Document MnXjBGQg7LjGB6YgBgO8gQO9

PB90-103870 TOXICOLOGICAL PROFILE FOR VINYL CHLORIDE Syracuse Research Corporation Syracuse, NY RECcJVSD "JAN 1 4 1991 Aug 89 U.S. DEPARTMENT OF COMMERCE National Technical Information Service UCC 107841 PB90-103670 Toxicological Profile for VINYL CHLORIDE Agency for Toxic Substances and Disease Registry U.S. Public Health Service REPRODUCED BY U.S. DEPARTMENT OF COMMERCE L- NATIONAL TECHNICAL INFORMATION SERVICE SPRINGFIELD, VA. 22161 lip ^ 7 07842 ATSDR/TP-88/ 25 TOXICOLOGICAL PROFILE FOR VINYL CHLORIDE Date Published -- August 1989 Prepared by: Syracuse Research Corporation under Contract No. 68-C8-0004 for Agency for Toxic Substances and Disease Registry (ATSDR) U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA) Technical editing/document preparation by: Oak Ridge National Laboratory under DOE Interagency Agreement No. 1857-B026-A1 I- UCC 107843 DISCLAIMER Mention of company name or product does not constitute endorsement by the Agency for Toxic Substances and Disease Registry. // UCC 107844 FOREWORD The Superfund Amendments and Reauthorization Act of 1986 (Public Law 99*499) extended and amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law (also known as SARA) directed the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare toxicological profiles for hazardous substances which are most commonly found at facilities on the CERCLA National Priorities List and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). The list of the 100 most significant hazardous substances was published in the Federal Register on April 17, 1987. Section 110 (3) of SARA directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. Each profile must include the following content: "(A) An examination, summary, and interpretation of available toxicological 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 which present a significant risk to human health of acute, subacute, and chronic health effects. (C) Where appropriate, an identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans." This toxicological profile is prepared in accordance with guidelines developed by ATSDR and EPA. The guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary, but no less often than every three years, as required by SARA. The ATSDR toxicological profile is intended to characterize succinctly the toxicological and health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature that describes a hazardous substance's toxicological properties. Other literature is 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. iii UCC 107845 Foreword Each C xicol glcal pr file begins with a public health statement, which describes in nontechnical language a substance's relevant toxicological properties. Following the statement is material that presents 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. Research gaps in toxicologic and health effects information are described in the profile. Research gaps that are of significance to protection of public health will be identified by ATSDR, the National Toxicology Program of the Public Health Service, and EPA. The focus of the profiles is on health and toxicological information; therefore, we have included this information in the front of the document. 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. Ve plan to revise these documents in response to public comments and as additional data become available; therefore, we encourage comment that will make the toxicological profile series of the greatest use. This profile reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR, EPA, the Centers for Disease Control, and the National Toxicology Program. It has also been reviewed by a panel of nongovernment peer reviewers and was made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. 0* James 0. Mason, M.D., Dr. P.H. Assistant Surgeon General Administrator, ATSDR iv UCC 107846 CONTENTS FOREWORD ................................................................................................................................ iii LIST OF FIGURES ................................................................................................................. ix LIST OF TABLES ................................................................................................................... xi 1. PUBLIC HEALTH STATEMENT ...................................................................... ............ 1.1 WHAT IS VINYL CHLORIDE? ............................................... ........................ 1.2 HOW MIGHT I BE EXPOSED TO VINYL CHLORIDE? ................................ 1.3 HOW DOES VINYL CHLORIDE GET INTO MY BODY? ................................ 1.4 HOW CAN VINYL CHLORIDE AFFECT MY HEALTH? .................................. 1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO VINYL CHLORIDE? ................................................................ 1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS? .......................................................................................... 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? ........................................................... I 1 1 2 2 2 3 -3 2. HEALTH EFFECTS SUMMARY ...................................................................................... 2.1 INTRODUCTION ................................................................................................. 2.2 LEVELS OF SIGNIFICANT EXPOSURE ......................................................... 2.2.1 Key Studies and Graphical Presentations ..................... 2.2.1.1 Inhalation ................................................................... 2.2.1.2 Oral ................................................................................ 2.2.1.3 Dermal ............................................................................ 2.2.2 Biological Monitoring as a Measure of Exposure and Effects ................................................................ 2.2.3 Environmental Levels as Indicators of Exposure and Effects ................................................................ 2.2.3.1 Levels found in the environment ................... 2.2.3.2 Human exposure potential ................................... 2.3 ADEQUACY OF DATABASE ................................................................................ 2.3.1 Introduction .................................................................................. 2.3.2 Health Effect End Points ....................................................... 2.3.2.1 Introduction and graphic summary ................ 2.3.2.2 Descriptions of highlights of graphs .... 2.3.2.3 Summary of relevant ongoing research .... 2.3.3 Other Information Needed for Human Health Assessment ....................................................................... 2.3.3.1 Pharmacokinetics and mechanisms of action ......................................................................... 2.3.3.2 Monitoring of human biological samples .. 2.3.3.3 Environmental considerations ......................... 7 7 8 8 8 15 15 15 16 16 18 19 19 19 19 22 23 23 23 24 24 3. CHEMICAL AND PHYSICAL INFORMATION ............................................................ 3.1 CHEMICAL IDENTITY ....................................................................................... 3.2 PHYSICAL AND CHEMICAL PROPERTIES ..................................................... 25 25 25 v UCC 107847 Contents 4. TOXICOLOGICAL DATA ................................................................................................. 4.1 OVERVIEW........................................................................................................... 4.2 TOXICOKINETICS ............................................................................................. 4.2.1 Absorption ...................................................................................... 4.2.1.1 Inhalation ................................................................. 4.2.1.2 Oral .............................................................................. 4.2.1.3 Dermal .......................................................................... 4.2.2 Distribution.................................................................................. 4.2.2.1 Inhalation ............ 4.2.2.2 Oral .............................................................................. 4.2.2.3 Dermal .......................................................................... 4.2.3 Metabolism ...................................................................................... 4.2.3.1 Inhalation ................................................................. 4.2.3.2 Oral ............................................................................... 4.2.3.3 Dermal ......................................................... 4.2.4 Excretion ......................................................................................... 4.2.4.1 Inhalation ................................................................. 4.2.4.2 Oral ............................................................................... 4.2.4.3 Dermal .......................................................................... 4.2.4.4 Parenteral ................................................................. 4.3 TOXICITY ....................................................................................................... 4.3.1 Lethality and DecreasedLongevity..................................... 4.3.1.1 Inhalation .................................................................. 4.3.1.2 Oral ............................................................................... 4.3.1.3 Dermal .......................................................................... 4.3.2 Systemic/Target Organ Toxicity ......................................... 4.3.2.1 Hepatotoxlclty ........................................................ 4.3.2.2 Nervous systemeffects ......................................... 4.3.2.3 Other systemic effects ...................................... 4.3.3 Developmental Toxicity .................................................. 4.3.3.1 Inhalation .................................................................. 4.3.3.2 Oral ............................................................................... 4.3.3.3 Dermal ........................................................................... 4.3.3.4 General discussion ................................................ 4.3.4 Reproductive Toxicity .............................................................. 4.3.4.1 Inhalation .................................................................. 4.3.4.2 Oral ................................................................................ 4.3.4.3 Dermal ............................... 4.3.4.4 General discussion................................................ 4.3.5 Genotoxieity .................................................................................. 4.3.5.1 Human .............................................................................. 4.3.5.2 Nonhuman....................................................................... 4.3.5.3 General discussion ................................................ 4.3.6 Carcinogenicity............................................................................ 4.3.6.1 Inhalation ................................................................... 4.3.6.2 Oral ................................................................................ 4.3.6.3 Dermal ............................................................................ 4.3.6.4 General discussion ................................................ 4.4 INTERACTIONS WITH OTHER CHEMICALS ................................................... 5. MANUFACTURE, IMPORT, USE, AND DISPOSAL................................................... 5.1 OVERVIEW............................................................................................................ 5.2 PRODUCTION ....................................................................................................... 5.3 IMPORT .................................................................................................................. 29 29 30 30 30 30 31 31 31 31 32 32 32 34 35 35 35 37 37 39 39 39 39 40 40 40 40 44 45 47 47 49 49 50 50 50 51 51 51 51 51 53 53 55 55 58 60 60 60 63 63 63 63 vi UCC A0-78*8 Contents 5.4 USES ................................................................................................................... 5.5 DISPOSAL.......................................................................................................... 6. ENVIRONMENTAL FATE ............................................................................................... 6.1 OVERVIEW.......................................................................................................... 6.2 RELEASES TO THE ENVIRONMENT ............................................................... 6.3 ENVIRONMENTAL FATE .................................................................................... 6.3.1 Air ...................................................................................................... 6.3.2 Water ................................................................................................. 6.3.3 Soil ................................................................................................. 7. POTENTIAL FOR HUMANEXPOSURE ........................................................................... 7.1 OVERVIEW .......................................................................................................... 7.2 LEVELS MONITORED ORESTIMATED IN THE ENVIRONMENT .................. 7.2.1 Air ...................................................................................................... 7.2.2 Water ................................................................................................. 7.2.3 Soil .................................................................................................. 7.2.4 Other ................................................................................................. 7.3 OCCUPATIONAL EXPOSURES ........................................................................... 7.4 POPULATIONS ATHIGHRISK ........................................................................ 8. ANALYTICAL METHODS ............................................................................................... 8.1 ENVIRONMENTAL MEDIA ................................................................................ 8.2 BIOMEDICAL SAMPLES .................................................................................... 9. REGULATORY AND ADVISORY STATUS .................................................................... 9.1 INTERNATIONAL............................................................................................... 9.2 NATIONAL.......................................................................................................... 9.2.1 Regulations .................................................................................... 9.2.1.1 Air .................................................................................. 9.2.1.2 Water .............................................................................. 9.2.1.3 Food ................................................................................. 9.2.1.4 Other .............................................................................. 9.2.2 AdvisoryGuidance ......................................................................... 9.2.2.1 Air ................................................................................... 9.2.2.2 Water .............................................................................. 9.2.3 Data Analysis ............................................................................. 9.2.3.1 Reference doses (RfDs) ........................................ 9.2.3.2 Carcinogenic potency ............................................. 9.3 STATE .................................................................................................................. 10. REFERENCES .................................................................................................................. 11. GLOSSARY...................................................................................................................... APPENDIX: PEER REVIEW.................................................................................................. 63 64 65 65 65 65 65 66 66 69 69 69 69 70 71 71 72 72 73 73 73 79 7$ 79 79 79 79 79 80 80 80 80 80 80 81 81 83 103 107 vii UCC 107849 LIST OF FIGURES 1.1 Health effects from breathing vinyl chloride .................................... 1.2 Health effects from ingesting vinyl chloride .................................... 2.1 Effects of vinyl chloride*-inhalation exposure ................................ 2.2 Effects of vinyl chloride--oral exposure ............................................. 2.3 Levels of significant exposure for vinyl chloride*inhalation................................................................................................................. 2.4 Levels of significant exposure for vinyl chloride*-oral ............ 2.5 Urinary output of thlodiglycolic acid from volunteers 12 h after exposure to vinyl chloride in air for 12 h ................ 2.6 Availability of information on health effects of vinyl chloride (human data) ......................................................................... 2.7 Availability of information on health effects of vinyl chloride (animal data) ............................ 6.1 Proposed metabolic pathways for vinyl chloride ............................... 4 5 9 10 11 12 17 20 21 33 Preceding page blank ix UCC 107850 LIST OF TABLES 3.1 Chemical identity of vinyl chloride ......................................................... 3.2 Physical and chemical properties of vinyl chloride ........................ 4.1 Excretion of radioactivity in rats exposed to -vinyl chloride in air for 6 h .................................................................................. 4.2 Percent of administered dose of radioactivity excreted 72 h following a single oral dose of -vinyl chloride in rats ........................................................................................................................ 4.3 Experimental protocol for animal exposure to vinyl chloride .. 4.4 Genotoxicity of vinyl chloride in vivo .................................................. 4.5 Genotoxicity of vinyl chloride in vitro ................................................ 4.6 Tumor incidence in male and female Sprague-Dawley rats exposed by inhalation to vinyl chloride 4 h/day, 5 days/week for 52 weeks ............................................................. 4.7 Tumor incidence in Wistar rats orally exposed to vinyl chloride ........................................................................................................ 8.1 Analytical methods for the quantification of vinyl chloride .. 26 27 36 38 41 52 54 57 59 75 Preceding page blank xi UCC 107851 1 1. PUBLIC HEALTH STATEMENT 1.1 VHAT IS VINYL CHLORIDE? Vinyl chloride is a colorless gas with a mild, sweet odor. It is a man-made chemical that does not occur naturally in the environment. Most of the vinyl chloride produced in the United States is used to make polyvinyl chloride (PVC). This material is used to manufacture a variety of plastic and vinyl products including pipes, wire and cable coatings, packaging materials, furniture and automobile upholstery, wall coverings, housewares, and automotive parts. Much smaller amounts of vinyl chloride are used as a cooling gas and in the manufacture of other compounds. 1.2 HOV MIGHT I BE EXPOSED TO VINYL CHLORIDE? Humans are exposed to vinyl chloride from environmental and occupational sources. Vinyl chloride has been found in at least 133 of 1,177 hazardous waste sites on the National Priorities List (NPL). Vinyl chloride is mainly released into the air and discharged in wastewater from the plastics industries (primarily vinyl chloride and PVC manufacturers). Most of the vinyl chloride that enters the environment eventually ends up in air where it gradually breaks down into less harmful substances. The levels of vinyl chloride found in the environment are usually more than a thousand times lower than levels found in occupational settings. Outdoor levels in the environment are usually expressed in terms of parts of vinyl chloride present in a billion parts of air or water (ppb). Outdoor levels of vinyl chloride result from the discharge of exhaust gases from factories that manufacture or process vinyl chloride, or evaporation from areas where chemical wastes are stored. Highest outdoor levels have been measured in air near vinyl chloride factories or over chemical waste storage areas. Tests published in 1976 suggest that the air inside new cars may contain levels of vinyl chloride higher than expected for that location, because vinyl chloride may seep into the air from the new plastic parts. Levels of vinyl chloride are expected to drop rapidly, however, when doors r windows are opened or when the heater or air conditioner is operated. Vinyl chloride that enters drinking water comes from factories that release wastes containing it into rivers and lakes and from its seepage into underground water in areas where chemical wastes containing it are stored. Small amounts of vinyl chloride can enter the drinking water from contact with polyvinyl chloride pipes. In the past, higher than expected amounts were present in foods packaged in plastic that contained vinyl chloride. Currently, the U.S. Food and Drug Administration (FDA) limits the amount of vinyl chloride allowed in packaging materials that contact food in order to limit the intake of vinyl chloride. UCC 107852 2 Seccion 1 Vinyl chloride manufacturing or processing factories may have indoor levels of vinyl chloride that are much higher than thos fr m utdoor sources. Levels expressed in terms f parts of vinyl chloride per million parts of air (ppm) have been measured in vinyl chloride manufacturing plants. 1.3 HOtf DOES VINYL CHLORIDE GET INTO MY BODY? The most likely way that vinyl chloride can enter your body is if you breathe air containing it. This path of exposure is of concern for persons employed in vinyl chloride manufacturing or processing, for people living in communities where vinyl chloride plants are located, and for individuals living near hazardous waste disposal sites. Vinyl chloride can also enter your body if you eat food or drink water containing it. Passage of vinyl chloride through the skin is not likely to be an important pathway. 1.A HOtf CAN VINYL CHLORIDE AFFECT MY HEALTH? Short-term exposures to very high levels of vinyl chloride in air can cause dizziness, stumbling and lack of muscle coordination, headache, unconsciousness, and death. Long-term exposure to lower but unmeasured amounts in factories where vinyl chloride is made or processed has caused "vinyl chloride disease." This disease is characterized by severe damage to the liver, effects on the lungs, poor circulation in the fingers, changes in the bones at the end of the fingers, thickening of the skin, and changes in the blood. An increased risk of developing cancer of the liver and possibly several other tissues has been linked with breathing air in factories containing vinyl chloride. Studies designed to determine if the low levels of vinyl chloride measured in outside air, drinking water, or food could cause harmful effects in humans have not been performed. Some of the health effects observed in humans have also been seen in laboratory animals. Effects on the nervous system of animals have occurred after short-term exposure to very high levels of vinyl chloride in air. Effects on the liver developed in animals after short-term exposure to high levels and after longer-term exposure to lower levels of vinyl chloride. Kidney effects also occurred after exposure to high levels. Laboratory animals developed cancer in several tissues after eating food or breathing air that contained vinyl chloride. Effects on the testes were seen in male rats that breathed air containing vinyl chloride, but information is not sufficient to determine whether humans exposed to vinyl chloride develop effects on the testes. 1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO VINYL CHLORIDE? Vinyl chloride can be measured in urine and body tissues, but the tests cannot be used to determine what levels of vinyl chloride you were exposed to. Measuring the amount of the major breakdown product of vinyl chloride in the urine may give some indication of recent exposure; however, people differ in the quantity of excretion of this breakdown product. Neither of these tests Is routinely available at your doctor's office. The laboratory tests commonly used by doctors to evaluate liver UCC 107853 Public Health Statement 3 damage and liver function are usually not helpful for d termining if liver damage from vinyl chloride exposure has occurred. 1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IH HARMFUL HEALTH EFFECTST The graphs on the following pages show the link between exposure to vinyl chloride and known health effects. In the first set of graphs labeled "Health effects from breathing vinyl chloride" (Fig. 1.1), exposure is expressed in parts of vinyl chloride per million parts of air (ppm). In the second set of graphs, the same relationship is shown for the known "Health effects from ingesting vinyl chloride" (Fig. 1.2). Exposures are expressed in milligrams of vinyl chloride per kilogram of body weight per day (mg/kg/day). In both graphs, effects in animals are shown on the left, effects in humans on the right. The first column, labeled "Short-term exposure," refers to effects associated with exposure durations of 14 days or less. The column labeled "Long-term exposure" refers to exposures lasting longer than 14 days. The levels marked on the graphs as "Minimal risk for effects other than cancer" are estimates based on information obtained from laboratory animals and, therefore, are subject to the uncertainties involved in using animal data to predict effects in humans. Vinyl chloride is regarded worldwide as a chemical that causes cancer in humans, but exposure levels necessary to cause cancer in humans are not known. The Environmental Protection Agency (EPA), therefore, used available data in animals to estimate that breathing air containing 1 ppm vinyl chloride every day for 70 years may place as many as 1,100 persons in a population of 10,000 (or 1,100,000 persons in a population of 10,000,000) at risk of developing cancer. Eating food containing 1 ppm vinyl chloride every day for 70 years may place as many as 644 persons in a population of 10,000 (or 644,000 persons in a population of 10,000,000) at risk of developing cancer. Similarly, drinking water containing 1 ppm vinyl chloride every day for 70 years may place as many as 657 persons in a population of 10,000 (or 657,000 persons in a population of 10,000,000) at risk of developing cancer. It should be noted that these risk values are plausible upper-limit estimates based on information obtained from animal studies. Actual risk levels are unlikely to be higher and may be lower. 