC packaging, "essentially zero" vinyl chloride enters food by contact with these products. Exposure to vinyl chloride can also occur in the workplace by breathing in any vapors in the air or if it comes into contact with your skin or eyes. Almost 80,000 people work with vinyl chloride at their jobs. This number includes workers who make vinyl chloride and PVC and workers who use PVC to make other objects such as pipes. Please refer to Chapter 5 for more information on ways that people are exposed to vinyl chloride. 1.4 HOW CAN VINYL CHLORIDE ENTER AND LEAVE MY BODY? If vinyl chloride comes into contact with your skin, negligible amounts may pass through the skin and enter your body. Vinyl chloride is more likely to enter your body when you breathe air or drink water containing it. This could occur near certain factories or hazardous waste sites or in the workplace. R&S 149024 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 1.0 PUBLIC HEALTH STATEMENT 4 Most of the vinyl chloride that you breathe in or swallow enters your blood rapidly. The vinyl chloride in your blood travels through your body. When some portion of it reaches your liver, it is changed into several different substances. Most of these new substances also travel in your blood. Once they reach your kidneys, they leave your body in your urine. Most of the vinyl chloride is gone from your body a day after you breathe it in or swallow it. The liver, however, makes some new substances that do not leave your body as rapidly. A few of these substances are more harmful than vinyl chloride because they react with chemicals inside your body and interfere with the way your body uses or responds to these chemicals. Some of these substances react in the liver and cause damage there. It takes more time for your body to get rid of these changed chemicals, but eventually your body will remove them as well. If you breathe in or swallow more vinyl chloride than your liver can chemically change, you will breathe out excess vinyl chloride. Chapter 2 contains more information on how vinyl chloride enters and leaves your body. 1.5 HOW CAN VINYL CHLORIDE 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. If you breathe high levels of vinyl chloride, you will feel dizzy or sleepy. These effects occur within 5 minutes at about 10,000 ppm of vinyl chloride. You can easily smell vinyl chloride at this concentration. If you breathe very high levels, you may pass out. You can rapidly recover from these effects if you breathe fresh air. Some people get a headache when they breathe fresh air immediately after breathing very high levels of vinyl chloride. People may die if they breathe extremely high levels of vinyl chloride. These levels are much higher than the levels that cause you to pass out. R&S 149025 "'DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 1.0 PUBLIC HEALTH STATEMENT 5 Studies in animals show that extremely high levels of vinyl chloride can damage the liver, lungs, and kidneys. These levels can also damage the heart and prevent blood clotting. The effects of drinking high levels of vinyl chloride are unknown. If you spill liquid vinyl chloride on your skin, it will numb the skin and cause redness and blisters. Some people who have breathed vinyl chloride over several years have developed changes in the structure of their livers. People are more likely to develop these changes if they breathe high levels of vinyl chloride. Some people who have worked with vinyl chloride have developed nerve damage, and others have developed an immune reaction. The lowest levels that cause liver changes, nerve damage, and the immune reaction in humans are not known. Certain jobs related to polyvinyl chloride production expose workers to very high levels of vinyl chloride. Some of these workers have problems with the blood flow in their hands. Their fingers turn white and hurt when they go into the cold. It may take a long time to recover when they go into a warm place. In some of these people, changes have appeared on the skin of their hands and forearms. Also, bones at the tips of their fingers have broken down. Studies suggest that some people may be more sensitive to these effects than others. Some men who work with vinyl chloride have complained of a lack of sex drive. Results of studies in animals show that long-term exposure may damage the sperm and testes. Some women who work with vinyl chloride have had irregular menstrual periods. Some have developed high blood pressure during pregnancy. Studies of women who live near vinyl chloride manufacturing plants could not prove that vinyl chloride causes birth defects. Studies using pregnant animals show that breathing vinyl chloride may harm their unborn offspring. Animal studies also show that vinyl chloride may cause increased numbers of miscarriages early in pregnancy. It may also cause decreased weight and delayed skeletal development in fetuses. The same very high levels of vinyl chloride that caused these fetal effects also caused adverse effects in the pregnant animals. Results from several studies suggest that breathing air or drinking water containing low levels of vinyl chloride may increase the risk of getting cancer. Studies of workers who have breathed vinyl chloride over many years showed cancer of the liver. Brain cancer, lung cancer, and some cancers of the blood also may be connected with breathing it daily for several years. Studies of long-term exposure in animals show that increases in cancer of the liver and mammary gland may occur at very low levels of R&S 149026 -- DRAFT FOR PUBLIC COMMENT"' VINYL CHLORIDE 1.0 PUBLIC HEALTH STATEMENT 6 vinyl chloride in the air. Studies show that animals fed low levels of vinyl chloride each day during their lifetime had an increased risk of getting liver cancer. The Department of Health and Human Services has determined that vinyl chloride is a known carcinogen. The International Agency for Research on Cancer has determined that vinyl chloride is carcinogenic to humans, and EPA has determined that vinyl chloride is a human carcinogen. More information on the health effects of vinyl chloride in humans and animals can be found in Chapter 2. 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO VINYL CHLORIDE? The results of several tests can sometimes show if you have been exposed to vinyl chloride, depending on the amount of your exposure and how recently it has happened. However, scientists do not know if these measurements can tell how much vinyl chloride you have been exposed to. These tests are not normally available at your doctor's office. Vinyl chloride can be measured in your breath, but the test must be done shortly after exposure. This test is not very helpful for measuring very low levels of the chemical. The amount of the major breakdown product of vinyl chloride, thiodiglycolic acid, in the urine may give some information about exposure. However, this test must be done shortly after exposure and is not a reliable indicator of the level of exposure. Also, exposure to other chemicals can produce the same breakdown products in your urine. Vinyl chloride can bind to genetic material in your body. The amount of this binding can be measured by sampling your blood or tissue. This measurement will give information about whether you have been exposed to vinyl chloride, but it is not sensitive enough to determine the effects on the genetic material resulting from exposure. For more information, see Chapters 2 and 6. 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The federal government develops regulations and recommendations to protect public health. Regulations can be enforced by law. Federal agencies that develop regulations for toxic substances include the Environmental Protection Agency (EPA), the Occupational Safety and Health R&S149027 "'DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 1.0 PUBLIC HEALTH STATEMENT 7 Administration (OSHA), and the Food and Drug Administration (FDA). Recommendations 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. 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 vinyl chloride include the following: Vinyl chloride is regulated in drinking water, food, and air. Because it is a hazardous substance, regulations on its disposal, packaging, and other forms of handling also exist. EPA requires that the amount of vinyl chloride in drinking water not exceed 0.002 milligrams per liter (mg/L) of water (0.002 ppm). In addition, EPA has issued health advisories for drinking water that are based on length of exposure. For short-term exposures of 1 or 10 days, EPA advises that drinking water levels not exceed 3.0 mg/L (3.0 ppm). For longer periods of exposure (up to approximately 7 years), levels should not exceed 0.05 mg/L (0.05 ppm) for adults. Children's intake should be limited to less than 0.01 mg/L (0.01 ppm) over long periods. A health advisory for lifetime exposure has not been issued. Under the EPA's Ambient Water Quality Criteria (AWQC) for the protection of human health, a concentration of zero has been recommended for vinyl chloride in ambient water. In order to limit intake of vinyl chloride through foods to levels considered safe, the FDA regulates the vinyl chloride content of various plastics. These include plastics that carry liquids and plastics that come into contact with food. The limits for vinyl chloride content vary depending on the nature of the plastic and its use. EPA has named vinyl chloride as a hazardous part of solid waste. If quantities greater than 1 pound (0.454 kilograms [kgJ) are released to the environment, the National Response Center of the federal government must be told immediately. R&S149028 `"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 1.0 PUBLIC HEALTH STATEMENT 8 OSHA regulates levels of vinyl chloride in the workplace. The maximum allowable amount of vinyl chloride in workroom air during an 8-hour workday in a 40-hour workweek is 1 ppm. The maximum amount allowed in any 15-minute period is 5 ppm. NIOSH recommends that the exposure limit (for a time-weighted average) for vinyl chloride in air be the lowest reliably detectable concentration. Workers exposed to any measurable amount of it must wear special breathing equipment. HPA sets emission standards for vinyl chloride and PVC plants., The amount of vinyl chloride allowed to be emitted varies depending on the type of production and discharge system used. Further regulations and guidelines that apply to vinyl chloride are presented in Chapter 7. 1.8 WHERE CAN I GET MORE INFORMATION? If you have any more questions or concerns, please contact your community or state health or environmental quality department or: Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road NE, Mailstop E-29 Atlanta, Georgia 30333 *Information line and technical assistance Phone: (404) 639-6000 Fax: (404) 639-6315 or 6324 ATSDR can also tell you the location of occupational and environmental health clinics. These clinics specialize in recognizing, evaluating, and treating illnesses resulting from exposure to hazardous substances. *To order toxicological profiles, contact: National Technical Information Service 5285 Port Royal Road Springfield, VA 22161 Phone (800) 553-6847 or (703) 487-4650 149029 DRAFT FOR PUBLIC COMMENT"* 1 VINYL CHLORIDE 2. HEALTH EFFECTS 9 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 on the toxicology of vinyl chloride. 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 lowestobserved-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 R&S 149030 `DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 10 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 users of the profiles to identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and figures may differ depending on the user's perspective. Public health officials and others concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals or exposure levels below which no adverse effects 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 vinyl chloride are indicated in Tables 2-1 and 2-2 and Figures 2-1 and 2-2. Because cancer effects could occur at lower exposure levels, the figures also show a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (1 O'4 to 10`7), as developed by EPA. Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for vinyl chloride. 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 noncancer health effects only and do not reflect a consideration of 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 R&S 149031 --DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 11 development or result from 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 h^s 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. 2.2.1 Inhalation Exposure 2.2.1.1 Death A report by Danziger (1960) described the deaths of two vinyl chloride workers. In one case, a worker exposed to high concentrations of vinyl chloride vapor emitted from an open valve was found dead. In another case, a worker responsible for cleaning a polymerization tank was found dead in the tank. Autopsies performed on these men showed congestion of the internal organs, particularly the lungs and kidneys, and failure of the blood to clot. Circumstances surrounding the deaths suggested that the deaths were due to breathing very high levels of vinyl chloride. No increase in mortality was noted in a prospective cohort study of 1,100 workers exposed to vinyl chloride compared to the controls (Laplanche et al. 1992). At the time of the study interview, 36% of the 1,100 workers were currently being exposed to vinyl chloride and 64% had been exposed in the past (Laplanche et al. 1987, 1992). Brief exposures to concentrations of vinyl chloride ranging from 100,000 to 400,000 ppm have been shown to be fatal in experimental animals such as rats (Lester et al. 1963; Mastromatteo et al. 1960), guinea pigs (Mastromatteo et al. 1960; Patty et al. 1930), and mice (Mastromatteo et al. 1960). At these concentrations, deaths occurred within 30-60 minutes. Male mice exposed to 30,000 ppm vinyl chloride for 5 days, 6 hours per day in a dominant lethal study showed increased mortality (Anderson et al. 1976). Increased mortality was also observed at much lower concentrations in maternal mice in a developmental toxicity study (John et al. 1977, 1981). In this study, maternal mice had an increased incidence of deaths following exposure to 500 ppm for 10 days during gestation. Decreased longevity was observed in intermediate-duration studies (Adkins et al. 1986; Drew et al. 1983; Feron et al. 1979a; Hong et al. 1981; Lee et al. 1978) and chronic-duration studies (Drew et al. R&S 149032 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 12 1983; Feron et al. 1979a; Viola 1970). A treatment-related increase in mortality was observed in mice exposed to 500 ppm of vinyl chloride for 6 hours per day, 5 days per week, for 6 months (Adkins et al. 1986). In mice and rats maintained for 12 months following a 6-month, 6-hour-per-day, 5-day-perweek exposure regime, decreased longevity was observed at concentrations as low as 50 ppm (Hong et al. 1981). However, statistical analyses of the data were not available to verify the significance of the decrease. Substantial increases in mortality of mice and rats exposed to 250 ppm vinyl chloride for 12 months were observed by Lee et al. (1977a, 1978). In addition, small increases in mortality of mice and rats during the 12-month exposure period were observed at 50 ppm in these reports. However, statistical analyses indicating the significance of these increases were not presented. The influence of the age of female animals at the time of exposure to vinyl chloride on survival was examined by Drew et al. (1983). In female hamsters exposed to 200 ppm, two strains of female mice exposed to 50 ppm, and female rats exposed to 100 ppm for 12 months, a higher death rate was observed when 2-month-old animals were exposed than when 8- or 14-month-old animals were exposed. Similar trends were observed when hamsters and mice were exposed to these concentrations for 6 months. These results do not necessarily indicate that young people are more susceptible to the lethal effects of vinyl chloride, since animals that were exposed later in life may have died of agerelated causes prior to the expression of the lethal effects. This study was limited in that only one dose of vinyl chloride was tested in each species. The highest NOAEL values and all reliable LOAEL values for death in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.2 Systemic Effects The highest NOAEL values and all reliable LOAEL values for each study with a systemic end point in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Respiratory Effects. Limited information is available on the acute effects from inhalation of vinyl chloride by humans. Autopsy findings from a man who died after being overcome by vinyl chloride vapor revealed the irritating nature of extremely high-level inhalation exposure. The lungs were found to be intensely hyperemic, and some desquamation of the alveolar epithelium had occurred (Danziger 1960). Reports regarding respiratory effects in workers who are occupationally exposed to vinyl R & S 149033 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' Key to* Species/ figure (strain) Exposure duration/ frequency ACUTE EXPOSURE Death Rat (NS) 30 min TABLE 2-1. Levels ol Significant Exposure to Vinyl Chloride - Inhalation System NOAEL (ppm) Less serious (ppm) LOAEL (effect) Serious (ppm) 300000 (5/5 died) Reference t Mastromatteo el al. 1960 Mouse (CD-I) 5d 6hr/d Mouse (CF-1) Mouse (NS) 10 d 7 hr/d Gd6-15 30 min 30000 M (11/20 died) Anderson et al. 1976 500 F (17% maternal death) John et al. 1977, 1981 200000 (1/5 died) Mastromatteo et al. 1960 Gn pig (NS) 30 min 300000 (1/5 died) Mastromatteo et al. 1960 Gn pig (NS) up to 8 hr 100000 (death) Patty etal. 1930 \ CO t'E06HS'8d TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) Key to* Species/ figure (strain) Exposure duration/ frequency Systemic 7 Rat 1, 5 d (Holteman) 6hr/d System Hepatic NOAEL (ppm) Less serious (PPm) LOAEL (effect) Serious (ppm) 50000 M 100000 M (hepatocellular vacuolization, increased AKT and SDH) 8 Rat (NS) 30 min Resp 100000 (lung hyperemia) o J>3 Hepatic 100000 200000 (fatty infiltration changes) Renal 200000 300000 (renal congestion) *n O 33 g Rat 1, 5 d Hepatic 50000 *TJ C (Holtzman) 6hr/d 0r~3 o o o s s 10 Rat 1d Hepatic 50000 M m2 (NS) 6hr/d i * ii Mouse (NS) 30 min Resp 100000 (lung hyperemia) Hepatic Renal 200000 300000 100000 (liver congestion) (degenerative tubular epithelium) Reference 1 Jaeger et al. 1974 Mastrcmatteo et al. 1960 z Reynolds et al. 1975a Reynolds et al. 1975b ro X 5 5 I m "H moH CO Mastromatteo et al. 1960 seoens'sy VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - inhalation (continued) a Key to figure Species/ (strain) Exposure duration/ frequency 12 Gn pig (NS) 30 min System Resp NOAEL (ppm) _______________________________ LOAEL (effect) Less serious Serious (ppm)_____________________________________ (ppm) 100000 (slight pulmonary hyperemia) Immuno/Lymphor 13 Gn pig (NS) 30 min Cardio Hepatic Endocr Ocular 400000 200000 400000 400000 r 400000 300000 (fatty degeneration) Neurological 14 Human 3d 2x/d 5min 15 Rat 1 hr (Fischer- 344) 4000 8000 NS (dizziness) 50000 16 Rat 2 wk (Fischer- 344) 5d/wk 1 hr/d 17 Rat (Holtzman) 1, 5 d 6hr/d 500 50000 100000 M (anesthesia) Reference Mastro matteo et al. 1960 i Mastromatteo et al. 1960 Lester et al. 1963 ro Im > X OH Hehir et al. 1981 Hehir et al. 1961 Jaeger et al. 1974 - cn 906WS'Sd VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' a Key to figure Species/ (strain) Exposure duration/ frequency 18 Rat (Sherman) 2 hr TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) NOAEL System_______(ppm) ______________________________ LOAEL (effect) Less serious Serious (ppm)_____________________________________ (ppm) 50000 (moderate intoxication) Reference + Lester et al. 1963 19 Rat (NS) 30 min 100000 (narcosis) Mastromatteo et al. 1960 20 Mouse (ICR) 1 hr 5000 50000 (ataxia) Hehiretai. 1981 21 Mouse (NS) 30 min 100000 (narcosis) Mastromatteo et al. 1960 22 Gn pig (NS) 30 min 23 Gn pig (NS) up to 8 hr 10000 100000 (tremor, loss ot consciousness) 25000 (narcosis) Mastromatteo et al. 1960 Patty etal. 1930 Reproductive 24 Mouse (CD-I) 5d 6hr/d 30000 M Anderson et al. 1976 zeoewssti o VINYL CHLORIDE CO S 2 | DRAFT FOR PUBLIC COMMENT Key to* Species/ figure (strain) Exposure duration/ frequency Developmental 25 Rat (SpragueDawley) 10 d 7hr/d Gd6-15 TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) System NOAEL (ppm) Less serious (ppm) LwnP> \C1 Serious (ppm) 2500 (ureter dilation) 26 Mouse (CF-1) 10 d 7hr/d Gd6-15 50 b 500 (delayed ossification) 27 Rabbit (New Zealand) 500 (delayed ossification) Reference John eta1. 1977, 1 1981 John et al. 1977, 1981 John et al. 1977, 1981 Cancer 28 Mouse (ICR) 1 hr 5000 (CEL: broncho-alveolar adenoma) Hehir et al. 1981 M X m > x Om to INTERMEDIATE EXPOSURE Death 29 Rat (CD) 1-10 mo 5d/wk 6hr/d 30 Mouse (A/J) 6 mo 5d/wk 6hr/d 50 (17/26 died) Hongetal. 1981 500 M (37/70 died) 500 F (23/70 died) 1 Adkins et al1966 *"-4 seosnsva VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' Key to figure Species/ (strain) Exposure duration/ frequency 31 Mouse (CD-I) 1-6 mo 5d/wk 6hr/d TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) System NOAEL (ppm) Less serious (ppm) LOAEL (effect) Serious (ppm) 50 (15/16 died) Systemic 32 Rat (Wistar) 3 mo 6d/wk 6 hr/d 33 Rat (Wistar) 6 mo 6d/wk 6 hr/d 34 Rat (Sherman) 19 d 8 hr/d Cardio Renal Cardio Hepatic Hemato 10 M 100 M (increased relative heart weight) 100 M 3000 M (increased relative kidney weight) 10 M (increased relative heart weight) 10 c M (increased relative liver weight) 50000 (decreased white blood cells) Hepatic Renal Derm 50000 50000 F 50000 (hepatocellular hypertrophy, large irregular vacuoles, compression of sinusoids, elevated relative liver weight) 50000 M (thin coats, scaly tails) 6S06t'tS'8U Reference 1 Hong et al. 1981 Bi el al. 1985 Bi et al. 1985 Lester et al. 1963 ro Xm > x m m HoO CD VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) a Key to figure Species/ (strain) Exposure-_-_--_-_--_-_--_--_-_--_-_--_-_--_-_--_-_--_-_--_-_--_-_--_-_--_--_-_--_-_--_-_---L-O---A--E--L---(-e--f-f-e- _ct)_____--_________________ duration/ NOAEL Less serious Serious frequency System (ppm)_______ (ppm)______________________________________ (ppm) Rat (Sherman) 92 d 5d/wk 8 hr/d Hemato 20006 (decreased white blood cells) Rat (Wistar) 10 mo 5d/wk 5 hr/d Hepatic 20000 Renat Musc/skel 20000 20000 M (moderate hepatocellular hypertrophy, fine to medium vacuoles, compression of sinusoids) Hepatic Renal Bd Wt 50 M 50 M (fatty changes) 500 M (increased kidney weight) 50 M (10% decrease body weight) 37 Rat (NS) 6 mo 5d/wk 0.5-7hr/d Hemato 200 38 Rat (Wistar) 10 mo 5d/wk 5tir/d Hepatic Renal Bd Wt Hepatic 200 200 100 (increased relative liver weight) 50 M (fatty changes) Reference Lester et al. 1963 Sokat et al. 1960 Torkelson et al. 1961 ro Xm > x m --ocmo{ Wisniewska-Kn ypl et al. 1980 to Ofr06KSVy VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) a Key to figure Species/ (strain) Exposure duration/ frequency 39 Mouse (NS) 1-6 mo 5d/wk 5hr/d System Hepatic NOAEL (ppm) _________________________________LOAEL (ellect) Less serious (ppm) Serious (ppm) 2500 M (hyperplasia of hepatocytes and activatedsinusoidal cells) 40 Mouse (CD-I) 8 wk 5d/wk 6 hr/d Hemato 1000 M Reference t Schaffner 1978 Sharma and Gehring 1979 41 Mouse (CD-I) 5-6 mo 5d/wk 5 hr/d Hepatic Renal Bd Wt Resp 42 Rabbit (NS) 6 mo 5d/wk 7hr/d Hepatic 1000 M 1000 M 100 1000 M (decreased liver weight) 2500 M (proliferation and hypertrophy of bronchial epithelium; hypersecretion of mucin; hyperplasia of alveolar epithelium) Suzuki 1978, 1981 200 (centriiobular degeneration Torkelson et al. and necrosis) 1961 Immuno/Lymphor 43 Rat (Wistar) 3 mo 6d/wk 6 hr/d Renal Bd Wt 200 200 100 M 3000 M (increased spleen weight) Bi etal. 1985 44 Rat (Wistar) 6 mo 6d/wk 6 hr/d 10 M (increased spleen weight) i Bi et al. 1985 l-KI6MS1Sd rn > l m o co VINYL CHLORIDE "DRAFT FOR PUBLIC COMMENT**' Key to"' Species/ figure (strain) Exposure duration/ frequency 45 Rat (Wistar) 10 mo 5d/wk 5hr/d TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) System NOAEL (ppm) . Less serious (ppm) LOAEL (effect) Serious (ppm) 50 M (increased spleen weight) 46 Mouse (CD-I) 2-8 wk 5d/wk 6hr/d 10 M (increased spontaneous lymphocyte proliferation) Reference Sokal et at. 1980 Sharma and Gehring 1979 Neurological 47 Rat 20 wk (Fischer- 344} 5d/wk Ihr/d 50 Hehir et al, 1981 Reproductive 48 Rat (Wistar) 3, 6 mo 6d/wk 6hr/d 49 Rat (CD) 11 wk 5d/wk 6hr/d 50 Rat (Wistar) 10 mo 5d/wk 5hr/d 1to0 M 100 M (decreased testes weight) Bietal. 1985 50 M 250 M (reduced male fertility) Short etal 1977 50 M 500 M (spermatogenic epithelial necrosis) Sokal etal-1980 im > x m mO--nn --CAi gyoetdS'sy VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) a Key to figure Species/ (strain) Exposure duration/ frequency System NOAEL (ppm) -----------------------Less serious (ppm) LOAEL (effect)___________________________________ Serious (ppm)_______________ Reference Cancer 51 Rat 6 mo (Fischer-344) 5d/wk 6hr/d 100 F (CEL: hepatic hemangiosarcoma, hepatocellular carcinoma, neoplastic nodules; mammary fibroadenoma) Drew et al. 1983 52 Rat (CD) 10 mo 5d/wk 6hr/d 250 (CEL: liver hemangiosarcoma, neoplastic nodules) Hong et at. 1981 53 Mouse (A/C) 6 mo 5d/wk 6hr/d 50 (CEL: pulmonary adenoma) Adkins etal. 1986 54 Mouse (B6C3F1) 6 mo 5d/wk 6hr/d 50 F (CEL: hemangiosarcoma of Drew et al. 1983 subcutis, peritoneum; mammary gland carcinoma) 55 Mouse (CD-I) 6 mo 5d/wk 6 hr/d 56 Mouse (CD-I) 1,3,6 mo 5d/wk 6hr/d 57 Mouse (Swiss) 30 wk 5d/wk 4hr/d 50 F (CEL: hemangiosarcoma of Drew etai. 1983 skin, peritoneum; mammary gland carcinoma; lung carcinoma) 50 F (CEL: mammary gland adenocarcinoma/ carcinoma) 1 Hong etal. 1981 50 (CEL: liver angiosarcoma Maltoni et al. and angioma) 1981 ro Xm > x m-n T| m o to e^ns^y TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) Key to figure Species/ (strain) duration/ frequency 58 Mouse (CD-I) 4 wk 5d/wk 6hr/d System NOAEL (ppm) ________________ LOAEL (effect)_____________________ Less serious (ppm) Serious (ppm) Reference 100 M (CEL: lung alveogenic tumors) Suzuki 1983 i 59 Hamster (Golden Syrian) 6 mo 5d/wk 6hr/d 60 Hamster (Golden Syrian) 30 wk 5d/wk 4hr/d i 200 F (CEL liver Drew et a!. 1983 hemangiosarcoma; skin hemangiosarcoma, spleen hemangiosarcoma; mammary gland carcinoma) 500 M (CEL: liver angiosarcoma) Maltoni et a(. 1981 CHRONIC EXPOSURE Systemic 61 Rat (Wistar) 12 mo 6d/wk 6 hr/d Hepatic Renal BdWt Reproductive 62 Rat (Wistar) 12 mo 6d/wk 6 hr/d 100 M 3000 M (increased liver weight) 10 M 10 M 100 M (increased kidney weight) 100 M {14% decrease body weight) 10 M 100 M (testicular necrosis) Bi et al. 1985 Bi et al. 1985 t'KienssH VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' Key to* Species/ figu (strain) Exposure duration/ frequency Cancer 63 Rat (Wistar) 12 mo 6d/wk 6 hr/d TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) System NOAEL (ppm) Less serious (ppm) LOAEL (effect) Serious (PPm) Reference 1 100 M (CEL: liver angiosarcoma; lung angiosarcoma) Bi et al. 1985 64 Rat 12, 18, 24 (Fischer- 344) mo 5d/wk 6 hr/d 65 Rat (CD) 1-12 mo 5d/wk 6 hr/d 100 F (CEL: hepatic hemangiosarcoma, hepatocellular carcinoma, neoplastic nodules; mammary gland fibroadenoma and adenocarcinoma) 250 F (CEL: hepatic hemangiosarcoma) Drew et al. 1983 Lee et al. 1978 66 Rat (SpragueDawley) 52 wk 5d/wk 4hr/d 5 F (CEL: mammary gland carcinoma) Maitoni et al. 1981 67 Mouse (B6C3F1) 12 mo 5d/wk 6 hr/d 50 F (CEL: hemangiosarcoma of Drewetal 1983 peritoneum, subcutis; mammary gland carcinoma) 68 Mouse 12, 18 mo (Swiss CD-I) 5d/wk' 6hr/d 50 F (CEL: lung; i Drew et al 1983 hemangiosarcoma of petitoneum, subcutis; mammary gland carcinoma) st'oet'tssb VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT Key to* Species/ figure (strain) Exposure duration/ frequency 69 Mouse (CD-I) 1-12 mo 5d/wk 6hr/d 70 Hamster (Golden Syrian) 12, 18, 24 mo 5d/wk 6hr/d TABLE 2-1. Levels of Significant Exposure to Vinyl Chloride - inhalation (continued) System NOAEL (ppm) Less serious (ppm) LOAEL (effect) Serious (ppm) Reference 50 B (CEL: hepatic hemangiosarcoma; bronchoalveolar adenoma; t Lee et al. 1977a, Lee et al. 1978 malignant lymphoma) 50 F (CEL: mammary gland adenoma and adenocarcinoma) 200 F (CEL: liver Drew et al. 1983 hemangiosarcoma; skin carcinoma, hemagio- sarcoma; spleen hemangiosarcoma; mammary gland carcinoma; stomach adenoma) "The number corresponds to entries in Figure 2-1. "Used to derive an acute-duration inhalation Minimal Risk Level (MRL) of 0.5 ppm. NOAEL converted to a Human Equivalent Concentration (HEC) before applying uncertainty factors. MRL obtained by dividing the NOAEL^ by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). cUsed to derive an intermediate-duration inhalation MRL of 0.03 ppm. LOAEL converted to an HEC before applying uncertainty factors. MRL obtained by dividing the NOAEL^ by an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). AKT = alpha-ketoglutarate transaminase; B = both; Bd Wt = body weight; Cardio = cardiovascular; CEL = Cancer Effect Level; d = day(s); Derm = dermal; Endocr = endocrine; F = female; Gd = gestation days(s); Gn pig = guinea pig; Hemato = hematological; hr = hour(s); Immuno/Lymphor = immunological/lymphoreticular; LOAEL = lowest-observed-adverse-effect level; M = male; min = minutes; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respiratory; SDH = sorbitol dehyrogenase; wk = week(s); x = time(s) ro Xm > x OmTmmHl 9P06PISsy VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT*' Figure 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation Acute (<14 days) Systemic & a (ppm) & 1,000,000 100,000 12g 1101120 8r rx rx nx 1r _5g 11m ...... ^OU7r-Q28r 3^8 *38 3^8-m111m2g IO2g iO3g M19939 30 11m12g 8r 3 2m 6g8r 129 O^OO 7r 9r 10r 10,000 ___ 1,000 _ 3m 100 17r 19r O 15r 14 A 17r 18r 20m o A 20m 14 O 16r 22g 23g o 23g 10 JS? 0<P & o 24m 3 25r 27h 33 26m O 26m 28m 1-- 0.01 -- r Rat m Mouse h Rabbit g Guinea pig s Hamster Key LOAEL for serious effects (animals) 3 LOAEL for less serious effects (animals) O NOAEL (animals) + CEL - Cancer Effect Level (animals) A LOAEL for less serious effect (humans) A NOAEL (humans) _______________ l_________________________ The number next to each point corresponds to entries in Table 2-1. | Minimal risk level for effects i other than cancer W '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. ro mT. > X m n TJ oH CO rtro> -VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' Figure 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) Intermediate (15-364 days) Systemic t (ppm) 100,000--------- 10,000 -- 33 34r3 034r3 3 1,000 __ 30m 41m 30m 100 3 32r o 40m o 37r 29r 31m 10 03 32r 33r 3 39m3 32r 40m 37f42h 32r 3#0 O 3 342h 36r 38r 3 33r o 3 40m o o36r 37r 42h O' 36 r o 40m oo 37r 42h 3 36 r 3 43r 4&9r o 3* 5cn0 r 52 r 54m 56m 58m 60s 59s 43r 3 o48roo 51 r 345r3 47ro49r50r 53m 55m 57m 44r 46m 48r 1 0.1 0.01 0.001 r Rat m Mouse h Rabbi! 9 Guinea pig s Hamster Key LOAEL for serious effects (animals) 3 LOAEL for less serious effects (animals) O NOAEL (animals) CEL - Cancer Effect Level (animals) A LOAEL for less serious effect (humans) A NOAEL (humans) The number next to each point corresponds to entries in Table 2-1 ] Minimal risk level for effects i other than cancer V/ *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. x m > 0 0--1i FO *4 ewewssa VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' Figure 2-1. Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) "" ...... ..... ......" Systemic Chronic (>365 days) " --111 ..... t A (ppm) 10,000 1,000 100 10 1 0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 0.00000001 0.000000001 0.0000000001 <s~ <s> 3 o61 r 61 r 61 r 62r 33 61 r o o o 61 r 61 r 62r 63r 65 r 64r 705 67m 68m 69m 69m 66r 10-4 10-5 10'6 1CT7 Estimated UpperBound Human Cancer Risk Levels Key r Rat m Mouse h Rabbit 9 Guinea pig s Hamster LOAEL for serious effects (animals) 3 LOAEL for less serious effects (animals) O NOAEL (animals) CEL - Cancer Effect Level (animals) A LOAEL for less serious effect (humans) A NOAEL (humans) The number next to each point corresponds to entries in Table 2-1. t Minimal risk level for effects i other than cancer `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. fO 1 2 q X m o--4 CO VINYL CHLORIDE 2. HEALTH EFFECTS 29 chloride are contradictory. Several epidemiologic studies found no increased incidence of respiratory disease among vinyl chloride workers (Gamble et al. 1976: Laplanche et al. 1987, 1992; NIOSH 1977), but several other epidemiologic surveys and case reports found evidence of pulmonary damage. The adverse respiratory effects reported in these studies include increased incidence of emphysema (Suciu et al. 1975; Wong et al. 1991), decreased respiratory volume and vital capacity, respiratory insufficiency (Suciu et al. 1975), decreased respiratory oxygen and carbon dioxide transfer (Ltoyd et al. 1984), pulmonary fibrosis of the linear type (Suciu et al. 1975), abnormal chest x-rays (Lilis et al. 1975, 1976). and dyspnea (Walker 1976). Interpretation of many of these results is confounded by the inclusion of smokers among those exposed to vinyl chloride and the concurrent exposure of many vinyl chloride workers to PVC resin dust, which is known to cause respiratory lesions (Mastrangelo et al. 1979). Brief inhalation of high concentrations of vinyl chloride caused respiratory inflammation in a variety of animals. A 30-minute exposure of guinea pigs, mice, and rats to 100,000 ppm of vinyl chloride produced slight hyperemia in all three species (Mastromatteo et al. 1960). Exposure to higher concentrations (200,000 ppm and 300,000 ppm) caused increased congestion, edema, and, at the highest concentrations, pulmonary hemorrhages in all three species (Mastromatteo et al. 1960). Tracheal epithelium was also absent in one guinea pig exposed to 400,000 ppm for 30 minutes (Mastromatteo et al. I960). Edema and congestion of the lungs of rats also were observed following a 2-hour exposure to 150,000 ppm (Lester et al. 1963). Histopathologic examination of mice exposed to 2.500 ppm vinyl chloride for 5 hours per day, 5 days per week, for 5-6 months revealed proliferation and hypertrophy of the bronchiolar epithelium, hyperplasia of the alveolar epithelium, hypersecretion of mucin (Suzuki 1978, 1980, 1981), increased endoplasmic reticulum and free ribosomes in Clara cells, and mobilization of alveolar macrophages (Suzuki 1980). These changes were observed irrespective of the recovery period (2 or 37 days) indicating that they were not readily reversible. However, these studies were severely limited by the small number of animals tested and the absence of a statistical analysis. Chronic exposure of rats to 5,000 ppm for 7 hours per day, 5 days per week, for 12 months produced hyperplasia of the olfactory epithelium, increased cellularity of the interalveolar septa of the lungs, and an increased incidence of pulmonary hemorrhages (Feron and Kroes 1979). Interstitial pneumonia and two incidences of hemorrhagic lungs were observed in rats exposed to 30,000 ppm of vinyl chloride "'DRAFT FOR PUBLIC COMMENT"* 149050 JO VINYL CHLORIDE 2. HEALTH EFFECTS 30 for 4 hours per day, 5 days per week, for 12 months (Viola et al. 1971). However, the statistical significance of the findings in the studies by Feron and Kroes (1979) and Viola et al. (1971) is unknown. Cardiovascular Effects. Occupational exposure to vinyl chloride has been associated with the development of Raynaud's phenomenon, a condition in which the fingers blanch and become numb with discomfort upon exposure to the cold. This condition has been reported most frequently among workers who cleaned the reactor tanks, a job which reportedly exposed workers to very high levels of vinyl chloride. It has also been reported in a worker exposed once to a vinyl chloride vapor leak (Ostlere et al. 1992). Although only a small percentage of vinyl chloride workers develop Raynaud's phenomenon (Laplanche et al. 1987, 1992; Lilis et al. 1975; Marsteller et al. 1975; Suciu et al. 1963, 1975; Veltman et al. 1975; Walker 1976), the incidence is significantly higher than in unexposed workers (Laplanche et al. 1987, 1992). Investigation of the peripheral circulation of workers afflicted with Raynaud's phenomenon has revealed thickening of the walls of the digital arteries (Harris and Adams 1967), narrowing of the arterial lumen (Veltman et al. 1975), vascular occlusions (Walker 1976), arterial occlusions (Preston et al. 1976; Veltman et al. 1975), tortuosity (Preston et al. 1976), hypervascularity (Preston et al. 1976), inflammatory infiltration of the arterioles (Magnavita et al. 1986), deposition of immune products along the vascular endothelium (Ward 1976), vasomotor impairment (Suciu et al. 1963), and impaired capillary microcirculation (Magnavita et al. 1986; Marioq et al. 1976). Three reports indicate that upon removal from exposure, Raynaud's phenomenon gradually disappears (Freudiger et al. 1988; Suciu et al. 1963, 1975). For further discussion of Raynaud's phenomenon, see Immunological/Lymphoreticular Effects (Section 2.2.1.3). Splenomegaly, with evidence of portal hypertension (dilated peritoneal veins and esophageal varices), has been reported by investigators studying the effects of vinyl chloride exposure (Marsteller et al. 1975). In addition, hypertension among vinyl chloride workers (NIOSH 1977; Suciu et al. 1975) and significantly increased mortality due to cardiovascular and cerebrovascular disease (Byren et al. 1976) have been reported. Investigators studying the anesthetic properties of vinyl chloride in dogs have observed that doses producing anesthesia (100,000 ppm, Oster et al. 1947; 150,000-900,000 ppm, Carr et al. 1949) also caused cardiac arrhythmias. Arrhythmias were characterized by intermittent tachycardia, extraventricular systoles, vagal beats, ventricular fibrillation, and atrioventricular block. However, the R& S 149051 "'DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2, HEALTH EFFECTS 31 statistical significance of these effects was not reported. No histopathological changes in the heart were noted in guinea pigs exposed to 400,000 ppm of vinyl chloride for 30 minutes (Mastromatteo et al. I960). A study by Bi et al. (1985) demonstrated an increase in the relative heart weight at concentrations of vinyl chloride as low as 10 ppm when administered to male rats for 6 hours per day, 6 days-per week, for 6 months. Heart weight was also increased after 3 months in rats exposed to 100 ppm under this regimen (Bi et al. 1985). Chronic exposure of rats to 5,000 ppm vinyl chloride 7 hours per day, 5 days per week, for 1 year resulted in increases in areas of myodegeneration in the heart and thickening of the walls of arteries (Feron and Kroes 1979). However, the statistical significance of this effect was not reported. Exposure of rats to 30,000 ppm of vinyl chloride for 4 hours per day, 5 days per week, for 1 year also produced thickening of the walls of small arterial vessels. The thickening was characterized by a proliferation of the endothelium. In some vessels, the thickening was severe enough to cause blockage of the lumen (Viola 1970). Gastrointestinal Effects. Approximately 32% of the vinyl chloride workers examined by Lilis et al. (1975) reported a history of "gastritis, ulcers (gastric and duodenal) and upper gastrointestinal bleeding." Because these subjects were not compared to workers who had not been exposed to vinyl chloride, the significance of these findings is unknown. Other symptoms reported by vinyl chloride workers included nausea, abdominal distension, and heartburn. Loss of appetite and nausea have been reported in Singapore workers exposed to 1-21 ppm vinyl chloride (Ho et al. 1991). However, these workers were selected on the basis of liver dysfunction. No studies were located regarding gastrointestinal effects in animals following inhalation exposure to vinyl chloride. Hematological Effects. Blood tests performed at autopsy from two workers whose deaths were believed to be due to exposure to extremely high levels of vinyl chloride revealed that the blood did not clot (Danziger 1960). Slight-to-severe thrombocytopenia in workers occupationally exposed to vinyl chloride was reported in several studies (Marsteller et al. 1975; Micu et al. 1985; Veltman et al. 1975), but Lilis et al. (1975) found no increased incidence of thrombocytopenia in vinyl chloride workers. A prospective study of female workers exposed to vinyl chloride at levels ranging from 0.2 to 130.7 ppm showed that the exposed workers had a significantly lower number of platelets than the R&S149052 "'DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 32 nonexposed controls during the early part of their pregnancies (weeks 8-10) but that this effect abated by the end of the pregnancy (34-38 weeks) following a period free from exposure (Bao et al. 1988). Splenomegaly was reported in a number of studies (Ho et al. 1991; Marsteller et al. 1975; Popper and Thomas 1975; Suciu et al. 1963; Veltman et al. 1975). Thrombocytopenia was found in both patients who did and did not present with splenomegaly (Veltman et al. 1975). Increased levels of a number of plasma proteins (a,- and c^-globulin) were reported in studies examining the effects df occupational exposure to vinyl chloride (Harris and Adams 1967; Suciu et al. 1975). A brief (30-minute) exposure of guinea pigs to 400,000 ppm vinyl chloride resulted in a failure of the blood to clot in the animals that died during the exposure (Mastromatteo et al. 1960). Mice that were exposed to 5,000 ppm vinyl chloride (6 days, 4 hours/day) or 10,000 ppm (5 days, 4 hours/day) showed an increased emergence of basophilic stippled erythrocytes (Kudo et al. 1990). This effect was also noted in mice that were exposed for 10 weeks to 50 ppm intermittently (4-5 days/week, 4 hours/day) or to 30-40 ppm continuously for 62 days (Kudo et al. 1990). Exposure of dogs and rats to 200 ppm, 7 hours per day, 5 days per week, for 6 months had no effect on hematologic values (Torkelson et al. 1961). Also, an 8-week exposure of mice to 1,000 ppm for 6 hours per day, 5 days per week had no effect on erythrocyte or leukocyte counts (Sharma and Gehring 1979). Exposure of rats to either 50,000 ppm for 8 hours per day for 19 consecutive days or 20,000 ppm for 8 hours per day, 5 days per week, for 92 days resulted in a decrease in white cells (Lester et al. 1963). Exposure of rats to 5,000 ppm vinyl chloride for 7 hours per day, 5 days per week, for 1 year caused slightly increased hematopoiesis in the spleen (Feron and Kroes 1979). The statistical significance of these results was not provided. Blood clotting time was decreased in rats exposed to 5,000 ppm for 1 year, but the statistical significance of these effects was not reported (Feron et al. 1979a). Musculoskeletal Effects. Acroosteolysis, or resorption of the terminal phalanges of the finger, was observed in a small percentage of workers occupationally exposed to vinyl chloride (Dinman et al. 1971; Lilis et al. 1975; Marsteller et al. 1975; Sakabe 1975; Veltman et al. 1975; Wilson et al. 1967), As with Raynaud's phenomenon, acroosteolysis was reported predominantly among polymerization tank cleaners. Bone lesions were most often confined to the terminal phalanges of the fingers, but in a few cases the bones of the toes (Harris and Adams 1967), feet (Preston et al. 1976), sacroiliac joint (Harris and Adams 1967), and arms, legs, pelvis, and mandible (Preston et al. 1976) were also involved. Development of acroosteolysis was most often preceded by Raynaud's phenomenon (Dinman et al. 1971; Freudiger et al. 1988; Harris and Adams 1967; Magnavita et al. 1986; Markowitz R&S149053 "DRAFT FOR PUBLIC COMMENT' VINYL CHLORIDE 2. HEALTH EFFECTS 33 et al. 1972; Preston et al. 1976; Sakabe 1975; Veltman et al. 1975; Wilson et al. 1967). In two reports, bone resorption was observed to progress despite discontinuation of exposure (Markowitz et al. 1972; Preston et al. 1976). However, in two other reports, improvement was observed after exposure ceased (Veltman et al. 1975; Wilson et al. 1967). Joint pain was also reported by Lilis et al. (1975). Although Sokal et al. (1980) found no alterations in the bones of male rats exposed to 20,000 ppm for 5 hours per day, 5 days per week, for 10 months, Viola (1970) observed skeletal changes in the bones of rats exposed to 30,000 ppm for 4 hours per day, 5 days per week, for 12 months. The statistical significance of these effects was not reported and only one dose was tested. Hepatic Effects. Throughout the early years of the use of vinyl chloride, workers experienced only a minimal degree of functional hepatic abnormalities. However, when it became apparent in the early 1970s that angiosarcoma of the liver was associated with long-term vinyl chloride exposure, an intensive effort was initiated by a number of investigators to characterize the hepatic effects of vinyl chloride. These studies revealed characteristic hepatic lesions produced by vinyl chloride exposure (Berk et al. 1975; Falk et al. 1974; Gedigke et al. 1975; Ho et al. 1991; Jones and Smith 1982; Lilis et al. 1975; Liss et al. 1985; Marstelleret al. 1975; NIOSH 1977; Popper and Thomas 1975; Suciu et al. 1975; Tamburro et al. 1984; Vihko et al. 1984). The incidence and severity of the effects correlated well with the duration of exposure (Gedigke et al. 1975; Lilis et al. 1975; NIOSH 1977). A further description of hepatic angiosarcoma may be found in Section 2.2.1.8. Routine noninvasive techniques revealed hepatomegaly in a limited number of workers (14-37%) (Ho et al. 1991; Lilis et al. 1975; Marstelleret al. 1975; NIOSH 1977; Suciu et al. 1963, 1975; Waxweiler et al. 1977). However, when peritoneoscopy was performed or biopsies were obtained from exposed workers. Marsteller et al. (1975) found a much higher prevalence of hepatic abnormalities. Only 37% of the workers studied by Marsteller et al. (1975) were diagnosed with hepatomegaly, but peritoneoscopy revealed a 50% incidence of granular changes in the liver surface and an 86% incidence of capsular fibrosis with increased numbers of capsular vessels. Histopathological examination of the biopsied tissue from these workers revealed an 80% incidence of collagenization of the sinusoidal walls, a 90% incidence of proliferation of cells lining the sinusoids, a 30% incidence of septal fibrosis, and degeneration of hepatocytes (incidence not specified). A number of other investigators observed similar changes in liver tissues obtained from workers exposed to vinyl chloride (Falk et al. 1974; Gedigke et al. 1975; Popper and Thomas 1975; Tamburro et al. 1984). Based on R&S 149054 --DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 34 these observations, a profile of vinyl chloride-induced liver damage was compiled which includes the following features: hypertrophy and hyperplasia of hepatocytes, activation and hyperplasia of sinusoidal lining cells, fibrosis of the portal tracts and the septa and intralobular perisinusoidal regions, sinusoidal dilation, and focal areas of hepatocellular degeneration. This pattern of changes was observed to be highly unusual and was similar to the hepatic changes produced by arsenic (Gedigke et al. 1975). In addition, the degenerative changes in hepatocytes appeared to be less severe when biopsy material was obtained from workers who had not been exposed to vinyl chloride recently. However, sinusoidal changes were not influenced by the length of time since the last exposure (Gedigke et al. 1975). One possible reason that the hepatotoxic effects of vinyl chloride went undetected for many years was the lack of sensitivity of standard biochemical liver function tests to detect the liver injury produced by vinyl chloride (Berk et al. 1975; Marsteller et al. 1975; Tamburro et al. 1984; Vihko et al. 1984). For example, the values obtained in several standard biochemical liver function tests (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma glutamyltranspeptidase) from workers with biopsy evidence of vinyl chloride-associated liver damage were not significantly higher than those from unexposed controls (Liss et al. 1985). Only serum bile acids (Berk et al. 1975; Liss et al. 1985) and/or indocyanine green clearance (Liss et al. 1985; Tamburro et al. 1984) correlated with liver injury. Furthermore, investigators have shown that levels of chenodeoxycholic acid (a serum bile acid) in asymptomatic vinyl chloride workers were elevated when compared to the 95% interval of values from a healthy reference population (Vihko et al. 1984). Brief exposure of animals to extremely high concentrations of vinyl chloride has been shown to cause hepatic damage. For example, acute exposure (30 minutes) of guinea pigs, mice, and rats to 300,000 ppm of vinyl chloride caused liver congestion or severe fatty degeneration (Mastromatteo et al. 1960). Exposure to 100,000 ppm for 6 hours caused centrilobular vacuolization and slightly increased alanine serum a-ketoglutarate transaminase activity in rats (Jaeger et al. 1974). However, exposure of rats to 50,000 ppm for 6 hours produced no observable effects on the liver (Reynolds et al. 1975a, 1975b). In contrast, a single-concentration study in which pregnant rats were continuously exposed to 1,500 ppm for 7-9 days during either the first or second trimester of pregnancy resulted in an increase in the liver-to-body weight ratio (Ungvary et al. 1978). Interestingly, a single 1-hour exposure of mice to 500, 5,000, or 50,000 ppm of vinyl chloride, followed by an 18-month observation period, resulted in an increased incidence of hepatocellular hypertrophy in these animals at R & S 149055 "'DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 35 terminal sacrifice (Hehir et al. 1981). The hypertrophy was not dose-dependent; thus, the significance of this effect is uncertain. In studies with longer durations of exposure, lower concentrations of vinyl chloride have produced hepatic toxicity. Symptoms of hepatotoxicity that have been observed in rats have included hepato cellular degeneration (Sokal et al. 1980; Torkelson et al. 1961; Wisniewska-Knypl et al. 1980), swelling of hepatocytes with compression of sinusoids (Lester et al. 1963), dilation of the rough endoplasmic reticulum (Du et al. 1979), proliferation (Sokal et al. 1980) or hypertrophy (WisniewskaKnypl et al. 1980) of smooth endoplasmic reticulum, changes in metabolic enzyme activities (Du et al. 1979; Wisniewska-Knypl et al. 1980), proliferation of reticulocytes (Sokal et al. 1980), and an increased liver-to-body-weight ratio (Bi et al. 1985; Lester et al. 1963; Sokal et al. 1980; Torkelson et al. 1961). For example, exposure of rats to 500 ppm for 7 hours per day, 5 days per week, for 4.5 months resulted in an increase in liver-to-body-weight ratio and granular degeneration (Torkelson et al. 1961). An increased liver-to-body weight ratio was also found in rats exposed to 100 ppm vinyl chloride for 7 hours per day, 5 days per week, for 6 months (Torkelson et al. 1961). Relative liver weight was decreased in mice exposed to 1,000 ppm vinyl chloride for 6 hours per day, 8 days per week, for 8 weeks (Sharma and Gehring 1979). Exposure of rats to 500 ppm for 5 hours per day, 5 days per week, for 10 months caused swelling of hepatocytes and proliferation of reticuloendothelial cells, increased liver weight, and cellular degeneration; at 50 ppm, small lipid droplets and proliferation of smooth endoplasmic reticulum were noted (Sokal et al. 1980). Histopathological examination of rats exposed to either 50.000 ppm vinyl chloride for 8 hours per day for 19 consecutive days or 20,000 ppm vinyl chloride for 8 hours per day, 5 days per week, for 92 days showed hepatocellular hypertrophy, vacuolization, and sinusoidal compression (Lester et al. 1963). Mice exposed to 2,500 ppm vinyl chloride 5 hours per day, 5 days per week, for up to 6 months showed histopathological changes in the liver that included hyperplasia of hepatocytes and activated sinusoidal cells (Schaffner 1978). Centrilobular necrosis and degeneration were noted in rabbits exposed to 200 ppm vinyl chloride 7 hours per day, 5 days per week, for 6 months (Torkelson et al. 1961). Also, exposure of rats to 50 ppm for 5 hours per day, 5 days per week, for 10 months produced fatty degeneration and proliferation of the smooth endoplasmic reticulum (Wisniewska-Knypl et al. 1980). The liver-to-body-weight ratio was shown to be increased in male rats exposed to 3,000 ppm vinyl chloride for 6 hours per day, 5 days per week for 12 months (Bi et al. 1985). Significantly increased liver-to-body-weight ratio was also observed in rats exposed to concentrations of vinyl chloride as low as 10 ppm for 6 hours per day, 6 days per week, for 6 months (Bi et al. R&S149056 `"DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 36 1985). Based on this value, an intermediate-duration MRL of 0.03 ppm was calculated as described in the footnote in Table 2-1, The relative NOAELs for a variety of species following a 6-month exposure to vinyl chloride indicated that mice andjnts were the most sensitive (NOAEL = 50 ppm), rabbits were the next most sensitive (NOAEL = 100 ppm), and dogs and guinea pigs were the least sensitive (NOAEL > 200 ppm) (Torkelson et al. 1961). Popper et al. (1981) compared histopathological findings from sections of liver from mice and rats exposed by Maltoni and LeFemine (1975) with the liver biopsy material obtained from vinyl chloride workers. Hyperplasia and hypertrophy of hepatocytes and/or sinusoidal cells, with areas of sinusoidal dilation, were observed in both humans and rodents. The major difference between the species was the greater degree of fibrosis, seen as reticulin deposition and collagen formation, in the livers of humans. Also, inflammatory cells were present in the livers of humans, but not of rodents. Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to vinyl chloride. Acute exposure of mice and rats to 300,000 ppm of vinyl chloride for 30 minutes resulted in kidney congestion. Also, the kidneys of one mouse out of five exposed to either 100,000 or 200,000 pm of vinyl chloride for 30 minutes showed degenerative changes (Mastromatteo et al. 1960). Exposure of- rats to 50,000 ppm for 8 hours per day for 19 consecutive days or 20,000 ppm for 8 hours per day, 5 days per week, for 92 days caused no adverse effects on the kidneys (Lester et al. 1963). However, exposures of male rats to 3,000 ppm for 6 hours per day, 6 days per week, for 3 months caused the kidney-to-body weight ratio to increase (Bi et al. 1985). After a 6-month observation period, there was also an increased kidney-to-body weight ratio noted in the male rats exposed to 100 ppm vinyl chloride for 6 hours per day, 6 days per week, for 12 months; no effect was noted at 10 ppm (Bi et al. 1985). Relative kidney weight was increased in male rats exposed to 500 ppm vinyl chloride for 5 hours per day, 5 days per week, for 10 months, although no histopathological changes to the kidney were noted (Sokal et al. 1980). No changes in kidney weight were reported when mice were exposed to 1,000 ppm vinyl chloride for 8 weeks, 5 days per week, 6 hours per day (Sharma and Gehring 1979). Urinalysis values were within normal limits in rats exposed to 200 ppm vinyl chloride for up to 7 hours per day, 5 days per week, for 6 months (Torkelson et al. 1961). One year of exposure to R&S149057 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 37 5,000 ppm vinyl chloride for 7 hours per day, 5 days per week caused increased kidney-to-body weight ratio (Feron et al. 1979a) and tubular nephrosis in rats (Feron and Kroes 1979). However, the statistical significance of these findings was not provided in the study. Endocrine Effects,*. A study of workers exposed to vinyl chloride in PVC manufacturing plants reported that most workers who presented with scleroderma were shown to have thyroid insufficiency (Suciu et al, 1963). No histopathological effects on the adrenals were reported in guinea pigs exposed to 400,000 ppm for 30 minutes (Mastromatteo et al. 1960). Rats exposed to 30,000 ppm vinyl chloride for 12 months, 5 days per week, 4 hours per day were found to have colloid goiter and markedly increased numbers of perifollicular cells (Viola 1970). Dermal Effects. Occupational exposure to vinyl chloride was observed to cause scleroderma-like skin changes on the hands of a small percentage of exposed workers (Freudiger et al. 1988; Lilis et al. 1975; Marsteller et al. 1975; Suciu et al. 1963, 1975; Veltman et al. 1975; Walker 1976). The skin changes were characterized by a thickening of the skin (Lilis et al. 1975; Markowitz et al. 1972; Ostlere et al. 1992; Preston et al. 1976; Veltman et al. 1975; Walker 1976), decreased elasticity (Lilis et al. 1975), and slight edema (Lilis et al. 1975; Suciu et al. 1975) and were almost exclusively observed in exposed individuals who also suffered from Raynaud's phenomenon. Skin biopsies revealed increased collagen bundles in the subepidermal layer of the skin (Harris and Adams 1967; Markowitz et al. 1972; Ostlere et al. 1992; Veltman et al. 1975). Biochemical analyses by Jayson et al. (1976) demonstrated that a high rate, of collagen synthesis was taking place in the affected skin. Most often the skin changes were confined to the hands and wrists, but Jayson et al. (1976) reported scleroderma-like skin changes on the hands, arms, chest, and face of one afflicted worker. Skin changes were observed in rats exposed to 30,000 ppm for 12 months (Viola 1970). The skin of the paws of the exposed rats showed areas of hyperkeratosis, thickening of the epidermis, edema, collagen dissociation, and fragmentation of the elastic reticulum. Interpretation of these results is limited by the absence of a statistical analysis and insufficient information on the treatment of control animals. Lester et al. (1963) reported that male rats exposed to 50,000 ppm vinyl chloride for 19 days. 8 hours per day had thin coats and scaly tails, while females exposed to the same concentration showed no effects. For further information regarding scleroderma-like responses to vinyl R&S 149058 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS chloride exposure, see Cardiovascular Effects (Section 2.2.1.2) and Immunological and Lymphoreticular Effects (Section 2.2.1.3). 