TOXICOLOGICAL PROFILE FOR 
 

VINYL CHLORIDE 
 


 


 


 


 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES 
 

Public Health Service 
 

Agency for Toxic Substances and Disease Registry
 

July 2006 
VINYL CHLORIDE ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and does not imply endorsement by the 

Agency for Toxic Substances and Disease Registry. 
VINYL CHLORIDE iii 

UPDATE STATEMENT 
 

A Toxicological Profile for Vinyl Chloride, Draft for Public Comment was released in 2004. This edition 

supersedes any previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry
 

Division of Toxicology and Environmental Medicine/Applied Toxicology Branch 
 

1600 Clifton Road NE 
 

Mailstop F-32 
 

Atlanta, Georgia 30333 
 
VINYL CHLORIDE iv 

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v 

FOREWORD 
 

This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic 

Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The 

original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised 

and republished as necessary. 

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects 

information for the hazardous substance described therein. Each peer-reviewed profile identifies and 

reviews the key literature that describes a hazardous substance’s toxicologic properties. Other pertinent 

literature is also presented, but is described in less detail than the key studies. The profile is not intended 

to be an exhaustive document; however, more comprehensive sources of specialty information are 

referenced. 

The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile 

begins with a public health statement that describes, in nontechnical language, a substance’s relevant 

toxicological properties. Following the public health statement is information concerning levels of 

significant human exposure and, where known, significant health effects. The adequacy of information to 

determine a substance’s health effects is described in a health effects summary. Data needs that are of 

significance to protection of public health are identified by ATSDR and EPA. 

Each profile includes the following: 

(A) The examination, summary, and interpretation of available toxicologic information and 

epidemiologic evaluations on a hazardous substance to ascertain the levels of significant human 

exposure for the substance and the associated acute, subacute, and chronic health effects; 

(B) A determination of whether adequate information on the health effects of each substance 

is available or in the process of development to determine levels of exposure that present a 

significant risk to human health of acute, subacute, and chronic health effects; and 

(C) Where appropriate, identification of toxicologic testing needed to identify the types or 

levels of exposure that may present significant risk of adverse health effects in humans. 

The principal audiences for the toxicological profiles are health professionals at the Federal, State, and 

local levels; interested private sector organizations and groups; and members of the public. 

This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been 

peer-reviewed. Staff of the Centers for Disease Control and Prevention and other Federal scientists have 

also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel 

and was made available for public review. Final responsibility for the contents and views expressed in 

this toxicological profile resides with ATSDR. 
vi 

*Legislative Background 

The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization 

Act (SARA) of 1986 (Public Law 99 499) which amended the Comprehensive Environmental Response, 

Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to 

prepare toxicological profiles for hazardous substances most commonly found at facilities on the 

CERCLA National Priorities List and that pose the most significant potential threat to human health, as 

determined by ATSDR and the EPA. The availability of the revised priority list of 275 hazardous 

substances was announced in the Federal Register on December 7, 2005 (70 FR 72840). For prior 

versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); 

October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17,1990 (55 FR 42067); 

October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); February 28, 1994 (59 FR 9486); 

April 29, 1996 (61 FR 18744); November 17, 1997 (62 FR 61332); October 21, 1999 (64 FR 56792); 

October 25, 2001 (66 FR 54014), and November 7, 2003 (68 FR 63098). Section 104(i)(3) of CERCLA, 

as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on 

the list. 
VINYL CHLORIDE vii 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children? 
 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)? 
 

Section 3.7 Children’s Susceptibility 
 

Section 6.6 Exposures of Children 
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-888-42-ATSDR or (404) 498-0110 Fax: (770) 488-4178 

E-mail: atsdric@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 
VINYL CHLORIDE viii 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, 

Elk Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 
VINYL CHLORIDE ix 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

G. Daniel Todd, Ph.D. 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA 

Obaid M. Faroon, Ph.D., D.V.M. 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA 

Dennis E. Jones, D.V.M. 

ATSDR, Division of Toxicology and Environmental Medicine, Atlanta, GA 

Michael H. Lumpkin, Ph.D. 

Syracuse Research Corporation, Atlanta, GA 

Julie Stickney, Ph.D. 

Syracuse Research Corporation, North Syracuse, NY 

Mario J. Citra, Ph.D. 

Syracuse Research Corporation, North Syracuse, NY 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1. Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3. Data Needs Review. The Research Implementation Branch reviews data needs sections to assure 

consistency across profiles and adherence to instructions in the Guidance. 

4. Green Border Review. Green Border review assures the consistency with ATSDR policy. 
VINYL CHLORIDE x 

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VINYL CHLORIDE xi 

PEER REVIEW 
 

A peer review panel was assembled for the pre-public comment vinyl chloride. The panel consisted of 

the following members: 

1.	 Finis L. Cavender, Ph.D., Consultant in Toxicology, Henderson, North Carolina; 

2. 	 Sam Kacew, Ph.D., Professor, Department of Cellular and Molecular Medicine, University of 

Ottawa, Ottawa, Ontario; and 

3.	 Andrew G. Salmon, Ph.D., Senior Toxicologist and Chief, Air Toxicology and Risk Assessment 

Unit, California Environmental Protection Agency, Lafayette, California. 

These experts collectively have knowledge of vinyl chloride's physical and chemical properties, 

toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and 

quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer 

review specified in Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, 

and Liability Act, as amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 
VINYL CHLORIDE xii 

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VINYL CHLORIDE xiii 

CONTENTS 
 

DISCLAIMER ..............................................................................................................................................ii 
 

UPDATE STATEMENT .............................................................................................................................iii 
 

FOREWORD ................................................................................................................................................v 
 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS....................................................................vii 
 

CONTRIBUTORS.......................................................................................................................................ix 
 

PEER REVIEW ...........................................................................................................................................xi 
 

CONTENTS...............................................................................................................................................xiii 
 

LIST OF FIGURES ..................................................................................................................................xvii 
 

LIST OF TABLES.....................................................................................................................................xix 
 

1. PUBLIC HEALTH STATEMENT..........................................................................................................1 
 

1.1 WHAT IS VINYL CHLORIDE?.....................................................................................................2 
 

1.2 WHAT HAPPENS TO VINYL CHLORIDE WHEN IT ENTERS THE ENVIRONMENT? .......2 
 

1.3 HOW MIGHT I BE EXPOSED TO VINYL CHLORIDE?............................................................3 
 

1.4 HOW CAN VINYL CHLORIDE ENTER AND LEAVE MY BODY?.........................................4 
 

1.5 	 HOW CAN VINYL CHLORIDE AFFECT MY HEALTH? ..........................................................5 
 

1.6 	 HOW CAN VINYL CHLORIDE AFFECT CHILDREN? .............................................................7 
 

1.7 	 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO VINYL CHLORIDE? .........7 
 

1.8 	 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 
 

VINYL CHLORIDE? ......................................................................................................................8 
 

1.9 	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 
 

PROTECT HUMAN HEALTH?.....................................................................................................9 
 

1.10 WHERE CAN I GET MORE INFORMATION?..........................................................................10 
 

2. RELEVANCE TO PUBLIC HEALTH .................................................................................................13 
 