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTHt EPA stated that community drinking water systems that regularly serve the same 25 persons for at least 8 months of the year must limit vinyl chloride in the drinking water to 2 jig/L (2 ppb), starting January 9, 1989. In order to limit intake of vinyl chloride in food to levels considered to be safe, the Food and Drug Administration (FDA) recently changed its regulations regarding the vinyl chloride content of various plastics that contact food and carry water used in food processing, and of plastics that are used in food packaging. Limits range from 5 to 50 ppm, depending on the nature of the plastic and its use. UCC 107854 4 Section 1 SHORT-TERM EXPOSURE (LESS THAN OR EQUAL T014 DAYS) EFFECTS IN ANIMALS CONC. IN AR (ppm) EFFECTS IN HUMANS LONG-TERM EXPOSURE (GREATER THAN 14 DAYS) EFFECTS IN ANIMALS CONC. IN AR (ppm) EFFECTS in HUMANS 10.000 EFFECTS ON BRAIN FUNCTION 10.000 KIDNEY EFFECTS------------------ QUANTITATIVE DATA WERE NOT AVAILABLE DEATH.UVER EFFECTS 1.000 100 100 TESTICULAR EFFECTS REDUCED LIFE SPAN- 10 UVER EFFECTS - 10 IS 1.0 0.1 0.1 Rfr 1.1. Haaltb affactt fraai hunts *tayl cUarU*. UCC 107855 SHORT-TERM EXPOSURE (LESS THAN OR EQUAL TO 14 DAYS) EFFECTS IN ANIMALS DOSE (mg/kg/day) EFFECTS IN HUMANS 1,000 DEATH QUANTITATIVE DATA WERE NOT AVAILABLE 100 Public Hemlth Statement 5 LONG-TERM EXPOSURE (GREATER THAN 14 DAYS) EFFECTS IN ANIMALS DOSE (mg/kg/day) EFFECTS IN HUMANS 1.000 100 10 EFFECTS ON-------- 10 BLOOD 1.0 1.0 DECREASED LIFE SPAN AND LIVER EFFECTS 0.01 0.01 0.001 0.001 Fig. 1.2. Health effects from ingesting rinyl chloride. MINIMAL RISK LEVELFOR EFFECTS OTHER THAN CANCER ucc 107856 6 Section 1 In order t control the handling of vinyl chloride, EPA haa named the chemical aa a hazardous component of solid waste. If quantities greater than 1 pound are released to the environment, the National Response Center of the Federal Government must be notified <""> diately. The Occupational Safety and Health Administration (OSHA) regulations state that a worker must not be exposed to a concentration of vinyl chloride in air that exceeds 1 ppm over any 8-hour work period in a 40-hour workweek and that the concentration must not exceed 5 ppm for more than 15 minutes. The National Institute for Occupational Safety and Health (NIOSH) recommends that workers exposed to any measurable amount of vinyl chloride wear an air-supplied respirator. EPA has determined that factories must limit the release of vinyl chloride in air to 10 ppm. 7 2. HEALTH EFFECTS SUMMARY 2.1 INTRODUCTION This section summarizes and graphs data on the health effects concerning exposure to vinyl chloride. The purpose of this section is to present levels of significant exposure for vinyl chloride based on key toxicological studies, epidemiological investigations, and environmental exposure data. The information presented in this section is critically evaluated and discussed in Sect. 4, Toxicological Data, and Sect. 7, Potential for Human Exposure. This Health Effects Summary section comprises two major parts. Levels of Significant Exposure (Sect. 2.2) presents brief narratives and graphics for key studies in a manner that provides public health officials, physicians, and other interested individuals and groups with (1) an overall perspective of the toxicology of vinyl chloride and (2) a summarized depiction of significant exposure levels associated with various adverse health effects. This section also includes information on the levels of vinyl chloride that have been monitored in human fluids and tissues and information about levels of vinyl chloride found in environmental media and their association with human exposures. The significance of the exposure levels shown on the graphs may differ depending on the user's perspective. For example, physicians concerned with the interpretation of overt clinical findings in exposed persons or with the identification of persons with the potential to develop such disease may be interested in levels of exposure associated with frank effects (Frank Effect Level, FEL). Public health officials and project managers concerned with response actions at Superfund sites may want information on levels of exposure associated with more subtle effects in humans or animals (Lowest-Observed-Adverse-Effect Level, LOAEL) or exposure levels below which no adverse effects (No-ObservedAdverse -Effect Level, NOAEL) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels, MRL) are of interest to health professionals and citizens alike. Adequacy of Database (Sect. 2.3) highlights the availability of key studies on exposure to vinyl chloride in the scientific literature and displays these data in three-dimensional graphs consistent with the format in Sect. 2.2. The purpose of this section is to suggest where there might be insufficient information to establish levels of significant human exposure. These areas will be considered by the Agency for Toxic Substances and Disease Registry (ATSDR), EPA, and the National Toxicology Program (NTP) of the U.S. Public Health Service in order t develop a research agenda for vinyl chloride. UCC 107858 8 Section 2 2.2 LEVELS OF SIGNIFICANT EXPOSURE To help public health professionals address the needs f persons living or working near hazardous waste sites, the toxicology data summarized In this section are organized first by route of exposure*Inhalation, Ingestion, and dermal--and then by toxicological end points that are categorized Into six general areas--lethality, systemic/target organ toxicity, developmental toxicity, reproductive toxicity, genetic toxicity, and carcinogenicity. The data are discussed in terms of three exposure periods--acute, Intermediate, and chronic. Two kinds of graphs are used to depict the data. The first type is a "thermometer" graph. It provides a graphical summary of the human and animal toxicological end points (and levels of exposure) for each exposure route for which data are available. The ordering of effects does not reflect the exposure duration or species of animal tested. The second kind of graph shows Levels of Significant Exposure (LSE) for each route and exposure duration. The points on the graph showing NOAELs and LOAELs reflect the actual doses (levels of exposure) used in the key studies. No adjustments for exposure duration or intermittent exposure protocol were made. Adjustments reflecting the uncertainty of extrapolating animal data to man, intraspecies variations, and differences between experimental vs actual human exposure conditions were considered when estimates of levels posing minimal risk to human health were made for noncancer end points. These minimal risk levels were derived for the most sensitive noncancer end point for each exposure duration by applying uncertainty factors. These levels are shown on the graphs as a broken line starting from the actual dose (level of exposure) and ending with a concavecurved line at its terminus. Although methods have been established to derive these minimal risk levels (Barnes et al. 1987), shortcomings exist in the techniques that reduce confidence in the projected estimates. Also shown on the graphs under the cancer end point are lowlevel risks (10'4 co 10*7) reported by EFA. In addition, the actual dose (level of exposure) associated with the tumor incidence is plotted. 2.2.1 Key Studies and Graphical Presentations Dose-response-duration data for the toxicity and carcinogenicity of vinyl chloride are displayed in two types of graphs. These data are derived from the key studies described in the following sections. The "thermometer" graphs in Figs. 2.1 and 2.2 plot exposure levels vs NOAELs and LOAELs for various effects and durations of inhalation and oral exposures, respectively. The graphs of levels of significant exposure in Figs. 2.3 and 2.4 plot end-point-specific NOAELs and LOAELs and minimal levels of risk for acute (<14 days), intermediate (15-364 days), and chronic (365 days) duration for inhalation and oral exposures, respectively. 2.2.1.1 Inhalation Lethality and decreased longevity. Acute occupational exposure to high unspecified concentrations of vinyl chloride has caused death in humans (ACGIH 1986a) probably due to narcosis. Guinea pigs exposed to UCC 107859 ANIMALS torn) .1 000.000 Health Effects Sunansry 9 HUMANS (Ppm) 1.000.000 BABBIT, LCjn. 2 h. CONTINUOUS 100.000 GUINEA PIG. NARCOSB AND DEATH. 30-00 MN. CONTINUOUS DOGS. ANESTHESIA RATS. INTOXICATION. 2 h. CONTWUOUS GUINEA PIG. ATAXIA. 1 MIN 10.000 RAT. RENAL TOXICITY. ANEMM. 18 MONTHS INTEHUTTENT O BABBIT. DEVELOPMENTAL TOXICITY. IS DAYS. INTERMITTENT --*RAT, DEVELOPMENTAL TOXICITY, 7-9 DAYS, INTERMITTENT 1.000 - T* MOUSE. ACUTE LETHALITY, HEPATOTCOOCITY. S DAYS. NTERUTTENT V MOUSE, BOOV WEIGHT LOSS! MONTHS. WTERUTTENT O RAT. DEVELOPMENTAL TOXICITY. 10 DAYS MTERAVTTENT [O MOUSE. ACUTE LETHALITY. INTERMITTENT jo MOUSE. BODY WEIGHT IT3.12 MONTHS. INTERMOTENT 100 - RAT. HEPATOTOXICITY. MONTHS. INTERMITTENT RAT. REDUCED BOOY WEIGHT. TESTICULAR EFFECTS. 12 MONTHS. INTERMITTENT O MOUSE. DEVELOPMENTAL TOXICITY. 10 DAYS. INTERMITTENT RAT. MOUSE. REDUCED SURVIVAL. S-12 MONTHS MTERMTTEHT RAT. HEPATOTOXICITY. 18 MONTHS INTERUTTENT RAT. UVER CANCER S2 WEEKS. MTERAITTENT HAMSTER MOUSE. UVER CANCER 30 WEEKS. INTERUTTENT 100.000 10.000 A CNS EFFECTS 1,000 100 - 10 - MOUSE, LUNG CANCER 4 WEEKS INTERUTTENT RAT, HEPATOTOXICITY. MONTHS INTERUTTENT RAT. REDUCED TODY WEIGHT, TESTICULAR EFFECTS. 18 MONTHS. INTERMffTENT 10 - LOAEL FOR ANNULS O NOAEL FOR ANIMALS A LOAEL FOR HUAAANS & NOAEL FOR HUMANS Fig. 2.1. Effects of Yiayl chloride--MuUHm exposure. ll-- A QENOTOXICITY UCC 107860 IQ Section 2 ANIMALS (mg/kg/day) 1000 RAT.LD* RAT, HEPATOXOCI7Y, 13 WEEKS 100 HUMANS QUANTITATIVE DATA WERE NOT AVAILABLE O RAT. HEPATOTOXICITY. 13 WEEKS RAT. HEMATOLOGIC EFFECTS, LIFETIME O RAT, HEMATOLOGIC EFFECTS, LIFETIME RAT. CANCER. LIFETIME RAT, DECREASED SURVIVAL, HEPATOTOXICITY, LIFETIME O RAT. DECREASED SURVIVAL, HEPATOTOTXJCITY, LIFETIME LQAEL O NQAEL Fig. IX Effects of vtayl chloiMe--oral expomre. 107861 Heel th Effects Sunsnery 11 ACUTE (SI 4 DAYS)____________ INTERMEDIATE (15-364 DAYS) DEVELOP- TARGET TARGET LETHALITY MENTAL ORGAN LETHALITY ORGAN REPRO DUCTION (ppm) 1,000.000 I- CHRONIC (2365 DAYS) DECREASED LONGEVITY TARGET ORGAN 100,000 - *0 d(CNS) r(CNS) CANCER 10,000 1,000 - Oh r A(CNS) Am (LIVER) 100 10 - Om #011 f (TESTIS) #r.m fr(UVER) 6 rRJVER) 1.0 - 0.1 - 0.01 - 0.001 - 10-* 0.0001 0.00001 - 10^ - ESTIMATED UPPER-BOUND HUMAN CANCER 10~* - R>SK LEVELS 0.000001 *- 10-T J h RABBIT 0 SyP*AP'G 0 9 r RAT m MOUSE * HAMSTER A LOAB. FOR HUMANS LOAEL FOR ANNULS O NOAEL FOR ANIMALS LOAEL ANO NOAEL M T>* SAME SPECKS I MMMAL RISK LEVEL I FOR EFFECTS OTHER 1 THAN CANCER KU Fig. 13. Levels of significant exposure for vinyl chloride--idulitiim, UCC 107862 12 Section 2 1.000 r AWTC (414 PAYS) DEVELOP- TARGET LETHALITY MENTAL OMAN MTERMBMATE (1SGB4 DAYS) TARGET REPROLETHALITY ORGAN DOCTION CHRONC (M05 0AVS) DECREASED TARGET LONGEVITY ORGAN CANCER 100 - r (LIVER) 10 - i- 0.1 - 9 Jr(HEMAT) f f(UVER) *f U/ 6 <> 0.01 - 0.001 0.0001 - o.ooooi - 0.000001 0.0000001 L Vi/ 10-*-. iir* - ESTIMATED UPPER-BOUND HUMAN CANCER RISK LEVELS 10"*- io-T- r RAT LOAEL O NOAEL LOAEL AND NOAEL ! M THE SAME SPECES I MPOMAL ASK LEVEL I TOR EFFECTS M ^ THE SAME SPECIES Fij. 14. Icfcb of significant exposure for vinyl eUorM>--orsL UCC 107863 Health Effects Summary 13 100,000 ppm died within 30 minutes as a result of central nervous system (CNS) depress! n (Patty et al. 1930). Levels pi tted as LOAELs n the graphs in Figs. 2.1 and 2.3 include a 2-h LC50 of 230,800 ppm in rabbits (EPA 1985a), a level of 100,000 ppm that was lethal in guinea pigs after 30 to 60 min (Patty et al. 1930), a level of 1,000 ppm that decreased survival in mice exposed intermittently for 5 days (Lee et al. 1977a), and a level of 50 ppm that decreased survival in rats and mice exposed intermittently for 6 to 12 months (Lee et al. 1977a, Hong et al. 1981). Systemic/target organ toxicity. Humans occupationally exposed to high levels of vinyl chloride have suffered from a syndrome called vinyl chloride disease, which displays manifold signs of toxicity involving the liver, CNS, and peripheral circulation and nerves. Exposures have not been quantified, however, and thresholds for this syndrome have not been identified. Important target organs in animals are the liver and CNS. CNS effects generally follow acute exposure to high levels (see Figs. 2.1 and 2.3), such as 8,000 ppm associated with CNS effects in humans (Lester et al. 1963), 70,000 ppm associated with anesthesia in dogs (Oster et al. 1947), and 50,000 ppm associated with intoxication in rats (Lester et al. 1963). CNS effects involving occupational exposure have been reported, but exposures have not been quantified (Dinceva et al. 1985, Perticoni et al. 1986, Halama et al. 1985). The liver appears to be the most sensitive organ in humans and animals. Acute hepatotoxicity was observed in mice dying after intermittent exposure to 1,000 ppm for 5 to 9 days (Lee et al. 1977a) * (see Figs. 2.1 and 2.3). In rats, exposures of intermediate (6 months) duration to 10 ppm were a L0AEL for liver effects (Bi et al. 1985) (see Figs. 2.1 and 2.3). A chronic LOAEL for liver effects in rats was observed at 50 ppm in a chronic (12 months) experiment (Lee et al. 1977a) (see Figs. 2.1 and 2.3). However, since this was the lowest concentration tested, a chronic N0AEL could not be determined. After 12-month exposure, 100 ppm was a LOAEL and 10 ppm was a NOAEL for reduced terminal body weights in rats (Bi et al. 1985) (Fig. 2.1). Minimal risk levels are not estimated in Fig. 2.3 based on liver toxicity at the acute level of 1,000 ppm, because this level was a frank effect level, and a NOAEL or LOAEL was not identified. A minimal risk level of 0.005 ppm for intermediate exposure is based on the LOAEL f r liver effects observed in rats exposed intermittently to 10 ppm for 6 months (Bi et al. 1985). Data were not sufficient to estimate a minimal risk level for chronic exposure. Developmental toxicity. Several epidemiology studies (Infante et al. 1976; Uaxweiler et al. 1977; Theriault et al. 1983; Edmonds et al. 1975, 1978) and evaluations of these studies (Hatch et al. 1981, Stallones 1987, Downs et al. 1977, The Vinyl Institute 1987) have investigated the effects of vinyl chloride exposure on the incidence of fetal loss and birth defects. No solid association has been found. Animal data identify a NOAEL for developmental toxicity in rabbits exposed intermittently to 2,500 ppm on days 6 to 18 of gestation (J hn et al. 1977). The same study identifies intermittent exposure of mice at 50 ppm on days 6 to 15 of gestation as a NOAEL. A NOAEL for rats of 1,500 ppm exposed intermittently on 10 days of gestation was identified from a study by Ungvary et al. (1978). The animal data are depicted in Figs. 2.1 and 2.3. UCC 107864 14 Section 2 Two studies indicating subtle effects at unusually low exposure levels (Hirkova et al. 1978, Sal'nikova and Kltsovskaya 1980) were insufficiently reported and judged t be inadequate for critical evaluation. Reproductive toxicity. Two occupational studies associated effects on sexual and endocrinological function in nan and women and on gynecological health in women with exposure to vinyl chloride (Makarov 1984, Makarov et al. 1984). Although exposure levels were estimated, the reports were inadequately reported for critical evaluation, and the data from these studies are not plotted on the graphs. In a 1-year study in rats, intermittent exposure to 100 ppm was a LOAEL for testicular effects and 10 ppm was a NOAEL (see Figs. 2.1 and 2.3) (Bi et al., 1985). In an earlier study, Torkelson et al. (1961) observed no effects on relative testicular weight in rats exposed intermittently to 500 ppm for 4.5 months or in dogs, rabbits, or guinea pigs exposed intermittently to 200 ppm for 6 months. The quality of this study was limited, however, because small numbers of animals were used. Genotoxlcity. Several studies reviewed in Sect. 4.3.5.1 on genotoxicity in humans suggest that vinyl chloride causes chromosomal aberrations in lymphocytes in occupationally exposed workers. The key study (Hansteen et al. 1978) identified a NOAEL of 1 ppm for this effect. Positive results were obtained in microorganisms in nonhuman systems, in the recessive lethal test in Drosophila and in other mammalian test systems (see Section 4.3.5.2 on genotoxicity in animals). Carcinogenicity. Several epidemiology studies, many of which have been reviewed by EFA (1985b), associated occupational exposure to vinyl chloride with cancers of the liver and possibly of the brain. Concentrations of vinyl chloride in the workroom air were not measured. In the key studies used by EFA (1985b) to derive an inhalation potency factor (Maltoni et al. 1980, 1981), rats were exposed intermittently to 1 to 30,000 ppm for 52 weeks, and mice and hamsters were exposed to 50 to 30,000 ppm for 30 weeks followed by an observation period. Estimation of carcinogenic potency was based on the incidence of liver angiosarcomas in rats. A statistically significant Increase in tumor incidence was observed in all three species at 50 ppm. Several other inhalation studies, reviewed in Sect. 4.3.6, Carcinogenicity, support the carcinogenicity of inhalation exposure to vinyl chloride. Studies by Suzuki (1981, 1983) appear to define intermittent exposure of mice to 10 ppm as a level associated with increased incidence of lung cancer. Mice were exposed for 4 weeks followed by a 41-week observation period. The concentration of 50 ppm associated with cancer in rats and hamsters and the concentration of 10 ppm associated with lung cancer in mice are depicted in Figs. 2.1 and 2.3. From the Incidence of liver angiosarcomas in rats of both sexes in the Maltoni et al. (1980, 1981) experiments, and based upon the absorbed doses of vinyl chloride, an upper bound q^* of 2.95 x 10*1 (mg/kg/day) was estimated by EPA (1985b). Assuming humans breathe 20 m^/day, absorb 50% of inhaled vinyl chloride, and weigh 70 kg each, estimated concentrations associated with cancer risks of 10*\ 10'^, 10', and 10*7 are 9 x io*^, 9 x 10*5, 9 x 10*, and 9 x 10*7 ppBf respectively (see Fig. 2.3). UCC 107865 Health Effects Summary 15 2.2.1.2 Oral Lethality and decreased longevity. Oral lethality data are limited to an LD50 in rats of 500 mg/kg (Sax 1984), and an effect level of 1.3 mg/kg/day and a NOAEL of 0.13 mg/kg/day In a lifetime dietary study in rats (Til et al. 1983) (see Figs. 2.2 and 2.4). Systemic/target organ toxicity. Oral toxicity data were not located for humans. The liver appears to be the critical target organs for animals orally exposed to vinyl chloride. In a 13-week gavage study in rats, 300 mg/kg/day was a L0AEL and 30 mg/kg/day was a NOAEL for hepatotoxicity (Feron et al. 1975) (see Figs. 2.2 and 2.4). A minimal risk level of 0.30 mg/kg/day is estimated for intermittent oral exposure based on the NOAEL of 30 mg/kg/day (see Fig. 2.4). In a lifetime dietary study in rats (Til et al. 1983), a LOAEL of 1.3 mg/kg/day and a NOAEL of 0.13 mg/kg/day for hepatotoxicity were identified (see Figs. 2.2 and 2.4). A minimal risk level for chronic oral exposure is estimated from the NOAEL of 0.13 mg/kg/day for hepatotoxicity because this dose is also a NOAEL for decreased longevity. The minimal risk level is -0.0013 mg/kg/day (see Fig. 2.4). Other effects observed in a lifetime dietary study In rats by Feron et al. (1981) include mild hematological changes at 14.1 mg/kg/day, but not at 5.0 mg/kg/day. These data are depict d in Fig. 2.2, but have no bearing on critical evaluation. Developmental toxicity. Data were not located regarding developmental toxicity in orally exposed humans or animals. Reproductive toxicity. Data were not located regarding reproductive toxicity in orally exposed humans or animals. Genotoxlcity. See Sect. 2.2.1.1 on genotoxicity associated with inhalation exposure. Carcinogenicity. Data were not located regarding cancer in orally exposed humans. In the key lifetime dietary study in rats (Feron et al. 1981) used by EFA (1985a, 1987a) to derive a potency estimate for oral exposure, rats were fed diets that provided vinyl chloride at doses of 1.8, 5.6, or 17.0 mg/kg/day for lifetime. An increased incidence of neoplastic nodules of the liver and/or hepatocellular carcinoma, statistically significant, was observed at 1.8 mg/kg/day in females and at 5.6 mg/kg/day in males. The lower dose is depicted in Fig. 2.4 as the lowest dose in animals associated with cancer. EPA (1985a, 1987a) estimated the upper-bound cancer potency at 2.3 (mg/kg/day)based n the combined incidence of liver and lung tumors in both sexes of rats. Doses associated with excess cancer risks of 10"^, 10*, 10*, and 10*^ are plotted in Fig. 2.4. 2.2.1.3 Dermal Pertinent data regarding toxicity in humans or animals dermally exposed to vinyl chloride were not located in the available literature. 2.2.2 Biological Monitoring as a Measure of Exposure and Effects Biological monitoring for exposure to vinyl chloride has had limited success. In an early study, Baretta et al. (1969) attempted to correlate postexposure concentrations of vinyl chloride in exhaled air UCC 107866 16 Section 2 with xposure levels. Although there was a very close r lationship between exposure levels i50 ppm and levels in expired air, the method does not appear to be useful at exposure concentrations <50 ppm. Methods have been devised to quantify vinyl chloride in urine (van Sittert and de Jong 1985) and tissue (Zuccato et al. 1979), but metabolism occurs so quickly that quantification of levels of unchanged compound in urine is not likely to reflect exposure levels, particularly at low concentrations. More recently, biological monitoring has focused on correlating urinary levels of thiodlglycolic acid, the major urinary metabolite of vinyl chloride (Green and Hathway 1977), with exposure levels in the air (Heger et al. 1982). The results, presented in Fig. 2.5, suggest a reasonable correlation between exposure concentration and urinary output of thiodlglycolic acid. In reviewing these data, however, Tarkowskl (1984) noted that a great deal of individual variation occurred, and the correlation was not strong enough to render this method reliable at exposure concentrations of <5 ppm. Tarkowskl (1984) concluded that no reliable method exists for biological monitoring of exposure to vinyl chloride. As indicated in Sect. 4.3.2.1, Hepatotoxicity, liver disease is probably the most common adverse effect associated with exposure to vinyl chloride. Generally, routinely performed biochemical screening and liver function screening tests have not been useful in monitoring the presence, severity, or progress of vinyl chloride disease (Lee et al. 1977b, Lilis et al. 1975). More recently, Doss et al, (1984) measured total urinary porphyrins and secondary urinary coproporphyrin in several patients with liver disease resulting from exposure to vinyl chloride. These investigators observed a correlation between slightly to moderately elevated total urinary porphyrin and the early stages of toxic liver disease. Particularly noted was a marked elevation in urinary coproporphyrin. In cases of chronic liver disease, total urinary porphyrin was markedly elevated to 3 to 6 times the upper normal limit, but coproporphyrin appeared to be elevated relatively less than was observed for acute toxicity. The investigators observed that elevated urinary coproporphyrin is a common clinical pathological finding in vinyl'chloride*related liver disease and may be useful in monitoring chronic exposure and progress of the clinical case, although other liver toxins and an inherited defect can also result in elevated urinary porphyrin. 2.2.3 Environmental Levels as Indicators of Exposure and Effects 2.2.3.1 Levels found in the environment Levels of vinyl chloride in environmental media are typically low and, generally, are not likely to result in significant human exposure. The most important medium for human exposure is air. Atmospheric levels in most places are usually below the level of detection (Stephens et al. 1986; Grimsrud and Rasmussen 1975a,b; Harkov et al. 1984; Wallace et al. 1984; EPA 1985b). Levels from trace to 8.8 mg/m^ (3.4 ppm) have been found near vinyl chloride production plants (Gordon and Meeks 1977, Pellizzarl et al. 1979, IARC 1979, EPA 1985b), and levels have ranged from undetectable to 30.8 /tg/m^ (0.012 ppm) over landfills (Stephens et UCC 107867 Health Effects Swanary 17 CONCENTRATION IN AIR (ppm) Fig. 2.5. Urinary output of thiodiglycolic acid from volunteers 12 h after exposure to vinyl chloride in air for 12 h. Source. Tarkowski 1984. UCC 107868 18 Section 2 al. 1986, Baker and Mackay 1985). Vinyl chloride in air over landfills may originate from the disp sal of vinyl chloride containing wastes or from the degradation of trichloroethylene, tetrachloroethylene, or 1,1,1trichloroethane (HSDB 1987, Vilson and Wilson 1985, Smith and Dragun 1984). It is unlikely that levels in ambient air would result in significant exposure. Several epidemiological studies associated occupational exposure with adverse health effects, including cancer; however, these studies (see Sect. 4, Toxicological Data) did not quantify exposure. A NIOSH survey of three vinyl chloride manufacturing plants reported a tlmeweighted average concentration of 0.18 to 69 mg/m-* (0.07 to 27 ppm) in workplace air (Fishbeln 1979). Concentrations In some plants were as high as 100 to 800 mg/m^ (39 to 315 ppm) (Fishbein 1979). There seems little doubt that occupational exposure remains the most important source of exposure to vinyl chloride. levels in drinking water as high as 10 Mg/1> have been detected (Dyksen and Hess 1982, HSDB 1987), but most monitoring studies have reported no detectable vinyl chloride in drinking water (HSDB 1987, Coniglio et al. 1980). Data were not located regarding the monitoring of vinyl chloride in soil, but exposure from contact with contaminated soil is likely to be negligible because dermal absorption is not considered significant (Hefner et al. 1975a). In the past, vinyl chloride had been detected in various foods as a result of migration from polyvinyl chloride food wrappings and containers (EPA 1985b). Currently, the FDA regulates the concentration of vinyl chloride monomer in polymers that contact food in order to restrict Intake of vinyl chloride to safe levels. 