38 Ocular Effects. Ocular effects that have been reported after inhalation exposure are believed to have resulted from direct contact of the vinyl chloride vapor with the eyes and are discussed under Dermal Exposure (Section 2.2.3.2). No studies were located regarding ocular effects in humans that were related solely to the inhalation of vinyl chloride. No histopathological changes were noted in the eyes of guinea pigs exposed to 400,000 ppm vinyl chloride for 30 minutes (Mastromatteo et al. 1960). Body Weight Effects. Several studies have reported that workers intoxicated by vinyl chloride experienced anorexia (Suciu et al. 1963, 1975). No effects on body weight were noted in ICR mice exposed to either 10,000 ppm vinyl chloride for 5 days, 4 hours per day or to 5,000 ppm vinyl chloride for 6 days, 4 hours per day (Kudo et al, 1990). No consistent or dose-related differences in body weight were noted between rats exposed to up to 50,000 ppm for 1 hour and control rats or in rats exposed to 500 ppm, 5 days per week, for 2 weeks (Hehir et al. 1981). However, statistical analysis was not performed. No changes in body weight were noted in rats exposed to 200 ppm vinyl chloride for 6 months, 5 days per week, 7 hours per day (Torkelson et al. 1961) or in mice exposed to 1,000 ppm vinyl chloride for 8 weeks, 5 days per week, 6 hours per day (Sharma and Gehring 1979). Normal body weights were reported in rabbits exposed to 200 ppm vinyl chloride for 6 months, 5 days per week, 7 hours per day (Torkelson et al. 1961). - Significant decreases were found in the body weight of rats exposed to 100 ppm vinyl chloride for 12 months, 6 hours per day, 6 days per week; these changes were not observed at 10 ppm (Bi et al. 1985). Significant decreases were also noted in mean body weights of rats exposed to 5,000 ppm vinyl chloride for 4-52 weeks, 5 days per week, 7 hours per day, but data were not quantified (Feron et al. 1979a). This study was limited since only one concentration was tested. Body weight was decreased (p<0.05) 10% in male rats exposed to 50 ppm vinyl chloride for 10 months, 5 hours per day, 5 days per week (Sokal et al. 1980). Maternal body weight gain was significantly decreased in mice exposed to 500 ppm for 7 hours per day during gestational days 6-15 (John et al. 1977). R&S149059 '"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 2.2.1.3 Immunological and Lymphoreticular Effects 39 A number of studies have examined the immunologic profile of workers occupationally exposed to vinyl chloride. A statistically significant increase in circulating immune complexes in workers exposed to vinyl chloride was observed when compared to levels in unexposed workers (Bogdanikowa and Zawilska 1984). The increase in circulating immune complexes was greatest in women and in those with duties involving exposure to relatively higher levels of vinyl chloride. Compared to controls, IgG levels were significantly increased in women exposed to the high levels of vinyl chloride in the same study. Studies of workers who have developed "vinyl chloride disease," a syndrome consisting of Raynaud's phenomenon, acroosteolysis, joint and muscle pain, enhanced collagen deposition, stiffness of the hands, and scleroderma-like skin changes, indicate that this disease may have an immunologic basis. Sera obtained from patients with varying degrees of severity of symptoms of vinyl chloride disease demonstrate a close correlation between the disease severity and the extent of the immunologic abnormality (Grainger et al. 1980; Langauer-Lewowicka et al. 1976; Ward 1976), although these symptoms have been reported without immunological findings (Black et al. 1986; Ostlere et al. 1992). The most frequent immunologic findings in workers with vinyl chloride disease are an increase in circulating immune complexes or cryoglobulinemia. In workers with the most severe clinical signs, there also are an increased incidence of B-cell proliferation, hyperimmunoglobulinemia (Ward 1976), cryoglobulinemia (Grainger et al. 1980), and complement activation (Grainger et al. 1980; Ward 1976). Evidence of a structurally altered immunoglobulin G (IgG) has been obtained, and it has proposed that vinyl chloride (or a metabolite) binds to IgG (Grainger et al. 1980). Should such binding occur, the resulting complex may be the antigenic substance that triggers the immune reaction. Based on the similarity of vinyl chloride disease and systemic sclerosis, which may be a genetically linked autoimmune disease. Black et al. (1983, 1986) examined the human lymphocyte antigen (HLA) phenotypes of patients with vinyl chloride disease. Many autoimmune diseases show statistically significant associations with certain HLA alleles. These authors found that when compared to unexposed controls or asymptomatic controls, workers with vinyl chloride disease had a significantly greater incidence of possessing the HLA-DR5 allele. Furthermore, among those with the disease, the severity of the symptoms was significantly related to the possession of the HLA-DR3 and B8 alleles. R&S 149060 "'DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 40 These authors concluded that susceptibility was increased in the presence of HLA-DR5 or a gene in linkage disequilibrium with it, and progression was favored by HLA-DR3 and B8. Splenomegaly was reported in a number of studies (Ho et al. 1991; Marsteller et al. 1975; Popper and Thomas 1975; Suciu et al, 1963; Veltman et al. 1975). No histopathological changes were noted in the spleen or lymph nodes of guinea pigs exposed to 400,000 ppm vinyl chloride for 30 minutes (Mastromatteo et al. 1960). An increase in the relative spleen weight was observed in rats exposed to 50 ppm for 5 hours per day, 5 days per week, for 10 months (Sokal et al. 1980). Although no dose response was evident, increased relative spleen weight was also reported by Bi et al. (1985) when rats were exposed to either 10 ppm for 6 hours per day, 6 days per week, for 6 months or 3,000 ppm for 6 hours per day, 6 days per week, for 3 months. The immunologic effects of vinyl chloride have been examined in mice (Sharma and Gehring 1979). Lymphocytes isolated from the spleens of mice exposed to concentrations as low as 10 ppm vinyl chloride for 4 weeks had increased spontaneous and lectin-stimulated transformation. This increase was not observed when lymphocytes from unexposed mice were cultured in the presence of vinyl chloride, indicating that a metabolite of vinyl chloride may be responsible for the increase. The highest NOAEL value and all reliable LOAEL values for immunological effects in guinea pigs, mice, and rats exposed in acute- and intermediate-duration studies are recorded in Table 2-1 and plotted in Figure 2-1. For further information on Raynaud's syndrome and scleroderma-like responses to vinyl chloride, see Cardiovascular and Dermal Effects (Section 2.2.1.2). 2.2.1.4 Neurological Effects Vinyl chloride was once considered for use as an inhalation anesthetic (ACGIH 1986). Investigators studying the effects of vinyl chloride exposure frequently report central nervous system symptoms that are consistent with the anesthetic properties of vinyl chloride. The most commonly reported central nervous system effects are ataxia or dizziness (Ho et al. 1991; Langauer-Lewowicka et al. 1983; Lilis et al. 1975; Marsteller et al. 1975; Spirtas et al. 1975; Suciu et al. 1963, 1975; Veltman et al. 1975), drowsiness or fatigue (Langauer-Lewowicka et al. 1983; Spirtas et al. 1975; Suciu et al. 1963, 1975; Walker 1976), loss of consciousness (NIOSH 1977), and/or headache (Langauer-Lewowicka et al. 1983; Lilis et al. 1975; Marsteller et al. 1975; NIOSH 1977; Spirtas et al. 1975; Suciu et al. 1963, R&S 149061 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 41 1975; Veltman et al. 1975). Other central nervous system effects that have been reported by vinyl chloride workers include euphoria and irritability (Suciu et al. 1963, 1975), visual and/or hearing disturbances (Marsteller et al. 1975), nausea (Marstcller et al. 1975; Spirtas et al. 1975), memory loss (Langauer-Lewowicka et al. 1983; Suciu et al. 1963, 1975), and nervousness and sleep disturbances (Langauer-Lewowicka et al. 1983; Suciu et al. 1963). Central nervous system tests revealed pyramidal signs and cerebellar disturbances in some exposed subjects (Langauer-Lewowicka et al. 1983); however, reliable estimates of exposure levels producing these effects were not available. Exposure of volunteers to known levels of vinyl chloride has provided some indication of the levels of vinyl chloride associated with the effects noted above. Volunteers exposed to 25,000 ppm vinyl chloride for 3 minutes, in a single-dose study, reported experiencing dizziness, disorientation, and burning sensations in the feet during exposure (Patty et al. 1930). Recovery from these effects was rapid upon termination of exposure, but the subjects developed headaches. Exposure of volunteers to concentrations of vinyl chloride ranging from 4,000 to 20,000 ppm for 5 minutes twice a day in periods separated by 6 hours on 3 consecutive days was studied by Lester et al. (1963). No effects were noted at 4,000 ppm. However, at 8,000 ppm one of six subjects reported feeling dizzy. The incidence of dizziness increased as the concentration increased. Nausea was experienced at higher concentrations, and recovery from all effects was rapid upon termination of exposure. Headaches developed following exposure to 20,000 ppm. Indications of an exposure-related peripheral neuropathy have been observed in a number of the occupational studies. A slight peripheral neuropathy, most severe in hands and feet, was diagnosed in 70% of the vinyl chloride workers examined in a study by Perticoni et al. (1986). The peripheral neuropathy was manifested as denervation-related fasciculations and fibrillations and increased duration and amplitude of motor unit potentials (indicating collateral sprouting). Similar effects were observed by Magnavita et al. (1986) in a case study of a vinyl chloride worker. Other peripheral nervous system symptoms have been reported by a number of investigators studying the effects of occupational exposure to vinyl chloride. The symptom most frequently reported was tingling (paresthesia) in the extremities (Lilis et al. 1975; Sakabe 1975; Spirtas et al. 1975; Suciu et al. 1963, 1975; Veltman et al. 1975; Walker 1976). Additional peripheral nervous system symptoms include numbness in the fingers (Lilis et al. 1975; Sakabe 1975), weakness (Langauer-Lewowicka et al. 1983; Suciu et al. 1963, 1975), depressed reflexes (NIOSH 1977), warmth in the extremities (Suciu et al. 1963, 1975), and pain in the fingers (Sakabe 1975). It is unclear whether some of these symptoms are associated with tissue anoxia R & S 149062 --DRAFT FOR PUBLIC COMMENT-- VINYL CHLORIDE 2. HEALTH EFFECTS 42 due to vascular insufficiency, or whether they represent the direct toxic effects of vinyl chloride on peripheral nerves. Acute exposure of a number of species to high levels of vinyl chloride has provided additional information on the characteristics of the central nervous system effects that are produced. Exposure of guinea pigs to TO,000 ppm for 8 hours (Patty et al. 1930) was observed to be without effects. Increasing the concentration to 25,000 ppm resulted in ataxia, which developed into unconsciousness during the 8-hour exposure period. As the concentration was increased, the development of unconsciousness was more rapid. At 100,000 ppm, Mastromatteo et al. (1960) observed the development of unconsciousness within 30 minutes. Mice experienced similar signs at approximately equivalent exposure levels. At 5,000 ppm, vinyl chloride was without effect during a l-hour exposure period. Increasing the concentration to 50,000 ppm caused ataxia and twitching (Hehir et al. 1981), and at 100,000 ppm for 30 minutes unconsciousness was produced, preceded by increased motor activity, incoordination, twitching, and tremors (Mastromatteo et al. 1960). Similar effects in rats were observed by Lester et al. (1963), Jaeger et al. (1974), and Mastromatteo et al. (1960). In contrast, in two reports using rats, exposure to 50,000 ppm for either 1 or 6 hours was without effect (Hehir et al. 1981; Jaeger et al. 1974). No effects were noted in rats exposed to 500 ppm vinyl chloride for 2 weeks (5 days/week, 1 hour/day) or in rats exposed to 50 ppm for 20 weeks (5 days/week, 1 hour/day) (Hehir et al. 1981). In addition, tolerance developed to the intoxicating effects of exposure to 50,000 ppm vinyl chloride after five or six 8-hour exposures (Lester et al. 1963). Chronic exposure of rats to high levels of vinyl chloride has produced damage to nervous tissue. Rats exposed to 30,000 ppm for 4 hours per day, 5 days per week, for 12 months in a single-concentration study were slightly soporific during exposures (Viola 1970; Viola et al. 1971). Following 10 months of exposure, the rats had decreased responses to external stimuli and disturbed equilibrium. Histopathological examination revealed diffuse degeneration of gray and white matter. Cerebellar degeneration in the Purkinje cell layer was pronounced. Also, peripheral nerve endings were surrounded and infiltrated with fibrous tissue (Viola 1970; Viola et al. 1971). Nonneoplastic lesions in the brain were not noted in rats exposed to 5,000 ppm for 7 hours per day, 5 days per week, for 12 months in a single-concentration study by Feron and Kroes (1979). The highest NOAEL values and all reliable LOAEL values for neurological effects in each species from acute- or intermediate-duration studies are recorded in Table 2-1 and plotted in Figure 2-1. R & S 149063 '"DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE p2.1.5 Reproductive Effects 2. HEALTH EFFECTS 43 A number of case reports of workers occupationally exposed to vinyl chloride suggest that sexual performance may be affected by vinyl chloride. However, these studies are limited by the lack of quantification of exposure levels and possible concomitant exposures to other chemicals. Sexual impotence was reported by 24% of the workers examined by Suciu et al. (1975). Approximately-20% of the workers examined by Veltman et al. (1975) complained of potency troubles. A loss of libido in 35% and impotence and decreased androgen secretion in 8% of workers exposed, at least once, to very high levels of vinyl chloride were also reported by Walker (1976). In retrospective and prospective studies by Bao et al. (1988), an increased incidence and severity of elevated blood pressure and edema during pregnancy (preeclampsia) were found in female workers exposed to vinyl chloride when compared to unexposed workers. Company records indicated that exposure levels ranged from 3.9 to 89.3 ppm during the retrospective study and from 0.2 to 130.7 ppm during the prospective study. More detailed information regarding the exposure levels was not resented. Although no studies were located that documented the effects of vinyl chloride on reproductive performance when both parental animals were exposed, two dominant lethal studies examined the reproductive performance of exposed males. A brief exposure (5 days, 6 hours per day) of mice to concentrations of vinyl chloride as high as 30,000 ppm had no effect on male fertility or pre- or postimplantation loss (Anderson et al. 1976). In contrast, exposure of male rats to concentrations as low as 250 ppm for 6 hours per day, 5 days per week, for 11 weeks caused a decrease in the ratio of pregnant to mated females, indicating a decrease in male fertility (Short et al. 1977). These results are supported by two studies using rats in which adverse effects of vinyl chloride on the testes were observed (Bi et al. 1985; Sokal et al. 1980). Exposure of rats to 100 ppm for 6 hours per day, 6 days per week, for 12 months caused a significant increase in the incidence of damage to the seminiferous tubules and depletion of spermatocytes (Bi et al. 1985). At the 6-month interim sacrifice, a significant decrease in testicular weight was also observed at 100 ppm. No effect on male reproductive organs was observed in this study at 10 ppm. A significant increase in damage to the spermatogenic epithelium and disorders of spermatogenesis were found with exposure to 500 ppm vinyl chloride for 5 hours per day, 5 days per week, for 10 months (Sokal et al. 1980). No significant decrease in ticular weight was found in rats exposed to 500 ppm for 7 hours per day, 5 days per week, for B&S 149064 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 44 4.5 months or in dogs, rabbits, or guinea pigs exposed to 200 ppm for 7 hours per day, 5 days per week, for 6 months (Torkelson et al. 1960). However, the quality of this study is limited because of the small number of animals tested. Exposures involved up to 10 rats or guinea pigs of each sex, 3 rabbits of each sex, and 1 dog of each sex. No histopathological data on the testes of these animals were presented. The highest NOAEL values and all reliable LOAEL values for reproductive effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.6 Developmental Effects Although evidence has been presented indicating that members of communities with nearby vinyl chloride polymerization facilities have significantly greater incidences of some forms of developmental toxicity, these studies failed to demonstrate a statistically significant correlation between the developmental toxicity and either parental occupation or proximity to the facility (Edmonds et al. 1978; Infante 1976; Rosenman et al. 1989; Theriault et al. 1983). The pregnancy outcome of wives of workers employed at a vinyl chloride polymerization facility was compared to the pregnancy outcome of wives of a control group made up of unexposed rubber workers and PVC fabricators believed to be exposed to "very low" levels of vinyl chloride (Infante et al. 1976a, 1976b). Pregnancy outcomes were determined based on the responses given by fathers on a questionnaire. Infante et al. (1976a, 1976b) and NIOSH (1977) reported a significant excess of fetal loss in the group whose husbands had been exposed to vinyl chloride. The greatest difference occurred in wives of men under 30 years of age, where fetal loss was 5.3% for controls and 20.0% for exposed workers. However, this study has been severely criticized based on the conduct of the study and method of statistical analysis used (Hatch et al. 1981; Stallones et al. 1987). Furthermore, Hatch et al. (1981) and Stallones et al. (1987) concluded that the study failed to demonstrate an association of parental exposure to vinyl chloride with increased fetal loss. Additional work by Infante (1976) and Infante et al. (1976b) examined the occurrence of congenital malformations among populations exposed to emissions from PVC polymerization facilities. A statistically significant increase in birth defects was observed in three cities in which polymerization facilities were located when compared to statewide and countywide averages. The greatest increases R&S 149065 DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 45 ere noted in malformations of the central nervous system, upper alimentary tract, and genital organs and in the incidence of club foot. However, this study has also been criticized based on the conduct and analyses used (Hatch et al. 1981; Stallones et al. 1987). These authors concluded that the study failed to demonstrate an association between exposure to emissions and the prevalence of birth defects. Furthermore, another study that examined the incidence of malformations in one of the cities studied by Infante (1976) concluded that, although the city had statistically increased incidences of congenital malformations, no correlation existed with parental proximity to the polymerization plant or with parental employment at the plant (Edmonds et al. 1975). In fact, more parents of control infants worked at the plant or lived closer to the plant than parents of infants with central nervous system malformations. Additional studies have also examined the prevalence of congenital malformations in populations exposed to emissions from polymerization facilities (Edmonds et al. 1978; Rosenman et al. 1989; Theriault et al. 1983). The incidence of central nervous system defects in a West Virginia county with a polymerization plant was compared to incidences in other regions in the United States with no known exposure to vinyl chloride (Edmonds et al. 1978). Although the rate of central nervous system ^ifects in the West Virginia county exceeded that in control areas, no correlation was noted between the increased central nervous system defects and parental occupation or potential exposure based on proximity to the plant or prevailing wind patterns. A significantly greater prevalence of birth defects was found in residents of a town with a polymerization facility than in three matched towns without potential for exposure to vinyl chloride (Theriault et al. 1983). The most commonly reported defects included those of the musculoskeletal, alimentary, urogenital, and central nervous systems. The incidences were observed to fluctuate with seasonal changes in emissions. However, no correlations were found between the presence of defects i and proximity of the residence to the plant or parental occupation. Also, other industrial emissions could not be eliminated as potential sources of the increased incidence of congenital malformations observed. No significant increases in birth defects were observed in a community with two polymerization facilities, but odds ratios for central nervous system defects were found to correlate with the amount of emissions from the individual facilities and with the distance of the residences of affected parents from e facilities (Rosenman et al. 1989). However, this study was limited by the small sample size. R&S 149066 '"DRAFT FOR PUBLIC COMMENT"' VINYL CHLORIDE 2. HEALTH EFFECTS 46 Pregnancy outcomes of mothers occupationally exposed to vinyl chloride for more than 1 year were compared to those of pregnant workers not exposed to vinyl chloride in retrospective and prospective studies (Bao et al. 1988). Company records indicated that exposure levels ranged from 3.9 to 89.3 ppm during the retrospective study and from 0.2 to 130.7 ppm during the prospective study. More detailed information regarding the exposure levels was not was not presented. The study authors concluded that exposure to vinyl chloride did not correlate with changes in sex ratio, birth weight or height, perinatal mortality, or the incidence of congenital abnormalities. A number of inhalation studies have examined the effects of vinyl chloride exposure on pregnancy outcome in animals. Results of these studies indicate that vinyl chloride produces developmental effects at concentrations that are also toxic to maternal animals. John et al. (1977, 1981) exposed rats and rabbits to 0, 500, or 2,500 ppm and mice to 0, 50, or 500 ppm throughout the period of organogenesis. Separate control groups were used for each of the mice exposure concentrations. Mice were most sensitive to the effects of vinyl chloride. In mice exposed to 500 ppm, maternal toxicity was evidenced by decreased food consumption, decreased body weight gain, and increased mortality (John et al. 1977, 1981). Delayed ossification was noted in fetuses at 500 ppm. The only significant fetal effect observed at 50 ppm was an increase in crown-rump length. The biological significance of this effect is unknown. Based on this NOAEL of 50 ppm, an acute-duration MRL of 0.5 ppm was calculated as described in the footnote in Table 2-1. In rats, 500 ppm caused decreased maternal weight gain and fetal weight, increased crown-rump length, and vertebral lumbar spurs. Increasing the exposure level to 2,500 ppm was not associated with a dose-dependent increase in these effects. The only effects observed at 2,500 ppm were decreased maternal food consumption and, in fetuses, an increased incidence of dilated ureters. In rabbits exposed to 500 ppm, maternal animals had decreased food consumption, and fetal animals had delayed ossification. These effects were not observed in rabbits at 2,500 ppm. However, the number of animals that were tested at 2,500 ppm was much lower than at 500 ppm (5 versus 20), thus no conclusions may be drawn as to the dose-response of these effects. Exposure of rats to either 0 or 1,500 ppm of vinyl chloride during the first, second, or third trimester of pregnancy was examined (Ungvary et al. 1978). In maternal animals, an increased liver-to-body weight ratio was observed in those exposed during the first and second trimesters, but no histopathologic alterations were found. A significant increase in resorptions was observed in animals exposed during the first trimester of pregnancy. Two central nervous system malformations R&S149067 -- DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS Microphthalmia and anophthalmia) were observed in exposed fetuses but not in controls, but the 47 incidence of these malformations did not reach statistical significance. This study is limited in that only a single concentration of vinyl chloride was tested, precluding conclusions as to the dose-response relationship of the effects observed. The effects of exposure of rats to vinyl chloride throughout gestation were examined by Mirkova-et al. (1978) and Sal'nikova and Kotsovskaya (1980). An unspecified number of pregnant rats were exposed to 0, 1.9, or 13.9 ppm for 4 hours per day for the 21 days of gestation. Fetuses were examined for abnormalities just prior to the end of gestation, and offspring were examined at 6 months postparturi tion (Sal'nikova and Kotsovskaya 1980). At 13.9 ppm, a decrease in maternal erythrocyte count was observed. At 1.9 and 13.9 ppm, fetuses had an increased incidence of hemorrhages, and at 13.9 ppm, increased edema. However, the affected organs were not specified. Rats examined at 6 months, following in utero exposure to 1.9 ppm, were found to have decreased hemoglobin and leukocytes and decreased organ weights (males: liver, kidney, spleen; females: lung, liver). In addition to these effects, exposure to 13.9 ppm in utero resulted in an increased hexanol sleep time and a decreased ability of the rats to orient themselves. Continuous exposure of an unspecified number of rats throughout gestation to 2.4 ppm of vinyl chloride resulted in decreased fetal weight and increased early postimplantation loss, hematomas, and hydrocephaly with intracerebral hematoma. Weanling rats had hepatotoxic effects including decreased bile enzyme activity, decreased bile secretion, decreased cholic acid content, and increased hexobarbital sleep time. No histological data on the livers of pups, or information regarding maternal health, or statistical analyses of the data were presented (Mirkova et al. 1978). Also, both this study and the report by Sal'nikova and Kotsovskaya (1980) failed to provide information on the number of animals in each test group. The highest NOAEL value and all reliable LOAEL values for developmental effects in mice, rats, and/or rabbits in acute-duration studies are recorded in Table 2-1 and plotted in Figure 2-1. Discussion of transplacental carcinogenic effects can be found in Section 2.2.1.8 (Cancer). R&S 149068 --DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2.2.1.7 Genotoxic Effects 2. HEALTH EFFECTS 48 Genotoxicity studies of vinyl chloride in humans include a large number of assays for chromosomal aberrations in the cultured lymphocytes of occupationally exposed workers. Studies completed through the mid-1980s generally found a statistically significant increase in the frequency of chromosomal aberrations, usually of the chromatid type (i.e., affecting only one of the two strands formed upon deoxyribonucleic acid [DNA] replication) but also including some chromosomal-type defects such as inversions, rings, and translocations, which affect the entire chromosome. Workers exposed to vinyl chloride for an average of 15 years were shown to have elevated levels of micronuclei and chromosomal aberrations when compared to the unexposed controls (Garaj-Vrhovac et al. 1990). Micronuclei counts were also increased (p<0.001) in a group of 52 workers exposed to vinyl chloride levels of 1.3-16.7 ppm compared to those of controls, but these increases were not observed in workers exposed to 0.3-7.3 ppm (Sinues et al. 1991). Increased sister chromatid exchanges have also been reported in occupationally exposed workers (Fucic et al. 1992; Kucerova et al. 1979; Sinues et al. 1991; hao et al. 1994). Sister chromatid exchange frequencies were increased (<0.001) compared to those of the controls at 0.003-7.3 ppm vinyl chloride (Sinues et al. 1991). A study examined 37 exposed workers and from 16 to 32 unexposed controls twice at intervals of from 2 to 2.5 years (Hansteen et al. 1978). Exposure levels during the time of the first sampling were measured at 25 ppm, and there was a statistically significant increase in aberrations among the exposed workers. At the subsequent examination, exposure levels had dropped to 1 ppm and the chromosomal aberra tions had returned to normal. There were no statistical differences between exposed subjects and controls in the percentage of chromosomal aberrations. It was reported that the increase of chromosome aberrations observed in workers exposed to 50 ppm returned to normal within 42 months when the cohort was sampled after exposure levels had been reduced to less than 5 ppm (Anderson et al. 1980). A positive correlation between frequency of chromosomal aberrations and length of exposure and history of exposure to excursion levels (up to 2.000 ppm) was reported by Purchase et al. (1978), who examined a cohort of 57 vinyl chloride workers, 19 on-site controls, and 5 off-site controls. The exposures for this cohort ranged from 1.000 ppm between 1945 and 1955 and 5 ppm since 1975. These authors also reported an effect on chromosomal aberrations from smoking. The reversibility of clastogenic effects was not seen, however, in another study of 12 current and 3 retired plastic industry workers who had been exposed to vinyl chloride while employed for 1.5-35 years (Fucic et al. 1992). Sister chromatid exchange R&S149069 "'DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 49 quencies were significantly higher in workers exposed to concentrations up to 2,000 ppm than in the controls. These findings showed no significant decrease in sister chromatid exchange frequencies from 8 days to 10 years after exposure (Fucic et al. 1992). Other papers on human subjects have focused on specific mechanisms involved in the clastogenic effects of vinyl chloride. A cohort of 67 workers exposed to approximately 5 ppm for an average of 15 years was reported to have a nonrandom distribution of chromatid and bichromatid breaks (Fucic et al. 1990). The most frequently affected areas of the genome were the terminal segments of the A, B, and C group chromosomes, suggesting that vinyl chloride or its metabolites interact more frequently with specific sites along the chromosome than would be expected. The study authors presented no correlation with particular fragile sites (gene sequences more prone to breakage than normal) or oncogene locations known to occur at these terminal segments. The implication is that the carcinogenicity of vinyl chloride could be at least partially explained by its nonrandom interaction with particular genes. These workers were also periodically exposed to 2,000 ppm for short periods. No specific information was given as to the frequency or duration of these events. ^.nalysis of serum samples taken from workers at French vinyl chloride polymerization plants showed that 4 out of 5 of those who developed angiosarcoma of the liver, 8 out of 9 who developed benign angiomatous lesions, and 22 out of 45 who had no evidence of liver lesions were positive for the presence of a mutant protein corresponding with the mutation of the c-ki-/w gene (DeVivo et al. 1994). This mutant protein was not found in the serum of any of the unexposed controls. A linear relationship was found between the frequency of the mutant protein in serum and the number of years of exposure, which might provide evidence for the linearity of carcinogenicity risk in humans (DeVivo et al. 1994). A study was performed to examine the p53 tumor suppressor genes and the murine double min-2 (MDM2) proto-oncogenes from tumors of five vinyl chloride workers, four with angiosarcoma of the liver and one with hepatocellular carcinoma (Hollstein et al. 1994). The p53 tumor suppressor gene was being tested for mutation, while the MDM2 proto-oncogene was being tested for amplification. No amplification of the MDM2 gene was detected; however, adenosine-to-thymidine missense mutations were found in the p53 gene in two of the angiosarcoma cases. R&S 149070 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS SO Animal studies of rats and mice exposed via inhalation to vinyl chloride have concentrated on identifying direct effects on the DNA. Increased alkylation of liver DNA and increased cell proliferation were reported by Laib et al. (1989). Both young and old rats were exposed to 600 ppm for 6 hours. The older male rats were sacrificed, and the young rats of both sexes and the adult females received a second 6-hour exposure following a 15-hour interval. The 30 young rats were apparently more susceptible to the effects of vinyl chloride, but only 3 male adults and-2 female adults were used for comparison. The role of chloroethylene oxide, a metabolite of vinyl chloride, was described by Gwinner et al. (1983). Rats exposed to 2,000 ppm vinyl chloride for 8 hours per day, 5 days per week, for 3 weeks beginning at 7 days of age demonstrated hepatocellular ATPase-deficient foci and alkylation of liver DNA. Rats exposed to either 2,2'-dichloro-diethylether(bis(chloroethyl)ether) or to chloroethanol did not form these foci, which are considered to be preneoplastic; these compounds do not metabolize to chloroethylene oxide, but rather to the aldehyde, suggesting that the aldehyde is not a mutagen in vivo. The types of adducts of vinyl chloride seen after in vivo exposure may depend on the length of exposure, the sensitivity of the method used, and on the animal species. The vinyl chloride-derived nucleoside, 7V-2,3-ethenoguanosine, has been identified in the liver of vinyl chloride-exposed rats. This nucleoside, when incorporated into DNA, has been shown to be an efficient mutagen that causes base-pair (i.e., purine to purine or pyrimidine to pyrimidine exchange) transitions during transcription (Singer et al. 1987). The identification of the etheno nucleosides has been reported to occur following inhalation exposure to vinyl chloride in rats (Bolt et al. 1986; Ciroussel et al. 1990; Eberle et al. 1989; Fedtke et al. 1990; Swenberg et al. 1992). Immature rats exposed in vivo formed six times more of this nucleoside, which correlated with the age-related sensitivity to carcinogenesis in these animals (Ciroussel et al, 1990). This age-related sensitivity to DNA adduct formation was also noted in an inhalation study of lactating rats and their 10-day-old pups exposed 4 hours per day, for 5 days to 600 ppm of vinyl chloride (Fedtke et al. 1990). Concentrations of two adducts found in the liver of the pups were fourfold higher than those found in the liver of the dams. Effects of vinyl chloride on DNA are not restricted to the rat. Induction of single-strand breaks in liver DNA of mice after inhalation of vinyl chloride was reported by Walles et al. (1988). R&S 149071 '"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2 HEALTH EFFECTS 51 Vinyl chloride has not been shown to be positive for dominant lethal effects in rats exposed to up to 30,000 ppm for 6 hours per day, for 5 days (Anderson et al. 1976; Purchase et al. 1975; Short et al. 1977), The studies showed no evidence of pre- or post-implantation loss among the untreated females mated to the exposed males. These results indicate that no germinal mutations were caused by these acute exposures. Table 2-5 lists the key in vivo studies of the genotoxicity of vinyl chloride. Other genotoxicity studies are discussed in Section 2.5. 2.2.1.8 Cancer The most compelling evidence for the carcinogenic potential of vinyl chloride in humans comes from the cluster of reports of greater than expected incidences of angiosarcoma of the liver in workers occupationally exposed to vinyl chloride (Byren et al. 1976; Creech and Johnson 1974; Fox and Collier 1977; Infante et al. 1976b; Jones et al. 198S; Laplanche et al. 1992; Monson et al. 1975; Pirastu et al. 1990; Rinsky et al. 1988; Simonato et al. 1991; Teta et al. 1990; Waxweiler et al. 1976; Weber et al. 1981; Wong et al. 1991; Wu et al. 1989). Angiosarcoma of the liver is considered to be a very rare type of cancer (25-30 cases per year in the United States) (Heath et al. 1975). However, approximately 30 years after the introduction of vinyl chloride for use in the industrial production of PVC, it became apparent that workers exposed to vinyl chloride had an unusually high incidence of this type of tumor. Investigators identified an increased likelihood of developing hepatic angiosarcoma among those exposed to the highest levels of vinyl chloride and those exposed to vinyl chloride for the longest duration (Fox and Collier 1977; Infante et al. 1976b; Jones et al. 1988; Rinsky et al. 1988; Weber et al. 1981; Wong et al. 1991; Wu et al. 1989). Based on this information, vinyl chloride is considered to be a carcinogen in humans (EPA 1994c; IARC 1987). Histopathological examination of liver tissue from humans with hepatic angiosarcoma has led to the hypothesis that angiosarcoma develops as a result of hyperplastic changes in sinusoidal cells. Areas of transition to angiosarcoma contained greatly increased numbers of sinusoidal cells with greatly expanded sinusoidal spaces. Also, hepatic cells were replaced by Fibrous tissue forming trabeculae. These areas also showed infiltration of angiosarcoma'cells. In fully developed angiosarcoma, multiple areas with nodules of angiosarcoma cells were noted, the centers of which exhibited hemorrhagic necrosis (Popper et al. 1981). R&S 149072 '"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 52 Other cancers that have shown a statistically significant increase in mortality among vinyl chloride workers, in at least some studies, include cancer of the brain and central nervous system, the lung and respiratory tract, and the lymphatic/hematopoietic system. With regard to cancer of the brain and central nervous system, Cooper (1981), Waxweiler et al, (1976), and Wong et al. (1981) reported statistically significant increases; Monson et al. (1975) reported an increase in central nervous system cancer mortality in a proportional mortality study; Byren et al. (1976), Simonato et al.41991), and Tabershaw and Gaffey (1974) reported increases that were not statistically significant; and Fox and Collier (1977), Jones et al. (1988), Thomas et al. (1987), and Wu et al. (1989) found no increase in cancer of the central nervous system among workers occupationally exposed to vinyl chloride. A significant increase in cancer of the respiratory tract was reported by Belli et al. (1987), Infante et al. (1976b), and Waxweiler et al. (1976) and also by Monson et al. (1975) in a proportional mortality study. However, studies by Cooper (1981), Fox and Collier (1977), Jones et al. (1988), Simonato et al. (1991), Wong et al. (1991), and Wu et al. (1989) did not find a significant increase. Although smoking history was not considered in the studies reporting a statistically significant increase in respiratory cancer, Waxweiler et al. (1976) noted that the types of respiratory tract cancer most frequently recorded were large-cell undifferentiated carcinoma or adenocarcinoma, which are two lung cancer types not usually associated with smoking. A statistically significant increase m cancers of the lymphatic/hematopoietic .system was reported by Rinsky et al. (1988), Smulevich et al. (1988), and Weber et al. (1981). Monson et al. (1975) also reported an increase in their proportional mortality study. However, no statistically significant increase in these types of cancer was reported by Infante et al. (1976b), Jones et al. (1988), or Wong et al. (1991). An increased incidence of malignant melanoma among vinyl chloride workers has been reported (Heldaas et al. 1984, 1987), but the significance of this finding has been disputed (Ten Berge 1987). Few studies directly address the incidence of cancer in women occupationally exposed to vinyl chloride. However, one study found that women employed in the production of vinyl chloride and PVC had a significantly greater chance of developing leukemia or lymphomas (Smulevich et al. 1988). Furthermore, the subgroup of women who were exposed to the highest levels of vinyl chloride had increased incidences of stomach cancer and the highest incidences of leukemia and lymphoma. No R&S149073 --DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 53 Significant increase in any type of cancer was observed in exposed males in this report, irrespective of the level of exposure. Studies in several species support the conclusion that vinyl chloride is carcinogenic. A large series of experiments was performed by Maltoni et al. (1981) using rats (Sprague-Dawley and Wistar), mice, and hamsters. All animals were chamber exposed; controls were chamber exposed to air only. ,,The test material was >99.9% pure. A complete gross and histopathological examination of every animal was performed. However, extremely limited histopathological data were presented and cancer incidences were presented only in summary tables. Also, survival of control animals was poor in some of the experiments, suggesting that animal care was inadequate or that unthrifty animals were used. Furthermore, statistical analyses, where present, appear to be based on a compilation of data from several individual studies. In one group of studies, Maltoni et al. (1981) exposed SpragueDawley rats to vinyl chloride for 52 weeks at concentrations ranging from 1 to 30,000 ppm. Animals were examined at the time of their spontaneous death. Statistically significant increases were noted in the incidence of mammary gland carcinomas at concentrations as low as 5 ppm in females, Zymbal gland carcinomas at 10,000 ppm and above, nephroblastoma at concentrations as low as 100 ppm in males and 250 ppm in females, liver angiosarcoma at concentrations as low as 50 ppm in females and 200 ppm in males, neuroblastoma at 10,000 ppm in females, and forestomach papillomas and acanthoma at 30,000 ppm. Other findings (though not statistically significant) that were considered important, based on historical data from their laboratory that indicated the rarity of certain tumors, include angiosarcoma and Zymbal gland carcinoma at 10 and 25 ppm and nephroblastoma at 25 ppm. Maltoni et al. (1981) also reported that decreasing the duration of exposure decreased the incidence of vinyl chloride-related tumors (nephroblastomas, liver angiosarcomas, Zymbal gland carcinomas, and, to some extent, neuroblastomas), but statistics were not presented to support this conclusion. Some variation in the target organs that developed tumors was observed when different species were exposed to vinyl chloride (Maltoni et al. 1981). Whereas angiosarcomas of the liver were reported to occur in rats, mice, and hamsters, mammary gland carcinomas were found only in rats and mice; Zymbal gland carcinomas, neuroblastomas, and nephroblastomas were found only in-rats; lung tumors were found only in mice; and melanomas, acoustical duct epithelial tumors, and leukemias were found only in hamsters. R&S149074 `"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 54 Other inhalation experiments support the carcinogenicity of vinyl chloride. Rats and mice exposed to 0. 50, 250, or 1,000 ppm for 6 hours per day, 5 days per week, for 6 months (Hong et al. 1981) or up to 12 months (Lee et al. 1977a, 1978) had a significantly increased incidence of hemangiosarcoma of the liver at >250 ppm. An increase in bronchioloalveolar adenoma of the lung and mammary gland tumors (adenocarcinomas, squamous and anaplastic cell carcinomas) were also observed in mice at >50 ppm, although it is unclear whether the increases in these tumor types are statistically significant (Lee et al. 1977a, 1978). Male rats exposed to concentrations as low as 100 ppm for 6 hours per day. 6 days per week, for 12 months had significantly increased incidences of angiosarcoma of the liver when sacrificed at 18 months (Bi et al. 1985). Rats exposed to 30,000 ppm vinyl chloride 4 hours per day, 5 days per week, for 12 months had an increased incidence of epidermoid carcinoma of the skin, adenocarcinoma of the lungs, and osteochondroma in the bones (Viola et al. 1971), and rats exposed to 5,000 ppm for 52 weeks had primary tumors in the brain, lung, Zymbal gland, and nasal cavity (Feron and Kroes 1979). However, these studies (Feron and Kroes 1979; Viola et al. 1971) are limited by the absence of statistical analysis of the data. A concentration-dependent increase in tumor formation (alveologenic adenomas of the lung, angiosarcomas of the liver, and adenosquamous carcinoma of the mammary gland) was observed in mice exposed to 0, 50, 200, or 2,500 ppm vinyl chloride in a study performed for the Manufacturing Chemists Association (Keplinger et al. 1975). However, no statistics were presented to support these conclusions. Furthermore, an audit of data performed for the Manufacturing Chemists Association (EPL 1979) indicated that mishandling of the tissues precluded making statements regarding the relationship of tumors other than angiosarcoma of the liver to vinyl chloride exposure. Female mice exposed to 50 ppm vinyl chloride showed increased incidence of hemangiosarcoma of the subcutis and peritoneum as well as tumors of the lung and mammary gland (Drew et al. 1983), i.e., hemangiosarcoma of the skin, spleen, or liver and mammary gland carcinomas. In a preliminary study with a limited number of animals, alveogenic lung tumors developed in 26 of 27 mice exposed to 2,500 or 6,000 ppm for 5-6 months (Suzuki 1978). A concentration-related increase in the incidence of alveogenic tumors was observed in a study in which a greater number of mice were exposed to 0-600 ppm for 4 weeks and then observed for up to 41 weeks postexposure (Suzuki 1983). A significant increase in the incidence of pulmonary adenomas was reported in mice exposed to 50 ppm for 6 months (Adkins et al. 1986). An increase in bronchioloalveolar adenoma was observed in a lifespan study in mice that were exposed to 50 ppm for 100 1-hour exposures, 500 ppm for 10 1-hour exposures, or 5.000 ppm for a single 1-hour exposure (Hehir et al. 1981). The statistical significance of these observations was not presented. R&S 149075 "'DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 55 Some data suggest that exposure of animals early in their lives may increase the likelihood of developing tumors or affect the type of tumor that develops. When hamsters, mice, and rats were exposed to vinyl chloride for periods of 6-24 months starting at various times after weaning, the incidence of tumors such as hemangiosarcoma of the liver, skin, spleen, and stomach angiosarcoma was greater when animals were exposed for 12 months immediately after weaning than if animals were held for 12 months and then exposed for the next 12 months (Drew et al. 1983). Fibroadenoma of the mammary gland was also increased in female rats exposed to 100 ppm of vinyl chloride for 6 hours per day, 5 days per week, over 6-24 months (Drew et al. 1983). Also, when pregnant rats were exposed to 6,000 ppm vinyl chloride from gestation day 12 through 18, the incidence of mammary gland carcinomas, Zymbal gland carcinomas, and forestomach epithelial tumors was reported to be greater in transplacentally exposed animals than in maternal animals (Maltoni et al. 1981). At 10,000 ppm in this study, nephroblastomas were increased in transplacentally exposed animals compared to maternal animals (Maltoni et al. 1981). No control group was used, however, and no statistics were presented to support the conclusions. Maltoni and Cotti (1988) also exposed pregnant rats to 2,500 ppm vinyl chloride starting on gestation day 12 and continued to expose both maternal animals and offspring for a total of 76 weeks. Hepatocarcinoma, hepatic angiosarcoma, and neuroblastoma were increased in treated animals compared to controls. The incidence of hepato carcinoma was reported to be much higher in offspring than in maternal animals. In contrast, the incidence of neuroblastomas was similar between offspring and parents, and hepatic angiosarcomas had only a slightly higher incidence and slightly shorter latency in offspring than parents. However, no statistics were presented to support these conclusions. Evidence for the genotoxic effects of vinyl chloride comes from the formation of DNA adducts after vinyl chloride exposure in vivo. The vinyl chloride-derived nucleoside, ;V-2,3-ethenoguanosine, has been identified in the liver of vinyl chloride-exposed rats. This nucleoside, when incorporated into DNA, has been shown to be an efficient mutagen that causes base-pair (i.e., purine to purine or pyrimidine to pyrimidine exchange) transitions during transcription (Singer et al. 1987). The identification of the etheno nucleosides has been reported to occur following inhalation exposure to vinyl chloride in rats (Bolt et al. 1986; Ciroussel et al. 1990; Eberle et al. 1989; Fedtke et al. 1990; Swenberg et al. 1992). Immature rats exposed in vivo formed six times more of this nucleoside, which correlated with the age-related sensitivity to carcinogenesis in these animals (Ciroussel et al. 1990). This age-related sensitivity to DNA adduct formation was also noted in an inhalation study of lactating rats and their 10-day-old pups exposed 4 hours per day, for 5 days to 600 ppm of vinyl chloride R&S149076 "'DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 56 (Fedtke et al. 1990). Concentrations of two adducts found in liver of pups were fourfold higher than those found in liver of dams. Further information on formation of DNA adducts can be found in Section 2.2.1.7. In general, the available evidence from inhalation studies in animals supports the Finding in humans; that vinyl chloride is a carcinogen by this route of exposure. The lowest doses tested that produced a tumorigenic response (Cancer Effect Level [CEL]) for each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.2 Oral Exposure All dosages of vinyl chloride administered in the diet are reported as mg/kg(body weight)/day unless otherwise specified. 2.2.2.1 Death No studies were located regarding lethal effects in humans following oral exposure to vinyl chloride. No studies were located regarding acute or intermediate lethal effects of vinyl chloride in animals. However, decreased longevity has been observed in rats as a result of chronic ingestion of vinyl chloride. Significant increases in mortality were observed by Feron et al, (1981) when Wistar rats were allowed to consume vinyl chloride doses as low as 5.6 mg/kg/day in the diet for 4 hours per day over a 2-year period. Also, the effects of consumption of vinyl chloride during a lifespan study in Wistar rats lasting almost 3 years (149 weeks) was examined by Til et al. (1983, 1991). These authors found decreased survival at a vinyl chloride dosage of 1.7 mg/kg/day. In both of these studies, vinyl chloride was administered by incorporating PVC resin that was high in vinyl chloride content into the diet. Vaporization of vinyl chloride from the diets was limited by presenting feed containing the vinyl chloride to the rats for only a 4-hour period. All reliable LOAEL values for death in rats following chronic exposure are recorded in Table 2-2 and plotted in Figure 2-2. R & S 149077 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2.2.2.2 Systemic Effects 2. HEALTH EFFECTS 57 The highest NOAEL values and all reliable LOAEL values for hematological, hepatic, dermal, and body weight effects in rats following chronic oral exposure are recorded in Table 2-2 and plotted in Figure 2-2. No studies were located regarding respiratory, cardiovascular, gastrointestinal, musculoskeletal, renal, or ocular effects in humans or animals following oral exposure to vinyl chloride. Hematological Effects. No studies were located regarding hematological effects in humans after oral exposure to vinyl chloride. Rats fed 17 mg/kg/day for 2 years showed decreased clotting time of the blood (Feron et al. 1981). No changes in thrombocyte count or prothrombin times were noted in Wistar rats fed diets containing high concentrations of vinyl chloride in PVC resin (1.7 mg/kg/day) for 149 weeks (Til et al. 1983, 1991). Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to vinyl chloride. Chronic exposure of rats to vinyl chloride in their feed for 149 weeks caused an increase in the incidence of basophilic foci of cellular alteration at 0.018 mg/kg/day (Til et al. 1983, 1991). This dose was used as the basis for a chronic oral MRL of 0.00002 mg/kg/day. Chronic oral exposure of rats fed vinyl chloride daily during a 4-hour period for 2 years also resulted in areas of hepatocellular alteration at concentrations as low as 1.8 mg/kg/day (Feron et al. 1981). In this study, areas of necrosis were observed in the liver of female rats fed 5.6 mg/kg/day and male rats fed 17 mg/kg/day (Feron et al. 1981). Increased incidence of hepatic cysts were found in female rats fed 1.7 mg/kg/day in the Til et al. (1983, 1991) studies. Dermal Effects. No studies were located regarding dermal effects in humans after oral exposure to vinyl chloride. R&S 149078 --DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' Species/ (strain) Exposure duration/ frequency/ (specific route) TABLE 2-2. Levels of Significant Exposure to Vinyl Chloride - Oral Systel" NOAEL (mg/kg/day) Less serious (mg/kg/day) LOAEL (effect) Serious (mg/kg/day) CHRONIC EXPOSURE Death Rat (Wistar) 2 yr 5d/wk 4hr/d (F) 5.6 (100% died) i Reference Feron at al. 1981 Rat (Wistar) 149 wk 4 hr/d (F) 1.7 M (48% died) 1.7 F (64% died) Til et al. 1983. 1991 Systemic Rat (Wistar) 2 yr 5d/wk 4 hr/d (F) Hemato Hepatic 5.6 17 (decreased clotting time) 1.8 (cellular alteration) 5.6 F (extensive necrosis) 17 M (extensive necrosis) Feron et al. 1981 Rat 2 yr Derm Ix/d (GO) 30 (increased skin thickness, collagen) Knight and Gibbons 1987 t Nt Im> H I O(m-nm1--/1n)11 6Z06HS'8b I tono VINYL CHLORIDE "DRAFT FOR PUBLIC COMMENT"* TABLE 2-2. Levels of Significant Exposure to Vinyl Chloride - Oral (continued) Key to* figure Species/ (strain) Exposure duration/ frequency/ (specific route) System NOAEL (mg/kg/day) Less serious (mg/kg/day) LOAEL (effect) Serious (mg/kg/day) 5 Rat (Wistar) 149 wk 4 hr/d (F) Hemato Hepatic Bd Wt 1.7 i 1.7 0.018b F (basophilic foci of cellular alteration) 1.7 M (clear or basophilic foci of cellular alteration) 1.7 F (hepatic cysts) Reference Til et al. 1983, 1991 Cancer 6 Rat (Wistar) 2 yr 5d/wk 4hr/d <F). (GO) 7 Rat (SpragueDawley) 52 wk 5x/wk (GO) 8 Rat (SpragueDawley) 52 wk 5x/wk (GO) 1.8 F (CEL: neoplastic nodules of Feron et al. liver) 1961 5.6 M (CEL: angiosarcoma of lung; neoplastic nodules of liver, hepatic angiosarcoma) 0.3 (CEL: liver angiosarcoma, hepatoma) Maltoni et al. 1981 16.65 F (CEL: liver angiosarcoma) Maltoni etal. 1981 50 M (CEL: liver angiosarcoma) \ ro Xm H>rI- mm O c--oi oeoewssu VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' Key to* figure Species/ (strain) Exposure duration/ frequency/ (specific route) 9 Rat (Wistar) 149 wk 4hr/d (F) TABLE 2-2. Levels of Significant Exposure to Vinyl Chloride - Oral (continued) System NOAEL (mg/kg/day) Less serious (mg/kg/day) LOAEL (effect) Serious (mg/kg/day) ' Reference 1.7 B (CEL: hepatic angiosarcoma) Til et ai. 1983, 1991 1.7 M (CEL: hepatocellular carcinoma) 1-7 F (CEL: neoplastic nodules of liver) ... -- . ... -- -- - --.----------- -- ________ - - -- - . _ _ --. "The number corresponds to entries in Figure 2-2. ''Used to derive a chronic oral Minimal Risk Level (MRL) of 0.00002 mg/kg/day; dose divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). 8 = both; Bd Wt = body weight; CEL = Cancer Effect Level; d = day(s); Derm = dermal; F = female; (F) = feed; (GO) = gavage-oil; Hemato = hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; wk = week(s); x = time(s); yr = year(s) ro S dj 1 o cn i806v ooi VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' Figure 2-2. Levels of Significant Exposure to Vinyl Chloride - Oral Chronic (>365 days) Systemic (mg/kg/day) 10,000 1,000 100 10 1 0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 0.00000001 0.000000001 0.0000000001 / & & <S>U I 3r 3 oo 3r 5r 3r 3 3r 3r 3 5r 5r 3 5r 3 4r o 5r 6r 8r 8r 9r 9r 9r 7r r Rat Key The number next to each point corresponds to entries in Table 2-2. LOAELfor serious effects (animals) 3 LOAEL for less serious effects (animals) o NOAEL (animals) CEL - Cancer Effect Level | Minimal risk level for effects i other than cancer V/ "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. 10'4 -i 10-5 -- Estimated UpperBound Hum,an icr6 -- Cancer Risk Levels lO'7 --I t ro jm: > m--mOnn Z806nS9U VINYL CHLORIDE 2. HEALTH EFFECTS 62 Daily administration of 30 mg/kg of vinyl chloride to rats by gavage for 2 years caused increased thickness, moisture content, and collagen content of the skin. Newly synthesized intermolecular and intramolecular collagen crosslinks were also significantly increased (Knight and Gibbons 1987). Body Weight Effects. No studies were located regarding body weight effects in humans after oral exposure to vinyl chloride. No changes in body weight were noted in Wistar rats fed 1.7 mg/kg/day vinyl chloride mixed with PVC powder in the diet for 149 weeks (Til et al. 1983, 1991). No studies were located regarding the following health effects in humans or animals after oral exposure to vinyl chloride: 2.2.2.3 Immunological and Lymphoreticular Effects 2.2.2.4 Neurological Effects 2.2.2.5 Reproductive Effects 2.2.2.6 Developmental Effects 2.2.2.7 Genotoxic Effects Genotoxicity studies are discussed in Section 2.5. 2.2.2.8 Cancer No studies were located regarding cancer in humans following oral exposure to vinyl chloride. Four studies were located that examined the carcinogenic potential of vinyl chloride in animals when administered by the oral route. In two of these studies, conducted for 149 weeks, vinyl chloride was added to the diet by incorporating PVC powder containing a high level of the monomer (Feron et al. 1981; Til et al. 1983, 1991). To limit volatilization of vinyl chloride from the diet, the rats were allowed access to the diet for only 4 hours per day. The actual intake of vinyl chloride in these reports was calculated by taking into consideration both the food consumption and the rate of vinyl chloride evaporation. Statistically significant increases in hepatic angiosarcoma of the liver were R&S 149083 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 63 observed in the 2-year study by Feron et al. (1981) at 5.6 mg/kg/day in males and 17 mg/kg/day in females. In the same study, statistically significant increases in neoplastic nodules of the liver were also observed at a concentration of 5.6 mg/kg/day in males but as low as 1.8 mg/kg/day in females (Feron et al. 1981). Also, in the 149-week study by Til et ai. (1983, 1991), statistically significant increases in hepatocellular carcinoma were observed in males at 1.7 mg/kg/day and hepatic neoplastic nodules in females at 1.7 mg/kg/day. An increased incidence of Zymbal gland tumors was-also observed in the study by Feron et al. (1981). Although the increase was not statistically significant, the tumors were considered to be treatment-related based on the historical rarity of this type of tumor. Two studies were located in which vinyl chloride was administered to Sprague-Dawley rats by gavage for 52 weeks. In one of these studies, a statistically significant increase in the incidence of hepatic angiosarcomas was observed at doses as low as 16.65 mg/kg/day in females and 50 mg/kg/day in males. Zymbal gland tumors at 16.65 and 50 mg/kg/day, even though not statistically significant, were considered to be treatment related because of the rarity of this type of tumor (Maltoni et al. 1981). Lower doses of vinyl chloride were also tested in a similar study in which hepatic angiosar comas were observed at doses as low as 0.3 mg/kg/day and Zymbal gland tumors at 1 mg/kg/day. Although neither of these findings reached statistical significance, the tumors were considered to be treatment related because of the historically rare observation of these tumor types in the colony (Maltoni et al. 1981). Based on the evidence of carcinogenicity in animals after oral exposure, it would be prudent to consider the potential for carcinogenic effects in humans by this route as well. The lowest doses tested that produced a tumorigenic response (CEL) in rats chronically exposed to vinyl chloride by the oral route are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.3 Dermal Exposure Dermal exposure to vinyl chloride may occur by skin contact with either gaseous or liquid vinyl chloride. Negligible amounts of gaseous vinyl chloride are absorbed through the skin (see also Section 2.3.1.3 regarding absorption by the dermal route). However, dermal exposure can also occur by direct contact of gaseous vinyl chloride with the eyes. Only studies that specifically relate to dermal contact R&S149084 "DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 64 of liquid vinyl chloride or ocular effects occurring with inhalation exposure to gaseous vinyl chloride are discussed below. 