2.1 	 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO VINYL CHLORIDE IN THE 
 

UNITED STATES.........................................................................................................................13 
 

2.2 	 SUMMARY OF HEALTH EFFECTS ..........................................................................................14 
 

2.3 	 MINIMAL RISK LEVELS (MRLs)..............................................................................................19 
 

3. HEALTH EFFECTS..............................................................................................................................25 
 

3.1 INTRODUCTION .........................................................................................................................25 
 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE.......................................25 
 

3.2.1 Inhalation Exposure ..............................................................................................................27 
 

3.2.1.1 Death ............................................................................................................................27 
 

3.2.1.2 Systemic Effects...........................................................................................................28 
 

3.2.1.3 Immunological and Lymphoreticular Effects...............................................................59 
 

3.2.1.4 Neurological Effects.....................................................................................................61 
 

3.2.1.5 Reproductive Effects....................................................................................................63 
 

3.2.1.6 Developmental Effects .................................................................................................65 
 

3.2.1.7 Cancer...........................................................................................................................69 
 

3.2.2 Oral Exposure........................................................................................................................76 
 

3.2.2.1 Death ............................................................................................................................76 
 

3.2.2.2 Systemic Effects...........................................................................................................77 
 

3.2.2.3 Immunological and Lymphoreticular Effects...............................................................82 
 

3.2.2.4 Neurological Effects.....................................................................................................82 
 

3.2.2.5 Reproductive Effects....................................................................................................82 
 
VINYL CHLORIDE xiv 

3.2.2.6 Developmental Effects .................................................................................................82 
 

3.2.2.7 Cancer...........................................................................................................................82 
 

3.2.3 Dermal Exposure...................................................................................................................84 
 

3.2.3.1 Death ............................................................................................................................84 
 

3.2.3.2 Systemic Effects...........................................................................................................85 
 

3.2.3.3 Immunological and Lymphoreticular Effects...............................................................85 
 

3.2.3.4 Neurological Effects.....................................................................................................85 
 

3.2.3.5 Reproductive Effects....................................................................................................86 
 

3.2.3.6 Developmental Effects .................................................................................................86 
 

3.2.3.7 Cancer...........................................................................................................................86 
 

3.3 GENOTOXICITY .........................................................................................................................86 
 

3.4 TOXICOKINETICS ......................................................................................................................97 
 

3.4.1 Absorption.............................................................................................................................99 
 

3.4.1.1 Inhalation Exposure......................................................................................................99 
 

3.4.1.2 Oral Exposure.............................................................................................................100 
 

3.4.1.3 Dermal Exposure ........................................................................................................100 
 

3.4.2 Distribution .........................................................................................................................101 
 

3.4.2.1 Inhalation Exposure....................................................................................................101 
 

3.4.2.2 Oral Exposure.............................................................................................................103 
 

3.4.2.3 Dermal Exposure ........................................................................................................103 
 

3.4.3 Metabolism..........................................................................................................................104 
 

3.4.3.1 Inhalation Exposure....................................................................................................104 
 

3.4.3.2 Oral Exposure.............................................................................................................106 
 

3.4.3.3 Dermal Exposure ........................................................................................................106 
 

3.4.4 Elimination and Excretion...................................................................................................107 
 

3.4.4.1 Inhalation Exposure....................................................................................................107 
 

3.4.4.2 Oral Exposure.............................................................................................................108 
 

3.4.4.3 Dermal Exposure ........................................................................................................109 
 

3.4.4.4 Other Routes of Exposure ..........................................................................................109 
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models ...........110 
 

3.5 MECHANISMS OF ACTION.....................................................................................................117 
 

3.5.1 Pharmacokinetic Mechanisms............................................................................................. 117 
 

3.5.2 Mechanisms of Toxicity......................................................................................................118 
 

3.5.3 Animal-to-Human Extrapolations.......................................................................................120 
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ............................121 
 

3.7 CHILDREN’S SUSCEPTIBILITY .............................................................................................124 
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT.......................................................................128 
 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Vinyl Chloride...............................129 
 

3.8.2 Biomarkers Used to Characterize Effects Caused by Vinyl Chloride.................................132 
 

3.9 INTERACTIONS WITH OTHER CHEMICALS.......................................................................134 
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ................................................. 136 
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS..................................................................... 138 
 

3.11.1 Reducing Peak Absorption Following Exposure ............................................................138 
 

3.11.2 Reducing Body Burden...................................................................................................139 
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects .........................................140 
 

3.12 ADEQUACY OF THE DATABASE..........................................................................................142 
 

3.12.1 Existing Information on Adverse Health Effects of Vinyl Chloride...............................142 
 

3.12.2 Identification of Data Needs ...........................................................................................144 
 

3.12.3 Ongoing Studies..............................................................................................................156 
 
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4. CHEMICAL AND PHYSICAL INFORMATION..............................................................................159 
 

4.1 CHEMICAL IDENTITY.............................................................................................................159 
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES..........................................................................159 
 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL..........................................................163 
 

5.1 PRODUCTION............................................................................................................................163 
 

5.2 IMPORT/EXPORT......................................................................................................................163 
 

5.3 USE..............................................................................................................................................166 
 

5.4 DISPOSAL ..................................................................................................................................166 
 

6. POTENTIAL FOR HUMAN EXPOSURE .........................................................................................169 
 

6.1 OVERVIEW ................................................................................................................................169 
 

6.2 RELEASES TO THE ENVIRONMENT ....................................................................................172 
 

6.2.1 Air .......................................................................................................................................172 
 

6.2.2 Water...................................................................................................................................174 
 

6.2.3 Soil ......................................................................................................................................174 
 

6.3 ENVIRONMENTAL FATE........................................................................................................177 
 

6.3.1 Transport and Partitioning...................................................................................................177 
 

6.3.2 Transformation and Degradation ........................................................................................178 
 

6.3.2.1 Air...............................................................................................................................178 
 

6.3.2.2 Water ..........................................................................................................................179 
 

6.3.2.3 Sediment and Soil.......................................................................................................180 
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ...................................181 
 

6.4.1 Air .......................................................................................................................................181 
 

6.4.2 Water...................................................................................................................................184 
 

6.4.3 Sediment and Soil ...............................................................................................................184 
 

6.4.4 Other Environmental Media................................................................................................185 
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE..........................................189 
 

6.6 EXPOSURES OF CHILDREN ...................................................................................................192 
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES................................................193 
 

6.8 ADEQUACY OF THE DATABASE..........................................................................................193 
 

6.8.1 Identification of Data Needs ...............................................................................................194 
 

6.8.2 Ongoing Studies ..................................................................................................................196 
 

7. ANALYTICAL METHODS ...............................................................................................................197 
 

7.1 BIOLOGICAL MATERIALS .....................................................................................................197 
 

7.2 ENVIRONMENTAL SAMPLES................................................................................................199 
 

7.3 ADEQUACY OF THE DATABASE..........................................................................................204 
 

7.3.1 Identification of Data Needs ...............................................................................................205 
 

7.3.2 Ongoing Studies ..................................................................................................................206 
 

8. REGULATIONS AND ADVISORIES ...............................................................................................207 
 

9. REFERENCES ....................................................................................................................................211 
 