2.2.3.2 Human exposure potential Monitoring data indicate that people living in the vicinity of vinyl chloride, FVC, or vinyl chloride copolymer manufacturers, or hazardous waste sites that contain vinyl chloride, would be exposed to this compound through inhalation of contaminated air, whereas people not living near these sources would be exposed to negligible levels. Locations of large industrial sources include, but are not limited to: Plaquemine, Louisiana; Houston, Texas; Lake Charles, Louisiana; Calvert City, Kentucky; Point Comfort, Texas; Oklahoma City, Oklahoma; Baton Rouge, Louisiana; Delaware City, Delaware; Pensacola, Florida; and Aberdeen, Massachusetts (CMR 1986a,b). The greatest likelihood for human inhalation exposure to vinyl chloride is occupational. NIOSH estimated that 27,000 workers are definitely exposed to vinyl chloride and as many as 2.2 million workers may probably be exposed (Slttig 1985). The level of vinyl chloride in drinking water Is expected to be highest in areas where the raw water supplies are contaminated with vinyl chloride. The most probable source of surface water contamination is wastewater from vinyl chloride, FVC, and vinyl chloride copolymer manufacturers. The most probable sources of groundwater contamination are landfills. It has been shown that use of FVC pipes may result in leaching of vinyl chloride monomer Into drinking water supplies; however, the concentrations in drinking water that occur from these pipes are below those expected to cause adverse health effects. UCC 107869 2.3 ADEQUACY OF DATABASE Health Effects Sunoary 19 2.3.1 Introduction Section 110 (3) of SARA directs the Administrator of ATSDR to prepare a toxicological profile for each of the 100 most significant hazardous substances found at facilities on the CERCLA National Priorities List. Each profile must include the following content: "(A) An examination, summary, and interpretation of available toxicological 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. (S) A determination of whether adequate information on the health effects of each substance is available or in the process f development to determine levels of exposure which present a significant risk to human health of acute, subacute, and chronic health effects. (C) Where appropriate, an identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans." This section Identifies gaps in current knowledge relevant to developing levels of significant exposure for vinyl chloride. Such gaps* are identified for certain health effect end points (lethality, systemic/target organ toxicity, developmental toxicity, reproductive toxicity, and carcinogenicity) reviewed in Sect. 2.2 of this profile in developing levels of significant exposure for vinyl chloride, and f r other areas, such as human biological monitoring and mechanisms of toxicity. The present section briefly summarizes the availability of existing human and animal data, identifies data gaps, and summarizes research in progress that may fill such gaps. Specific research programs for obtaining data needed to develop levels of significant exposure for vinyl chloride will be developed by ATSDR, NTP, and EPA in the future. 2.3.2 Health Effect End Points 2.3.2.1 Introduction and graphic summary The availability of data for health effects in humans and animals is depicted on bar graphs in Figs. 2.6 and 2.7, respectively. The bars of full height indicate that there are data to meet at least one of the following criteria: 1. For noncancer health end points, one or more studies are available that meet current scientific standards and are sufficient to define a range of toxicity from no-effect levels (NOAELs) to levels that cause effects (LOAELs or FELs). 2. For human carcinogenicity, a substance is classified as either a "known human carcinogen" or "probable human carcinogen" by both EPA and the International Agency for Research on Cancer (IARC) UCC 107870 S e ctio n 2 ucc HUMAN DATA ro o SUFFICENT REFORMATION* SOME INFORMATION NO INFORMATION LtTHALITT ACUTC MTCHWOIATK z_______________________ STtTCHtC TOXICITY OIVCLOAMENTAl MMOOUCTIVI CAHOHOOEHICmf / TOXICITY TOXICITT o-vl 00 Fig. 2.6. Availability of infornation oo bealtb effects of Tiayl chloride (baiaaa data). *sl t ANIMAL DATA V_ SUFFICIENT 'INFORMATION* J SOME riiINFORMATION J NO ^FORMATION H e a lth E ffa c ts Si zibioi oon ACUTE INTERMEDIATE CHRONIC /_____________________ / Toxicrrv VSTEHIC TOXICITY DEVELOPMENTAL REPRODUCTIVE toxicity CARCINOOENKITT `Sufficient information exlsta to meet at least one of the criteria tor cancer or noncancer end points. Fig. 2.7. Availability of information on health effects of vinyl chloride (animal data). 3 ro 22 Section 2 (qualitative), and the data are sufficient to derive a canc r potency fact r (quantitative). 3. For animal carcin genicity, a substance causes a statistically significant number of tumors in at least one species, and the data are sufficient to derive a cancer potency factor. 4. There are studies that show that the chemical does not cause this health effect via this exposure route. Bars of half height indicate that "some" information for the end point exists, but does not meet any of these criteria. The absence of a column indicates that no information exists for that end point and route. 2.3.2.2 Descriptions of highlights of graphs Figure 2.6 shows that human dose-response data for oral and dermal exposure are lacking. Data are available that associate high inhalation levels of vinyl chloride with mortality in acute occupational exposure, but exposure levels were not quantified; therefore, the graphs indicate "some" but not "adequate" data. Data were not located for acute or intermediate inhalation exposure to vinyl chloride. Many epidemiological studies and case studies have characterized the syndrome known as vinyl chloride disease in occupationally exposed humans (see paragraph on vinyl chloride disease from inhalation exposure, human, in Sect. 4.3.2.3). Several epidemiology studies have investigated the effects of vinyl chloride exposure on the incidence of fetal loss and birth defects. No solid association was found, and the date are considered "inadequate" for developmental toxicity in humans. Two studies suggest that occupational exposure interferes with normal sexual activity and compromises gynecological health (Makarov 1984, Makarov et al. 1984). These data are inadequately reported for critical evaluation, and, consequently, the graph for reproductive toxicity indicates "some" data. Although vinyl chloride is clearly a human carcinogen based on occupational data (see Sect. 4.3.6.1 on carcinogenicity from inhalation exposure, human), exposures were not quantified, and the data are classified as "some." The lack of dermal data is not problematical since dermal absorption of vinyl chloride vapor is expected to be insignificant compared with inhalation absorption (Hefner et al. 1975a). Although there is a lack of oral data in humans,, data in relevant animal models are sufficient to estimate significant levels of exposure for intermediate and chronic oral exposure. Deficiencies in the human inhalation toxicity data are somewhat more noteworthy because animal data are sufficient for estimating a minimal risk level for intermediate duration but not for chronic inhalation exposure. From Fig. 2.7 it is apparent that the database for inhalation exposure in animals is more extensive than for humans. Inhalation data for acute lethality, intermediate duration toxicity, developmental toxicity, and carcinogenicity are sufficient for critical evaluation and are defined as "adequate." Inhalation data for chronic systemic toxicity are Inadequate for defining a range of toxicity and, therefore, are graphically depicted as "some." UCC 107873 Health Effects Summary 23 The oral database Is more nearly compl t . Data "adequate" for risk assessment are available for intermediate and chronic toxicity and carcinogenicity. However, acute lethality data, limited to an LDso in rats (Sax 1984), were judged to be "some." Data were lacking for acute systemic, developmental, and reproductive toxicity. Since oral exposure is possible, the data gap regarding developmental and reproductive toxicity should be filled. 2.3.2.3 Summary of relevant ongoing research Peter Foiles at the American Health Foundation in New York City will conduct a study sponsored by the National Cancer Institute to develop monoclonal antibodies that will aid in the detection of cyclic DNA adducts in humans exposed to environmental carcinogens. The study may contribute to our knowledge of adducts that are formed in humans from vinyl chloride exposure and the role these adducts play in human carcinogenesis (NTIS 1987). Peter Guengerich at the Department of Biochemistry at Vanderbilt University in Nashville, Tennessee, will investigate the bioactivation and covalent binding of metabolites of vinyl halides, including vinyl chloride. This work, sponsored by the National Institute of Environmental Health Sciences, may contribute to our understanding of the impact of specific enzymes in the liver and other organs to the toxification and detoxification of vinyl chloride (NTIS 1987). D.P. Brown at NIOSH in Cincinnati, Ohio, is updating cohort mortality studies on several chemicals and mixtures, including vinyl chloride. It is hoped that the updated studies may provide sufficient statistical analyses to provide more definitive information regarding the association of vinyl chloride with various types of cancer (NTIS 1987). J.R. Giacin at Michigan State University has been investigating the migration of monomers in plastics into food stimulants. This project, sponsored by the U.S. Department of Agriculture, may allow more accurate estimation of the exposure of the population to vinyl chloride from foods packaged in plastic (NTIS 1987). According to Dow Chemical Co. (1988), an update of the Fox and Collier (1977) British study of occupational exposure to vinyl chloride is imminent. 2.3.3 Other Information Needed for Human Health Assessment 2.3.3.1 Pharmacokinetics and mechanisms of action The pharmacokinetics of vinyl chloride in humans exposed by inhalation is relatively well understood, but little is known of oral and dermal pharmacokinetics. The gap in human pharmacokinetic knowledge is not a concern because the pharmacokinetics of oral vinyl chloride in relevant animal models is well understood, and dermal exposure is not likely to be significant. Metabolism to an epoxide and an aldehyde provides reactive intermediates thought to be responsible for the carcinogenicity and probably the hepatotoxiclty of the compound in UCC 107874 24 Section 2 animals and humans. Further understanding of the mechanism of aetl n on thar systeas, such aa the CMS, could bo gained. 2.3.3.2 lfonlt ring f human biological samples The aost practical biological monitoring procedure appeara to be quantification of urinary output of thiodlglyeolic acid, the predominant urinary metabolite of vinyl chloride (Heger et al. 1982). Individual variation, however, renders this method unreliable at exposure concentrations <5 ppm (Tarkovski 1984). 2.3.3.3 Environmental considerations Limited data are available regarding the vinyl chloride levels in foodstuffs. Monitoring data on levels of vinyl chloride in food contained in PVC packaging materials are needed. Intake of vinyl chloride by ingestion of contemlneted food was assumed to be negligible, based on strict IDA regulstions and one laboratory study (Kontominas et al. 198S) that simulated actual food packaging and food storage conditions. This assumption should be verified with monitoring data. Data on the amount of leaching of vinyl chloride from rigid PVC water pipes into drinking water need to be obtained. Monitoring data alone cannot reveal the extent of the leaching problem because monitoring data frequently reflect levels in drinking water supplies before transport through PVC distribution systems. Limited data are available on the persistence of vinyl chloride in the environment, particularly in surface waters, soil, and groundwater. Although a half*life for vinyl chloride in surface water has been estimated, significant uncertainty exists. Due to lack of data, it was not possible to estimate a half-life for vinyl chloride in soil or groundwater. UCC 107875 25 3. CHEMICAL AMD PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Data pertaining to the chenical identity of vinyl chloride are listed in Table 3.1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of vinyl chloride are presented in Table 3.2. UCC 107876 26 Section 3 Table 3.1. Chemical identity of vinyl chloride Parameter Chemical name Synonyms and trade names Chemical formula Wiswesser line notation Chemical structure Value References Chloroethene Vinyl chloride, chloroethylene, ethylene monochloride, monochloroethylene, VC, VCM, vinyl C monomer C2HjC1 GlUl SANSS 1987 SANSS 1987 HSDB 1987 HSDB 1987 H Cl \c -- / C /\ HH Identification numbers CAS Registry No. NIOSH RTECS No. EPA Hazardous Waste No. OHM-TADS No. DOT/UN/NA/IMCO Shipping No. STCC No. Hazardous Substances Data Bank No. National Cancer Institute No. 75-01-4 KU9625000 U043 7216947 1086 49 057 92 169 None available HSDB 1987 HSDB 1987 HSDB 1987 HSDB 1987 HSDB 1987 HSDB 1987 HSDB 1987 ucc A07877 Chemical and Physical Information 27 Table 3.2. Physical and chemical properties of vinyl chloride Property Value References Molecular weight Color Physical state Odor Odor threshold Water Air Melting point Boiling point Autoignition temperature Solubility Water Organic solvents Density, g/cm3 Vapor density (air -- 1) Log octanol-water partition coefficients Vapor pressure Henry's law constant Refractive index Flashpoint Flammability limits Conversion factors ppm (v/v) to mg/m3 in air mg/m3 to ppm (v/v) in air 62.5 Colorless Gas Mild, sweet 3.4 ppm (w/v) 3,000 ppm (v/v) -- 153.8C -- 13.4C 472C 2,763 mg/L at 25C 1,100 mg/L at 25C Soluble in hydrocarbons, oil, alcohol, chlorinated solvents, and most common organic liquids 0.969 ( -- 14.28C) 2.15 1.36 2,660 mm Hg at 258C 1.2 (atm*m3)/mol at 10C 1.3700 at 208C -- 77.75 (open cup) 4-22 vol % ppm (v/v) -- 2.60 mg/m3 mg/m3 " 0.39 ppm (v/v) Cowfer and Magistro 1983 Cowfer and Magistro 1983 Cowfer and Magistro 1983 Verschueren 1983 Amoore and Hautula 1983 Amoore and Hautula 1983 Cowfer and Magistro 1983 Cowfer and Magistro 1983 Cowfer and Magistro 1983 EPA 1985b Cowfer and Magistro 1983 Cowfer and Magistro 1983 Cowfer and Magistro 1983 Verschueren 1983 EPA 1987b Verschueren 1983 EPA 1985b EPA 1985b Cowfer and Magistro 1983 Cowfer and Magistro 1983 UCC 107878 29 4. TOXICOLOGICAL DATA 4.1 OVERVIEW Much of the data summarized in this section is reviewed in two recent EPA documents (EPA 1985a,b). Respiratory and gastrointestinal absorption of vinyl chloride appears to be rapid. In one briefly reported study it was estimated that humans retain -42% of vinyl chloride inhaled at concentrations of 3 to 24 ppm. Animal studies suggest that gastrointestinal absorption is nearly complete. Dermal absorption of vinyl chloride vapors is not likely to result in toxicity. Distribution of absorbed vinyl chloride may be widespread, with highest levels of parent compound located In fat; but metabolism and excretion occur so rapidly that highest levels of excretory products are located in the liver and kidney, the primary organs of metabolism and excretion. Regardless of the route of administration, inhalation or oral, metabolism proceeds via oxidation and subsequent conjugation with sulfhydryl groups. An important oxidative pathway involves mixedfunction oxidase and results in reactive electrophilic Intermediates, 2-chloroethylene oxide and 2-chloroacetaldehyde, which bind to liver macromolecules and may be responsible for the toxicity and oncogenicity associated with vinyl chloride. Excretion of polar metabolites is predominantly through the urine; when metabolic pathways are saturated, substantial amounts of unmetabolized vinyl chloride are exhaled. At sublethal doses, the liver is the primary target organ for carcinogenic and noncarcinogenic effects of vinyl chloride in humans and animals. The significant feature of the toxicity of vinyl chloride is its carcinogenicity. In occupationally exposed humans and in animals exposed orally or by inhalation, an increased incidence of liver and brain tumors, and possibly other types of tumors, can be attributed to vinyl chloride. Other symptoms in occupationally exposed humans are collectively termed "vinyl chloride disease," and include acroosteolysis, circulatory disturbance in the extremities, Raynaud syndrome, scleroderma, hematological effects, and effects on the lungs, as well as effects on the liver. No counterpart of the human disease has been produced in experimental animals. In occupationally exposed humans, vinyl chloride is genotoxic. This effect is associated with an increase in chromosomal aberrations in peripheral lymphocytes, and it appears to be reversible when exposures are reduced to dl ppm. Vinyl chloride is mutagenic in a number of microbial and other test systems. Electrophilic metabolites of vinyl chloride, 2-chloroethylene oxide and 2-chloroacetaldehyde, have been shown to bind to maeromolecules. 2-Chloroethylene oxide forms adducts with DNA. These mechanisms may explain the toxicity and carcinogenicity of vinyl chloride. Preceding page blank UCC 107879 30 Section 4 4.2 TOXICOKINETICS 4.2.1 Abs rption 4.2.1.1 Inhalation Hunan. Krajewskl et al. (1980) exposed young male volunteers to vinyl chloride monomer concentrations of 7.5 to 60 mg/m^ (3 to 24 ppm) by gas mask for 6 h. The authors did not report whether steady state had been achieved, and the data were inadequate to determine this point. Retention was estimated by measuring the difference between inhaled and exhaled concentrations. Retention reached a maximum within 15 min and declined rapidly after 30 min of exposure, after which it increased to a relatively constant value. An average retention of 42% was estimated. Although the results varied among the individuals tested, the percentage retained appeared to be independent of the concentration inhaled. Animal. 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 dos that is absorbed, tfithey (1976) determined that peak blood levels occurred at 30 min in rats exposed head only to 7,000 ppm. Bolt et al. (1977) placed rats that had been pretreated with 6-nitro-l,2,3benzothiadiazole to completely block the metabolism of vinyl chloride in a closed chamber containing 0.4 to 0.5 ppm -vinyl chloride. Radioactivity in the chamber air declined only for the first 15 min of exposure, indicating that equilibrium between atmospheric and tissue levels of radioactivity had occurred, suggesting rapid uptake by the tissues of the rats. 4.2.1.2 Oral Human. Data regarding the oral absorption of vinyl chloride by humans were not located. Animal. Several studies in rats indicate that vinyl chloride is rapidly and probably completely absorbed from the gastrointestinal tract. Vithey (1976) administered single 10 mL (44 to 92 mg/kg) oral doses of vinyl chloride in aqueous solution and observed that blood levels of vinyl chloride peaked in 10 to 20 min. Vatanabe et al. (1976a) administered single gavage doses of 0.05, 1, and 100 mg/kg ^-^C-vinyl chloride in com oil and measured the amount of radioactivity excreted in expired air, urine, and feces, as well as the amount retained in the carcass, at 72 h. The fraction of the administered dose recovered in the feces, roughly indicative of the proportion unabsorbed, ranged from 0.47 to 2.39%, suggesting that absorption was nearly complete. Total recovery, however, ranged from 82.3 to 91.3%, suggesting substantial loss of radioactivity. Feron et al. (1981) provided rats with diets containing nominally 20, 60, or 200 ppm vinyl chloride monomer (from powdered polyvinyl chloride containing a high level of the monomer) for 4 h and measured the fecal excretion of vinyl chloride over 23 h from the start of the feeding period. Fecal excretion accounted for 8, 10, and 17% of the vinyl chloride present in the low, middle, and high diets, respectively. The investigators hypothesized that the vinyl . chloride recovered from the feces was encapsulated by polyvinyl chloride UCC 107880 Toxicological Data 31 and was n t available to the rats for absorption, and that abs rptlon of available vinyl chloride was virtually complete. 4.2.1.3 Dermal Human. Data regarding the dermal absorption of vinyl chloride by humans were not located. Animal. Animal data suggest that dermal absorption of vinyl chloride gas Is not likely to be significant. Hefner et al. (1975a) placed all but the heads of two anesthetized rhesus monkeys In chambers containing 800 or 7,000 ppm -vinyl chloride for 2.5 or 2 h, respectively, to measure the uptake of radioactivity. On the basis f vinyl chloride measured In expired air and radioactivity measured in selected tissues, the Investigators estimated dermal absorption of 0.031 and 0.023% of the available vinyl chloride at 800 and 7,000 ppm, respectively. The investigators concluded that dermal absorption was far less significant than Inhalation absorption. 4.2.2 Distribution 4.2.2.1 Inhalation Human. Data regarding the distribution of vinyl chloride in the tissues of humans exposed by inhalation were not located. Animal. Data from rat studies suggest that the distribution f inhaled vinyl chloride is rapid and widespread but depends on metabolism. Buchter et al. (1977) exposed rats to ^C-vinyl chlorid t determine tissue distribution of radioactivity. In rats pretreated with 6-nitro-l,2,3-benzothiadlazole to block metabolism of vinyl chloride, the highest levels of radioactivity 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 radioactive metabolites were located in the liver and kidney. At 10 min after a 5-min exposure of rats to 20,000 ppm ^C-vinyl chloride, Duprat et al. (1977) detected radioactivity in the liver, bile duct, digestive tract, and kidney. At 3 h after the exposure described above, radioactivity was also detected in the urinary tract, salivary and lacrimal glands, thymus, and skin. Immediately after a 5-h exposure to -vinyl chloride at 50 ppm, tissue levels of radioactivity, expressed as percent incorporated per gram of tissue, were 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). Watanabe et al. (1976b) exposed rats to 10 or 100 ppm ^C-vlnyl chloride for 6 h and measured radioactivity in tissues 72 h later. In order of decreasing concentration, radioactivity (present as nonvolatile metabolites) was detected in the liver, kidney, skin, lung, muscle, carcass, plasma, and fat. 4.2.2.2 Oral Human. Data regarding the tissue distribution of vinyl chloride in orally exposed humans were not located. Animal. Vatanabe et al. (1976a) measured the level of radioactivity present as nonvolatile metabolites In tissues of rats 72 h ucc 107881 32 Section 4 after single 0.05 to 100-mg/kg gavage dos s of 14C-vinyl chloride in corn oil. Highest levels occurred in the liv r, -2 to S tines higher than in the other tissues examined (skin, plasma, muscle, lung, fat, and carcass). 4.2.2.3 Dermal Data regarding the distribution of vinyl chloride following dermal exposure of humans or experimental animals were not located. 4.2.3 Metabolism 4.2.3.1 Inhalation Human. In the only human data located, Sabadle et al. (1980) examined the ability of aryl hydrocarbon hydroxylase In the S-9 fraction from surgically obtained liver specimens to metabolize vinyl chloride to electrophiles mutagenic to Salmonella typhlauriua TA1530. The number of revertants per plate were compared with that 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, but a ninefold individual variation was observed. Animal. Hefner et al. (1975b) exposed rats to vinyl chloride in a closed chamber at concentrations of -50 to 1,000 ppm for 52.5 to 356.3 min. 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, appeared to follow first-order kinetics with a half-life of 86 min at <100 ppm. At >220 ppm, metabolism was slowed to a half-life of 261 min, suggesting saturation of the pathway predominant at <100 ppm. Pretreatment with ethanol depressed the rate of metabolism >83% at <100 ppm but <47% at >1,000 ppm. Pretreatment with SKF 525-A, however, had no effect at <100 ppm but depressed metabolism 19% at >1,000 ppm. The authors postulated three alternative pathways for metabolism, as depicted in Fig. 4.1. At low concentrations, sequential oxidation to 2chloroethanol, 2-ehloroacetaldehyde, and 2-chloroacetie acid involving alcohol dehydrogenase (inhibited by pretreatment with ethanol) appeared to be the predominant pathway. Little 2-chloroacetle acid was formed, however, probably because 2-chloroacetaldehyde conjugated rapidly with ubiquitous aulfhydryl groups. When the alcohol dehydrogenase pathway became saturated, 2-chloroethanol may have been oxidized by catalase in the presence of hydrogen peroxide (H202) to a peroxide, which may have undergone subsequent dehydration to form 2-chloroacetaldehyde. An alternative pathway may have involved oxidation by nixed-function oxidase to form a highly reactive epoxide intermediate, 2-chloroethylene oxide, which spontaneously rearranged to form 2-chloroacetaldehyde. Hefner et al. (1975b) reported urinary excretion of polar metabolites and 2-chloroacetic acid by rats exposed by inhalation. Other animal data expand the hypotheses of Hefner et al. (1975b). Hultmark et al. (1979) used an in vitro technique to determine that metabolism was HADPH-dependent, located in the microsomal fraction of UCC 107882 Toxicologic*! Dat* 33 CIHC - CH2 VWYL CHLORIDE I CIHgC - ch2oh 2-CHLOROETHANOL MIXED FUNCTION OXDASE h2o2 CATALASE ALCOHOL DEHYDROGENASE CIH2C - CHO 5 2-CHLOROACETALDEHYDE O /\ * H2C - CH I Cl 2-CHLOROETHYLENE OXIDE cih2c - ch2ooh 2-CHLOROETHYLHYDROPEROXDE t CIH2C - COOH 2-CHLOROACETIC ACD Fig. 4.1. Proposed Metabolic pathways for rfayi chloride. UCC 107883 34 Seccion 4 the liver, and probably involved nixed-function oxidase. Bolt et al. (1977) reported that pretreatnent with 6-nitro-l,2,3-benzothiadiazole was sufficient to totally block netab lian f vinyl chloride in rats expos d to -0.45 ppn in a closed systen for 5 h. Bolt et al. (1977) and Bolt (1986) interpreted this observation to strongly suggest that metabolisn of vinyl chloride proceeds primarily through a nixed-function oxidase pathway with likely production of an epoxide intermediate, because 6-nitro-l,2,3-benzothiadiazole is known to inhibit some microsomal cytochrome P-450 oxidation pathways. Bolt et al. (1977) and Filser and Bolt (1979) exposed rats in a closed system to 100 or 1,000 ppm -vinyl chloride. By measuring the disappearance of radioactivity with time, they determined 250 ppm to be the threshold at which saturation of metabolic pathways occurs. A metabolic rate (Vgax) of 110 jimol/h/kg was estimated for rats. In a similar experiment in rhesus monkeys, metabolic saturation was observed to occur at 200 ppm, with a Vmax of 50 jimol/h/kg (Buchter et al. 1980). The Vmax of 50 /imol/h/kg was suggested as a closer approximation of metabolism In humans than the value of 110 /tmol/h/kg estimated for rats by Filser and Bolt (1979). Inhalation exposure has been associated with reduction in liver nonprotein sulfhydryl concentration in the rat (Hefner et al. 1975b, Bolt et al. 1976b), particularly at exposure concentrations >100 ppm (Vatanabe et al. 1978a, Jedrychowskl et al. 1984). Urinary metabolites identified in rats exposed by inhalation Include polar compounds resulting from conjugation with sulfhydryl groups at low exposure concentrations (Vatanabe et al. 1976b, Hefner et al. 1975b) and 2-chloroaeetic acid at high exposure concentrations (Hefner et al. 1975b). Several investigators have observed the binding of nonvolatile metabolites of l^C-vinyl chloride to liver macromolecules in vitro and in rats exposed by inhalation (Kappus et al. 1976; Guengerich and Vatanabe 1979; Guengerich et al. 1979, 1981; Vatanabe et al. 1978a,b). In single-exposure experiments at different concentrations, the extent f macromolecular binding increased proportionately to the amount of vinyl chloride metabolized and disproportionately to the exposure concentration (Vatanabe et al. 1978a). The extent of macromolecular binding was Increased by repeated exposure to vinyl chloride (Vatanabe et al. 1978b) and by pretreatment with phenobarbltal (Guengerich and Vatanabe 1979). Macromolecular binding has been attributed to the reactive intermediate 2-chloroethylene oxide, which may bind to DNA and RNA, and to its rearrangement product, 2-chloroacetaldehyde, which may bind to protein molecules (Guengerich et al. 1979, 1981; Guengerich and Vatanabe 1979; Vatanabe et al. 1978a,b; Kappus et al. 1976; Bolt 1986). 