2.2.3.1 Death No studies were located regarding lethal effects in humans or animals after dermal exposure to vinyl chloride. 2.2.3.2 Systemic Effects No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, or renal effects in humans or animals after dermal exposure to vinyl chloride. Dermal Effects. Vinyl chloride exists as a liquid when stored under pressure. However, when it is released from pressurized containers, it rapidly vaporizes into gas. A man who had liquid vinyl chloride sprayed on his hands developed second degree burns. At first, the man reported that his hands felt numb. Within a short period, the hands had developed marked erythema and edema (Harris 1953). No studies were located regarding dermal effects in animals after dermal exposure to vinyl chloride. Ocular Effects. Local burns on the conjunctiva and cornea were observed in a man who died after exposure to an unknown quantity of vinyl chloride vapor escaping from an open valve (Danziger 1960). No ocular effects were noted in guinea pigs exposed for 30 minutes to up to 400,000 ppm vinyl chloride in inhalation chambers (Mastromatteo et al. 1960). 2.2.3.3 Immunological and Lymphoreticular Effects No studies were located regarding immunological and lymphoreticular effects in humans or animals following dermal exposure to vinyl chloride. R&S 149085 "'DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2.2.3A Neurological Effects 2. HEALTH EFFECTS 65 A man who had liquid vinyl chloride sprayed on his hands initially reported that his hands felt numb (Harris 1953). No studies were located regarding neurological effects in animals after dermal exposure to vinyl chloride. No studies were located regarding the following health effects in humans or animals after dermal exposure to vinyl chloride: 2.2.3.5 Reproductive Effects 2.2.3.6 Developmental Effects 2.2.3.7 Genotoxic Effects Genotoxicity studies are discussed in Section 2.5. 2.2.3.8 Cancer No studies were located regarding cancer in humans or animals following dermal exposure to vinyl chloride. 2.3 TOXICOKINETICS Studies in humans and animals, although sparse, have shown that vinyl chloride is readily absorbed through the lungs. Men exposed to vinyl chloride for 6 hours were reported to have relatively constant retention after about 30 minutes of exposure indicating that saturation of the major metabolic pathway did not occur (Krajewski et al. 1980). Rats exposed to vinyl chloride by inhalation, were found to have peak blood levels after 30 minutes of exposure to 7,000 ppm, which decreased rapidly after removal (Withey 1976). No studies were located that reported the absorption of vinyl chloride after oral exposure in humans. In animals, vinyl chloride has been found to be rapidly and almost completely absorbed from the gastrointestinal tract after oral exposure (Watanabe et al. 1976a; Withey R & S 149086 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 66 1976) , with peak blood levels occurring 10-20 minutes after dosing (Withey 1976). No studies were located that reported the absorption of vinyl chloride in humans after dermal exposure. Based upon a single study in monkeys, dermal absorption of vinyl chloride vapor is not likely to be significant (Hefner et al. 1975a). No studies were located that reported tissue distribution after inhalation, oral, or dermal exposure to vinyl chloride in humans or after dermal exposure in animals. Animal studies indicate that the distribution of inhaled vinyl chloride is rapid and widespread; however, its storage in the body is limited due to rapid metabolism and excretion. Metabolites of vinyl chloride have been found in the liver, kidney, spleen, skin, and brain as well as in other tissues, but the percentages in these tissues is relatively small (Bolt et al. 1976a; Buchter et al. 1977; Watanabe et al. 1976b). Vinyl chloride metabolites have not been shown to accumulate more in tissues after repeated exposure than after a single exposure (Watanabe et al. 1978a). Vinyl chloride has been found to cross the placenta after inhalation exposure (Ungvary et al. 1978). After a single oral dose of radiolabelled vinyl chloride in rats, radioactivity levels were much greater in the liver than in other tissues examined (skin, plasma, muscle, lung, fat, and carcass) (Watanabe et al. 1976a). After inhalation exposure, vinyl chloride metabolism in humans is attributed to the cytochrome P-450 monooxygenases in the liver (Sabadie et al. 1980). Metabolism has been shown to follow first-order kinetics in rats, with pathway saturation beginning to be noticeable at 100 ppm (Hefner et al. 1975b). Metabolism occurs via the oxidation of vinyl chloride by mixed function oxidases (MFO) to form an epoxide intermediate, 2-chloroethylene oxide, which spontaneously rearranges to form 2-chloroacetaldehyde. Intermediates are detoxified primarily via glutathione conjugation; conjugated products are excreted in urine as substituted cysteine derivatives. A rodent study using a pretreatment that inhibited cytochrome P-450 oxidation pathways indicated that metabolism through an MFO pathway that produced an epoxide intermediate was the primary route of metabolism (Bolt et al. 1977) . Macromolecular binding has been attributed to the reactive intermediate 2-chloroethylene oxide, which binds to DNA and RNA (ribonucleic acid), and its reaction product, 2-chloroacetaldehyde, which binds to protein molecules (Guengerich and Watanabe 1979; Guengerich et al, 1979, 1981; Kappus et al. 1976; Watanabe et al. 1978a, 1978b). No studies were located regarding vinyl chloride metabolism in humans after oral or dermal exposure or in animals after dermal exposure. Data obtained in rats after oral exposure to vinyl chloride indicate consistency with metabolic pathways proposed for inhalation exposure (Green and Hathway 1975, 1977; Watanabe and R&S149087 '"DRAFT FOR PUBLIC COMMENT"' VINYL CHLORIDE 2. HEALTH EFFECTS 67 Gehring 1976; Watanabe et al. 1976a). Metabolic saturation appears to occur after a single gavage dose of between 1 and 100 mg/kg/day (Watanabe et al. 1976a). After inhalation exposure in humans, exhalation of unmetabolized vinyl chloride is not a major pathway of elimination at low concentrations (Krajewski et al. 1980). Animal studies have shown that exhalation of vinyl chloride as a major route of excretion, after inhalation exposure, is dependent upon the exposure concentration. In rats exposed to 10 ppm for 6 hours, 70% of radioactivity recovered were metabolites excreted through the urine (Watanabe and Gehring 1976; Watanabe et al. 1976b). Saturation of metabolism occurred at 1,000 ppm. At 5,000 ppm, most vinyl chloride appeared to be unmetabolized in expired air, and approximately 27% of recovered radioactivity had been excreted in urine (Watanabe et al. 1978a). The proportion of recovered radioactivity exhaled as carbon dioxide or excreted in feces changed very little with increased exposure concentrations. Pulmonary excretion of unaltered vinyl chloride followed first-order kinetics despite increases in exposure concentrations; urinary excretion of radioactivity was biphasic. No studies were located regarding excretion in humans after oral or dermal exposure to vinyl chloride or in animals after dermal exposure. Oral exposure of rats to vinyl chloride showed that metabolic saturation occurred at 20 mg/kg (Green and Hathway 1975; Watanabe and Gehring 1976; Watanabe et al. 1976a). At 100 mg/kg, both pulmonary and urinary excretion of vinyl chloride or its metabolites, respectively, were biphasic, while pulmonary excretion of vinyl chloride was monophasic at less than 1 mg/kg (Watanabe et al. 1976a). 2.3.1 Absorption 2.3.1.1 Inhalation Exposure - Inhalation absorption of vinyl chloride is rapid in humans. Young adult male volunteers were exposed to vinyl chloride monomer concentrations of 2.9, 5.1, 11.7, or 23.5 ppm by gas mask for 6 hours (Krajewski et al. 1980). Retention was estimated by measuring the difference between inhaled and exhaled concentrations. An average retention of 42% was estimated. Although the results varied among the individuals tested, the percentage retained was independent of the concentration irthaled. .Since retention did not change with increasing vinyl chloride concentrations, it appears that saturation of the major pathway of overall metabolism did not occur in this exposure regimen. R & S 149088 -- DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 68 Animal data, while demonstrating that inhalation absorption of vinyl chloride occurs readily and rapidly, are not sufficient to quantitatively determine the proportion of an inhaled dose that is absorbed. Physiologically based pharmacokinetic (PBPK) models that have been developed to provide these estimates are discussed in Section 2.3.5. Peak blood levels occurred at 30 minutes in rats exposed (head-only) to 7,000 ppm (Withey 1976). On removal from the vinyl chloride atmosphere, blood levels fell rapidly. After 2 hours, concentrations were barely detectable. Rats that had been pretreated with 6-nitro-l,2,3-benzothiadiazole to completely block the metabolism of vinyl chloride were placed in a closed chamber containing approximately 0.5 ppm radiolabelled (l4C) vinyl chloride (Bolt et al. 1977). Radioactivity in the chamber air declined only for the first 15 minutes of exposure, indicating that equilibrium between atmospheric and tissue levels of radioactivity had occurred, suggesting rapid uptake by the tissues of the rats. One might expect that people would be likely to equilibrate within 1 hour. 2,3.1.2 Oral Exposure No studies were located regarding absorption in humans after oral exposure to vinyl chloride. Several studies in rats indicate that vinyl chloride is rapidly and virtually completely absorbed from the gastrointestinal tract. Peak blood levels of vinyl chloride were observed within 10-20 minutes after dosing in rats administered single oral doses (44-92 mg/kg) of vinyl chloride in aqueous solution (Withey 1976). Peak blood levels varied from 6 to greater than 40 pg/mL. Data from another study in which rats were administered single gavage doses of 0.05, 1, and 100 mg/kg l4C-vinyl chloride (in com oil) suggested that almost complete absorption of vinyl chloride occurred (Watanabe et al. 1976a). The fraction of the administered dose recovered in the feces, roughly indicative of the proportion unabsorbed, ranged from 0.47% to 2.39%; total recovery ranged from 82.3% to 91.3%, Loss of radioactivity might be attributed either to experimental error or to incomplete sampling of the carcass. Fecal excretion was measured in rats fed 0, 1.8, 5.6, and 17.0 mg/kg/day of vinyl chloride monomer (from powdered PVC containing a high level of the monomer) (Feron et al. 1981). Fecal excretion accounted for 8%, 10%, and 17% of the vinyl chloride present in the low-, middle-, and high-dose groups, respectively. The investigators hypothesized that the vinyl chloride recovered from the feces was encapsulated by PVC and was not available to the rats for absorption, and that absorption of available vinyl chloride was virtually complete. R&S149089 `"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2.3.1.3 Dermal Exposure 2. HEALTH EFFECTS 69 No studies were located regarding absorption in humans after dermal exposure to vinyl chloride. Animal data suggest that dermal absorption of vinyl chloride vapor is not likely to be significant. Dermal absorption measured in two rhesus monkeys was estimated to be 0.031% and 0.023% of the total available vinyl chloride at 800 and 7,000 ppm, respectively, after a 2-2.5 hour exposure (Hefner et al. 1975a). The investigators concluded that, after short-term exposure to high concentrations, dermal absorption was far less significant than inhalation absorption. 2.3.2 Distribution Representative vinyl chloride partition coefficients for humans, rats, mice, and hamsters can be found in Table 2-3. These partition coefficients were estimated using a vial equilibration technique. Further details about how the values were obtained, including the number of experiments completed and whether the errors shown are standard deviations or standard errors, were not provided. In general, concentrations of vinyl chloride found in fat are higher than would be found in other tissues. Partition coefficients for vinyl chloride range from 10-20 (fat/air) and 1-3 (muscle/air, blood/air, and liver/air). In animal studies, females have shown greater partitioning to fat than males. 2.3.2.1 Inhalation Exposure No studies were located regarding tissue distribution in humans after inhalation exposure to vinyl chloride. Data from rat studies suggest that the distribution of inhaled vinyl chloride is rapid and widespread, but storage of vinyl chloride in the body is limited by rapid metabolism and excretion. In rats exposed to 14C-vinyl chloride and pretreated with 6-nitro-l,2,3-benzothiadiazole to block metabolism of vinyl chloride by microsomal cytochrome P-450 oxidation pathways, the highest levels of radiolabel were located in the fat, with lesser amounts in the blood, liver, kidney, muscle, and spleen. When metabolism was not blocked, the highest levels of radiolabelled metabolites were located in the liver and kidney (Buchter et al. 1977). Immediately after a 5-hour exposure to IJC-vinyl chloride at 50 ppm, tissue levels of l4C-activity, expressed as the percentage incorporated per gram of tissue, were R & S 149090 "'DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT' TABLE 2-3. Vinyi Chloride Partition Coefficients Species Rata Mouse3 Hamster3 Humanb Strain CDBR F-344 Wistar B6C3F, CD-I Golden Syrian NA Sex M F M F M F M F M F M F NR Blood/air 1.80.22 2.1 0.44 1.6+0.33 1.60.11 2.1 0.31 1.60.07 2.80.22 2.60.14 2.30.07 2.40.16 2.70.15 2.20.47 1.16 aFrom Air Force 1990b; values determined using vial equilibration method bFrom EPA (1987g) F = female; M = male; NA = not applicable; NR = not reported Partition Coefficient Liver/air Muscle/air 3.00.41 1.70.43 2.02.0 2.1 0.17 2.70.56 1,50.28 - - - - 3.40.36 1.30.28 - 2.20.70 1.30.25 2.1 0.70 2.40.46 2.70.58 1.60.22 - - - - 2.60.46 2.00.28 _ Fat/air 11.8+0.81 I9.20.96 11.80.81 21.11.3 10.21.6 22.30.54 - - - - 14.35.3 21.12.0 _ ro m>rx~ X om(T"0HF,I 1606WS5y I O-Sj VINYL CHLORIDE 2. HEALTH EFFECTS 71 highest in the kidney (2.13%) and liver (1.86%), with lower levels in the spleen (0.73%) and brain (0.17%) (Bolt et al. 1976a). Radioactivity in tissue was measured in rats 72 hours after exposure to 10 or 1,000 ppm l4C-vinyl chloride for 6 hours. In order of decreasing concentration for rats exposed to 10 ppm, l4C-labeled compounds (expressed as percentage), present as nonvolatile metabolites, were detected in the liver (0.14), kidney (0.08), skin (0.07), lung (0.07), muscle (0.05), carcass (0.05), plasma (0.05), and fat (0.03). For rats exposed to 1,000 ppm, radiolabel (expressed as percentage) was detected in the liver (0.15), skin (0.12), kidney (0.06), carcass (0.05), lung (0.05), muscle (0.04), fat (not detected), and plasma (not detected) (Watanabe et al. 1976b). There was no difference in the routes or rate of excretion between repeated-dose versus single-dose exposure of rats to 5,000 ppm of l4C-vinyl chloride (Watanabe et al. 1978a). The concentration of radiolabel detected in tissues 72 hours after exposure revealed no statistically significant difference between rats exposed once or repeatedly to vinyl chloride. Percentages of radioactivity detected in tissues are as follows (for single and repeated doses, respectively): liver (0.12)(0.16), kidney (0.06)(0.07), skin (Q.05)(0.08), carcass (0.03)(0.04), fat (not detected)(not detected). Placenta] transfer of vinyl chloride can occur rapidly in rats. Female rats exposed to approximately 0, 2,000, 7,000, or 13,000 ppm vinyl chloride for 2.5 hours on gestational day 18 showed high concentrations of vinyl chloride in maternal and fetal blood and amniotic fluid. The maternal blood had the highest levels (Ungvary et al. 1978). 2.3.2.2 Oral Exposure No studies were located regarding tissue distribution in humans after oral exposure to vinyl chloride. The level of ,4C-nonvolatile metabolites was measured in tissues of rats 72 hours after single gavage doses (0.05-100 mg/kg) of l4C-vinyl chloride in corn oil (Watanabe et al. 1976a). The highest levels of radioactivity for each dose level occurred in the liver. Theses levels were 2-5 times higher than in the other tissues examined (skin, plasma, muscle, lung, fat, and carcass). 2.3.2.3 Dermal Exposure No studies were located regarding tissue distribution for humans or animals after dermal exposure to vinyl chloride. R & S 149092 -- DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2.3.3 Metabolism 2.3.3.1 Inhalation Exposure 2. HEALTH EFFECTS 72 Metabolism can be qualitatively estimated from gas uptake experiments in which, after initial absorption of vinyl chloride, continued absorption is largely attributed to metabolism. Krajewski et al. (1980) exposed young men to vinyl chloride monomer at concentrations of 2.9, 5.1, 11.7, and 23.5 ppm by gas mask for 6 hours. Retention was estimated by determining the difference between the inhaled and exhaled concentrations. Individual variation was present; however, the percentage retained was found to be independent of the concentration inhaled. Since the retention did not change with increasing vinyl chloride concentrations, it appears that saturation of the major metabolic pathway did not occur in this exposure regimen. Metabolism of vinyl chloride was attributed to the cytochrome P-450 monooxygenases in the S-9 fraction from surgically obtained human liver specimens. These preparations metabolized vinyl chloride to electrophiles that were mutagenic to Salmonella typhimurium TA1530 (Sabadie et al. 1980). When compared with the number of revertants per plate resulting from identically prepared S-9 fractions from female strain BD IV rats, human S-9 fractions induced mutations (and presumably metabolism to a reactive electrophile) to an average 84% of the extent mediated by rat S-9. However, a ninefold individual variation was observed. Early work on the metabolism of vinyl chloride in animals indicated that metabolism is a dosedependent, saturable process. Proposed pathways most currently accepted for the metabolism of vinyl chloride are shown in Figure 2-3. Rats were exposed to vinyl chloride in a closed chamber at concentrations of about 50-1,000 ppm for 52.5-356.3 minutes (Hefner et al. 1975b). Additional rats pretreated with ethanol (to inhibit alcohol dehydrogenase activity) or SKF 525-A (to inhibit microsomal oxidase activity) were similarly exposed. Metabolism, estimated by measuring the rate of disappearance of vinyl chloride from the closed system, followed first-order kinetics with a half-life of 86 minutes at less than 100 ppm. At greater than 220 ppm, metabolism was slowed to a half-life of 261 minutes, suggesting saturation of the pathway predominant at 100 ppm. Pretreatment with ethanol depressed the rate of metabolism by approximately 83% at less than 100 ppm but by approximately 47% at greater than 1,000 ppm. Pretreatment with SKF 525-A, however, had no effect at less than 100 ppm but depressed metabolism by 19% at greater than 1,000 ppm. The authors postulated R&S149093 "'DRAFT FOR PUBLIC COMMENT'" VINYL CHLORIDE 2. HEALTH EFFECTS Figure 2-3. Proposed Metabolic Pathways for Vinyl Chloride* cihc=ch2 . vinyl chloride mixed function oxidase o /\ * h2c-ch I Cl 73 C2 carbon dioxide (oxidative decarboxylation) HOOC-CH2-S-CH2-COOH thiodiglycolic acid (thiodiacetic acid)** * Derived from Bolt et al. (1980): Cogliano and Parker (1992); Hefner et al. (1975b); Plugge and Safe (1977) ** Excreted in urine "'DRAFT FOR PUBLIC COMMENT'" R&S149094 VINYL CHLORIDE 2. HEALTH EFFECTS 74 alternative pathways for vinyl chloride metabolism. They suggested that at low concentrations sequential oxidation to 2-chloroethanol, 2-chloroacetaldehyde, and 2-chloroacetic acid involving alcohol dehydrogenase (inhibited by pretreatment with ethanol) appeared to be the predominant pathway. Little 2-chloroacetic acid was formed, however, possibly because 2-chloroacetaldehyde conjugated rapidly with ubiquitous sulfhydryl groups. The authors further speculated that when the alcohol dehydrogenase pathway became saturated, 2-chloroethanol could be oxidized by catalase in the presence of hydrogen peroxide (H202) to a peroxide, which could undergo subsequent dehydration to form 2-chloroacetaldehyde. However, it appears that the only support for this proposed metabolism of vinyl chloride by alcohol dehydrogenase comes from studies demonstrating metabolic inhibition by alcohol. This is not recognized as a direct pathway for metabolism of vinyl chloride in modern PBPK modeling studies. It is possible that ethanol exerts its effects by inhibiting specific P-450 enzymes involved in the metabolic activation of vinyl chloride. The major metabolic pathway of vinyl chloride involves oxidation by mixed-function oxidases to form a highly reactive epoxide intermediate, 2-chloroethylene oxide, which spontaneously rearranges to form 2-chloroacetaldehyde (Guengertch et al. 1979, 1981; Gwinner et al. 1983; Laib 1982). These intermediates are detoxified mainly through conjugation with glutathione catalyzed by glutathione iS-transferase, The conjugated products are excreted in urine as substituted cysteine derivatives and include thiodiglycolic acid, 5-formyl-methylcysteine, and /V-acetyl-S-(2-hydroxyethyl)cysteine (Bolt et al. 1980; Hefner et al. 1975b). Uiinary metabolites identified in rats exposed by inhalation include polar compounds at low exposure concentrations (Hefner et al. 1975b; Watanabe et al. 1976b) and 2-chloroacetic acid at high exposure concentrations (Hefner et al. 1975b). Isolated rat liver cells converted^ IJC-vinyl chloride into nonvolatile metabolites (Hultmark et al. 1979). Using this in vitro technique, it was determined that metabolism was NADPH-dependent, located in the microsomal fraction of the liver, and probably involved a mixed-function oxidase. Pretreatment with 6-nitro-l,2,3-benzothiadiazoie, an inhibitor of some microsomal cytochrome P-450 oxidation pathways, was sufficient to totally block the metabolism of vinyl chloride in rats exposed to 0.45 ppm in a closed system for 5 hours (Bolt et al. 1977). This observation suggests that metabolism of vinyl chloride proceeds primarily through a mixed-function oxidase pathway with likely production of an epoxide intermediate. R&S149095 '"DRAFT FOR PUBLIC COMMENT"' VINYL CHLORIDE 2. HEALTH EFFECTS 75 Inhalation exposure of high concentrations of vinyl chloride has also been associated with a reduction in the liver nonprotein sulfhydryl concentration in the rat. These results are consistent with conjugation of the metabolites of vinyl chloride with limited reserves of glutathione and/or cysteine (Bolt et al. 1976b; Hefner et al. 1975b; Jedrychowski et al. 1984; Watanabe et al. 1978b). Saturation of metabolic pathways was observed in rats and monkeys that were exposed in a closed system l4C-vinyl chloride (Bolt et al. 1977; Buchter et al, 1980; Filser and Bolt 1979). In rats, metabolic saturation was determined to occur at approximately 250 ppm and a metabolic rate (Vmjx) of 110 pmol/hour/kg was estimated (Bolt et al. 1977; Filser and Bolt 1979). In a similar experiment in rhesus monkeys, metabolic saturation occurred at 200 ppm, with a Vmilx of 50 pmol/hour/kg (Buchter et al. 1980). The Vmilx of 50 pmol/hour/kg that was estimated using rhesus monkeys was suggested as a closer approximation of metabolism in humans than the value of 110 pmol/hour/kg estimated for rats by Filser and Bolt (1979). Several investigators have observed the binding of nonvolatile metabolites of l4C-vinyl chloride to liver macromolecules in vitro and in rats exposed by inhalation (Guengerich and Watanabe 1979; Guengerich et al. 1979, 1981; Kappus et al. 1976; Watanabe et al. 1978a, 1978b). In single*exposure experiments at different concentrations, the extent of macromolecular binding increased proportionately to the amount of vinyl chloride metabolized and disproportionately to the exposure concentration (Watanabe et al. 1978b). The extent of macromolecular binding was increased by repeated exposure to vinyl chloride (Watanabe et al. 1978a) and by pretreatment with phenobarbital (Guengerich and Watanabe 1979). Macromolecular binding has been attributed to the reactive intermediate 2-chloroethvlene oxide, which has been shown to bind to DNA and ribonucleic acid (RNA), and to its rearrangement product, 2-chloroacetaldehyde, which has been shown to bind to protein molecules (Guengerich and Watanabe 1979; Guengerich et al. 1979, 1981; Kappus et al. 1976; Watanabe et al. 1978a, 1978b). 2.3.3.2 Oral Exposure No studies were located regarding metabolism in humans after oral exposure to vinyl chloride. Urinary metabolites identified from rats ingesting l4C-vinyl chloride are consistent with the metabolic pathways postulated for inhalation exposure, in particular with the formation of 2-chloroethylene oxide R&S149096 '"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 76 and 2-chloroacetaldehyde. Metabolites identified include A/-acetyl-5-(2-hydroxyethyl)cysteine, 2-chloroacetic acid, and thiodiglycoiic acid (Green and Hathway 1975, 1977; Watanabe and Gehring 1976; Watanabe et al. 1976a). Metabolic saturation appears to occur with a single gavage dose of between 1 and 100 mg/kg/day (Watanabe et al. 1976a). 2.3.3.3 Dermal Exposure No studies were located regarding metabolism in humans or animals after dermal exposure to vinyl chloride. 2.3.4 Elimination and Excretion 2.3.4.1 Inhalation Exposure Human data suggest that exhalation of unmetabolized vinyl chloride is not an important pathway of elimination at low exposure concentrations. The mean concentration in expired air for humans exposed for 6 hours to air containing 2.9-23.5 ppm ranged from 0.21 to 1.11 ppm, representing up to 3.6-4.73% of the inhaled concentration (Krajewski et al. 1980). Animal studies indicate that the importance of exhalation of vinyl chloride as a major route of excretion varies with the exposure concentration. The mode of excretion of vinyl chloride and its metabolites following inhalation exposure of animals to different concentrations reflects the saturation of metabolic pathways. The cumulative excretion of radioactivity over a 72-hour postexposure period was measured in rats exposed to 10-1,000 ppm (Watanabe and Gehring 1976; Watanabe et al. 1976b) or 5,000 ppm (Watanabe et al. 1978a) uC-vinyl chloride for 6 hours. Radioactivity expired as carbon dioxide or vinyl chloride, excreted in the urine and feces, and retained in the carcass was expressed as a percentage of the total radioactivity recovered. The results suggest that metabolism was nearly complete at 10 ppm, because less than 2% of the recovered radioactivity occurred as unchanged parent compound. The predominant route for excretion of radioactive metabolites was through the urine, accounting for about 70% of the recovered radioactivity. Metabolism became saturated at 1,000 ppm, since unchanged vinyl chloride increased to 12.3% and urinary radioactivity decreased to 56.3%. At 5,000 ppm, more than half the recovered radioactivity appeared as unchanged vinyl chloride in expired air, and urinary excretion accounted for about 27% of the recovered activity. Generally, there was R&S 149097 '"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 77 little change in the proportion of recovered radioactivity excreted in the feces or exhaled as carbon dioxide. The percentage of the radioactivity retained in the carcass and tissues appeared to be somewhat decreased at 5,000 ppm compared with 10 and 1,000 ppm, suggesting preferential retention of metabolites rather than unchanged vinyl chloride. Pulmonary excretion of unaltered vinyl chloride in rats followed first-order kinetics regardless, of exposure concentrations, with half-lives of 20.4, 22.4, and 30 minutes following 6-hour exposures at 10, 1,000, and 5,000 ppm, respectively. The urinary excretion of radioactivity was biphasic, with the second or slow phase accounting for less than 3% of the total urinary excretion. Half-lives for the rapid (first-order) phase were estimated at 4.6, 4.1, and 4.5 hours, at 10, 1,000, and 5,000 ppm, respectively. Urinary metabolites included /V-acetyl-5-(2-hydroxyethyl)cysteine, thiodiglycolic acid, and possibly 5-(2-hydroxyethyl)cysteine (Watanabe et al. 1976b). Identification of these metabolites of vinyl chloride in the urine indicates that vinyl chloride is transformed in the body to a reactive metabolite, which is then detoxified by reaction with glutathione (GSH, gammaglutamylcysteinylglycine). Subsequently the glutamic acid and glycine moieties of the tripeptide are cleaved, and the cysteine conjugate of the reactive metabolite of vinyl chloride is either acetylated or further oxidized and excreted. 2.3.4.2 Oral Exposure No studies were located regarding excretion in humans after oral exposure to vinyl chloride. Single oral doses of HC-vinyl chloride (0.05, 0.25, 1.0, 20, 100, and 450 mg/kg) were administered to rats, and the excretion of radioactivity was monitored over a 72-hour period (Green and Hathway 1975; Watanabe and Gehring 1976; Watanabe et al. 1976a). A striking increase in exhalation of unchanged vinyl chloride and compensatory decreases in urinary and fecal excretion of radioactivity and exhalation of carbon dioxide were observed at greater than 20 mg/kg, suggesting that metabolic saturation had occurred at that dosage. At less than 1.0 mg/kg, the predominant route of elimination was urinary excretion of polar metabolites. Exhalation of unchanged vinyl chloride was generally complete within 3^1 hours, but excretion of metabolites continued for days (Green and Hathway 1975). Pulmonary excretion of vinyl chloride appeared to be monophasic at less than 1.0 mg/kg, with a half-life of about 55-58 minutes (Watanabe R&S149098 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 78 et al. 1976a). At 100 mg/kg, pulmonary excretion of vinyl chloride was biphasic, with half-lives of 14.4 and 40.8 minutes for the rapid and slower phases, respectively. Urinary excretion of radioactivity was biphasic, with the rapid phase accounting for more than 97% of total urinary radioactivity and having half-lives of 4.5^1.6 hours for dosages of 0.05-100 mg/kg. Metabolites identified in the urine of orally treated rats were consistent with the formation of 2-chloroethylene oxide and 2-chloroacetaldehyde (Green and Hathway 1977; Watanabe et al. 1976a), as postulated for metabolism following inhalation exposure. The major metabolites were identified as thiodiglycolic acid and A/-acetyl-S-(2-hydroxyethyl)cysteine (Watanabe et al. 1976a). /V-Acetyl-5(2-chloro-ethyl)cysteine and 5-(2-chloroethyl)cysteine have also been identified as have smaller amounts of radiolabelled urea, glutamic acid, and 2-chloroacetic acid (Green and Hathway 1975). 2.3.4.3 Dermal Exposure No studies were locating regarding excretion in humans or animals after dermal exposure to vinyl chloride. 2.3.4.4 Other Routes of Exposure The elimination of radioactivity following mtraperitoneal administration of l4C-vinyl chloride to rats resembles the pattern observed following inhalation or oral administration. Following an mtraperitoneal dose of 0.25 mg/kg, exhalation of unchanged vinyl chloride, exhalation of carbon dioxide, and urinary and fecal excretion of radioactivity accounted for 43.2%, 11.0%, 43.1%, and 1.8% of the administered dose, respectively (Green and Hathway 1975). At 450 mg/kg, exhaled vinyl chloride increased to 96.2% of the administered dose, carbon dioxide decreased to 0.7%, urinary radioactivity decreased to 2.6%, and fecal radioactivity decreased to 0.1%. Small doses administered intravenously were eliminated very rapidly and almost entirely by exhalation of unchanged vinyl chloride. Green and Hathway (1975) administered a 0.25-mg/kg intravenous dose of l4C-vinyl chloride to rats and recovered 80% of the dose within 2 minutes and 99% within 1 hour as unchanged compound in expired air. R&S149099 "DRAFT FOR PUBLIC COMMENT*** - VINYL CHLORIDE 2. HEALTH EFFECTS 79 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 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. R&S149100 "'DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 80 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 2-4 shows a conceptualized representation of a PBPK model. If PBPK models for vinyl chloride 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. Summary of PBPK/PD Models Models have been developed to predict the metabolism and distribution of vinyl chloride. EPA (1987g) developed a PBPK model to estimate the metabolized dose of vinyl chloride coupled to a multistage model to estimate cancer risk in animals. This PBPK model consists of four compartments, the liver, fat group, highly perfused tissue, and poorly perfused tissue. All metabolism was assumed to occur in the liver by one saturable pathway (Michaelis-Menten Kinetics) and by a first-order metabolism pathway. The physiologic parameters used were values from an EPA draft "Reference Physiologic Parameters in Pharmacokinetic Modeling" by Dr. Curtis Travis of the Oak Ridge National Laboratory. The number of rats predicted to develop liver cancer by the model was similar to that observed in completed studies. The dose delivery of the vinyl chloride model developed by EPA (1987g) was further validated by the Air Force (1990b) study with additional vinyl chloride metabolism studies in rats. At low concentrations, this model fit in vivo data in rats by Gehring et al. (1978) well, but at concentrations R&S149101 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS Figure 2-4. Conceptual Representation of a Physiologically-based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance 81 '------ Chemical in air contacting skin Note: This is a conceptual representation of a physiologically-based pharmacokinetic (PBPK) model for a hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation. "DRAFT FOR PUBLIC COMMENT*" R&S149102 VINYL CHLORIDE 2. HEALTH EFFECTS 82 above 25 ppm, the model predicted a greater amount of vinyl chloride metabolism than observed. The Air Force (1990b) then made modifications in the model to improve the fit with actual data. In the first modification, both vinyl chloride and the epoxide metabolite were assumed to react with glutathione. This model had difficulty predicting glutathione depletion at high doses; for example, it predicted glutathione depletions higher than observed at 4,600-5,800 ppm vinyl chloride. The second alternative model, in which only the product of the first-order metabolism was assumeddo react with glutathione, also predicted glutathione depletions higher than observed at high concentrations. To improve the model, the investigators suggested the addition of a low affinity glutathione pathway. Using data obtained from Wright Patterson Air Force Base, the Air Force (1990b) extended the first glutathione conjugation model, developed in rats, to different strains of rats, mice, and hamsters. Vinyl chloride gas uptake experiments were completed in which animals were exposed to various concentrations of vinyl chloride in closed chambers for up to 6 hours, and the disappearance of vinyl chloride was monitored. The glutathione content of the animals was also measured immediately after exposure. Using data from these studies and the physiologic parameters shown in Table 2-4, the investigators estimated metabolic parameters for vinyl chloride and the rate constant for the conjugation of vinyl chloride with glutathione (Table 2-5). Using the metabolic parameters determined from the gas uptake experiments, the model predictions showed good agreement with the actual data for all the strains tested. It does not appear that the investigators further validated the model with data from studies other than those used to determine the metabolic parameters. This model was not used to estimate metabolized doses for humans because the investigators indicated that human data to estimate all the required parameters were not available. They suggested that allometry may have to be used to estimate some of the parameters for humans. Clewell et al. (1995) used PBPK modeling coupled with a linearized multistage model to predict human cancer risk. The model again had four compartments as described for the EPA (1987g) study, and the same EPA physiologic parameters were used. Partition coefficients were from in vitro experiments and are shown in Table 2-3. Metabolism was modeled by two saturable pathways: one high affinity, low capacity (P450 2E1), and one low affinity, high capacity (2C11/6 and 1A1/2). The metabolic parameters used were not provided, but they were estimated from the Air Force (1990b) model. This model assumed that the metabolites (chloroethylene oxide and chloroacetaldehyde) were further degraded to carbon dioxide, or reacted with glutathione, or reacted with DNA. The parameters "DRAFT FOR PUBLIC COMMENT*** ; i ! cfaiooj <foc. o CO VINYL CHLORIDE 2. HEALTH EFFECTS 83 TABLE 2-4. Physiological Parameters Used to Estimat Paramet rs from Vinyl Chloride Gas Uptake Experiments3 Parameter Ventilation rate (L/hour/body weight074) Total cardiac output (L/hour/body weight074) Blood flow to the liver (fraction of total cardiac output) Blood flow to highly perfused tissue (fraction of total cardiac output) Blood flow to fat (fraction of total cardiac output) Blood flow to poorly perfused tissue (fraction of total cardiac output) ^j^Volume of tissue (L/body weight) Rats 14 14 0.25 0.51 0.09c 0.15C 0.04 Mice 23-25b 23-25b 0.24 0.52 0.05 0.20 0.04 Hamsters 13 13 0.24 0.52 0.09 0.15 0.04 Volume of highly perfused tissue (L/body weight) 0.04 0.05 0.05 Volume of fat tissue (L/body weight) 0.07-0. ld 0.04 0.07 Volume of poorly perfused tissue (L/body weight) 0.72-0.75d 0.78 0.75 "From Air Force (1990b); units of body weight were not provided. bVentilation rates and total cardiac outputs were 23 for male B6C3F, mice, 25 for female B6C3F, mice, 28 for female CD-I mice, and 35 for male CD-I mice. cMale Wistar rats blood flow to fat = 0.08 and blood flow to slowly perfused tissue = 0.16. dFemale F-344 and female Wistar rats had volume of fat tissue = 0.07 and volume of slowly perfused tissue = 0.75; male F-344 and female Wister rats had volume of fat tissue = 0.08 and volume of slowly perfused tissue = 0.74; male Wister and male CDBR rats had volume of fat tissue = 0.1 and volume of slowly perfused tissue - 0.72. R&S149104 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE "D R A FT FOR PUBLIC COMMENT*' TABLE 2-5. Estimates of Metabolic Parameters Obtained from Vinyl Chloride Gas Uptake Experiments3 Species Rat Mouse Hamster Strain CDBR F-344 Wistar B6C3F, CD-I Golden Syrian V max Kfc Sex (mg/hour/body weight0,7) (body weightVhour) M 2.5 F 2.47 M 3.17 F 2.95 M 3.11 F 2.97 M 5.89 F 5.53 M 6.99 F 5.54 M 4.94 F 4.76 0.63 1.0 1.08 1.03 0.45 1.55 5.5 8.93 5.1 6.62 1.67 2.06 Kgsc (body weighta3/Hour/pmol/L GSH) ND 0.000241 0.000249 0.000227 0.000093 0.00040 0.000827 0.00167 0.000563 0.000809 ND 0.000330 a From Air Force {1990b) F = female; GSH = glutathione; Kfc = first order of epoxide formation; Kgsc = rate constant for conjugation of vinyl chloride with glutathione; M = male; ND = not determined; Vmax = maximum velocity of reaction S0f6t'fS'8U 03 VINYL CHLORIDE 2. HEALTH EFFECTS 85 *ot stated) for reactions of the metabolites were estimated from vinylidene chloride data (D'Souza and Andersen 1988) using appropriate allometric scaling. Based on this PBPK model and a linearized multistage model using liver angiosarcoma data from animal studies, the human risk estimates for lifetime exposure to 1 ppb vinyl chloride ranged from 1.1 to 15.7 per million persons (Clewell et al. 1995). Based on the incidence of liver angiosarcoma in human epidemiological studies, the risk estimates for lifetime exposure to 1 ppb vinyl chloride were 0.4-4.22 per million persons. Clewell et al. (1995) indicate that the risk estimates using PBPK modeling are about 30-50 times lower than estimates using external dose calculations based on the linearized multistage model. 2.4 MECHANISMS OF ACTION 2.4.1 Pharmacokinetic Mechanisms Vinyl chloride appears to be rapidly and completely absorbed following inhalation and oral exposure (Bolt et al. 1977; Krajewski et al. 1980; Watanabe et al. 1976a; Withey 1976). No information was located regarding the mechanism of absorption. Distribution of vinyl chloride in the body is rapid and idespread. Storage is limited by rapid metabolism and excretion (Bolt et al. 1976a). The primary route of excretion of metabolites of vinyl chloride is through urine. Urinary metabolites that have been identified include N-acetyl-S-(2-hydroxyethyl)cysteine, thiodiglycolic acid, and possibly S-(2hydroxyethyl)cysteine (Watanabe et al. 1976b). The presence of these metabolites indicates that vinyl chloride undergoes transformation to a reactive metabolite, which is subsequently detoxified by a reaction with glutathione. The glutamic acid and glycine moieties of the tripeptide are cleaved, and the cysteine conjugate of the reactive metabolite is either acetylated or further oxidized and excreted. Little vinyl chloride is excreted unchanged in exhaled air, except at high exposure concentrations. However, vinyl chloride can be excreted unchanged in exhaled air if metabolic pathways become saturated at high exposure concentrations (Green and Hathway 1975; Watanabe and Gehring 1976; Watanabe et al. 1976a, 1978a). 2.4.2 Mechanisms of Toxicity The mechanisms of toxicity for noncancer effects of vinyl chloride have not been completely elucidated. Vinyl chloride disease exhibits many of the characteristics of autoimmune diseases Raynaud's phenomenon and scleroderma). B-cell proliferation, hyperimmunoglobulinemia, and R&S149106 --DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 86 complement activation, as well as increased circulating immune complexes or cryoglobulinemia have been noted in affected workers, indicating stimulation of immune response (Bogdanikowa and Zawilska 1984; Grainger et al. 1980; Ward 1976). Mechanisms for the vascular changes, such as those occurring with Raynaud's phenomenon, have been proposed by Grainger et al. (1980) and Ward (1976). According to these mechanisms, a reactive vinyl chloride intermediate metabolite, such as 2-chloroethylene oxide or 2-chloroacetaldehyde, binds to a protein such as IgG. The altered protein initiates an immune response, with deposition of immune products along the vascular endothelium. Circulating immune complexes are proposed to precipitate in response to exposure to the cold, and these precipitates are propose^ to cause blockage of the small vessels. Resorptive bone changes in the fingers, also characteristic of vinyl chloride disease, may be due to activation of osteoclast secondary to vascular insufficiency in the finger tips, but this mechanism has not been conclusively demonstrated. It has been hypothesized that cardiac arrhythmia reported after vinyl chloride exposure may result from sensitization of the heart to circulatory catecholamines, as occurs with other halogenated hydrocarbons. However, the mechanism for these effects has not been elucidated. Peripheral nervous system symptoms such as paresthesia, numbness, weakness, warmth in the extremities, and pain in the fingers have been reported after vinyl chloride exposure (LangauerLewowicka et al. 1983; Suciu et al. 1963, 1975; Waxweiler et al. 1977). It is not known whether these effects represent direct toxic effects of vinyl chloride on peripheral nerves or whether they are associated with tissue anoxia due to vascular insufficiency. Vinyl chloride is a known human and animal carcinogen. It has been associated with both an increased incidence of hepatic angiosarcomas and hepatotoxicity. The mechanism for these liver effects has been well studied. It is believed that a reactive epoxide intermediate of vinyl chloride, 2-chloroethylene oxide, interacts directly with DNA and produce alkylation products such as 3,/Vfethenocytidine, 1 ^-ethenoadenosine, and 7,A/-(2-oxoethyl)-guanosine. This alkylation results in a highly efficient base-pair substitution that leads to neoplastic transformation. The epoxide intermediate is formed when vinyl chloride is oxidized by the P-450 isoenzymes. The mechanisms for clastogenic effects of vinyl chloride exposure were examined by Fucic et al. (1990). Since chromatid and bichromatid breaks most frequently occurred in the terminal A, B, and C R&S149107 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 87 group chromosomes, the authors suggested that vinyl chloride or its metabolites might interact with specific sites along the chromosome. This implies that the carcinogenicity of vinyl chloride can be explained in part by its nonrandom interaction with particular genes. 2.4.3 Animal-toi-Human Extrapolations Limited information is available regarding the toxicokinetic differences between species. Toxicokinetic data in humans are limited (Krajewski et al. 1980; Sabadie et al. 1980), but a primate, study suggested that metabolism may saturate at lower concentrations in primates than rats (Buchter et al. 1980). This is suggestive of a lower saturation point in humans. Correlation of toxic effects between humans and animals with regard to respiratory, cardiovascular, hematological, hepatic, dermal, immunological, neurological, reproductive, and cancer effects has been noted. Renal effects, including increased relative kidney weight and an increase in severity of tubular nephrosis, have been reported in several rat studies (Bi et al. 1985; Feron and Kroes 1979; Feron et al. 1979a), but no evidence of renal effects has been shown in humans. Thus, it is unclear whether the renal effects reported in rats represent a lesion that can be attributed to vinyl chloride exposure that is unique to rats or whether the effects represent an increase in severity of a naturally occurring lesion. From the limited data available, however, it does not appear that the rat is the most appropriate species for use in studies of renal toxicity. 2.5 RELEVANCE TO PUBLIC HEALTH The major route of exposure to vinyl chloride by humans living near hazardous waste sites is via inhalation. Vinyl chloride may be present in ambient air near hazardous waste sites as a result of its volatilization from leaks in storage containers, or from contaminated soil or water. Vinyl chloride can also be produced by the anaerobic dehalogenation of tetrachloroethylene and trichloroethylene (Smith and Dragun 1984). Oral exposure to vinyl chloride via ingestion of contaminated water may also occur. Dermal exposure to liquid vinyl chloride is highly unlikely because of its low boiling point (-13.4C). However, vinyl chloride is generally transported as a liquid in pressurized containers, and puncture of such a container at a hazardous waste site could result in brief exposure of the skin to liquid vinyl chloride, although this is unlikely. It is more likely that dermal exposure to vinyl chloride R&S149108 "'DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 88 would occur through domestic bathing or showering using contaminated groundwater. Dermal exposure to gaseous vinyl chloride may also occur, but a study using rats indicated that absorption of vinyl chloride across the skin is very limited (Hefner et al. 1975a). Additional sources of potential exposure not directly related to living near hazardous waste sites, but which may also apply in such cases, include inhalation of emissions from vinyl chloride production or PVC manufacturing facilities, ingestion of water contaminated as a result of the leaching of vinyl chloride from PVC pipes, or ingestion of foods contaminated as a result of vinyl chloride leaching from PVC products used in food production or storage. The FDA now regulates the amount of vinyl chloride in PVC products that may be available to leach into foods; thus this mode of exposure is likely to be negligible. With a vapor density of 2.15, in areas of high concentration vinyl chloride vapor tends to disperse slowly, collecting in low spots such as ditches (Fire 1986). In low concentrations such as those expected near hazardous waste sites, it will quickly be dispersed into the atmosphere. The effects that have been reported to occur in humans in response to vinyl chloride exposure come almost exclusively from studies of workers exposed by inhalation in the workplace. Because women traditionally have not been employed in PVC-manufacturing positions in North America and Western Europe, most of the data on humans from these areas concerns effects in males. Also, virtually all of the epidemiological studies are limited by the absence of data on the actual levels to which workers were exposed. However, studies in animals by the inhalation and oral routes provide an indication of the doses of vinyl chloride that may be associated with these effects. Acute high-level exposure of humans to vinyl chloride is associated with the development of signs of intoxication such as dizziness, drowsiness, and/or headache. Reports from vinyl chloride workers and studies in animals indicate that loss of consciousness may also be associated with exposure to very high levels. Two deaths connected with occupational exposure to vinyl chloride have been reported. Autopsy results from these men as well as autopsy results from animals dying from extremely highlevel exposures indicate that levels of vinyl chloride producing death may cause lung and kidney irritation and inhibition of blood clotting. Cardiac arrhythmias have also been reported in animals as a result of acute exposure to very high levels of vinyl chloride (Carr et al. 1949; Oster et al. 1947). However, because these effects have not been reported in humans after exposure to high R&S149109 '"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS concentrations of vinyl chloride, it appears unlikely that persons exposed to low levels of vinyl chloride will experience these effects. 