10. GLOSSARY ......................................................................................................................................267 
 
VINYL CHLORIDE xvi 

APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1 
 

B. USER'S GUIDE ..................................................................................................................................B-1 
 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS......................................................................C-1 
 

D. INDEX ................................................................................................................................................D-1 
 
VINYL CHLORIDE xvii 

LIST OF FIGURES 
 

3-1. Levels of Significant Exposure to Vinyl Chloride—Inhalation ......................................................... 44 
 

3-2. Levels of Significant Exposure to Vinyl Chloride—Oral .................................................................. 81
 

3-3. Proposed Metabolic Pathways for Vinyl Chloride .............................................................................98 
 

3-4. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a 
 

Hypothetical Chemical Substance....................................................................................................112 
 

3-5. Existing Information on Health Effects of Vinyl Chloride...............................................................143 
 

6-1. Frequency of NPL Sites with Vinyl Chloride Contamination..........................................................170 
 
VINYL CHLORIDE xviii 

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VINYL CHLORIDE xix 

LIST OF TABLES 
 

3-1. Levels of Significant Exposure to Vinyl Chloride—Inhalation ......................................................... 29 
 

3-2. Levels of Significant Exposure to Vinyl Chloride—Oral .................................................................. 78
 

3-3. Genotoxicity of Vinyl Chloride In Vivo .............................................................................................87 
 

3-4. Genotoxicity of Vinyl Chloride In Vitro ............................................................................................89 
 

3-5. Vinyl Chloride Partition Coefficients...............................................................................................102 
 

3-6. Physiological Parameters Used to Estimate Parameters from Vinyl Chloride Gas Uptake
 

Experiments......................................................................................................................................114 
 

3-7. Estimates of Metabolic Parameters Obtained from Gas Uptake Experiments .................................115 
 

4-1. Chemical Identity of Vinyl Chloride ................................................................................................160 
 

4-2. Physical and Chemical Properties of Vinyl Chloride .......................................................................161 
 

5-1. Facilities that Produce, Process, or Use Vinyl Chloride...................................................................164 
 

5-2. U.S. Production Capacity of Vinyl Chloride ....................................................................................165 
 

6-1. Releases to the Environment from Facilities that Produce, Process, or Use Vinyl Chloride ...........173 
 

6-2. Emissions of Vinyl Chloride Organized by State in 1996................................................................175 
 

6-3. Vinyl Chloride Levels in Ambient Urban Air ..................................................................................183 
 

6-4. Residual Vinyl Chloride Monomer in Food and Nonfood Packaging Items from Store 
 

Shelves .............................................................................................................................................186 
 

6-5. Residual Vinyl Chloride Monomer in Food Products......................................................................187 
 

6-6. Vinyl Chloride Levels in Five Polyvinyl Chloride Manufacturing Facilities Located in 
 

Taiwan..............................................................................................................................................190 
 

6-7. Time-Weighted Average Exposure to Workers in Polyvinyl Chloride Manufacturing Facilities 
 

Located in Taiwan............................................................................................................................191 
 

7-1. Analytical Methods for Determining Vinyl Chloride in Biological Samples...................................198 
 

7-2. Analytical Methods for Determining Vinyl Chloride in Environmental Samples............................200 
 

8-1. Regulations and Guidelines Applicable to Vinyl Chloride ..............................................................208 
 
VINYL CHLORIDE xx 

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VINYL CHLORIDE 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about vinyl chloride and the effects of exposure to it. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in 

the nation. These sites are then placed on the National Priorities List (NPL) and are targeted for 

long-term federal clean-up activities. Vinyl chloride has been found in at least 616 of the 

1,662 current or former NPL sites. Although the total number of NPL sites evaluated for this 

substance is not known, the possibility exists that the number of sites at which vinyl chloride is 

found could increase in the future as more sites are evaluated. This information is important 

because these sites may be sources of exposure, and exposure to this substance can harm you. 

When a substance is released either from a large area, such as an industrial plant, or from a 

container, such as a drum or bottle, it enters the environment. Such a release does not always 

lead to exposure. You can be exposed to a substance only when you come in contact with it. 

You may be exposed by breathing, eating, or drinking the substance, or by skin contact. 

If you are exposed to vinyl chloride, many factors will determine whether you will be harmed. 

These factors include the dose (how much), the duration (how long), and how you come in 

contact with it. You must also consider any other chemicals you are exposed to and your age, 

sex, diet, family traits, lifestyle, and state of health. 
VINYL CHLORIDE 2 

1. PUBLIC HEALTH STATEMENT 

1.1 	 WHAT IS VINYL CHLORIDE? 

Vinyl chloride is known also as chloroethene, chloroethylene, ethylene monochloride, or 

monochloroethylene. At room temperature, it is a colorless gas, it burns easily, and it is not 

stable at high temperatures. Vinyl chloride exists in liquid form if kept under high pressure or at 

low temperatures. Vinyl chloride has a mild, sweet odor, which may become noticeable at 

3,000 parts vinyl chloride per million parts (ppm) of air. However, the odor is of little value in 

preventing excess exposure. Most people begin to taste vinyl chloride in water at 3.4 ppm. 

Vinyl chloride is a manufactured substance that does not occur naturally; however, it can be 

formed in the environment when other manufactured substances, such as trichloroethylene, 

trichloroethane, and tetrachloroethylene, are broken down by certain microorganisms. 

Production of vinyl chloride in the United States grew at an average rate of about 7% from the 

early 1980s to the early 1990s, with current growth at about 3% annually. Most of the vinyl 

chloride produced in the United States is used to make a polymer called polyvinyl chloride 

(PVC), which consists of long repeating units of vinyl chloride. PVC is used to make a variety 

of plastic products including pipes, wire and cable coatings, and packaging materials. Other uses 

include furniture and automobile upholstery, wall coverings, housewares, and automotive parts. 

At one time, vinyl chloride was used as a coolant, as a propellant in spray cans, and in some 

cosmetics. However, since the mid-1970s, vinyl chloride mostly has been used in the 

manufacture of PVC. Refer to Chapter 4 for more information about the chemical and physical 

properties of vinyl chloride. For more information about the production and use of vinyl 

chloride, see Chapter 5. 

1.2 	 WHAT HAPPENS TO VINYL CHLORIDE WHEN IT ENTERS THE 

ENVIRONMENT? 

Most of the vinyl chloride that enters the environment comes from vinyl chloride manufacturing 

or processing plants, which release it into the air or into waste water. EPA limits the amount that 

industries can release. Vinyl chloride also is a breakdown product of other synthetic chemicals. 

Vinyl chloride has entered the environment at hazardous waste sites as a result of improper 
VINYL CHLORIDE 3 

1. PUBLIC HEALTH STATEMENT 

disposal or leakage from storage containers or spills, but some may result from the breakdown of 

other chemicals. In addition, vinyl chloride has been found in tobacco smoke at very low levels. 

Liquid vinyl chloride evaporates easily. Vinyl chloride in water or soil evaporates rapidly if it is 

near the surface. Vinyl chloride in the air breaks down in a few days, resulting in the formation 

of several other chemicals including hydrochloric acid, formaldehyde, and carbon dioxide. 