4.2.3.2 Oral Human. Data regarding the metabolism of vinyl chloride by orally exposed humans were not located. Animal. Urinary metabolites identified from rats orally exposed to 14C-vinyl chloride are consistent with the metabolic pathways postulated for inhalation exposure, in particular with the formation of 2-chloroethylene oxide and 2-chloroacetaldehyde. Metabolites identified UCc 107884 Toxicological Data 35 include N*acetyl-S-(2-hydroxyethyl)cysteine, N-acetyl-S-(2chloroethyl)cysteine, 2-chloroacetic acid, thiodiglycolic acid, and glutamic acid (Vatanabe et al. 1976a; Vatanabe and Gehring 1976; Green and Hathway 1975, 1977). Metabolic saturation appears to occur with a single gavage dose of >1 and <100 mg/kg/day (Vatanabe et al. 1976a). 4.2.3.3 Dermal Data regarding metabolism in humans or animals dentally exposed to vinyl chloride were not located. 4.2.4 Excretion 4.2.4.1 Inhalation Human. Human data suggest that exhalation of unmetabolized vinyl chloride is not an important pathway of elimination at low exposure concentrations. Krajewski et al. (1980) exposed humans to air containing 7.5 to 60 mg/m^ for 6 h and measured the mean concentration in expired air for 30 min at termination of exposure. Mean concentrations in expired air ranged fun undetectable to 2.84 mg/m^, representing up to 3.60 to 4.73% of the inhaled concentration. In a study available as a brief abstract, Shu et al. (1986) reported that urinary concentration of thiodiglycolic acid Increased with increasing air concentration of vinyl chloride in an occupational * setting. Urinary concentrations of thiodiglycolic acid peaked within 20 h. The investigators suggested that daily urinary output of thiodiglycolic acid might be a satisfactory biological index of exp sure to vinyl chloride. Animal. The mode of excretion of vinyl chloride and its metabolites following inhalation exposure of animals to different concentrations reflects the saturation of metabolic pathways at low concentrations discussed in Sect. 4.2.3.1, in the subsection on metabolism in animals after inhalation exposure. The cumulative excretion of radioactivity over a 72-h postexposure period was measured in rats exposed to 10 or 1,000 ppm (Vatanabe and Gehring 1976, Vatanabe et al. 1976b) or 5,000 ppm (Vatanabe et al. 1978b) ^C-vinyl chloride for 6 h. Radioactivity expired as C02 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 presented in Table 4.1 suggest that metabolism was nearly complete at 10 ppm, because <2% of the recovered radioactivity occurred as unchanged parent compound. The predominant route for excretion of radioactive metabolites was through the urine, accounting for -70% of the recovered radioactivity. Metabolism appeared to be 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, and urinary excretion accounted for -27% of the recovered activity. Generally, there was little change in the proportion of recovered radioactivity excreted in the feces or exhaled as C02. The percentage of the radioactivity retained in the carcass and tissues appeared to be somewhat decreased at UCC 107885 36 Soctiem 4 Table 4.1. Excretion of radioactivity in rats exposed to MC-rinyl chloride in air for 6 h Radioactivity expressed as percent of total recovered Exposure concentration (ppm) 10 1,000 5,000 Expired vinyl chloride Expired CO2 Urine Feces Carcass and tissues 1.61 12.09 67.97 4.45 13.84 12.26 12.30 56.29 4.21 14.48 54.5 8.0 27.1 3.2 7.3 Source: Watanabe and Gehring 1976; Watanabe et al. 1976b, 1978b. UCC 107886 Toxicological Data 37 5,000 ppm compared with 10 and 1,000 ppm, suggesting preferential retention of metabolites rather than unchanged vinyl chloride. Pulmonary xeretlon f unaltered vinyl chi ride appear d to f llow first-order kinetics regardless of exposure concentrations, with halflives of 20.4, 22.4, and 30 min at 10, 1,000, and 5,000 ppm. The urinary excretion of radioactivity was blphasic, with the second or slow phase accounting for <3% of the total urinary excretion. Half-lives for the rapid (first-order) phase were estimated at 4.6, 4.1, and 4.5 h, respectively. Urinary metabolites Included N-acetyl-S-(2hydroxyethyl)cysteine, thlodlglyeollc acid, and possibly S-(2hydroxyethyl)cystelne. 4.2.4.2 Oral Human. Data regarding the excretion of vinyl chloride by orally exposed humans were not located. Animal. In experiments In the United States (Vatanabe et al. 1976a, Vatanabe and Gehrlng 1976) and Great Britain (Green and Hathvay 1975), which studied the similarities of pharmacokinetics following Inhalation and oral exposure, single oral doses of -vinyl chloride were administered to rats, and the excretion of radioactivity was monitored over a 72-h period. Details are presented In Table 4.2. A striking increase in exhalation of unchanged vinyl chloride and compensatory decreases in urinary and fecal excretion of radioactivity . and exhalation of C02 were observed at &20 mg/kg, suggesting that metabolic saturation had occurred at that dosage. At l.O mg/kg, th predominant route of elimination was urinary excretion of polar metabolites. Exhalation of unchanged vinyl chloride was generally complete within 3 to 4 h, but excretion of metabolites continued for days (Gr en and Hathway 1975). Pulmonary excretion of vinyl chloride appeared t be monophaslc at l.O mg/kg, with a half-life of -55 to 58 min (Vatanabe et al. 1976a), At 100 mg/kg, pulmonary excretion of vinyl chloride was blphasic, with half-lives of 14.4 and 40.8 min for the rapid and slower phases, respectively. Urinary excretion of radioactivity was blphasic, with the rapid phase accounting for >97% of total urinary radioactivity and having half-lives of 4.5 to 4.6 h for dosages of 0.05 to 100 mg/kg. Metabolites Identified In the urine of orally treated rats were consistent with the formation of 2-chloroethylene oxide and 2chloroacetaldehyde (Vatanabe et al. 1976a, Green and Hathway 1977), as postulated for metabolism following Inhalation exposure. The major metabolite was Identified as thlodlglyeollc acid; nearly equivalent amounts of H-acetyl-S-(2-hydroxyethyl)cysteine were Identified (Vatanabe et al. 1976a, Green and Hathway 1975). Smaller amounts of radiolabeled S-(2-ehloroethyl)eysteine, urea, glutamic acid, and 2-chloroacetic acid were also Identified (Green and Hathway 1975). 4.2.4.3 Dermal Data regarding the metabolism of vinyl chloride following dermal exposure of humans or animals were not located. UCC 107887 38 Section 4 Table 4.2. Percent of administered dose of radioactivity excreted 72 h following a single oral dose of 14C-vinyl chloride in rats Dose (mg/kg) 0.05* 0.25* 1.0* 20* 100* 450* Expired As vinyl chloride As CO2 Urine Feces Carcass 1.43 8.96 68.34 2.39 10.13 Total 91.25 3.7 13.5 75.1 4.6 NR' 96.9 2.13 13.26 59.30 2.20 11.10 88.83 41.6 4.8 22.6 1.0 11.0 81.0 66.64 2.52 10.84 0.47 1.83 82.30 91.9 0.7 5.4 0.7 NR 98.7 *Watanabe and Gehring 1976, Watanabe et al. 1976a. *Green and Hathaway 1975. 'Not reported. 107888 Toxicological Data 39 4.2.4.4 Parenteral Human. Data regarding th metabolism of parenterally administered vinyl chloride In humans were n t located. Animal. The elimination of radioactivity following Intraperlt neal administration of -vinyl chloride to rats resembles the pattern observed following Inhalation and oral administration. Following an Intraperltoneal dose of 0.25 mg/kg, exhalation of unchanged vinyl chloride, exhalation of C02, 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, C02 decreased to 0.7%, urinary radioactivity decreased to 2.6%, and fecal radioactivity remained unchanged. 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 ^C-vinyl chloride to rats and recovered 80% of the dose within 2 min and 99% within 1 h as unchanged compound from expired air. 4.3 TOXICITY 4.3.1 Lethality and Decreased Longevity 4.3.1.1 Inhalation Human. ACGIH (1986a) and EPA (1985a) reviewed early reports of acute toxicity at high levels resulting in lethality among occupationally exposed workers. Deaths appeared to be due to narcosis. Exposure levels were not reported, and an LClo cannot be identified. Animal. Patty et al. (1930) reported that narcosis and death occurred within 30 to 60 min in guinea pigs exposed to 10% vinyl chloride (100,000 ppm). EPA (1985a) reviewed a number of acute studies in animals and reported 2-h LC50 values ranging from 117,500 ppm f r mice to 230,800 ppm for rabbits. Mastromatteo et al. (1960) exposed rats, mice, and guinea pigs (five per sex per group) to 10, 20, 30, or 40% (guinea pigs only) vinyl chloride in air (100,000, 200,000, 300,000, or 400,000 ppm) for 30 min. One guinea pig exposed to 40% died; all mice, rats, and one guinea pig exposed to 30% died; one mouse but n rats or guinea pigs exposed to 20% died. Long-term studies in rats and mice associate intermittent exposure to 50 ppm with decreased longevity. Lee et al. (1977a, 1978) exposed rats and mice (36 per sex per species) to 0, 50, 250, or 1,000 ppm, 6 h/day, 5 days/week for up to 12 months. Acute lethality associated with toxic hepatitis and tubular necrosis of the renal cortex occurred in mice after 5 to 9 days at 1,000 ppm. Shortened life span attributed to noncarcinogenic effects of vinyl chloride occurred in all exposed groups of both species. In a subsequent study, Hong et al. (1981) exposed mice (8 to 28 per sex per group) and rats (4 to 16 per sex per group) to 0, 50, 250, or 1,000 ppm, 6 h/day, 5 days/week for up to 6 months (mice) or 10 months (rats), followed by a 12-month observation period. A decrease in longevity related to concentration and duration of exposure was UCC 107889 40 Section 4 observed in both species at all exposure c ncentrations, which was attributed to a combination of systemic toxicity and tumor devel pment. 4.3.1.2 Oral Human. Data regarding reduced longevity in humans orally exposed to vinyl chloride were not located. Animal. Sax (1984) reported an oral LDSO In rats of 500 mg/kg. The key lifetime oral study is that submitted by Til et al. (1983), in which male and female Vistar rats were fed diets containing polyvinyl chloride with a high level of the monomer. Dietary intakes of vinyl chloride monomer were estimated at 0, 0.014, 0.13, and 1.3 mg/kg/day. Croups consisted of 100 rats per sex except for the high group, which contained 50 rats per sex. Mortality was slightly but significantly increased in high-group rats, starting at 68 weeks of treatment. No effects on longevity were observed at 0.13 mg/kg/day, which is considered the NOAEL for decreased survival. An earlier lifetime study in rats from this laboratory (Feron et al. 1981) supports the NOAEL for reduced survival of 0.13 mg/kg/day. In this experiment, diets containing polyvinyl chloride with high levels of vinyl chloride monomer provided intakes of 0, 1.7, 5.0, or 14.1 mg/kg/day. A marked and statistically significant increase in mortality occurred at 5.0 mg/kg/day. Females at 1.7 mg/kg/day had a slight but not statistically significant increase in mortality. 4.3.1.3 Dermal Data regarding lethality or reduced longevity in dermally exposed humans or animals were not located in the available literature. 4.3.2 Systemic/Target Organ Toxicity 4.3.2.1 Hepatotoxiclty Inhalation, human. Several epidemiologic studies have associated occupational exposure with impaired liver function and/or biochemical or histological evidence of liver damage (Berk 1976, Buchancova et al. 1985, Gedigk et al. 1975, Marsteller et al. 1975, Popper and Thomas 1975, Doss et al. 1984, Lilis et al. 1975, Tamburro 1984, Tamburro et al. 1984). Several of these studies have been reviewed by EPA (1985a,b). Thresholds for hepatotoxiclty cannot be identified, because data regarding exposure concentrations and duration were not available. Negative results, however, were reported in liver status screening studies in 422 exposed and 202 control workers in one large vinyl chloride manufacturing and polymerization plant (Lee et al. 1977). Inhalation, animal. In the Lee et al. (1977a) study described in Sect. 4.3.1.1, in the subsection on lethality and decreased longevity in animals after inhalation exposure, acute hepatotoxiclty was observed in mice dying after intermittent exposure to 1,000 ppm vinyl chloride for 5 to 9 days. In an Intermediate-length animal inhalation study (Torkelson et al. 1961), several species were exposed intermittently for up to 6 months, as detailed in Table 4.3. Air-exposed controls were maintained. uc 107890 Toxicologic*! D*t* 41 Table 4J. Experimental protocol for animal exposure to vinyl chloride Species Number of animals/group Males Females Dose of vinyl chloride (ppm) Exposure schedule* (hours/day) Exposure duration (months) Rats Guinea pigs Rabbits Dogs 10 20-24 5 10 10-12 3 1 10 24 0 0 8-12 3 1 500 50, 100, or 200 100 or 200 50 7 7 0.5, 1, 2, or 4 1, 2, or 4 50, 100, or 200 7 50, 100, or 200 7 50, 100, or 200 7 4.5 6 6 6 6 6 6 "All animals were exposed 5 days/week. Source: Torkelson et al. 1961. UCC 107891 42 Section A Parameters of liver toxicity evaluated inelud d gross and hist path logic examination, measurement of relative organ weights, and determination of serum levels of enzymes associated with liver damage. Biochemical parameters of liver status were within normal limits at all exposure concentrations, but histopathologic lesions occurred in rats exposed to 500 ppm and in rabbits exposed to 200 ppm. Elevated relative liver weights appeared to be the most sensitive indicator of hepatotoxicity and were observed in rats at 100 ppm, 7 h/day, but not at 50 ppm by the same schedule. In a study designed primarily to evaluate effects on the testis (see Sect. 4.3.4.1, in the subsection on reproductive toxicity in animals after inhalation exposure), Bi et al. (1985) reported a concentration-related and significant elevation in relative liver weight in rats exposed to 10, 100, or 3,000 ppm, 6 h/day, 6 days/week for 6 months. The 10-ppm concentration is considered a LOAEL for liver effects in intermediate-length exposures. The longer-term study by Lee et al. (1977a) in which rats and mice were exposed to 0, 50, 250, or 1,000 ppm, 6 h/day, 5 days/week for up to 12 months (Sect. 4.3.1.1, in the subsection on lethality and decreased longevity in animals after inhalation exposure) failed to identify a NOAEL for hepatotoxiclty. Lee et al. (1977a) observed no adverse effects on biochemical parameters of rats or mice exposed to 250 ppm. Several mitotic figures, indicating increased rate of cell division, were observed in the livers of rats exposed to 50 or 1,000 ppm at 8 to 9 months, and increased rate of DNA synthesis was observed at 50 ppm. Since the liver is a known target organ for the toxicity and oncogenicity of vinyl chloride, these effects are judged to be potentially adverse, and 50 ppm is considered an effect level in this study. Feron et al. (1979a) exposed rats to 0 or 5,000 ppm, 7 h/day, 5 days/week for 4, 13, 26, or 52 weeks and observed histopathologic alteration of the liver after 13 weeks and ulras truetural alteration after only 4 weeks of exposure. Oral, human. Data were not located regarding hepatotoxiclty In orally exposed humans. Oral, animal. A gavage study in rats identifies 30 mg/kg as a NOAEL and 100 mg/kg as a L0AEL for liver effects in an intermediatelength study. Feron et al. (1975) administered vinyl chloride in soybean oil by gavage to groups of 15 rats per sex at 0, 30, 100, or 300 mg/kg, 6 days/week for 13 weeks. Parameters of liver toxicity evaluated included serum biochemistry, relative liver weight, and histopathologic and histochemical examination at all dosages and electron microscopy at 0 and 300 mg/kg. No effects were observed at 30 mg/kg, equivalent to 26 mg/kg/day. Reduced blood sugar and slightly altered hepatocytes were observed at 100 and 300 mg/kg. A dose-related increase in relative liver weight was observed and became statistically significant only at 300 mg/kg. Hypertrophic rough endoplasmic reticulum was observed at 300 mg/kg. The key long-term oral study that defines thresholds for hepatotoxiclty was reported by Til et al. (1983) and was described In Sect. 4.3.1.2, in the subsection on lethality and decreased longevity in animals after inhalation exposure. Diets provided dally dosages of 0, ucc 107892 Toxicological Data 43 0.014, 0.13, or 1.3 mg/kg/day to rats for their lifetime. There were no effects on general app arance, behavior, food c nsumptlon, body weight, or limited hematologic and biochemical parameters. Relative rgan weights were not evaluated. Noncarcinogenic adverse histopathol gic effects were confined to the liver and consisted of hepatocellular alteration and hepatic cysts in both sexes at 1.3 mg/kg/day. An increased incidence of basophilic foci were observed in both sexes at 1.3 mg/kg/day and only in females in the two lower dosage groups. Lacking a dose-related increase in the incidence of basophilic foci and hlstopathological evidence of adverse effects at 0.13 mg/kg/day, such as were observed at the higher dosage, basophilic foci in the liver of rats of one sex may be considered a nonadverse, although compound-related, effect. The dosage of 0.13 mg/kg/day, therefore, may be considered a NOAEL, and 1.3 mg/kg/day may be considered a LOAEL for hepatotoxicity. An earlier lifetime study from this laboratory supports the NOAEL for hepatotoxicity of 0.13 mg/kg/day. Feron et al. (1981) fed diets containing polyvinyl chloride with high levels of vinyl chloride monomer to rats that provided intakes of 0, 1.7, 5.0, or 14.1 mg/kg/day. An Increased incidence cf several histopathologic lesions, some of which were probably preneonlastic, were observed in the livers of rats from all treated groups. Dermal. Data regarding hepatotoxicity associated with dermal exposure of humans or animals to vinyl chloride were not located. General discussion. Symptoms and signs of liver disease associated with occupational exposure to vinyl chloride include pain or discomfort in the right-hand upper quadrant of the abdomen, hepatomegaly, splenomegaly, portal hypertension, thrombocytopenia, esophageal varices, and evidence of fibrosis and cirrhosis; however, these observations are not pathognomonic for vinyl-chloride-induced liver disease (Lilis et al. 1975, Popper and Thomas 1975, Lee et al. 1977b). Severity of the clinical picture appeared to correlate positively with duration of exposure (Lilis et al. 1975). Biochemical screening and liver function tests generally have not been useful to monitor the presence or progress of the disease (Lee et al. 1977b, Lilis et al. 1975), although recently, Doss et al. (1984) noted that increased urinary porphyrin and coproporphyrin occurred consistently in cases of liver disease induced by vinyl chloride and other industrial hepatotoxins. A number of investigators have noted that metabolites of vinyl chloride bind covalently to hepatocellular macromolecules and may be important in the mechanism of carcinogenesis (Bolt et al. 1976b, Bolt 1986, Kappus et al. 1976, Watanabe et al. 1978a, Watanabe and Gehring 1976). A mechanism for noncarcinogenic liver effects has not been postulated; however, since many of the lesions observed in the livers of vinyl-chloride-exposed rats are considered preneoplastic (Feron et al. 1981), it seems reasonable to suspect that macromolecular binding of reactive intermediates may be involved in noncarcinogenic toxicity. Support is derived from the data of Jaeger et al. (1977), who observed that mixed-function oxidase inducers Aroclor 1254 and phenobarbital potentiate the acute hepatotoxicity in rats exposed to vinyl chloride by inhalation. Pretreatment with SKF 525-A, a mixed-function oxidase inhibitor, prevented vinyl-chloride-induced toxicity. UCC 107893 44 Section 4 It should be noted that the oral NOAEL for hepatotoxicity in a chronic study (Til et al. 1983) was far below the NOAEL in a subchronic study (F ron et al. 1975). At least for oral xposure, the duration f exposure appears to be of major importance. 4.3.2.2 Nervous system effects Inhalation, human. Vinyl chloride was once considered for use as an inhalation anesthetic (ACGIH 1986a). Acute exposures to 0.8 to 2.0% vinyl chloride (8,000 to 20,000 ppm) have been associated with dizziness, giddiness, euphoria, ataxia, headache, and narcosis (Nicholson et al. 1975, Lester et al. 1963). Recent data from the foreign literature suggest that subtle signs of neurotoxicity may be associated with occupational exposure. Mild distal axonal neuropathy was reported in the legs of 45/64 exposed vinyl chloride workers, which was suggestive to the Investigators of a dying-back syndrome (Perticoni et al. 1986). Halama et al. (1985) associated neurologic and psychiatric disease with occupational exposure. Dinceva et al. (1985) reported electroencephalogram (EEG) changes that they thought were indicative of early evidence of neurotoxicity in workers exposed to vinyl chloride in combination with other organic solvents. Exposure levels were not reported by these authors. Inhalation, animal. Oster et al. (1947) anesthetized dogs with -7 to 50% (70,000 to 500,000 ppm) vinyl chloride and concluded that its use as an anesthetic was unsuitable because of cardiac and muscular effects. Lester et al. (1963) exposed rats to concentrations ranging from 5 to 15% (50,000 to 150,000 ppm) for up to 2 h to evaluate CNS effects. Moderate intoxication was observed at 5%, loss of reflexes was observed at 5 to 10%, and deep surgical anesthesia was reached at 15%. Patty et al. (1930) produced ataxia and narcosis in guinea pigs exposed to 2.5 to 5% (25,000 to 50,000 ppm) vinyl chloride for 2 to 5 min. Nervous system effects and histopathologic lesions in the brain were not reported in mice exposed to 50 ppm 6 h/day, 5 days/week for up to 12 months (Lee et al. 1977a) or in rats exposed to 5,000 ppm 7 h/day, 5 days/week for 12 months (Feron and Kroes 1979). Oral. Neurological effects have not been reported in orally exposed humans or in rats treated by gavage with vinyl chloride in soya bean oil at 300 mg/kg, 6 days/week for 13 weeks (Feron et al. 1975) or at 300 mg/kg, 5 days/week for 84 weeks (Feron et al. 1981). Dermal. Neurologic effects in dentally exposed humans or animals have not been reported. General discussion. CNS effects appear to be a manifestation of acute Inhalation exposure to high levels of vinyl chloride in humans and animals (Nicholson et al. 1975, Lester et al. 1963) that may result in death, at least in animals (Lester et al. 1963, Mastromatteo et al. 1960). Recent human data provide some evidence that chronic exposure to vinyl chloride may result in neurologic or psychiatric effects (Perticoni et al. 1986, Dinceva et al. 1985, Halama et al. 1985). Further investigation is needed. Neurologic signs or effects on the brain have not been reported in chronic inhalation studies in rats and mice (Lee et al. 1977a; Feron and Kroes 1979; Feron et al. 1975, 1981). UCC 107894 Toxicologies1 Data 45 4.3.2.3 Other systemic effects Vinyl chloride dlseese from inhalation exposure, human. Vinyl chloride disease is the name given to the total clinical syndrome associated with occupational exposure. It Includes a syndrome known as acroosteolysls or dissolution of the ends of the distal phalanges of the hands, circulatory disturbance In the extremities, Raynaud syndrome, scleroderma, hematologic effects, and effects on the lungs, as well as the liver effects previously discussed (Halama et al. 1985, Sakabe 1975, Lllls et al. 1975, Markowitz et al. 1972, Vllson et al. 1967, Dlnman et al. 1971, Preston et al. 1976). In addition, Mlcu et al. (1985) reported obscure effects of unknown toxicological significance on enzyme levels of leukocytes and thrombocytes of exposed workers. Other investigat rs have reported elevated levels of circulating IgG (Bogdanikowa and Zawllska 1984) or immune complexes (Vard 1976) as part of the syndr me, but the biological significance of these effects is not clear. Vinyl chloride disease from inhalation exposure, animal. Lee t al. (1977a, 1978) exposed rats and mice to vinyl chloride at 0, 50, 250, or 1,000 ppm 6 h/day, 5 days/week for up to 12 months, as described in Sect. 4.3.2.1, in the subsection on hepatotoxicity in animals after inhalation exposure. Parameters of toxicity evaluated included general appearance, feed consumption, body weight, hematology, clinical chemistry, macrophage counts of pulmonary washings, cytogenic examination of bone marrow cultures, senographic radiography of the long bones of the limbs, gross necropsy, selected organ weights, and histopathologic examination of a comprehensive set of organs and tissues. Abnormalities observed in the mice included body weight loss at 1,000 ppm after 8 months of normal growth and elevated pulmonary macrophage count in mice from all exposure groups that had bronchoalveolar adenoma. Because of its association with lung tumors, an elevated pulmonary macrophage count in mice In this study is not considered a noncarcinogenic toxic effect. Rats exposed to 1,000 ppm had reduced body weights compared with controls. Other noncarcinogenic adverse effects were not observed in rats. B1 et al. (1985) exposed rats to 10, 100, or 1,000 ppm 6 h/day, 6 days/week for 12 months to evaluate effects on the testis (see Sect. 4.3.4.1, in the subsection on reproductive toxicity in animals after inhalation exposure). At termination of exposure, a concentrationrelated decrease in body weights was evident and became statistically significant at 100 ppm. Effects on body weight were not reported by Torkelson et al. (1961) in rats (n 12) exposed for 7 h/day, 5 days/week to 500 ppm for 4.5 months or to 200 ppm for 6 months, or in dogs (n - 1), guinea pigs (n - 10), or rabbits (n - 3) exposed to 200 ppm by the same schedule. The value of this study is jeopardized by small animal group sizes. In a series of studies on rats exposed to 0 or 5,000 ppm 7 h/day, 5 days/week for 1 year, adverse effects not previously discussed included slightly reduced growth, hematologic evidence of anemia, decreased blood clotting time, and minor biochemical alterations of uncertain biological significance (Feron et al. 1979a,b; Feron and Kr es 1979). Effects on the kidney were noted and included elevated relative kidney weights, slightly increased blood urea nitrogen (BUM), altered UCC 107895 46 Section 4 urinalysis param ters, and increased intensity of progressive n phrosis, all compared with controls. Other nonearcinogenic 1 sions se n in treated rats included mild alterations of the Zymbal glands and lungs, increased splenic hematopoiesis, degeneration of the'myocardium and thickening of the walls of the arteries, and hyperplasia of the olfactory epithelium. Vinyl chloride disease from oral exposure, human. Data regarding effects of vinyl chloride in orally exposed humans were not located. Vinyl chloride disease from oral exposure, animal. In a 13-week study described in Sect. 4.3.2.1, in the