89 Longer-term exposure of humans in occupational settings has been associated with the development of a number of other toxic effects. However, exposure levels in these studies are generally not quantified, and thresholds for the effects have not been identified. Histopathological changes characteristic of vinyl chloride exposure have been reported to take place in the liver. These changes include extensive fibrosis and hypertrophy and hyperplasia of both hepatocytes and sinusoidal cells. These changes in liver structure develop in the absence of overt symptoms of liver toxicity, and standard biochemical measures of liver function have been of little value in detecting them. Reports indicate that peripheral neuropathy may also develop in some workers occupationally exposed to vinyl chloride. In addition, toxic effects on male reproductive function may occur. Studies in animals indicate that vinyl chloride may cause fetal resorptions, delayed development, and an increased incidence of the soft tissue anomaly, dilated ureter. When animals were exposed in utero, some changes in liver function were observed during adolescence. A syndrome referred to as vinyl chloride disease has been observed in a small percentage of vinyl chloride workers, many of whom were employed as polymerization tank cleaners. This job exposed workers to very high levels of vinyl chloride. Vinyl chloride disease is very similar to systemic sclerosis and includes some or all of the following symptoms: Raynaud's phenomenon (fingers blanch and numbness and discomfort are experienced upon exposure to the cold), acroosteolysis (resorption of the terminal bones of the fingers and/or toes), joint and muscle pain, enhanced collagen deposition, stiffness of the hands, and scleroderma-like skin changes. Studies in animals support these findings. In addition, renal nephrosis and developmental toxicity have been reported to occur in animals exposed to vinyl chloride, but similar results have not been confirmed in humans. Studies in both humans and animals indicate that vinyl chloride is carcinogenic. Hepatic angiosarcoma has been identified in workers exposed to vinyl chloride by the inhalation route. Also, there are some studies that indicate that cancers of the central nervous system, respiratory tract, and lymphatic and hematopoietic systems may occur in humans following inhalation exposure. Studies in a variety of species exposed by both the inhalation and oral routes show an increased incidence of hepatic angiosarcoma. Therefore, is appropriate to consider that vinyl chloride is carcinogenic by the oral route as well. R&S149110 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS Minimal Risk Levels for Vinyl Chloride 90 Inhalation MRLs Studies in humans did not provide sufficient data regarding exposure levels and their correlation with observed effects. Therefore animal studies were used for the derivation of MRLs. An acute-duration inhalation MRL of 0.5 ppm was derived from a NOAEL of 50 ppm for developmental effects in mice exposed 7 hours/day from gestational days 6-15 (John et al. 1977, 1981). No adverse maternal or fetal effects were noted at 50 ppm, except a slight increase in fetal crown-rump length that was not observed at 500 ppm. Adjustment for intermittent exposure was not performed because vinyl chloride readily reaches steady state, is rapidly metabolized and excreted, and neither it nor its metabolites tend to accumulate. The NOAEL was converted to a Human Equivalent Concentration and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). * An intermediate-duration inhalation MRL of 0.03 ppm was derived from a LOAEL value of 10 ppm for increased relative liver weight in rats (Bi et al. 1985). The dose was not adjusted for intermittent exposure because vinyl chloride readily reaches steady state, is rapidly metabolized and excreted, and neither it nor its metabolites tend to accumulate. The LOAEL was converted to a Human Equivalent Concentration and divided by an uncertainty factor of 300 (3 for use of a minimal LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). Increased relative liver weight (Sokal et al. 1980; Torkelson et al. 1961) and adverse histopathological changes (Lester et al. 1963; Schaffner 1978; Sokal 1980; Wisniewska-KnypI et al. 1980) have been observed in several other intermediate-duration inhalation studies. The study by Bi et al. (1985) shows hepatotoxicity (increased relative liver weight) at exposure levels slightly lower than those other studies. Additional support for the selection of 10 ppm as the lowest LOAEL comes from other organ weight changes observed by Bi et al. (1985) at 10 ppm and from another study demonstrating immunostimulation at 10 ppm (Sharma and Gehring 1979). No chronic-duration inhalation MRL was derived for vinyl chloride because of the absence of a suitable LOAEL or NOAEL for derivation. The lowest LOAEL (100 ppm) from a chronic-duration -- DRAFT FOR PUBLIC COMMENT'" VINYL CHLORIDE 2. HEALTH EFFECTS 91 ^tudy was for a serious end point (testicular necrosis) in a rat toxicity study (Bi et al. 1985). MRLs are not derived using serious end points. In addition, carcinogenicity was observed at concentrations equal to and less than 100 ppm (Bi et al. 1985; Drew et al. 1983; Lee et al. 1978; Maltoni et al. 1981). Oral MRLs Studies in humans did not provide sufficient data regarding exposure levels and their correlation with observed effects. Therefore animal studies were used for the derivation of MRLs. A chronic-duration oral MRL of 0.00002 mg/kg/day was derived from a LOAEL value of 0.018 mg/kg/day for an increased incidence of basophilic foci of cellular alteration in the livers of rats (Til et al. 1983, 1991). The MRL value was obtained by dividing the LOAEL by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). The selection of this end point is supported by an earlier study from the same laboratory (Feron et al. 1981) that showed increased areas of cellular alteration consisting of clear foci, basophilic foci, and eosinophilic foci in the liver of rats at the lowest dose tested (1.8 mg/kg/day). No acute- or intermediate-duration oral MRLs were derived for vinyl chloride because of an absence of data on the effects of oral exposure to vinyl chloride for these duration categories. Death. Vinyl chloride, at sufficiently high levels, may be fatal to humans following inhalation exposure. The autopsy report by Danziger (1960) regarding the deaths of two vinyl chloride workers showed congestion of the internal organs, particularly the kidneys and lungs, and failure of the blood to clot, but did not estimate the levels to which these workers had been exposed. Inhalation exposure of animals for as brief a period as 30 minutes to concentrations of vinyl chloride ranging from 100,000 to 400,000 ppm have been reported to be lethal to rats, mice, and guinea pigs (Lester et al. 1963; Mastromatteo et al. I960; Patty et al. 1930). The cause of death was attributed to respiratory failure secondary to central nervous system depression in one study (Lester et al. 1963). However, reports of cardiac arrhythmicity at similar levels (Carr et al. 1949; Oster et al. 1947) suggest that cardiac arrest may have contributed to the deaths. The levels of vinyl chloride found to cause death in animals are extremely high and unlikely to exist under most environmental conditions (with the exception of R&S 149112 '"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 92 concentrated emissions from a large point source). However, increased mortality was observed in pregnant mice when they were exposed to 500 ppm for 10 days during gestation (John et al. 1977, 1981). Therefore, it is possible that pregnancy might increase the susceptibility to the effects of vinyl chloride. Due to the limited solubility of vinyl chloride in water, acute ingestion of a lethal dose of vinyl chloride^ in contaminated water is improbable. Thus, it is unlikely that acute exposure to low levels of vinyl chloride in the air or water near hazardous waste sites will cause death. No increase in mortality was noted in a prospective cohort study of 1,100 workers exposed to vinyl chloride compared to the controls (Laplanche et al. 1992). Longer term, low-level exposures have been associated with decreased survival in a number of animal inhalation exposure studies (Adkins et al. 1986; Drew et al. 1983; Feron et al. 1979a; Hong et al. 1981; Lee et al. 1978; Viola 1970) and oral exposure studies (Feron et al. 1981; Til et al. 1983, 1991). Decreased survival of rats and mice was observed at inhalation exposures as low as 50 ppm for 6 hours per day, 5 days per week, for up to 10 months (Hong et al. 1981) and oral exposures as low as 1.7 mg/kg/day over the course of a lifetime (Til et al. 1983, 1991). The decreased survival noted in these studies may be a reflection of increased mortality due to cancer induction by vinyl chloride. The significance of a shortened lifespan in animals following low-level chronic exposure with regard to potential adverse effects in humans is unknown. Systemic Effects Respiratory Effects. Both autopsy reports from workers with vinyl chloride-related deaths (Danziger 1960) and animal studies using extremely high levels of vinyl chloride (100,000 ppm and above) (Lester et al. 1963; Mastromatteo et al. 1960) indicate that such levels of vinyl chloride cause respiratory irritation by the inhalation route. It is unlikely that respiratory irritation will result from exposure to low levels of vinyl chloride in the air near hazardous waste sites. Studies of workers who have been occupationally exposed to vinyl chloride give mixed results regarding the chronic respiratory effects of vinyl chloride. Gamble et al. (1976), Laplanche et al. (1987), and NIOSH (1977) reported no adverse respiratory effects associated with occupational vinyl chloride exposure. However, other investigators found increased incidences of emphysema, decreased respiratory volume and vital capacity, respiratory insufficiency, decreased respiratory oxygen and R & S 1 4 9 1 13 -- DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 93 irbon dioxide transfer, pulmonary fibrosis, and abnormal chest x-rays (Lilis ct al. 1975, 1976; Lloyd et al. 1984; Suciu et al. 1975; Walker 1976; Wong et al. 1991). Factors that may confound the interpretation of these results include a smoking history and exposure to PVC resin dust or to other chemicals. Histopathologic examination of rats and mice exposed to vinyl chloride for periods of 6 months or a year provide some supportive evidence for the respiratory pathology associated with high-level exposure (2,500, 5,000, or 30,000 ppm) (Feron and Kroes 1979; Suzuki 1978, 1980, 1981; Viola et al. 1971). These studies have identified changes such as proliferation and hypertrophy of the bronchiolar epithelium, hypersecretion of mucin, hyperplasia of the alveolar epithelium, mobilization of alveolar macrophages, increased pulmonary hemorrhages, and interstitial pneumonia. Cardiovascular Effects. A small percentage of workers exposed to vinyl chloride develop vinyl chloride disease. One of the symptoms of this disease is a condition referred to as Raynaud's phenomenon, in which the fingers blanch and feel numb and uncomfortable upon exposure to the cold. Arteriography and biopsy material from afflicted workers indicate that exposure to vinyl chloride may ^ause blockage of the blood vessels supplying the hand, hypervascularity, and a thickening of the blood vessel walls (Harris and Adams 1967; Preston et al. 1976; Veltman et al. 1975; Walker 1976). Vinyl chloride disease has been reported to be an autoimmune response similar to systemic sclerosis. Mechanisms for the vascular effects have been proposed by Grainger et al. (1980) and Ward (1976), which relate the vascular response to the immunologic changes observed in these workers. According to these mechanisms, a reactive vinyl chloride intermediate metabolite, such as 2-chloroethylene oxide or 2-chloroacetaldehyde, binds to a protein such as IgG. The altered protein initiates an immune response, with deposition of immune products along the vascular endothelium. Circulating immune complexes are proposed to precipitate in response to exposure to the cold, and these precipitates are proposed to cause blockage of the small vessels. Studies in rodents exposed by inhalation to high levels of vinyl chloride have reproduced these symptoms to some extent. Thickening of the arterial vessel walls has been observed in rats exposed to high concentrations of vinyl chloride for a year (Feron and Kroes 1979; Viola 1970). Threshold levels for the production of this effect have not been determined. However, because of the appearance of aynaud's phenomenon only in workers with exposure to very high levels of vinyl chloride, it is R & S 1 4 9 1 14 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 94 presumed unlikely that persons exposed to low levels of vinyl chloride near hazardous waste sites would be affected. Limited data are available regarding cardiovascular-related deaths in humans (Byren et al. 1976); however, cardiac arrhythmias have been produced in dogs exposed by inhalation to extremely high levels of vinyl chloride (Carr et al. 1949; Oster et al. 1947). It is unlikely that persons"exposed to low levels of vinyl chloride in the air or water near hazardous waste sites will develop cardiac rhythm abnormalities. Gastrointestinal Effects. Although gastrointestinal effects such as gastritis and ulcers were reported in vinyl chloride workers, the significance of these effects is not known because no unexposed workers were used as controls (Lilis et al. 1975). Other effects that have been reported, such as nausea, were found in workers who had been selected based upon liver dysfunction (Ho et al. 1991). Based upon the limited data available, it appears unlikely that persons exposed to low levels of vinyl chloride near hazardous waste sites would experience gastrointestinal effects. Hematological Effects. The blood of both humans and animals that died as a result of acute exposure to extremely high levels of vinyl chloride did not clot (Danziger 1960; Mastromatteo et al. 1960). Slight-to-severe thrombocytopenia has been observed in vinyl chloride workers in several (Marstellar et al. 1975; Micu et al. 1985; Veltman et al. 1975), but not all (Lilis et al. 1975), studies. However, studies in animals using nonlethal concentrations of vinyl chloride have indicated that such levels result in a decreased clotting time. In a study by Feron et al. (1979a), a decrease was observed in the time necessary for blood to clot in rats exposed to 5,000 ppm for 1 year. However, the statistical significance of these effects was not reported. A decreased clotting time was observed in rats whose oral intake of vinyl chloride in the diet was 17 mg/kg/day for 2 years (Feron et al. 1981). Thus, it is uncertain whether persons exposed to low levels of vinyl chloride near hazardous waste sites would experience abnormal clotting times. Musculoskeletal Effects. Another characteristic of vinyl chloride disease is acroosteolysis, in which the terminal phalanges of the fingers are resorbed. Acroosteolysis in vinyl chloride workers was observed to be preceded by Raynaud's phenomenon in most instances (Dinman et al. 1971; Freudiger et al. 1988; Harris and Adams 1967; Magnavita et al. 1986; Markowitz et al. 1972; Preston et al. 1976; Sakabe 1975; Veltman et al. 1975; Wilson et al. 1967). It is unclear whether the resorptive R&S149115 --DRAFT FOR PUBLIC COMMENT*" -VINYL CHLORIDE 2. HEALTH EFFECTS 95 ^bone changes are due to activation of osteoclasts secondary to vascular insufficiency in the finger tips. Because acroosteolysis was observed exclusively in workers with very high levels of exposure, it is unlikely that persons exposed to low levels of vinyl chloride near hazardous waste sites would be affected. Hepatic Effects. Changes in the liver have been observed in humans exposed to vinyl chloride'via inhalation. The characteristic pattern of changes consists of hypertrophy and hyperplasia of hepatocytes and sinusoidal cells; sinusoidal dilation associated with damage to the cells lining the sinusoids and/or sinusoidal occlusion associated with crowding due to cellular hypertrophy and hyperplasia; focal areas of hepatocellular degeneration due to disruption of hepatic circulation; and fibrosis of portal tracts, septa, and intralobular perisinusoidal regions (Falk et al. 1974; Gedigke et al. 1975; Marsteller et al. 1975; Popper and Thomas 1975; Popper et al. 1981; Tamburro et al. 1984). These findings are supported by studies in animals (Popper et al. 1981; Sokal et al. 1980; Torkelson et al. 1961). The primary difference between effects observed in animals and humans was the greater degree of fibrosis (reticulin and collagen deposition) in human liver tissue. Structural changes occurred in the livers of humans and animals with little or no change in serum hepatic enzyme activities. Most likely this was because of the limited scope of the necrotic changes. An intermediateduration inhalation MRL was derived based on hepatic toxicity in male rats observed in a study by Bi et al. (1985). Acute degenerative changes were also seen in the livers of animals that inhaled extremely high levels of vinyl chloride (Mastromatteo et al. 1960), but it is unlikely for persons briefly exposed to low levels of vinyl chloride near hazardous_waste sites to develop similar degenerative changes. Hepatotoxicity has also been observed in chronic oral studies. Areas of cellular alteration and necrosis were observed in rats orally exposed to vinyl chloride (Feron et al. 1981; Til et al. 1983, 1991). A chronic-duration oral MRL was derived based on the hepatic toxicity observed in the Til et al. (1983, 1991) study. Based on the above data, it would be prudent to consider that persons exposed to low levels of vinyl chloride in the air or in contaminated water at hazardous waste sites over long periods of time may develop similar hepatic changes. Renal Effects. No evidence of human renal disease has been reported in studies of workers occupationally exposed to vinyl chloride. However, increased severity of tubular nephrosis and "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 96 increased kidney-to-body weight ratios were observed in rats exposed to concentrations of vinyl chloride ranging from 100 to 5,000 ppm for periods of up to a year (Bi et al. 1985; Feron and Kroes 1979; Feron et al. 1979a). It is unclear whether the effects observed in rats represent an increase in severity of naturally occurring tubular nephrosis in rats, or whether these effects represent a lesion attributable to the toxic effects of vinyl chloride on the kidney. Thus, insufficient data are available to predict whether persons exposed to low levels of vinyl chloride over long periods may d6velop renal toxicity. Endocrine Effects. One study of workers exposed to vinyl chloride found a thyroid insufficiency in most of those with scleroderma (Suciu et al. 1963). Thyroid changes were also noted in rats exposed to high levels of vinyl chloride for 1 year (Viola 1970). In guinea pigs, no histopathological changes in the adrenal glands were reported after an acute exposure to 400,000 ppm (Mastromatteo et al. 1960). Insufficient data are available to predict whether exposure to low levels of vinyl chloride may cause endocrine effects in humans living near hazardous waste sites. Dermal Effects. The third most common characteristic of vinyl chloride disease that was identified in persons with exposure to very high levels of vinyl chloride (such as polymerization tank cleaners) is thickening of the subepidermal layer of the skin. The changes in the skin may appear as maculae above the joints of the fingers or rope-like bundles on the hands and forearms (Lilis et al. 1975; Marsteiler et al. 1975; Suciu et al. 1963, 1975; Veltman et al. 1975; Walker 1976). Analysis of biopsied tissue indicates that the thickening is due to increased synthesis and deposition of collagen (Jayson et al. 1976). In most cases, the skin changes are also preceded by Raynaud's phenomenon. Thickening of the skin and increased collagen content have been reproduced to some extent in rats administered high concentrations of vinyl chloride by gavage (Knight and Gibbons 1987). Based on the appearance of this effect predominantly in persons with exposure to very high levels of vinyl chloride, it is unlikely that low-level exposures near hazardous waste sites would cause similar effects. Ocular Effects. Local burns on the conjunctiva and cornea were observed in a man who died after exposure to an unknown quantity of vinyl chloride vapor escaping from an open valve (Danziger 1960). However, ocular effects have not been observed either in other workers or in animals (Mastromatteo et al. 1960) exposed to high concentrations of vinyl chloride in test chambers. It is unlikely that ocular effects will occur in persons exposed to low levels of vinyl chloride in the air near hazardous waste sites. R & S 1 4 9 1 17 "'DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 97 Body Weight Effects. Workers who had been intoxicated by vinyl chloride were reported to have experienced anorexia (Suciu et al. 1963, 1975), but no consistent changes in body weight were reported in rats exposed to up to 50,000 ppm for acute durations (Hehir et al. 1981; Kudo et al. 1980). No changes in body weight were reported in rats, mice, or rabbits exposed to 200 or 1,000 ppm vinyl chloride for up to 6 months (Sharma and Gehring 1979; Torkelson et al. 1961). Body weight changes were noted in rats exposed to either 50 ppm vinyl chloride (10 months, 5 days per week, 5 hours per day), or 5,000 ppm vinyl chloride (4-52 weeks, 5 days per week, 7 hours per day) (Feron et al. 1979a; Sokal et al. 1980). Maternal body weight gain was significantly decreased in mice exposed to 500 ppm during gestation days 6-15 (John et al. 1977, 1981). Thus, it appears that there might be some change in body weight associated with vinyl chloride exposure; however, data are not adequate to draw this conclusion with certainty. Immunological and Lymphoreticular Effects. Increased levels of circulating immune complexes and immunoglobulins have been observed in vinyl chloride workers indicating a stimulatory effect of vinyl chloride on the immune system (Bogdanikowa and Zawilska 1984). When workers with vinyl chloride disease were examined, a correlation between the severity of the symptoms of vinyl chloride disease (Raynaud's phenomenon, acroosteolysis, joint and muscle pain, enhanced collagen deposition, stiffness of the hands, scleroderma-like skin changes) and the magnitude of the immune response was observed (Grainger et al. 1980; Langauer-Lewowicka et al. 1976; Ward 1976). The most frequent immunologic findings in workers with vinyl chloride disease were an increase in circulating immune complexes or cryoglobulinemia. As the severity of the clinical signs of vinyl chloride disease increased, there was an increase in B-cell proliferation, hyperimmunoglobulinemia, and complement activation. Because of the similarity of vinyl chloride disease with the proposed autoimmune disease, systemic sclerosis, and the association of many autoimmune diseases with certain inherited genetic characteristics, the human lymphocyte antigen (HLA) phenotypes of vinyl chloride workers both with and without vinyl chloride disease were examined (Black et al. 1983, 1986). The study authors * determined that susceptibility to vinyl chloride disease was increased in the presence of the HLA-DR5 allele or a gene in linkage disequilibrium with it, and progression of the disease to its more severe forms was favored by HLA-DR3 and HLA-B8. '"DRAFT FOR PUBLIC COMMENT*** ^ co wi, <o CD VINYL CHLORIDE 2. HEALTH EFFECTS 98 Stimulation of the immune response has been observed in mice exposed to low-to-moderate levels of vinyl chloride via inhalation for several weeks (Sharma and Gehring 1979). Thus, it may be possible for persons exposed to low levels of vinyl chloride in the air or water near hazardous waste sites to develop immune stimulation. The threshold for developing an autoimmune response in susceptible persons is unknown. N urological Effects. Central nervous system depression is the earliest symptom associated with acute high-level vinyl chloride exposure in humans and animals. Concentrations as low as 8,000 ppm may cause dizziness in humans exposed by inhalation (Lester et al. 1963). Workers exposed to vinyl chloride, before occupational standards were made more rigorous, complained of dizziness, drowsiness, euphoria, nausea, headache, and occasional loss of consciousness (Ho et al. 1991; LangauerLewowicka et al. 1983; Lilis et al. 1975; Marsteller et al. 1975; NIOSH 1977; Spirtas et al, 1975; Suciu et al. 1963, 1975; Veltman et al. 1975; Walker 1976). These symptoms were most frequently experienced by those employed in positions with the greatest exposure to vinyl chloride (cleaners of the autoclaves used to synthesize PVC). A state of unconsciousness was produced in animals acutely exposed via inhalation to concentrations of approximately 100,000 ppm (Jaeger et al, 1974; Mastromatteo et al. 1960). It is unlikely that exposure to low levels of vinyl chloride in air or water near hazardous waste sites would cause central nervous system depression. Reports by Magnavita et al. (1986) and Perticoni et al. (1986) suggest that peripheral nerve damage may occur in occupationally exposed workers. Chronic inhalation exposure of animals to high levels of vinyl chloride caused nerve damage and cerebellar degeneration (Viola 1970; Viola et al. 1971). However, threshold levels for this effect are unknown. Thus, it is unknown whether persons exposed to low levels of vinyl chloride in air or water near hazardous waste sites would experience nerve damage. Reproductive Effects. Studies in humans indicate that the male reproductive function may be adversely affected by exposure to vinyl chloride. Decreased androgen levels have been found in workers occupationally exposed to vinyl chloride (Walker 1976). Also workers have complained of impotency and decreased libido (Suciu et al 1975; Veltman et al. 1975; Walker 1976). These findings "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 99 are supported by histopathological evidence of testicular damage (Bi et al. 1985; Sokai et al. 1980) and decreased male fertility (Short et al. 1977) in rats exposed by inhalation. Fewer studies have reported the effects of vinyl chloride on the reproductive function in females. Reduced hemoglobm levels during pregnancy and an increased incidence of elevated blood pressure and edema during pregnancy (preeclampsia) have been observed by Bao et al. (1988). Studies designed to examine these effects in animals were not located. At present, it is unclear whether adverse reproductive effects could occur in persons exposed to low levels of vinyl chloride in the air or water near hazardous waste sites. However, it would be prudent to consider the possibility of reproductive effects in environmentally exposed populations. Dev lopmental Effects. Although a statistically significant increase in congenital abnormalities has been observed in members of some communities located near a vinyl chloride processing facility, reports have failed to establish a statistically significant association between developmental toxicity and either parental occupation or proximity to the facility (Edmonds et al. 1978; Infante et al. 1976; Rosenman et al. 1989; Theriault et al. 1983). In contrast, a number of inhalation studies using pregnant animals have shown developmental toxicity consisting of resorptions, delayed ossification, and dilated ureters. These effects occurred when animals were exposed during the first trimester of pregnancy and at high levels of vinyl chloride (500-2,500 ppm) (John et al. 1977, 1981; Ungvary et al. 1978). However, these levels also produced maternal toxicity characterized by increased liver weight, decreased food consumption and weight gain, and increased mortality. Adverse postnatal effects have been observed in rats following in utero exposure to low levels of vinyl chloride (Sal'nikova and Kotsovskaya 1980). Therefore, it would be prudent to consider the possibility of developmental effects in environmentally exposed human populations as well. Genotoxic Effects. Vinyl chloride is mutagenic in S. typhimurium (Andrews et al. 1976; Bartsch et al. 1975, 1976; de Meester et al. 1980: Elmore et al. 1976: Poncelet et al. 1980; Simmon et al. 1977), but only in strains reverted by base-pair substitution by alkylating agents rather than by frameshift mutations (Bartsch et al. 1976; duPont 1992a, 1992b). Metabolic activation is necessary for any mutagenic activity in this system (Rannug et al. 1974) or for a maximal response (Simmon et al. 1977). In addition, vinyl chloride in the vapor phase is mutagenic, but not when it is dissolved in water (Poncelet et al. 1980). R&S 149120 -- DRAFT FOR PUBLIC COMMENT'" VINYL CHLORIDE 2. HEALTH EFFECTS 100 Concentrations of vinyl chloride tested in vitro range from 0.275% (Shaliin 1976) to 40% (duPont 1992a). Shaliin (1976) reported negative results for 0.275% and 0.55% in Saccharomyces cerevisiae. In S. typhimurium, a doubling of revertants has been reported to occur at about 5% vinyl chloride (Victorin and Stahlberg 1988a). Vinyl chloride was found to be mutagenic in Chinese hamster ovary cells (duPont 1992c). There is evidence that in S. typhimurium and E. coli it is the oxidation of vinyl chloride to the reactive intermediates 2-chloroethylene oxide and 2-chloroacetaldehyde that is responsible for the mutagenicity of vinyl chloride (Jacobsen et al. 1989; McCann et al. 1975; Rannug et al. 1976). Chloroacetaldehyde appears to be less genotoxic in yeast and Chinese hamster V79 cells than 2-chloroethylene oxide (Hubemian et al. 1975; Loprieno et al. 1977) and has been shown to inhibit DNA synthesis in avian cells (Kandala et al. 1990). However, 2-chloroacetaldehyde has been shown to react directly with single-stranded DNA, which then caused base changes and subsequent reversion in Escherichia coli when the DNA was inserted via phage (Jacobsen et al. 1989). Identification of the etheno-derived nucleosides as DNA and RNA adducts following vinyl chloride exposure provides one mechanism for the mutagenicity of this compound (Laib and Bolt 1977). There is evidence that chloroethylcne oxide is responsible for the formation of the etheno-DNA adducts, which in turn cause base-pair substitutions (Barbin et al. 1985a). These findings support the in vivo studies (see Section 2.2.1.7) that indicate that 2-chloroethylene oxide is responsible for DNA alkylation as well as preneoplastic foci in the liver. Key in vivo genotoxicity studies are presented in Table 2-6 and in vitro genotoxicity studies arc presented in Table 2-7. Cancer. A large number of studies have reported a greater than expected incidence of a rare type of cancer, angiosarcoma of the liver, among workers exposed to vinyl chloride (Byren et al. 1976; Creech and Johnson 1974; Fox and Collier 1977; Infante et al. 1976b; Jones et al. 1988; Laplanche et al. 1992; Monson et al. 1975; Pirastu et al. 1990; Rinsky et al. 1988; Simonato et al. 1991; Teta et al. 1990; Waxweiler et al. 1976; Weber et al. 1981; Wong et al. 1991; Wu et al. 1989). Other types of cancer that have shown a statistically significant increase in incidence among vinyl chloride workers, in at least some studies, include cancer of the brain and central nervous system, the lung and respiratory tract, and the lymphatic/hematopoietic system (Belli et al. 1987; Cooper 1981; Infante et al. 1976b; R & S 149121 '"DRAFT FOR PUBLIC COMMENT**' VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT Table 2-6. Genotoxicity of Vinyl Chloride In Vivo Species (test system) Mouse Rat Human lymphocyte End point Dominant lethal Dominant lethal Chromosomal aberration Sister chromatid exchange Micronuclei Chromosomal aberration Rat DNA alkylation Mouse Rat DNA alkylation - = negative result; + = positive result; DNA = deoxyribonucleic acid Results _ -- -- + - + + + + + + + + + + + + + + + + + + + + + + Reference Purchase et al. 1975 Anderson et al. 197*6 Short et al. 1977 Anderson and Richardson 1981 Hansteen et al. 1978 Kucerova et al. 3 979 Sinues et al. 1991 Fucic et al. 1992 Garaj-Vrhovac et al. 1990 Hansteen et al. 1978 Kucerova et al. 1979 Purchase et al. 1978 Ducatman et al. 1975 Anderson et al. 1980 Fucic et al. 1990 Funes-Cravioto et al. 1975 Hrivnak et al. 1990 Garaj-Vrhovac et al. 1990 Laib et al. 1989 Gwinner et al. 1983 Singer et al. 1987 Bolt et al. 1986 Ciroussel al. 1990 Eberle et al. 1989 Osterman-Golkar et al. 1977 Walles et al. 1988 Green and Hathaway 1978 VINYL CHLORIDE Table 2-7. Genotoxicity of Vinyl Chloride In Vitro DRAFT FOR PUBLIC COMMENT' Species (test system) Salmonella typhimurium TA100, TA1535 TA98, TA1537, TA1538 Escherichia coli Saccharomyces cerevisiae Schizosaccharomyces pomhe Chinese hamster ovary cells Bacillus subtilis Rat liver microsomes QT6 (avian cells) End point Reverse mutation Base-pair substitution Frameshift mutation Forward mutation Rec-repair RNA alkylation Inhibition of DNA synthesis With activation + + + + Not tested + + + + + + -- Not applicable Not tested + Not applicable + Not tested Not applicable Not applicable Without activation + s+ + - + + + Not tested + + -- + - + - - + + 1 Reference Rannug et al. 1974 Bartsch et al. 1975, 1976 Andrews et al. 1976 Simmon et a!. 1977 Elmore et al. 1976 Poncelet et al. 1980 de Meester et al. 1980 Victorin and Stahlberg 1988a McCann et al. 1975 Rannug et al. 1976 duPont 1992a, l992b Jacobsen et al. 1989 Shahin 1976 Luprieno et al. 1977 Huberman et al. 1975 duPont 1992c Elmore et ai. 1976 Laib and Bolt 1977 Kandala et al. 1990 X > HX m mO~n </> + = positive result; - = negative result; DNA -- deoxyribonucleic acid; RNA = ribonucleic acid 102 VINYL CHLORIDE 2. HEALTH EFFECTS 103 mulevich et al. 1988; Waxweiler et al. 1976; Weber et al. 1981; Wong et al. 1981). Because women traditionally have not been employed in PVC-manufacturing positions in North America and Western Europe, virtually all of the information available from occupational studies in these areas is based on the responses of males to vinyl chloride. One study by Smulevich et al. (1988) reporting on Soviet males and females occupationally exposed to vinyl chloride indicates that females may have higher incidences of stomach cancer, leukemias, and lymphomas than males. An increased incidence of angiosarcoma of the liver has been found after inhalation of vinyl chloride vapor by a variety of animal species (Maltoni et al. 1981). Although no studies examining the incidence of carcinogenic effects in humans exposed to vinyl chloride by the oral route have been located, vinyl chloride incorporated into the diet of rats has been demonstrated to cause an increased incidence of hepatic angiosarcoma (Maltoni et al. 1981). Based on these and other findings, the National Toxicology Program of the Department of Health and Human Services has determined vinyl chloride to be a carcinogen (DHHS 1994). In addition, the International Agency for Research on Cancer (IARC) has concluded that sufficient evidence for carcinogenicity in humans and animals exists and has placed vinyl chloride in carcinogenicity category 1, i.e., carcinogenic to humans (IARC 1987). PA also has concluded that sufficient evidence of carcinogenicity exists in humans and animals and as classified vinyl chloride according to its classification scheme as a Group A carcinogen, i.e., a human carcinogen (EPA 1994c). Because the epidemiological evidence does not provide sufficient exposure and incidence data to quantify risk based solely on human data, cancer potency factors for inhalation and oral exposure have been calculated based on animal studies. An upper bound q,* of 2.95x10 1 (mg/kg/day)'1 for inhalation exposure was estimated by EPA (1985c) based on the incidence of hepatic angiosarcoma observed in rats in the inhalation study by Maltoni et al. (1981). An upper bound q,* for oral exposure was estimated by EPA (1985b) to be 2.3 (mg/kg/day)"1 based on the combined incidence of liver and lung tumors in rats in the study by Feron et al. (1981). Doses associated with excess cancer risks of IO"1, 10'5, and 10'6 by the inhalation and oral routes are plotted in Figures 2-1 and 2-2, respectively. There are ample data on the genotoxicity of vinyl chloride in both humans and animals. Information on the mechanisms by which this compound may exert its carcinogenic effects have been elucidated from both in vitro and in vivo studies. Vinyl chloride is metabolized to 2-chIoroethylene oxide, which interacts directly with DNA and RNA, producing alkylation products such as 3,N4-etheno- R&SI49124 '"DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 104 Swenberg et al. 1992). This alkylation results in highly efficient base-pair substitution. It appears that the oxide is the ultimate genotoxic intermediate of vinyl chloride, which is consistent with data on the carcinogenicity of the oxirane derivatives of vinyl chloride. 2.6 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself, substancespecific metabolites in readily obtainable body fluid(s), or excreta. However, several factors can confound use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to vinyl chloride are discussed in Section 2.6.1. Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are not often substance specific. They also may not R&S149125 "'DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS lUb directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of rects caused by vinyl chloride are discussed in Section 2.6.2. A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other,,characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.8, Populations That Are Unusually Susceptible. 2.6.1 Biomarkers Used to Identify or Quantify Exposure to Vinyl Chloride Exposure to vinyl chloride may be monitored to some extent by the identification and quantitation of a number of parameters. For example, following acute exposure to moderate to high levels, vinyl chloride can be measured in expired air. The expiration of vinyl chloride follows first-order kinetics; therefore, this parameter may be directly correlated with exposure levels (Baretta et al. 1969). This measure may provide the most direct evidence of vinyl chloride exposure. However, measurement of exposure by this technique is limited by the rapidity of excretion of vinyl chloride in expired air. The lf-life of vinyl chloride in expired air has been determined to be between 20 and 30 minutes following an inhalation exposure and to be approximately 60 minutes following an oral exposure (Watanabe and Gehring 1976; Watanabe et al. 1976b, 1978a, 1978b). Thus, testing must be initiated as soon as possible following termination of exposure. Furthermore, measurement of vinyl chloride in expired air has limited utility for low-level exposures (<50 ppm) because of competition with rapid metabolic processes (Baretta et al. 1969). In addition, it provides no information on the duration of exposure. Thiodiglycolic acid is a major metabolite of vinyl chloride that is excreted in the urine. Measurement of thiodiglycolic acid in urine has been used to monitor workers occupationally exposed to vinyl chloride (Muller et al. 1979). However, although this metabolite is used to estimate levels of exposure, the amount of thiodiglycolic acid in the urine will vary according to individual metabolic idiosyncracies. Also, metabolism of vinyl chloride to thiodiglycolic acid is a saturable process. Therefore, when exposure exceeds a certain level, the excretion of vinyl chloride as thiodiglycolic acid will plateau (Watanabe and Gehring 1976), Furthermore, the rate of metabolism of vinyl chloride to thiodiglycolic acid may be influenced by the presence of liver disease, ethanol, or certain other B&S 149126 `"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 108 which measure liver function, are more sensitive indicators of the hepatic damage resulting from vinyl chloride exposure. Two such assays are the indocyanine clearance test and measurement of serum bile acid levels (Berk et al. 1975; Liss et al. 1985; Vihko et al. 1984). Liver biopsy may provide the most accurate identification of vinyl chloride-associated liver damage (Liss et al. 198*5). This is because of the characteristic pattern of hepatic histopathology associated with vinyl chloride-induced damage (Popper et al. 1981). However, liver biopsy is an invasive procedure with attendant risks, and, therefore, may not be justified. Individual exposure to vinyl chloride has been linked to angiosarcoma and benign angiomatous lesions based on the monitoring of serum found to be positive for the presence of the mutant protein Asp 13 c-Ki-raj p21, which was not present in control individuals (DeVivo et al. 1994). Additionally, this protein was found in the serum of 49% of exposed workers who had no apparent liver lesions. It may be possible to utilize the presence of this mutant protein for the early detection of angiosarcoma of the liver. The symptoms and signs associated with vinyl chloride disease (Raynaud's phenomenon, scleroderma like skin changes, and acroosteolysis) are similar to those observed in systemic sclerosis. Vinyl chloride disease may be differentiated from systemic sclerosis by the absence of antinuclear antibodies in the blood and association of vinyl chloride disease with vinyl chloride exposure (Black et al. 1983, 1986). Raynaud's phenomenon is an early symptom of vinyl chloride disease. However, cyanosis and blanching of fingers with exposure to cold may be the result of a number of other conditions such as connective tissue disorders, mechanical arterial obstruction, hyperviscosity of the blood, or exposure to drugs, chemicals, or vibrating tools (Freudiger et al. 1988). Thus, other potential causes must be eliminated before this syndrome can be used to identify vinyl chloride disease. The symptoms associated with vinyl chloride disease have been attributed to vinyl chloride-induced changes in the microvasculature (Grainger et al. 1980). Capillary abnormalities in the hands may be detected using wide-field capillary microscopy and have been proposed to represent an early manifestation of the effects of vinyl chloride (Marioq et al. 1976). Also, immunofluorescent examination of biopsy material from the skin may be used to identify circulating immune complexes and their deposition on the vascular endothelium (Ward 1976). R&S149127 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 109 hromosomal aberrations found in lymphocytes may be indicative of the genotoxic effects of vinyl chloride (Anderson et al. 1980; Ducatman et al. 1975; Fucic et al. 1990, 1992; Funes-Cravioto et al. 1975; Garaj-Vrhovac et al. 1990; Hansteen et al. 1978; Hrivnak et al. 1990; Kucerova et al. 1979; Purchase et al. 1978; Sinues et al. 1991). However, any of a number of genotoxic substances can cause chromosomal aberrations. Also, de Jong et al. (1988) have found that variability in the control population may obscure the observation of low-level chromosomal aberrations in persons exposed to low levels of vinyl chloride. G-banding analysis appeared to provide a more sensitive indication of chromosomal alteration than sister chromatid exchanges (Zhao et al. 1994). The DNA adducts produced by the reactive intermediary metabolites of vinyl chloride, including l,A6-ethenoadenosine and 3,jV4-ethenocytidine, may be more specific indicators of vinyl chloride's genotoxic potential. 2.7 INTERACTIONS WITH OTHER SUBSTANCES A number of studies have been performed that examine the effect of agents intended to alter the metabolism of vinyl chloride on its toxicity. For example, the effects of phenobarbital pretreatment on vinyl chloride-induced hepatotoxicity have been examined by Jaeger et al. (1974, 1977), Jedrychowski et al. (1985), and Reynolds et al. (1975a, 1975b). Pretreatment of rats with phenobarbital for 7 days ^irior to a 4-hour vinyl chloride exposure caused an increase in microsomal cytochrome P-450 activity (Reynolds et al. 1975b) and enhanced hepatotoxicity (Jaeger et al. 1974, 1977; Jedrychowski et al. 1985; Reynolds et al. 1975a, 1975b). In these studies, in the absence of the phenobarbital pretreatment, a single exposure to approximately 50,000 ppm had no detectable adverse effect on the livers of exposed rats. However, following phenobarbital pretreatment, 50,000 ppm of vinyl chloride produced increased serum activity of hepatic enzymes (Jaeger et al. 1977; Jedrychowski et al. 1985), areas of hepatic necrosis (Reynolds et al. 1975a), or both (Jaeger et al. 1974; Reynolds et al. 1975b). Another agent known to increase mixed function oxidase activity, Aroclor 1254, was also tested for its ability to enhance vinyl chloride-induced hepatotoxicity (Conolly and Jaeger 1979; Conolly et al. 1978; Jaeger et al. 1977; Reynolds et al. 1975b). Pretreatment of rats with Aroclor 1254 for several days prior to exposure to vinyl chloride resulted in an increase in serum activity of hepatic enzymes (Conolly and Jaeger 1979; Conolly et al. 1978; Jaeger et al. 1977; Reynolds et al. 1975b) and areas of hepatic necrosis (Conolly et al. 1978; Reynolds et al. 1975b). "'DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 110 Additional support for a role for mixed function oxidases in the enhanced toxicity of vinyl chloride was obtained using SKF525A, a mixed function oxidase inhibitor. If SKF525A was administered following phenobarbital pretreatment and before vinyl chloride exposure, it blocked the ability of phenobarbital pretreatment to enhance vinyl chloride-induced hepatotoxicity (Jaeger et al. 1977). The role of glutathione conjugation in vinyl chloride-induced toxicity was also examined (Conolly and Jaeger 1979; Jaeger et al. 1977). The investigators hypothesized that depletion of glutathione might enhance the toxicity of vinyl chloride by preventing the excretion of toxic intermediary metabolites. However, diethylmaleate, an agent known to deplete hepatic glutathione levels, had no effect on the toxicity produced by vinyl chloride following pretreatment with either phenobarbital (Jaeger et al. 1977) or Aroclor 1254 (Conolly and Jaeger 1979). Trichloropropene oxide (TCPO), another agent known to deplete hepatic glutathione, caused enhancement of the hepatic toxicity produced by Aroclor 1254 pretreatment and vinyl chloride exposure, but only when the animals had been fasted prior to vinyl chloride exposure (Conolly and Jaeger 1979). The study authors hypothesized that the enhancement of vinyl chloride toxicity was a result of the ability of TCPO to inhibit epoxide hydrase rather than its ability to deplete glutathione levels. The lack of the effect of glutathione depletion indicates that the glutathione pathway is not very important at normal levels of exposure. Although the depletion of cellular glutathione levels did not appear to enhance vinyl chloride toxicity, treatment with cysteine, the rate-limiting precursor in hepatic glutathione synthesis, increased hepatic glutathione levels and provided partial protection against the toxic effects produced by Aroclor 1254 and vinyl chloride (Conolly and Jaeger 1979). The effects of the interaction of ethanol with vinyl chloride on development were tested by John et al. (1977). In this study, animals were exposed to vinyl chloride in the presence and absence of 15% ethanol in the drinking water during pregnancy. Ethanol caused a decrease in maternal food consumption and maternal weight gain in mice, rats, and rabbits and enhanced incidence of skeletal abnormalities in mice, and to a lesser extent, in rats. Interpretation of these results is clouded by the absence of an ethanol-exposed control group and the current recognition of the adverse effects of ethanol on pregnancy outcome. In the experiment by Radike et al. (1981), ethanol-consuming rats exposed to vinyl chloride for a year had an enhanced incidence of hepatic angiosarcomas, hepatomas, and lymphosarcomas, earlier onset of R & S 149129 "'DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 111 mktne tumors, and an enhanced death rate. The incidence of vinyl chloride-induced angiosarcomas was otentiated by ethanol, whereas the increased incidences of hepatoma and lymphosarcomas by ethanol were additive in nature. The effects of smoking on chromosomal aberrations in vinyl chloride-exposed workers was examined by Hrivnak et al. (1990rwho found no effect of smoking in 43 workers exposed for an average of 1 1.2 years to levels of vinyl chloride ranging from 0.8 to 16 ppm. Most cytogenetic studies of the effects of smoking in humans have reported no effect on chromosomal aberrations, although the sister chromatid exchange frequency is usually elevated. 2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A susceptible population will exhibit a different or enhanced response to vinyl chloride than will most persons exposed to the same level of vinyl chloride in the environment. Reasons may include genetic makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These parameters may result in reduced detoxification or excretion of vinyl chloride, or compromised function of organs affected by vinyl chloride. Populations who are at greater risk due to Pieir unusually high exposure to vinyl chloride are discussed in Section 5.6, Populations With Potentially High Exposures. Data suggest that the following subsets of the human population may be unusually susceptible to the toxic effects of vinyl chloride: fetuses; infants; young children; people with liver disease, irregular heart rhythms, impaired peripheral circulation, or systemic sclerosis; people with exposure to organochlorine pesticides; and those consuming ethanol or barbiturates or taking Antabuse for alcoholism. Also, persons who possess the HLA-DR5, HLA-DR3, and B8 alleles may be at increased risk. Vinyl chloride can cross the placenta and enter the blood of the fetus (Ungvary et al. 1978). Studies by Drew et al. (1983), John et al. (1977, 1981), and Maltoni et al. (1981) have shown that animals exposed by inhalation prior to adolescence or during pregnancy may have a greater death rate and increased likelihood of developing cancer than adult animals exposed for similar periods. This may relate to the length of the induction period of hepatic angiosarcoma rather than to an increased susceptibility of the young, per se. It is also possible that there are explanations for these findings. R&S149130 'DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 112 Cogliano and Parker (1992) suggested that in the multistage model of carcinogenesis, carcinogens that induce an initial transition early in the life of an animal would be more effective since there would be a longer period of time remaining in the lifespan for completion of the remaining transitions. Their empirical model of the effect of age at exposure on the development of cancer suggests that there is an age-sensitive period of exposure to vinyl chloride. Vinyl chloride is metabolized in the liver in a multistep process. The intermediary metabolites of vinyl chloride, 2-chloroethylene oxide and 2-chloroacetaldehyde, have been suggested to be responsible for some of the adverse effects produced by vinyl chloride. Thus, activation of the enzyme system responsible for production of these toxic metabolites would be expected to increase the toxicity of vinyl chloride exposures. 2-Chloroethylene oxide is formed by action of the mixed function oxidase system associated with cytochrome P-450. The barbiturate, phenobarbital, and the organochlorine pesticide, Aroclor 1254, increased mixed function oxidase activity and have been shown to greatly increase the hepatotoxicity of vinyl chloride (Conolly and Jaeger et al. 1979; Conolly et al. 1978; Jaeger et al. 1974, 1977; Jedrychowski et al. 1985; Reynolds et al. 1975a, 1975b). Thus, persons taking barbiturates or who might be exposed to organochlorine pesticides that are known to induce microsomal enzymes (such as Aroclor 1254) would be expected to be at increased risk for developing vinyl chloride-induced hepatotoxicity. Radike et al. (1981) demonstrated that cthanol-consuming rats exposed to vinyl chloride had an increased incidence of cancer and an earlier death rate than animals exposed to vinyl chloride in the absence of ethanol. Some persons consume the agent, Antabuse, to curb the desire for alcohol. In its role as a therapeutic agent, Antabuse blocks aldehyde dehydrogenase and causes a build-up of acetaldehyde, which is emetic, in the body when alcohol is consumed. If persons taking Antabuse are exposed to vinyl chloride, the alternative metabolic pathway for vinyl chloride metabolism will be blocked, causing more vinyl chloride to be metabolized to the toxic metabolite, 2-chloroethylene oxide. Thus, these persons may be at increased risk for hepatotoxicity, cancer, and early death. Very high levels of vinyl chloride have been demonstrated to cause cardiac arrhythmias in dogs (Carr et al. 1949; Oster et al. 1947). Persons with a propensity to develop cardiac arrhythmias due to heart R&S149131 --DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 113 isease or damage may be at an increased risk of having heart beat irregularities when exposed to high concentrations of vinyl chloride. Vinyl chloride has been shown to cause decreased circulation in the hands and fingers of some persons. Persons with impaired circulation due to some other cause such as connective tissue disorders, systemic sclerosis, hyperviscosity of the blood, or use of vibrating tools, may experience more severe impairment of the circulation. Work by Black et al, (1983, 1986) has shown that persons with the HLA allele HLA-DR5 may have an increased likelihood of developing vinyl chloride disease, and those with the alleles HLA-DR3 and B8 may have an increased severity of the disease. 2.9 METHODS FOR REDUCING TOXIC EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to vinyl chloride. However, because some of the treatments discussed may be xperimental and unproven, this section should not be used as a guide for treatment of exposures to vinyl chloride. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. The following texts provide specific information about treatment following exposures to vinyl chloride: Bronstein and Currance 1988; Haddad and Winchester 1990; Stutz and Ulin 1992. 2.9.1 Reducing Peak Absorption Following Exposure Limited information from humans and results from animal studies indicate that vinyl chloride is rapidly and virtually completely absorbed following inhalation and oral exposure, but animal studies suggest that dermal absorption of vinyl chloride vapor is not likely to be significant (see Section 2.3.1). Efforts to reduce absorption following acute exposure to vinyl chloride should focus on removing the individual from the site of exposure and decontaminating exposed areas of the body. Vinyl chloride gas is relatively dense and accumulates at ground level. Therefore, the subject should be moved from low lying areas. Contaminated skin may be washed with soap and water. It is suggested that eyes exposed to vinyl chloride be copiously irrigated with water or normal saline # Bronstein and Currance 1988; Haddad and Winchester 1990; Stutz and Ulin 1992). Because of its "'DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 114 volatility, it is unlikely that vinyl chloride would be ingested unless it had been dissolved in a solvent. If such ingestion of vinyi chloride occurs, it is suggested that water or milk be administered for dilution if the patient can swallow, has a good gag reflex, and is not drooling (Bronstein and Currance 1988; Stutz and Ulin 1992). In addition, gastric lavage and administration of activated charcoal have been suggested as means to reduce absorption of vinyl chloride. Induction of emesis is contraindicated (Bronstein and Currance 1988; Haddad and Winchester 1990; Stutz and Ulin 1992). 2.9.2 Reducing Body Burden Because of its rapid metabolism and excretion, vinyl chloride does not tend to accumulate in the body. As discussed in Section 2.3.3, the metabolism of vinyl chloride is a dose-dependent, saturable process. Vinyl chloride is oxidized primarily by the microsomal mixed-function oxidase system (cytochrome P-450) to a reactive epoxide intermediate (2-chloroethylene oxide), which can rearrange to 2-chloroacetaldehyde or conjugate with glutathione to form S-formylmethyl glutathione. Very little vinyl chloride is excreted unchanged in the exhaled air. However, when metabolic saturation occurs at high exposure concentrations (approximately 1,000 ppm following inhalation exposure in rats [Watanabe and Gehring 1976; Watanabe et al. 1976b] and approximately 20 mg/kg following oral administration to rats [Green and Hathway 1975; Watanabe and Gehring 1976; Watanabe et al. 1976a]), vinyl chloride is excreted unchanged in expired air. Therefore, a possible means to enhance the elimination of vinyl chloride without allowing its biotransformation to toxic intermediates is to saturate this oxidative pathway by administration of substances known to be metabolized via this route. Saturation of the P-450 system may occur with drugs such as phenytoin or dicumerol (Goodman and Gilman 1980). However, the effectiveness of these agents in blocking the P-450 metabolism of vinyl chloride has not been tested, and it is unclear whether toxic doses would be necessary to overcome the relative affinities of the enzymes for vinyl chloride versus these agents. In addition, the potential toxicity of any side products of these substances would need to be considered in any protocol. Several agents induce activity of the microsomal enzymes and could potentially increase the toxicity of vinyl chloride. Administration of such substances would be contraindicated. 2.9.3 Interfering with the Mechanism of Action for Toxic Effects Following acute, high-level exposure, vinyl chloride behaves as an anesthetic and causes central nervous system and respiratory depression (see Sections 2.2.1.4 and 2.2.2.4). Therefore, basic life R&S149133 --DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 115 port measures, such as supplemental oxygen and cardiopulmonary resuscitation, are suggested in such instances (Bronstein and Currance 1988; Haddad and Winchester 1990; Stutz and Ulin 1992). In addition, like other halogenated hydrocarbons, vinyl chloride may sensitize the heart to the effects of circulating catecholamines. Therefore, the patient's cardiac rhythm should be monitored, and the use of isoproterenol, epinephrine, or other sympathomimetic drugs should be avoided (Haddad and Winchester 1990). Vinyl chloride is a known human and animal carcinogen; long-term exposure to this compound is associated with an increased incidence of hepatic angiosarcomas (see Section 2.2.1.8). Vinyl chloride is also hepatotoxic. The mechanism by which vinyl chloride induces its carcinogenic and toxic effect on the liver has been well studied. It is currently believed that these effects are mediated by a reactive epoxide intermediate of vinyl chloride, 2-chloroethylene oxide, which interacts directly with DNA and RNA producing alkylation products such as 3,A'l-ethenocytidine, 1 ,A*-ethenoadenosine, and 7-/V-(2-oxoethyl)-guanosine. This alkylation results in highly efficient base-pair substitution, leading to neoplastic transformation (see Section 2.4). As discussed above, this epoxide intermediate is formed when vinyl chloride is oxidized by the P-450 isoenzymes. Interference with this metabolic pathway, merefore, could reduce the toxic and carcinogenic effects of vinyl chloride by reducing the amount of poxide produced. A number of dmgs, such a cobaltous chloride, SKF-535-A, and 6-1,2,3-benzothioadiazole, have been reported to inhibit P-450 enzymes. Pretreatment with 6-1,2,3-benzothioadiazole completely blocked the metabolism of vinyl chloride in rats exposed to 0.45 ppm in a closed system for 5 hours (Bolt et al. 1977). P-450 metabolism also results in products that can be more readily eliminated than can the parent compound. Hence, any side products of the drugs and their potential to increase the biological half-life of vinyl chloride would also need to be considered in any protocol. In fact, a study by Buchter et al. (1977) showed that substantial unmetabolized vinyl chloride accumulated in fatty tissue when 6-nitro-l,2,3-benzothioadiazole was used to block P-450 metabolism. The study did not examine the fate of vinyl chloride in fatty tissue after P-450 metabolism was reactivated, but it likely that vinyl chloride would leave the fat slowly and be metabolized. Thus, while P-450 metabolism would probably reduce the generation of toxic metabolites in the short term, it is unclear whether the generation of toxic metabolites could be completely avoided. Further research to determine which isozymes are involved in the metabolism to the reactive intermediates, as well as which isozymes are involved in enhancing the elimination of vinyl chloride, could lead to the development of strategies to selectively inhibit specific isozymes and us reduce the toxic effects of vinyl chloride. '"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 116 Because vinyl chloride is detoxified by conjugation with glutathione and/or cysteine (see discussion above and Section 2.3.3), ensuring sufficient glutathione stores in the body (e.g., by treatment with /V-acetyl cysteine) may reduce the possibility of toxic effects following acute exposure to vinyl chloride. Vinyl chloride disease has been reported in a small percentage of workers exposed to this compound. One of the symptoms of this condition is Raynaud's syndrome (blanching, numbness, and discomfort of the fingers upon exposure to cold). Studies of these individuals demonstrated that vinyl chloride may cause blockage of the blood vessels supplying the hand, hypervascularity, and a thickening of the blood vessel walls (Harris and Adams 1967; Preston et al. 1976; Veltman et al. 1975; Walker 1976). Several investigators have suggested that the mechanism for vinyl chloride disease may be an autoimmune response similar to systemic sclerosis. Grainger et al. (1980) and Ward (1976) proposed that a reactive vinyl chloride intermediate metabolite, such as 2-chloroethylene oxide or 2-chloroacetaldehyde, binds to a protein such as IgG. The altered protein initiates an immune response, with deposition of immune products along the vascular endothelium. Cold temperatures could cause the precipitation of these immune complexes resulting in blockage of the blood vessels. Another characteristic of vinyl chloride disease is acroosteolysis, in which the terminal phalanges of the fingers are resorbed. This condition has been noted predominantly in workers who first had Raynaud's syndrome (Dinman et al. 1971; Freudiger et al. 1988; Harris and Adams 1967; Magnavita et al. 1986; Markowitz et al. 1972; Preston et al. 1976; Sakabe 1975; Veltman et al. 1975; Wilson et al. 1967). The resorptive bone changes may be due to activation of osteoclasts secondary to vascular insufficiency in the finger tips, but this remains to be demonstrated conclusively. Other manifestations of vinyl chloride disease include joint and muscle pain, enhanced collagen deposition, stiffness of the hands, and scleroderma-like skin changes. Increased levels of circulating immune complexes and immunoglobulins have been observed in vinyl chloride workers, suggesting a stimulatory effect of vinyl chloride on the immune system (Bogdanikowa and Zawilska 1984). A correlation between the severity of the symptoms of vinyl chloride disease and the magnitude of the immune response was observed (Grainger et al. 1980; Langauer-Lewowicka et al. 1976; Ward 1976). Research on the genetic characteristics of workers with this disease has demonstrated that the susceptibility to vinyl chloride disease was increased in the presence of the HLA-DR5 allele or a gene in linkage disequilibrium with it, and progression of the disease to its more severe forms was favored by HLADR3 and B8 (Black et al. 1983, 1986). If vinyl chloride disease is mediated by an immune mechanism in individuals with a genetic predisposition, then the effects of this disease may be R&SJ49j 35 "DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 2. HEALTH EFFECTS 117 itigated by administration of drugs used to treat other similar autoimmune diseases (e.g., azathioprine, cyclophosphamide, and prednisone). However, the toxicity associated with the use of these drugs must also be considered. 2.10 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of vinyl chloride is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of vinyl chloride. 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 kthat all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 2.10.1 Existing Information on Health Effects of Vinyl Chloride The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to vinyl chloride are summarized in Figure 2-5. The purpose of this figure is to illustrate the existing information concerning the health effects of vinyl chloride. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not necessarily imply anything about the quality of the study or studies, nor should missing information in this figure be interpreted as a "data need." A data need, as defined in ATSDR's Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from the scientific literature. R&S149136 '"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 118 FIGURE 2-5. Existing Information on Health Effects of Vinyl Chloride Inhalation Oral Dermal Existing Studies Animal --DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 119 Virtually all of the literature regarding health effects in humans comes from studies of workers exposed to vinyl chloride during the production of PVC. Case reports and cohort studies describe some acute health effects and a wide range of long-term health effects. The predominant mode of exposure in these studies is via inhalation. These studies are limited by the lack of reliable data on individual exposure levels. No studies were found regarding the health effects of oral exposure. One case report examined the effects of dermal exposure to liquid vinyl chloride, but exposure byjhis route is not expected to contribute significantly to producing adverse health effects because of the limited absorption of vinyl chloride through the skin. A large number of studies examining the health effects of inhaled vinyl chloride by animals were reviewed. As can be seen in Figure 2-5, no information is available on the acute systemic, immunologic, neurologic, reproductive, developmental, or genotoxic effects of exposure of animals by the oral route. No information is available regarding the health effects of exposure by the dermal route, but toxicokinetic studies indicate that this route is not an important means of exposure. 