Some vinyl chloride can dissolve in water. Vinyl chloride can migrate to groundwater and can 

be in groundwater due to the breakdown of other chemicals. Vinyl chloride is unlikely to build 

up in plants or animals that you might eat. For more information about what happens to vinyl 

chloride in the environment, see Chapter 6. 

1.3 HOW MIGHT I BE EXPOSED TO VINYL CHLORIDE? 

Because vinyl chloride usually exists in a gaseous state, you are most likely to be exposed to it 

by breathing it. Vinyl chloride is not normally found in urban, suburban, or rural air in amounts 

that are detectable by the usual methods of analysis. However, vinyl chloride has been found in 

the air near vinyl chloride manufacturing and processing plants, hazardous waste sites, and 

landfills. The amount of vinyl chloride in the air near these places ranges from trace amounts to 

over 1 ppm. Levels as high as 44 ppm were found in the air at some landfills. You can also be 

exposed to vinyl chloride in the air through tobacco smoke from cigarettes or cigars (both active 

smoking and second-hand smoke). Levels of vinyl chloride in tobacco smoke are very low, 

usually around 5–30 nanograms per cigarette (a nanogram is 0.000000001 gram). 

You can be exposed to vinyl chloride by drinking water from contaminated wells. Most drinking 

water supplies do not contain vinyl chloride. In a 1982 survey, vinyl chloride was found in 

fewer than 1% of the 945 groundwater supplies tested in the United States. The concentrations 

in groundwater were up to 0.008 ppm. Other studies have reported vinyl chloride in 

groundwater at concentrations at or below 0.38 ppm. At one time, the flow of water through 

PVC pipes added very low amounts of vinyl chloride to water. For example, in one study of 

newly installed pipes, the drinking water had 0.001 ppm of vinyl chloride. No current 
VINYL CHLORIDE 4 

1. PUBLIC HEALTH STATEMENT 

information is available about the amount of vinyl chloride released from PVC pipes into water. 

In the past, vinyl chloride could get into food stored in materials containing PVC, but the U.S. 

government now regulates the amount of vinyl chloride in food packaging materials. When less 

than about 1 ppm of vinyl chloride is trapped in PVC packaging, vinyl chloride in detectable 

amounts does not enter food by contact with these products. 

People who work at facilities that make vinyl chloride or PVC usually are exposed to higher 

levels than the general population. Work exposure occurs primarily from breathing air that 

contains vinyl chloride, but workers also are exposed when vinyl chloride contacts the skin or 

eyes. Based on studies using animals, it is possible that if vinyl chloride comes into contact with 

your skin or eyes, extremely small amounts could enter your body. 

Please refer to Chapter 6 for more information on ways that people are exposed to vinyl chloride. 

1.4 HOW CAN VINYL CHLORIDE ENTER AND LEAVE MY BODY? 

If vinyl chloride gas contacts your skin, tiny amounts may pass through the skin and enter your 

body. Vinyl chloride is more likely to enter your body when you breathe air or drink water 

containing it. This could occur near certain factories or hazardous waste sites or in the 

workplace. At low levels (<20 ppm), most of the vinyl chloride that you breathe or swallow 

enters your blood rapidly, then travels throughout your body. When some portion of it reaches 

your liver, your liver changes it into several substances. Most of these new substances also 

travel in your blood; once they reach your kidneys, they leave your body in your urine. Most of 

the vinyl chloride is gone from your body a day after you breathe or swallow it. The liver, 

however, makes some new substances that do not leave your body as rapidly. A few of these 

new substances are more harmful than vinyl chloride because they react with chemicals inside 

your body and interfere with the way your body normally uses or responds to these chemicals. 

Some of these substances react in the liver and, depending on how much vinyl chloride you 

breathe in, may produce damage there. Your body needs more time to get rid of these changed 

chemicals, but eventually removes them as well. If you breathe or swallow more vinyl chloride 
VINYL CHLORIDE 5 

1. PUBLIC HEALTH STATEMENT 

than your liver can chemically change, you will breathe out excess vinyl chloride. Chapter 3 

contains more information about how vinyl chloride enters and leaves your body. 

1.5 HOW CAN VINYL CHLORIDE AFFECT MY HEALTH? 

Scientists use many tests to protect the public from harmful effects of toxic chemicals and to find 

ways to treat people who have been harmed. 

One way to learn whether a chemical will harm people is to determine how the body absorbs, 

uses, and releases the chemical. For some chemicals, animal testing may be necessary. Animal 

testing may also help identify health effects, such as cancer or birth defects. Without laboratory 

animals, scientists would lose a basic method for getting information needed to make wise 

decisions that protect public health. Scientists have the responsibility to treat research animals 

with care and compassion. Scientists must comply with strict animal-care guidelines because 

laws today protect the welfare of research animals. 

If you breathe high levels of vinyl chloride, you will feel dizzy or sleepy. These effects occur 

within 5 minutes if you are exposed to about 10,000 ppm of vinyl chloride. You can easily smell 

vinyl chloride at this concentration. It has a mild, sweet odor. If you breathe still higher levels 

(25,000 ppm), you may pass out. You can rapidly recover from these effects if you breathe fresh 

air. Some people get a headache when they breathe fresh air immediately after breathing very 

high levels of vinyl chloride. People who breathe extremely high levels of vinyl chloride can 

die. Studies in animals show that extremely high levels of vinyl chloride can damage the liver, 

lungs, and kidneys. These levels also can damage the heart and prevent blood clotting. The 

effects of ingesting vinyl chloride are unknown. If you spill liquid vinyl chloride on your skin, it 

will numb the skin and produce redness and blisters. 

Some people who have breathed vinyl chloride for several years have changes in the structure of 

their livers. People are more likely to develop these changes if they breathe high levels of vinyl 

chloride. Some people who have worked with vinyl chloride have nerve damage, and others 

develop an immune reaction. The lowest levels that produce liver changes, nerve damage, and 
VINYL CHLORIDE 6 

1. PUBLIC HEALTH STATEMENT 

immune reaction in people are not known. Certain jobs related to PVC production expose 

workers to very high levels of vinyl chloride (i.e., pools of liquid vinyl chloride in vats or 

autoclaves). Some of these workers have problems with the blood flow in their hands. Their 

fingers turn white and hurt when they go into the cold and may take a long time to recover when 

they go into a warm place. In some of these people, changes have appeared on the skin of their 

hands and forearms. Also, bones at the tips of their fingers have broken down. Studies suggest 

that some people may be more sensitive to these effects than others. 

Some men who work with vinyl chloride have complained of a lack of sex drive. Studies in 

animals showed that long-term exposure can damage the sperm and testes. Some women who 

work with vinyl chloride have reported irregular menstrual periods. Some have developed high 

blood pressure during pregnancy. 

Results from several studies have suggested that breathing air or drinking water containing 

moderate levels (100 ppm) of vinyl chloride might increase their risk for cancer. However, the 

levels used in these studies were much higher than levels found in the ambient air and/or most 

drinking water supplies. Studies of workers who have breathed vinyl chloride over many years 

showed an increased risk for cancer of the liver. Brain cancer, lung cancer, and some cancers of 

the blood also may be connected with breathing vinyl chloride over long periods. Studies of 

long-term exposure in animals showed that cancer of the liver and mammary gland may increase 

at very low levels of vinyl chloride in the air (50 ppm). Lab animals fed low levels of vinyl 

chloride each day (2 mg/kg/day) during their lifetime had an increased risk of getting liver 

cancer. 