subsection on hepatotoxicity in animals after oral exposure, Feron et al. (1975) treated rats with vinyl chloride at 0, 30, 100, or 300 mg/kg 6 days/week. Parameters of toxicity not previously discussed included general appearance and behavior, body weight, food consumption, hematology, selected blood chemistry and urinalysis tests, gross appearance on necropsy, relative weights of major organs, and histopathologic appearance of a wide range of organs and tissues. Minor hematologic and biochemical changes were observed but were not considered to be adverse. Decreased relative adrenal weight was observed in males at 300 mg/kg but was not considered toxicologically significant. No adverse response was reported in other organs or tissues. In a lifetime study also described in Sect. 4.3.2.1, in the subsection on hepatoxicity in animals after oral exposure, Feron et al. (1981) fed rats diets that provided 0, 1.7, 5.0, or 14.1 mg/kg/day vinyl chloride. An additional group was treated by gavage with 300 mg/kg 5 days/week. Parameters of toxicity evaluated Included general appearance and behavior, body weight, food consumption, hematology, blood chemistry, urinalysis, gross appearance at necropsy, and histopathologic examination of a wide range of tissues from controls and the two higher-dose groups, with a more limited histopathologic examination of low-dose rats. Lethargy and poor condition were reported at 5.0 mg/kg/day, apparently in rats that developed tumors. Nonearcinogenic effects included reduced blood clotting time and increased splenic hematopoiesis at 14.1 but not at 5.0 mg/kg/day. Vinyl chloride disease from dermal exposure. Data regarding toxic effects of vinyl chloride in dermally exposed humans or animals were not located. Vinyl chloride disease, general discussion. Vinyl chloride disease in humans appears to involve a large number of organ systems and tissues, including the liver, as discussed in Sect. 4.3.2.3, in the subsection on vinyl chloride disease in humans after inhalation exposure (Halama et al. 1985, Sakabe 1975, Lllis et al. 1975, Markowitz et al. 1972, Vilson et al. 1967, Dlnman et al. 1971, Preston et al. 1976). It is not possible to determine the critical effect in humans (the effect that occurs at the lowest exposure) because quantitative human exposure data were not provided. Animals exposed orally or by inhalation manifest cancerous and noncancerous liver effects similar to those seen in humans, but other effects seen in humans, such as acroosteolysia, Raynaud syndrome, and scleroderma, have not been reproduced In animals, even at very high exposures. Liver effects appear to be the critical end UCC 107896 DUE TO CIRCUMSTANCES BEYOND OUR CONTROL, PAGES 47 AND 48 OF THIS REPORT IS MISSING. ALTHOUGH ALL EFFORTS TO OBTAIN THE MISSING PAGES HAVE BEEN UNSUCCESSFUL, WE ARE MAKING THE REMAINDER OF THIS REPORT AVAILABLE TO THE PUBLIC. L UCC 107897 Toxicological Data 49 and may represent a chemical-induced effect. Signs f maternal r developmental toxicity were not observed in rabbits at either 500 or 2,500 ppm. Ungvary et al. (1978) exposed gr ups of pregnant CFY rats continuously to -1,500 ppm on gestation days 8 to 14 or 14 to 21 in a study that identified a NOAEL for developmental toxicity in rats. Controls consisted of groups of rats that were chamber exposed to air only on gestation days 8 to 14 or 14 to 21. An additional control group consisted of unexposed rats that were not subjected to the chamber. Groups contained 14 to 28 litters, and the litter was a unit of comparison for fetal effects. Maternal toxicity was manifested by increased relative liver weight in dams exposed on gestation days 8 to 14 and slightly reduced body weight gain in dams exposed on days 14 to 21. There was no evidence of fetal toxicity or teratogenicity. In another part of this study, rats were exposed as described above on gestation days 1 to 9 and simultaneously injected subcutaneously with physiologic saline. Compared with air-exposed controls treated with physiologic saline, these rats had significantly increased relative liver weights and fetal wastage, and a slight but not statistically significant increase in the percentage of fetuses with body weights <3.3 g. The investigators also observed one fetus with anophthalmia and one with microphthalmia in rats exposed during days 1 to 9, as well as a tendency for increased fetal wastage in rats exposed on days 8 to 14. They suggested that the developmental toxicity of vinyl chloride sh uld be tested by continuous exposure throughout the period of organogenesis. In a Bulgarian study, Mirkova et al. (1978) exposed pregnant rats to 0 or 6.15 mg/m^ (2.4 ppm) continuously throughout gestation. Fetotoxic effects included early postimplantation fetal loss, reduced fetal body weights, retarded ossification, and fetal hematomas. Teratogenic effects in luded anomalies of the brain. In offspring from rats allowed to deliver, liver function at 1 month of age was compromised, as indicated by increased hexobarbital sleeping time. In a Russian study, Sal'nikova and Kotsovskaya (1980) exposed pregnant rats to 0, 4.8, or 35.5 mg/m^ (0, 1.9, or 13.9 ppm) 4 h/day throughout gestation. Maternal effects included decreased REC count and decreased urinary excretion of hippuric acid at 13.9 ppm. Fetal hemorrhages were reported at both exposure levels, and fetal edema was reported at 35.5 mg/m^. In offspring of rats allowed to deliver, behavioral changes were reported at 35.5 mg/m^, and liver effects, hematologic and biochemical effects, and altered relative organ weights were reported in both groups. 4.3.3.2 Oral Data regarding developmental toxicity in orally exposed humans animals were not located. r 4.3.3.3 Dermal Data regarding developmental toxicity in dermally exposed humans or animals were not located. UCC 107898 SO SeetioA,, , 4.3.3.4 Gen rel discussion Early epidemlol gic data suggested an ass clatl n betw en paternal occupati nal exp sure t vinyl chloride and fetal loss (Infante et al. 1976, Waxweiler et al. 1977) and between parental residence in a region with a vinyl chloride plant and an increased incidence of birth defects (Infante et al. 1976). Subsequent evaluations of this study (Hatch et al. 1981, Stallones et al. 1987, Downs et al. 1977, The Vinyl Institute 1987) severely criticize its conduct and statistical analysis and seriously question its ability to detect the end points reported. Other studies (Edmonds et al. 1975, 1978; Theriault et al. 1983) found no association between parental residence in a region with a vinyl chloride plant and the incidence of birth defects. Developmental toxicity was not observed in animals exposed for 7- to 12-day periods during organogenesis at levels below those also associated with severe maternal toxicity (John et al. 1977, Ungvary et al. 1978). Ungyary et al. (1978), however, noted evidence of developmental toxicity in rats exposed in the first trimester compared with rats exposed later in gestation and suggested that valid testing should involve exposure during the entire gestation period. A Bulgarian study reported both fetotoxicity and teratogenicity in rats exposed continuously to a low concentration throughout gestation (Mirkova et al. 1978). The protocol and results were incompletely reported; hence, the study cannot be properly evaluated. Reporting problems also preclude proper evaluation of a Russian study (Sal'nikova and Kotsovskaya 1980) that reported developmental toxicity in rats intermittently exposed to low levels throughout gestation. These studies, however, underscore the need for further testing, using continuous exposure at low levels throughout gestation. 4.3.4 Reproductive Toxicity 4.3.4.1 Inhalation Human. Russian studies examined sexual function and hormone levels in men (Makarov 1984) and sexual function and gynecological health in women (Makarov et al. 1984) occupationally exposed to vinyl chloride and in unexposed control groups. Sexual function was evaluated by questionnaire, hormone levels were measured, and women were given gynecological examinations. Exposures were reported as low, not exceeding 1 maximum allowable concentration (MAC) (30 ng/vr or -12 ppm); average, in the range of 1 to 5 MAC (12 to 60 ppm); or significant, exceeding 5 MAC (60 ppm). An exposure* and duration*related decline in sexual function was reported in exposed men and women. Ovarian dysfunction, benign uterine growths, and prolapsed genital organs were reported in 77% of exposed women. Animal. B1 et al. (1985) exposed groups of 75 adult male Vlstar rats to 0, 10, 100, or 3,000 ppm, 6 h/day, 6 days/week for up to 12 months to evaluate effects on the testes. Relative testicular weight, evaluated only after 6 months of exposure, was significantly reduced at 100 and 3,000 ppm. Histopathological examination revealed a concentration-related increase in the incidence of testicular degeneration significant at 100 ppm. In an earlier study, Torkelson et al. (1961) observed no effects on relative testicular weight in rats UCC 107899 Toxicological Data 51 exposed t 500 ppm 7 h/day, 5 days/week for 4.5 months, or in dogs, rabbits, or guinea pigs exp sed to 200 ppm 7 h/day, 5 days/week for 6 months. The quality of this study was limit d, h wever, because of the small numbers of animals tested. Exposures involved up to 12 rats/sex and 12 guinea pigs/sex, 3 rabbits/sex, and 1 dog/sex. 4.3.4.2 Oral Data regarding the reproductive effects of vinyl chloride in orally exposed humans or animals were not found in the literature. 4.3.4.3 Dermal Data regarding the reproductive effects of vinyl chloride in dermally exposed humans or animals were not found. 4.3.4.4 General discussion Data regarding the reproductive effects of exposure to vinyl chloride are limited. Human data associating occupational exposure with reduced sexual function in both sexes and impaired gynecological health in women (Makarov 1984, Makarov et al. 1984) are not adequately reported for proper evaluation; therefore, such data cannot be used to identify thresholds. Whereas animal data do associate exposure to vinyl chloride with testicular effects, sexual performance and fertility were not tested. 4.3.5 Genotoxicity 4.3.5.1 Human Genotoxicity studies of vinyl chloride in humans include a large number of chromosomal aberration tests in the peripheral lymphocytes of occupationally exposed workers (Table 4.4). These tests (Ducatman et al. 1975, Funes-Cravioto et al. 1975, Purchase et al. 1978, Hansteen et al. 1978, Kucerova et al. 1979, Katsova and Pavlenko 1985), with the exception of a less rigorously performed and reported Dow Chemical Company study (Kilian et al. 1975), generally suggest a mutagenic role for vinyl chloride. The key study in this group is Hansteen et al. (1978), in which blood from 37 exposed workers and from 16 to 32 unexposed controls was examined twice at intervals of 2 to 2.5 years. Exposure levels during the time of first sampling were measured at 25 ppm, and there was a statistically significant increase in the percent of peripheral lymphocytes with chromosomal aberrations. When these workers were subsequently reexamined, exposure levels had dropped to 1 ppm, and there were no statistical differences between exposed and controls in the percentage of chromosomal aberrations. Anderson et al. (1980) observed an increase in lymphocytes with chromosomal aberrations in another cohort at exposure levels estimated at 50 ppm. The incidence of aberrations was returning to normal, however, when the cohort was resampled after exposure levels had been reduced to <5 ppm. In a Russian paper (Katsova and Pavlenko 1985), 0.1 mg/m^ (-0.04 ppm) was suggested as a no-effect level for chromosomal UCC 107900 52 Section 4 Table 4.4. Genotoxicity of vinyl chloride in vivo End point Species/test system Result References Recessive lethal Drosophila melanogaster + Verburgt and Vogel 1977 Dominant lethal D. melanogaster -- Verburgt and Vogel 1977 Mouse " Purchase et al. 1975, Anderson et al. 1976 Sex chromosome loss D. melanogaster -- Verburgt and Vogel 1977 Chromosomal translocation D. melanogaster -- Verburgt and Vogel 1977 Chromosomal aberration Rat + Anderson and Richardson 1981 Mouse + Walles and Holmberg 1984 Human lymphocyte + Hansteen et al. 1978 Sister chromatid exchange Human lymphocyte -- Hansteen et al. 1978 Human lymphocyte + Kucerova et al. 1979 Chromosomal aberration Human lymphocyte + Kucerova et al. 1979 Human lymphocyte + Purchase et al. 1975, 1978 Human lymphocyte + Ducatman et al. 1975 Chromosomal aberration Human lymphocyte + Funes-Cravioto et al. 1975 Human lymphocyte + Katsova and Pavlenko 1985 Human lymphocyte -- Kilian et al. 1975 Micronucleus test Mouse + Jenssen and Ramel 1980 RNA alkylation" Rat + Laib and Bolt 1977 DNA alkylation Rat 4- Laib et al. 1985 DNA alkylation Mouse + Osterman-Golkar et al. 1977 Rat + Green and Hathway 1978 "Although RNA alkylation is not a genotoxic effect, the results of this test are supportive evi dence that vinyl chloride metabolites interact with nucleic acids. UCC A0790A Toxicological Data 53 aberratl ns. The study was insufficiently reported to allow critical evaluation, h wever, and the NOAEL from the Hansteen et al. (1978) study is accepted. 4.3.5.2 Nonhuman It is beyond the scope of this document to evaluate all data regarding the mutagenicity of vinyl chloride in nonhuman systems. Representative data, largely taken from a recent EPA (1985b) review, are presented in Tables 4.4 and 4.5. Vinyl chloride is mutagenic in Salmonella typhimurium (Rannug et al. 1974; Bartsch et al. 1975, 1976; Andrews et al. 1976; Simmon et al. 1977; Elmore et al. 1976; Poncelet et al. 1980; de Meester et al. 1980), but only in strains reverted by base-pair substitution by alkylating agents rather than by frameshift mutations (Bartsch et al. 1976). Metabolic activation may be necessary for any mutagenic activity in this system (Rannug et al. 1974) or for a maximal response (Simmon et al. 1977). Results in other microbial systems were mixed. Vinyl chloride was positive for recessive lethal effects but negative for dominant lethal effects, chromosomal translocation, and sex chromosome loss in Drosophila melanogaster (Verburgt and Vogel 1977). The investigators suggested that the negative results in the dominant lethal test may indicate that metabolites capable of causing chromosomal damage did not reach the germ cells. Negative results were obtained for the dominant lethal test in mice (Purchase et al. 1975, Anderson et al. 1976). Positive results were obtained in mutation and cell transformation tests and in chromosomal aberration tests in in vivo and in vitro mammalian systems (Styles 1977, Drevon and Kuroki 1979, Jenssen and Ramel 1980, Valles and Holmberg 1984, Laib and Bolt 1977, Lalb et al. 1985, Anderson and Richardson 1981). Positive results were also reported for DNA alkylation tests in rats (Green and Hathway 1978) and mice (Osterman-Golkar et al. 1977) and for RNA alkylation in rat liver microsomes (Laib and Bolt 1977). 4.3.5.3 General discussion Evidence strongly implicates the oxidation of vinyl chloride to the reactive intermediates 2-chloroethylene oxide and 2-chloroacetaldehyde as being responsible for mutagenicity in the systems discussed above. Reports indicate that 2-chloroethylene oxide and 2-chloroacetaldehyde are manyfold more active in 5. typhimurium than the parent compound or other oxidation products of vinyl chloride such as 2-chloroethanol or chloroacetic acid (Rannug et al. 1976, Bartsch 1976, McCann et al. 1975). 2-Chloroethylene oxide has also been shown to be responsible for base-pair substitutions in Escherichia coll (Barbin et al. 1985a), to be highly mutagenic in gene mutation and gene conversion tests in yeasts (Loprieno et al. 1977), and to Induce mutations in Chinese hamster V79 cells (Huberman et al. 1975). In vitro testing has shown that 2-chloroethylene oxide is capable of alkylating DNA to form 7-(2-oxoethyl)guanine as the principal adduct (Barbin et al. 1985b). This adduct has not been shown to cause errors in DNA replication in an in vitro test with E. coll DNA polymerase I, and the role of DNA alkylation in mutagenesis is unclear. UCC 107902 54 Section 4 Table 4.5. Genotoxkity of vteyl chloride la thro End point Species/test system Result Without With activation activation References Reverse mutation Salmonella typhimurium S. typhimurium S. typhimurium S. typhimurium S. typhimurium S. typhimurium Forward or reverse mutation Reverse mutation Forward mutation Rec-repair Forward mutation Cell transformation RNA alkylation' Escherichia coli Saccharomycts ctrcvisiae Schiiosaccharomycts pombe Bacillus subtilis Chinese hamster cell V79 Neonatal hamster kidney cells Rat liver microsomes + + + + -- + + + + + + + NT* + + NT + NT NA* NA NA Kannug et aL 1974 Bartsch et aL 1973, 1976 Andrews et aL 1976 Simmon et aL 1977 Elmore et aL 1976 Poncelet et aL I960, de Mccster et aL 1980 Gteim et aL 1973 Shahin 1976 Loprieno et aL 1977 Elmore et aL 1976 Drevon and Kurolri 1979 Styles 1977 Laib and Bolt 1977 "Not tested. "Not applicable. "Although RNA alkylation la not a gcnotoxic effect, the remits of this test are supportive evidence that vinyl chloride metabolites interact with nucleic adds. UCC 107903 4.3,6 Carcinogenicity Toxicological Data 55 4.3.6.1 Inhalation Human. Several reports (Tabershaw and Gaffey 1974, Honson et al. 1975, Waxweiler et al. 1976, Nicholson et al. 1975, Heath et al. 1975, Lills et al. 1975, Popper and Thomas 1975, Bryen et al. 1976, Fox and Collier 1977, Heldaas et al. 1984, Geryk and Zudova 1986) associate human cancer with occupational exposure to vinyl chloride. The most recent review of the human data is that of EPA (1985b). Since none of the human studies quantify exposures sufficiently for quantitative risk assessment, no single report is chosen as a key study. In a review of these data, IARC (1979) concluded that the human data constitute "sufficient" evidence for the carcinogenicity of the compound. EPA (1985b) classified vinyl chloride in IARC Group 1; subsequently, EPA (1987b) placed this compound in Carcinogen Assessment Group A. Both classifications reflect the designation of vinyl chloride as a known human carcinogen. The incidence of liver cancer, in particular angiosarcoma, provides the most convincing e/idence for the carcinogenicity of vinyl chloride because the expected background level (25 to 30 cases per year in the United States) is extremely low (Heath et al. 1975). Most of the epidemiologic studies cited above reported a higher observed/expected ratio for liver cancer than for cancers of any other site. Other cancers associated with vinyl chloride exposure include tumors of the brain and CNS, the lung and respiratory tract, the digestive tract, and the lymphocytic/hematopoietic system, although statistical significance was not necessarily reached (Monson et al. 1975, Uaxweiler et al. 1976, Bryen et al. 1976). Fox and Collier (1977), however, concluded that there is no evidence that cancers other than those of the liver are associated with exposure to vinyl chloride. More recent and larger unpublished epidemiology studies (Vong et al. 1986, Doll 1987), however, while supporting the association of exposure with liver and brain cancer, report no association between exposure and increased risk from lung and respiratory cancer, lymphocytic/hematopoietic cancer, or melanoma. Heldaas et al. (1984) also reported an unusual number of cases of malignant melanoma of the skin in exposed workers. Generally, prolonged exposure (employment) increased the risk of cancer, particularly if intermittent high exposures have occurred (Bryen et al. 1976, Heath et al. 1975). Tabershaw and Gaffey (1974) noted that an increased risk of malignancy correlated with an increased "exposure index," an interplay of level and duration of exposure. Fox and Collier (1977), however, reported little correlation with duration of exposure. Animal. The key animal inhalation studies of carcinogenicity are the series of experiments by Maltoni et al. (1980, 1981) in Sprague* Dawley rats, Swiss mice, and golden hamsters. A report of interim results was published earlier (Maltoni and Lefemine 1975). 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. Mice and hamsters were exposed to vinyl chloride concentrations of 50 to 10,000 ppm for 30 weeks, followed by an observation period of 51 weeks (mice) or UCC 107904 56 Section 4 79 weeks (hamsters). Exposure levels and results from the most comprehensive and longest term experiments In rats are presented in Table 4.6. The Investigators noted that Increased Incidence of tumors occurred at 50 ppm In all species tested. All species shoved an Increase In the incidence of liver angiosarcoma. In addition to the tumor types presented in Table 4.6, the authors associated extra hepatic angiosarcomas, hepatomas, Zymbal gland carcinomas, and neuroblastomas in rats with exposure to vinyl chloride. Other inhalation experiments support the carcinogenicity of vinyl chloride. Rats, mice, and hamsters were exposed to 50 to 2,500 ppm vinyl chloride for 9 or 12 months (Keplinger et al. 1975, MCA 1980). All species developed liver angiosarcomas in a concentration-related manner at 50 ppm, the lowest level tested. Metastases to lymph nodes or lung were common. Rats also developed Zymbal gland tumors at 50 ppm and brain tumors at 200 ppm, and mice developed lung tumors at 50 ppm. Viola et al. (1971) exposed rats to 3% vinyl chloride (30,000 ppm) for 12 months and observed primary tumors of the skin, lungs, and bones. Feron and Kroes (1979) exposed rats to 0 or 5,000 ppm for 52 weeks and observed primary tumors in treated rats in the brain, lung, Zymbal gland, and nasal cavity. Lee et al. (1977a, 1978) exposed rats and mice to 0, 50, 250, or 1,000 ppm, 6 h/day, 5 days/week for up to 12 months; subsequently, they observed an increased incidence of hemangiosarcoma of the liver in rats at 250 ppm, as well as bronchoalveolar adenoma of the lung, mammary tumors, and hemangiosarcoma of the liver and other organs in mice at 50 ppm. In a later study from the same laboratory, Hong et al. (1981) exposed rats and mice to 0, 50, 250, or 1,000 ppm, 6 h/day, 5 days/week for up to 6 months, followed by a 12-month observation period. Tumor types attributed to vinyl chloride exposure in rats were those observed by Lee et al. (1977a, 1978), in addition to bronchoalveolar lung tumors at 250 ppm and mammary tumors at all exposure concentrations. Suzuki (1978, 1981, 1983) also observed lung tumors as a primary carcinogenic response of mice to vinyl chloride. Lung tumors developed in 26 of 27 mice exposed to 2,500 or 6,000 ppm for 5 to 6 months (Suzuki 1978). Concentration-related increased Incidences of lung tumors were observed in studies in which mice were exposed to 0 to 100 or 0 to 600 ppm for 4 weeks and then observed for up to 41 weeks postexposure (Suzuki 1981, 1983). It appeared that 10 ppm was a level associated with an increased incidence of lung tumors in mice in these studies. Hehir et al. (1981) reported an increased incidence of lung tumors in mice given single 1-h exposures to 5,000 or 50,000 ppm. Inhalation data In three species suggest that age at exposure has an effect on carcinogenic response. Drew et al. (1983) exposed rats, mice, and hamsters to concentrations of 50 to 200 ppm for periods of 6 to 24 months. Exposures were started at 0, 6, 12, or 18 months after weaning. All three species had a maximal oncogenic response when exposed during the first 12 months of life. Exposures begun after a 12-month holding period did not produce a carcinogenic response. Maltonl et al. (1983) and Cotti et al. (1983) exposed rats in utero from gestation day 12 and after birth to 1 year of age to 2,500 ppm and observed very high incidences of liver and brain tumors. Liver angiosarcoma, with an average latency period of 50 weeks, developed in 32 of 56 males and In ToxicologicMl Dmtm 57 Table 4.6. Tumor inddeuce in male and female Sprague-Dawley rats exposed by inbalatkm to vinyl chloride 4 h/day, 5 days/week for 52 weeks Exposure level (ppm) Duration of study (weeks) Incidence of liver angiosarcoma Incidence of kidney nephroblastoma 0 1 5 10 25 50 100 150 200 250 500 2,500 6,000 10,000 30,000 135-147 147 147 147 147 135 143 143 143 135 135 135 135 135 68 0/363 0/118 0/119 1/119 5/120 1/60 1/120 6/119 12/120 3/59 6/60 13/60 13/59 7/60 18/60 0/363 0/118 0/119 0/119 1/120 1/60 10/120 11/119 7/120 5/59 6/60 6/60 5/59 5/60 NR* Not reported. Source: Maltonietal. 1980, 1981. Ucc 107906 58 Section 4 38 of 55 females. Brain tumors, with an averag latency of 48 weeks, developed In 27 of 57 males and In 28 of 57 females. Lower Incidences f tumors developed In rats exposed for only 7 days In utero. Maltonl et al. (1980, 1981) exposed rats to 6,000 or 10,000 ppm In utero on days 12 to 18 of gestation and continued to observe them for 115 weeks. In 54 high-dose progeny, there were 3 with Zymbal gland carcinoma, 2 with angiosarcoma, and 1 with nephroblastoma of the brain. In 32 low-dose progeny, 1 developed Zymbal gland carcinoma and 2 had angiosarcoma. Radlke et al. (1988) exposed pregnant Sprague-Dawley rats to vinyl chloride at 600 ppm 5 h/day on gestation days 9*21. An additional group was also exposed through the lactation period. The occurrence of angiosarcoma in offspring of dams exposed during gestation confirms the transplacental carcinogenicity of vinyl chloride. Additional exposure during lactation greatly increased the incidence of liver tumors. 