2.10.2 Identification of Data Needs Acute-Duration Exposure. Populations in areas that contain hazardous waste sites may be exposed to vinyl chloride for brief periods. Exposure most likely would occur by inhalation, but relatively brief oral and dermal exposures are also possible. There are acute inhalation exposure data in humans and animals that indicate that the central nervous system is a major target organ of vinyl chloride toxicity. Symptoms of central nervous system depression ranging from dizziness and drowsiness to loss of consciousness have been observed in humans and animals as a result of brief exposure to very high levels of vinyl chloride (Hehir et al. 1981; Jaeger et al. 1974; Lester et al. 1963; Mastromatteo et al. 1960; Patty et al. 1930). A threshold for central nervous system effects appears to be approximately 8,000 ppm (Lester et al. 1963). Extremely high concentrations of vinyl chloride produce respiratory irritation and death in humans and animals by the inhalation route (Danziger 1960; Lester et al. 1963; Mastromatteo et al. 1960; Patty et al. 1930). Based on studies in animals, the threshold for these effects appears to be in the range of 100,000-400,000 ppm (Lester et al. 1963; Mastromatteo et al. 1960; Patty et al. 1930). However, increased death was noted in pregnant mice at 500 ppm (John et al. 1977, 1981). Extremely high concentrations of vinyl chloride produce cardiac arrhythmias in dogs exposed by the inhalation route (Carr et al. 1949; Oster et al. 1947). No threshold was reported for these effects; acute inhalation studies examining the incidence of cardiac irregularities R&S149138 "DRAFT FOR PUBLIC COMMENT' VINYL CHLORIDE 2. HEALTH EFFECTS 120 at a variety of lower doses may be helpful in determining the threshold for this effect. Pharmacokinetic data indicate that similar end points might be expected if sufficiently high doses could be consumed by the oral route. However, the solubility characteristics of vinyl chloride in aqueous media (1,100-2,763 mg/L at 25C) (Cowfer and Magistro 1983; EPA 1985b) indicate that achieving concentrations of vinyl chloride in excess of 5,000 ppm may be extremely difficult. Animal studies indicate that an adverse effect on the fetus is the most sensitive end point observed following brief inhalation exposures to vinyl chloride (John et al. 1977, 1981; Ungvary et al. 1978). Concentrations as low as 500 ppm were observed to cause adverse effects on developing fetuses (John et al. 1977, 1981). The NOAEL (50 ppm) in this study was used to derive an acute-duration inhalation MRL. Animal studies examining the developmental, neurological, and systemic effects of the highest doses achievable in drinking water would be helpful for determining whether any effects would occur when vinyl chloride-contaminated groundwater or food products are consumed. One report described severe frostbite with second degree burns on the hands of a man resulting from the rapid evaporation of spilled liquid vinyl chloride (Harris 1953). A toxicokinetic study using two monkeys indicates that absorption of vinyl chloride vapor by the dermal route is exceedingly small (Hefner et al. 1975a); thus, studies examining the effects of acute-duration dermal exposure do not seem warranted. However, if further toxicokinetics studies contradict these findings, acute-duration dermal exposure studies in animals may be needed. A report was located regarding hepatic and respiratory effects observed 18 months following a single 1-hour inhalation exposure to vinyl chloride (Hehir et al. 1981). However, limitations in the study diminished its reliability. Because of the implications of chronic effects from acute exposure, confirmation of these results in^another study would be valuable. Intermediate-Duration Exposure. No studies in humans specifically address intermediate-duration effects by any route. Most epidemiological studies of occupationally exposed persons have concentrated on persons who have been employed over several years. A study with reliable quantification of exposure levels that examined the effects experienced by vinyl chloride workers in their first year of exposure would be helpful for predicting the effects that might be observed in populations exposed to hazardous waste sites for similar periods of time. However, at current low levels of exposure in the workplace, it may be difficult to demonstrate effects. There is a large database describing the effects of intermediate-duration inhalation exposures in animals (Adkins et al. 1986; Bi et al. 1985; Drew et al. 1983; Du et al. 1979; Feron et al. 1979a, 1979b; Hong et al. 1981; R&S149139 "DRAFT FOR PUBLIC COMMENT'" VINYL CHLORIDE 2. HEALTH EFFECTS 121 Lee et al. 1978; Lester et al. 1963; Maltoni et al. 1981; Mirkova et al. 1978; Sal'nikova and Kotsovskaya 1980; Schaffner 1978; Sharma and Gehring 1979; Short et al. 1977; Sokal et al. 1980; Suzuki 1978, 1981; Torkelson et al. 1961; Wisniewska-Knypl et al. 1980). Animals exposed to vinyl chloride vapor for more than 2 weeks and less than a year have experienced effects on the liver, kidneys, lungs, and blood (Bi et al. 1985; Du et al. 1979; Feron et al. 1979a, 1979b; Lester et al. 1963; Sal'nikova and Kotsovskaya 1980; Schaffner 1978; Sokal et al. 1980; Torkelson et al. 1.961; Wisniewska-Knypl et al. 1980). Data were sufficient to determine an intermediate-duration inhalation MRL based on liver effects. However, the MRL was based on a LOAEL and a no-effect level in animals would be more suitable for MRL derivation. Extremely limited information was available regarding oral intermediate-duration effects. One chronic study presented interim sacrifice data that identified relative weight and histopathological changes in the liver (Feron et al. 1981). However, only a single-dose group was compared to controls, precluding determination of the dose-response of the effects observed. Thus, no MRL for oral intermediate-duration exposures could be determined. Additional studies examining the effects of oral exposure to vinyl chloride would be helpful for predicting effects that might be observed in humans consuming contaminated drinking water or foods over a similar period of time. As noted above, absorption of vinyl chloride vapor through the skin is not expected to be significant (Hefner et al. 1975a); thus, additional dermal exposure studies do not seem warranted. However, if further toxicokinetics studies contradict these findings, other intermediate-duration dermal exposure studies may be needed. Chronic-Duration Exposure and Cancer. A large number of studies of workers exposed to vinyl chloride have identified a wide range of target organs that may be affected by chronic-duration inhalation of vinyl chloride (Bao et al. 1988; Bencko et al. 1988; Berk et al. 1975; Black et al. 1983, 1986; Bogdanikowa and Zawilska 1984; Brugnami et al. 1988; Byren et al. 1976; Creech and Johnson 1974; Dinman et al. 1971; Falk et al. 1974; Freudiger et al. 1988; Gedigke et al. 1975; Grainger et al. 1980; Harris and Adams 1967; Jayson et al. 1976; Jones and Smith 1982; Langauer-Lewowicka et al. 1976; Laplanche et al. 1987; Lee et al. 1977b; Lelis et al. 1975; Liss et al. 1985; Lloyd et al. 1984; Magnavita et al. 1986; Marioq et al. 1976; Markowitz et al. 1972; Marsteller et al. 1975; Micu et al. 1985; Miller 1975; NIOSH 1977; Perticoni et al. 1986; Popper and Thomas 1975; Popper et al. 1981; Preston et al. 1976; Sakabe 1975; Spirtas et al. 1975; Suciu et al. 1963, 1975; Tamburro et al. 1984; Veltman et al. 1975; Vihko et al. 1984; Walker 1976; Ward 1976; Wilson et al. 1967; Wong et al. 1991). The target organs include the liver, lungs, blood, immune system, cardiovascular system, skin, bones, nervous system, and the reproductive organs. These studies are severely limited in that ovvsHS'gy "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 122 individual exposure levels have not been documented. In general, studies in animals provide supportive evidence for these effects and give indications of the exposure levels that may be associated with them (Bi et al. 1985; Feron and Kroes 1979; Feron et al. 1979a, 1979b; Lee et al. 1981; Viola 1970; Viola et al. 1971). No information was available regarding chronic-duration oral exposure in humans. However, studies in animals indicate that the liver, blood, and skin are target organs for oral exposure to vinyl chloride (Feron et al. 1981; Knight and Gibbons 1987; Til et al. 1983, 1991). A chronic-duration oral MRL of 0.00002 mg/kg/day was derived from a LOAEL based on liver effects in rats (Til et al. 1983, 1991). No information was available regarding effects of chronic-duration dermal exposure in humans or animals, but absorption of vinyl chloride through the skin was not significant in an acute-duration exposure study in monkeys (Hefner et al. 1975a). Thus, dermal exposure studies do not seem warranted. However, if further toxicokinetics studies contradict these findings, then other intermediate-duration dermal exposure studies may be needed. There is sufficient evidence to indicate that vinyl chloride is carcinogenic to humans (Belli et al. 1987; Brugnami et al. 1988; Byren et al. 1976; Chung and Keh 1987; Cooper et al. 1981; Creech and Johnson 1974; Davies et al. 1990; Fitzgerald and Griffiths 1987; Fox and Collier 1977; Gelin et al. 1989; Geryk and Zudova 1986; Hagmar et al. 1990; Heldass et al 1987; Infante et al. 1976b; Jones et al. 1988; Monson al. 1975; Pirastu et al. 1990; Rinsky et al. 1988; Smulevich et al. 1988; Teta et al. _ 1990; Waxweiler et al. 1981; Weber et al. 1981; Williamson and Ramsden 1988; Wong et al. 1991; Wu et al. 1989) and animals (Bi et al. 1985; Drew et al. 1983; Feron and Kroes 1979; Feron et al. 1979a; Lee et al. 1978; Maltoni et al. 1981; Viola et al. 1971) exposed via inhalation and in animals (Feron et al. 1979a; Maltoni et al. 1981; Til et al. 1983, 1991) exposed via the oral route. The mechanism for carcinogenicity appears to be associated with the formation of reactive intermediates. Genotoxicity. There are substantial data on clastogenesis in humans exposed to vinyl chloride that indicate that this chemical acts as a potent genotoxicant (Anderson et al. 1980; Ducatman et al. 1975; Fucic et al. 1990; Funes-Cravioto et al, 1975; Hansteen et al. 1978; Hrivnak et al. 1990; Kucerova et al. 1979; Purchase et al. 1978). These findings are supported by both animal studies and in vitro studies that show positive genotoxicity in a variety of microbial organisms, cultured cell lines, and isolated nucleic acid assays (Anderson and Richardson 1981; Andrews et al. 1976; Barisch 1975; R & S 149141 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 123 Bartsch et al. 1976; Bolt et al. 1986; Ciroussel et al. 1990; de Meester et al. 1980; Eberle et al. 1989; Green and Hathway 1978; Gwinner et al. 1983; Hansteen et al. 1978; Huberman et al. 1975; Jacobsen et al. 1989; Kandala et al. 1990; Laib and Bolt 1977; Laib et al. 1989; Loprieno et al. 1977; McCann et al. 1975; Osterman-Golkar et al. 1977; Poncelet et al. 1980; Rannug et al. 1974, 1976; Simmon et al. 1977; Singer et al. 1987; Victorin and Stahlberg 1988a; Walles et al. 1988). There are also data supporting the premise that it is the chloroethylene oxide metabolite that is ultimately responsible for the direct action on the DNA (Jacobsen et al. 1989; McCann et al. 1975; Rannug et al. 1974. 1976). and that the mechanism involves alkylation and subsequent base-pair substitution (Barbin et al. 1985a). There is a study that indicates that the clastogenic effects of vinyl chloride exposure in humans are reversible (Anderson et al. 1980); additional studies on the fate of the alkylated DNA in workers after an exposure-free interval would be useful for predicting the mechanisms involved in the latency period for carcinogenesis. In addition, further work elucidating the genotoxic role of chloroacetaldehyde would be useful in explaining the inconsistent findings regarding the effects of this metabolite on clastogenesis and the induction of carcinogenesis. Reproductive Toxicity. Data from a number of epidemiological studies provide suggestive evidence of adverse effects on male and female reproductive function. Sexual impotence and decreased androgen levels were found in men exposed occupationally to vinyl chloride (Suciu et al. 1975; Veltman et al. 1975; Walker 1976). In women exposed to vinyl chloride, menstrual disturbances and an increased incidence of elevated blood pressure and edema during pregnancy (preeclampsia) were observed (Bao et al. 1988). Although no reports of two-generation reproduction studies in animals were located, two studies examining a range of toxic effects in rats indicate that vinyl chloride is toxic to the testes (Bi et al. 1985; Sokal et al. 1980). A two-generation reproduction study in animals would be helpful to assess whether adverse effects on the rate of conception could be correlated with damage to the male reproductive organs or whether disturbances in female menstrual activity could be verified. Also, animal models of preeclampsia could be tested to determine the mechanism by which vinyl chloride might cause this effect. Well-designed and welEconducted epidemiological studies examining such changes would also be helpful. No data are available on the possible reproductive toxicity resulting from oral exposure to vinyl chloride. Oral studies that use drinking water as the vehicle of administration would be particularly useful because contaminated groundwater is a potentially significant source of human exposure. R&S149142 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 124 Developmental Toxicity. The epidemiological studies that have addressed developmental toxicity in offspring of humans who have been exposed to vinyl chloride are controversial. Although some of these purport to show a significant association between birth defects and vinyl chloride exposure (Infante 1976; Infante et al. 1976a, 1976b; NIOSH 1977), their design and analysis have been severely criticized (Hatch et al. 1981; Stallones et al. 1987). At this time, there are insufficient human data to provide a definitive answer to this question. A well-designed and well-conducted epidemiological study examining potential developmental end points would be helpful. There are data showing that vinyl chloride is a developmental toxicant in animals when exposure is by inhalation (John et al. 1977, 1981; Mirkova et al. 1978; Sal'nikova and Kotsovskaya 1980; Ungvary et al. 1978). Continuous lowlevel exposure appears to be the most toxic (Mirkova et al. 1978; Ungvary et al. 1978), but the studies that indicate this are flawed. Additional studies examining exposure to low levels of vinyl chloride throughout gestation would be helpful in settling this issue. This issue is particularly important because women living in the vicinity of hazardous waste sites have the potential to be exposed to low levels of vinyl chloride on a continuous basis. It would also be helpful to determine whether pregnancy increases the susceptibility to vinyl chloride in the mother. Also, studies in animals suggest that offspring exposed in utero may experience adverse effects after birth (Mirkova et al. 1978; Sal'nikova and Kotsovskaya 1980), although these studies are also flawed. There are no data for oral exposures. Because of this deficiency, oral studies examining a range of developmental end points would be useful in assessing the possibility of these effects in humans. Immunotoxicity. Studies of workers occupationally exposed to vinyl chloride suggest that the immune system may be activated by vinyl chloride (Bogdanikowa and Zawilska 1984). Some data suggest that reactive intermediates may bind to proteins in the body, sufficiently altering them so that they become antigenic (Grainger et al. 1980). In some instances, an autoimmune-like syndrome develops. The likelihood of this may be associated with the possession by individuals of specific genetic determinants (HLA alleles) (Black et al. 1983, 1986). Because of the low incidence of the autoimmune response in humans, the immunotoxicity may be best further studied in one of the strains of mice known to have a propensity for developing autoimmune diseases. Also, additional epidemiological studies examining the immune response of exposed populations may be helpful. R&S149143 "DRAFT FOR PUBLIC COMMENT*" -VINYL CHLORIDE 2. HEALTH EFFECTS 125 Neurotoxicity. A number of studies in humans (Lester et al. 1963; Patty et al. 1930) and animals (Hehir et al. 1981; Jaeger et al. 1974; Lester et al. 1963; Mastromatteo et al. 1960; Patty et al. 1930) demonstrate that vinyl chloride is a central nervous system depressant following brief high-level inhalation exposures. Two studies in animals have also found degenerative effects in central nervous system tissue following chronic inhalation exposure to high levels of vinyl chloride (Viola 1970; Viola et al. 1971). It is unknown whether these degenerative changes might also occur at lower doses; thus, a study examining the effects of a range of lower doses would be informative. In addition, relatively recent studies present suggestive evidence that vinyl chloride may also produce peripheral nerve damage in humans exposed chronically via inhalation (Langauer-Lewowicka et al. 1976; Magnavita et al. 1986; Perticoni et al. 1986; Sakabe 1975; Walker 1976). Animal studies examining histopathological and electrophysiological end points in peripheral nerves would be helpful for assessing what doses may be associated with this effect. Epidemiological studies examining exposed populations for subclinical peripheral nerve damage would be helpful. Oral exposure studies in animals would be beneficial for assessing the likelihood that populations exposed to contaminated water might develop symptoms of neurotoxicity. Epidemiological and Human Dosimetry Studies. Virtually all of the data on effects in humans following inhalation exposure to vinyl chloride come from epidemiological studies of workers exposed during the production of PVC (Bao et al. 1988; Bencko et al. 1988; Berk et al. 1975; Black et al. 1983, 1986; Bogdanikowa and Zawilska 1984; Brugnami et al. 1988; Byren et al. 1976; Creech and Johnson 1974; Dinman et al. 1971; Falk et al. 1974; Freudiger et al. 1988; Gedigke et al. 1975; Grainger et al. 1980; Harris and Adams 1967; Jayson et al. 1976; Jones and Smith 1982; LangauerLewowicka et al. 1976; Laplanche et al. 1987; Lee et al. 1977b; Lilis et al. 1975; Liss et al. 1985; Lloyd et al. 1984; Magnavita et al. 1986; Marioq et al. 1976; Markowitz et al. 1972; Popper et al. 1981; Preston et al. 1976; Sakabe 1975; Spirtas et al. 1975; Suciu et al. 1963, 1975; Tamburro et al. 1984; Veltman et al. 1975; Vihko et al. 1984; Walker 1976; Ward 1976; Waxweiler et al. 1977; Wilson et al. 1967; Wong et al. 1991). These studies are limited by the absence of information on individual exposure levels. Also, in North America and Western Europe, only limited numbers of females have been studied. For the most part, studies examining the carcinogenic potential of vinyl chloride have been adequate to distinguish an increased incidence of the rare cancer, angiosarcoma (Byren et al. 1976; Creech and Johnson 1974; Fox and Collier 1977; Infante et al. 1976b; Jones et al. 1988; Monson al. 1975; Pirastu R&S149144 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2. HEALTH EFFECTS 126 et al. 1990; Rinsky et al. 1988; Teta et al. 1990; Waxweiler et al. 1976; Weber et al. 1981; Wong et al. 1991; Wu et al. 1989). However, many studies have used cohorts that are too small to detect smaller increases in other types of cancer (respiratory, central nervous system, lymphatic, or hematopoietic). Epidemiological studies designed to investigate reproductive and developmental effects of vinyl chloride have not been useful, in part because of a poor choice of statistical analysis, inadequate controls, lack of effects due to current low levels of exposure, or failure to take into account other chemical exposures. Additional cohort studies of these end points would be useful for examining these effects in humans. Clastogenic effects have been used as a dosimeter for exposures to radioactive substances, and work has been done to use this approach for chemical exposures as well. More data on quantified exposures and well-controlled cytogenetic studies would be useful in developing a method for monitoring populations living near hazardous waste sites. In addition, as noted above, well-designed and well-conducted epidemiological studies examining the incidence of peripheral neuropathies, developmental toxicity (birth defects, miscarriages, delayed prenatal development, postnatal hepatotoxicity), reproductive toxicity (male infertility, menstrual irregularity, preeclampsia in pregnant women), and immune reactivity in exposed populations would also be helpful. Biomarkers of Exposure and Effect Exposure. Several potential biomarkers for exposure to vinyl chloride have been identified. Vinyl chloride measured in expired air is an adequate indicator of recent, moderate-to-high-leve! exposure (Baretta et al. 1969). However, for low-level exposures or exposures that occur over 1-2 hours prior to the time of measurement, this biomarker is not useful. Thiodiglycolic acid, a major urinary metabolite of vinyl chloride, has been used to monitor workers occupationally exposed to vinyl chloride (Muller et al. 1979). However, this biomarker is rapidly excreted, and, therefore, the period of its utility is limited (Watanabe and Gehring 1976; Watanabe et al. 1978, 1979b). Also, thiodiglycolic acid is not specific for vinyl chloride; it may also be produced as a result of the metabolism of 1,1 dichloroethene, ethylene oxide, or 2,2-dichloroethylether (Norpoth et al. 1986; Pettit 1986). R&S149145 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 2. HEALTH EFFECTS 127 The DNA adducts 1 .A^-ethenoadenosine and 3,yV4-ethenocytidine may be used to indicate vinyl chloride exposure, although studies correlating the levels of these adducts with exposure levels are still lacking. These products remain in the body longer than free vinyl chloride or thiodiglycolic acid, thereby increasing the period after exposure that a potential exposure may be detected (Bolt 1986; Guengerich and Watanabe 1979; Guengerich et al. 1979, 1981; Kappus et al. 1976; Watanabe et al. 1987a, 1987b). However, the presence of these adducts cannot indicate how long it has been since exposure occurred. In addition, these adducts are formed as the result of binding of the intermediary metabolites with nucleic acids, and other compounds producing the same intermediary metabolites will also produce these adducts. For example, these adducts have been identified as a result of exposure to vinyl bromide, ethyl carbamate, acrylonitrile, 2-cyanoethylene, and 1,2-dichIoroethane (Bolt et al. 1986; Svensson and Osterman-Golkar 1986). Studies attempting to identify a metabolite more specific to vinyl chloride may be helpful in developing a biomarker that may be used to facilitate future medical surveillance, which can lead to early detection and possible treatment. Effect. With regard to biomarkers of effect of vinyl chloride exposure, numerous indicators have been examined. The central nervous system depression associated with brief high-level exposures is easily determined by observation. The hepatic changes that may develop during longer-term exposures are difficult to detect by standard biochemical liver function tests (Berk et al. 1975; Liss et al. 1985; Vihko et al. 1984). In contrast, tests of clearance such as the indocyanine clearance test or measurement of serum bile acid levels are more specific and sensitive indicators of vinyl chlorideinduced liver damage (Berk et al. 1975; Liss et al. 1985; Vihko et al. 1984). Angiosarcoma of the liver is a rare tumor type that has been shown to result from vinyl chloride exposure. However, other agents are known to cause angiosarcoma of the liver, such as arsenic and Thorotrast (Gedigke et al. 1975; Marsteller et al. 1975). The cyanosis and blanching of the fingers in response to exposure to the cold may be an early indicator for the development of vinyl chloride disease. However, other conditions also known to cause these symptoms include connective tissue disorders, mechanical arterial obstruction, hyperviscosity of the blood, and exposure to drugs, chemicals, or vibrating tools (Black et al. 1983, 1986; Freudiger et al. 1988). The presence of basophilic stippled erythrocytes has been reported after inhalation exposure of mice to vinyl chloride (Kudo et al. 1990). Further study is needed to determine whether this parameter could be used as a biomarker of effect in humans. Finally, measurement of chromosomal aberrations may indicate the genotoxic effects of vinyl chloride (Anderson et al. 1980; Ducatman et al. 1975; Fucic et al. 1990). However, these aberrations do not specifically indicate vinyl chloride-induced damage. Also, DNA adducts may signal the potential to R&S149146 '"DRAFT FOR PUBLIC COMMENT' VINYL CHLORIDE 2. HEALTH EFFECTS 128 develop genotoxic effects. Further work identifying the correlation between the adducts and genotoxic effects would be useful. Absorption, Distribution, Metabolism, and Excretion. There are few data on humans for all toxicokinetic parameters across all exposure routes (Krajewski et al. 1980; Sabadie et al. 1980). There are a number of animal studies describing the absorption, distribution, metabolism, "and excretion of vinyl chloride administered via the oral (Feron et al. 1981; Green and Hathway 1978; Watanabe and Gehring 1976; Watanabe et al. 1987a, 1987b; Withey 1976) and inhalation (Bolt et al. 1976a, 1977; Buchter et al. 1977, 1980; Filser and Bolt 1979; Guengerich and Watanabe 1979; Hefner et al. 1975b; Jedrychowski et al. 1984, 1985; Ungvary et al. 1978; Watanabe and Gehring 1976; Watanabe et al. 1978a, 1978b; Withey 1976) routes, but few describing the toxicokinetics of vinyl chloride administered via the dermal route. One study in monkeys found an extremely limited absorption of vinyl chloride vapor across the skin (Hefner et al, 1975a). However, only two animals were used, and this was the only study located that examined toxicokinetics after dermal exposure. If there is negligible absorption resulting from dermal exposure, then additional studies examining toxicokinetics from dermal exposures are not warranted; another study verifying the limited nature of dermal absorption, however, would be reassuring. Furthermore, the intermediary metabolites of vinyl chloride appear to be responsible for many of the toxic effects observed. Therefore, information regarding differences in the metabolic pattern according to sex, age, nutritional status, and species and correlations to differences in health effects would also be useful. Comparative Toxicokinetics. The absorption, distribution, metabolism, and excretion have been studied in animals (Bolt et al. 1976a, 1977; Buchter et al. 1977, 1980; Filser and Bolt 1979; Feron et al. 1981; Green and Hathway 1975; Guengerich and Watanabe 1979; Hefner et al. 1975b; Jedrychowski et al. 1984, 1985; Ungvary et al. 1978; Watanabe and Gehring 1976; Watanabe et al. 1976a, 1976b, 1978a, 1978b; Withey 1976), but information on toxicokinetics in humans is extremely limited (Krajewski et al. 1980; Sabadie et al. 1980). Human and animal data indicate that similar target organs (liver, central nervous system) for the toxic effects of vinyl chloride exist, suggesting some similarities of kinetics. Limited information is available regarding interspecies differences in kinetics. Most toxicokinetic studies have been conducted using rats (Bolt et al. 1976a, 1977; Buchter et al. 1977; Filser and Bolt 1979; Feron et al. 1981; Green and Hathway 1975; Guengerich and Watanabe 1979; Hefner et al. 1975b; Jedrychowski et al. 1984, 1985; Ungvary et al. 1978; Watanabe and Gehring 1976; Watanabe et al. 1976a, 1976b, 1978a, 1978b; Withey 1976), but one study in "DRAFT FOR PUBLIC COMMENT"* R&S149147 t VINYL CHLORIDE 2. HEALTH EFFECTS 129 primates (Buchter et al. 1980) indicates that metabolism may saturate at lower concentrations in primates than rats. This may suggest a lower saturation point in humans also. Modeling studies might continue to provide information on the toxicokinetics of vinyl chloride in humans. Methods for Reducing Toxic Effects. Vinyl chloride appears to be rapidly and completely absorbed following inhalation and oral exposure (Bolt et al. 1977; Krajewski et al. 1980; Watanabe et al. 1976a; Withey 1976). Methods used to reduce absorption immediately after exposure include removal from the source of exposure, cleansing contaminated body parts, and, in cases of ingestion, speeding the removal of unabsorbed material from the gastrointestinal tract (Bronstein and Currance 1988; Haddad and Winchester 1990; Stutz and Ulin 1992). No information was located regarding the mechanism of absorption. Additional experiments examining the mechanism of absorption and potential means of interfering with that mechanism would be useful. Distribution of vinyl chloride in the body is rapid and widespread, but storage is limited by rapid metabolism and excretion (Bolt et al. 1976a; Buchter et al. 1977; Watanabe et al. 1976a, 1976b, 1978a). The toxicity of vinyl chloride has been attributed to the formation of reactive epoxide metabolites. No information was located regarding removal of these toxic metabolites from the body once they have been formed, but information from toxicokinetic studies suggest that vinyl chloride metabolism to toxic metabolites may be reduced. Saturation of the metabolic pathways for vinyl chloride can result in the clearance of unmetabolized vinyl chloride in exhaled air (Green and Hathway 1975; Watanabe and Gehring 1976; Watanabe et al. 1976a, 1976b, 1978a). Studies examining the effectiveness and endogenous toxicity of the agents used to block the metabolic pathways (cobaltous chloride, SKF-535-A, 6-nitro-1,2,3benzothiadiazole) would provide useful information. Another strategy for reducing the formation of toxic metabolites includes increasing the pool of glutathione for use in metabolism to nontoxic metabolites. Studies examining the effectiveness of this procedure would also be helpful. Vinyl chloride disease may be mediated by an autoimmune mechanism (Grainger et al. 1980; Ward 1976). Further studies continuing to examine the role of autoimmune responses in vinyl chloride disease, the genetic factors resulting in greater susceptibility to the disease, and the effectiveness of drugs that block immune responses in reducing the symptoms of'vinyl chloride disease would also provide valuable information. R & S 149148 '"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 2.10.3 On-going Studies 2. HEALTH EFFECTS 130 On-going studies regarding the health effects of vinyl chloride were reported in the Federal Research in Progress File (FEDR1P 1994) database and CRIS/USDA (1994). Table 2-8 presents a summary of on-going studies that address the health effects of vinyl chloride. -1 R&S149149 --DRAFT FOR PUBLIC COMMENT' VINYL CHLORIDE 2. HEALTH EFFECTS TABLE 2-8. On-going Studies on Vinyl Chloride3 131 Investigator Affiliation I. Hertz-Piccioto University of North Carolina at Chapel Hill J. Miller University of Wisconsin at Madison R. Prough University of Louisville Medical School S. Rappaport University of North Carolina at Chapel Hill B. Singer T. Skopek University of California, Lawrence Berkeley Laboratory University of North Carolina at Chapel Hill J. Solomon New York University Medical Center J. Swenberg University of North Carolina at Chapel Hill J. Wong University of Louisville, Belknap Campus Research description Sponsor Measuring biomarkers of genotoxicity and human variability in response to vinyl chloride Metabolism and DNA adducts of vinyl chloride and its epoxide in rodent and human tissues Biochemical biomarkers of exposure; metabolism of vinyl chloride in rat and human hepatocytes Dose-response relationships for adducts of hemoglobin and serum albumin for use as biomarkers of exposure Biochemical mechanisms of vinyl chloride carcinogenesis NIEHS NCI NIEHS NIEHS NCI Frequency and distribution of mutations induced by vinyl chloride at (hprt) locus in mouse model and human lymphoblastoid cells in vitro Formation of 3-alkyl uracil adducts from aliphatic epoxides in rats after inhalation exposure Comparison of formation of DNA adducts in target and nontarget tissues and in peripheral blood lymphocytes Produce monoclonal antibodies to synthetic antigens of vinyl chloride metabolites NIEHS NIEHS NIEHS NIEHS "Sources: CRIS/USDA (1994); FEDRIP (1994) DNA = deoxyribonucleic acid R&S149150 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 3. CHEMICAL AND PHYSICAL INFORMATION 133 3.1 CHEMICAL IDENTITY Information regarding the chemical identity of vinyl chloride is located in Table 3-1. This information includes synonyms, chemical formula and structure, and identification numbers. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Information regarding the physical and chemical properties of vinyl chloride is located in Table 3-2. R&S149152 --DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE CHEMICAL AND PHYSICAL INFORMATION TABLE 3-1. Chemical Identity of Vinyl Chloride 134 Characteristic Chemical name Synonym(s) Registered trade name(s) Chemical formula Chemical structure Identification numbers: CAS registry NIOSH RTECS EPA hazardous waste OHM/TADS DOT/UN/NA/IMCO shipping HSDB NCI Information Reference Vinyl chloride Chloroethene; chloroethylene; 1 -chloroethylene; ethylene monochloride; monovinylchloride; monochloroethene; monochloroethylene; Trovidur; VC; VCM; vinyl chloride monomer No data C2H3C1 H Cl \/ C=c /\ HH HSDB-1994 Fire 1986; HSDB 1994 HSDB 1994 75-01-4 KU9625000 U043 7216947 1086 169 No data HSDB 1994 HSDB 1994 HSDB 1994 HSDB 1994 HSDB 1994 HSDB 1994 CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/Intemational Maritime Dangerous Goods Code; EPA - Environmental Protection Agency; HSDB - Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; OHM/TADS - Oil and Hazardous Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemicals Substances SSo w SSlspi `"DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE CHEMICAL AND PHYSICAL INFORMATION TABLE 3-2. Physical and Chemical Identity of Vinyl Chloride 135 Property Molecular weight Color Physical state Melting point Boiling point Density: at -14.2C at 15C at 20C Vapor density Odor Odor threshold: Water Air Solubility: Water at 25C Organic solvent(s) Partition coefficients: Log Kow Log Km Vapor pressure: at 20C at 25C Henry's law constant: at 10C Autoignition temperature Flashpoint Flammability limits Conversion factors ppm to mg/m3 in air mg/m3 to ppm in air Explosive limits Information 62.5 Colorless Gas -153.8C -13.4C 0.969 g/cm3 0.9195 g/cm3 0.9106 g/cm3 2.16 Sweet 3.4 ppm 3,000 ppm 2,763 mg/L 1,100 mg/L Soluble in hydrocar- bons, oil, alcohol, chlorinated solvents, and most common organic liquids 1.36 1.99 2,530 mmHg 2,660 mmHg 1.2 (atm-m3)/mol 472C -77.75C (open cup) 3.6-33 volume % 1 ppm = 2.60 mg/m3 1 mg/m3 - 0.39 ppm 4-22 volume % Reference Sax and Lewis 1989 Cowfer and Magistro 1983 Cowfer and Magistro 1983 Cowfer and Magistro 1983 Cowfer and Magistro 1983 Cowfer and Magistro 1983 Sax and Lewis 1989 NIOSH 1986 Fire 1986 HSDB 1990 Amoore and Hautala 1983 Amoore and Hautala 1983 EPA 1985b Cowfer and Magistro 1983 Cowfer and Magistro 1983 NIOSH 1986 Lyman et al. 1982 IARC 1979 Sax and Lewis 1989 EPA 1985b Cowfer and Magistro 1983 Cowfer and Magistro 1983 NIOSH 1986 NIOSH 1986 NIOSH 1986 NIOSH 1986 R&S149154 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 4. PRODUCTION, IMPORT, USE, AND DISPOSAL 137 4.1 PRODUCTION Production of vinyl chloride monomer in the United States was approximately 13.75 billion pounds in 1993 (C&EN 1994; USITC 1994), an increase of nearly 22%. This exceeds the latest available U.S. estimated total production capacity figures (beginning of 1993) of 12.79 billion pounds at the beginning of 1993 (SRI 1993) and represents a substantial recent increase in production and capacity, even if vinyl chloride production is at full capacity. Previously, vinyl chloride production had grown only 1-5% per year over the last 5 years (C&EN 1994). Over the last 10 years, vinyl chloride production has grown at an average rate of about 7%, not including the large increase in 1993, although production volumes were fairly volatile (C&EN 1994). Vinyl chloride is currently produced in the United States by 10 companies at 12 facilities, which are as follows (SRI 1994): Westlake Monomers Corporation in Calvert City, Kentucky; Borden Chemicals and Plastics in Geismar, Louisiana; Dow Chemical in Oyster Creek, Texas, and in Plaquemine, Louisiana; Georgia Gulf Corporation in Plaquemine, Louisiana; PPG Industries in Lake Charles, Louisiana; Vista Chemical Company in Lake Charles, Louisiana; B.F. Goodrich Company in LaPorte, Texas: Formosa Plastics Corporation in Baton Rouge, Louisiana, and in Point Comfort, Texas; Occidental Chemical Corporation in Deer Park, Texas; and Oxymar in Ingleside, Texas. Table 4-1 summarizes the facilities in the United States that manufacture or process vinyl chloride. This information was obtained from the 1992 Toxic Chemical Release Inventory (TRI92), and it summarizes the reported release data for 1992 (TRI92 1994). Table 4-1 also lists the maximum amounts of vinyl chloride that are present at these sites and the end uses of the vinyl chloride. Vinyl chloride was first produced commercially in the 1930s by reacting hydrogen chloride with acetylene. Currently, vinyl chloride is produced commercially by the chlorination of ethylene through one of two processes, direct chlorination or oxychlorination. Direct chlorination reacts ethylene with chlorine to produce 1,2-dichloroethane. Similarly, oxychlorination produces 1,2-dichloroethane, but this is accomplished by reacting ethylene with dry hydrogen chloride and oxygen. After both processes, the 1,2-dichloroethane is subjected to high pressures (2.5-3.0 megapascals) and temperatures R&S149156 -- DRAFT FOR PUBLIC COMMENT*" PRODUCTION, IMPORT, USE, AND DISPOSAL " DRAFT FOR PUBLIC COMMENT' Table 4-1. Facilities That Manufacture or Process Vinyl Chloride Facility Location' Range of maximum amounts on site in pounds i Activities and uses KEYSOR-CENTURY CORP. UNION CARBIDE CORP. FORMOSA PLASTICS CORP. GEORGIA GULF CORP. WESTLAKE PVC CORP. UNION CARBIDE CHEMICALS BF GOODRICH CO. BORDEN CHEMICALS & PLASTICS BF GOODRICH CO. AIR PRODS. & CHEMICALS INC. WESTLAKE PVC CORP. WESTLAKE MONOMERS CORP. VULCAN MATERIALS CO. BORDEN CHEMICALS Sc PLASTICS PPG IND. INC. SAUGUS, CA TORRANCE, CA DELAWARE CITY, DELAWARE CITY, PACE, FL TUCKER, GA HENRY, IL DE DE 1,000,000-9,999,999 10,000-99,999 1,000,000-9,999,999 1,000,000-9,999,999 1,000,000-9,999,999 100,000-999,999 1,000,000-9,999,999 ILLIOPOLIS, IL LOUISVILLE, KY CALVERT CITY, KY CALVERT CITY, KY CALVERT CITY, KY GEISMAR, LA No Data 1,000,000-9,999,999 10,000-99,999 1,000,000-9,999,999 1,000,000-9,999,999 100,000-999,999 GEISMAR, LA No Data LAKE CHARLES, LA No Data CERTAINTEED CORP . VISTA CHEMICAL CO. FORMOSA PLASTICS CORP. SULPHUR, LA WESTLAKE, LA BATON ROUGE, LA 1,000,000-9,999,999 No Data 1,000,000-9,999,999 RHONE POULENC BASIC CHEMICALS DOW CHEMICAL CO., BATON ROUGE, LA PLAQUEMINE, LA 10,000-99,999 No Data As a reactant As a reactant As a reactant As a reactant As a reactant As a reactant As a reactant; As a product component As a reactant As a reactant As a reactant As a reactant Produce; For sale/distribution Produce; For on-siteuse/processing; As a by-product; As a reactant Produce; For on-site use/processing; For sale/ distribution; As a reactant Produce; For sale/distribution; As a by-product; As an impurity; As a reactant As a reactant Produce; For sale/distribution Produce; For on-site use/processing; For sale/distribution; As a by-product; As a reactant Ancillary uses ^ Produce; For sale/distribution; As a reactant; As a manufacturing aid; Ancillary uses < z-< nx o2 Dm isiensw PRODUCTION, IMPORT, USE. AND DISPOSAL DRAFT FOR PUBLIC COMMENT' Facility Table 4-1. Facilities That Manufacture or Process Vinyl Chloride (continued) Location3 Range of maximum amounts on site in pounds Activities and uses BF GOODRICH CO. GEORGIA GULF CORP. PLAQUEMINE, LA PLAQUEMINE, LA 100,000-999,999 No Data UNION CARBIDE CORP. MARINE SHALE PROCESSORS INC. OCCIDENTAL CHEMICAL CORP, DOW CHEMICAL USA MILES INC. VISTA CHEMICAL CO. OCCIDENTAL CHEMICAL CORP. BF GOODRICH CO. GOODYEAR TIRE & RUBBER CO. VYGEN CORP. BF GOODRICH AVON LAKE VISTA CHEMICAL CO. OCCIDENTAL CHEMICAL CORP. GREENWOOD PLATING DOW CHEMICAL CO. HAHNVILLE, LA AMELIA, LA ADDIS, LA MIDLAND, MI KANSAS CITY, MO ABERDEEN, MS BURLINGTON, NJ PEDRICKTOWN, NJ NIAGARA FALLS, NY ASHTABULA, OH AVON LAKE, OH OKLAHOMA CITY, OK POTTSTOWN, PA GREENWOOD, SC FREEPORT, TX No Data 1,000-9,999 100,000-999,999 100,000-999,999 100,000-999,999 No Data 1,000,000-9,999,999 1,000,000-9,999,999 100,000-999,999 100,000-999,999 1,000,000-9,999,999 1,000,000-9,999,999 1,000,000-9,999,999 1,000,000-9,999,999 No Data SHINTECH INC. FORMOSA PLASTICS CORP. FREEPORT, TX POINT COMFORT, TX No Data No Data UNION CARBIDE CHEMICALS & UNION CARBIDE CHEMICALS OCCIDENTAL CHEMICAL CORP. RHONE-POULENC BASIC CHEMICALS GARLAND, TX TEXAS CITY, TX LA PORTE, TX HOUSTON, TX 100,000-999,999 1,000,000-9,999,999 1,000,000-9,999,999 10,000-99,999 As a reactant Produce; For on-site use/processing; For sale/distribution; As a reactant As a by-product As a reactant As a reactant As a reactant; Ancillary uses As a reactant As a reactant As a reactant As a reactant As a reactant As a reactant As a reactant As a reactant As a reactant As a product component Produce; As a by-product; As an impurity; As a reactant; As a chemical processing aid Import; For on-site use/processing; As a reactant Produce; For on-site use/processing; As a by-product; As a reactant As a reactant As a reactant Ancillary uses Ancillary uses < z-i~< oX 5X o o(Oa estews^y Table 4-1. Facilities That Manufacture or Process Vinyl Chloride (continued) Facility OCCIDENTAL CHEMICAL CORP. BF GOODRICH CO. OCCIDENTAL CHEMICAL CORP. GEON CO. OCCIDENTAL CHEMICAL CORP. BONDCOTE CORP. Location3 PASADENA, TX DEER PARK, TX DEER PARK, TX LA PORTE, TX GREGORY, TX PULASKI, VA Range of maximum amounts on site in pounds No Data 1,000,000-9,999,999 No Data No Data No Data 100,000-999,999 i Activities and uses As a reactant As a reactant Produce; For sale/distribution Produce; For sale/distribution Produce; For sale/distribution As a formulation component Source: TRI92 1994 a Post office state abbreviation used < 2-< O XrOX~ om a PRODUCTION, IMPORT. USE, AND DISPOSAL DRAFT FOR PUBLIC COMMENT' 69t-6HS?d o VINYL CHLORIDE 4 PRODUCTION. IMPORT, USE. AND DISPOSAL 141 (550-550C). This causes the 1,2-dichloroethane to undergo pyrolysis, or thermal cracking, which forms the vinyl chloride monomer and hydrogen chloride. The vinyl chloride monomer is then isolated (Cowfer and Magistro 1985). The technical grade product is available in 99.9% purity (HSDB 1994). Efforts are being made to minimize by-product formation in 1,2-dichloroethane pyrolysis (Cowfer and Magistro 1985). 4.2 IMPORT/EXPORT Imports of vinyl chloride totaled 119 million pounds in 1992 and 164 million pounds in 1991 (CPS 1993). Imports have been steadily declining from a high of 302 million pounds in 1989, prior to which they had been increasing (CPS 1993). Exports of vinyl chloride were 1.63 billion pounds in 1992, down from the all time high of 1.78 billion pounds in 1991. Over the past 20 years, exports of vinyl chloride have fluctuated fairly widely, but have been generally increasing an average of about 17% per year since 1975. 4.3 USE Vinyl chloride is an important industrial chemical because of its wide variety of end-use products and the low cost of producing polymers from it. Furthermore, polyvinyl chloride (PVC) is one of the most efficient construction materials available when analyzed on an energy-equivalent basis (Cowfer and Magistro 1985). Major end-use products include PVC products, such as automotive parts and accessories, furniture, packaging materials, pipes, wall coverings, and wire coatings, as well as vinyl chloride-vinyl acetate copolymer products, such as films and resins (Cowfer and Magistro 1985; Eveleth et al. 1990), End-use data for 1992 indicate that 98% of vinyl chloride monomer production is for making polyvinyl chloride and various polyvinyl chloride copolymers; the other 2% is for miscellaneous uses (CPS 1993). Vinyl chloride has been used in the past as a refrigerant, as an extraction solvent for heat-sensitive materials, and in the production of chloroacctaldehyde and methyl chloroform (IARC 1979). In the United States, limited quantities of vinyl chloride were used as an aerosol propellant and as an ingredient of drug and cosmetic products; however, these practices were banned by the EPA in 1974 (IARC 1979; HSDB 1994). '"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 4.4 DISPOSAL 4. PRODUCTION, IMPORT, USE, AND DISPOSAL 142 Since vinyl chloride has been identified by EPA as a hazardous material, its disposal is regulated under the Federal Resource Conservation and Recovery Act (RCRA) (EPA 1993d). The transportation of hazardous materials for disposal is regulated by the Department of Transportation in compliance with this act (DOT 1993). The recommended method of disposal is total destruction by_incineration. The temperature of the incinerator must be sufficient to ensure the complete combustion of the vinyl chloride in order to prevent the formation of phosgene. The recommended temperature range for incineration is 450-1,600C, with residence times of seconds for gases and liquids, and hours for solids (HSDB 1994). If in solution, the vinyl chloride product may need to be adsorbed onto a combustible material prior to incineration. Recommended materials include vermiculite, sawdust, or a sand-soda ash mixture (90/10) covered with wood and paper (OHM/TADS 1985). The vinyl chloride can also be dissolved in a flammable solvent prior to incineration. An acid scrubber should be used in conjunction with the incinerator in order to remove any hydrogen chloride that is produced by the combustion process (HSDB 1994; OHM/TADS 1985). Alternatively, chemical destruction may be used, especially with small quantities. One-to-two days is generally sufficient for complete destruction (HSDB 1994). Aqueous by-product solutions from the production of vinyl chloride are usually steam-stripped to remove volatile organic compounds, neutralized, and then treated in an activated sludge system to remove nonvolatile organic compounds remaining in the waste water (Cowfer and Magistro 1983). R&S149161 '"DRAFT FOR PUBLIC COMMENT' VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 143 5.1 OVERVIEW Vinyl chloride has been identified in at least 493 of the 1,416 hazardous waste sites that have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 1995). However, the number of sites evaluated for vinyl chloride is not known. The frequency of these sites within the United States can be seen in Figure 5-1. Of these sites, 491 are located in the United States and 2 are located in the Commonwealth of Puerto Rico (not shown). Vinyl chloride is used almost exclusively in the United States by the plastics industry for the production of PVC and several copolymers. Anthropogenic sources are responsible for all of the vinyl chloride found in the environment. Most of the vinyl chloride released to the environment is eventually transported to the atmosphere, whereas lesser amounts are transported to groundwater. Vinyl chloride has been detected in the ambient air in the vicinity of vinyl chloride and PVC manufacturing plants and hazardous waste sites. The compound has also leached into groundwater from spills, landfills, and industrial sources. Effluents and emissions from vinyl chloride and PVC manufacturers are responsible for most of vinyl chloride released to the environment. When released to the atmosphere, vinyl chloride is expected to be removed by reaction with photochemically generated hydroxyl radicals (half-life = 1-2 days). Reaction products include hydrochloric acid, formaldehyde, formyl chloride, acetylene, chloroacetaldehyde, chloroacetylchloranil, and chloroethylene epoxide. In photochemical smog, the half-life of vinyl chloride is reduced to a few hours. When released to water, volatilization is expected to be the primary fate process. In waters containing photosensitizers, such as humic materials, sensitized photodegradation may also be important. When released to soil, vinyl chloride will either volatilize rapidly from soil surfaces or leach readily through soil, ultimately entering groundwater. Segments of the general population living in the vicinity of emission sources are exposed to vinyl chloride by inhalation of contaminated air. Average daily intake of vinyl chloride by inhalation for R & S 149162 "DRAFT FOR PUBLIC COMMENT*" FIGURE 5-1. FREQUENCY OF NPL SITES WITH VINYL CHLORIDE CONTAMINATION < 2 xn O3r3* O ' POTENTIAL FOR HUMAN EXPOSURE "DRAFT FOR PUBLIC COMMENT*" FREQUENCY It 4-4-MI 1 TO 10 SITES 30 TO 30 SITES ^Derived from HazDat 1995 e9i6nssa 11 TO 23 SITES AA TO AB SITES VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 145 these people ranges from trace amounts to 2,100 pg/day. The average daily intake of vinyl chloride by inhalation is expected to be essentially zero for the remainder of the population. The majority of the general population is not expected to be exposed to vinyl chloride through ingestion of drinking water. The average daily intake of vinyl chloride through diet is predicted to be essentially zero. Workers, particularly in plastic industries, are exposed to vinyl chloride mainly by inhalation, with some absorption through the skin possible. The National Occupational Exposure Survey, conducted by NIOSH from 1981 to 1983, estimated that 81,314 workers employed at 3,711 plant sites were potentially exposed to vinyl chloride (NOES 1990). 5.2 RELEASES TO THE ENVIRONMENT 5.2.1 Air The major source of vinyl chloride releases to the environment is believed to be emissions and effluents from plastic industries, primarily vinyl chloride and PVC manufacturers. Worldwide emissions of vinyl chloride into the atmosphere during 1982 totalled approximately 400 million pounds (Hartmans et al. 1985). Another emission source is tobacco smoke which has been found to contain 5.6-28 ng vinyl chloride per cigarette (Hoffman et al. 1976). According to TRI data for 1992 (TRI92 1994), an estimated total of 1.1 million pounds of vinyl chloride, amounting to 99.6% of the total environmental releases, was discharged to the air from the manufacturing and processing facilities in the United States in 1992 (Table 5-1). The TRI data should be used with caution because only certain types of facilities are required to report. This is not an exhaustive list. 5.2.2 Water Vinyl chloride released in waste water from the plastics industries is expected to volatilize fairly rapidly (on the order of hours to days) into the atmosphere. Another source of release to groundwater is the anaerobic reductive dehalogenation of 1,1,2-trichloroethylene, tetrachloroethylene, and 1,1,1trichloroethane to vinyl chloride at hazardous waste sites (Smith and Dragun 1984). Vinyl chloride leaches into groundwater from spills, landfills, and industrial sources (e.g., the plastics industry). According to data collected from the analysis of leachates and monitoring wells at sites where R&S149164 "DRAFT FOR PUBLIC COMMENT*" POTENTIAL FOR HUMAN EXPOSURE DRAFT FOR PUBLIC COMMENT' Table 5-1. Releases to the Environment from Facilities That Manufacture or Process Vinyl Chloride Reported amounts released in pounds per year State* City Facility Air Water Underground Total Land injection environment1. potrw transfer Of f-site waste transfer CA SAUGUS CA TORRANCE DE DELAWARE CITY DE DELAWARE CITY FL PACE GA TUCKER IL HENRY IL ILLIOPOLIS KY CALVERT CITY KY CALVERT CITY KY CALVERT CITY KY LOUISVILLE LA ADDIS LA AMELIA LA BATON ROUGE LA BATON ROUGE LA GEISMAR LA GEISMAR LA HAHNVILLE LA LAKE CHARLES LA PLAQUEMINE LA PLAQUEMINE LA PLAQUEMINE LA SULPHUR LA WESTLAKE MI MIDLAND MO KANSAS CITY MS ABERDEEN NJ BURLINGTON NJ PEDRICKTOWN NY NIAGARA FALLS OH ASHTABULA KEYSOR-CENTURY CORP. 875 UNION CARBIDE CORP. 19 FORMOSA PLASTICS CORP. 116,942 GEORGIA GULF CORP. 28,100 WESTLAKE PVC CORP. UNION CARBIDE CHEMICALS 10,745 17 BF GOODRICH CO. 42,000 BORDEN CHEMICALS & PLASTICS 71,74 0 AIR PRODS. & CHEMICALS INC. 137 WESTLAKE PVC CORP. 16,058 WESTLAKE MONOMERS CORP. 17,180 BF GOODRICH CO. 6,300 OCCIDENTAL CHEMICAL CORP. 14,100 MARINE SHALE PROCESSORS INC. 770 FORMOSA PLASTICS CORP. 26,170 RHONE POULENC BASIC CHEMICALS 210 VULCAN MATERIALS CO. 1,4 00 BORDEN CHEMICALS & PLASTICS 32,314 UNION CARBIDE CORP 56 PPG IND. INC. 14,900 DOW CHEMICAL CO. 4,900 BF GOODRICH CO. 4,300 GEORGIA GULF CORP. 35,100 CERTAINTEED CORP. 13,600 VISTA CHEMICAL CO. 13,057 DOW CHEMICAL USA 1,725 MILES INC. 926 VISTA CHEMICAL CO. 30,062 OCCIDENTAL CHEMICAL CORP 31,200 BF GOODRICH CO. 40,000 GOODYEAR TIRE & RUBBER CO. 74,509 VYGEN CORP. 44,400 1 25 23 6 148 6 21 2 250 5 1 40 41 14 250 875 19 116,942 28,101 10,745 17 42,025 71,763 137 16,058 17,180 6,300 14,406 770 26,318 210 1,406 1 32,336 56 14,900 4,902 4,550 35,100 13,605 13,058 1,725 926 30,102 31,241 40,014 74,509 44,650 20 5 336 64 303 1,097 12,670 340 3 1,040 31 72 12 65 13 345 21 10 < -< r OX ox om cn 05 S9t6nssd POTENTIAL FOR HUMAN EXPOSURE DRAFT FOR PUBLIC COMMENT' Table 5-1. Releases to the Environment from Facilities That Manufacture or Process Vinyl Chloride {continued} Reported amounts released in pounds per year State* City Facility Air Water Underground Total POTW Off-site Land injection environment1' transfer waste transfer OH AVON LAKE OK OKLAHOMA CITY PA POTTSTOWN SC GREENVJOOD TX DEER PARK TX DEER PARK TX FREEPORT TX FREEPORT TX GARLAND TX GREGORY TX HOUSTON TX LA PORTE TX LA PORTE TX PASADENA TX POINT COMFORT TX TEXAS CITY VA PULASKI BF GOODRICH AVON LAKE 12,800 VISTA CHEMICAL CO. 19,800 OCCIDENTAL CHEMICAL CORP. 100,861 GREENWOOD PLATING 2, 920 BF GOODRICH CO. 1, 539 OCCIDENTAL CHEMICAL CORP. 6, 900 DOW CHEMICAL CO. 14,960 SHINTECH INC. 32,089 UNION CARBIDE CHEMICALS & 8 OCCIDENTAL CHEMICAL CORP. 753 RHONE-POULENC BASIC CHEMICALS 5 OCCIDENTAL CHEMICAL CORP. GEON CO. 6,311 OCCIDENTAL CHEMICAL CORP. 92,400 FORMOSA PLASTICS CORP. 41,713 UNION CARBIDE CHEMICALS 23,975 BONDCOTE CORP. 10 Totals 1, 101,156 6 3,100 30 15 3 21 902 3,103 12,800 19,800 100,867 6,020 1,539 6,900 14,960 82,119 8 753 5 6,326 92,403 41,734 23,975 10 1 1,105,165 83 170 12 10 2,950 20,399 17 145,192 2 11,615 474 196,493 Source: TRI92 1994 ` Post office state abbreviations used b The sum of all releases of the chemical to air, land, water, and underground injection wells by a given facility POTW = publicly owned treatment works Z< 01 5 am cn 99L6HSSd "4 VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 148 groundwater was contaminated by municipal solid waste landfill leachate, vinyl chloride was present in both the leachates and the groundwater samples (Sabel and Clark 1984). According to TRI data for 1992 (TRI92 1994), an estimated total of 902 pounds of vinyl chloride, constituting less than 0.08% of the total environmental releases, was discharged to the water from the manufacturing" and processing facilities in the United States in 1992 (Table 5-1). The TRI data should be used with caution because only certain types of facilities are required to report. This is not an exhaustive list. 5.2.3 Soil Vinyl chloride can enter into the soil from leachates at hazardous waste sites and by underground injection. This release is, however, only a small fraction of the total environmental discharge. According to TRI data for 1992 (TRI92 1994), an estimated total of 3,107 pounds of vinyl chloride, amounting to less than 0.28% of the total environmental releases, was discharged to the soil from manufacturing and processing facilities in the United States in 1992 (Table 5-1). Among the total 1.1 million pounds of vinyl chloride discharged to the environment, only 1 pound was reported to have been injected to the underground. The TRI data should be used with caution because only certain types of facilities are required to report. This is not an exhaustive list. 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partitioning Based on a vapor pressure of 2,660 mmHg at 25C, essentially all vinyl chloride in the atmosphere is expected to exist in vapor form (Eisenreich et al. 1981; Verschueren 1983). Consequently, removal from the atmosphere by dry deposition is not expected to be an important fate process. The primary removal process for vinyl chloride from natural water systems is volatilization into the atmosphere. Henry's law constant value of 1.2 atm-m3/mol at 10C indicates that vinyl chloride should partition rapidly to the atmosphere. The half-life for vinyl chloride volatilization from a typical pond, river, and lake has been estimated to be 43.3, 8.7, and 34.7 hours, respectively. These values are based on an experimentally determined reaeration rate ratio of approximately 2 and assumed R&S149167 "DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE t 149 oxygen reaeration rates of 0.008, 0.04, and 0.01 per hour for a typical pond, river, and lake, respectively (EPA 1982a). Predicted half-lives should be considered rough estimates since the presence of various salts in natural water systems may affect the volatility of vinyl chloride significantly (EPA 1979d). Many salts have the ability to form complexes with vinyl chloride and can increase its water solubility; therefore, the presence of salts in natural waters may significantly influence the amounT of vinyl chloride remaining in the water (EPA 1979d). The relatively high vapor pressure of vinyl chloride indicates that the compound volatilizes quite rapidly from dry soil surfaces (Verschueren 1983). The effective half-life (due to volatilization and degradation) of vinyl chloride placed 10 cm deep in dry soil is predicted to be 12 hours (Jury et al. 1984). Vinyl chloride is soluble in water and thus can leach through the soil and travel to groundwater before evaporation can occur (Cowfer and Magistro 1983). Experimental data regarding adsorption of vinyl chloride to soil were not located. Based on the regression equations given by Lyman et al. (1982), Sabljic (1984), and Kenaga and Goring (1980), the soil organic carbon adsorption coefficient (KM) for vinyl chloride was estimated to range from 14 to 131. These KM values suggest a very low sorption tendency, meaning that this compound would be highly mobile in soil. Thus, vinyl chloride has the potential to leach into groundwater. Vinyl chloride is soluble in most common organic solvents (Cowfer and Magistro 1983). In situations where organic contaminants exist in relatively high concentrations (e.g., landfills, hazardous waste sites), cosolvation of vinyl chloride could have the effect of reducing its volatility, thus causing it to have even greater mobility than indicated by estimated K^, values. Vinyl chloride's high vapor pressure and low octanol/water partition coefficient (log Kow = 1.23) indicates that it bioaccumulates to a very limited extent (EPA 1982a). The bioconcentration factor (BCF) of an organic chemical can be estimated from the Kow or water solubility. Based on the regression equation given by Veith et al. (1980), the estimated BCF of 5.1 indicates limited bioconcentration in aquatic organisms. Freitag et al. (1985) measured BCFs in algae, fish, and activated sludge. The BCFs for algae, fish, and activated sludge were 40, less than 10, and 1,100, respectively. The very low value for fish, in comparison to the algae and activated sludge, may suggest a detoxification process in higher developed organisms such as fish. Lu et al. (1977) examined the bioaccumulation of l4C-vinyl chloride in a closed model aquatic ecosystem over a 3-day R & S 149168 '"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 150 period. The high volatility of vinyl chloride minimized any potential bioaccumulation. Relatively low tissue concentrations found in fish suggested that vinyl chloride is not biomagnified in aquatic food chains to any substantial degree. 