The U.S. Department of Health and Human Services has determined that vinyl chloride is a 

known carcinogen. The International Agency for Research on Cancer has determined that vinyl 

chloride is carcinogenic to people, and EPA has determined that vinyl chloride is a human 

carcinogen. 

More information about the adverse health effects of vinyl chloride in humans and animals can 

be found in Chapters 2 and 3. 
VINYL CHLORIDE 7 

1. PUBLIC HEALTH STATEMENT 

1.6 HOW CAN VINYL CHLORIDE AFFECT CHILDREN? 
 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

No studies are available that specifically address the effects of vinyl chloride in children. Studies 

of women who live near vinyl chloride manufacturing plants did not show that vinyl chloride 

produces birth defects. Studies using pregnant animals showed that breathing high levels of 

vinyl chloride (5,000 ppm) can harm unborn baby animals. Animal studies also show that vinyl 

chloride can produce more miscarriages early in pregnancy and decrease weight and delay 

skeletal development in fetuses. These same very high levels of vinyl chloride also caused 

harmful effects in the pregnant animals. Inhalation studies with animals have suggested that 

vinyl chloride might affect growth and development. Animal studies also suggest that infants 

and young children might be more susceptible than adults to vinyl chloride-induced cancer. 

1.7 	 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO VINYL 

CHLORIDE? 

If your doctor finds that you have been exposed to substantial amounts of vinyl chloride, ask 

whether your children might also have been exposed. Your doctor might need to ask your state 

health department to investigate. 

You can take some steps to limit your exposure to vinyl chloride. Very low levels of vinyl 

chloride exist in the ambient air, but these levels are usually not high enough to be a cause of 

concern. If you live near a hazardous waste site, municipal landfill, or a chemical plant that 

produces vinyl chloride or PVC, you might be exposed to higher levels of this compound than 

the general public. Vinyl chloride can leach from plastic PVC bottles or containers used to 

contain foods or beverages, but government agencies such as the Food and Drug Administration 

(FDA) have restricted the amount of vinyl chloride that can be present in these packages. 
VINYL CHLORIDE 8 

1. PUBLIC HEALTH STATEMENT 

Tobacco smoke contains low levels of vinyl chloride, so limiting your family’s exposure to 

cigarette or cigar smoke may help reduce their exposure to vinyl chloride. 

People who work in facilities that manufacture or use vinyl chloride could be exposed to high 

levels of this chemical. The Occupational Safety and Health Administration (OSHA) regulates 

these levels and employers must comply with these rules. If you work in an industry that 

manufactures or uses vinyl chloride, strictly adhere to the rules provided by the safety officer and 

always use respirators when advised. 

1.8 	 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN 

EXPOSED TO VINYL CHLORIDE? 

The results of several tests can sometimes show if you have been exposed to vinyl chloride, 

depending on the amount of your exposure and how recently it happened. However, scientists 

do not know whether these measurements can tell how much vinyl chloride you have been 

exposed to. These tests are not normally available at your doctor's office. Vinyl chloride can be 

measured in your breath, but the test must be done shortly after exposure. This test is not very 

helpful for measuring very low levels of the chemical. The amount of the major breakdown 

product of vinyl chloride, thiodiglycolic acid, in the urine may give some information about 

exposure. However, this test must be done shortly after exposure and does not reliably indicate 

the level of exposure. Also, exposure to other chemicals can produce the same breakdown 

products in your urine. Vinyl chloride can bind to genetic material in your body. The amount of 

this binding can be measured by sampling your blood and other tissues. This measurement will 

give information about whether you have been exposed to vinyl chloride, but it is not sensitive 

enough to determine the effects on the genetic material resulting from exposure. For more 

information, see Chapters 3 and 7. 
VINYL CHLORIDE 9 

1. PUBLIC HEALTH STATEMENT 

1.9 	 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. 

Regulations can be enforced by law. The EPA, the Occupational Safety and Health 

Administration (OSHA), and the Food and Drug Administration (FDA) are some federal 

agencies that develop regulations for toxic substances. Recommendations provide valuable 

guidelines to protect public health, but cannot be enforced by law. The Agency for Toxic 

Substances and Disease Registry (ATSDR) and the National Institute for Occupational Safety 

and Health (NIOSH) are two federal organizations that develop recommendations for toxic 

substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels, that is, levels of a 

toxic substance in air, water, soil, or food that do not exceed a critical value that is usually based 

on levels that affect animals; they are then adjusted to levels that will help protect humans. 

Sometimes these not-to-exceed levels differ among federal organizations because they used 

different exposure times (an 8-hour workday or a 24-hour day), different animal studies, or other 

factors. 

Recommendations and regulations are also updated periodically as more information becomes 

available. For the most current information, check with the federal agency or organization that 

provides it. Some regulations and recommendations for vinyl chloride include the following: 

Vinyl chloride is regulated in drinking water, food, and air. Because it is a hazardous substance, 

regulations on its disposal, packaging, and other forms of handling also exist. EPA requires that 

the amount of vinyl chloride in drinking water not exceed 0.002 milligrams per liter (mg/L) of 

water (0.002 ppm). Under the EPA's Ambient Water Quality Criteria for the protection of 

human health, a concentration of 0.025 micrograms per L (μg/L) of water (0.025 ppb) was 

established for protecting human health from water and organism ingestion and 2.4 micrograms 

per L (μg/L) of water (2.4 ppb) was determined for consumption of organisms only. 
VINYL CHLORIDE 10 

1. PUBLIC HEALTH STATEMENT 

To limit intake of vinyl chloride through foods to levels considered safe, FDA regulates the vinyl 

chloride content of various plastics. These include plastics that carry liquids and plastics that 

contact food. The limits for vinyl chloride content vary depending on the nature of the plastic 

and its use. 

EPA has established a reportable quantity for vinyl chloride. If quantities of more than 1 pound 

(0.454 kilograms) are released to the environment, the National Response Center of the federal 

government must be told immediately. 

OSHA regulates levels of vinyl chloride in the workplace. No employee may be exposed to 

vinyl chloride at levels greater than 1 ppm averaged over any 8-hour period or levels greater than 

5 ppm averaged over any period exceeding 15 minutes. NIOSH recommends that the exposure 

limit (for a time-weighted average [TWA]) for vinyl chloride in air be the lowest reliably 

detectable concentration. Workers exposed to any measurable amount of it must wear special 

breathing equipment. EPA sets emission standards for vinyl chloride and PVC plants. The 

amount of vinyl chloride allowed to be emitted varies depending on the type of production and 

the discharge system used. 

Further regulations and guidelines that apply to vinyl chloride are presented in Chapter 8. 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These 

clinics specialize in recognizing, evaluating, and treating illnesses that result from exposure to 

hazardous substances. 