4.3.6.2 Oral Human. Data regarding the carcinogenicity of vinyl chloride in orally exposed humans were not found. Animal. Cancer types observed in orally treated rats resemble those observed from inhalation exposure. In the key oral study, Feron et al. (1981) exposed groups of Vistar rats to vinyl chloride in the diet by incorporating polyvinyl chloride (PVC) powder containing a high level of the monomer. Diets were fed 4 h/day, and food consumption and body weights were monitored. Volatilization of vinyl chloride from the diet was estimated, and dosages of vinyl chloride available to the rats were also estimated. In addition, one group received vinyl chloride by gavage 5 days/week. Pertinent data are summarized in Table 4.7. Exposure was for the lifetime of the rats. Treatment of the 300-mg/kg gavage group was terminated at 84 weeks because of high mortality. The liver tumor incidence data presented in Table 4.7 suggest that angiosarcomas predominated at high dosages but chat hepatocellular carcinomas predominated at low dosages. In addition to tumors of the liver and lung, the Investigators attributed exposure to the development of extra hepatic abdominal angiosarcomas and Zymbal gland tumors. They also noted some evidence that exposure enhanced the development of abdominal mesotheliomas and adenocarcinomas of the mammary gland. Other oral studies indicate that the type of tumor observed may depend on the dosage given. Maltonl (1977) treated rats by gavage at 16.7 or 50 mg/kg/day for 52 weeks followed by an 84-week observation period. An increased incidence of liver angiosarcomas and kidney nephroblastomas was attributed to vinyl chloride. Zymbal gland carcinomas may also have been the result of exposure to vinyl chloride. Til et al. (1983), in a lifetime study, administered vinyl chloride in the diet (from PVC containing a high level of of the monomer) to rats at dosages of 0.014 to 1.3 mg/kg/day. Males at 1.3 mg/kg/day had a small but significantly Increased incidence of hepatocellular carcinoma. Females at 1.3 mg/kg/day had a significantly increased incidence of hepatic neoplastic nodules, along with a suggestive but not significant increase in hepatocellular carcinoma. Tumorigenic effects were not seen at lower doses. UCC 107907 Toxicological Data 59 Table 4.7. Tmmt hddsace la Wtatar rats orally exposed to riuyl ebbtide' Duration of Dose* treatment Target Sex (mg/kg/day) (weeks) Vehicle/method organ Tumor type Tumor incidence (P value) F 300 F 17.0 F 5.6 F 1.8 F 0.0 M 300 M 17.0 M 5.6 M 1.8 M 0.0 84 143 143 143 NArf 84 143 143 143 NA Soybean oil/ gavage PVC/diet PVC/diet PVC/diet Untreated diet only Soybean oil/ gavage PVC/diet PVC/diet PVC/diet Untreated diet only Liver Neoplastic nodule Hepatocellular carcinoma 2/54 0/54 Lung Liver Lung Liver Lung Liver Lung Liver Lung Liver Lung Liver Lung Liver Lung Liver Liver Lung Angiosarcoma Angiosarcoma Neoplastic nodule Hepatocellular carcinoma Angiosarcoma Angiosarcoma Neoplastic nodule Hepatocellular carcinoma Angiosarcoma Angiosarcoma Neoplastic nodule Hepatocellular carcinoma Angiosarcoma Angiosarcoma Neoplastic nodule Hepatocellular carcinoma Angiosarcoma Angiosarcoma Neoplastic nodule Hepatocellular carcinoma Angiosarcoma Angiosarcoma Neoplastic nodule Hepatocellular carcinoma Angiosarcoma Angiosarcoma Neoplastic nodule Hepatocellular carcinoma Angiosarcoma Angiosarcoma Neoplastic nodule Hepatocellular carcinoma Angiosarcoma Angiosarcoma Neoplastic nodule Hepatocellular carcinoma Angiosarcoma Angiosarcoma 29/54 23/54 44/57 (P < 0.001)' 29/57 (P < 0.001)' 9/57 (P< 0.001)' 5/57 (P < 0.05)' 39/59 (P < 0.001)' 19/59 (P < 0.001)' 2/59 3/59 26/58 (P < 0.01)' 4/58 0/58 0/58 2/57 2/57 0/57 0/57 3/55 1/55 27/57 19/55 23/59 (P < 0.001)' 8/59 (P< 0.001)' 27/59 (P < 0.001)' 19/59 (P<0.0)' 7/56 (P < 0.01)' 2/56 (P<0.01)' 6/56 (P < 0.05)' 7/56 1/58 1/58 0/58 0/58 0/55 0/55 0/55 0/55 'Duration of (tody araa 143 weeks; purity of oompouad was not reported. 'Dosage given 5 days/week. 'Compand with controls using chi-square. "Not applicable. Source. Feroo at aL 1981. ucc^98 60 Section 4 4.3.6.3 D real Data regarding th carcinogenicity of vinyl chloride in dernally exposed humans or aninals were not found. 4.3.6.4 General discussion The data reviewed indicate that there is some similarity in cancer types in experimentally exposed animals and occupationally exposed humans. The human data present the strongest statistical case for associating occupational exposure with liver angiosarcoma (Monson et al. 1975, Vaxweiler et al. 1976, Bryen et al. 1976, Fox and Collier 1977). The Incidence of cancer of the brain, lung, and digestive tract, although not always statistically significant, is suggestive of a vinyl chloride etiology. More recent larger unpublished studies (tfong et al. 1986, Doll 1987) associate vinyl chloride exposure with liver angiosarcoma and possibly with tumors of the brain, but not with tumors of the lung or digestive tract. The substantial amount of animal data also presents the strongest association for liver angiosarcoma (Maltonl et al. 1980, 1981; MCA 1980; Feron and Kroes 1979). Statistically significant Increases have also been observed for lung cancer in mice (Lee et al. 1978; Hong et al. 1981; Suzuki 1978, 1981, 1983), and biologically significant increases have been reported for brain cancer in rats (Feron and Kroes 1979; MCA 1980; Maltoni et al. 1980, 1981). Animal data suggest that both the young and the prenatal organism are susceptible to vinyl-chloride-Induced cancer (Maltonl et al. 1980, 1981, 1983; Drew et al. 1983; Radlke et al. 1988). It is generally agreed that oxidation to 2-chloroethylene oxide, a highly electrophilic intermediate, is responsible for the mutagenicity of vinyl chloride (Gwinner et al. 1983, Valno 1978). In vitro testing has shown 2-chloroethylene oxide capable of alkylating DMA to form 7-(2-oxoethyl)guanine as the principal adduct (Barbin et al. 1985b). This adduct has not been shown to be involved in genetic miscoding, and the role of DNA alkylation in carcinogenesis is unclear. 4.4 INTERACTIONS WITH OTHER CHEMICALS A series of investigations describes the Interactions of vinyl chloride with various other compounds, which clarifies the role of metabolism in the toxicity of this compound. In all studies, the acute toxicity to the liver of rats exposed by inhalation to high concentrations, as manifested by serum levels of enzymes indicative of liver damage and the histopathologlcal appearance of the liver, was the end point evaluated. In the first study (Jaeger et al. 1974), pretreatment of rats with phenobarbltal resulted in liver damage as measured by biochemical and histopathologlcal parameters. Liver damage was not detected in nonpretreated rats. The investigators suggested that phenobarbltal had induced the mixed-function oxidase (MFO) system to enhance metabolism of vinyl chloride to a toxic intermediate. In subsequent experiments (Reynolds et al. 1975, Conolly at al. 1978), pretreatment with the polychlorinated biphenyl (PCB) mixture Aroclor 1254 was also observed to cause acute exposure to vinyl chloride to result in hepatotoxicity. The same mechanism, induction of hepatic MFO, UCC 107909 Toxicological Data 61 was suggested to result In oxidation f vinyl chloride to the epoxide, 2-chlor ethylene oxid . Conolly and Jaeger (1978, 1979) investigated the effect of chemicals that regulate xenobiotic metabolism on vinyl-chloride'induced hepatotoxicity. Trichloropropene oxide (TCPO), which depletes glutathione and inhibits epoxide hydrase conversion of an epoxide to its corresponding less-toxic alcohol, was found to enhance the toxicity of vinyl chloride in fasted PCB-pretreated rats, but not in fed pretreated rats. Since nonprotein sulfhydryl concentrations in the liver in TCPO-treated rats did not differ from those in control rats, the investigators suggested that the enhanced toxicity in TCPO-treated rats resulted from inhibition of epoxide hydrase rather than from glutathi ne depletion. The lack of effect in fed rats was judged to underscore the importance of epoxide hydrase in the detoxification of epoxide in glutathione-depleted rats. In other parts of these same studies, cysteine, the rate-limiting precursor of glutathione, was able to block depletion of nonprotein sulfhydryl in the liver and thus reduce the intensity of liver toxicity in PCB-pretreated, vinyl-chloride-exposed rats. Treatment of fed rats with diethylmaleate, another glutathione depleting agent, reduced liver nonprotein sulfhydryl to levels attained in fasted rats, but did not increase hepatotoxicity. Several studies evaluated the interaction of ethanol with vinyl chloride, because ethanol has been shown to slow metabolism of vinyl chloride in rats. Radike et al. (1988) provided drinking water containing 5% ethanol to pregnant rets exposed concurrently to vinyl chloride in the air on days 9-21 of gestation in a perinatal carcinogenesis study. The occurrence of angiosarcoma of the liver, lung, and muscle confirmed the transplacental oncogenicity of vinyl chloride. Exposure to ethanol had no apparent effect on the incidence of angiosarcoma. John et al. (1977) exposed rats, mice, and rabbits to 15% ethanol in drinking water concurrently with vinyl chloride in air during organogenesis. The investigators stated that ethanol exacerbated some of the fetal and maternal effects of vinyl chloride. The most striking effects of ethanol were a marked reduction in food intake, ranging from 33% (mice) to 83% (rabbits) compared with animals exposed to vinyl chloride alone, and a commensurate reduction in maternal body weight gain. UOC 107910 Preceding page blank 63 5. MANUFACTURE, IMPORT, USE, AND DISPOSAL 5.1 OVERVIEW Vinyl chloride is produced at 11 locations in the United States. During 1986, 8.439 billion lb of this chemical were produced in the United States. It is produced by thermal cracking of ethylene dichloride. Vinyl chloride is used almost exclusively in the United States for the production of polyvinyl chloride (PVC) and several copolymers. These compounds yield a wide range of end-use products which are used by industries and consumers. 5.2 PRODUCTION Domestic production of vinyl chloride during 1986 was 8.439 billion lb (USITC, 1987). This required essentially all of the available production capacity in 1986. In 1985, 7.8 billion lb of vinyl chloride was produced in the United States (C&EN 1987). Manufacturers and sites of production are as follows (SRI 1988): Borden Chemical in Geismar, Louisiana; Dow Chemical in Oyster Creek, Texas, and Plaquemine, Louisiana; Formosa Plastics in Baton Rouge, Louisiana, and Point Comfort, Texas; Georgia-Gulf in Plaquemine, Louisiana; BF Goodrich in Calvert City, Kentucky, and La Porte, Texas; PPG Industries in Lake Charles, Louisiana; Occidental Chemical in Deer Park, Texas; and Vista Chemical in Lake Charles, Louisiana. Vinyl chloride is produced commercially by thermal cracking of ethylene dichloride (EDC). EDC used in this process is made by either direct chlorination of ethylene using liquid chlorine, or oxychlorination of ethylene using dry hydrochloric acid and oxygen (Cowfer and Magistro 1985). Vinyl chloride is usually supplied as a liquid under pressure (IARC 1979). The technical grade product is available in 99.9% purity (Sax and Lewis 1987). 5.3 IMPORT Imports of vinyl chloride were -200 million lb in 1987 (C&EN 1987). 5.4 USES The use pattern for vinyl chloride is as follows (CMR 1986a): polyvinyl chloride (PVC), 85%; exports, 13%; and other, mostly copolymer use, 2%. This use pattern indicates that vinyl chloride monomer is used almost exclusively in the United States by the plastics industry. Very small amounts are used as a refrigerant gas and as an intermediate in the production of chlorinated compounds (Curry and Rich 1980, Gosselin et al. 1984, IARC 1979). Limited quantities of vinyl chloride were used in the United States as an aerosol propellant and as an ingredient of UCC 107911 64 Section 5 drug and cosmetic products; however, these practices have been discontinued (EPA 1985b). Vinyl chi ride is industrially Important because of its inherent flame retardant properties, its wide variety of e.d-use products, and the low cost of producing polymers from vinyl chloride (Cowfer and Magistro 1985). Principal end-use products include: PVC pipes, wire and cable coatings, packaging materials, furniture and automobile upholstery, wall coverings, housewares, and automotive parts and accessories; vinyl chloride-vinyl acetate copolymer floor coverings, phonographic records, and flexible film; vinyl chloride-acrylonitrile battery cell separators; and vinyl chloride-vinylidine chloride copolymer food packaging film (Curry and Rich 1980, Salkind and Pearlman 1978, Farkas 1980). 5.5 DISPOSAL EPA requires that persons who generate, transport, treat, store, or dispose of this compound comply with regulations of the Federal Resource Conservation and Recovery Act (RCRA). The recommended method of disposal, reported by Sittig (1985), involves the incineration of this chemical after mixing it with another combustible fuel. Care should be taken to ensure that complete combustion has taken place in order to avoid formation of phosgene. An acid scrubber is required to remove HC1. In addition to this method, other disposal techniques have been developed for the recovery of vinyl chloride from PVC latexes (Sittig 1985). UCC 107912 65 6. ENVIRONMENTAL FATE 6.1 OVERVIEW Information regarding the environmental fate and transport of vinyl chloride is limited. Effluents and emissions from vinyl chloride and PVC manufacturers are responsible for the majority 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 to 1.8 days). Reaction products include HC1, formaldehyde, formyl chloride, acetylene, chloroacetaldehyde, chloroacetylchloranil, and chloroethylene. In photochemical smog situations, vinyl chloride has a half-life of 3 to 7 h. When released to water, volatilization is expected to be the primary fate process (half-life - 8.7 to 43.3 h). 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. 6.2 RELEASES TO THE ENVIRONMENT The major source of release of vinyl chloride to the environment is believed to be emissions and effluents from plastic industries (primarily vinyl chloride and PVC manufacturers). Vinyl chloride released in wastewater is expected to volatilize fairly rapidly (on the order of hours to days) into the atmosphere. Other sources of release include disposal of vinyl chloride wastes in landfills, incomplete combustion of PVC, tobacco smoke, spills, and biodegradation of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane (IARC 1979, HSDB 1987, Wakeman and Johnson 1978, Wilson and Wilson 1985, Smith and Dragun 1984). EPA estimated that prior to 1975, 110 million kg/year of vinyl chloride escaped into the atmosphere from PVC production facilities in the United States (IARC 1979). Worldwide emissions of vinyl chloride into the atmosphere during 1982 was -400 million lb (Hartmans et al. 1985). 6.3 ENVIRONMENTAL FATE 6.3.1 Air Based on a vapor pressure of 2,660 mm Hg at 25*C, essentially all vinyl chloride in the atmosphere is expected to exist in vapor form (Verschueren 1983, Eisenreich et al. 1981). Consequently, removal from the atmosphere by dry deposition is not expected to be an important fate process. Vinyl chloride has a relatively high partition coefficient between air and water (H - 50), which suggests that significant amounts UCC 107913 66 Section 6 of vinyl chloride would not be removed from the atmosphere by wet deposition (EPA 1985b). Reaction of vinyl chi ride vapor with ph tochemically generated hydroxyl radicals is predicted to be the primary degradation mechanism for this compound in the atmosphere. The half*life for this reaction in the typical atmosphere has been -1.5 to 1.8 days (EPA 1985b). Products of this reaction are HC1, formaldehyde, formyl chloride, carbon monoxide, carbon dioxide, chloroacetaldehyde, acetylene, chloroethylene, chloroacetylchloranil, and H20 (EPA 1985b). In photochemical smog situations, the reaction half-life of vinyl chloride is predicted to range between 3 and 7 h (HSDB 1987). Reaction with ozone (half-life 4.2 to 33 days), reaction with oxygen atoms [0(3p)] (half-life - 373 to 532 days), and direct photolysis are relatively insignificant degradation mechanisms in the atmosphere (EPA 1985b). 6.3.2 Water The primary loss process for vinyl chloride in natural water systems is volatilization into 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 h, respectively. These values are based on an experimentally determined reaeration rate ratio of -2 and assumed oxygen reaeration rates of 0.008, 0.04, and 0.01 hour'* for a typical pond, river, and lake, respectively (EPA 1985b). 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 1985b). In waters containing photosensitizers, such as humic materials, photodegradation may be fairly rapid. This suggests that in some waters sensitized photodegradation would also be a significant removal mechanism (HSDB 1987, EPA 1985b). Chemical hydrolysis of vinyl chloride does not appear to be environmentally important. The hydrolytic half-life for vinyl chloride has been estimated to be <10 years (EPA 1985b). Vinyl chloride is not expected to oxidize chemically by reaction with photochemlcally generated hydroxyl radicals, molecular oxygen, or alkyl peroxy radicals in natural water systems. Limited available data on the biodegradation of vinyl chloride Indicate that this compound is resistant to microbial degradation under aerobic conditions (EPA 1985b). Vinyl chloride is not expected to adsorb significantly to suspended solids and sediments in water or bloaccumulate significantly in aquatic organisms (HSDB 1987). 6.3.3 Soil The relatively high vapor pressure of vinyl chloride (2,660 mm Hg at 25*0) Indicates that this compound should volatilize quite rapidly from dry soil surface. The effective half-life (due to volatilization) of vinyl chloride placed 10 cm deep in dry soil is predicted to be 12 h (EPA 1985b). Evaporation from moist soil surfaces is also expected to be significant since this compound does not adsorb strongly to soil and appears to volatilize fairly rapidly from water. yCC 1079U Environments! Fste 67 Experimental data regarding adaorption of vinyl chloride to s il were not located. Based on the regression equations given by Lyman et al. (1982) and Sabljic (1984), the soil adsorption co fficient (Koc) for vinyl chloride has been estimated to range between 17 and 131. These Koc values suggest 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 conon 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 its estimated Koc* Based on data in aquatic media, chemical reaction of vinyl chloride in soil does not appear to be a significant fate process, and it appears that vinyl chloride would be resistant to biodegradation under aerobic conditions. \JCC 107915 Preceding page blank 69 7. POTENTIAL FOR HUMAN EXPOSURE 7.1 OVERVIEW Anthropogenic sources are responsible for all of the vinyl chloride found in the environment. Vinyl chloride has been found in at least 133 of 1,177 hazardous waste sites on the National Priorities List (View data base 1989). Most of the vinyl chloride released to the environment will eventually locate in the atmosphere while much smaller amounts will eventually locate in groundwater. Vinyl chloride has been detected in the ambient air in the vicinity of vinyl chloride and PVC manufacturing plants and hazardous waste sites. Vinyl chloride is expected to leach into groundwater from spills, landfills, and industrial sources. 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 these people ranges from trace amounts to 2,100 j*g/day. The average^ daily intake of vinyl chloride by inhalation is expected to be essentially zero for the remainder of the population. However, short term inhalation exposure to elevated levels may occur during use of new cars. This is due to volatilization of vinyl chloride from vinyl polymers within the car interior. The majority of the general population is not expected to be exposed to vinyl chloride through ingestion of drinking water. However, people who have PVC water pipes that have not been treated adequately to remove vinyl chloride monomer may ingest -0.06 to 2.8 pg/day of vinyl chloride from drinking water. The average daily intake of vinyl chloride through diet is predicted to be essentially zero. NIOSH estimated that 27,000 workers are definitely exposed to vinyl chloride and that workers probably exposed may be as many as 2.2 million. Intake is expected to occur primarily through inhalation and less importantly by absorption through skin. Workplace air in some PVC manufacturing plants was found to contain 100 to 800 mg/m^ (39 t 312 ppm) vinyl chloride with peak concentrations of up to 87,300 mg/m^ (34,000 ppm). A NIOSH survey of three vinyl chloride manufacturers reported a time-weighted-average exposure of 0.18 to 70 mg/m^ (0.07 to 27 ppm) vinyl chloride in workplace air. 7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 7.2.1 Air Air in rural/remote and urban/suburban areas of the United States typically contain no detectable amount of vinyl chloride (Stephens et al. 1986; Grimsrud and Rasmussen 1975a,b; Harkov et al. 1984; Wallace et al. 1984; EPA 1985b). Limited monitoring data indicate that in areas UCC 107916 70 Section 7 near vinyl chloride and p lyvinyl chloride manufacturers, the concentration of vinyl chi ride in air typically ranges from trac levels to -105 pg/uP (Gordon and Meeks 1977, Pellizzari et al. 1979, IARC 1979, EPA 1985b), but may exceed 2,600 pg/n? (1 ppm) (Fishbein 1979). Elevated levels of vinyl chloride may also be found in the vicinity of hazardous waste landfills. Concentrations ranging from below detection limits to 5 to 8 pg/w? (0.002 to 0.003 ppm) have been monitored in the air above some landfills (Stephens et al. 1986, Baker and Mackay 1985). Homes near a hazardous waste site in Southern California were found to contain levels as high as 1,040 pg/u? (0.4 ppm) (Stephens et al. 1986). 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 Intake of air is 20 m^/day, the average daily intake of vinyl chloride by people living in source-dominated areas has been estimated to range from trace amounts to 2,100 pg/6a.y. 7.2.2 Water Vinyl chloride has been detected at varying concentrations in surface, ground, and drinking waters throughout the United States (EPA 1985b). Concentrations as high as 9.8 pg/L in surface water, 380 pg/L in groundwater, and 10 pg/L in drinking water have been reported (Dyksen and Hess 1982, HSDB 1987). There was no report in the literature of vinyl chloride being detected in sediment. The level of vinyl chloride in groundwater in the United States was determined during the 1982 EPA Groundwater Supply Survey. Water supplies from 945 sites geographically located throughout the United States were studied. Results indicate that vinyl chloride was positively identified in only 0.74% of groundwater supplies (detection limit 1 pg/L). The maximum concentration detected was 8.4 pg/L (Westrlck et al. 1984). Other studies have also reported the occurrence of vinyl chloride in groundwater throughout the United States at levels at or below 380 pg/L (Cotruvo 1985, Goodenkauf and Atkinson 1986, Page 1981, Coniglio et al. 1980, Stuart 1983). The concentration of vinyl chloride in finished drinking waters in the United States was studied during the 1976-1977 EPA National Organics Monitoring Survey (NOMS). Only 2 samples out of 113 contained detectable levels (>0.1 pg/L), and these averaged 0.14 pg/L (HSDB 1987). Results of other studies also Indicate that the majority of drinking water supplies in the United States contain no detectable levels of vinyl chloride (HSDB 1987, Coniglio et al. 1980). Based on these studies, it is assumed that the average daily Intake of vinyl chloride by Ingestion of drinking water for most persons in the United States would be essentially zero. Estimates provided in EPA (1985a) indicate that 0.9% of the United States population is exposed to levels of vinyl chloride in drinking water 1.0 pg/L and 0.3% of the population is exposed to levels >5 pg/L. UCC 107917 Potential for Human Exposure 71 7.2.3 Soil Monitoring data for vinyl chloride In soil w re not located In th available literature. 7.2.4 Other In the past, vinyl chloride had been detected In various foods as a result of nlgratlon from polyvinyl chloride food wrappings and containers (EFA 1985b). Vinyl chloride has been found in vinegar at levels up to 9.4 ppm, in edible oils at 0.15 to 14.8 ppm, and in butter at 0.05 ppm when these foods were packaged and stored in PVC containers (IARC 1979). At present, the Food and Drug Administration (FDA) regulates use of vinyl chloride polymers available for use in production of articles Intended to contact food. These articles include food packaging materials, coatings, plastisols, gaskets, and parts for food processing (see Sect. 9, Regulatory and Advisory Status). A recent study on the migration of vinyl chloride from PVC under conditions closely simulating actual food packaging and storage revealed that at very low concentrations of vinyl chloride in PVC packaging material, there was essentially zero migration of vinyl chloride (Kontominas et al. 1985). It is reported that migration of vinyl chloride from rigid PVC water pipes into drinking water occurs and that It is directly proportional to the residual level of vinyl chloride in the pipe itself. Under certain conditions, reaction with chlorine in the water may result in the complete removal of vinyl chloride from drinking water (Fishbein 1979, Ando and Sayato 1984). During one study, it was found that drinking water that ran through recently Installed PVC pipes contained vinyl chloride at 1.4 pg/L, while water that ran through a 9-year-old system contained 0.03 to 0.06 pg/L (HSDB 1987). This is in agreement with the conclusion of Berens and Daniels (1976) that PVC pipe containing less than or equal to 1 ppm residual vinyl chloride monomer would result in vinyl chloride concentrations of less than 2 pg/L under any expected service conditions. This suggests that use of PVC pipe in water distribution systems contributes to intake of vinyl chloride through ingestion of contaminated drinking water. Assuming that the average daily intake of water is 2 L, the average intake of vinyl chloride from water contaminated with vinyl chloride from PVC pipes is expected to range from 0.06 to 2.8 pg/day. During an.EPA study, detectable levels of vinyl chloride monomer (detection limit 0.05 ppm) were found in two out of seven new 1975 model cars. Levels of vinyl chloride in these two cars ranged from 0.4 to 1.2 ppm. Ventilation of the car interiors led to the dissipation of vinyl chloride. The cars involved in this 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 since the source of vinyl chloride was believed to be volatilization from vinyl plastics (Hedley et al. 1976). Due to the limited nature of this data and the fact that this study is somewhat dated, no conclusions could be drawn regarding levels of vinyl chloride monomer in interior air of cars currently being produced. UCC 107918 72 Section 7 Vinyl chloride has been detected In tobacco smoke (EPA 1985b). Cigarettes and little cigars have been found to contain 5.6 t 28 ng vinyl chloride per cigarette (IARC 1979). 7.3 OCCUPATIONAL EXPOSURES NIOSH estimates definite worker exposure to vinyl chloride to be 27,000 persons and probable worker exposure to be 2.2 million (Sittig 1985). This includes -5,000 workers employed in vinyl chloride synthesis, 5,000 workers involved with polymerization processes, and as many as 350,000 workers associated with fabrication plants. Exposure is believed to occur primarily through inhalation and less frequently by absorption through skin (Sittig 1985). In the past, concentrations of vinyl chloride in workplace air in some plants producing FVC have been reported to range from 100 to 800 mg/m^ (39 to 315 ppm) with peak concentrations up to 87,300 mg/m^ (34,000 ppm) (IARC 1979). Currently, the Occupational Safety and Health Administration (OSHA) sets standards for occupational exposure to vinyl chloride (see Sect. 9, Regulatory and Advisory Status). A recent NIOSH survey of three vinyl chloride plants Indicated that the time-weighted*average exposure to vinyl chloride varied between 0.2 to 70 mg/m^ (0.07 to 27 ppm) (IARC 1979). 