5.3.2 Transformation and Degradation 5.3.2.1 Air Reaction of vinyl chloride vapor with photochemically generated hydroxyl radicals is predicted to be the primary degradation mechanism for this compound in the atmosphere (Cox et al. 1974; Howard 1976; Perry et al. 1977). Products of this reaction are hydrochloric acid, formaldehyde, formyl chloride, carbon monoxide, carbon dioxide, chloroacetaldehyde, acetylene, chloroethylene epoxide, chloroacetylchloranil, and water (Muller and Korte 1977; Woldbaek and Klaboe 1978). Under conditions of photochemical smog, the half-life of vinyl chloride would be reduced to a few hours (Carassitti et al. 1977). Reaction with ozone and direct photolysis are less important degradation mechanisms of vinyl chloride in the atmosphere (EPA 1976a, 1985c; Zhang et al. 1983). Vinyl chloride in the vapor phase does not absorb light of wavelengths above 220 nm; therefore, direct photolysis will not occur in the atmosphere (EPA 1976a). 5.3.2.2 Water The primary removal process for vinyl chloride from surface waters is volatilization into the atmosphere. Vinyl chloride in water does not absorb ultraviolet radiation above 218 nm; therefore, direct photolysis in the aquatic environment is expected to be a slow process (EPA 1976a). No photolysis occurred over a 90-hour period. In waters containing photosensitizers, such as humic materials, photodegradation may be fairly rapid. If so, in some waters, sensitized photodegradation may also be an important removal mechanism (EPA 1976a). The hydrolytic half-life of vinyl chloride has been estimated to be less than 10 years at 25C (EPA 1976a). Since the volatilization rate of vinyl chloride is much more rapid than the predicted rate of hydrolysis, hydrolysis is not a significant aquatic fate (EPA 1976a, 1979d). Vinyl chloride is not oxidized chemically by reaction with photochemically generated molecular oxygen in natural water systems (EPA 1976a). Experiments carried out at 20 mg/L vinyl chloride in water saturated with R&S149169 `DRAFT FOR PUBLIC COMMENT' VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 151 molecular oxygen at elevated temperatures showed that after 12 hours at 85C, no degradation of vinyl chloride could be detected. At temperatures and oxygen concentrations in natural waters, therefore, vinyl chloride will not be degraded by molecular oxygen at a significant rate (EPA 1976a). The limited amount of existing data indicates that vinyl chloride is resistant to microbial degradation. EPA (1976a) found that an isolated microbial culture containing two species of bacteria and three, mixed fungal populations was unable to biodegrade vinyl chloride over a 5-week period at concentrations of 20-120 mg/L (20-120 ppm). EPA (1977) observed no change in the biochemical oxygen demand in raw sewage seed (used as a microbial inoculum) and raw sewage seed plus vinyl chloride at 20C over a 25-day period. The authors interpreted this to mean that no biodegradation of vinyl chloride occurred. 5.3.2.3 Sediment and Soil The majority of vinyl chloride present on soil surfaces will volatilize to the atmosphere. Vinyl chloride is also mobile in soil and susceptible to leaching (Lyman et al. 1982). The presence of other organic solvents, such as those found at hazardous waste sites, may affect the mobility of the substance in the soil (Cowfer and Magistro 1983). Photodegradation on the surface of soils is expected, since sensitized photodegradation in water occurs. Several laboratory studies have indicated that both aerobic and anaerobic biodegradation of vinyl chloride can occur in soils and aquifer materials via a number of mechanisms (Barrio-Lage et al. 1990; Davis and Carpenter 1990; Castro et al. 1992a, 1992b), although these degradation precesses were generally slow. More recently, Nelson et al. (1993) investigated methanotrophic degradation of vinyl chloride using a laboratory-scale methanotrophic attached-film, expanded-bed bioreactor and found that this technique is an efficient way to degrade vinyl chloride, with the removal efficiency greater than 90%. '"DRAFT FOR PUBLIC COMMENT*" TJ 9M VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air 152 Air in rural/remote and urban/suburban areas of the United States typically contains no detectable amount of vinyl chloride (EPA 1982f; Grimsrud and Rasmussen 1975a, 1975b; Harkov et al. 1984; Stephens et al. 1986; Wallace et al. 1984). Limited monitoring data indicate that in areas near vinyl chloride and PVC manufacturing facilities, the concentration of vinyl chloride in air typically ranges from trace levels to 105 pg/m3 (0.041 ppm) (EPA 1979a, 1982f; Gordon and Meeks 1977), but may exceed 2,600 pg/m3 (1 ppm) (Fishbein 1979). Elevated levels of vinyl chloride may also be found in the vicinity of hazardous waste sites and municipal landfills. Concentrations ranging from below detection limits to 5-8 pg/m3 (0.002-0.003 ppm) have been measured in the air above some landfills (Baker and Mackay 1985; Stephens et al. 1986). Homes near one hazardous waste site in southern California were found to contain levels as high as 1,040 pg/m3 (0.4 ppm) (Stephens et al. 1986) and homes near another site between 1 and 9 ppb (Miller and Beizer 1985). Gaseous emissions from 20 Class II (nontoxic) landfills in southern California were analyzed for vinyl chloride (Wood and Porter 1987). Vinyl chloride was found in emissions from 85% of the landfills tested, and concentra tions greater than 2,600 pg/m3 (I ppm) were detected in more than half of the landfill emissions. The concentration of vinyl chloride measured in this study ranged from 0.624 to 114.4 mg/m3 (0.24 to 44 ppm). Based on their observations, the authors concluded that the presence of vinyl chloride at these landfills was due to either illegal disposal or in situ generation by the degradation of chlorinated - solvents by bacteria and other microbes (Wood and Porter 1987). 5.4.2 Water Vinyl chloride has been detected at varying concentrations in surface water, groundwater, and drinking water throughout the United States. Concentrations of vinyl chloride in drinking water wells and surface water in New York State were found to be 50 pg/L (0.05 ppm) and 10 pg/L (0.01 ppm), respectively (Burmaster 1982). Monitoring studies in nine states have identified concentrations as high as 380 pg/L (0.38 ppm) in groundwater (Dyksen and Hess 1982). The level of vinyl chloride in groundwater in the United States was determined during the 1982 EPA Groundwater Supply Survey (Westrick et al. 1984). Water supplies from 945 sites throughout the R&S149171 --DRAFT FOR PUBLIC COMMENT*" * _#  VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 153 United States were studied. Vinyl chloride was positively identified in only 0.74% of the 945 groundwater supplies (detection limit 0.001 ppm). It was reported that 0.5% of 186 random sample sites and 3.8% of 158 nonrandom sample sites contained detectable levels of vinyl chloride. The maximum concentrations at the random and nonrandom sites were 1.1 pg/L (0.0011 ppm) and 8.4 pg/L (0.0084 ppm), respectively (Westrick et al. 1984). Approximately half of the samples were taken from a random list of water systems, which were subdivided into two sets of systems--those serving fewer than 10,000 people and those serving more than 10,000 people. The nonrandom samples were taken from systems selected by the states, using groundwater sources that were likely to show volatile organic compounds in drinking water (Westrick et al. 1984). Other studies have reported the occurrence of vinyl chloride in groundwater samples collected throughout the United States at levels at or below 380 pg/L (0.38 ppm) (Cotruvo 1985; EPA 1982f; Goodenkauf and Atkinson 1986; Stuart 1983). 5.4.3 Sediment and Soil Monitoring data for vinyl chloride in soil were not located in the available literature. 5.4.4 Other Environmental Media In the past, vinyl chloride has been detected in various foods and bottled drinking water as a result of migration from PVC food wrappings and containers (Benfenati et al. 1991; Gilbert et al. 1980). Vinyl chloride has been found in vinegar at levels up to 98,000 pg/L (9.8 ppm), in edible oils at 300-1,800 pg/L (0.3-18.0 ppm), and in alcoholic beverages at 0.0-8,400 pg/L (0.0-8.4 ppm) when these foods were packaged and stored in PVC containers (Williams 1976; Williams and Miles 1975). Current data on levels of vinyl chloride in different foods were not located. At present, FDA regulates the use of PVC polymers in food packaging materials and the amount of residual monomer in polymers. In a modeling study on the migration of vinyl chloride from PVC which used liquid chromatography to simulate migration conditions in actual food packaging and storage, results revealed that at the very low concentrations (less than 1 ppm) of residual vinyl chloride monomer in PVC packaging material, "essentially zero" migration of the vinyl chloride monomer into foods occurs (Kontominas et al. 1985). Vinyl chloride levels were determined in Italian drinking water bottled in PVC; levels ranged from 13 to 83 ppt (mean 48 ppt) (Benfenati et al. 1991). It was also determined R&S149172 --DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 154 that there was a progressive migration of vinyl chloride from the bottle to the water, which occurred at a rate of 1 ng/L/day (Benfenati et al. 1991). Vinyl chloride has been detected in drinking water. A study by EPA (19820 estimated that 12 of 11,202 public_water supplies that used surface water as their primary source had levels of vinyl chloride between 1.0 and 5.0 pg/L; none had levels above 5 pg/L. Another study found"that drinking water that ran through PVC pipes contained vinyl chloride at 1.4 pg/L (0.0014 ppm), whereas water that ran through a PVC system 9 years older contained 0.03-0.06 pg/L (3x10 s-6xl0'5 ppm) (Dressman and McFarren 1978). The migration of vinyl chloride from rigid PVC water pipes into drinking water was directly proportional to the residual level of vinyl chloride in the pipe itself. Current data on levels of vinyl chloride in drinking water and on the potential for leaching of vinyl chloride monomer from PVC pipes were not located. Under certain test conditions, vinyl chloride monomer in drinking water reacts with chlorine and is converted to chloroacetaldehyde and chloroacetic acid (Ando and Sayato 1984). Information concerning the effect of this reaction on drinking water supplies that are pretreated with chlorine and the extent of this reaction were not stated. During an EPA study, detectable levels of vinyl chloride monomer (detection limit 0.05 ppm) were found in indoor air samples taken from two of seven new 1975 model cars. Levels of vinyl chloride in indoor air in the two cars ranged from 400 to 1,200 pg/L (0.4 to 1.2 ppm). Ventilation of the car interiors led to the dissipation of vinyl chloride. The cars involved in the study had a high ratio of plastic to interior volume and were expected to provide worst-case concentrations for vinyl chloride in interior car air (EPA 1976b). Because of the limited nature of these data and the fact that this study is somewhat dated, no conclusions can be drawn regarding levels of vinyl chloride monomer in interior air of cars currently being produced. Vinyl chloride has been detected in tobacco smoke. Cigarette smoke and small cigar smoke have been found to contain 5.6-27 ng vinyl chloride per cigarette (Hoffman et al. 1976). 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE Inhalation is the most probable route of exposure for the general population. Typical values for the average daily intake of vinyl chloride by inhalation in urban/suburban and rural/remote areas have been estimated to be essentially zero. Assuming that the average adult intake of air is 20 m3/day, the R & S 1 4 9 1 73 --DRAFT FOR PUBLIC COMMENT"* . VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 155 average daily intake of vinyl chloride by people living in the vicinity of emission sources has been estimated to range from trace amounts to 2,100 pg (EPA 1979a, 1982f; Gordon and Meeks 1977). The majority of drinking water supplies in the United States contain no detectable levels of vinyl chloride (EPA 1982f; Westrick et al. 1984). Based on this conclusion, it is estimated that the average daily intake of vinyl cjiloride by ingestion of drinking water for most people in the United States is essentially zero (at or below 0.028 pg/kg/day [EPA 1982f]). Estimates provided by EPA (1985b) indicate that 0.9% of the U.S. population is exposed to levels of vinyl chloride in drinking water greater than or equal to 1.0 pg/L, and 0.3% of the population is exposed to levels greater than 5 pg/L. The National Occupational Exposure Survey (NOES), conducted by NIOSH from 1981 to 1983, estimated that 81,314 workers employed at 3,711 plant sites were potentially exposed to vinyl chloride in the United States (NOES 1990). The NOES database does not contain information on the frequency, concentration, or duration of exposure; the survey provides only estimates of workers potentially exposed to chemicals in the workplace. Exposure is believed to occur primarily through inhalation with some possible absorption through the skin (Sittig 1985). 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES Individuals located near or downwind of production facilities, hazardous waste disposal sites, and landfills may potentially be exposed to higher than background ambient atmospheric levels of vinyl chloride. For specific levels associated with health effects, see Section 2.7. Individuals living near hazardous waste sites and landfills may also be exposed to vinyl chloride in their drinking water. Workers involved in the production or polymerization of vinyl chloride may constitute a group at risk because of the potential for occupational exposure. 5.7 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of vinyl chloride 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 vinyl chloride. R&S149174 "'DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 156 The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 5.7.1 Identification of Data Needs Physical and Chemical Properties. The physical and chemical properties of vinyl chloride are sufficiently well characterized to permit estimation of its environmental fate (Amoore and Hautala 1983; Cowfer and Magistro 1983; EPA 1985b; Fire 1986; HSDB 1994; IARC 1979; Lyman et al. 1982; Sax and Lewis 1989). Production, Import/Export, Use, Release, and Disposal. According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit substance release and off-site transfer information to the EPA. The Toxics Release Inventory (TRI), which contains this information for 1992, became available in May of 1994. This database will be updated yearly and should provide a list of industrial production facilities and emissions. Vinyl chloride is released primarily to the atmosphere via emissions from vinyl chloride and PVC manufacturing facilities (Hartmans et al. 1985; SRI 1990a, 1990b, 1993, 1994; TRI92 1994). The risk of exposure to vinyl chloride is highest for workers in the plastics industry and populations living near industrial areas or hazardous waste sites. Current production, use, and manufacturing methods are well described in the literature (Cowfer and Magistro 1985; Eveleth et al. 1990; HSDB 1994; IARC 1979; SRI 1990a, 1990b, 1993, 1994; TRI92 1994; USITC 1994). More current information on releases and disposal methods might assist in estimating potential exposures to vinyl chloride, particularly for populations living near hazardous waste sites. Environmental Fate. Vinyl chloride is transported in and partitioned to the air and water and is also partitioned to air from water (EPA 1982a). Experimental data regarding the partitioning of vinyl chloride to soil are needed. Vinyl chloride is transformed in the atmosphere by photooxidation (Carassiti et al. 1978; Cox et al. 1974; EPA 1976a; 1985c; Howard 1976; Muller and Korte 1977; --DRAFT FOR PUBLIC COMMENT"* , - VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 157 Perry et al. 1977; Woldbaeck and Klaboe 1978; Zhang et al. 1983). It is removed from surface water and groundwater mainly by volatilization and photodegradation (EPA 1976a). Information regarding the transformation and degradation in soil would be helpful in defining the potential pathways for human exposure. Bioavailability from Environmental Media. Vinyl chloride can be absorbed following inhalation (Bolt et al. 1977; Krajewski et al. 1980; Withey 1976), oral (Feron et al. 1981; Watanabe et al. 1976a; Withey 1976), and, to a much lesser extent, dermal exposure (Hefner et al. 1975a). These routes of exposure may be of concern to humans because of the potential of vinyl chloride to contaminate air (Baker and MacKay 1985; EPA 1979a; Fishbein 1979; Gordon and Meeks 1977; Stephens et al. 1986; Wood and Porter 1987), water (Burmaster 1982; Cotruvo 1985; Dyksen and Hess 1982; Goodenkauf and Atkinson 1986; Stuart 1983; Westrick et al. 1984), and food (Gilbert et al. 1980; Williams 1976; Williams and Miles 1975). Information regarding the bioavailability from ingestion and dermal contact of contaminated soils would be helpful, particularly for populations living near hazardous waste sites, although vinyl chloride is not believed to be absorbed through skin. Food Chain Bioaccumulation. Vinyl chloride can bioconcentrate to a limited extent in aquatic organisms (EPA 1982; Freitag et al. 1985). Biomagnification of vinyl chloride in terrestrial and aquatic food chains does not appear to be important because of its high volatility and the fact that it is readily metabolized by higher-trophic-level organisms (Freitag et al. 1985; Lu et al. 1977). No data were located regarding biomagnification in terrestrial foodchains. Exposure Levels in Environmental Media. Reliable monitoring data for the levels of vinyl chloride in contaminated media at hazardous waste sites are needed so that the information obtained on levels of vinyl chloride in the environment can be used in combination with the known body burden of vinyl chloride to assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. Vinyl chloride has been detected in air (Baker and Mackay 1985; EPA 1979a; Fishbein 1979; Gordon and Meeks 1977; Stephens et al. 1986; Wood and Porter 1987), water (Burmaster 1982; Cotruvo 1985; Dyksen and Hess 1982; Goodenkauf and Atkinson 1986; Stuart 1983; Westrick et al. 1984), sediment (Wang et al. 1985), and food (Gilbert et al. 1980; Williams 1976; Williams and Miles 1975). Intake data for the general population from the various media are available (EPA 1979a, 1985b; Gordon and Meeks 1977; Westrick et al. 1984). Data on levels of vinyl chloride in soils are needed. Site-specific data on concentrations of vinyl chloride in air, soil, and water would R&S149176 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 158 be helpful in estimating the risk of exposure for populations living in the vicinity of hazardous waste sites. Also, current data on the extent of release (if any) of vinyl chloride from PVC pipes and from car interiors are needed to estimate the risk of exposure of the general population. Exposure Levels in Humans. This information is necessary for assessing the need to conduct health studies on these populations. Vinyl chloride has been detected in human tissues and fluids as a result of occupational exposure to the substance. No information on biological monitoring studies for the general population was located. More information on exposure levels for populations living in the vicinity of hazardous waste sites would be helpful. Exposure Registries. No exposure registries for vinyl chloride 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. 5.7.2 On-going Studies Dr. S. Fogel (Cambridge Analytical Association) is examining the feasibility of in situ biodegradation of chlorinated ethenes, specifically vinyl chloride, in contaminated drinking water aquifers. Three microbiological processes have been identified with a high probability of achieving the complete biodegradation of vinyl chloride. The results may enable the design of a specific aquifer restoration plan in which the subsurface environment is modified to create a microbiological barrier across the path of an approaching contaminant plume. After isolating methane-utilizing bacteria that can also degrade vinyl chloride. Dr. Fogel will perform chemical analysis of the methantrophic degeneration products of certain contaminants to determine whether toxic by-products are formed. In addition, he is also working with a laboratory-scale treatment column to use the methantrophic organisms for the removal of chlorinated aliphatics from wastewater (FEDRIP 1994).I. I. Hertz-Piccioto (University of North Carolina at Chapel Hill) is examining vinyl chloride in relation to the ability to generalize soil dispersion and biodegradation models and persistence in the environment (FEDRIP 1994). Models developed for the evaluation of biotransformation and soil "'DRAFT FOR PUBLIC COMMENT'" VINYL CHLORIDE 5. POTENTIAL FOR HUMAN EXPOSURE 159 dispersion are expected to be used in conjunction with epidemiological studies of populations with potential for exposure (FEDRIP 1994). James Swenberg (University of North Carolina at Chapel Hill) is investigating the hydrogeological and ecological factors contributing to variability in human population exposure to vinyl chloride (FEDRIP 1994). Microbial transformations that can affect toxicity and mobility of chemicals, such as vinyl chloride, in the subsurface environment will be examined. Multicomponent, multiphase flow and transport processes in subsurface systems will also be investigated. The U.S. Department of Agriculture is funding investigations by R. Spalding and A. Drexner (University of Nebraska Water Research Center) on the remediation of vinyl chloride using small aerosols (FEDRIP 1994). The ultimate aim of the study is to determine whether sprinkler irrigation is an effective remediation technique for groundwater contaminated by vinyl chloride (FEDRIP 1994). R&S149178 DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 6. ANALYTICAL METHODS 161 The purpose of this chapter is to describe the analytical methods that are available for detecting, measuring, and/or monitoring vinyl chloride, its metabolites, and other biomarkers of exposure and effect to vinyl chloride. 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 may be included that modify previously used methods to obtain lower detection limits and/or to improve accuracy and precision. 6.1 BIOLOGICAL MATERIALS The analytical method used to analyze for the presence of vinyl chloride in biological media is separation by gas chromatography (GC) combined with detection by mass spectrometry (MS), flame ionization detector (FID), or electron capture detector (ECD). Vinyl chloride and/or its metabolite, thiodiglycolic acid, have been detected in breath, urine, blood, and tissues. Breath samples can be preconcentrated by cryogenic trapping. The two methods most commonly used to prepare liquid and solid samples are preconcentration by a purge-and-trap technique or headspace analysis. Preconcentration not only increases the sensitivity but, in certain instances, may decrease the sample separation time prior to quantitation. Details of commonly used analytical methods for several types of biological media are presented in Table 6-1. Vinyl chloride was determined in exhaled air by preconcentration with a multistage cryogenic trapping system followed by thermal desorption using GC/FID, GC/ECD, and GC/MS (Conkle et al. 1975). Sensitivity is in the low-ppb range. The authors noted that the reproducibility of the subject/sampling system was inconclusive. The quantitative data reflected considerable scatter, apparently indicating the R&S149180 "DRAFT FOR PUBLIC COMMENT*** ANALYTICAL METHODS DRAFT FOR PUBLIC COMMENT' TABLE 6-1. Analytical Methods for Determining Vinyl Chloride in Biological Materials Sample matrix Breath Breath Urine Urine Preparation method Analytical method Sample detection limit Percent recovery Breath collected in pipets lined with Saran film; direct injection into gas chromatograph GC/FID a Cryogenic trapping of expired air; thermal desorption into gas chromatograph GC/FID, GC/ECD, and GC/MS Acidified and desiccated overnight; add methanol; derivatize with diazomethane; add ionexchange resin GC/MS Internal standard added to urine; acidification and ethyl acetate extraction; evaporation of solvent; addition of A'-trimethylsilyldiethylamine in pyridine (1:1);' injection into gas chromatograph GC/FID, GC/MS NR NR NR NR 50 ng/mL NR 10 mg/L NR , Reference Baretta et ai. 1969 Conkle et al. 1975 Muller et al. 1979 Draminski and Trojanowska 1981 < Z -< oXl~ o5 m tstens^y s ::: TABLE 6-1. Analytical Methods for Determining Vinyl Chloride in Biological Materials (continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Blood and tissues Extraction in ethanol-water mixture, incubation, injection into gas chromato graph. Tissue preparation also includes freezing and homogenization before the extraction procedure GC/FID 5 ng/mL blood 75-79% blood 30 ng/g tissue 76-92% tissue Reference ^ Zuccato et al. 1979 GC/ECD = gas chromatography/electron capture detector; GC/FID = gas chromatography/flame ionization detector; GC/MS - gas chromatography/mass spectrometry; NR = not reported ANALYTICAL METHODS DRAFT FOR PUBLIC COMMENT' zstens'sa 8 VINYL CHLORIDE 6. ANALYTICAL METHODS 164 variability of the biological system and the trace nature of the compound. The additional requirement for long-term coupling (30-60 minutes) of the sampling system to the subject probably limits the method to industrial health applications, with relatively robust subjects (Conkle et al. 1975). Baretta et al. (1969) monitored exposure to vinyl chloride through breath analysis. The breath samples were collected in pipets with plastic caps lined with six layers of Saran film identical to that used for the construction of Saran air sampling bags. Aliquots were drawn from the pipets and injected directly into a gas chromatograph equipped with FID. Detectability of vinyl chloride in the exhaled air by this method becomes limited when air concentrations in the workplace are below 50 ppm. Vinyl chloride has been measured in rat blood and tissues using headspace GC/FID (Zuccato et al. 1979). In headspace analysis, the gaseous layer above the sample is injected into the gas chromatograph. Sample preparation steps for rat blood and tissues involve extraction in an ethanolwater mixture, incubation, and direct injection into the gas chromatograph. Sample preparation for tissues includes an extra step involving freezing and homogenization before the extraction procedure. Accuracy varied, ranging from about 75% to 92% recovery. The method is sensitive to 5 ng/mL vinyl chloride in blood and 30 ng/g in tissues. Muller et al. (1979) employed GC/MS as a selective biomonitoring method for the quantitative measurement of thiodiglycolic acid, a urinary metabolite of vinyl chloride. They reported a sensitivity of 50 ng/mL. Precision was generally good. The authors noted that some thiodiglycolic acid has been found in supposedly unexposed subjects. Therefore, exposure to low levels of vinyl chloride could be masked by background metabolic levels within normal limits. This may limit the application of biological monitoring for the measurement of vinyl chloride following low-level exposure (Muller et al. 1979; van Sittert and de Jong 1985). In a study by Jedrychowski et al. (1984), urinary excretion of thiodiglycolic acid was determined using GC/FID. The urine was extracted twice with ethyl acetate prior to analysis. No recovery data were given for this method. 6.2 ENVIRONMENTAL SAMPLES Analysis of environmental samples is similar to that of biological samples. The most common methods used to detect vinyl chloride in environmental samples are GC/MS, GC/ECD, and GC/FID. Preconcentration of samples is usually done by sorption on solid sorbent for air and by the purge-and-trap method for liquid and solid matrices. Alternatively, headspace above liquid and solid R&S149183 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 6. ANALYTICAL METHODS 165 samples may be analyzed without preconcentration. Details of commonly used analytical methods for several types of environmental samples are presented in Table 6-2. The primary method of analyzing vinyl chloride in air is GC combined with either MS, ECD, or FID. Air samples are usually pumped through a sample collection column with Tenax-GC, coconut activated charcoal, or spherocarb (a carbon molecular sieve material) as the most common adsorbents. Several authors have noted that Tenax-GC displays poor retention for vinyl chloride when the compound is present in the very low-ppb range (Bozzelli and Kabbekus 1979; Krost et al. 1982; McMurry and Tarr 1978). Vinyl chloride is thermally desorbed from the collection column and concentrated on a cryogenic trapping column located on the gas chromatograph. Vapors are heatreleased from the trapping column directly to the gas chromatograph (Bozzelli and Kabbekus 1979; Krost et al, 1982). Grab samples of air can also be obtained and preconcentrated on a cryogenic column (Rasmussen et al. 1977). The limit of detection for GC/MS and GC/ECD is in the sub-ppb range (Bozzelli and Kabbekus 1979; Harsch et al. 1979; Krost et al. 1982; Rasmussen et al. 1977). Accuracy is generally good (Bozzelli and Kabbekus 1979). With careful technique, precision is adequate, ranging from 5% to 20% (Bozzelli and Kabbekus 1979; McMurray and Tarr 1978). Trace amounts of vinyl chloride in air and water were detected employing GC/ECD after derivatization to 1,2-dibromochloroethane (Wittisiepe et al. 1990, 1993). Air samples were taken by drawing a known volume directly through an ice-cooled adsorption tube. Water samples were purged with an inert gas before being drawn through the adsorption tube. The tubes were eluted with carbon disulfide, and the vinyl chloride was derivatized with bromine water to form 1,2-dibromochloroethane. This derivatization technique is used for enhancement of sensitivity with GC/ECD. The derivative was determined by capillary GC with ECD. The detection limits for air and water samples are 50 ng/m1 and 0.4 ng/L (0.4 parts per trillion), respectively. Results from recovery experiments with dosed water indicated that accuracy was good. Vinyl chloride can be detected in drinking water, groundwater, waste water, and leachate from solid waste. Analysis of vinyl chloride is done by purge-and-trap or headspace GC. The primary analytical method is separation by GC combined with MS, ECD, FID, Hall's electrolytic conductivity detector (HECD), or another type of halogen specific detector (HSD). In most methods, vinyl chloride is R&S149184 '"DRAFT FOR PUBLIC COMMENT*** ANALYTICAL METHODS DRAFT FOR PUBLIC COMMENT TABLE 6-2. Analytical Methods tor Determining Vinyl Chloride in Environmental Samples Sample matrix Preparation method Analytical method Occupational air Ambient indoor and outdoor air Air Air Vinyl chloride in air adsorbed in activated carbon trap and desorbed by carbon disulfide GC/FID Air containing vinyl chloride passed through activated carbon trap and desorbed by dichloromethane or carbon GC/FID Adsorption on Tenax-GC, or SKC Carbon, then thermal desorption GC/MS Air prefiltered by NajSjOj-treated glass fiber filter was passed through spherocarb - adsorbent cartridge and thermally desorbed GC/FID, GC/MS, GC/ECD i Sample detection limit 0.04 pg per sample Percent recovery 94% 1-64 mg/m3 5 ppb NR 0.33 ppb NR 0.005 ppb NR : Reference NIOSH 1994 IARC 1978 Krost et al. 1982 Harkov et al. 1983, 1984 l < Z-< r~ O Xr~ O5 o OO)) ANALYTICAL METHODS DRAFT FOR PUBLIC COMMENT' TABLE 6-2. Analytical Methods for Determining Vinyl Chloride in Environmental Samples (continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference < Z-< 01 o X Dm Automobile exhaust Air Air Air Drinking water Exhaust samples contained in aluminized plastic bags 1 GC/FID Trapped in cold Tenax-GC trap; thermal desorption GC/FID Sample collected in pressurized canister is passed through a freezeout loop and subsequently heated GC/ECD Sample collected in polyester-coated plastic bags concentrated by freezeout and subsequently heated GC/FID Samples collected in serum reaction bottles; purge and trap technique GC/HSD, GC/MS 0.02 ppm NR 0.01 ppb 0.4 ppb NR NR 89.6% at 6 ppb; 100% at 60 ppb NR NR NR Hasanen et al. 1979 Ives 1975 CD Harsch et al. 1979; Rasmussen et al. 1977 McMurray and Tarr 1978 Dressman and McFarren 1978 gsieHS'SH ANALYTICAL METHODS DRAFT FOR PUBLIC COMMENT TABLE 6-2. Analytical Methods for Determining Vinyl Chloride in Environmental Samples (continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery 1 Reference Drinking water and waste water Groundwater, liquid, and solid matrices Water Drinking water Migration of monomer into drinking water from PVC pipes Purge and trap in ' Tenax-GC; thermal desorption GC/HSD, GC/MS (EPA Methods 601 and 624) Purge at 45C and trap in Tenax-GC; thermal desorption GC/HSD (EPA Method 8010) Purge into Carbosieve'v S III; desorption with CS2 and bromine derivation GC/ECD Purge and trap in Tenax-GC; thermal desorption GC/Hail detector, GC/PID (EPA Methods 502.2 and 524.2) Small sections put in water in sealed serum vial for a number of days at 20C; solution directly injected into gas chromatograph GC/FID 0.18 ppb (HSD) 0.18 ppb 0.4 ng/L 0.04 ppb (Hall detector); 0.02 ppb (PID) NR 102% at 0.8-32.3 ppb 102% at 0.82-32.3 ppb 98.9% at 6.25 ng/L62.5 pg/L 100-119% at 5-10 ppb NR APHA 1985; EPA I982d EPA 1982e Wiltsiepe et al. 1993 Reding 1987 Ando and Sayato 1984 V Z8L6t'iS'SfH i. ANALYTICAL METHODS DRAFT FOR PUBLIC COMMENT TABLE 6-2. Analytical Methods for Determining Vinyl Chloride in Environmental Samples (continued) Sample matrix Preparation method Analytical method Water Landfill gas Sediment and oyster Sample in seated vial is equilibrated at constant temperature; headspacd gas injected into gas chromatograph GC/F1D Gas from landfill sites sampled by PTFE tubing inside drive-in piezometers was adsorbed in Tenax-GC or Porapak, a sorbent; trapped sample desorbed and concentrated in liquid N2-cooled loop and flash desorbed GC/MS Homogeneous sample mixed with water and vinyl chloride purged into a closed loop injected into gas chromatograph GC/ECD Sample detection limit <1 ppb Percent recovery NR 0.04-0.8 ppm NR 2 ng/g (sediment) 4 ng/g (oyster) NR Reference IARC 1978 Young and Parker 1984 Wang et al. 1985 \ < 1"< OX ox ^ 88t6HS$y ANALYTICAL METHODS DRAFT FOR PUBLIC COMMENT' TABLE 6-2. Analytical Methods for Determining Vinyl Chloride in Environmental Samples (continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery 1 Reference < Z-< 5OO2r~ om Landfill gas Food (orange drink, wine, oiive oil) Foodstuffs Sample collected in 2( L evacuated glass bulb; gas directly injected into gas chromatograph GC/FID Sample sealed in vials and equilibrated at 40C for 2 hours injected into gas chromatography GC/FID Sample sealed in vials and equilibrated at 40C for a minimum of 2 hours; headspace gas injected into gas chromatograph GC/FID NR NR NR NR 1-5 ppb NR Wood and Porter 1987 Chudy and Crosby 1977 at IARC 1978 CS2 = carbon disulfide; EPA = Environmental Protection Agency; GC/ECD = gas chromatography/electron capture detector; GC/FID = gas chromatography/flame ionization detector; GC/HSD = gas chromatography/halogen specific detector; GC/MS = gas chrbmatography/mass spectrometry; GC/PID = gas chromatography/photoionization detector; HSD = halogen specific detector; N2 = nitrogen; Na^SjOj = sodium thiosulfate; NR = not reported; PID = photoionization detector; PTFE = polytetrafluorethylene; PVC = polyvinyl chloride SBtewS'Sd VINYL CHLORIDE 6. ANALYTICAL METHODS 171 liberated from the liquid matrix by purging with an inert gas and concentrated by trapping on a suitable solid sorbent. Vinyl chloride is thermally desorbed and backflushed onto the column of the gas chromatograph with an inert gas. Detection of vinyl chloride is generally achieved using HECD, HSD, or MS (APHA 1985; EPA 1982d, 1982e; IARC 1978; Reding 1987). The limit of detection is in the sub-ppb range for halogen specific detectors (APHA 1985; EPA 1982d, 1982e) and in the lowppb range for MS (EPA 1982d). Accuracy is greater than 98% and precision ranges from 11 % to 25% for GC/HECD and GC/MS (EPA 1982d). Recently, EPA made improvements in methods for measuring volatile organic chemicals. The major change is the use of smaller sample volumes allowed by increased use of capillary gas chromatographic columns. Capillary columns provide better resolution, minimum detection limits, and less column bleed than packed columns (Reding 1987). Vinyl chloride has been measured in sediment using GC/ECD with sensitivity in the low-ppb range. Accuracy and precision data were not given (Wang et al. 1985). No information on analysis of vinyl chloride in soil was located. GC/HSD of headspace gases is the EPA-recommended method for solid matrices with sensitivity in the sub-ppb range. Accuracy (101.9%) is good and precision (11.4%) is adequate (EPA 1982d). Vinyl chloride levels in food have been determined using GC/FID. Headspace analysis is a common method of preparation of foods with sensitivity in the low-ppb range (IARC 1978). 6.3 ADEQUACY OF THE DATABASE Section !04(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 vinyl chloride 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 vinyl chloride. 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 R & S 149190 '"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 6. ANALYTICAL METHODS 172 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 Exposure. Methods are available for measuring vinyl chloride and/or its metabolite, thiodiglycolic acid, in breath, urine, blood, and tissue (Baretta et al, 1969; Conkle et al. 1975; Draminski and Trojanowska 1981; Muller et al. 1979; Zuccato et al. 1979). These methods are sensitive for measuring levels at which health effects might occur, and for measuring higher background levels that might be found in specific populations known to be exposed to elevated levels of vinyl chloride (e.g., workers in the plastics industry and individuals living in the vicinity of hazardous waste sites). Measurement of urinary thiodiglycolic acid can be used as an indicator of vinyl chloride intake as long as individual variability in metabolism due to such factors as liver disease, use of drugs, and alcohol intake can be accounted for (Hefner et al. 1975b; Muller et al. 1979). Exposure to vinyl chloride at concentrations below 1-5 ppm could be masked by background metabolic levels of thiodiglycolic acid within normal limits (Muller et al. 1979). Also, the formation of thiodiglycolic acid is not unique to vinyl chloride exposure (Norpoth et al. 1986a; Pettit 1986). The methods are generally reliable, although increased precision for most methods would increase reliability. Background levels for the general population are ill defined (EPA 1985b). Further research on the relationship between lowlevel exposure and levels of vinyl chloride in biological media would be helpful in assessing the risks and health effects of chronic, low-level exposure. Effect. Existing methods are sensitive for measuring levels of vinyl chloride and its metabolite, thiodiglycolic acid, in individuals affected by exposure to very high levels of vinyl chloride (Baretta et al. 1969; Conkle et al. 1975; Draminski and Trojanowska 1981; Muller et al. 1979; Zuccato et al. 1979). Also, methods are available to detect DNA adducts produced by the reaction of vinyl chloride metabolites with DNA (Eberle et al. 1989; Young and Santella 1988). These DNA adducts are specific indicators of vinyl chloride's genotoxic potential. These methods, however, are not sufficiently sensitive to determine the genotoxic effects resulting from low-level exposure. Correlations between levels detected in biological tissues and fluids and specific observed effects for R&S149191 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 6. ANALYTICAL METHODS 173 lower levels of exposure are not established. Additional research in this area would allow better assessment of existing methods and would help in defining areas in which improvements are needed. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Existing methods for determining vinyl chloride in air (Harsch et al. 1979; Hasanen et al. 1979; Harkov et al. 1983, 1984; IARC 1978; Ives 1975; Krost et al. 1982; McMurry and Tarr 1978; NIOSH 1994; Rasmussen et al. 1977) and water (Ando and Sayato 1984; APHA 1985; Dressman and McFarren 1978; EPA 1982d, 1982e; IARC 1978; Reding 1987), the media of most concern for human exposure, are sensitive, reproducible, and reliable for measuring background levels in the environment. Research investigating the relationship between levels measured in air and water and observed health effects could increase our confidence in existing methods and/or indicate where improvements are needed. Methods specifically relating to the analysis of vinyl chloride in soils were not located. EPA does, however, have sensitive and reliable methods for determining the concentration of vinyl chloride in soil matrices (EPA 1982e), which include contaminated soils. 6.3.2 On-going Studies James Swenberg (University of North Carolina at Chapel Hill), in his work on DNA adducts as biomarkers of exposure and effect, is developing ultrasensitive methods with high specificity to quantitate the dose of vinyl chloride reaching DNA (FEDRIP 1994). R&S149192 "DRAFT FOR PUBLIC COMMENT4" J#(D3> 4CD* CD CO VINYL CHLORIDE 7. REGULATIONS AND ADVISORIES 175 The international, national, and state regulations and guidelines regarding vinyl chloride in air, water, and other media are summarized in Table 7-1. ATSDR has derived three MRL values for vinyl chloride. An acute-duration inhalation MRL of 0.5 ppm was derived for vinyl chloride based upon a NOAEL for developmental effects for mice (John et al. 1977, 1981). An intermediate-duration inhalation MRL of 0.03 ppm was derived for vinyl chloride based upon increased relative liver weight in rats (Bi et al. 1985). A chronic-duration oral MRL of 0.00002 mg/kg/day was derived for vinyl chloride based upon areas of cellular alteration in the livers of rats (Til et al. 1983, 1991). No EPA reference dose (RfD) or reference concentration (RfC) exist for vinyl chloride (IRIS 1995). The FDA is responsible for regulating vinyl chloride as an indirect food additive. With regard to components of coatings, paper, and paperboard, the FDA states that when vinyl chloride is copolymerized with certain other substances, it is a safe food-contact surface. The amount of vinyl chloride content permitted varies depending on the nature of the polymer and its use (FDA 1994). "'DRAFT FOR PUBLIC COMMENT'" VINYL CHLORIDE 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Vinyl Chloride 176 Agency Description Information References INTERNATIONAL I ARC NATIONAL Regulations: a. Air: EPA OSHA b. Water: EPA ODW FDA c. Food: FDA Carcinogenic classification Group l1 IARC 1987 Concentration in exhaust gases from formation and purification of vinyl chloride shall not exceed" Reactor opening loss from each reactor not to exceed (of polyvinyl chloride product) Concentration of vinyl chloride in an exhaust gas stream from polyvinyl reactors or strippers not to exceed Daily weighted average emission concentration of vinyl chloride from polyvinyl chloride product for dispersion resins (excluding latex resins) may not exceed Daily weighted average emission concentration of vinyl chloride from polyvinyl chloride product for dispersion resins (including latex resins) may not exceed PEL TWA 10 ppm 0.02 g/kg 10 ppm 2.02 g/kg 0.42 g/kg 1 ppm STEL (15 minutes) 5 ppm Direct employee exposure to liquid vinyl Yes chloride not allowed MCL 0.002 mg/L Quality standards for bottled water not to exceed 0.002 mg/L Indirect food additive for use only as a component of adhesives Component of paper and paperboard in contact with aqueous and fatty foods Yes Yes EPA 1993b (40 CFR 61.63); EPA 1986c; EPA 1990b EPA 1993b (40 CFR 61.64); EPA 1986c; EPA 1990b EPA 1993 b (40 CFR 61.64); EPA 1986c; EPA 1990b EPA 1993b (40 CFR 61.64); EPA 1986c; EPA 1990b EPA 1993b (40 CFR 61.64); EPA 1986c; EPA 1990b OSHA 1993a (29 CFR 1910.1017); OSHA 1993b OSHA 1993a (29 CFR 1910.1017); OSHA 1993b OSHA 1993a (29 CFR 1910.1017); OSHA 1993b EPA 1989b (40 CFR 14 142, 143); EPA 1987d; EPA 1994c FDA 1993 (21 CFR 103 FDA 1994 (21 CFR 175.105); FDA 1977b FDA 1994 (21 CFR 176.170) "DRAFT FOR PUBLIC COMMENT" VINYL CHLORIDE 7. REGULATIONS AND ADVISORIES 177 TABLE 7-1. Regulations and Guidelines Applicable to Vinyl Chloride (continued) Agency Description Information References NATIONAL (Cont.) d. Other: EPA OERR EPA OSW EPA OTS Guidelines: a. Air: ACGIH EPA NIOSH b. Water: EPA ODW Reportable quantity: CERCLA Statutory RQ Designated as a Toxic Pollutant under Section 307(a)(1) of the Federal Water Pollution Control Act Designated as a Hazardous Substances under CERCLA Listing as a Hazardous Waste: Heavy ends from distillation of vinyl chloride monomer production Listing as a Hazardous Waste: Discarded commercial chemical products offspecification species, container residues, and spill residues thereof Listing as a Hazardous Constituent 0.454 kg Yes Yes Yes Yes Yes Designated as a Hazardous Air Pollutant under Section 112 of the Clean Air Act Groundwater Monitoring Requirement Yes Yes Toxic Chemical Release Reporting, Community Right-to-Know Yes EPA 1994a (40 CFR 302); EPA 1987e EPA 1994f (40 CFR 401.15); EPA 1979b EPA 1994a (40 CFR 302); EPA 1987e EPA 1993e (40 CFR 261.32); EPA 1981c EPA 1993a (40 CFR 261.33); EPA 1980b EPA 1993d (40 CFR 261, Appendix VIII); EPA 1988b EPA 1993f (40 CFR 61.01); EPA 1990b EPA 1993c (40 CFR 264, Appendix IX); EPA 1987c EPA 1994e (40 CFR 372); EPA 1987f TLV TWA STEL Carcinogenic Classification RfC (Inhalation) REL TWA: lowest reliably detectable concentration NIOSH considers vinyl chloride to be an occupational and potential human carcinogen 13 mg/m3, 5 ppm No data Group Al' No data Yes Yes ACGIH 1993 IRIS 1995 NIOSH 1990 NIOSH 1990 MCLG Category Health Advisories: 1-day (child) 10-day (child) Longer term (child) Longer term (adult) Lifetime 0 I 3.0 mg/L 3.0 mg/L 0.01 mg/L 0.05 mg/L Not recommended EPA 1989b (40 CFR 141 142); EPA 1987d; EPA 1994c EPA 1994c R&S149196 `"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 7. REGULATIONS AND ADVISORIES 178 TABLE 7-1. Regulations and Guidelines Applicable to Vinyl Chloride (continued) Agency Description Information References NATIONAL (Com.) EPA OWRS Other: DHHS NTP EPA `ATE gulations and Guidelines: Air: Arizona Arizona Arizona California Connecticut Florida Florida Florida Florida-Fort Lauderdale Kansas Kansas Louisiana Maine Massachusetts Massachusetts Maryland Michigan Nevada New York North Carolina Oklahoma Ambient Water Quality Criteria for Protection of Human Health1 Ingesting water and organisms: 10"' 106 io-7 Ingesting organisms only: 10' 10* 10'7 Drinking water: 10' io-* 10'7 Is a known carcinogen RfD (oral) Carcinogen classification Unit risk (inhalation) Unit risk (oral) q," (inhalation) q,' (oral) 20 pg/L 2.0 pg/L 0.2 pg/L 5.246 pg/L 525 pg/L 52.5 pg/L 1.5 pg/L 0.15 pg/L 0.015 pg/L Yes No data Group AJ 8.4x10"' (pg/m3)'1 5.4x10-' (pg/L)'1 2.95x10-' (mg/kg/day)'1 2.3 (mg/kg/day)'1 Acceptable Ambient Air Concentrations (I hour) (24 hour) "^Annual) (NA) (8 hour) (24 hour) (8 hour) (Annual) (8 hour) (Annual) (Annual) (Annual) (NA) (24 hour) (Annual) (NA) (Annual) (8 hour) (Annual) (Annual) (24 hour) 17 pg/m3 4.4 pg/m3 0.012 pg/m3 0.0 50.0 pg/m3 24.0 pg/m3 100.0 pg/m3 0.14 pg/m3 0.10 mg/m3 0.244 pg/m3 0.0238 pg/m3 1.19 pg/m3 0.00 3.47 pg/m3 0.38 pg/m3 0.00 0.40 pg/m3 0.238 mg/m3 0.400 pg/m3 0.00038 mg/m3 127.0 pg/m3 EPA 1980c EPA 1980c EPA 1980c EPA 1985b DHHS 1994 IRIS 1995 EPA 1994c EPA 1994d EPA 1994d EPA 1985c EPA 1985b NAT1CH 19 R&S 149197 --DRAFT FOR PUBLIC COMMENT VINYL CHLORIDE 7. REGULATIONS AND ADVISORIES 179 TABLE 7-1. Regulations and Guidelines Applicable to Vinyl Chloride (continued) Agency Description Information References STATE (Cont.) PennsylvaniaPhiladelphia PennsylvaniaPhiladelphia South Carolina South Dakota Texas Texas Vermont Virginia Washington Kentucky Montana Alabama Arizona Colorado Delaware Florida Georgia Illinois Indiana Iowa Kentucky Louisiana Maryland Mississippi Missouri Montana Nebraska New Mexico North Carolina North Dakota Oklahoma Pennsylvania Tennessee Utah Virginia West Virginia Wisconsin Arizona Connecticut Missouri (Annual) 2.57 ppb (Annual) 2.40 ppb (24 hour) (8 hour) (30 minutes) (Annual) (Annual) (24 hour) (Annual) 50.0 pg/m3 50.0 pg/m3 130.0 pg/m3 13.0 pg/m3 0.20 pg/m3 130.0 pg/m3 0.023 pg/m3 Ambient Air Emissions Limitations for Class 1 areas (24-hour average) Designated as a Hazardous Air Pollutant and subject to regulations Permit required to construct and operate an air contamination source project if yearly emissions exceed: 15 pg/m3 15 pg/m3 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 1 ton 1 ton 1 ton CELDS 1990 CELDS 1990 EPA 1985d (40 CFR 61.01) CELDS 1990 DRAFT FOR PUBLIC COMMENT' i R&S149198 VINYL CHLORIDE 7. REGULATIONS AND ADVISORIES 180 TABLE 7-1. Regulations and Guidelines Applicable to Vinyl Chloride (continued) Agency Description Information References STATE (Cont.) New York _ Wisconsin South Carolina Delaware Louisiana Oregon Wisconsin Wisconsin Wisconsin Water: Alabama Arizona California Connecticut Florida Kansas Maine Massachusetts Minnesota New Jersey Rhode Island Vermont Oklahoma Alabama California Colorado Connecticut Florida Georgia Idaho Illinois Indiana Iowa Prevention of Significant Deterioration Adopted air pollution control standards found in EPA 1978 (40 CFR 52.21) Sources exempt from air monitoring requirements if net emissions increase is: (24 hour) (24 hour) (24 hour) (24 hour) Hazardous Air Contaminants without Acceptable Ambient Concentrations requiring applications of Lowest Achievable Emission Rates Exemption from requirement of Construction or Modification and New Operation Permits for Air Pollutant Sources if emissions do not exceed 1 ton 1 ton Yes 15 pg/m3 15 pg/m3 15 pg/m3 15 pg/m3 300 pounds/year 1 ton/year CELDS 1990 CELDS 1990 WAC 1988 CELDS 1990 Drinking water quality guidelines and standards - MAL in drinking water MCL in drinking water 2pg/L 2pg/L 0-5 pg/L 2 pg/L 1 pg/L 2 pg/L 0.15 pg/L 2 Pg/L 2 pg/L 2 pg/L 2 pg/L 2 pg/L 0.002 mg/L 0.002 mg/L 0.0005 mg/L 0.002 mg/L 0.002 mg/L 0.001 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0,002 mg/L FSTRAC 1990 CELDS 1994 CELDS 1994 R&S149199 "DRAFT FOR PUBLIC COMMENT VINYL CHLORIDE 7. REGULATIONS AND ADVISORIES 181 TABLE 7-1. Regulations and Guidelines Applicable to Vinyl Chloride (continued) Agency Description Information References STATE (Corn.) Kentucky Massachusetts Missouri Montana Nebraska New Jersey New York North Carolina North Dakota Ohio Puerto Rico Rhode Island South Carolina South Dakota Tennessee Texas Utah Virginia West Virginia Wisconsin Wisconsin Wisconsin _ MCLG 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.005 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.002 mg/L 0.0002 mg/L 0.000015 mg/L Public Health Groundwater Quality Standards: Enforcement Standard Preventative Action Limit Human Cancer Criteria 0.015 pg/L 0.0015 pg/L Public Water Supply Warm water sport fish communities Cold water communities Great Lakes communities Nonwater Supply Warm water sport fish communities Cold water communities Warm water forage and limited forage fish communities and limited aquatic life 0.15 pg/L 0.15 pg/L 0.15 pg/L 10 pg/L 3.7 pg/L 30 pg/L CELDS 1994 WAC 1985 WAC 1985 Wisconsin, Department of Natural Resources 1987 "DRAFT FOR PUBLIC COMMENT VINYL CHLORIDE 7. REGULATIONS AND ADVISORIES 182 TABLE 7-1. Regulations and Guidelines Applicable to Vinyl Chloride (continued) Agency Description Information References STATE (Cont.) c. Other: - Kentucky Listed as hazardous waste (from specific sources) Yes NREPC 1994 (401 KAR 31:040) "Group I: Carcinogenic to humans ''Applies to reactors, strippers, mixing, weighing, and holding containers and to monomer recovery systems 'Because of its carcinogenic potential, the EPA-recommended concentration for vinyl chloride in ambient water is zero. However, because attainment of this level may not be possible, levels which correspond to upper-bound incremental lifetime cancer risks of 10'3, 10'6, 10'1 are estimated. JGroup A: Human carcinogen 'Group Al: Confirmed human carcinogen ACGIH = American Conference of Governmental Industrial Hygienists; CERCLA = Comprehensive Environmental Response, Compensation, and Liability Act; CFR = Code of Federal Regulations; DHHS = Department of Health and Human Services; EPA = Environmental Protection Agency; FDA = Food and Drug Administration; IARC = International Agency for Research on Cancer; MAL = Maximum Allowable Level; MCL = Maximum Contaminant Level; MCLG = Maximum Contaminant Level Goal; NA = not applicable; 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; RfC = Reference Concentration; RfD = Reference Dose; RQ = Reportable Quantity; STEL = Short Term Exposure Limit; TLV = Threshold Limit Value; TWA = Time-Weighted Average `"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 183 *ACGIH. 1986. Threshold limit values and biological exposure indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 623-626. ACGIH. 1991. Documentation of the TLVs and BEIs, sixth ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1693-1701. ACGIH. 1993. 1993-1994 threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists. Adkins B Jr, Van Stee EW, Simmons JE, et al. 1986. Oncogenic response of strain A/J mice to inhaled chemicals. J Toxicol Environ Health 17:311-322. Air Force. 1990a. Development and validation of methods for applying pharmacokinetic data in risk assessment. Volume 1. Executive Summary/Introduction. Wright-Patterson AFB, OH: U.S. Air Force, Air Force Systems Command, Human Systems Division, Harry G. Armstrong Aerospace Medical Research Laboratory. NTIS No. AD-A237 365/2. Air Force. 1990b. Development and validation of methods for applying pharmacokinetic data in risk assessment. Volume 5. Vinyl Chloride. Wright-Patterson AFB, OH: U.S. Air Force, Air Force Systems Command, Human Systems Division, Harry G. Armstrong Aerospace Medical Research Laboratory. NTIS No. AD-A237 365/2. Amoore JE, Hautala E. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J Appl Toxicol 3:272-290. Andersen ME, Krishnan K. 1994. Relating in vitro to in vivo exposures with physiologically based tissue dosimetry and tissue response models. In: Salem H, ed. Animal test alternatives: Refinement, reduction, replacement. New York, NY: Marcel Dekker, Inc., 9-25. Anderson D, Richardson CR. 1981. Issues relevant to the assessment of chemically induced chromosome damage in vivo and their relationship to chemical mutagenesis. Mutat Res 90:261-272. Anderson D, Hodge MCE, Purchase IFH. 1976. Vinyl chloride: Dominant lethal studies in male CD-I mice. Mutat Res 40:359-370. Anderson D, Richardson CR, Weight TM, et al. 1980. Chromosomal analyses in vinyl chloride exposed workers: Results from analysis 18 and 42 months after an initial sampling. Mutat Res 79:151-162. Cited in text "DRAFT FOR PUBLIC COMMENT*" R&S 149201 VINYL CHLORIDE 8. REFERENCES 184 *Ando M, Sayato Y. 1984. Studies on vinyl chloride migration into drinking water from polyvinyl chloride pipe and reaction between vinyl chloride and chlorine. Water Research 18:315-318. *Andrews AW, Zawistowski ES, Valentine CR. 1976. A comparison of the mutagenic properties of vinyl chloride and methyl chloride. Mutat Res 40:273-275. Anonymous. 1989. Vinyl chloride and polyvinyl chloride: Toxicology. January 1978-February 1989 (Citations from"the Life Sciences Collection Database), Issue 8. NTIS/PB89-855811. Apfeldorf R, Infante PF. 1981. Review of epidemiologic study results of vinyl chloride-related compounds. Environ Health Perspect 41:221-226. *APHA, 1985. Standard methods for the examination of water and wastewater, 16th ed. Washington, DC: American Public Health Association, American Water Works Association and Water Pollution Control Federation, 591-602. Atkinson R, Pitts JN Jr. 1977. Rate constants for the reaction of oxygen (3P) atoms with vinyl fluoride, vinyl chloride, and vinyl bromide over the temperature range 298-442K. J Chem Phys 67:2488-2491. *Baker LW, MacKay KP. 1985. Hazardous waste management. Screening models for estimating toxic air pollution near a hazardous waste landfill. Journal of the Air Pollution Control Association 35:1190-1195. Balkon J, Leary JA. 1979. An initial report on a comprehensive, quantitative screening procedure for volatile compounds of forensic and environmental interest in human biofluids by GC/MS. J Anal Toxicol 3:213-215. *Bao Y-S, Jiang H, Liu J. 1988. [The effects of vinyl chloride on pregnancy, parturition, and fetal development among female workers]. Chin J Prev Med 22:343-346. (Chinese) Barbin A, Bartsch H. 1989. Nucleophilic selectivity as a determinant of carcinogenic potency (TD50) in rodents: A comparison of mono- and bi-functional alkylating agents and vinyl chloride metabolites. Mutat Res 215:95-106. *Barbin A, Besson F, Perrard MH, et al. 1985a. Induction of specific base-pair substitution in E. coli ttpA mutants by chloroethylene oxide, a carcinogenic vinyl chloride metabolite. Mutat Res 152:147-156. Barbin A, Laib RJ, Bartsch H. 1985b. Lack of miscoding properties of 7-(2-oxoethyl)guanine, the major vinyl chloride-DNA adduct. Cancer Res 45:2440-2444. Bardin CW, Taketo T, Gunsalus GL, et al. 1982. The detection of agents that have toxic effects on the testis and male reproductive tract. In: Hunt VR, Smith MK, Worth D, eds. Environmental factors in human growth and development. Banbury Report No 11, Cold Spring Harbor Laboratory, 337-354.