Toxicological profiles also are available on-line at www.atsdr.cdc.gov and on CD-ROM. You 

can request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information 
VINYL CHLORIDE 11 

1. PUBLIC HEALTH STATEMENT 

and technical assistance number at 1-888-42ATSDR (1-888-422-8737), by e-mailing 

atsdric@cdc.gov, or by writing to: 

Agency for Toxic Substances and Disease Registry 

 Division of Toxicology and Environmental Medicine 

1600 Clifton Road NE 

 Mailstop F-32 

 Atlanta, GA 30333 

 Fax: 1-770-488-4178 

For-profit organizations may request copies of final Toxicological Profiles from 

National Technical Information Service (NTIS) 

5285 Port Royal Road 

 Springfield, VA 22161 

 Phone: 1-800-553-6847 or 1-703-605-6000 

 Web site: http://www.ntis.gov/ 
VINYL CHLORIDE 12 

1. PUBLIC HEALTH STATEMENT 

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VINYL CHLORIDE 13 

2. RELEVANCE TO PUBLIC HEALTH 
 

2.1 	 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO VINYL CHLORIDE IN THE 

UNITED STATES 

Vinyl chloride is a one of the highest production volume chemicals in the world, with a current worldwide 

demand of roughly 16 billion pounds annually. Approximately 98% of all vinyl chloride produced is 

used to manufacture polyvinyl chloride (PVC). These PVC materials become end products in automotive 

parts, packaging products, pipes, construction materials, furniture, and a variety of other products. 

Most vinyl chloride released to the environment will eventually partition to air, where it is degraded by 

atmospheric oxidants such as hydroxyl radicals. Very low levels of vinyl chloride are usually present in 

ambient air with concentrations typically around 1 μg/m3

 (0.4 ppb) or less. In areas in close proximity to 

vinyl chloride production facilities, higher airborne levels are often observed. Elevated levels of vinyl 

chloride may also be found in the vicinity of hazardous waste sites and municipal landfills. This may be 

due to the presence of vinyl chloride or the microbial degradation of other chlorinated solvents to form 

vinyl chloride. Vinyl chloride is highly mobile in soil, and as a consequence, is occasionally detected in 

groundwater and drinking water in the United States at levels in the parts per billion (ppb) range, although 

the rapid rate of volatilization generally reduces the potential for vinyl chloride to leach substantially into 

groundwater. 

The general population is primarily exposed to vinyl chloride from inhalation of ambient air and the 

ingestion of foods or other items that may contain low levels of vinyl chloride that has leached from a 

PVC container. Vinyl chloride possesses high mobility in the plastic and can leach into the food, 

beverages, or water that is ultimately ingested by the consumer. Dietary exposure to vinyl chloride from 

PVC packages used for food has been calculated by several agencies and, based upon estimated average 

intakes in the United Kingdom and the United States, an exposure of <0.0004 μg/kg/day was estimated 

for the late 1970s and early 1980s. People who smoke or work where vinyl chloride is produced or used 

may be exposed to higher levels of vinyl chloride. 
VINYL CHLORIDE 14 

2. RELEVANCE TO PUBLIC HEALTH 

2.2 SUMMARY OF HEALTH EFFECTS 

The effects of vinyl chloride exposure have been studied in humans and animals, with similar results 

being exhibited in all species. Vinyl chloride exposure in humans is most likely to occur by inhalation or 

oral exposure routes. Effects from dermal exposures are unlikely, as vinyl chloride is not well absorbed 

across the skin. Chronic-duration, occupational exposures to high levels of vinyl chloride have resulted in 

a specific suite of effects in humans, including narcotic effects, Raynaud’s phenomenon (blanching and 

numbness of fingers and discomfort experienced upon exposure to cold temperatures), acroosteolysis, 

scleroderma-like skin changes, hepatocellular alterations, and the development of hepatic angiosarcoma, a 

liver cancer that is quite rare in the general U.S. population. Laboratory animal exposure to vinyl chloride 

has resulted in neurological, liver, and cancer effects as well as respiratory, reproductive, developmental, 

and lymphoreticular effects. Though acute inhalation exposure of mice to vinyl chloride resulted in a 

developmental effect (on which the oral acute-duration Minimal Risk Level [MRL] is based), liver and 

neurological effects were observed consistently in vinyl chloride workers and several animal species 

across exposure durations, suggesting that these are the principal effects of vinyl chloride exposure. 

The liver is the most sensitive target organ for vinyl chloride toxicity for both intermediate- and chronicduration inhalation and chronic-duration oral exposures. The sensitivity of the liver to acute-duration 

effects is difficult to assess, since studies of acute-duration exposures either reported liver effects from 

high exposures of ≥20,000 ppm or focused on reproductive and developmental effects. The sensitivity of 

the liver to vinyl chloride exposure is consistent with the proposed mechanism of action in which 

metabolism of vinyl chloride via mixed function oxidases (MFO), specifically CYP2E1, results in the 

formation highly reactive metabolites. These metabolites have been shown to bind to DNA and 

hepatocellular proteins. Thus, the prevalence of MFO activity in the liver and resulting production of 

reactive metabolites results in the observed sensitivity of the liver to cancer and noncancer effects. 

Occupational studies have identified a consistent group of liver effects resulting from vinyl chloride 

exposure, including hypertrophy, hyperplasia of hepatocytes and sinusoidal cells, portal fibrosis, 

sinusoidal dilation, and focal cellular degeneration. Animal studies demonstrate that the intensity of 

effects increased with increasing dose, ranging from cellular hypertrophy and sinusoidal compression, to 

vacuolization, hepatic hyperplasia, fibrosis, and necrosis. Longer duration exposures resulted in 

manifestation of effects at lower doses. In animal studies, the lowest observed adverse noncancer effects 

in the liver included liver cell polymorphisms and development of hepatic cysts resulting from chronic 

oral exposures of 2 mg/kg/day; centrilobular hypertrophy and fatty liver changes resulted from 

intermediate-duration inhalation exposures of 10 and 50 ppm, respectively. In addition to noncancer 
VINYL CHLORIDE 15 

2. RELEVANCE TO PUBLIC HEALTH 

effects, the liver was sensitive to tumor development. For intermediate- and chronic-duration inhalation 

and chronic-duration oral exposures, the development of liver angiosarcoma resulted from exposures as 

low as 50 ppm and 0.2 mg/kg/day, respectively. The development of pre-neoplastic basophilic foci 

resulted from chronic oral exposures of 0.02 mg/kg/day. 

Neurological effects of vinyl chloride have been observed following inhalation exposures. No data were 

available for neurological effects resulting from oral exposures. Inhalation-related neurological effects in 

humans include dizziness, drowsiness and fatigue, headache, euphoria and irritability, nervousness and 

sleep disturbances, nausea, visual and hearing disturbances, and loss of consciousness. Signs of 

pyramidal and cerebellar disturbances have also been observed. Dizziness has been reported by 

volunteers acutely exposed to 8,000 ppm, while nausea and subsequent headache resulted from exposures 

of 20,000 ppm. Peripheral neurological effects have been reported, including parasthesia, tingling or 

warmth in the extremities, numbness or pain in the fingers, and depressed reflexes. A variety of effects in 

animals from acute-duration inhalation exposures include ataxia, decreased coordination, twitching, 

tremors, and unconsciousness. Chronic-duration exposures resulted in damaged nerve tissue, including 

degeneration of brain tissue and fibrosis of peripheral nerve endings. 