7.4 POPULATIONS AT HIGH RISK Data were not located specifically regarding subpopulations unusually sensitive to the effects of vinyl chloride. Individuals located near or downwind of production facilities, hazardous waste disposal sites, and landfills may potentially be exposed to higher ambient atmospheric levels. Workers involved in the production or polymerization of vinyl chloride may constitute a group at risk because of the potential for occupational exposure. Since the mid 1970s, however, atmospheric levels in the workplace have often been reduced to si ppm (Fishbeln 1979, Kilian et al. 1975, Hansteen et al. 1978). Inhalation studies in animals demonstrated that exposure early in life resulted in greater risk of developing cancer than did exposure later in life (Drew et al. 1983). Although human studies that address the effect of age on cancer risk were not located, the animal data suggest that exposure during the younger years may result in increased cancer risk. Other animal studies suggest that prenatal exposure may increase cancer risk (Maltoni et al. 1980, 1981; Radike et al. 1988). Although human data were not located, the animal data may suggest that the prenatal exposure of humans to vinyl chloride may increase risk of cancer. Animal studies have demonstrated that pretreatment with xenoblotlcs or drugs that induce mixed-function oxidase (MFO) potentiates the hepatotoxicity of vinyl chloride (Jaeger et al. 1974, Reynolds et al. 1975, Conolly et al. 1978). Although human data were not located, the animal data suggest that human exposure to environmental pollutants or drugs that induce MFO may result in increased sensitivity to vinyl chloride. UCC 107919 73 8. ANALYTICAL METHODS A variety of methods are available for the analysis of vinyl chloride in environmental and biological matrices. The methods of choice will depend on the nature of the sample matrix; the required precision, accuracy, and detection limit; the cost of analysis; and the turnaround time of the methodology. Preconcentration of samples may not only increase the sensitivity but also, in certain instances, decrease the time required for sample separation prior to quantification. The best sensitivity and specificity for vinyl chloride quantification are obtained with Hall detectors and photoionization detectors (Reding 1987). Hass spectrometry, although less sensitive than the most sensitive detectors, is often used as a confirmatory tool for vinyl chloride analysis. Details of analytical methodologies for vinyl chloride are given in IARC (1978). 8.1 ENVIRONMENTAL MEDIA Some of the more commonly used analytical methods for the quantification of vinyl chloride are given in Table 8.1, Other methods that are less sensitive (e.g., infrared analyzer and continuous monitoring instruments) and less commonly used (e.g., semiconductor devices) are given in IARC (1978). Details of sample collection, sample preservation, sample pretreatment, and quantification methods are provided in the cited references In Table 8.1. 8.2 BIOMEDICAL SAMPLES The concentrations of vinyl chloride measured in environmental samples may not reflect the concentration to which persons are exposed. Proper biological monitoring not only can be used to support environmental monitoring but also potentially may provide more accurate data on exposure levels. The two biological media that have been used most extensively as promising indicators of vinyl chloride exposure are breath and urine. A close agreement has been found between postexposure breath concentrations and the ambient vinyl chloride levels in both environmental and industrial conditions (Baretta et al. 1969, Tarkowski 1984). However, problems with quantification of low concentrations of vinyl chloride in exhaled air at ambient sir levels of <50 ppm has led to limited application of this method (Tarkowski 1984). A reasonable correlation was noted between urinary output of thiodiglycolic acid, the principal metabolite of vinyl chloride, and ambient levels to which persons were exposed (Heger et el. 1982). Measurement of urinary thiodiglycolic acid can be used as an indicator of vinyl chloride intake only as long as individual variability in metabolism due to such factors as liver disease, use of drugs, and alcohol intake can be accounted for. Therefore, it appears that there UCC 107920 74 Section 8 is no suitable biological medium that can be used as a reliable indicator for vinyl chlorid exposure (Tarkovski 1984). Th comm nly used methods for the quantification of vinyl chloride in biological media are given in Table 8.1. UCC 107921 I Table 1.1. Amlytical elhsds far the quuaWcntioa of flnyl chloride Sample matrix Sample preparation Occupational air Ambient indoor and outdoor afar Air Air Air Automobile eibauat Air Air Air Drinking water and wartewater Vinyl chloride la air absorbed in acthrated carboa trap and deaoircd byCSj Air oontaialng vinyl chloride pawed through acthrated carbon trap and deaobred by dichloromethane or carbon disulfide Adsorption on TenaaOC; thermal desorption Grab sample collected in electro- pfttiihfd ned Air preflhered by NsjSjOjtreated (law fiber filter was passed throu|h spherocarb adsorbent cartridge and thermally desorbed Bahanst samples taken into aluminized plastic bags Trapped in coM Teaax-OC trap; thermal dttorptkM Sample collected in pressurized canister Is pawed through a froezeout loop and aubsequently heated Sample collected in polyeater-coated plastic bags concentrated by freezoout and subsequently heated Purge and trap in Tenax GC; thermal desorption Groundwater, liquid, Purge at 45*C and trap in Tenax GC; and solid matrices thermal desorption Qnaatificatioa method* OC/FID GC/FID Detection limit 0.8 ppb 4ppb Accuracy/ % recovery References 94% at NIOSH 1984 0.4-26 ppm NR* IARC 1978, Miller and Beizer 1985 HRGC/MS GC/MS at subambieet temperature HRGC/FID and HRGC/MS 0.33 ppb 0.005 ppb 0.005 ppb NR NR NR Krostet al 1982 Grimsntd and Rnamuaaen I975a,b Harkov et aL 1983, 1984 HRGC/FID GC/FID GC/ECD GC/FID 20 ppb NR 0.01 ppb 0.006 ppb NR 79-104 at 6-60 ppb NR NR HgsInenetaL 1979 Ires 1975 Rasmussen et aL 1977, Harach et aL 1979 McMurry and Terr 1978 GC/HSD, GC/MS (EPA Method No. 601 and 624) GC/HSD (EPA Method No-8010) 0.18 ppb (HSD) 0.18 ppb 102% at 0.82-32.3 ppb 102% at 0.82-32.3 ppb EPA 1982a, APHA 1985 EPA 19838* L/T A n a ly tic a l Methods Z36Z.01- 0 0 0 S ection 8 \jCC 107923 Table *.1 autrix Drtafctag water Migration of monomer tato drinking water for potr**yi Pfo Water oyster Fargo and trap ia Teaax OC; thermal SauB aactiona pat ia water la Mated serene rial for a aamber of days at 20*C; solution directly injected lato a gas Quantification method0 Detection limit Accuracy/ % reoovuy References HRGC/Hall detector, HROC/PID (EPA Method 5012, 524.2) OC/FID 0.04 ppb (Hall) 0.02 (FID) NR 100-119 at S-IOppb NR Reding I9S7 Aado aad Sayato 19*4 Sample la aealed rial la equilibrated at ewaataat temperature; headapace gaa tajected tato a gat chromatograph Oaa from laadflll shot sampled by PTFE taUeg inside drive-la piezoeneten was abaorbed in Teaax OC sorbent; trapped mfllt doMvbsd ud coaoeatnted k Hqeid Nj-cooled loop and flash dcaorbed Homegeaeoaa sample mixed with water and riayl chloride purged lato a doted loop; gat ia dated loop injected lato a gaa oc/fid OC/MS OC/ECD <1 ppb NR 0.04-0.1 ppm NR IARC 197* Young and Parker 19*4 2 ppb (aedimeat) NR Waaget aL 19SS Food (orange drink, wise, ofire oil) Foodatnffia Breath Bttath Sample sealed ia rials and equilibrated at 40*C for 2 h; headspace gat tajected tato a gas chromatograph Sample aealed la rials aad equilibrated at 40*C for a miaimum of 2 h; headspace gaa tajected tato a gaa chromatograph Cryogenic trapping of expired air, thermal desorption lato a gas chromatograph Breath collected ta Tedlar bag la ooaceatrated by Teaax OC adaorbeat aad thermally desorbed OC/FID OC/FID OC/FID, OC/ECD aad OC/MS OC/MS NR l-Sppb NR ipp* NR Cbody aad Crosby 1977 NR IARC 197* NR 77-110 CoaUeetaL ms miL ms vl o\ TiUe 8.1 (< Sample matrix Whole blood, plant)a, and eenun Blood, urine Urine Sample preparation Sample equilibrated in a sealed vial at 65*C; headspace gas injected into a gat chromatograph Sample purged and trapped in Tenax GC; thermally desorbed Sample solvent extracted, extract methylated, and cleaned by ion-exchange resin Quantification method GC/ECD GC/MS GC/MS or HRGC/MS Tissue (liver, lung, kidney, brain) Tissue Homogenized samples mixed with ethanolwater mixture equilibrated in a sealed vial at 70*C; headspace gas injected into a gat chromatograph Sample mixed with a proteolytic enzyme incubated at (5*0; headspace gat analyzed GC/FID GC/ECD Detection Emit NR Screening method 50 ppb (urinary thiodiglycoltc acid) 30 ppb Accuracy/ % recovery References NR Ramsey and Flanagan 1982 NR NR 75-92% Balkon and Leary 1979 van Sittert and defong 1985, MWeret aL 1979 Zuccatoet aL 1979 NR NR Ramsey and Flannagan 1982 aOC -- Ow chromatography; HROC " high-resolution gat chromatography; FID - flame ionization detection; MS " maaa spectrometry, ECD -- electron ipture detector; HSD -- halide-sensitive detector; FID -- pbotoionizatioo detector. "Not reported. A n a ly tic a l Methods UCC 107924 'j Preceding page blank 79 9. REGULATORY AND ADVISORY STATUS 9.1 INTERNATIONAL Advisory guidance Issued by the World Health Organization (WHO) f r vinyl chloride was not located In the available literature. 9.2 NATIONAL 9.2.1 Regulations 9.2.1.1 Air The Occupational Safety and Health Administration (OSHA 1983) regulations for vinyl chloride state that a worker must not be exposed to a concentration of >1 ppm over any 8-h period and that a worker must not be exposed to >5 ppm for any period of time exceeding 15 minutes. Direct contact with liquid vinyl chloride Is prohibited. EFA (1982c) has established emission standards for vinyl chloride released to the atmosphere by vinyl chloride and polyvinyl chloride plants. Emissions are not to exceed 10 ppm. 9.2.1.2 Water Pursuant to the Safe Drinking Water Act, EPA (1987c) promulgated a maximum contaminant level (MCL) for vinyl chloride of 0.002 mg/L, equivalent to an estimated cancer risk of 10*^. This regulation is to become effective January 9, 1989, and is to apply to all community drinking water systems that regularly serve the same 25 persons for at least 8 months/year. Vinyl chloride is regulated under the Clean Water Act Effluent Guidelines for the following industrial point sources: steam electric, asbestos industry, timber products processing, metal finishing, paving and roofing, paint formulating, Ink formulating, gum and wood, and carbon black (EPA 1988). 9.2.1.3 Food The Food and Drug Administration (FDA 1986) recently proposed t amend Its regulations regarding the vinyl chloride content of polymers used in packaging materials or processing equipment for foods. Depending on the nature of the polymer and its use, proposed vinyl chloride content may range from 5 to 50 ppm. UCC 107925 80 Section 9 9.2.1.4 Other EPA (1982d) has designated vinyl chloride as a hazardous constituent of solid waste and requires that it be handled in accordance with the regulations governing the sane. EPA (1987d) lists a reportable quantity (RQ) for vinyl chloride of 1 lb, but proposes that the RQ be changed to 10 lb. The RQ is the quantity that, if released to the environment, must be reported immediately to the National Response Center. 9.2.2 Advisory Guidance 9.2.2.1 Air The American Conference of Governmental Industrial Hygienists (ACG1H 1986b) recommends a Threshold Limit Value (TLV)-TWA for vinyl chloride of 5 ppm and a Short-Term Exposure Limit (STEL) of 10 ppm with the notation that the compound is a recognized human carcinogen. The National Institute of Occupational Safety and Health (NIOSH 1975) concluded that a TLV for vinyl chloride was inappropriate because of its carcinogenicity. NIOSH (1975) recommended that any workers exposed to vinyl chloride should wear an air-supplied respirator. 9.2.2.2 Water An EPA (1980) study, based on an upper-bound human q* of 1.74 x 10*2 (mg/kg/day)'1 calculated from the incidence of tumors in a preliminary report of an inhalation study in rats (Halton! and Lafemine 1975), estimated levels in ambient water of 20, 2, and 0.2 ftg/L associated with cancer risks of 10*5, 10*, and 10*?, respectively, assuming daily consumption of 2 L water and 6.5 g fish and shellfish. For consumption of fish and shellfish alone, water concentrations of 5,246, 525, and 52.5 ftg/L correspond to cancer risk estimates of 10*5, 10*, and 10*7, respectively. More recently, EPA (1985a, 1987b) estimated that cancer risk levels of 10*^, 10*5, and io* would result from daily consumption of drinking water containing vinyl chloride at 1.5, 0.15, and 0,015 /ig/L, respectively, using an upper-bound limit q.* value of 2.3 (mg/kg/day)* *. EPA (1985a, 1987a) promulgated health advisories for vinyl chloride In drinking water. A 10-day health advisory of 2.6 mg/L was based on a NOAEL of 30 mg/kg/day in a 13-week gavage study by Feron et al. (1975). Because data were not sufficient for derivation of a 1-day health advisory, the 10-day health advisory was adopted as a conservative 1-day health advisory. Longer term health advisories of 0.013 mg/L for a 10-kg child and 0.046 mg/L for an adult were estimated from the NOAEL of 0.13 mg/kg/day in a lifetime dietary study in rats (Til et al. 1983). 9.2.3 Data Analysis 9.2.3.1 Reference doses (RfDs) Reference doses for vinyl chloride have not been estimated by EPA. UCC 107926 Regulatory and Advisory Status 81 9.2.3.2 Carcinogenic potency Vinyl chloride has been classified In IARC Group 1 (1ARC 1987) and EPA Class A (EPA 1987a). By either classification scheme, the designations have the same meaning, that evidence is sufficient to consider vinyl chloride carcinogenic to humans. EPA has derived several estimates of carcinogenic potency for vinyl chloride for both oral and inhalation exposure. In an early estimate, EPA (1980) derived a q_* for human oral exposure of 1.74 x 10`2 (mgAg/day)-* based on preliminary reports of the incidence of total tumors in rats of both sexes exposed to vinyl chloride by inhalation at concentrations up to 10,000 ppm (Haltoni and Lefemine 1975). A subsequent estimate of potency for oral exposure is 2.3 (mg/kg/day)'* which appears in EPA (1987a) and represents the most recent analysis. This estimate was based on the incidence of lung and liver tumors in both sexes of rats exposed for lifetime to diets that contained vinyl chloride (Feron et al. 1981). The first estimate for carcinogenic potency by inhalation exposure, 2.5 x lO-2 (mg/kg/day)'1 derived in EPA (1984), was based on the same preliminary inhalation data (Haltoni and Lefemine 1975) that was used as the basis of the EPA (1980) oral estimate. A more recent estimate of 2.95 x 10"! (mg/kg/day)"l (EPA 1985b) was based on the final report of the incidence of liver angiosarcomas in male and female rats exposed for up to 1 year to concentrations up to 30,000 ppm (Haltoni et al. 1980, 1981). 9.3 STATE No state guidelines were available. UCC 107927 Preceding page blank 83 10. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1986a. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed. Cincinnati, Ohio: ACGIH, pp. 623-626. ACGIH (American Conference of Governmental Industrial Hygienists). 1986b. Threshold Limit Values for Chemical Substances in the Work Environment Adopted by ACGIH with Intended Changes for 1986-87. Cincinnati, Ohio: ACGIH, p. 33. 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. Anderson D, Richardson CR. 1981. Issues relevant to the assessment of * chemically induced chromosome damage in vivo and their relationship to chemical mutagenesis. Hutat 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, Adams WG. 1980. Chromosomal analyses in vinyl chloride exposed workers. Results from analysis 18 and 42 months after an initial sampling. Hutat Res 79:151-162. Andrews AW, Zawistowski ES, Valentine CR. 1976. A comparison of the mutagenic properties of vinyl chloride and methyl chloride. Hutat Res 40:273-275. Ando H, Sayato Y. 1984. Studies on vinyl chloride migration into drinking water from polyvinyl chloride pipe and reaction between vinyl chloride and chlorine. Water Res 18(3):315-318. APHA (American Public Health Association). 1985. AWWA (American Water Works Association)/WPCF (Water Pollution Control Federation). Standard Hethods for the Examination of Water and Wastewater, 16th ed. Washington, D.C.: APHA, pp. 591-602. Baker LW, HacKay KP. 1985. Hazardous waste management. Screening models for estimating toxic air pollution near a hazardous waste landfill. J Air Pollut Control Assoc 35(11):1190-1195. * Key studies. UCC 107928 84 Section 10 Balkon J, Leary JA. 1979. An initial report on a comprehensive, quantitative screening procedure for volatile compounds of forensic and envir nmental interest in human biofluids by GC/MS. J Anal Toxicol 3:213-215. Barbin A, Besson F, Ferrard HH, et al. 1985a. Induction of specific base-pair substitutions in E. coll trpA 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. 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 (cited in Tarkovski 1984). Barnes D, Beilin J, DeRosa C, et al. 1987. Reference Dose (RfD): Description and use in health risk assessments. Appendix A of the Integrated Risk Information System (IRIS). Washington, D.C.: Office of Health and Environmental Assessment, Office of Research and Development. EPA 600/8-86-0321. Bartsch H. 1976. Predictive value of mutagenicity tests in chemical carcinogenesis. Mutat Res 38:177-190. Bartsch H, Malavellle C, Montesano R. 1975. Human, rat and mouse livermediated mutagenicity of vinyl chloride in 5. typhlanrlua strains. Int J Cancer 15:429-437. Bartsch H, Malavellle 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. Berens AR, Daniels CA. 1976. Prediction of vinyl chloride monomer migration from rigid FVC pipe. Polymer Engineering and Science 16(8):15-21. Berk PD. 1976. Vinyl chloride-associated liver disease. Ann Int Med 84:717-731 (cited in EPA 1985a). * Bi V, Wang Y, Huang M, Meng D. 1985. Effect of vinyl chloride on testis in rats. Ecotoxlcol Environ Saf 10(2):281-289. Bogdanikova B, Zawllska J. 1984. Immune complexes in the serum of patients occupationally exposed to vinyl chloride. Przeglad Lekarski 41(3):253-257. Bolt HM. 1986. Metabolic activation of vinyl chloride, formation of nucleic acid adducts and relevance to carcinogenesis. IARC Sci Publ 70:261-268. References 85 Bolt HM, Kappus H, Buchter A, Bolt W. 1976a. Disposition of (1,214C) vinyl chloride in the rat. Arch Toxic 1 35:153-162 (cited in EPA 1985b). Bolt HH, Kappus H, Kaufmann R, et al. 1976b. Metabolism of l^C-vlnyl chloride in vitro and in vivo. INSERM Symposia Series, IARC Scientific Publications N 13. INSERM 52:151-164.j Bolt HM, Lalb RJ, Kappus H, Buchter A. 1977. Pharmacokinetics of vinyl chloride in the rat. Toxicology 7(2):179-188. Bryen D, Engholm G, Englund A, Uesterholm P. 1976. Mortality and cancer morbidity in a group of Swedish VCM and PCV production vorkers. Environ Health Perspect 17:167-170 (cited In EPA 1985b). Buchancova J, Reznak I, Horak V, Altmann F, Svehlova L, Suchova E, Sramkova E. 1985. Scintigraphic pictures of the liver in vorkers after a long-term exposure to vinyl chloride. Pracov Lek 37(6):190-194. Buchter A, Bolt HM, Kappus H, Bolt V. 1977. Tissue distribution of 1,2-^C-vinyl chloride in the rat. Int Arch Occup Environ Health 39(l):27-32. (In German, English abstract.) Buchter A, Filser JG, Peter H, Bolt HM. 1980. Pharmacokinetics of vinyl chloride in the rhesus monkey. Toxicol Lett 6(1):33-36. C&EN (Chemical and Engineering News). 1987. Key Chemicals: Vinyl Chloride. 65(1):10. Chudy JC, Crosby NT. 1977. Some observations on the determination of monomer residues in foods. Food Cosmet Toxicol 15:547-551. CMR (Chemical Marketing Reporter). 1986a. Chemical Profile: Vinyl Chloride. June 2, 1986. New York, N.Y.: Schnell Pub. Co. CMR (Chemical Marketing Reporter). 1986b. Chemical Profile: Polyvinyl Chloride. June 9, 1986. New York, N.Y.: Schnell Pub. Co. Coniglio WA, Miller K, MacKeever D. 1980. The occurrence of volatile organics in drinking water. Criteria and Standards Division. Science and Technology Branch. Exposure Assessment Project. Conkle JP, Camp BJ, Velch BE. 1975. Trace composition of human respiratory gas. Arch Environ Health 30:290-295. Conolly RB, Jaeger RJ. 1978. Effects of cysteine, diethylmaleate and trichloropropane oxide on acute vinyl chloride hepatotoxicity. Toxicol Appl Pharmacol 45(1):338. 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. UCC 107930 86 Section 10 Conolly RB, Jaeger RJ, Szabo S. 1978. Acute hepatotoxicity of ethylene, vinyl fluoride, vinyl chloride, and vinyl bromide after Aroclor 1254 pr=!treatment. Exp Mol Path 1 28:25-33. Cocruvo JA. 1985. Organic micropollutants in drinking water. Sci Total Environ 47:7-26. Cotti G, Balgimigli L, Mandrioli A, Maltoni C. 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, N.Y.: Wiley Interscience, pp. 865-885. Cowfer JA, Magistro AJ. 1985. Vinyl polymers: Vinyl chloride. In KirkOthmer Concise Encyclopedia of Chemical Technology. New York, N.Y.: John Wiley and Sons, Inc., pp. 1229-1230. Curry S, Rich S. 1980. The Kline Guide to the Chemical Industry. 4th ed., Fairfield, N.Y.: Charles H. Kline and Co. 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. Dinceva E, Kolev P, Dalbokova D. 1985. EEG changes in workers exposed to long-term combined effect of a mixture of organic solvents and vinyl chloride. Khig Zdraveopaz 29(1):8-15. (In Russian: English abstract). Dinman BD, Cook WA, Whitehouse WM, Magnuson HJ, Ditcheck T. 1971. Occupational acroosteolysis. I. An epidemiological study. Arch Environ Health 22:61-73. Doll R. 1987, Effects of exposure to vinyl chloride: An assessment of the evidence. Unpublished study commissioned by ICI, BP, Norsk Hydro, Dow Chemical and B.F. Goodrich. Doss M, Lange CE, Veltman G. 1984. Vinyl chloride-induced hepatic coproporphyrinuria with transition to chronic hepatic porphyria. Klin Wochenschr 62(4):175-178. Dow Chemical Company. 1988. Comments of the Dow Chemical Company on ATSDR's Toxicological Profile for Vinyl Chloride. Midland, Mich. April 21, 1988. Downs TD, Stallones RA, Frankowski RF, Labarthe DR. 1977. Vinyl chloride, birth defects, and fetal wastage. A critical review. Unpublished study prepared by Research Statistics, Inc. for The Society of Plastic Industries, Inc. UCC 107931 References 87 Drevon C, Kuroki T. 1979. Mutagenicity f vinyl chloride, vinylidene chloride and chloroprene In V79 Chinese hamster cells. Mutat Res 67:173-182. Drew RT, Boorman GA, Haseman JK, McConnell EE, Busey WM, Moore JA. 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. Ducatman A, Hirschhorn K, Selikoff IJ. 1975. Vinyl chloride exposure and human chromosome aberrations. Mutat Res 31:163-168. Duprat F, Fabry JP, Gradlskl D, Magadur JL. 1977. Metabolic approach to industrial poisoning: Blood kinetics and distribution of l^C-vinyl chloride (VCM). Acta Pharmacol Toxicol Suppl (Kbh) 41(1);142-143 (cited In EPA 1985b). Dyksen JE, Hess AF, III. 1982. Alternatives for controlling organics in groundwater supplies. J Am Water Works Assoc 74:394-403. Edmonds LD, Falk H, Nissim JE. 1975. Congenital malformations and vinyl chloride. Lancet ii:1098. Edmonds LD, Anderson CE, Flynt JW, James LM. 1978. Congenital central nervous system malformations and vinyl chloride monomer exposure: A community study. Teratology 17:137-142. Eisenreich SJ, Looney BB, Thornton JD. 1981. Airborne organic contaminants in the Great Lakes ecosystem. Environ Sci Technol 15(1):30-38. Elmore JD, Wong JL, Laumbach AD, Streips UN. 1976. Vinyl chloride mutagenicity via the metabolites chlorooxirane and chloroacetaldehyde monomer hydrate. Biochem Biophys Acta 442(3):405-419 (cited in EPA 1985b). EPA (Environmental Protection Agency). 1980. Ambient Water Quality Criteria Document for Vinyl Chloride. Cincinnati, Ohio: Environmental Criteria and Assessment Office. EPA 440/5-80-078. NTIS PB 81-117889. EPA (Environmental Protection Agency). 1982a. Methods for Organic Chemical Analysis of Municipal and Industrial Wastewater. Test Meth d: Purgeable Halocarbons Method 601 and Purgeable - Method 624. EPA Report 600/4-82-057, Environmental Monitoring and Support Laboratory, EPA, Cincinnati, Ohio, pp. 601-1 to 601-10 and 624-1 to 624-12. EPA (Environmental Protection Agency). 1982b. Test Methods for Evaluating Select Waste. Physical/Chemical Methods. Method 8010 Halogenated Volatile Organics. Office of Solid Waste and Emergency Response, EPA, Washington, D.C., pp. 8010-1 to 8010-12. UCC 107932 88 Secclon 10 EPA (Environmental Protection Agency). 1982c. Emission standard for ethylene dichloride, vinyl chloride, and polyvinyl choride. 40 CIR 61.65. EPA (Environmental Protection Agency). 1982d. Identification and listing of hazardous waste. 40 CFR 261, Append VIII. EPA (Environmental Protection Agency). 1984. Health Effects Assessment for Vinyl Chloride. Cincinnati, Ohio: Environmental Criteria and Assessment Office. EPA 540/1-86-036. EPA (Environmental Protection Agency). 1985a. Drinking Water Criteria Document for Vinyl Chloride. Washington, D.C.: Office of Drinking Water, EPA. NTIS PB86-118320. EPA (Environmental Protection Agency). 1985b. Health and Environmental Effects Profile for Chloroethene. Cincinnati, Ohio: Environmental Criteria and Assessment Office. EGAO-CIN-P155. EPA (Environmental Protection Agency). 1986. The Total Exposure Assessment Methodology (TEAM) Study. Final report. Washington, D.C.: Office of Research and Development, Environmental Monitoring Systems Division. RTI/2391/00-03 F. EPA (Environmental Protection Agency). 1987a. Vinyl Chloride Health Advisory. Draft. Washington, D.C.: Office of Drinking Water. EPA (Environmental Protection Agency). 1987b. Graphical Exposure Modelling System (GEMS). CLOGP. Online. Washington, D.C.: EPA, Office of Toxic Substances. EPA (Environmental Protection Agency). 1987c. National primary drinking water regulations - synthetic organic chemicals; monitoring for unregulated contaminants; final rule. Fed Reglst 52(130):25690-25717. EPA (Environmental Protection Agency). 1987d. Reportable quantity adjustments. Fed Regist 52(50):8140-8186. EPA (Environmental Protection Agency). 1988. Analysis of Clean Water Act Effluent Guidelines Pollutants. Summary of the Chemicals Regulated by Industrial Point Source Category 40 CFR Farts 400-475. Draft. Prepared by the Industrial Technology Division (WH 552). Office of Water Regulations and Standards, Office of Water, EPA, Washington, D.C. Farkas DF. 1980. Food Processing. In Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 11. New York, N.Y.: John Wiley & Sons, pp. 180-181. FDA (Food and Drug Administration). 1986. Proposed uses of vinyl chloride polymers. Fed Reglst 51(22);4177-4185. UCC 107933 References 89 Feron VJ, Kroes R. X979. One-year tiae-sequence Inhalation toxicity study of vinyl chloride in rats. II. Morphol gical changes in the respirat ry tract, ceruminous glands, brain, kidneys, heart and spleen. Toxicology 13(2):131-141. * Feron VJ, Speek AJ, Villens MI, Van Buttaun D, Groot AP. 1975. Observations on the oral adninlstratlon and toxicity of vinyl chloride in rats. Food Cosnet Toxicol 13(6):633-638. Feron VJ, Spit BJ, linsel HR, Kroes R. 1979a. One-year tine-sequence inhalation toxicity study of vinyl chloride in rats. III. Morphological changes in the liver. Toxicol 13:143-154. Feron VJ, Kruysse A, Til HP. 1979b. One-year tine-sequence Inhalation toxicity study of vinyl chloride in rats. I. Growth, nortality, haematology, clinical chemistry, and organ weights. Toxicol 13:25-35. * Feron VJ, Hendrlksen CFM, Speek AJ, Til HP, Spit BJ. 1981. Lifespan oral toxicity study of vinyl chloride in rats. Food Cosmet Toxicol 19(3):317-333. Filser JG, Bolt HM. 1979. Pharmacokinetics of halogenated ethylanes in rats. Arch Toxicol 42(2):123-136. Fishbein L. 1979. Potential halogenated Industrial carcinogenic and mutagenic chemicals. I. Halogenated unsaturated hydrocarbons. Sci Total Environ 11:111-161. 