* *Baretta ED, Stewart RD, Mutchler JE. 1969. Monitoring exposures to vinyl chloride vapor: Breath analysis and continuous air sampling. Am Ind Hyg Assoc J 30:537. R&S149202 'DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 8. REFERENCES 185 *Bames DG, Dourson M. 1988. Reference dose (RfD): Description and use in health risk assessments. Regul Toxicol Pharmacol 8:471-486. *Barrio-Lage GA, Parsons FZ, Narbaitz RM, et al. 1990. Enhanced anaerobic biodegradation of vinyl chloride in groundwater. Environmental Toxicology and Chemistry 9(4):403-415. *Bartsch H. 1976. Predictive value of mutagenicity test in chemical carcinogenesis. Mutat Res 38:177-190. *Bartsch H, Malaveille C, Montesano R. 1975. Human, rat and mouse liver-mediated mutagenicity of vinyl chloride in S. typhimurium strains. Int J Cancer 15:429-437. *Bartsch H. Malaveille C, Montesano R. 1976. The predictive value of tissue-mediated mutagenicity assays to assess the carcinogenic risk of chemicals. IARC Sci Publ 12:467-491. Baxter PJ. 1976. Clinical aspects of vinyl chloride disease: Epidemiological studies of PVC manufactureres and fabricators, and primary angiosarcoma of the liver. Proc R Soc Med 69:279-299. Beaumont JJ, Breslow NE. 1981. Power considerations in epidemiologic studies of vinyl chloride workers. Am J Epidemiol 114:725-734. Beauregard RR. 1987. Defining landfill toxics: California SWATS wastes. The Management of World Wastes 30:24-25. Bedard RG. 1976. Biodegradability of organic compounds. U.S. Environmental Protection Agency, Washington, D.C., 94. NTIS PB-264707. "Belli S, Bertazzi PA, Comba P, et al. 1987. A cohort study on vinyl chloride manufacturers in Italy: Study design and preliminary results. Cancer Lett 35:253-261. *Bencko V, Wagner V, Wagnerov'a M, et al. 1988. Immunobiochemical profiles of workers differing in the degree of occupational exposure to vinyl chloride. J Hyg Epidemiol Microbiol Immunol 32:375-384. *Benfenati E, Natangelo M, Davoli E, et al. 1991. Migration of vinyl chloride into PVC-bottled drinking-water assesed by gas chromatography-mass spectrometry. Food Chem Toxicol 29(2); 131-134. Berens AR, Daniels CA. 1976. Prediction of vinyl chloride monomer migration from rigid PVC pipe. Polymer Engineering and Science 16:8-14. Berk PD. 1976. Vinyl chloride-associated liver disease. Ann Int Med 84:717-731. *Berk PD, Martin JF, Waggoner JG. 1975. Persistence of vinyl chloride induced liver injury after cessation of exposure. Ann NY Acad Sci 31:70-77. Betz WR, Maroldo SG, Wachob GD. 1989. Characterization of carbon molecular sieves and activated charcoal for use in airborne contaminant sampling. Am Ind Hyg Assoc J 50:181-187. R&S149203 "`DRAFT FOR PUBLIC COMMENT"' VINYL CHLORIDE 8. REFERENCES 186 *Bi W, Wang Y, Huang M, et al. 1985. Effect of vinyl chloride on testis in rats. Ecotoxicology and Environmental Safety 10:281-289. Black C, May G, Csuka ME, et al. 1992. Activity of oxidative routes of metabolism of debrisoquin, mephenytoin, and dapsone is unrelated to the pathogenesis of vinyl chloride-induced disease. Clin Pharmacol Ther 52:659-667. Black C, Pereira S, McWhirter A, et al. 1986. Genetic susceptibility to scleroderma-like syndrome in symptomatic and asymptomatic workers exposed to vinyl chloride. J Rheumatol 13:1059-1062. Black CM, Welsh KI, Walker AE, et al. 1983. Genetic susceptibility to scleroderma-like syndrome induced by vinyl chloride. Lancet 1:53-55. Bob West Associates. 1980. Review and audit of IBT No. 663-03222, chronic vapor inhalation toxicity study with vinyl chloride (ethylene-derived) in albino rats, albino mice, and golden hamsters for the Manufacturing Chemists Association. Report to Manufacturing Chemists Association (now Chemical Manufacturing Association), Washington, DC, by Bob West Association, Inc., Standford, CT. FYI-OTS-0480-0065. Bogdanikowa B, Zawilska J. 1984. Immune complexes in the serum of patients occupationally exposed to vinyl chloride. Przegl Lek 41:253-257. Bolt HM. 1978. Pharmacokinetics of vinyl chloride. Gen Pharmacol 9:91-95. Bolt HM. 1986. Metabolic activation of vinyl chloride, formation of nucleic acid adducts and relevance to carcinogenesis. IARC Sci Publ 70:261-268. Bolt HM. 1988. Roles of etheno-DNA adducts in tumorigenicity of olefins. Critical Reviews in Toxicology 18:299-309. Bolt HM, Filser JG, Buchter A. 1981. Inhalation pharmacokinetics based on gas uptake studies: 3. A_ pharmacokinetic assessment in man of peak concentrations of vinyl chloride. Arch Toxicol 48:213-228. Bolt HM, Filser JG, Laib RJ, et al. 1980. Binding kinetics of vinyl chloride and vinyl bromide at very low doses. In: Quantitative aspects of risk assessment in chemical carcinogenesis. Arch Toxicol Suppl 3:129-142. Bolt HM, Kappus H, Buchter A, et al. 1976a. Disposition of (1,2-I4C) vinyl chloride in the rat. Arch Toxicol 35:153-162. Bolt HM, Kappus H, Kaufmann R, et al. 1976b. Metabolism of 14C-vinyl chloride in vitro and in vivo. IARC Scientific Publications N 13. INSERM Symposia Series 52:151-163. Bolt HM, Laib RJ, Kappus H, et al. 1977. Pharmacokinetics of vinyl chloride in the rat. Toxicology 7:179-188. Bolt HM, Laib RJ, Peter H, et al. 1986. DNA adducts of halogenated hydrocarbons. J Cancer Res Clin Oncol 112:92-96. R&S 149204 "'DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 187 Bond GG, McLaren EA, Cartmill JB, et al. 1987. Cause-specific mortality among male chemical workers. Am J Ind Med 12:353-383. *Bozzelli JW, Kebbekus BB. 1979. Analysis of selected volatile organic substances in ambient air, final report Apr-Nov 1978. Newark, NJ: NJ Institute of Technology, 80. *Bronstein AC, Currance PL, eds. 1988. Emergency care for hazardous materials exposure. St. Louis, MO: CV Mosby Company, 143-144. Brooks SM. 1982. Pulmonary manifestations of vinyl and polyvinyl chloride. Comments. Chest 81:262-264. *Brugnami G, Abbritti G, Morelli A, et al. 1988. Liver angiosarcoma in a vinyl chloride polymerization plant worker: Report of the seventh Italian case. Med Lav 79:34-41. *Buchter A, Bolt HM, Kappus H, et al. 1977. [Tissue distribution of l,2-14C-vinyl chloride in the rat). Int Arch Occup Environ Health 39:27-32. (German) *Buchter A, Filser JG, Peter H, et al. 1980. Pharmacokinetics of vinyl chloride in the rhesus monkey. Toxicol Lett 6:33-36. *Burmaster DE. 1982. The new pollution groundwater contamination. Environ 24:6-13, 33-36. *Byren D, Engholm G, Englund A, et al. 1976. Mortality and cancer morbidity in a group of Swedish VCM and PCV production workers. Environ Health Perspect 17:167-170. C&EN. 1987. Key Chemicals: Vinyl chloride. Chemical and Engineering News 65:10 *C&EN. 1994. Facts and figures for the chemical industry. Chemical and Engineering News 72(27):28-36. *Carassiti V, Chiorboli C, Bignozzi CA, et al. 1977. Atmospheric photo-oxidation of vinyl chloride: A generalized treatment of the relative rates of product formation. Ann Chim 67:499-512. *Carr J, Burgison RM, Vitcha JF, et al. 1949. Anesthesia: XXXIV. Chemical constitution of hydrocarbons and cardiac automaticity. J Pharmacol Exp Ther 97:1-3. *Castro CE, Riebeth DM, Belser NO. 1992a. Biodehalogenation - the metabolism of vinyl chloride by methylosinus-trichosporium OB-3b - a sequential oxidative and reductive pathway through chloroethylene oxide. Environmental Toxicology and Chemistry. 11(6):749-755. *Castro CE, Wade RS, Riebeth DM, et al. 1992b. Biodehalogenation - rapid metabolism of vinyl chloride by a soil Pseudomonas sp. direct hydrolysis of a vinyl C-C1 bond. Environmental Toxicology and Chemistry 11(6):757-764.* *CELDS. 1990. Computer-Environmental Legislative Data Systems. University of Illinois, Urbana, Illinois. R&S149205 '"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 188 *CELDS. 1994. Computer-Environmental Legislative Data Systems. University of Illinois, Urbana, Illinois. Chieco P, Normanni P, Moslen MT, et al. 1986. Quantitative histochemistry of benzaldehyde dehydrogenase in hepatocellular carcinomas of vinyl chloride-treated rats. J Histochem Cytochem 34:151-158. *Chudy JC, Crosby NT. 1977. Some observations on the determination of monomer residues in foods. Food Cosmet Toxicol 15:547-551. *Chung C-S, Keh DCT. 1987. Angiosarcoma of the liver with metastasis: Report of a case. J Formosan Med Assoc 86:1312-1315. *Ciroussel F, Barbin A, Eberle G, et al. 1990. Investigations on the relationship between DNA ethenobase adduct levels in several organs of vinyl chloride-exposed rats and cancer susceptibility. Biochem Pharmacol 39:1109-1113. *Clewell HJ III, Andersen ME. 1985. Risk assessment extrapolations and physiological modeling. Toxicol Ind Health 1(4): 111-131. *ClewelI HJ, Gentry JM, Gearhart BC, et al. 1995. Considering pharmacokinetic and mechanistic information in cancer risk assessments for environmental contaminants: examples with vinyl chloride and trichloroethylene. Chemosphere (in press). Cline PV, Viste DR. 1985. Migration and degradation patterns of volatile organic compounds. Waste Management Research 3:351-360. CMA. 1986a. Draft report-epidemiology study of vinyl chloride workers. Report to Chemical Manufacturers Association, Washington, DC by Environmental Health Associates, Oakland, CA. EPA/OTS Public Files. 8EHQ-0986-0629. Fiche No. 0510570 (3). CMA. 1986b. An update of an epidemiologic study of vinyl chloride workers (1942-1982). Report to Chemical Manufacturers Association, Washington, DC by Environmental Health Associates, Oakland, CA. EPA/OTS Public Files. FYI-OTS-1086-0509. Fiche No. 0000509-1 (1). *Cogliano VJ, Parker JC. 1992. Some implications of toxicology and pharmacokinetics for exposure assessment. Journal of Exposure Analysis and Environmental Epidemiology, Supp 1:189-207. Cone JE, Harrison R, Reiter R. 1987. Patients with multiple chemical sensitivities: Clinical diagnostic subsets among an occupational health clinic population. Occup Med-State of the Art Rev 2:721-738. *Conkle JP, Camp BJ, Welch BE. 1975. Trace composition of human respiratory gas. Arch Environ Health 30:290-295. *Conolly RB, Jaeger RJ. 1979. Acute hepatotoxicity of vinyl chloride and ethylene: Modification by trichloropropane oxide, diethylmaleate, and cysteine. Toxicol Appl Pharmacol 50:523-531.* *Conolly RB, Jaeger RJ, Szabo S. 1978. Acute hepatotoxicity of ethylene, vinyl fluoride, vinyl chloride, and vinyl bromide after aroclor 1254 pretreatment. Exp Mol Pathol 28:25-33. R&S 149206 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 189 *Cooper WC. 1981. Epidemiologic study of vinyl chloride workers: Mortality through December 31, 1972. Environ Health Perspect 41:101-106. Cordasco EM, Demeter SL, Kerkay J, et al. 1980. Pulmonary manifestations of vinyl chloride and oolyvinyl chloride (interstitial lung disease): Newer aspects. Chest 78:828-834. 'Cotruvo JA. 1985. Organic micropollutants in drinking water. An overview. Sci Total Environ 47:7-26. Cotti G, Valgimigli L, Mandrioli A, et al. 1983. Suitable models for long-term bioassays of therapeutic and toxic effects of antiblastic drugs. Brain tumors of neuronal cells and primitive bipotential precursors produced in sprague-dawley rats by vinyl chloride. Dev Oncol 15:376-378. *Cowfer JA, Magistro AJ. 1983. Vinyl chloride. In: Kirk-Othmer encyclopedia of chemical technology. Vol. 23. New York, NY: Wiley Interscience, 865-885. *Cowfer JA, Magistro AJ. 1985. Vinyl polymers: Vinyl chloride. In: Kirk-Othmer concise encyclopedia of chemical technology. New York, NY: John Wiley and Sons, Inc., 1229-1233. *Cox RA, Enggleton AEJ, Sandalls FJ. 1974. Photochemical reactivity of vinyl chloride. Oxfordshire, England: Are Harwell, 16. AERE-R7820. *CPS. 1993. Chemical synopsis: vinyl chloride. Chemical Products Synopsis, Asbury Park, NJ: Mannsville Chemical Products Corp. *Creech JL, Johnson MN. 1974. Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Med 16:150-151. *CRIS/USDA. 1994. Current Research Information Systems/U.S. Department of Agriculture. Beltsville, MD: U.S. Department of Agriculture. Curry S, Rich S. 1980. The Kline guide to the chemical industry. 4th ed,, Fairfield, NY: Charles H. Kline and Co. Czirjak L, Bokk A, Csonton G, et al. 1989. Clinical findings in 61 patients with progressive systemic sclerosis. Acta Dermato-Venereol 69:533-536. Dahar WS, Bond GG, McLaren EA, et al. 1988. Update to vinyl chloride mortality study. J Occup Med 30:648-649. *Danziger H. 1960. Accidental poisoning by vinyl chloride: Report of two cases. Can Med Assoc J 82:828-830. *Davies MFP, Curtis M, Howat JMT. 1990. Cutaneous hemangioendothelioma: A possible link with chronic exposure to vinyl chloride. Br J Ind Med 47:65-67.* *Davis JW, Carpenter CL. 1990. Aerobic biodegradation of vinyl chloride in groundwater samples. Appl Environ Microbiol 56(12):3878-3880. R&S149207 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 190 *de Jong G, van Sittert NJ, Natarajan AT. 1988. Cytogenetic monitoring of industrial populations potentially exposed to genotoxic chemicals and of control populations. Mutat Res 204:451-464. *de Meester C, Duverger-van Bogaert M, Lambotte-Vandepaer M, et al. 1980. Mutagenicity of vinyl chloride in the Ames test. Possible artifacts related to experimental conditions. Mutat Res 77:175-179. Delassus PT, Schmidt DD. 1981. Solubilities of vinyl chloride and vinylidine chloride in water, J Chem Eng Data 26:274-276. Denenberg BA, Miller RW, Kriesel RS. 1975. Instrumentation for continuous VCM monitoring. American Laboratory 7:49-57. *DeVivo I, Marion M-J, Smith SJ, et al. 1994. Mutant c-Ki-ras protein in chemical carcinogenesis in humans exposed to vinyl chloride. Cancer Causes Control 5:273-278. *DHHS. 1994. Seventh annual report on carcinogens summary. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program. Dilling WL, Bredeqeg CJ, Tefertiller NB. 1976. Organic photochemistry. XIII. Simulated atmospheric photodecomposition rates of methylene chloride, 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene and other chlorinated compounds in dilute aqueous solutions. Environ Sci Technol 10:351-356. *Dinman BD, Cook WA, Whitehouse WM, et al. 1971. Occupational acroosteolysis. I. An epidemiological study. Arch Environ Health 22:61-73. Doll R. 1988. Effects of exposure to vinyl chloride: An assessment of the evidence. Scand J Work Environ Health 14:61-78. Doss MO. 1987. Porphyrinurias and occupational disease. Ann NY Acad Sci 514:204-218. Doss M, Lange CE, Veltman G. 1984. Vinyl chloride-induced hepatic coproporphyrinuria with transition to chronic hepatic porphyria. Klin Wochenschr 62:175-178. *DOT. 1993. Hazardous materials regulations. U.S. Department of Transportation. Code of Federal Regulations 49 CFR 171.2. Dow Chemical Company. 1991. Occupational health summary report unit 1 (vinyl chloride production) with cover sheets and letter dated June 20, 1991. Dow Chemical Company, Health and Environmental Sciences. Midland, MI. NTIS/OTS publication no. 0529863. *Draminski W, Trojanowska B. 1981. Chromatographic determination of thiodiglycolic acid--a metabolite of vinyl chloride. Arch Toxicol 48:289-292. *Dressman RC, McFarren EF. 1978. Determination of vinyl chloride migration from polyvinyl chloride pipe into water. Journal of the American Water Works Association 70:29-30. Drevon C, Kuroki T. 1979. Mutagenicity of vinyl chloride, vinylidene chloride and chloroprene in V79 Chinese hamster cells. Mutat Res 67:173-182. R&S149208 "'DRAFT FOR PUBLIC COMMENT'" VINYL CHLORIDE 8. REFERENCES 191 *Drew RT, Boorman GA, Haseman JK, et al. 1983. The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters. Toxicol Appl Pharmacol 68:120-130. Drury JS, Hammons AS. 1979. Investigations of selected environmental pollutants: 1,2-Dichloroethane. EPA-560/2-78-0006. D'Souza RW, Andersen ME. 1988. Physiologically based pharmacokinetic model for vinylidene chloride. Toxicol Appl Pharmacol 95:230-240. Du JT, Sandoz JP, Tseng MT, et al. 1979. Biochemical alterations in livers of rats exposed to vinyl chloride. J Toxicol Environ Health 5:1119-1132. *Ducatman A, Hirschhom K, Selikoff IJ. 1975. Vinyl chloride exposure and human chromosome aberrations. Mutat Res 31:163-168. *du Pont. 1992a. Initial submission: in vitro microbial mutagenicity studies of chloroethylene with cover letter dated 05/08/92 and attachments. E.I. du Pont de Nemours & Co. EPA No. OTS0539817. *du Pont. 1992b. Initial submission: Mutagenicity activity of chloroethylene in the Salmonella/microsome assay with cover letter dated 05/08/92 and attachments. E.I. du Pont de Nemours & Co. EPA No. OTS0539547. du Pont. 1992c. Initial submission: Chloroethylene: Chinese hamster ovary assay for mutagenicity with cover letter dated 05/08/92 and attachments. E.I. du Pont de Nemours & Co. EPA No. OTS0539535. Dyksen JE, Hess AF III. 1982. Alternatives for controlling organics in groundwater supplies. Journal of the American Water Works Association 74:394-403. Eberle G, Barbin A, Laib RJ, et al. 1989. l,N6-etheno-2'-deoxyadenosine and 3,N4-etheno-2'deoxycytidine detected by monoclonal antibodies in lung and liver DNA of rats exposed to vinyl chloride. Carcinogenesis 10:209-212. *Edmonds LD, Anderson CE, Flynt JW, et al. 1978. Congenital central nervous system malformations and vinyl chloride monomer exposure: A community study. Teratology 17:137-142. Edmonds LD, Falk H, Nissim JE. 1975. Congenital malformations and vinyl chloride. Lancet; ii: 1098. Eisenreich SJ, Looney BB, Thornton JD. 1981. Airborne organic contaminants in the Great Lakes ecosystem. Environmental Science and Technology 15:30-38. Elmore JD, Wong JL, Laumbach AD, et al. 1976. Vinyl chloride mutagenicity via the metabolites chlorooxirane and chloroacetaldehyde monomer hydrate. Biochem Biophys Acta 442:405-419. EPA. 1975a. National emission standards for hazardous air pollutants. U.S. Environmental Protection Agency. Code of Federal Regulations 21 CFR 61.01. R&S 149209 `"DRAFT FOR PUBLIC COMMENT' VINYL CHLORIDE S REFERENCES 192 EPA. 1975b. National emission standards for hazardous air pollutants: Proposed standard for vinyl chloride. U.S. Environmental Protection Agency, Federal Register 40(248):59532-59552. *EPA. 1976a. Dynamic behavior of vinyl chloride in aquatic ecosystems. Atlanta, GA: U.S. Environmental Protection Agency, Environmental Research Lab. EPA-600/3-76-00-1. NTIS PB-249 302. *EPA. 1976b: Sampling of automobile interiors for vinyl chloride monomer. Research Triangle Park, NC: U.S. Environmental Protection Agency. EPA-600/2-76-124. NTIS PB-258648. *EPA. 1977. An index of refractory organics. Ada, OK: U.S. Environmental Protection Agency. EPA-600/2-77-174. EPA. 1978. Prevention of significant deterioration of air quality. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 52.21. *EPA. 1979a. Formulation of preliminary assessment of halogenated organic compounds in man and environmental media. Research Triangle Park, NC: U.S. Environmental Protection Agency. EPA/560/13-79-006. *EPA. 1979b. Identification of conventional pollutants. U.S. Environmental Protection Agency. Federal Register 44(147):44501-44503. EPA. 1979c. Toxic pollutants. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 401.15. *EPA. 1979d. Water-related environmental fate of 129 priority pollutants. Volume II. Wahington, DC: U.S. Environmental Protection Agency. EPA-440/4-79-0298, 49-1 - 49-10. *EPA. 1980a. Ambient water quality criteria for vinyl chloride. Cincinnati, OH: U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office. EPA 440/5-80-078. NTIS PB Si ll 7889. *EPA. 1980b. Hazardous waste management system: Identification and listing of hazardous waste, interim rule. U.S. Environmental Protection Agency. Federal Register 45(229):78530-78550. *EPA. 1980c. Water quality criteria documents; availability. U.S. Environmental Protection Agency. Federal Register 45(231 ):79318-79341. EPA. 1981a. Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 261.33. EPA. 1981b. Hazardous waste front specific sources. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 261.32.* *EPA. 1981c. Hazardous waste management system: Identification and listing of hazardous waste, final rule. U.S. Environmental Protection Agency. Federal Register 46(11):4614-4620. R&S149210 '"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 193 *EPA. 1982a. Aquatic fate process data for organic priority pollutants. Washington, DC: U.S. Environmental Protection Agency, Office of Water Regulations and Standards, 155-156, 409-433. EPA 440/4-81-014. EPA. 1982b. Emission standard for ethylene dichloride. vinyl chloride, and polyvinyl chloride. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 61.65. EPA. 1982c. Identification and listing of hazardous waste. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 261, Append VIII. *EPA. 1982d. Methods for organic chemical analysis of municipal and industrial wastewater. Test method: Purgeable halocarbons - method 601 and Purgeable - Method 624. Cincinnati, OH: U.S. Environmental Protection Agency, Environmental Monitoring and Support Laboratory, EPA 600/4-82057, 601-1 to 601-10 and 624-1 to 624-12. *EPA. I982e. Test methods for evaluating solid waste. Physical/chemical methods. Method 8010 Halogenated volatile organics. Washington, DC: U.S. Environmental Protection Agency, Office of Solid Waste and Emergency Response, 8010-1 to 8010-12. *EPA. 1982f. Occurrence of vinyl chloride in drinking water, food and air. Washington, DC: U.S. Environmental Protection Agency, Criteria and Standards Division. EPA-68-01-6388. NTIS PB95-183158. EPA. 1984. Health effects assessment for vinyl chloride, Cincinnati, OH: U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office. EPA 540/1-86-036. EPA. 1985a. Designation, reportable quantities, and notification. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 302. *EPA. 1985b. Drinking water criteria document for vinyl chloride. Washington, DC: U.S. Environmental Protection Agency, Office of Drinking Water. NTIS PB86-118320. *EPA. 1985c. Health and environmental effects profile for chloroethene. Cincinnati, OH: U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office. ECAO-CIN-P155. *EPA. 1985d. Lists of pollutants and applicability of part 61. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 61.01. EPA. I985e. Methods for sampling and analysis of breath. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment. EPA/600/8-85/019, NTIS PB85-243277. EPA. 1986a. Determination of reportable quantities for hazardous substances. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 117. EPA. 1986b. Emission standard for vinyl chloride plants. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 61.63. '"EPA. 1986c. Emission standard for vinyl chloride plants. U.S. Environmental Protection Agency. Federal Register 51(189):34909. R&S 149211 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 194 EPA. 1986d. The total exposure assessment methodology (TEAM) study. Final report. Washington, DC: U.S. Environmental Protection Agency, Office of Research and Development, Environmental Monitoring Systems Division. RTI/2391/00-03F. EPA. 1987a. Graphical exposure modelling system (GEMS). CLOGP. Washington, DC: U.S. Environmental Protection Agency, Office of Toxic Substances. EPA. 1987b. Ground-water monitoring list. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 264, Appendix IX. *EPA. 1987c. List (phase 1) of hazardous constituents for ground-water monitoring. U.S. Environmental Protection Agency. Federal Register 52(131):25942-25952. *EPA. 1987d. National primary drinking water regulations- Synthetic organic chemicals: Monitoring for unregulated contaminants. U.S. Environmental Protection Agency. Federal Register 52(130):2569025717. *EPA. 1987e. Reportable quantity adjustments. U.S. Environmental Protection Agency. Federal Register 52(50):8140-8186. *EPA. I987f. Toxic chemical release reporting: Community right-to-know. U.S. Environmental Protection Agency. Federal Register 52(107):21152-21208. *EPA. 1987g. Incorporation of biological information in cancer risk assessment: example - vinyl chloride. Washinton, DC: U.S. Environmental Protection Agency, Office of Research and Development, Office of Health and Environmental Assessment. NTIS No. PB87-198982. EPA. 1988a. Hazardous constituents. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 261, Appendix VIII. *EPA. 1988b. Hazardous waste management system: Identification and listing of hazardous waste, _ .. technical corrections. U.S. Environmental Protection Agency. Federal Register 53(78): 13382-13393. EPA. 1988c. Toxic chemical_release reporting: Community right-to-know. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 372. EPA. 1989a. Interim methods for development of inhalation reference doses. U.S. Environmental Protection Agency. EPA/600/8-88/066F. *EPA. 1989b. National primary drinking water regulations. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 141, 142, 143. EPA. 1990a. Health effects assessment summary tables: Third quarter FY-1990. Cincinnati, OH: U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Environmental Assessment and Criteria Office.* *EPA. 1990b. National emission standards for hazardous air pollutants; revisions to vinyl chloride; equipment leaks of volitile hazardous air pollutants. U.S. Environmental Protection Agency. Federal Register 55:28346-28349. R&S149212 --DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 195 EPA. 1992. National emission standards for hazardous air pollutants; amendment to vinyl chloride rule. U.S. Environmental Protection Agency. Federal Register 57(247):60998-60999. ``EPA. 1993a. Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. Code of Federal Regulations 40 CFR 261.33. *EPA. 1993b. Emissions standard for vinyl chloride and polyvinyl chloride plants. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 61.63, 61.64. *EPA. 1993c. Groundwater monitoring list. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 264, Appendix IX. *EPA. 1993d. Hazardous constituents. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 261, Appendix VIII. *EPA. 1993e. Hazardous waste from specific sources. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 261.32. *EPA. 1993f. National emissions standards for hazardous air pollutants. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 61.01. '`EPA. 1994a. Designation, reportable quantities, and notification. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 302. EPA. 1994b. Determination of reportable quantities for hazardous substances. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 117. *EPA. 1994c. Drinking water regulations and health advisories. U.S. Environmental Protection Agency, Office of Water, Washington, D.C. *EPA. 1994d. Health effects assessment summary tables FY 1994; Supplement number 2. U.S. Environmental Protection Agency, Washinton D.C. EPA 540-R-94-114. NTIS PB94-921102. *EPA. 1994e. Toxic chemical release reporting; Community right-to-know. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 372. *EPA. 1994f. Toxic pollutants. U.S. Environmental Protection Agency. Code of Federal Regulations 40 CFR 410.15. *EPL. 1979. Vinyl chloride pathology report. Report to Chemical Manufacturers Association, Washington, DC by Experimental Pathology Laboratories. EPL. 1980. Pathology report on the brains from mice, hamsters, and rats exposed to vinyl chloride in IBT study 663-03222 (with cover letter). Report to Chemical Manufacturers Association, Washington, DC, by Experimental Pathology Laboratories. FYI-OTS-0480-0065. Fiche No. 0000065-0 (4).* *Eveleth WT, Kollonitsch V, Slater K, eds. 1990. Kline guide to the U.S. chemical industry. 5th ed. Fairfield, NJ: Kline & Co. 196-201. R & S 149213 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 196 Falk H, Waxweiler RJ. 1976. Clinical aspects of vinyl chloride disease: Epidemiological studies of vinyl chloride health effects in the United States. Proc R Soc Med 69:303-306. *Falk H, Creech JL Jr, Heath CW Jr, et al. 1974. Hepatic disease among workers at a vinyl chloride polymerization plant. JAMA 230:59-63. Farkas DF. 1980. Food Processing. In Kirk-Othmer encyclopedia of chemical technology, Vol. 11. New York, NY: John Wiley & Sons, 180-181. FDA. 1977a. Indirect food additives: Adhesives and components of coatings. U.S. Department of Health and Human Services, Food and Druf Administration. Code of Federal Regulations 21 CFR 175.105. *FDA, 1977b. Indirect food additives: Adhesives and components of coatings. U.S. Department of Health and Human Services, Food and Drug Administration. Federal Register 42(50): 14534-14554. FDA. 1977c. Indirect food additives: Adhesives and components of coatings, paper and paperboard components, polymers. U.S. Department of Health and Human Services, Food and Drug Administration. Code of Federal Regulations 21 CFR 175, 176, 177. FDA. 1986. Proposed uses of vinyl chloride polymers. U.S. Department of Health and Human Services, Food and Drug Administration. Federal Register 51:4177-4185. *FDA. 1993. Quality standards for foods with no identity standards; bottled water. U.S. Department of Health and Human Services, Food and Drug Administration. Federal Register 58(2):378-381. *FDA. 1994. Indirect food additives: Adhesives and components of coatings, paper and paperboard components, polymers. U.S. Department of Health and Human Services, Food and Drug Administration. Code of Federal Regulations 21 CFR 175, 176, 177. *FEDRIP. 1994. Federal Research in Progress: Vinyl chloride. Dialog Information Services, Inc, October 1994. *Fedtke N, Boucheron JA, Walker VE, et al. 1990. Vinyl chloride-induced DNA adducts. II: Formation and persistence of 7-(2-oxoethyl)guanine and N2,3-ethenoguanine in rat tissue DNA. Carcinogenesis 11 (8): 1287-1292. *Feron VJ, Kroes R. 1979. One-year time-sequence inhalation toxicity study of vinyl chloride in rats. II. Morphological changes in the respiratory tract, ceruminous glands, brain, kidneys, heart and spleen. Toxicology 13:131-141. *Feron VJ, Hendriksen CFM, Speek AJ, et al. 1981. Lifespan oral toxicity study of vinyl chloride in rats. Food and Cosmetic Toxicology 19:317-333.* *Feron VJ, Kruysse A, Til HP. 1979a. One-year time-sequence inhalation toxicity study of vinyl chloride in rats. I. Growth, mortality, haematology, clinical chemistry, and organ weights. Toxicology 13:25-35. R&S149214 '"DRAFT FOR PUBLIC COMMENT*** VJNYL CHLORIDE 8. REFERENCES 197 Feron VJ, Speek AJ, Willems MI, et al. 1975. Observations on the oral administration and toxicity of vinyl chloride in rats. Food and Cosmetic Toxicology 13:633-638. *Feron VJ, Spit BJ, Immel HR, et al. 1979b. One-year time-sequence inhalation toxicity study of vinyl chloride in rats. III. Morphological changes in the liver. Toxicology 13:143-154. Feron VJ, Woutersen RA, Spit BJ. 1986. Pathology of chronic nasal toxic responses including cancer. Chem Ind Inst Toxicol ^er 7:67-89 *Filser JG, Bolt HM. 1979. Pharmacokinetics of halogenated ethylenes in rats. Arch Toxicol 42:123-136. *Fire FL. 1986. Vinyl chloride. Fire Engineering 139:39-43. *Fishbein L. 1979. Potential halogenated industrial carcinogenic and mutagenic chemicals. I. Halogenated unsaturated hydrocarbons. Sci Total Environ 11:111-161. ^Fitzgerald EJ, Griffiths TM. 1987. Computed tomography of vinyl chloride induced angiosarcoma of liver. Br J Radiol 60:593-595. Fogel MM, Taddeo AR, Fogel S. 1986. Biodegradation of chlorinated ethenes by a methane-utilizing mixed culture. Appl Environ Microbiol 51:720-724. Forbes A, Portmann B, Johnson P, et al. 1987. Hepatic sarcomas in adults: A review of 25 cases. Gut 28:668-674. *Fox AJ, Collier PF. 1977. Mortality experience of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain. Br J Ind Med 34:1-10. *Freitag D, Ballhorn L, Geyer H, et al. 1985. Environmental hazard profile of organic chemicals: An experimental method for the assessment of the behavior of organic chemicals in the ecosphere by means of simple laboratory tests with l4C labelled chemicals. Chemosphere 14:1589-1616. Freitag D, Lay JP, Korte F. 1984. Environmental hazard profile-test results as related to structures and translation into the environment. In: Kaiser KLE, ed,, QSAR Environ Toxicol Proc Workshop Quant Struct Act Relat., Dordrecht, Neth: Reidel, Pp. 111-136. *Freudiger H, Bounameaux H, Garcia J. 1988. Acroosteolysis and Raynaud's phenomenon after vinyl chloride exposure. Vasa 17:216-218. Friedman LC, Schroder LJ, Brooks MG. 1986. Recovery of several volatile organic compounds from simulated water samples: Effect of transport and storage. Environmental Science and Technology 20:826-829.* *Froment O, Marion M-J, Lepot D, et al. 1991. Immunoquantitation of von Willebrand factor (factor VUI-related antigen) in vinyl chloride exposed workers. Cancer Lett 61(6):201-206. "DRAFT FOR PUBLIC COMMENT*" uBC/1 sN> VINYL CHLORIDE 8. REFERENCES 198 *FSTRAC. 1990. Summary of state and federal drinking water standards and guidelines, February, 1990. Federal-State Toxicology and Regulatory Alliance Committee, Chemical Communication Subcommittee. *Fucic A, Garaj-Vrhovac V, Dimitrovic B, et al. 1992. The persistence of sister-chromatid exchange frequencies in men occupationally exposed to vinyl chloride monomer. Mut Res 281(2): 129-132. *Fucic A, Horvat D, Dimitrovic B. 1990. Localization of breaks induced by vinyl chloride in the human chromosomes of lymphocytes. Mutat Res 243:95-99. Fuerst RG, Logan TJ, Midgett MR, et al. 1989. Sampling and analysis experiments for improved characterization of products of incomplete combustion. Journal of the Air Pollution Control Association 39:969-974. Fujimoto T, Rennert AM, Wijnen MHJ. 1970. Primary steps in the photolysis of vinyl chloride. Ber Bunsenges Phys Chem 74:282-286. *Funes-Cravioto F, Lambert B, Lindsten J, et al. 1975. Chromosome aberrations in workers exposed to vinyl chloride. Lancet l(Feb 22):459. Gagnon C. 1988. The role of environmental toxins in unexplained male infertility. Seminars in Reproductive Endocrinology 6:369-376. ^Gamble J, Liu S, McMichael AJ, et al. 1976. Effect of occupational and nonoccupational factors on the respiratory system of vinyl chloride and other workers. J Occup Med 18:659-670. *Garaj-Vrhovac V, Fucic A, Horvat D. 1990. Comparison of chromosome aberration and micronucleus induction in human-lymphocytes after occupational exposure to vinyl chloride monomer and microwave radiation. Periodicum Biologomm 92(4):41-416. *Gargas ML, Burgess RJ, Voisard DE, et al. 1989. Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol Appl Pharmacol 98:87-99. *Gedigke P, Muller R, Bechtelsheimer H. 1975. Morphology of liver damage among polyvinyl chloride production workers. A report on 51 cases. Ann NY Acad Sci 246:278-285. *Gehring PJ, Watanabe, PG, Park CN. 1978. Resolution of dose-response toxicity data for chemicals requiring metabolic activation: Example-vinyl chloride. Toxicol Appl Pharmacol 44:581-591.* *Gelin M, Van de Stadt J, Rickaert F, et al. 1989. Epithelioid hemangioendothelioma of the liver following contact with vinyl chloride: Recurrence after orthotopic liver transplantation. J Hepatol 8:99-106. Geryk E, Zudova Z. 1986. [Vinyl chloride as occupational health hazardl. Prac Lek 38:1-8. (Czech) Gholson AR, Storm JF, Jayanty RKM, et al. 1989. Evaluation of canisters for measuring emissions of volatile organic air pollutants from hazardous waste incineration. Journal of the Air Pollution Control Association 39:1210-1217. R&S149216 `"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 199 ^Gilbert SG, Miltz J, Giacin JR, 1980, Transport considerations of potential migrants from food packaging materials. Journal of Food Processing and Preservation 4:27-49. Gleichmann E, Kimber I, Purchase IFH. 1989. Immunotoxicoiogy: Suppressive and stimulatory effects of drugs and environmental chemicals on the immune system a discussion. Arch Toxicol 63:257-273. *Goodenkauf O, Atkinson JC. 1986. Occurrence of volatile organic chemicals in Nebraska groundwater. Ground Water 24:231-233. *Goodman LS, Gilman A, eds. 1980. The pharmicological basis of thereputics. New York, NY: MacMillan Publishing Company, 16. *Gordon SJ, Meeks SA. 1977. A study of gaseous pollutants in the Houston, Texas area. AIChE Symposium Series 73:84-94. Gosselin RE, Smith RP, Hodge HC. 1984. Clinical toxicology of commercial products, 5th ed. Baltimore, MD: Williams and Wilkins. 11-166. Gossett RW, Brown DA, Young DR. 1983. Predicting the bioaccumulation of organic compounds in marine organisms using octanol/water partition coefficients. Mar Pollut Bull 14:387-392. Graedel TE. 1978. Chemical compounds in the atmosphere. New York, NY: Academic Press, 1148. *Grainger RG, Walker AE, Ward AM. 1980. Vinyl chloride monomer-induced disease: Clinical, radiological, and immunological aspects. In: Induced Disease, Drug Irradiation. Occupation. Preger L,, ed. Grune and Stratton, New York. 191-214. *Green T, Hathway DE. 1975. The biological fate in rats of vinyl chloride in relation to its oncogenicity. Chem Biol Interact 11:545-562. *Green T, Hathway DE. 1977. The chemistry and biogenesis of the S-containing metabolites of vinyl chloride in rats. Chem Biol Interact 17:137-150. *Green T, Hathway DE. 1978. Interactions of vinyl chloride with rat-liver DNA in vivo. Chem Biol Interact 22:211-224. Greim H, Bonse G, Radwan Z, et al. 1975. Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxirane formation. Biochem Pharmacol 24:2013-2017. *Grimsrud EP, Rasmussen RA. 1975a. The analysis of chlorofluorocarbons in the troposphere by gas chromatography-mass spectrometry. Atmos Environ 9:1010-1013. *Grimsrud EP, Rasmussen RA. 1975b. Survey and analysis of halocarbons in the atmosphere by gas chromatography-mass spectrometry. Atmos Environ 9:1014-1017. Guengerich FP. 1982. Metabolism of vinyl halides: in vitro studies on roles of potential activated metabolites. Biological reactive intermediates II. Proceedings of the Second International Symposium, Chemical Mechanisms and Biological Effects. Part A. New York, NY: Plenum Press, 685-692. R&S149217 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 200 Guengerich FP. 1986. Covalent binding to apoprotein is a major fate of heme in a variety of reactions in which cytochrome P-450 is destroyed. Biochem Biophys Res Commun 16:193-198. ""Guengerich FP, Watanabe PG. 1979. Metabolism of (l4C)- and (36Cl)-labeled vinyl chloride in vivo and in vitro. Biochem Pharmacol 28:589-596. "Guengerich FP, Crawford WM, Jr, Watanabe PG. 1979. Activation of vinyl chloride to covalently bound metabolites: Roles of 2-chloroethylene oxide and 2-chloroacetaldehyde. Biochemistry 18:51775182. Guengerich FP, Kim D-H, Iwasaki M. 1991. Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. Chem Res Toxicol 4(2): 168-179. ""Guengerich FP, Mason PS, Stott WJ, et al. 1981. Roles of 2-haloethylene oxide and 2haloacetaldehydes derived from vinyl bromide and vinyl chloride in irreversible binding to protein and DNA. Cancer Res 41:4391-4398. *Gwinner LM, Laib RJ, Filser JG, et al. 1983. Evidence of chloroethylene oxide being the reactive metabolite of vinyl chloride towards DNA: Comparative studies with 2,2'-dichlorodiethyl ether. Carcinogenesis 4:1483-1486. ""Haddad LM, Winchester JF, eds. 1990. Clinical management of poisoning and overdose. Philadelphia, PA: W.B. Saunders Company, 516, 1209, 1214, 1224, 1227-1229. ""Hagmar L, Akesson B, Nielson J, et al. 1990. Mortality and cancer morbidity in workers exposed to low levels of vinyl chloride monomer at a polyvinyl chloride processing plant. Am J Ind Med 17:553-565. "Hansteen IL, Hillestad L, Thiis-Evensen E, et al. 1978. Effects of vinyl chloride in man: A cytogenetic follow-up study. Mutat Res 51:271-278. ""Harkov R, Kebbekus B, Bozzelli JW, et al. 1983. Measurement of selected volatile organic compounds at three locations in New Jersey during the summer season. Journal of the Air Pollution Control Association 33:1 177-1183. ""Harkov R, Kebbekus B, Bozzelli JW, et al. 1984. Comparison of selected volatile organic compounds during the summer and winter at urban sites in New Jersey. Sci Total Environ 38:259-274. Harkov R, Kebbekus B, Bozzelli JW. 1987. Volatile organic compounds at urban sites in New Jersey. In: Lioy PJ, Daisey JM, eds.. Toxic Air Pollution: A Comprehensive study of Non-Criteria Air Pollutants. Chelsea, MI: Lewis Publishers, Inc., 67-90. ""Harris DK. 1953. Health problems in the manufacture and use of plastics. Br J Ind Med 10:255-268. ""Harris DK, Adams WGF. 1967. Acro-osteolysis occurring in men engaged in the polymerization of vinyl chloride. Br Med J 3:712-714. ""Harsch DE, Cronn DR, Slater WR. 1979. Expanded list of halogenated hydrocarbons measurable in ambient air. Journal of the Air Pollution Control Association 29:975-976. R&S149218 --DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 201 *Hartmans S, deBont JAM, Tramper J, et al. 1985. Bacterial degradation of vinyl chloride. Biotech Letters 7:383-388. *Hasanen E, Soininen V, Pyysalo H, et al. 1979. On the occurrence of aliphatic chlorine and bromine compounds in automobile exhaust. Atmos Environ 13:1217-1219. *Hatch M, Kline J, Stein Z. 1981. Power considerations in studies of reproductive effects of vinyl chloride and some structural analogs. Environ Health Perspect 41:195-201. *HAZDAT. 1995. Agency for Toxic Substance and Disease Registry (ATSDR), Atlanta, GA. *Heath CW Jr, Fable H, Creech JL Jr. 1975. Characteristics of cases of angiosarcoma of the liver among vinyl chloride workers in the United States. Ann NY Acad Sci 246:231-236, *Hefner RE Jr, Watanabe PG, Gehring PJ. 1975a. Percutaneous absorption of vinyl chloride. Toxicol Appl Pharmacol 34:529-532. * Hefner RE Jr, Watanabe PG, Gehring PJ. 1975b. Preliminary studies of the fate of inhaled vinyl chloride monomer in rats. Ann NY Acad Sci 246:135-148. *Hehir RM, McNamara BP, McLaughlin J, Jr, et al. 1981. Cancer induction following single and multiple exposures to a constant amount of vinyl chloride monomer. Environ Health Perspect 41:63-72. *Heldaas SS, Andersen AA, Langard S. 1987. Incidence of cancer among vinyl chloride and polyvinyl chloride workers: Further evidence for an association with malignant melanoma. Br J Ind Med 44:278-280. *Heldaas SS, Langard SL, Andersen A. 1984. Incidence of cancer among vinyl chloride and polyvinyl chloride workers. Br J Ind Med 41:25-30, *Ho SF, Phoon WH, Gan SL, et al. 1991. Persistent liver dysfunction among workers at a vinyl chloride monomer polymerization plant. J Soc Occup Med 41(1):10-16. *Hoffmann D, Patrianakos C, Brunnemann KD, et al. 1976. Chromatographic determination of vinyl chloride in tobacco smoke. Anal Chem 48:47-50. *Hollstein M, Marion M-J, Lehman T, et al. 1994. P53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers. Carcinogenesis 15(1): 1-3.* *Hong CB, Winston JM, Thornburg LP, et al. 1981. Follow-up study on the carcinogencity of vinyl chloride and vinylidene chloride in rats and mice: Tumor incidence and mortality subsequent to exposure. J Toxicol Environ Health 7:909-924. Hopkins J. 1979. Vinyl chloride--Part 1: Metabolism. Food and Cosmetic Toxicology 17:403-405. *Howard CJ. 1976. Rate constants for the gas-phase reactions of hydroxyl radicals with ethylene and halogenated ethylene compounds. J Chem Phys 65:4771-4777. R&S1492J9 '"DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 202 *Hrivnak L, Rozinova Z, Korony S, et al. 1990. Cytogenetic analysis of peripheral blood lymphocytes in workers exposed to vinyl chloride. Mutat Res 240:83-85. HSDB. 1990. Hazardous Substances Data Bank. National Library of Medicine, National Toxicology Information Program, Bethesda, MD. May 23, 1990. *HSDB. 1994. Hazardous Substances Data Bank. National Library of Medicine, National Toxicology Information Program, Bethesda, MD. September 23, 1994. *Huberman E, Bartsch H, Sachs I. 1975. Mutation induction in Chinese hamster V79 cells by two vinyl chloride metabolites, chloroethylene oxide and 2-chloroacetaldehyde. Int J Cancer 16:639-644. *HuItmark D, Sundh K, Johansson L, et al. 1979. Ethanol inhibition of vinyl chloride metabolism in isolated rat hepatocytes. Chem Biol Interact 25:1-6. *IARC. 1978. Methods for the measurement of vinyl chloride in polyvinyl chloride, air, water, and foodstuffs. In: Egan H, Squireel DCM, Thain W, Davis W, eds. Environmental Carcinogens Selected Methods of Analysis. Lyons, France: World Health Organization, International Agency for Research on Cancer. IARC Sci Pub No 22. *IARC. 1979. Monographs on the evaluation of the carcinogenic risk of chemicals in humans. Vinyl chloride, polyvinyl chloride and vinyl chloride-vinyl acetate copolymers. Lyons, France: World Health Organization, International Agency for Research on Cancer. WHO, IARC 19:377-401; 419-438. *IARC. 1987. IARC monographs on the evaluation of carcinogenic risks to humans. Overall evaluations of carcinogenicity: An updating of IARC monographs Volumes 1 to 42. Lyons, France: World Health Organization, International Agency for Research on Cancer. WHO, IARC; Suppl 7:38-74. Ierardi M, Brunner P, Cichon EJ. 1987. Groundwater restoration at McClellan AFB. In: Bennett G, Bennett J, eds. Superfund '87: Proceedings of the 8th National Conference, November 16-18, Washington, DC, The Hazardous Materials Control Research Institute, 204, 207. *Infante PF. 1976. Oncogenic and mutagenic risks in communities with polyvinyl chloride production facilities. Ann NY Acad Sci 271:49-57. *Infante PF, Wagoner JK, McMichael AJ, et al. 1976a. Genetic risks of vinyl chloride. Lancet (April 3) 734-735. *Infante PF, Wagoner JK, Waxweiler RJ. 1976b. Carcinogenic, mutagenic, and teratogenic risks associated with vinyl chloride. Mutat Res 41:131-142. IRIS. 1994. Integrated Risk Information System. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.* *Ives NF. 1975. Sensitive trapping and gas chromatographic method for vinyl chloride in air samples. J Assoc Off Anal Chem 58:457-460. R&S149220 "'DRAFT FOR PUBLIC COMMENT*' VINYL CHLORIDE 8. REFERENCES 203 Jacobsen JS, Humayun MZ. 1990. Mechanisms of mutagenesis by the vinyl chloride metabolite chloroacetaldehyde. Effect of gene-targeted in vitro adduction of M13 DNA on DNA template activity in vivo and in vitro. Biochemistry 29(2):496-504. *Jacobsen JS, Perkins CP, Callahan JT, et al. 1989. Mechanisms of mutagenesis by chloroacetaldehyde. Genetics 121:213-222. *Jaeger RJ, Murphy SD, Reynolds ES, et al. 1977. Chemical modification of acute hepatotoxicity of vinyl chloride monomer in rats. Toxicol Appl Pharmacol 41:597-607. *Jaeger RJ, Reynolds ES, Conolly RB, et al. 1974. Acute hepatic injury by vinyl chloride in rats pretreated with phenobarbital. Nature 252:724-726. '"Jayson MIV, Bailey AJ, Black C, et al. 1976. Clinical aspects of vinyl chloride disease: Collagen studies in acroosteolysis. Proc R Soc Med 69:295-297. *Jedrychowski RA, Sokal JA, Chmielnicka J. 1984. Influence of exposure mode on vinyl chloride action. Arch Toxicol 55:195-198. *Jedrychowski RA, Sokal JA, Chmielnicka J. 1985. Comparison of the impact of continuous and intermittent exposure to vinyl chloride, including phenobarbital effect. J Hyg Epidemiol Microbiol Immunol 29:111 -120. Jenssen D, Ramel C. 1980. The micronucleus test as part of a short-term mutagenicity test program for the prediction of carcinogenicity evaluated by 143 agents tested. Mutat Res 75:191-202. *John JA, Smith FA, Leong BKJ, et al. 1977. The effects of maternally inhaled vinyl chloride on embryonal and fetal development in mice, rats, and rabbits. Toxicol Appl Pharmacol 39:497-513. *John JA, Smith FA, Schwetz BA. 1981. Vinyl chloride: Inhalation teratology study in mice, rats, and rabbits. Environ Health Perspect 41:171-177. Jones JH. 1981. Worker exposure to vinyl chloride and polyvinyl chloride. Environ Health Perspect 41:129-136. *Jones DB, Smith PM, 1982. Progression of vinyl chloride induced hepatic fibrosis to angiosarcoma of the liver. Br J Ind Med 39:306-307. *Jones RD, Smith DM, Thomas PG. 1988. A mortality study of vinyl chloride monomer workers employed in the United Kingdom in 1940-1974. Scand J Work Environ Health 14:153-160. *Jury WA, Spencer WF, Farmer WJ. 1984. Behavior assessment model for trace organics in soil: III. Application of screening model. J Environ Qual 13:573-579. *Kandala JC, Mrema JEK, Deangelo A, et al. 1990. 2 Chloroacetaldehyde and 2 chloroacetal are potent inhibitors of DNA synthesis in animal cells. Biochem Biophys Res Commun 167:457-463.* *Kappus H, Bolt HM, Buchter A, et al. 1976. Liver microsomal uptake of [14C] vinyl chloride and transformation to protein alkylating metabolites in vitro. Toxicol Appl Pharmacol 37:461-471. R&S 149221 '"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 204 Kastner M, Hoppenheidt K, Hanert HH. 1988. Bacterial transformation reactions in groundwater aquifers contaminated with chlorinated hydrocarbons purification techniques. In: Wolf K, Van Den Brink WJ, Colon FJ, eds. Contaminated Soil '88: Second International Netherlands Organization for Applied Scientific Research/Federal Ministry of Research and Technology Conference, Hamburg, West Germany, April 11-15, 1988, 1235-1238. *Kenaga EE, Goring CAI. 1980. Relationship between water solubility, soil-sorption, octanol-water partitioning, and concentration of chemicals in biota. In: Eaton JG, Parrish PR, Hendricks AC, eds. Aquatic Toxicology. American Society for Testing and Materials, 78-115. *Keplinger ML, Goode JW, Gordon DE, et al. 1975. Interim results of exposure of rats, hamsters, and mice to vinyl chloride. Ann NY Acad Sci 246:219-224. Kessler E, Brandt-Rauf PW. 1987a. Occupational cancers of the brain and bone. Occupational Cancer and Carcinogenesis 2:155-163. Kessler E, Brandt-Rauf PW. 1987b. Occupational cancers of the nervous system. Seminars in Occupational Medicine 2:311-314. Kilian DJ, Picciano DJ, Jacobson CB. 1975. Industrial monitoring: A cytogenic approach. Ann NY Acad Sci 269:4-11. Kinigakis P, Miltz J, Gilbert SG. 1987. Partition of VCM in plasticized PVC-food simulant systems. Journal of Food Processing and Preservation 11:247-256. * Knight KR, Gibbons R. 1987. Increased collagen synthesis and cross-link formation in the skin of rats exposed to vinyl chloride monomer. Clin Sci 72:673-678. Koch R, Nagel M. 1988. Quantitative structure activity relationships in soil. Sci Total Environ 77:269-276. Kollar V, Kemka R, Misianik J, et al. 1988. Determination of vinyl chloride and vinyl acetate in working atmosphere. Chem Pap 42:147-160. *Kontominas MG, Gupta C, Gilbert SG. 1985. Interaction of vinyl chloride with polyvinyl chloride in model food systems by HPLC chromatography: Migration aspects. Lebensmittel-Wissenschaft und Technologie 18:353-356. *Krajewski J, Dobecki M, Gromiec J. 1980. Retention of vinyl chloride in the human lung. Br J Ind Med 37:373-374. Kramer CG, Mutchler JE. 1972. The correlation of clinical and environmental measurements for workers exposed to vinyl chloride. Am Ind Hyg Assoc J 33:19.* *Krishnan K, Andersen ME. 1994. Physiologically based pharmacokinetic modeling in toxicology. In: Hayes W, ed. Principles and methods of toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 149188. R&S 149222 '"DRAFT FOR PUBLIC COMMENT'" VINYL CHLORIDE 8. REFERENCES 205 *Krishnan K, Andersen ME, Clewell HJ III, et al. 1994. Physiologically based pharmacokinetic modeling of chemical mixtures. In: Yang, RSA, ed. Toxicology of chemical mixtures. New York, NY: Academic Press, 399-437. *Krost KJ, Pellizzari ED, Walburn SG, et al. 1982. Collection and analysis of hazardous organic emissions. Anal Chem 54:810-817. *Kucerova M, Polivkova Z, Batora J. 1979. Comparative evaluation of the frequency of chromosomal aberrations and the SCE numbers in peripheral lymphocytes of workers occupationally exposed to vinyl chloride monomer. Mutat Res 67:97-100. *Kudo YY, Yamada S, Nakamura I, et al. 1990. On the changes in peripheral red cells in mice exposed to vinyl chloride monomer. Pol J Occup Med 3(3):301-10. Kurzel RB, Cetrulo CL. 1981. The effect of environmental pollutants on human reproduction, including birth defects. Environmental Science and Technology 15:625-640. *Laib RJ. 1982. Specific covalent binding and toxicity of aliphatic halogenated xenobiotics. Rev Drug Metabol Drug Interact 3:1-48. *Laib RJ, Bolt HM. 1977. Alkylation of RNA by vinyl chloride metabolites in vitro and in vivo: Formation of l-N-6-ethenoadenosine. Toxicology 8:185-195. *Laib RJ, Bolt HM, Cartier R, et al. 1989. Increased alkylation of liver DNA and cell turnover in young versus old rats exposed to vinyl chloride correlates with cancer susceptibility. Toxicol Lett 45:231-239. *Langauer-Lewowicka H, Dudziak Z, Byczkowska Z, et al. 1976. Cryoglobulinemia in Raynaud's phenomenon due to vinyl chloride. Int Arch Occup Environ Health 35:197-207. *Langauer-Lewowicka H, Kurzbauer H, Byczkowska Z, et al. 1983. Vinyl chloride diseaseneurological disturbances. Int Arch Occup Environ Health 52:151-157. *Laplanche A, Clavel F, Contassot JC, et al. 1987. Exposure to vinyl chloride monomer: Report on a cohort study. Br J Ind Med 44:711-715. *Laplanche A, Clavel-Chapelon F, Contassot JC, et al. 1992. Exposure to vinyl chloride monomer results of a cohort study after a 7 year follow-up. Br J Ind Med 49(2): 134-137. * Lee FI, Harry DS. 1974. Angiosarcoma of the liver in a vinyl chloride worker. Lancet 1:1316-1318. *Lee CC, Bhandari JC, Winston JM, et al. 1977a. Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ Health Perspect 21:25-32. *Lee CC, Bhandari JC, Winston JM, et al. 1978. Carcinogenicity of vinyl chloride and vinylidene chloride. J Toxicol Environ Health 4:15-30.* *Lee FI, Harry DS, Adams WG, et al. 1977b. Screening for liver disease in vinyl chloride workers. Br J Ind Med 34:142-147. R&S 149223 DRAFT FOR PUBLIC COMMENT*' VINYL CHLORIDE 8. REFERENCES 206 * Lester D, Greenberg LA, Adams WR. 1963. Effects of single and repeated exposures of humans and rats to vinyl chloride. Am Ind Hyg Assoc J 24:265-275. *Leung H-W. 1993. Physiologically-based pharmacokinetic modeling. In: Ballantyne B, Marrs T, Turner P, eds. General and applied toxicology. New York, NY: Stockton Press, 1:153-164. Lilis R. 198L Review of pulmonary effects of polyvinyl chloride and vinyl chloride exposure. Conference to reevaluate the toxicity of vinyl chloride monomer, polyvinyl chloride and^structural analogs, Bethesda, MD. Environ Health Perspect 41:167-170. *Lilis R, Anderson H, Miller A, et al. 1976. Pulmonary changes among vinyl chloride polymerization workers. Chest 69:299-303. *Lilis R, Anderson H, Nicholson WJ, et al. 1975. Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann NY Acad Sci 246:22-41. *Liss GM, Greenberg RA, Tamburro CH. 1985. Use of serum bile acids in the identification of vinyl chloride hepatotoxicity. Am J Med 78:68-76. *Lloyd MH, Gauld S, Copland L, et al. 1984. Epidemiological study of the lung function of workers at a factory manufacturing polyvinyl chloride. Br J Ind Med 41:328-333. Longo LD. 1980. Environmental pollution and pregnancy: Risks and uncertainties for the fetus and infant. Am J Obstet Gynecol 137:162-173. *Loprieno N, Barale R, Baroncelli S, et al. 1977. Induction of gene mutations and gene conversions by vinyl chloride metabolites in yeast. Cancer Res 46:253-257. *Lu P-Y, Metcalf RL, Plummer N, et al. 1977. The environmental fate of 3 carcinogens: Benzo(a)pyrene, benzidine, and vinyl chloride evaluated in laboratory model ecosystems. Arch Environ Contam Toxicol 6:129-142. *Lyman WJ, Reehl WF, Rosenblatt DH. 1982. Handbook of chemical property estimation methods. Environmental Behavior of Organic Compounds. New York, NY: McGraw Hill Book Co., 4-9. *Magnavita N, Bergamaschi A, Garcovich A, et al. 1986. Vasculitic purpura in vinyl chloride disease: A case report. Angiology 37:382-388. Makarov IA. 1984. [Sexual disorders in male workers occupationally exposed to methylmethacrylate and vinyl chloride]. Gig Tr Prof Zabol 6:19-23. (Russian) Makarov IA, Solovyeva MS, Gnelitsky GI. 1984. [Sexual disorders in women chronically exposed to methylmethacrylate and vinyl chloride]. Gig Tr Prof Zabol 3:22-27 (Russian) Maltoni C. 1977. Recent findings on the carcinogenicity of chlorinated olefins. Environ Health Perspect 21:1-5.* *Maltoni C, Cotti G. 1988. Carcinogenicity of vinyl chloride in Sprague-Dawley rats after prenatal and postnatal exposure. Ann NY Acad Sci 534:145-159. H < S S l4 g 2 2 4 "DRAFT FOR PUBLIC COMMENT"* . VINYL CHLORIDE 8. REFERENCES 207 *Maltoni C, Lefemine G. 1975. Carcinogenicity bioassays of vinyl chloride: Current results. Ann NY Acad Sci 246:195-218. Maltoni C, Lodi P. 1981. Results of sputum cytology among workers exposed to vinyl chloride and to polyvinyl chloride. Environ Health Perspect 41:85-88. Maltoni C, Cotti G, Yalgimigli L, et al. 1983. Suitable models for long-term bioassays of the therapeutic and toxic effects of antiblastic drugs: Liver angiosarcomas produced in sprague-dawley rats by vinyl chloride. Dev Oncol 15:339-341. Maltoni C, Lefemine G, Ciliberti A, et al. 1980. Vinyl chloride carcinogenicity bioassays (BT project) as an experimental model for risk identification and assessment in environmental and occupational carcinogenesis. Epidemiol Anim Epidemiol Hum: Cas Chlorure Vinyle Monomere (Reun Club Cancerog Chim), 20th, Meeting Date 1979, 11-112. Publ Essent, Paris, France. *Maltoni C, Lefemine G, Ciliberti A, et al. 1981. Carcinogenicity bioassays of vinyl chloride monomer: A model of risk assessment on an experimental basis. Environ Health Perspect 41:3-29. Maltoni C, LeFemine G, Ciliberti A, et al. 1984. Experimental research on vinyl chloride carcinogenesis. Archives of Research on Industrial Carcinogenesis, Vol. II. Princeton, NJ: Princeton Scientific Publishers. *Maricq HR, Johnson MN, Whetstone CL, et al. 1976. Capillary abnormalities in polyvinyl chloride production workers: Examination by in vivo microscopy. JAMA 236:1368-1371. *Markowitz SS, McDonald CJ, Fethiere W, et al. 1972. Occupational acroosteolysis. Arch Derm 106:219-223. *MarstelIer HJ, Lelbach WK, Muller R, et al. 1975. Unusual splenomegalic liver disease as evidenced by peritoneoscopy and guided liver biopsy among polyvinyl chloride production workers. Ann NY Acad Sci 95U34. *MastrangeIo G, Manno M, Marcer G, et al. 1979. Polyvinyl chloride pneumoconiosis: epidemiological study of exposed workers. J Occup Med 21:540-542. *Mastromatteo E, Fisher AM, Christie H, et al. 1960. Acute inhalation toxicity of vinyl chloride to laboratory animals. Am Ind Hyg Assoc J 394-398. *McCann J, Simmon V, Streitwieser D, et al. 1975. Mutagenicity of chloroacetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene dichloride), chloroethanol (ethylene chlorohydrin), vinyl chloride and cyclophosphamide. Proc Nat Acad Sci 72:3190-3193. McConnell G, Ferguson DM, Pearson CR. 1975. Chlorinated hydrocarbons and the environment. Endeavor 34:13-18. McCord CP. 1970. A new occupational disease is bom. J Occup Med 12:234. McKone TE, Howard RA. 1992. Estimating dermal uptake of nonionic organic chemicals from water and soil: I. Unified fugacity-based models for risk assessments. Risk Analysis 12(4):543-556. R&S149225 "`DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 8. REFERENCES 208 *McMurry JR, Tarr J. 1978. Vinyl chloride in Texas' ambient air. Proceedings of the Annual Technical Meeting of the Institute of Environmental Sciences. 