Human studies of reproductive and developmental effects from vinyl chloride exposure resulted in 

equivocal results. Studies examining parental employment and/or residential proximity to vinyl chloride 

facilities and birth defects reported links to fetal loss and defects of the central nervous system, alimentary 

tract, genitalia, and incidence of club foot. Other studies found no such association or suggested that 

inappropriate or inadequate study designs and statistical methodology were employed. In animals, a few 

studies have identified reproductive and developmental effects. Decreased testicular weight, reduced 

male fertility, and spermatogenic epithelial necrosis resulted from intermediate-duration inhalation 

exposures of 100–500 ppm, but were not observed in rats exposed to up to 1,100 ppm. Gestational 

exposures of 2,500 ppm resulted in ureter dilation in rat offspring, while delayed ossification was 

observed following 500 ppm exposures in mice. This exposure also resulted in 17% maternal mortality. 

A no-observed-adverse-effect level (NOAEL) of 50 ppm was associated with delayed ossification in mice 

and is the basis for the acute-duration inhalation MRL. 

The Department of Health and Human Services has determined vinyl chloride to be a known human 

carcinogen. The International Agency for Research on Cancer (IARC) has concluded that sufficient 

evidence for carcinogenicity in humans and animals exists and has placed vinyl chloride in 

carcinogenicity category 1 (i.e., carcinogenic to humans). Similarly, EPA concluded that vinyl chloride is 
VINYL CHLORIDE 16 

2. RELEVANCE TO PUBLIC HEALTH 

a known human carcinogen by the inhalation route of exposure, based on human epidemiological data. 

By analogy, vinyl chloride is considered a known human carcinogen by the oral route because of positive 

animal bioassay data as well as pharmacokinetic data allowing dose extrapolation across routes. By 

inference, EPA considers vinyl chloride highly likely to be carcinogenic by the dermal route because it 

acts systemically. EPA derived an inhalation unit risk of 8.8x10-6 per μg/m3

 for continuous lifetime 

exposure from birth based on the incidence of liver tumors observed in rats exposed to vinyl chloride via 

inhalation. An inhalation unit risk of 4.4x10-6 per μg/m3

 for continuous lifetime exposure during 

adulthood was also estimated by EPA. An oral slope factor for continuous lifetime exposure from birth 

was estimated by EPA to be 1.5 per mg/kg/day based on the incidence of liver tumors in rats. An oral 

slope factor of 7.5x10-1 per mg/kg/day for continuous lifetime exposure during adulthood was also 

estimated by EPA. 

Noncancerous hepatotoxicity and carcinogenicity of vinyl chloride are discussed in greater detail below. 

The Reader is referred to Section 3.2, Discussion of Health Effects by Route of Exposure, for additional 

information on other effects. 

Noncancerous Hepatic Effects. The liver appears to be the most sensitive target organ of vinyl 

chloride toxicity. Liver effects serve as the basis for the intermediate-duration inhalation MRL and the 

chronic-duration oral MRL (see Section 2.3). Changes in the liver have been observed in workers 

exposed to unknown levels of vinyl chloride via inhalation. The characteristic pattern of changes detected 

by peritoneoscopy and confirmed in several studies include hypertrophy and hyperplasia of hepatocytes 

and sinusoidal cells; sinusoidal dilation associated with damage to the cells lining the sinusoids and/or 

sinusoidal occlusion associated with crowding due to cellular hypertrophy and hyperplasia; focal areas of 

hepatocellular degeneration due to disruption of hepatic circulation; and fibrosis of portal tracts, septa, 

and periportal and intralobular perisinusoidal regions. In fact, the extent of hepatic fibrosis appears to 

represent the primary difference between effects observed in animals and humans, as reticulin and 

collagen deposition in human liver tissue was greater than that observed in animals. Species differences 

in fibrosis may also have been impacted by co-exposure to ethanol via alcohol consumption. Case studies 

suggest that portal fibrosis and portal hypertension contributed to worker mortality. Further, liver 

cirrhosis was implicated in increased mortality in an IARC update of a multi-center cohort of workers 

exposed to moderate to high concentrations of vinyl chloride and in a cohort of workers from five PVC 

production sites in Taiwan. Though the critical confounding factor of alcohol consumption by workers at 

these sites was not considered, an analysis of another large cohort of vinyl chloride workers suggested 

that vinyl chloride exposure was an independent risk factor for liver cirrhosis, which exhibited a 
VINYL CHLORIDE 17 

2. RELEVANCE TO PUBLIC HEALTH 

synergistic interaction with alcohol consumption. Regardless of species differences, it is possible that the 

development of fibrosis resulted via an immune-mediated mechanism rather than cytotoxicity, as 

structural changes occurring in the livers of humans and animals were not generally accompanied by 

changes in serum hepatic enzyme activities. The lack of change in serum biochemistry may have been 

due to the limited scope of the necrotic changes. 

These findings in epidemiology studies are supported by studies in animals. The animal data indicate a 

progression of effects across doses and durations. Acute- and intermediate-duration effects seen in the 

livers of animals that inhaled 50,000–300,000 ppm of vinyl chloride included fatty liver changes, 

hepatocellular hypertrophy, vacuolization, sinusoidal compression, and liver congestion. Centrilobular 

degeneration and necrosis resulted from intermediate-duration exposure of 50–200 ppm. Centrilobular 

hypertrophy occurred in rats following an intermediate-duration inhalation of 10 ppm. The dose-related 

progression of effect intensity from the minimally adverse increase in size of centrilobular hepatocytes to 

degeneration and necrosis is consistent with the appearance of highly reactive metabolites due to focused 

MFO metabolism of vinyl chloride in the liver (see discussion below). Low-level intermediate- and 

chronic-duration inhalation exposures of 50 ppm also resulted in the development of hepatic 

angiosarcoma, though it is not known if carcinogenicity was preceded by or independent of a progression 

of non-cancer effects. Chronic oral exposures resulted in areas of cellular alteration, polymorphism, and 

necrosis in the livers of rats given 2 mg/kg/day vinyl chloride in the diet, while the appearance of 

basophilic foci, considered a pre-neoplastic lesion, occurred following exposures of 0.02 mg/kg/day. 

Though the mechanism of toxicity for liver effects of vinyl chloride is not well understood, the parent 

compound is metabolized to the reactive metabolites 2-chloroethylene oxide and, subsequently, 

2-chloroacetaldehyde via MFOs, whose activity is primarily concentrated in the liver. The presence of 

the reactive 2-chloroacetaldehyde likely results in protein adduction, which can interfere with normal 

cellular function, resulting in cytotoxicity. This is consistent with the progression of effects from 

hypertrophy to fatty changes, hyperplasia, and necrosis. The effects of hepatic fibrosis may be a 

secondary effect of the initiation of immune responses to cytotoxicity. This is consistent with enhanced 

collagen deposition observed in workers, which is believed to be an immune-mediated response. 

Cancer. The development of cancer in humans as a result of vinyl chloride exposure has been 

demonstrated in a number of studies of workers in the vinyl chloride production industry. The strongest 

evidence comes from the cluster of reports of greater than expected incidences of liver angiosarcoma. 