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 34:110. Funes-Cravioto F, Lambert B, Lindsten J, et al. 1975. Chromosome aberrations in workers exposed to vinyl chloride. Lancet 1:459. Gedigk P, Muller R, Bechtelsheimer H. 1975. Morphology of liver damage among polyvinyl chloride production workers. A report on 51 cases. Ann NY Acad Sci 246:279-285. Geryk E, Zudova Z. 1986. Vinyl chloride as occupational health hazard. Pracov Lek 38(1):1-8. (Czech: English translation). Goodenkauf 0, Atkinson JC. 1986. Occurrence of volatile organic chemicals in Nebraska groundwater. Ground Vater 24(2):231-233. Gordon SJ, Meeks SA. 1977. A study of gaseous pollutants in the Houston, Texas area. AICHE Symp Ser 73:84-94. Gosselin RE, Smith RP, Hodge HC. 1984. Clinical Toxicology of Commercial Products, 5th ed. Baltimore, Md.: Williams and Vllklns, p. 11-166. Green T, Hathway DE. 1975. The biological fate in rats of vinyl chloride in relation to its oncogenicity. Chen Biol Interact 11:545-562. UCC 107934 90 Section 10 Green T, Hathvay DE. 1977. The chemistry and biogenesis of the S-containing metabolites of vinyl chloride In rats. Chem Bi 1 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, Reichert D, Hensehler D. 1975. Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxlrane formation. Blochem 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, Watanabe PG. 1979. Metabolism of (^C)- and (^6ci)labeled vinyl chloride in vivo and in vitro. Blochem 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 18:5177-5182. Guengerich FP, Mason PS, Stott WJ, Fox TR, Watanabe PG. 1981. Roles of 2-haloethylene oxide and 2-haloacetaldehydes 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, Bolt HM. 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. Halama J, Becker-Stone S, Halama JM. 1985. Das haemanglosarkom der bei arbeitem in der FVC-Industrie and ardere VC-bedlngte erkrankungen mlt angiologish-dermatologischer, heptalc,giseher, radiologischer and neurologischer symptomatlk. Der Radiolog 25(l):22-29. (In German, English abstract.) * Hansteen IL, Hillestad L, Thlis-Evensen E, Heldaas SS. 1978. Effects of vinyl chloride in man; A cytogenetic follow-up study. Mutat Res 51:271-278. Harkov R, Kebbekus B, Bozzelli JW, Lioy PJ. 1983. Measurement of selected volatile organic compounds at three locations in New Jersey during the summer season. J Air Pollut Control Assoc 33:1177-1183. References 91 Harkov R, Kebbekus B, Bozzelll JW, Lloy PJ, Daisey J. 1984. Comparison of selected volatile organic compounds during the summer and winter at urban sites in New Jersey. Sci Total Environ 38:259*274. Harsch DE, Cronn DR, Slater HR. 1979. Expanded list of halogenated hydrocarbons measurable in ambient air. J Air Follut Control Assoc 29:975-976. Hartmans S, Bont JAM, Tramper J, Luyben KChAM. 1985. Bacterial degradation of vinyl chloride. Biotech Letters 7(6):383-386. Hatch M, Kline J, and Stein Z. 1981. Power considerations in studies of reproductive effects of vinyl chloride and some structural analogs. Environ Health Perspeet 41:195-201. Hasanen E, Soininen V, Pyysalo H, Leppamaki E. 1979. On the occurrence of aliphatic chlorine and bromine compounds in automobile exhaust. Atmos Environ 13:1217-1219. Heath Ctf Jr, Fable H, Creech JL Jr. 1975. Characteristics of cases of angiosarcoma of the livers among vinyl chloride workers in the United States. Ann NY Acad Sci 246:231-236. Hedley UH, Cheng JT, McCormick RJ, Lewis WA. 1976. Sampling of Automobile Interiors for Vinyl Chloride Monomer. EPA-600/2-76-124. NTIS PB-258648. 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. Heger M, Muller G, Norpath K. 1982. Untersuchungen zur Beziehung zwischen Vinylchlorid (VCM) - Aufnalslne und Metabolitenausscheidung bei 15 VCM-Exponierten. Int Arch Occup Environ Health 50:187 (cited in Tarkowski 1984). Hehir RM, McNamara BP, McLaughlin J Jr, Wllligan DA, Bierbower G, Hardisty JF. 1981. Cancer induction following single and multiple exposures to a constant amount of vinyl chloride monomer. Environ Health Perspeet 41:63-72. HeIdaas SS, Langard SL, Andersen A. 1984. Incidence of cancer among vinyl chloride and polyvinyl chloride workers. Br J Ind Med 41:25-30, * Hong CB, Winston JM, Thornburg LP, Lee CC. 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. UCC 107936 92 Section 10 HSDB (Hazardous Substances Data Bank). 1987. Natl nal Library of Medicine Report 169, Online: September 1987. Hubeman 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. Hultmark D, Sundh K, Johansson L, Arrhenius E. 1979. Ethanol inhibition of vinyl chloride metabolism in isolated rat hepatocytes. Chem Biol Interact 25(1):l-6. 1ARC (International Agency for Research on Cancer). 1978. Methods for the measurement of vinyl chloride in poly(vinyl chloride), air, water, and foodstuffs. In Environmental Carcinogens Selected Methods of Analysis. Egan H, Squireel DCM, Thaln V, Davis V, eds. IARC Sci Pub No 22. IARC (International Agency for Research on Cancer). 1979. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals in Humans. Vinyl chloride, polyvinyl chloride and vinyl chloride-vinyl acetate polymers. Lyons, France: World Health Organization, IARC 19:377-401; 419-438. IARC (International Agency for Research on Cancer). 1987. Vinyl Chloride. In: IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Vol. 1 to 42. Lyons, France: World Health Organization, IARC Suppl 7:373-376. Infante FF. 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, Waxweller RJ, Falk H. 1976. Genetic risks of vinyl chloride. Lancet (April 3) 734-735. Ives NF. 1975. Sensitive trapping and gas chromatographic method for vinyl chloride in air samples. J Assoc Off Anal Chem 58:457-460. Jaeger RJ, Reynolds ES, Conolly RB, Moslen MT, Szabo S, Murphy SD. 1974. Acute hepatic injury by vinyl chloride in rats pretreated with phenobarbltal. Nature 252(5485):724-726. Jaeger RJ, Murphy SD, Reynolds ES, Szabo S, Moslen MT. 1977. Chemical modification of acute hepatotoxiclty of vinyl chloride monomer in rats. Toxicol Appl Pharmacol 41:597-607. Jedrychowski RA, Sokal JA, Chmielnicka J. 1984. Influence of exposure mode on vinyl chloride action. Arch Toxicol 55(3):195-198. 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. UCC 107937 References 93 John JA, Smith FA, Le ng BKJ, Schvetz BA. 1977, The effects f maternally Inhaled vinyl chi ride on embry nal and fetal dev 1 pment in mice, rats, and rabbits. Toxic 1 Appl Fharmac 1 39:497*513. Juhe VS, Lange CE, Stein G, Veltman G. 1974. Uber die sog. Vinylchlorldkrankhelt. Berufs-Dermatosen 22:4-22. (In German, English abstract.) Kappus H, Bolt HM, Buchter A, Bolt V. 1976. Liver microsomal uptake f [l&c] vinyl chloride and transformation tp protein alkylating metabolites in vitro. Toxicol Appl Pharmacol 37:461-471. Katsova LD, Pavlenko GI. 1985. Cytogenetic examination of the workers of chemical industry. Mutat Res 147:301-302. Keplinger ML, Goode JV, Gordon DE, Calandra JC. 1975. Interim results f exposure of rats, hamsters, and mice to vinyl chloride. Ann NY Acad Sci 246:219-224. Kilian DJ, Picclano DJ, Jacobson CB. 1975. Industrial monitoring: A cytogenic approach. Ann NY Acad Sci 269:4-11. Kontominas MG, Gupta C, Gilbert SG. 1985. Interaction of vinyl chloride with polyvinyl chloride in model food systems by HPLC chromatography: . Migration aspects. Lebensm-tfiss u-Technol 18(6):353-356. Krajewski J, Dobecki M, Gromiec J. 1980. Retention of vinyl chloride in the human lung. Br J Ind Med 37(4):373-374. Krost KJ, Pellizzari ED, Valburn SG, Hubbard SA. 1982. Collection and analysis of hazardous organic emissions. Anal Chen 54:610-817. Kucerova M, Polivkova Z, Batora J. 1979. Comparative evaluation of th frequency of chromosomal aberrations and the SCE numbers in peripheral lymphocytes of workers occupationally exposed to vinyl chloride monomer. Mutat Res 67:97-100. Lalb RJ, Bolt HM. 1977. Alkylation of RNA by vinyl chloride netabolit a In vitro and in vivo: Formation of l-N-6-ethenoadenosine. Toxicology 8:185-195. Laib RJ, Barbln A, Bartsch H. 1984. Evidence that vinyl chloride alters the fidelity of replication: Studies with ehloroethylene oxide treated poly(dG-dC). Naunyn-Schmied Arch Pharmacol 325(suppl): R17. Laib RJ, Doeijer G, Bolt HM. 1985. Detection of N2, N-3-ethenoguanine in liver-DNA hydrolysates of young rats and after exposure of the animals to (14C) vinyl chloride. J Cancer Res Clin Oncol 109(2):A7. * Lee CC, Bhandarl JC, Vinston JM, et al. 1977a. Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ Health Perspect 21:25-32. ucc 107938 94 Section 10 Lee FI, Harry DS, Adana WG, Litchfield M. 1977b, Screening for liver disease in vinyl chloride workers, hr J Ind Med 34:142-147. Lee CC, Bhandari JC, Winston JM, House VB, Dixon RL, Woods JS. 1978. Carcinogenicity of vinyl chloride and vinylidene chloride. J Toxicol Environ Health 4:15-30. 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. Lilis R, Anderson H, Nicholson WJ, Daum S, Fischbein AS, Selikoff IJ. 1975. Prevalence of disease among vinyl chloride and polyvinyl chloride workers. Ann NY Acad Sci 246:22-41. 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. Lyman WJ, Reehl WF, Rosenblatt DH. 1982. Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw Hill Book Co., New York, N.Y., pp. 4-9. Makarov IA. 1984. Sexual disorders in male workers occupationally exposed to methyl-methacrylate vinyl chloride. (Trans: 1-11) Gig Tr Prof Zabol 6:19-23. Makarov IA, Solovyeva MS, Gnelitsky GI. 1984. On sexual disorders in women chronically exposed to methylmethacrylate and vinyl chloride. Gig Tr Prof Zabol 3:22-27 (Trans.) Maltoni C, Lefemine G. 1975. Carcinogenicity bioassays of vinyl chloride. Current results. Ann NY Acad Sci 246:195-218. Maltoni C. 1977. Recent findings on the carcinogenicity of chlorinated olefins. Environ Health Perspect 21:15. * 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 Chlm), 20th, Meeting Date 1979, pp. 11-112. Publ Easent, Paris, France. * Maltoni C, Lefemine G, CilibertI A, et al. 1981. Carcinogenicity bloassays of vinyl chloride monomer: A model of risk assessment on an experimental basis. Environ Health Perspect 41:329. Maltoni G, Cottl, Valglmlgll L, Mandrloll A. 1983. Suitable models for long-term bioassays of the therapeutic and toxic effects of antlblastlc drugs: Liver angiosarcomas produced in Sprague-Davley rats by vinyl chloride.* Dev Oncol 15:339-341. UCC 107939 References 95 Harkovitz SS, McDonald CJ, Fethiere V, Kerzner MS. 1972. Occupational acroosteolysls. Arch Darn 106:219-223. Marateller HJ, Laibach UK, Muller R, Gedigk P. 1975. Unusual splenomegallc liver disease as evidenced by peritoneoscopy and guided liver biopsy among polyvinyl chloride production workers. Ann NY Acad Sci 95-134. Mastromatteo E, Fisher AM, Christie H, Danziger H. 1960. Acute inhalation toxicity of vinyl chloride to laboratory animals. Am Ind Hyg Assoc J, pp. 394-398. MCA (Manufacturing Chemists Association). 1980. Letter regarding the study and report of effects of vinyl chloride. FYI-OTS-0480-0065 (cit d in EPA 1985b). McCann J, Simmon V, Streitvieser D, Ames BN. 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 USA 72(8):3190-3193. McMurry JR, Tarr J. 1978. Vinyl chloride in Texas' ambient air. Proc Ann Tech Meet - Inst Environ Sci, pp. 149-155. Micu D, Mihailescu E, Vilau C, Tarpa A, Chircu V, Zgoanta C. 1985. The value of some cytoenzymochemical 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(2):115-120. Miller JJ, Beizer MB. 1985. Air quality in residences adjacent to an active hazardous waste disposal site. APCA Annual Meeting, June 16-21, pp. 2-17. Mirkova E, Mihailova A, Nosko M. 1978. Embryotoxic and teratogenic effects in vinyl chloride. (Trans: 1-6) Khig Zdraveopaz 21(5):440-443. (In Bulgarian: English translation). Monson RR, Peters JM, Johnson MN. 1975. Proportional mortality among vinyl chloride workers. Environ Health Perspect 11:75-77. Muller G, Norpoth K, Wickrama-Singhe RH. 1979. An analytical method using GC-MS for the quantitative determination of urinary thiodiglycolic acid. Int Arch Occup Environ Health 44:185-191. Nicholson WJ, Hammond EC, Seidman H, Selikoff IJ. 1975. Mortality experience of a cohort of vinyl chloride-polyvinyl chloride workers. Ann NY Acad Sci 246:225-230. NIOSH (National Institute for Occupational Safety and Health). 1975. Recommended Standard__ Occupational Exposure to Vinyl Chloride. NTIS PB-246-691 (cited in EPA 1985b). UCC 107940 96 Section 10 NIOSH (National Institute for Occupati nal Saf ty and Health). 1984. NIOSH Manual f Analytical M thods. 3rd ed. Vol. 2. Vinyl chloride in air. Method No. 1007, Washington, D.C.: U.S. Government Printing Office, pp. 1007-1 to 1007-4. NTIS (National Technical Information Service). 1987. Federal Research in Progress. Online: September 28, 1987. OSHA (Occupational Safety and Health Administration). 1983. OSHA Safety and Health Standards. 29 CFR 1910.1017, pp. 670-671. Oster RH, Carr CJ, Krantz JC. 1947. Anesthesia XXVII. Narcosis with vinyl chloride. Anesthesiology 8:359-361. Qsterman-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. Page GW. 1981. Comparison of groundwater and surface water for patterns and levels of contamination by toxic substances. Environ Sci Technol 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. Pubici Health Rep 45:1963-1971. Pellizzari ED, Erickson MD, Zweidinger RA. 1979. Formulation of preliminary assessment of halogenated organic compounds in man and environmental media. Research Triangle Park, NC: Environmental Protection Agency. EPA/560/13-79-006. Perticoni GF, Abbritti G, Cantisani TA, Bond L, Mauro L. 1986. Polineuropathy in workers with long exposure to vinyl chloride. Electro-physiological study. Electromyogr Clin Neurophysiol 26(l):41-47. Poncelet F, de Meester C, Duverger-van Bogaert M, et al. 1980. Influence of experimental factors on the mutagenicity of vinylic monomers. Arch Toxicol Suppl 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. Preston BJ, Jones KL, Grainger RG. 1976. Clinical aspects of vinyl chloride disease. Proc Soc Med 69:284-306. Purchase IFH, Richardson CR, Anderson D. 1975. Chromosomal and dominant lethal effects of vinyl chloride. Lancet 410-411. Purchase IF, Richardson CR, Anderson D, et al. 1978. Chromosomal analysis in vinyl chloride exposed workers. Mutat Res 57:325-334 (cited in Anderson et al. 1980). UCC 107941 .References 97 Radike MJ, Varkany J, Steamer K, et al. 1988. Perinatal carcinogenesis induced by inhaled vinyl chloride. Toxicologist 8(1):166. 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, Johansson A, Ramel C, tfachtmelster CA. 1974. The mutagenicity of vinyl chloride after metabolic activation. Ambio 3:194-197 Rannug U, Gothe R, Vachtmelster CA. 1976. The mutagenicity of chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable metabolites of vinyl chloride. Chem Biol Interact 12:251-263. Rasmussen RA, Harsch DE, Sveany PH, Krasnec JP, Cronn DR. 1977. Determination of atmospheric halocarbons by a temperature-programmed gas chromatographic freeze-out concentration method. J Air Pollut Control Assoc 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, Moslen MT, Szabo S, et al. 1975. Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene. Am J Pathol 81:219-231. Sabadle N, Malavellle C, Camus AH, Bartsch H. 1980. Comparison of the hydroxylation of benzo(a)pyrene with the metabolism of vinyl chloride, n-nitrosonorpholine, and n-nitroso-n'methylplperazine to mutagens by human and rat liver microsomal fractions. Cancer Res 409(1):119-126, Sabljic A. 1984. Prediction of the nature and strength of soil sorption of organic pollutants by molecular topology. J Agric Food Chem 32:243246. Sakabe H. 1975. Bone lesions among polyvinyl chloride production v rkers in Japan. Ann NY Acad Sci 246:78. Sal'nikova LS, Kitsovskaya 1A. 1980. Effect of vinyl chloride on embryogenesls of rats. (Trans: 1-7) Gig Tr Prof Zabol (3):46-47. Salkind AJ, Pearlman E. 1978. Batteries, secondary (alkaline cells). In Kirk-Othmer Encyclopedia of Chemical Technology. Vol. 3. New York, N.Y.: John Wiley & Sons, p. 605. SANSS (Structure and Nomenclature Search System). 1987. Chemical Information Systems. Online: September 1987. Sax NI, Ed. 1984. Dangerous Properties of Industrial Materials. 6th ed. New York: Van Nostrand Reinhold Co., p. 2728. UCC 107942 98 Section 10 Sax Nl, Levis RJ, eds. 1987. Hawley's Condensed Chemical Dieti nary. 11th ed. New York: Van N strand Reinhold Co., p. 1223. Shahin MM. 1976. The nonmutagenielty and recombinogenicity of vinyl chloride in the absence of metabolic activation. Mutat Res 40:269*272. Shu P, et al. 1986. Study on excretine regularity of thiodiglycolic acid in urine of vinyl chloride-exposed workers. Chin J Prev Med 20(2):87-89. Simmon VP, Kauhanen K, Tardlff 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. Elsevier/North Holland Biomedical Press, Amsterdam, pp. 249-258. Singley JE. 1984. Vater (Municipal Treatment). In Kirk-Othmer Encyclopedia of Chemical Technology Vol. 24:387. Sittig M. 1985. Handbook of Toxic and Hazardous Chemicals and Carcinogens. 2nd ed. Park Ridge, N.J.: Noyes Publications, pp. 918-921. Smith LR, Dragun J. 1984. Degradation of volatile chlorinated aliphatic priority pollutants in groundwater. Environ Int 10(4):291-298. SRI. 1988. 1988 Directory of Chemical Producers. SRI International, Menlo Park, Calif., p. 1049. Stallones RA. 1987. The use and abuse of subgroup analysis in epidemiological research. Prev Med 16:183*194. Stephens RD, Ball NB, Mar DM. 1986. A multimedia study of hazardous waste landfill gas migration. In Pollutants in a Multimedia Environment. Y Cohen, ed. New York, N.Y.: Plenum Press, pp. 265*287. Stuart JD. 1983. Organics transported thru selected geological media: Assessment of organics transported away from industrial waste disposal sites. Comm Unlv Storrs Inst of Hater Resources. NTIS PB83-224246, pp. 1-10. Styles JA. 1977. A method for detecting carcinogenic organic chemicals using mammalian cells in culture. Br J Cancer 36(5):558-563 (cited in EFA 198ba). Suzuki Y. 1978. Pulmonary tumors induced in mice by vinyl chloride monomer. Environ Res 16:285*301. Suzuki Y. 1981. Neoplastic and nonneoplastic effects of vinyl chloride in mouse lung. Environ Health Perspect 41:31-52. Suzuki Y. 1983. Noimeoplastlc effect of vinyl chloride in mouse lung-lower doses and short-term exposure. Environ Res 32:91-103. UCC 107943 References 99 Tabershaw IR, Gaffey WR. 1974. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J Occup Med 16(8):509-518. Tamburro CH. 1984. Relationship of vinyl monomers and liver cancers: angiosarcoma and hepatocellular carcinoma. Semin Liver Dis, May 1984. 4(2):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. Theriault G, Iturra H, Gingras S. 1983. Evaluation of the association between birth defects and exposure to ambient vinyl chloride. Teratology 27:359-370. The Vinyl Institute. 1987. Potential effects of vinyl chloride on human offspring. Unpublished study. Medical Subcommittee of the Technical Committee, Wayne, N.J. * Til HP, Immel HR, Feron VJ. 1983. Lifespan oral carcinogenicity study of vinyl chloride in rats. Final report. Civo Institutes, TOO. Report No. V 93.285/291099 (cited in EPA 1985a, 1987a). Torkelson TR, Oygen F, Rowe VK. 1961. The toxicity of vinyl chloride as determined by repeated exposure of laboratory animals. Am Ind Hyg Ass c J 22:354-361. Umana M, Warner M, Sheldon LS. 1985. Methods for sampling and analysis of breath. EPA/600/8-85/019 and NTIS PB85-243277. Ungvary G, Hudak A, Tatrai E, Lorincz M, Folly G. 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(1):45-54. USITC (United States International Trade Commission). 1987. Synthetic Organic Chemicals: United States Production and Sales, 1986. USITC Publication 2009. Washington, D.C., p. 212. 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 Toxic 23(1):23-31. Verburgt FG, Vogel E. 1977. Vinyl chloride mutagenesis in Drosophila melanogaster. Mutat Res 48:327-336. UCC 107944 100 Section 10 Verschu ren K. 1983. Handbook of Environmental Data on Organic Chemicals, 2nd ed. New York, N.Y.: Van Nostrand Reinhold Company, pp. 1185-1186. View data base. 1989. Agency for Toxic Substances and Disease Registry (ATSDR). Atlanta, Ga.: Office of External Affairs, Exposure and Disease Registry Branch, February 1989. Viola PL, Bigotti A, Caputo A. 1971. Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31:516-522 (cited in EPA 1985b). Wakeham ZB, Johnson HR. 1978. Vinyl chloride formation from the thermal degradation of poly(vlnyl chloride). Polymer Eng Sci 18(5):404-407. Wallace LA, Pelllzzari 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. Wang T, Lenahan R, Kanlk M. 1985. Impact of trichloroethylenecontaminated groundwater discharged to the main canal and Indian River Lagoon, Vero Beach, Florida. Bull Environ Contam Toxicol 34:578-586. Ward AH, Undoon S, Watkins J, Walker AE, Drake CS. 1976. Evidence of an immune complex disorder in vinyl chloride workers. Proc R Soc Med 69:289-290. Watanabe FG, 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 [^C] vinyl chloride after single oral administration. Toxicol Appl Pharmacol 36(2):339-352. Watanabe PG, McGowan GR, Madrid EO, Gehring PJ. 1976b. Fate of [^C] vinyl chloride following inhalation exposure in rats. Toxicol Appl Pharmacol 37:49-59. Watanabe PG, Zempel JA, Pegg DG, Gehring PJ. 1978a. Hepatic macromoleeular binding following exposure to vinyl chloride. Toxicol Appl Pharmacol 44(3):571-579. Watanabe FG, Zempel JA, Gebring PJ. 1978b. Comparison of the fate of vinyl chloride following single and repeated exposure in rata. Toxic Appl Pharmacol 44:391-399. Waxweiler RJ, Stringer W, Wagner JR, Jones J, Falk H, Carter C. 1976. Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Scl 271:40-48. UCC 107945 References 101 Waxweiler RJ, Falk H, McMlchael A, Mallov JS, Grivas AS. 1977. A crosssectional epidemiologic survey of vinyl chloride workers. NTIS PB274193. Westrick JJ, Hello JW, Thomas RF. 1984. The groundwater supply survey. J Am Water Works Assoc 76:52-59. Wilson JT, Wilson BH. 1985. Biotransformation of trichloroethylene in soil. Appl Environ Microbiol 49:242-243. Wilson RH, McCormick WE, Tatum CF, Creech JL. 1967. Occupational acroosteolysis report of 31 cases. JAMA 201:577-580. Withey JR. 1976. Pharmacodynamics and uptake of vinyl chloride monomer administered by various routes to rats. J Toxicol Environ Health 1:381-394. Wong 0, Whorton MD, Ragland D, et al. 1986. An update of an epidemiologic study of vinyl chloride workers. Prepared by Environmental Health Associates, Inc. or Chemical Manufacturers Association. 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. American Society for Testing and Materials, Philadelphia, Pa., pp. 24-41. Zuccato E, Mancuccl F, Fanelli R and Mussini E. 1979. Head-space gaschromatographic analysis of vinyl chloride monomer in rat blood and tissues. Xenobiotica 9:27-31. UCC 107946 Preceding page blank 103 11. GLOSSARY Acute Exposure--Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Bloconcentration 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 time period. Carcinogen--A chemical capable of inducing cancer. Ceiling value (CL)--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. Embryotoxlclty and Fetotoxlelty--Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing featur 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. Frank Effect Level (PEL)--That level of exposure which produces a statistically or biologically significant increase in frequency or severity of unmistakable adverse effects, such as irreversible functional Impairment or mortality, in an exposed population when compared with its appropriate control. 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 (IDLE)--The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. UCC 107947 104 Section 11 Intermediate Exposure-'Exposure to s chemical for a duration of 15-364 days, as specified in the Toxicological Profiles. Immun logic 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. Key Study--An animal or human toxicological study that best illustrates the nature of the adverse effects produced and the doses associated with those effects. Lethal Concentratlon(LO) (LCLO)--The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration(50) (LCso)--A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. Lethal Dose(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(50) (LD50)--The dose of a chemical which has been calculated 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 which produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Lowest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a study or group of studies which produces statistically or biologically significant Increases in frequency or severity of 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 expoaure to a chemical that is likely to be without an appreciable risk of deleterious effects (noneancerous) 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. 107948 Glossary 105 Neurotoxicity--The ccurrence of adverse effects on the nervous system following exposure to a chemical. No-Observed-Adverse-Effect Level (NOAZL)--That dose of chemical at which there are 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. No-Observed-Effect Level (NOEL)--That dose of chemical at which there are no statistically or biologically significant increases in frequency or severity of effects seen between the exposed population and its appropriate control. Permissible Exposure Limit (PEL)--An allowable exposure level in workplace air averaged over an 8-h shift. q.*--The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q^* can be used to calculate an estimate of carcinogenic potency, the incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and pg/w? 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 lb or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are measured over a 24-h period. Reproductive Toxicity--The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system* The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Short-Term Exposure Limit (STEL)--The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TUA may not be exceeded. UCC 107949 106 Section 11 Target Organ T xicity--This ter* cov re a broad range f adverse effects on target organs or physiological systems (e.g.f renal, cardiovascular) extending from th se arising through a single limited exposure to th se 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 (TVA)--An allowable exposure concentration averaged over a normal 8-h workday or 40-h workweek. Uncertainty Factor (UP)*-A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of humans, (3) the uncertainty in extrapolating from data obtained In a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors Is set equal to 10. UCC 107950 107 APPENDIX: PEER REVIEW A peer review panel was assembled for vinyl chloride. The panel consisted of the following members: Dr. Richard Honson, Harvard University, and Dr. Anthony Guarino, South Alabama University. 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 the Superfund Amendments and Reauthorization Act of 1986, Section 110. A joint panel of scientists from ATSDR and EPA has 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 their approval of the profile's final content. The responsibility for the content of this profile lies with the Agency for Toxic Substances and Disease Registry. UCC 107951