149-153. Mergler-Volkl R, Nerger M, Schule J. A contribution to the biodegradation of volatile chlorinated hydrocarbons in groundwater and sewage. In: Wolf K, Van Den Brink WJ, Colon FJ, eds. Contaminated soil '88: Second International Netherlands Conference Organized for Applied Scientific Research. Federal Ministry of Research and Technology Conference, Hamburg, West Germany. *Micu D, Mihailescu E, Vilau C, et al: 1985. The value of some cytoenzymo-chemical investigations of the leukocytes and platelets in estimating the effects of occupational exposure to benzene, vinyl chloride, and carbon disulphide. Rev Roum Med-Med Int 23:115-120. Milby TH. 1977. Cancer control monograph: Vinyl chloride. Menlo Park, Califonria, SRI International. Milde G, Nerger M, Mergler R. 1988. Biological degradation of volatile chlorinated hydrocarbons in groundwater. Water Sci Technol 20:67-74. *MiIler A. 1975. Pulmonary function defects in nonsmoking vinyl chloride workers. Environ Health Perspect 11:247-250. Miller A, Teirstein AS, Chuang M, et al. 1975. Changes in pulmonary function in workers exposed to vinyl chloride and polyvinyl chloride. Ann NY Acad Sci 246:252. *MilIer JJ, Beizer MB. 1985. Air quality in residences adjacent to an active hazardous waste disposal site. Air Pollution Control Association Annual Meeting, June 16-21, 2-17. *Mirkova E, Mihaylova A, Nosko M. 1978. [Embryotoxic and teratogenic effects in vinyl chloride]. Higiena i zdraveopazane 21:440-443. (Bulgarian) MIS. 1990. ATSDR Management Information System. Agency for Toxic Substances and Disease ~ Registry, Atlanta, GA. September 24, 1990. Molton PM, Hallen RT, Payne JW. 1987. Study of vinyl chloride formation at landfill sites in California. Government Reports Announcements & Index (GRA&I), Issue 13. *Monson RR, Peters JM, Johnson MN. 1975. Proportional mortality among vinyl chloride workers. Environ Health Perspect 1 1:75-77. Monster AC. 1986. Biological monitoring of chlorinated hydrocarbon solvents. J Occup Med 28:586588. Morton WE. 1986. Expanding awareness of the hazards of vinyl-chloride. West J Med 148:74-75. *Miiller JPH, Korte F. 1977. [Contributions to ecological chemistry CXXXVI. Short report on the unsensitized photooxidation of chloroethylenes]. Chemosphere 6:341-346. (German) Muller R, Lingens F. 1986. Microbial degradation of halogenated hydrocarbons: A biological solution to pollution problems? Angew Chem Int Ed Engl 25:779-789. R&S 149226 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 209 Muller G, Norpoth K, Kusters E, et al. 1978. Determination of thiodiglycolic acid in urine specimens of vinyl chloride exposed workers. Int Arch Occup Environ Health 41:199-205. *Muller G, Norpoth K, Wickramasinghe RH. 1979. An analytical method using GC-MS for the quantitative determination of urinary thiodiglycolic acid. Int Arch Occup Environ Health 44:185-191. *NAS/NRC. 1989. Biologic markers in reproductive toxicology. National Academy of Sciences/National Research Council. Washington, DC: National Academy Press, 15-35. *NATICH. 1994. National Air Toxics Information Clearinghouse: Data base report on state, local, and EPA air toxics activities. U.S. Environmental Protection Agency, Office of Air Quality Planning and Standards. Washington, D.C. November 11, 1994. *Nelson YM, Jewell WJ. 1993. Vinyl chloride biodegredation with methanotrophic attached films. Journal of Environmental Engineering-ASCE 119(5):890-907. Nicholson WJ, Hammond EC, Seidman H, et al. 1975. Mortality experience of a cohort of vinyl chloride-polyvinyl chloride workers. Ann NY Acad Sci 246:225-230. *NIOSH. 1977. A cross-sectional epidemiologic survey of vinyl chloride workers. Cincinnati, OH: U.S Department of Health and Human Services, National Institute for Occupational Safety and Health, Division of Surveillance, Hazard Evaluations, and Field Studies. NTIS PB274193. NIOSH. 1986. Chemical review: Vinyl chloride. Dangerous properties of industrial materials report 6:13-43. Washington, DC: U.S. Department of Health and Human Services, National Institute for Occupational Safety and Health. NIOSH publication no. 00188891. *NIOSH. 1990. NIOSH pocket guide to chemical hazards. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, Washington D.C., 4-5, 224-225. *NIOSH. 1994. NIOSH manual of analytical methods. 4rd ed. Vol. 2. Vinyl chloride in air. Method No. 1007. Washington, DC: U.S. Department of Health and Human Services, National Institute for Occupational Safety and Health, 1007-1 to 1007-4. NIOSH/OSHA. 1978. Vinyl halides-carcinogenicity. Washington, DC: U.S. Department of Health and Human Services, National Institute of Occupational Safety and Health and U.S. Department of Labor, Occupational Safety and Health Administration. Current Intelligence Bulletin No. 28. *NOES. 1990. National Occupational Exposure Survey. U.S. Department of Health and Human Services, National Institute for Occupational Safety and Health, Cincinnati, OH. July 1, 1990. *Norpoth K, Heger M, Mueller G, et al. 1986. Investigations on metabolism genotoxic effects and carcinogenicity of 2,2-dichlorodiethyl ether. J Cancer Res Clin Oncol 112:125-130.* *NREPC. 1994. Kentucky waste management regulations. Frankfort, KY: Department for Environmental Protection, Natural Resources and Environmental Protection Cabinet. 401 KAR 31:040 1, 8-9. R&S149227 "DRAFT FOR PUBLIC COMMENT' VINYL CHLORIDE 8. REFERENCES 210 *OHM/TADS. 1985. Oil and Hazardous Materials/Technical Assistance Data System. December 5, 1985. Olsen GW, Hearn S, Cook RR, et al. 1989. Mortality experience of a cohort of Louisiana chemical workers. J Occup Med 31:32-34. OSHA. 1974a. Occupational safety and health standards: Vinyl chloride. U.S. Department of Labor, Occupational Safety and Health Administration. Code of Federal Regulations 29 CFR-1910.1017. OSHA. 1974b. Standard for exposure to vinyl chloride. U.S. Department of Labor, Occupational Safety and Health Administration. Federal Register 39(194):35896-35898. OSHA. 1983. OSHA safety and health standards. U.S. Department of Labor, Occupational Safety and Health Administration. Code of Federal Regulations 29 CFR 1910.1017. OSHA. 1989. Air contaminants: Final rule. U.S. Department of Labor, Occupational Safety and Health Administration. Federal Register 54(12):2920-2960. *OSHA. 1993a. Occupational safety and health standards: vinyl chloride. U.S. Department of Labor, Occupational Safety and Health Administration. Code of Federal Regulations 29 CFR 1910.1017. *OSHA. 1993b. Occupational safety and health standards: vinyl chloride. U.S. Department of Labor, Occupational Safety and Health Administration. Federal Register 58(124):35310. *Oster RH, Carr CJ, Krantz JC. 1947. Anesthesia XXVII. Narcosis with vinyl chloride. Anesthesiology 8:359-361. *Osterman-Golkar S, Jultmark D, Segerback D, et al. 1977. Alkylation of DNA and proteins in mice exposed to vinyl chloride. Biochem Biophys Res Comm 76:259-266. *Ostlere LS, Harris D, Buckley C, et al. 1992. Atypical systemic-sclerosis following exposure to vinyl chloride monomer - a case report and review of the cutaneous aspects of vinyl chloride disease. Clin Exp Dermatol 17(3):208-210. Pau JC, Knoll JE, Midgett MR. 1988. Evaluation of a process gas chromatograph as a continuous emission monitor for benzene and vinyl chloride. Journal of the Air Pollution Control Association 38:1528-1529. Page GW. 1981. Comparison of groundwater and surface water for patterns and levels of contamination by toxic substances. Environmental Science and Technology 15:1475-1481. *Patty FA, Yapt WP, Waite CP. 1930. Acute response of guinea pigs to vapors of some new commercial organic compounds. V. Vinyl chloride. Public Health Rep 45:1963-1971.'* *Perry RA, Atkinson R, Pitts JN Jr. 1977. Rate constants for the reaction of hydroxyl radicals with vinyl fluoride, vinyl chloride, and vinyl bromide over the temperature range 229-426K. J Chem Phys 67:458-462. R&S149220 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 211 *Perticoni GF, Abbritti G, Cantisani TA, et al. 1986. Polineuropathy in workers with long exposure to vinyl chloride. Electro-physiological study. Electromyogr Clin Neurophysiol 26:41-47. *Pettit BR. 1986. The analysis of thiodiglycollic-acid by selected ion monitoring. Clin Chim Acta 156:85-90. *Pirastu R, Comba P, Reggiani A, et al. 1990. Mortality from liver disease among Italian vinyl chloride monomer/polyvinyl chloride manufacturers. Am J Ind Med 17:155-161. Pleil JD, Oliver KD, McClenny WA. 1988. Ambient air analyses using nonspecific flame ionization and electron capture detection compared to specific detection by mass spectroscopy. Journal of the Air Pollution Control Association 38:1006-1010. *PIugge H. Safe S. 1977. Vinyl chloride metabolism - a review. Chemosphere 6:309-325. Plumb RH Jr. 1987. A comparison of ground water monitoring data from CERCLA and RCRA sites. Ground Water Monit Rev 7:94-100. Polakowska B. 1990. [Functional disorders of the nervous system in those currently occupationally exposed to the mixture of chloroorganic solvents and vinyl chloride]. Med Pr 41(l):39-43. (Polish) *Poncelet F, de Meester C, Duverger-van Bogaert M, et al. 1980. Influence of experimental factors on the mutagenicity of vinylic monomers. Arch Toxicol SuppI 4:63-66. *Popper H, Thomas LB. 1975. Alterations of liver and spleen among workers exposed to vinyl chloride. Ann NY Acad Sci 246:172-194. *Popper H, Maltoni C, Selikoff IJ. 1981. Vinyl chloride-induced hepatic lesions in man and rodents: A comparison. Liver 1:7-20. Poy F, Cobeili L, Banfi S, et al. 1987. Determination of vinyl chloride monomer residue in polyvinyl chloride at the parts-per-billion level with an automatic purge-and-trap technique. J Chromatogr 395:281-290. *Preston BJ, Jones KL, Grainger RG. 1976. Clinical aspects of vinyl chloride disease: Acroosteolysis. Proc R Soc Med 69:284-306. Pritchard PH. 1988. Fate of pollutants. J Water Pollut Control Fed 60:983-994. *Purchase IFH, Richardson CR, Anderson D. 1975. Chromosomal and dominant lethal effects of vinyl chloride. Lancet 410-411. Purchase IFH, Richardson CR, Anderson D. 1976. Clinical apsects of vinyl chloride disease: . Chromosomal effects in peripheral lymphocytes. Proc R Soc Med 69:290-292. ^Purchase IFH, Richardson CR, Anderson D, et al. 1978. Chromosomal analysis in vinyl chloride exposed workers. Mutat Res 57:325-334. R&S149229 "'DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 8. REFERENCES 212 Purchase IFH, Stafford J, Paddle GM. 1987. Vinyl chloride: An assessment of the risk of occupational exposure. Food Chem Toxicol 25:187-202. Radding SB, Liu DH, Johnson HL, et al. 1977. Review of the environmental fate selected chemicals. NTIS 68-01-2681. *Radike MJ, .Stemmer K, Bingham E. 1981. Effect of ethanol on vinyl chloride carcinogenesis. Environ Health Perspect 41:59-62. Ramsey JD, Flanagan RJ. 1982. Detection and identification of volatile organic compounds in blood by headspace gas chromatography as an aid to the diagnosis of solvent use. J Chromatogr 240:423-444. *Rannug U, Gothe R, Wachtmeister CA. 1976. The mutagenicity of chloroethylene oxide, chloroacetaldehyde, 2-chloroethanoI and chloroacetic acid, conceivable metabolites of vinyl chloride. Chem Biol Interact 12:251-263. *Rannug U, Johansson A, Ramel C, et al. 1974. The mutagenicity of vinyl chloride after metabolic activation. Ambio 3:194-197 Rappoport Z, Gal A. 1969. Vinylic cations from solvolysis. I. The trianisylvinyl halide system. J Am Chem Soc 91:5246-5254. Rashad MM, Elbelbessy SF, Hussein NG, et al, 1994. Effect on some enzyme-activities of occupational exposure to vinyl chloride monomer for 5 consecutive years. Medical Science Research 22(4):289-290. *Rasmussen RA, Harsch DE, Sweany PH, et al. 1977. Determination of atmospheric halocarbons by a temperature-programmed gas chromatographic freeze-out concentration method. Journal of the Air Pollution Control Association 27:579-581. *Reding R. 1987. Chromatographic monitoring methods for organic contaminants under the Safe Drinking Water Act. J Chromatogr Sci 25:338-344. *Reynolds ES, Jaeger RJ, Murphy SD. 1975a. Acute liver injury by vinyl chloride: Involvement of endoplasmic reticulum in phenobarbital-pretreated rats. Environ Health Perspect 11:227-233. Reynolds ES, Moslen MT, Szabo S, et al. 1975b. Hepatotoxicity of vinyl chloride and 1,1dichloroethylene. Am J Pathol 81:219-231. *Rinsky RA, Ott G, Ward E, et al. 1988. Study of mortality among chemical workers in the Kanawha Valley of West Virginia. Am J Ind Med 13:429-438. Roberts PV, Hopkins GD, Mackay DM, et al. 1990. A field evaluation of in-situ biodegradation of chlorinated ethenes: part I, methodology and field site characterization. Ground Water 28(4):591-604. Rogers JC. 1986. Analysis of vinyl chloride monomer in ambient air by gas chromatography. Proceedings of the 1986 EPA/APCA Symposium on Measurement of Toxic Air Pollutants, Raleigh, North Carolina. R&S149230 --DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 8. REFERENCES 213 *Rosenman KD, Rizzo JE, Conomos MG, et al. 1989. Central nervous system malformations in relation to polyvinyl chloride production facilities. Arch Environ Health 44:279-282. Rosli M, Zimmerli B, Marek B. 1975. [Residues of vinyl chloride-monomer in edible oils]. Mitteilungen aus dem Gebiete der Lebensmitteluntersuchung und Hygiene 66:507-511. (German) *Sabadie N, Malaveille C, Camus AM, et al. 1980. Comparison of the hydroxylation of benzo(a)pyrene with the metabolism of vinyl chloride, n-nitrosonorpholine, and n-nitroson'methylpiperazine to mutagens by human and rat liver microsomal fractions. Cancer Res 409:119-126. *Sabel GV, Clark TP. 1984. Volatile organic compounds as indicators of municipal solid waste leachate contamination. Waste Management Research 2:119-130. *Sabljic A. 1984. Prediction of the nature and strength of soil sorption of organic pollutants by molecular topology. J Agric Food Chem 32:243-246. *Sakabe H. 1975. Bone lesions among polyvinyl chloride production workers in Japan. Ann NY Acad Sci 246:78-79. *Sal'nikova LS, Kotsovskaya IA, 1980. [Effect of vinyl chloride on embryogenesis of rats]. Gig Tr Prof Zabol 46-47. (Russian) Sanhueza E, Heicklen J. 1975. Oxidation of chloroethylene. J Phys Chem 79:677-681. Santella RM. 1988. Monitoring human exposure to carcinogens by DNA adduct measurement. Cell Biol Toxicol 4:511-516. Sato A, Endoh K, Kaneko T, et al. 1991. A simulation study of physiological factors affecting pharmacokinetic behaviour of organic solvent vapours. Br J Ind Med 48(5):342-347. Sax NI, Lewis RJ, eds. 1987. Hawley's condensed chemical dictionary. 11th ed. New York, NY: Van Nostrand Reinhold Co., 1223. *Sax NI, Lewis RJ, eds. 1989. Dangerous properties of industrial materials. 7th ed. New York, NY: Van Nostrand Reinhold Co., 3473-3474. Sayers RR, Yant WP, Waite CP, et al. 1930. Acute response of guinea pigs to vapors of some new commercial organic compounds: I. Ethylene dichloride. Pub Health Rep 45(5):225-239. *Schaffner F. 1978. Effect of long-term vinyl chloride exposure in mouse liver structure. Falk Symp 25:189-199. Schnorr TM. 1988. NlOSH epidemiologic studies of pregnancy outcomes. Reproductive Toxicology 2:247-251. SCIsearch. 1990. Vinyl chloride. Dialog Information Services, Institute for Scientific Information. July 1990. R&S 149231 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 214 Sever LE, Hessol NA. 1985. Toxic effects of occupational and environmental chemicals on the testes. Thomas JA, Korach KA, McLachlan JA, editors. Target organ toxicology series: Endocrine toxicology. New York, NY: Raven Press, 211-248. *Shahin MM. 1976. The nonmutagenicity and recombinogenicity of vinyl chloride in the absence of metabolic activation. Mutat Res 40:269-272. *Sharma RP, Gehring PJ. 1979. Immunologic effects of vinyl chloride in mice. Ann NY Acad Sci 31:551-563. ""Short RD, Minor JL, Winston JM, et al. 1977. A dominant lethal study in male rats after repeated exposures to vinyl chloride or vinylidene chloride. J Toxicol Environ Health 3:965-968. Silka LR, Wallen DA, 1988. Observed rates of biotransformation of chlorinated aliphatics in groundwater. In: Superfund 1988, Proc 9th Natl Conf. Haz Mat Control Res Inst, 138-141. "Simmon VF, Kauhanen K, Tardiff RG. 1977. Mutagenic activity of chemicals identified in drinking water. Proc Second Int Conf Environ Mutagens, Edinburgh, July 11-15, 1977. Progress in Genetic Toxicology. Amsterdam: Elsevier/North Holland Biomedical Press. 249-258. "Simonato L, L'Abbe KA, Andersen A, et al. 1991. A collaborative sudy of cancer incidence and mortality among vinyl chloride workers. Scan J Work Environ Health 17(3): 159-169. "Singer B, Spengler SJ, Chavez F, et al. 1987. The vinyl chloride-derived nucleoside, N2,3ethenoguanosine, is a highly efficient mutagen in transcription. Carcinogenesis 8:745-747. Singh HB, Salas LJ, Smith AJ, et al. 1981. Measurements of some potentially hazardous organic chemicals in urban environments. Atmos Environ 15:601-612. Singley JE. 1984. Water (municipal treatment). In: Kirk-Othmer encyclopedia of chemical technology. Vol. 24, 387. "Sinues B, Sanz A, Bernal ML, et al. 1991. Sister chromatid exchanges, proliferating rate index, and micronuclei in biomonitoring of internal exposure to vinyl chloride monomer in plastic industry workers. Toxicol Appl Pharmacol 108(l):37-45. "Sittig M. 1985. Handbook of toxic and hazardous chemicals and carcinogens. 2nd ed. Park Ridge, NJ: Noyes Publications, 918-921. "Smith LR, Dragun J. 1984. Degradation of volatile chlorinated aliphatic priority pollutants in groundwater. Environmental International 10:291-298. "Smulevich VB, Fedotova IV, Filatova VS. 1988. Increasing evidence of the rise of cancer in workers exposed to vinyl chloride. Br J Ind Med 45:93-97. Sobel W, Bond GG, Skowronski BJ, et al. 1987. A soft tissue sarcoma case control study in a large multi-chemical manufacturing facility. Chemosphere 16:2095-2099. R&S 149232 '"DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 215 *Sokal JA, Baranski B, Majka J, et al. 1980. Experimental studies on the chronic toxic effects of vinyl-chloride in rats. J Hyg Epidemiol Microbiol Immunol 24:285-294. *Spirtas R, McMichael AJ, Gamble J, et al. 1975. The association of vinyl chloride exposures with morbidity symptoms. Am Ind Hyd Assoc J 36:779-789. *SRI. 1990a. 1990_Directory of chemical producers. Menlo Park, CA: SRI International, 1064. *SRI. 1990b. 1990 Directory of chemical producers. Supplement. Menlo Park, CA: SRI International, 66. *SRI. 1993. Directory of chemical producers. Menlo Park, CA: SRI International, 1006. *SRI. 1994. Directory of chemical producers. Menlo Park, CA: SRI International, 994. *Stallones RA. 1987. The use and abuse of subgroup analysis in epidemiological research. Prev Med 16:183-194. Stellman JM. 1985. Statistical and practical problems of cohort study design: Occupational Hazards in the health care industry. National Cancer Institute Monograph No. 67. ^Stephens RD, Ball NB, Mar DM. 1986. A multimedia study of hazardous waste landfill gas migration. In: Pollutants in a Multimedia Environment. Cohen Y, ed. New York, NY: Plenum Press, 265-287. Storetvedt-Heldaas S, Andersen AA, Langard S. 1987. Incidence of cancer among vinyl chloride and polyvinyl chloride workers: Further evidence for an association with malignant melanoma. Br J Ind Med 44:278-280. Strik JJTWA. 1987. Porphyrins in urine as an indication of exposure to chlorinated hydrocarbons. Ann NY Acad Sci 514:219-221. *Stuart JD. 1983. Organics transported thru selected geological media: Assessment of organics transported away from industrial waste disposal sites. Comm Univ Storrs Inst of Water Resources. NTIS PB 83-224246; 1-10. Studniarek M, Durski K, Liniecki J, et al. 1989. Effects of vinyl chloride on liver function of exposed workers, evaluated by measurements of plasma clearance of the 99mTc-N-2,4-dimethylacetaniliodiminodiacetate complex. J Appl Toxicol 9:213-218. *Stutz DR, Ulin S, eds. 1992. Hazardous materials injuries. A handbook for pre-hospital care. Third edition. Beltsville, MD: Bradford Communications Corporation, 286-287. Styles JA. 1977. A method for detecting carcinogenic organic chemicals using mammalian cells in culture. Br J Cancer 36:558-563.* *Suciu I, Drejman I, Valeskai M. 1963. [Investigation of the diseases caused by vinyl chloride]. Med Intern 15:967-977. (Romanian) R&S 149233 DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 216 *Suciu I, Prodan L, Ilea E, et al. 1975. Clinical manifestations in vinyl chloride poisoning. Ann NY Acad Sci 246:53-69. Sugita M, Masuda Y, Tsuchiya K. 1986. Early detection and signs of hepatoangiosarcoma among vinyl chloride workers. Am J Ind Med 10:411-417. *Suzuki Y. 1978. Pulmonary tumors induced in mice by vinyl chloride monomer. Environ Res 16:285-301. *Suzuki Y. 1980. Nonneoplastic effects of vinyl chloride in mouse lung. Environ Res 21:235-253. *Suzuki Y. 1981. Neoplastic and nonneoplastic effects of vinyl chloride in mouse lung. Environ Health Perspect 41:31-52. *Suzuki Y. 1983. Neoplastic effect of vinyl chloride in mouse lung--lower doses and short-term exposure. Environ Res 32:91-103. *Svensson K, Osterman-Golkar S. 1986. Covalent binding of intermediates to hemoglobin in the mouse as an approach to studying the metabolic pathways of 1,2-dichloroethane. In: Singer, B and Bartsh, H eds. The role or cyclic acid adducts in carcinogenesis and mutagenesis. Lyon, France: World Health Organization, International Agency for Research on Cancer, 269-279. Sweeney MH, Beaumont JJ, Waxweiler RJ, et al. 1986. An investigation of mortality from cancer and other causes of death among workers employed at an east Texas chemical plant. Arch Environ Health 41:23-28. *Swenberg JA, Fedtke N, Ciroussel F, et al. 1992. Etheno adducts formed in DNA of vinyl chloride-exposed rats are highly persistent in liver. Carcinogenesis 13(4):727-729. Tabacova S. 1986. Maternal exposure to environmental chemicals. Neurotoxicology 7:421-440. *Tabershaw IR, Gaffey WR. 1974. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J Occup Med 16:509-518. Tamburro CH. 1984. Relationship of vinyl monomers and liver cancers: angiosarcoma and hepatocellular carcinoma. Semin Liver Dis, May 1984. 4:158-169. *Tamburro CH, Makk L, Popper H. 1984. Early hepatic histologic alterations among chemical (vinyl monomer) workers. Hepatology 4:413-418. Tarkowski S. 1984. Preventive measure against occupational hazards in the PVC production industry. Prog Clin Biol Res 141:177-189. Taylor KJW, Barett JJ, Williams DMJ, et al. 1976. Clinical aspects of vinyl chloride disease: Preliminary results of grey-scale ultrasonography in the detection of vinyl chloride related liver and spleen disease. Proc R Soc Med 69:292-295. Telliard WA, Rubin MB, Rushneck DR. 1987. Control of pollutants in waste water. J Chromatogr Sci 25:322-327. R&S 149234 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 217 *Ten Berge WF. 1987. Incidence of cancer among vinyl chloride and polyvinyl chloride workers: Further evidence for an association with malignant melanoma. Br J Ind Med 44:718-719. *Teta MJ, Schnatter AR, Ott MG, et al. 1990. Mortality surveillance in a large chemical company: The union carbide corporation experience, 1974-1983. Am J Ind Med 17:435-447. *Theriault G, Iturra H, Gingras S. 1983. Evaluation of the association between birth defects and exposure to ambientT vinyl chloride. Teratology 27:359-370. Thibodeaux LJ, 1981. Estimating the air emissions of chemicals from hazardous waste landfills. Journal of Hazardous Materials 4:235-244, *Thomas TL, Stewart PA, Stemhagen A, et al. 1987. Risk of astrocytic brain tumors associated with occupational chemical exposures: A case-referent study. Scand J Work Environ Health 13:417-423. *Til HP, Feron VJ, Immel HR. 1991. Lifetime (149-week) oral carcinogenicity study of vinyl chloride in rats. Food Chem Toxicol 29(10):713-718. *Til HP, Immel HR, Feron VJ. 1983. Lifespan oral carcinogenicity study of vinyl chloride in rats. Final report. Civo Institutes, TNO. Report No. V 93.285/291099. *Torkelson TR, Oyen F, Rowe VK. 1961. The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Am Ind Hyg Assoc J 22:354-361. *TRI92. 1994. Toxic Chemical Release Inventory, National Library of Medicine, National Toxicology Program, Bethesda, MD. Tuazon EC, Atkinson R, Aschmann SM. et al. 1988. Atmospheric reactions of chloroethenes with the hydroxy radical. International Journal of Chemical Kinetics 20:241-266. Tzouwara-Karayanni S, Demertzis PG, Kontominas MG. 1987. Adsorption of vinyl chloride onto plasticized polyvinyl chloride by classical partition in the presence of various simulating solvents: Migration aspects. Lebensmittel-Wissenschaft und Technologie 20:202-206. *Ungvary G, Hudak A, Tatrai E, et al. 1978. Effects of vinyl chloride exposure alone and in combination with trypan blue-applied systematically during all thirds of pregnancy on the fetuses of CFY rats. Toxicology 11:45-54. *USITC. 1994. Synthetic organic chemicals: United States production and sales, 1992. Washington, DC: United States International Trade Commission. USITC Publication 2720, 1-3, table 3-19.. Uzych L. 1988. Human male exposure to vinyl chloride and possible teratogenic and mutagenic risks: A review. Hum Toxicol 7:517-527. Vaino H. 1978. Vinyl chloride and vinyl benzene (styrene) - Metabolism, mutagenicity, and carcinogenicity. Chem Biol Interact 22:117-124.* *van Sittert NJ, de Jong G. 1985. Biomonitoring of exposure to potential mutagens and carcinogens in industrial populations. Food Chem Toxicol 23:23-31. R&S149235 DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 8. REFERENCES 218 Van Duuren BL. 1988. Direct-acting alkylating and acylating agents. DNA adduct formation. Structure-activity and carcinogenesis. Ann NY Acad Sci 534:620-634. *Veith GD, Macek KJ, Petrocelli SR, et al. 1980. An evaluation of using partition coefficients and water solubility to estimate bioconcentration factors for organic chemicals in fish. In: Aquatic Toxicology, ASTM STP 707, JG Eaton, Parrish PR, Hendricks AC, eds. American Society for Testing and Materials. 116-129. *Veltman G, Lange CE, Juhe S, et al. 1975. Clinical manifestations and course of vinyl chloride disease. Ann NY Acad Sci 246:6-17. Verburgt FG, Vogel E. 1977. Vinyl chloride mutagenesis in Drosophila melanogaster. Mutat Res 48:327-336. *Verschueren K. 1983. Handbook of Environmental Data on Organic Chemicals, 2nd ed. New York, NY: Van Nostrand Reinhold Company; 1185-1186. *Victorin K, Stahlberg M. 1988a. A method for studying the mutagenicity of some gaseous compounds in Salmonella typhimurium. Environ Mol Mutagen 11:65-77. Victorin K, Stahlberg M. 1988b. Photochemical formation of mutagenic compounds from alkenes and ozone or nitrogen dioxide. Environ Mol Mutagen 11:79-91. *Vihko R, Vihko P, Maentausta O, et al. 1984. Assessment of early hepatotoxicity: Biological monitoring and surveillance of workers exposed to chemicals. Aitio A, Riihimaki V, Vainio J, eds. Washington, DC: Hemosphere Publishing Co., 309-313. *Viola PL. 1970. Pathology of vinyl chloride. Med Lav 61:174-180. *Viola PL, Bigotti A, Caputo A. 1971. Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31:516-522. Vogel TM, Criddle CS, McCarty PL. 1987. Transformations of halogenated aliphatic compounds. Environmental Science and Technology 21:722-736. *WAC. 1985. Groundwater quality. Wisconsin Administrative Code. Chapter NR 140. Department of Natural Resources. WAC. 1988. Control of hazardous pollutants. Wisconsin Administrative Code. Chapter NR 445. Department of Natural Resources. Wagnerova M, Wagner V, Znojemska S, et al. 1988. Factors of humoral resistance in workers exposed to vinyl chloride with a view to smoking habits. J Hyg Epidemiol Microbiol Immunol 32:265-272. Wagnerova M, Znojemska S, Wagner V, et al. 1986. Humoral factors of resistance in the cohort of workers exposed to vinyl chloride in the span of six years, concerning the influence of smoking. Czech Med 9:210-217. "DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 8. REFERENCES 219 Wagoner JK, Infante PF, Apfeldorf RB. 1980. Toxicity of vinyl chloride and polyvinyl chloride as seen through epidemiologic observations. J Toxicol Environ Health 6:1101-1107. Waite GP, Patty FA, Yant WP. 1930. Acute response of guinea pigs to vapors of some new commercial organic compounds. III. "Cellosolve." Pub Health Rep 45(26):1459-1466. Wakeman IB, Johnson HR. 1978. Vinyl chloride formation from the thermal degradation of polyvinyl chloride. Polymer Engineering and Science 18:404-407. *Walker AE. 1976. Clinical aspects of vinyl chloride disease: Skin. Proc R Soc Med 69:286-289. *Wallace LA, Pellizzari E, Hartwell T, et al. 1984. Personal exposure to volatile organic compounds. Environ Res 35:293-319. Walles AA, Holmberg B. 1984. Induction of single-strand breaks in DNA of mice after inhalation of vinyl chloride. Cancer Lett 25:13-18. *WaIIes SAS, Holmberg B, Svensson K, et al. 1988. Induction of single-strand breaks in liver DNA of mice after inhalation of vinyl chloride. Methods for Detecting DNA Damaging Agents in Humans: Applications in Cancer Epidemiology and Prevention, IARC Scientific Publications No. 89, Bartsch H, Hemminki K, O'Neill IK, eds. Lyon, France: International Agency for Research on Cancer, 227-231. Wang YL, Zhao XH. 1987. Occupational health of working women in China. Asia-Pacific Journal of Public Health 4:66-71. *Wang T, Lenahan R, Kanik M. 1985. Impact of trichloroethylene-contaminated groundwater discharged to the main canal and Indian River Lagoon, Vero Beach, Florida. Bull Environ Contam Toxicol 34:578-586. *Ward AM. 1976. Clinical aspects of vinyl chloride disease: Evidence of an immune complex disorder in vinyl chloride workers. Proc R Soc Med; 69:289-290. *Watanabe PG, Gehring PJ. 1976. Dose-dependent fate of vinyl chloride and its possible relationship to oncogenicity in rats. Environ Health Perspect 17:145-152. *Watanabe PG, McGowan GR, Gehring PJ. 1976a. Fate of [UC] vinyl chloride after single oral administration in rats. Toxicol Appl Pharmacol 36:339-352. *Watanabe PG, McGowan GR, Madrid EO, et al. 1976b. Fate of [l4C] vinyl chloride following inhalation exposure in rats. Toxicol Appl Pharmacol 37:49-59. *Watanabe PG, Zempel JA, Gebring PJ. 1978a. Comparison of the fate of vinyl chloride following single and repeated exposure in rats. Toxicol Appl Pharmacol 44:391-399. *Watanabe PG, Zempel JA, Pegg DG, et al. 1978b. Hepatic macromolecular binding following exposure to vinyl chloride. Toxicol Appl Pharmacol 44:571-579.* *Waxweiler RJ, Smith AH, Falk H, et al. 1981. Excess lung cancer risk in a synthetic chemicals plant. Environ Health Perspect 41:159-165. R&S 149237 --DRAFT FOR PUBLIC COMMENT*' VINYL CHLORIDE 8. REFERENCES 220 *Waxweiler RJ, Stringer W, Wagner JK, et al. 1976. Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Sci 271:40-48. *Weber H, Reinl W, Greiser E. 1981. German investigations on morbidity and mortality of workers exposed to vinyl chloride. Environ Health Perspect 41:95-99. Weinbren K. 1976. Clinical aspects of vinyl chloride disease: Histopathology of liver lesions associated with exposure to vinyl chloride monomer. Proc R Soc Med 69:299-303. *Westrick JJ, Mello JW, Thomas RF. 1984. The groundwater supply survey. Journal of the American Water Works Association 76:52-59. WHO. 1986. Diseases caused by toxic halogen derivatives of aliphatic and aromatic hydrocarbons. Early detection of occupational diseases. Geneva, Switzerland: World Health Organization, 102-121. ^Williams DT. 1976. Confirmation of vinyl chloride in foods by conversion to l-chloro-1,2dibromothane. J Assoc Off Anal Chem 59:32-34. *Williams DT, Miles WF. 1975. Gas-liquid chromatographic determination of vinyl chloride in alcoholic beverages, vegetable oils, and vinegars. J Assoc Off Anal Chem 58:272-275. *Williamson IG, Ramsden RT. 1988. Angiosarcoma of maxillary antrum--association with vinyl chloride exposure. J Laryngol Otol 102:464-467. Williamson J, Kavanagh B. 1987. Vinyl chloride monomer and other contaminants in PVC welding fumes. Am Ind Hyg Assoc J 48:432-436. Wilson JT, Wilson BH. 1985. Biotransformation of trichloroethylene in soil. Appl Environ Microbio 49:242-243. *Wilson RH, McCormick WE, Tatum CF, et al. 1967. Occupational acroosteolysis report of 31 cases. JAMA 201:577-580. Wilson BH, Smith GB, Rees JF. 1986. Biotransformations of selected alkylbenzenes and halogenated aliphatic hydrocarbons in methanogenic aquifer material: A microcosm study. Environmental Science and Technology 20:997-1002. *Wisconsin Department of Natural Resources. 1987. Wisconsin Department of Natural Resouces. Order of the state of Wisconsin natural resources board repealing, renumbering, renumbering and amending, amending, repealing and recreating, and creating rules. Section 27, Chapter NR 105. Surface Water Quality Criteria for Toxic Substances. *Wisniewska-Knypl JM, Klimczak J, Kolakowski J. 1980. Monooxygenase activity and ultrastructural changes of liver in the course of chronic exposure of rats to vinyl chloride. Int Arch Occup Environ Health 46:241-249.* *Withey JR. 1976. Pharmacodynamics and uptake of vinyl chloride monomer administered by various routes to rats. J Toxicol Environ Health 1:381-394. R&S 149238 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 8. REFERENCES 221 *Wittsiepe J, Selenka F, Jackwerth E. 1990. Gas-chromatographic determination of trace amounts of vinyl-chloride in water and air after derivation to 1,2-bromochloroethane. Fresenius Journal of Analytical Chemistry 336:322-327. *Wittsiepe J. Wallschlager D, Selenka F, et al. 1993. Gas-chromatographic determination of trace amounts of vinyl chloride and dichloroethenes in water after purge-and-trap preconcentration and conversion into their dibrominated derivatives. Fresenius Journal of Analytical Chemistry 346(12): 1028-1034. *Woldbaek T, Klaboe P. 1978. The photochemical reaction of vinyl chloride with oxygen studied by infared spectroscopy. Spectrochimica Acta 34:481-487. Wolf K, Holland R, Rajaratnam A. 1987. Vinyl chloride contamination: The hidden threat. Journal of Hazardous Materials 15:163-184. *Wong O, Whorton MD, Foliart DE, et al. 1991. An industry-wide epidemiologic study of vinyl chloride workers, 1942-1982. Am J Ind Med 20(3):317-334. Wong O, Whorton MD, Ragland D, et al. 1986. An update of an epidemiologic study of vinyl chloride workers, 1942-1982. Prepared by Environmental Health Associates, Inc. for Chemical Manufacturers Association, Oakland, CA. *Wood JA, Porter ML. 1987. Hazardous pollutants in class II landfills. JAPCA 37:609-615. *Wu W, Steenland K, Brown D, et al. 1989. Cohort and case-control analyses of workers exposed to vinyl chloride: An update. J Occup Med 31:518-523. Young P, Parker A. 1984. Vapors and odors and toxic gases from landfills. In: Hazardous and Industrial Waste Management and Testing: Third Symposium. ASTM STP 851. LP Jackson, AR Rohlik, PA Conway, eds. Philadelphia, PA: American Society for Testing and Materials. 24-41. * Young TL, Santella RM, 1988. Development of techniques to monitor for exposure to vinyl chloride: Monoclonal antibodies to ethenoadenosine and ethenocytidine. Carcinogenesis 9:589-592. Young DR, Gossett RW, Baird RB, et al. 1983. Wastewater inputs and marine bioaccumulation of priority pollutant organics off Southern California. In: Water Chlorination: Environ Impact Health Eff 4:871-884. *Zhang J, Hatakeyama S, Akimoto H. 1983. Rate constants of the reaction of ozone with trans-1,2dichloroethene and vinyl chloride in air. International Journal of Chemical Kinetics 15:655-668. *Zhao M-Y, Ying C-J, Shao N, et al. 1994, The study of health effects of vinyl chloride air pollution on population. Biomed Environ Sci 7:136-143. Zielhuis RL, Stijkel A, Verberk MM, et al. 1984. Plastic Monomers. Health Risks to Female Workers in Occupational Exposure to Chemical Agents. Berlin: Springer-Verlag, 42-47. Zimmerman HJ. 1986. Effects of alcohol on other hepatotoxins. Alcoholism 10:3-15. `"DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 8. REFERENCES 222 *Zuccato E, Mancucci F, Fanelli R, et al. 1979. Head-space gas-chromatographic analysis of vinyl chloride monomer in rat blood and tissues. Xenobiotica 9:27-31. R&S 149240 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE 223 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 -- Exposure to a chemical for 365 days or more, as specified in the Toxicological Profiles. Developmental Toxicity -- The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death. EPA Health Advisory -- An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days, as specified in the froxicological Profiles. `DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 9. GLOSSARY 224 Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. In Vitro -- Isolated from the living organism and artificially maintained, as in a test tube. In Vivo -- Occurring within the living organism. Lethal Concentration(LO) (LClo) -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration^, (LCS0) -- 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(LO) (LDlo) -- The lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Dose(S0, (LD50) -- The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time(S0, (LTS0) -- 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 (Knw) - The equilibrium ratio of the concentration's 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. R&S149242 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE 9. GLOSSARY 225 q,* -- The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the nultistage procedure. The q,* can be used to calculate an estimate of carcinogenic potency, the ncremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and jg/m3 for air). Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during-a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate 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 ire measured over a 24-hour period. Reproductive Toxicity -- The occurrence of adverse effects on the reproductive system that may result fom exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related mdocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, ertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of his system. jUiort-Term Exposure Limit (STEL) -- The maximum concentration to which workers can be exposed R>r up to 15 min continually. No more than four excursions are allowed per day, and there must be at east 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Parget 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 (TDS0) -- 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. JFs 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 ;xtrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty n using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. R&S 149243 "`DRAFT FOR PUBLIC COMMENT"* NYL CHLORIDE A-1 APPENDIX A MINIMAL RISK LEVEL WORKSHEETS -hemical Name: Vinyl Chloride )AS Number: 75-01-4 )ate: August 1995 'rofile Status: Draft 4 Update toute: [x] Inhalation [ ] Oral Juration: [x] Acute [ ] Intermediate [ ] Chronic Sraph Key: 26 ipecies: Rat linimal Risk Level: 0.5 [ ] mg/kg/day [x] ppm Reference: John et al. 1977, 1981 xperimental design: CF-1 mice were exposed to vinyl chloride at concentrations of 0, 50, and i00 ppm for 7 hours/day on gestational days 6-15 (John et al. 1977, 1981). Concurrent control iroups were used, one for each dose level. Control groups were sham-exposed to filtered oom air. Exposure was conducted in chambers of 3.7 m3 volume under dynamic conditions. Animals were observed daily for clinical signs, and maternal body weights were determined .everal times during gestation. Animals were euthanized on gestational day 18 by carbon iioxide inhalation. Maternal liver weight was determined and uterine horns were examined. :etuses were weighed, measured (crown-rump length), sexed, and subjected to gross and listopathological examinations. iffects noted in study and corresponding doses: At 50 ppm, the NOAEL, the only effect noted vas a slight increase in crown-rump length (p< 0.05), and this was not considered to be an idverse effect. However, delayed fetai ossification (p< 0.05) was seen at the LOAEL of >00 ppm. In addition, an increase in resorptions at 500 ppm was considered to have been vithin historical control limits. Significant changes in percentage resorption, litter size, and fetal Dody weight would not have been observed at 500 ppm if comparison had been made to the jther control group. There was frank maternal toxicity at 500 ppm (17% death). Dose end point used for MRL derivation: x] NOAEL [ ] LOAEL Jncertainty Factors used in MRL derivation: [ ] 10 for use of a minimal LOAEL [x] 10 for extrapolation from animals to humans [xj 10 for human variability DRAFT FOR PUBLIC COMMENT-- VINYL CHLORIDE APPENDIX A A-2 Was a conversion used from ppm in food or water to a mg/bodv weight dose? No. If so, explain: If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: Since vinyl chloride readily reaches steady state, is rapidly metabolized and excreted, and neither it nor its metabolites are accumulated, periodicity is attained. Therefore, no adjustment for intermittent exposure is necessary. The NOAEL was converted to a Human Equivalent Concentration (HEC) by multiplying the ratio of the partition coefficients in mice to that of humans (XAIX,,). Since the partition coefficient in mice is greater than that in humans, as seen in Table 2-3 of the profile, a default value of 1 is used for the ratio. In accordance with ATSDR policy, if a default value of 1 is used for the ratio, then the NOAEL is not changed and a full uncertainty factor of 10 is needed for extrapolation from animals to humans. An uncertainty factor (UF) of 100 (10 for extrapolation from animals to humans and 10 for human variability) was applied. The acute inhalation MRL was calculated as follows: MRL = NOAELhec - UF = (50 ppm x X/JXh) -f (10 x 10) = (50 ppm x 1) + 100 = 0.5 ppm. Other additional studies or pertinent information which lend support to this MRL: Delayed ossification (500 ppm, the lowest dose tested) was the only developmental effect observed in a rabbit developmental study (John et al. 1977; 1981). R&ST49246 "DRAFT FOR PUBLIC COMMENT*** i INYL CHLORIDE APPENDIX A A-3 Chemical Name: Vinyl Chloride ,AS Number: 75-01-4 )ate: August 1995 Yofile Status: Draft 4 Update toute: [x] Inhalation [ ] Oral )uration: [ ] Acute [x] Intermediate [ ] Chronic Sraph Key: 33 Species: Rat vlinimal Risk Level: 0,03 [ ] mg/kg/day [x] ppm Reference: Bi et al. 1985 Experimental design: Groups of 75 adult male Wistar rats were exposed to 0, 10, 100, or i.OOO ppm vinyl chloride by inhalation 6 hours/day, 6 days/week for 12 months, with sacrifices it 3, 6, 12, and 18 months after initial exposure. Animals were deprived of food and water :uring exposure. The effluent values for the influx of vinyl chloride into the exposure chambers 10, 100, and 3,000 ppm) were 5.3, 20, and 330 mL/min, and for fresh air were 624, 132, and ;7.2 mL/min, respectively. Animals were weighed once per month before and after exposure ind observed for symptoms twice a day. The organs (kidney, liver, spleen, heart, and testes) of dead or euthanized animals were weighed; gross and histopathological examinations were performed on the testes, lungs, liver, heart, kidneys, spleen, and brain. Effects noted in study and corresponding doses: Statistically significant (p < 0.001) increases ti liver-to-body weight ratio were observed at a LOAEL of 10 ppm at 6 months exposure, and dose-response was evident at higher doses. Significant (p < 0.05) increases in heart- and spleen-to-body weight ratios were also noted at this dose level. At higher dose levels (100 ppm tnd above), decreased testicular weight was observed. Increased incidence of damage to 'eminiferous tubules was observed, presumably after 12 months of exposure (not specified). Dose end point used for MRL derivation: ] NOAEL [x] LOAEL Uncertainty Factors used in MRL derivation: [x] 3 for use of a minimal LOAEL [xj 10 for extrapolation from animals to humans [x] 10 for human variability Was a conversion used from ppm in food or water to a mo/body weight dose? No. If so, explain: If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: Since vinyl chloride readily reaches steady state, is rapidly metabolized and excreted, and neither it nor its metabolites are accumulated, periodicity is attained. Therefore, no adjustment for intermittent exposure is necessary. The LOAEL was converted to a Human .Equivalent Concentration (HEC) by multiplying the ratio of the partition coefficients in rats to ^hat of humans (V^h)- Since the partition coefficient in rats is greater than that in humans, as R&S149247 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE APPENDIX A A-4 ! seen in Table 2-3 of the profile, a default value of 1 is used for the ratio. In accordance with ATSDR policy, if a default value of 1 is used for the ratio, then the LOAEL is not changed and a full uncertainty factor of 10 is needed for extrapolation from animals to humans. An uncertainty factor (UF) of 300 (3 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability) was used to calculate the MRL as follows: MRL = LOAELhec -s- UF; MRL = 10 ppm x A,aA.h = (3x10x10) = 10 ppm x 1 + 300 = 0.03 ppm. Other additional studies or pertinent information which lend support to this MRL; Liver enlargement and/or histopathological changes have been noted in a number of intermediate-duration inhalation studies in animals (Lester et al. 1963; Schaffner 1978; Sokal et al. 1980, Torkelson et al. 1961; Wisniewska-Knypl et al. 1980). The study by Bi et al. 1985 shows these effects at a somewhat lower dosage. Additional support comes from a study citing immunostimulation in mice at 10 ppm (Sharma and Gehring 1979). R & S 149248 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE APPENDIX A A-5 Chemical Name: Vinyl Chloride CAS Number: 75-01-4 Date: August 1995 Profile Status: Draft 4 Update Route: [ ] Inhalation [x] Oral Duration: [ ] Acute [ ] Intermediate [x] Chronic Graph Key: 5 Species: Rat Minimal Risk Level: 2 x 10'5 [x] mg/kg/day [ ] ppm Reference: Til et al. 1983, 1991 Experimental design: Groups of 100 Wistar rats of each sex (except for highest dose group, which contained 50 of each sex) were administered vinyl-chloride-monomer-enriched polyvinyl chloride powder in feed 4 hours/day for 149 weeks. Three dose groups (0.018, 0.17, and 1.7 mg/kg/day, representing the actual oral intake of vinyl chloride in feed) plus two control groups were used. Authors also calculated the exposure levels of vinyl chloride for the animal. These levels represent the oral intake minus the amount of vinyl chloride excreted in feces, which was considered to be still enclosed in PVC granules and therefore not bioavailable. Animals were observed until death or sacrifice in extremis, then organs were weighed and histopathologically examined. An uncertainty factor (UF) of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability) was used to derive the MRL: MRL = p.018/1000 = 0.00002 mg/kg/day. Effects noted in study and corresponding doses: Females fed 0.018 mg/kg/day, the LOAEL, displayed an increase in the number of hepatocellular basophilic foci indicating cellular alteration. This increase was also observed at the intermediate dose (0.17 mg/kg/day). At the highest dose (1.7 mg/kg/day), increased incidences of liver cell polymorphism, hepatic cysts, foci of cellular alteration, neoplastic nodules, and hepatocellular carcinomas and angiosarcoma were observed. Dose end point used for MRL derivation: [ ] NOAEL [x] LOAEL Uncertainty Factors used in MRL derivation: [x] 10 for use of a LOAEL [xj 10 for extrapolation from animals to humans [x] 10 for human variability Was a conversion used from ppm in food or water to a mq/bodv weight dose? No. If so, explain: If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: N/A "DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE APPENDIX A A-6 Other additional studies or pertinent information which lend support to this MRL: This MRL is reinforced by a study by Feron et al. (1981) in which rats were fed diets containing PVC powder. Increased areas of cellular alteration (consisting of clear foci, basophilic foci, and eosinophilic foci) were observed in the liver of rats at an oral intake of vinyl chloride monomer of 1.8 mg/kg/day. 0 S 3 6 H S 18 y DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE 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 upperbound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse- Effect Levels (NOAELs), Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs). The legends presented below demonstrate the application of these tables and figures. Representative examples of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure. LEGEND See LSE Table 2-11 (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), F and chronic (365 days or more) are presented within each relevant route of exposure. In this "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE APPENDIX B B-2 example, an inhalation study of intermediate exposure duration is reported. For quick reference to health effects occurring from a known length of exposure, locate the applicable exposure period within the LSE table and figure. (3) Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table (see key number 18). (4) 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). (5) Species The test species, whether animal or human, are identified in this column. Section 2.5, "Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 2.3, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent human doses to derive an MRL. (6) Exposure Frequencv/Duration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELs from different studies. In this case (key number 18), rats were exposed to 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. (7) 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. (8) 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"). (9) LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific endpoint used to quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10 ppm. MRLs are not derived from Serious LOAELs. (10) Reference The complete reference citation is given in chapter 8 of the profile. (11) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious R & S 149252 DRAFT FOR PUBLIC COMMENT*** VINYL CHLORIDE APPENDIX B B-3 effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses not causing measurable cancer increases. (12) Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in the footnotes. Footnote "b" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm. LEGEND See Figure 2-1 LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure concentrations for particular exposure periods. (13) Exposure Period The same exposure periods appear as in the LSE table. In this example, health effects observed within the intermediate and chronic exposure periods are illustrated. (14) Health Effect These are the categories of health effects for which reliable quantitative data exists. The same health effects appear in the LSE table. (15) Levels of Exposure concentrations or doses for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in mg/kg/day. (16) NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates to a NOAEL for the test species-rat. The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table). (17) CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 corresponds to the entry in the LSE table. (18) Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q,*). (19) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. R&S 149253 DRAFT FOR PUBLIC COMMENT*** TABLE 2-1. Levels of Significant Exposure to [Chemical x] - Inhalation ' Key to figure51 Species Exposure frequency/ duration System *$ INTERMEDIATE EXPOSURE f-7 1 Systemic 4. l i 18 Rat 13 wk Resp 5d/wk 6hr/d NOAEL (ppm) LOAEL (effect) Less serious (ppm) Serious (ppm) ;8'S 36 ;i^l l 10 (hyperplasia) Reference 10 i Nitschke et al. 1981 CHRONIC EXPOSURE Cancer 38 Rat 18 mo 5d/wk 7hr/d 20 (CEL, multiple organs) Wong et al. 1982 39 Rat 89-104 wk 5d/wk 6hr/d 40 Mouse 79-103 wk 5d/wk 6hr/d 10 (CEL, lung tumors. NTP 1982 nasal tumors) 10 (CEL, lung tumors. NTP 1982 hemangiosarcomas) a The number corresponds to entries in Figure 2-1. - 6 Used to derive an intermediate inhaiation Minimal Risk Level (MRL) of 5 x 10'3 ppm; dose adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). CEL = cancer effect level; d = days(s); hr = hour(s); LOAEL = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no observed-adverse-effect level; Resp = respiratory; wk = week(s) t'SSSHS'Sd VINYL CHLORIDE DRAFT FOR PUBLIC COMMENT*' > Figure 2-1. Levels of Significant Exposure to [Chemical X] - Inhalation Acute (Si 4 days) Systemic Intermediate (15-364 days) Systemic -> (ppm) 10000 & <? ^ Jf / <f J* -SP 1000 100 10 1 > * 8.& ---------------- *'9i8r 30r 31r o 33r 28m 3 22m 3 29r O 37m 3 35m 34r 3 27 r 0.1 0.01 0.001 -- 0.0001 0.00001 -- 0.000001 0.0000001 Key r Rat m Mouse h Rabbit g Guinea Pig k Monkey 0 LOAEL for serious effects (animals) 3 LOAEL for less serious effects (animals) O NOAEL (animats) ^ CEL - Cancer Effect Level 1 Minimal risk level for effects 1 other than cancer V The number next to each point corresponds to entries in the accompanying table. ` 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. 38r 40m 39r 10'^ -- 10*5 -- Estimated Upper Bound .Human Cancer 1CT6 -- Risk Levels io-7- <--------- >"Tm0J g x CD W <!n SS26KSSd VINYL CHLORIDE APPENDIX B B-6 Chapter 2 (Section 2.5) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions. 1. What effects are known to occur in humans? 2. What effects observed in animals are likely to be of concern to humans? 3. What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites? The section covers end points in the same order they appear within the Discussion of Health Effects by Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included. The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed. Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not meant to support regulatory action; but to acquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2.5, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.7, "Interactions with Other Substances," and 2.8, "Populations that are Unusually Susceptible" provide important supplemental information. MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology the Environmental Protection Agency (EPA) provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (RfDs). R&S149256 DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE APPENDIX B B-7 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-adverseeffect 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. R&S 149257 "DRAFT FOR PUBLIC COMMENT"* VINYL CHLORIDE APPENDIX C ACRONYMS, ABBREVIATIONS, AND SYMBOLS ACGIH ADME AML atm ATSDR BCF BEI BSC C CDC CEL CERCLA CFR Ci CLP cm CML CNS d DHEW DHHS DOL ECG EEG EPA EKG F F. FAO FEMA FIFRA fpm _ ft FR g GC gen HPLC hr IDLH I ARC ILO in Kd American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion acute myeloid leukemia atmosphere Agency for Toxic Substances and Disease Registry bioconcentration factor Biological Exposure Index Board of Scientific Counselors Centigrade Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations curie Contract Laboratory Program centimeter chronic myeloid leukemia 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 C-1 R&S149259 "DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE APPENDIX C kg kkg Koc ^Ow L LC LCU LCS() LDu LDjo LOAEL LSE m MA mCi mg min mL mm mm Hg mmol mo mppcf MRL MS NCE NIEHS NIOSH NIOSHTIC ng nm NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL PCE Pg pmol PHS PMR PPb ppm kilogram metric ton organic carbon partition coefficient octanol-water partition coefficient liter liquid chromatography lethal concentration, low Hethal concentration, 50% kill lethal dose, low lethal dose, 50% kill lowest-observed-adverse-effect level Levels of Significant Exposure meter trans,trans-muconic acid millicurie milligram minute milliliter millimeter millimeters of mercury millimole month millions of particles per cubic foot Minimal Risk Level mass spectrometry normochromatic erythrocytes 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 polychromatic erythrocytes picogram picomole Public Health Service proportionate mortality ratio parts per billion parts per million R&S149260 "'DRAFT FOR PUBLIC COMMENT*" VINYL CHLORIDE APPENDIX C ppt REL RfD RTECS sec SCE SIC SMR STEL STORET TLV TSCA TRI TWA UMDNJ U.S. UF yr WHO wk > > < < % a P 5 Y pm Mg 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 short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average University of Medicine and Dentistry New Jersey 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 C-3 R&S 149261 tr U.S GOVERNMENT PRINTING OFFICE:1995-639-414 "DRAFT FOR PUBLIC COMMENT"* HISTORICAL BACKGROUND TO CMA INDUSTRY-WIDE VCM STUDY < 1971 Acute (anesthesia) and chronic (acroosteolysis) health effects reported among vinyl chloride workers. 1971 Viola et al. reported carcinogenicity of VCM in lab animals; tumors found included liver angiosarcomas. 1973 MCA sponsored epidemiology study of 8,384 VCM workers in 34 plants by Tabershaw-Cooper Associates. 1974 Creech and Johnson reported cases of angiosarcoma of the liver among B.F. Goodrich VCM workers. 1974 JMR 8/14/95 Preliminary results of MCA study confirmed high risk of angiosarcoma of the liver and indicated possible increased risks for brain, respiratory, and lymphatic cancers. Dow Confidential HISTORICAL BACKGROUND TO CMA INDUSTRY-WIDE VCM STUDY 1974 OSHA revised PEL for VCM from 500 ppm to 50 ppm and then to 1 ppm. 1981 Cooper extended CMA epidemiology study through 1972 for 10,173 workers in 37 plants and reported continuing excesses of angiosarcoma and brain cancer. 1986 Wong and Whorton updated CMA study through 1982, finding excesses of angiosarcoma, brain cancer and emphysema but no excess for lung cancer or lymphatic cancers. 1991 Wong and Whorton published results of update through 1982. 1993 JMR 8/14/95 CMA and Wong exchanged letters to the editor regarding brain cancer and emphysema findings. Dow Confidential 2 of 2 R & S 149263 PROPOSED VCM/BRAIN CANCER STUDY, UNIV. OF LOUISVILLE y C. Tamburro, MD, has proposed to evaluate brain cancer among present and former Goodrich VCM workers using modified casecontrol methods. Cost to CMA about $100K. Dow Confidential INDUSTRY-WIDE VCM COHORT MORTALITY STUDY UPDATE Progress y CMA VCM Health Committee awarded contract for epidemiology study to Dr. Kenneth Mundt et al.. Applied Epidemiology, Inc., Amherst MA. y Study process began 3/1/95, scheduled for completion by 3/31/97, cost $350K prorated according to each company's 1994 nameplate capacity. y CMA, AEI, and J. Ramlow have completed and submitted National Death Index application to identify cohort deaths between 1982 and 1992. JMR 8/7/95 Dow Confidential lof 2 INDUSTRY-WIDE VCM COHORT MORTALITY STUDY UPDATE y AEI has drafted a study protocol according to CMA GEP's and is having it peer-reviewed by third-party scientists V AEI is preparing necessary software and death rate files for the updating the mortality analysis when all the old and new data have been collected. Roadblocks y Contract calls for CMA to faciliate transfer of data from previous contractor, ENSR, to AEI. ENSR has shipped work history data to AEI, but cannot locate death certificates. y CMA is negotiating to have unedited data tapes sent to AEI in lieu of death certificates. JMR 8/7/95 Dow Confidential 2 of 2 ATSDR DATA NEEDS FOR VCM Background y September 1992: ATSDR announced priority needs for reproductive and developmental data: ^Two-generation reproductive tox study. >Two-species developmental tox study. y September, 1994: EPA announced proposed test rule based on ATSDR request, plus neurotoxicity test requirement. Progress y November 1994: CMA VCM Health Com mittee agreed to work towards MOU with ATSDR by 5/31/95 (via outside counsel). JMR 8/7/95 Dow Confidential lof 2 ATSDR DATA NEEDS FOR VCM y March 1995: CMA submitted proposed protocol for the reproductive study plus a review of existing developmental data. y May 1995: ATSDR requested proposed protocol for 2-generation reproductive study with a "piggy-back" 1-species developmental substudy. y June 1995: CMA submitted proposed protocol as requested, estimated cost to be $400-600K prorated to each company's nami--1 ^ capacity. y July 1995: EPA considering prop possible neurotox. add-on; ATSI peer reviewers, agrees that MOL v could not have been met. JMR 8/7/95 Dow Confidential 2 of 2