Though no exposure data were available for these workers, there is a convincing association between 
VINYL CHLORIDE 18 

2. RELEVANCE TO PUBLIC HEALTH 

vinyl chloride exposure and the development of liver angiosarcoma, as this type of liver cancer is 

considered to be very rare in humans (25–30 cases/year in the United States). The latency period for the 

development of hepatic angiosarcoma appears to be quite lengthy, as angiosarcoma continues to occur in 

workers employed prior to 1960; workers diagnosed after 1975 showed a latency of 27–47 years. 

Other types of cancer that have shown a significant increase in incidence among vinyl chloride workers 

include hepatocellular carcinoma and cholangiocellular carcinoma, cancer of the lung and respiratory 

tract, the lymphatic/hematopoietic system, and the brain and central nervous system. However, 

uncertainty exists in the association of vinyl chloride exposure and some soft tissue tumors. A metaanalysis of data for over 22,000 workers suggested no excess cancer risk for soft tissue sarcoma, brain, 

lymphoid, and hematopoietic system cancers. More recent follow-up studies have failed to find a 

significant association between vinyl chloride exposure and respiratory tract and brain cancer. 

Studies in several animal species support the conclusion that vinyl chloride is carcinogenic. In rats, 

chronic exposure to 5–5,000 ppm vinyl chloride vapors resulted in significant incidence of mammary 

gland carcinomas, Zymbal’s gland carcinomas, nephroblastoma, and liver angiosarcoma. Intermediateand chronic-duration exposures of 50–2,500 ppm vinyl chloride resulted in significant incidence of liver 

angiosarcoma, carcinoma, and angioma, lung adenoma, mammary gland carcinoma, adipose tissue 

hemangiosarcoma, and hemangiosarcoma of the subcutis and peritoneum in mice. With the exception of 

liver angiosarcomas, which have been observed in all species (including humans), there is little 

consistency in tumor types across species. Chronic-duration oral administration of 2–6 mg/kg/day of 

vinyl chloride resulted in the development of neoplastic liver nodules, hepatocellular carcinoma, and lung 

and liver angiosarcoma in rats. 

Studies in rats, mice, and hamsters provide evidence that exposure early in life increases the risk of 

hemangiosarcoma in liver, skin, and spleen, stomach angiosarcoma, and mammary gland carcinoma, as 

compared to the risk associated with exposure after 12 months of age. Due to the latency period for vinyl 

chloride-induced cancer, exposure of animals early in life may have increased the likelihood of 

developing tumors and affect the type of tumor that develops. 

The metabolism of vinyl chloride to the highly reactive metabolites, the observance of DNA adduction in 

mechanistic studies, and the observed carcinogenicity resulting from a single, high level inhalation 

exposure in animals, suggest that the primary mechanism of vinyl chloride carcinogenicity involves direct 

DNA interactions rather than secondary responses to cytotoxicity. The mutation profile of DNA adducts 
VINYL CHLORIDE 19 

2. RELEVANCE TO PUBLIC HEALTH 

formed by the reactive metabolites of vinyl chloride, 2-chloroethylene oxide and 2-chloroacetaldehyde, 

includes the four cyclic etheno-adducts 1,N6

-ethenoadenine, 3,N4-ethenocytosine, 3,N2-ethenoguanine, 

and 1,N2

-ethenoguanine. These adducts produce base-pair transitions during transcription and DNA 

crosslinks. Such mutations have resulted in the mutation of ras oncogenes, as observed in hepatic 

angiosarcoma tumors of workers exposed to high levels of vinyl chloride. Further, mutations in the 

p53 tumor suppressor gene, which has been associated with a variety of tumor types, have been identified 

in vinyl chloride workers. Mutations in p53 of vinyl chloride-exposed rats were similar to those reported 

in humans. 

2.3 MINIMAL RISK LEVELS (MRLs) 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for vinyl chloride. 

An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an 

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are 

derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive 

health effect(s) for a specific duration within a given route of exposure. MRLs are based on 

noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for 

acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. 

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

Inhalation MRLs 

Epidemiological and case studies in humans did not provide sufficient data regarding exposure levels and 

durations and their correlation with hepatic, neurological, immunological, and carcinogenic effects. 

Therefore, animal studies were used for the derivation of inhalation MRLs. 
VINYL CHLORIDE 20 

2. RELEVANCE TO PUBLIC HEALTH 

•	 An MRL of 0.5 ppm has been derived for acute-duration inhalation exposure (≤14 days) to vinyl 

chloride. 

A number of studies in animals identified acute-duration lowest-observed-adverse-effect levels 

(LOAELs) for frank narcosis and severe lung, liver, and kidney damage following exposures of 5,000– 

400,000 ppm of vinyl chloride. Exposure of pregnant rats to 2,500 ppm 7 hours/day over gestational 

days 6–15 resulted in ureter dilation in the offspring (John et al. 1977, 1981). In the same study, pregnant 

mice exposed to 500 ppm for the same duration exhibited delayed ossification in the fetuses. A NOAEL 

of 50 ppm was identified for mice. 

The study of John et al. (1977, 1981) study serves as the principal study for the derivation of an acuteduration inhalation MRL based on the NOAEL of 50 ppm for delayed ossification. In this study, groups 

of 19–26 pregnant CF-1 mice were exposed to 0, 50, or 500 ppm vinyl chloride for 7 hours/day on 

gestational days 6–15 (John et al. 1977, 1981). No adverse maternal or fetal effects were noted at 

50 ppm, with the exception of an increase in crown-rump length that was not observed at 500 ppm. At 

the LOAEL of 500 ppm, delayed ossification was observed. A significant increase in fetal resorptions 

and reduced litter size at 500 ppm was considered to have been within historical control limits. There was 

frank maternal toxicity at 500 ppm (17% death). 

The duration-adjusted NOAEL (NOAELADJ) was calculated as follows: 

NOAELADJ = 50 ppm x 7 hours / 24 hours = 15 ppm 

The human equivalent concentration (NOAELHEC) for an extrarespiratory effect produced by a 

category 3 gas, such as vinyl chloride, was calculated by multiplying the NOAELADJ by the ratio of the 

blood:gas partition coefficients in animals and humans ([Hb/g]A / [Hb/g]H). Since the partition coefficient in 

mice is greater than that in humans, a default value of 1 is used for the ratio, resulting in a NOAELHEC of 

15 ppm. The acute-duration inhalation MRL of 0.5 ppm was derived by dividing the NOAELHEC of 

15 ppm by an uncertainty factor of 30 (3 for species extrapolation with dosimetric adjustment and 10 for 

human variability). 
VINYL CHLORIDE 21 

2. RELEVANCE TO PUBLIC HEALTH 

•	 An MRL of 0.03 ppm has been derived for intermediate-duration inhalation exposure (15– 

364 days) to vinyl chloride. 

Reduced male fertility, decreased tested weight, and spermatogenic epithelial necrosis was observed in 

male rats exposed from 11 weeks to 10 months to 100–500 ppm vinyl chloride (Bi et al. 1985; Short et al. 

1977; Sokal et al. 1980). Decreased white blood cell counts resulted from exposure of rats to 20,000 ppm 

for 3 months (Lester et al. 1963), while increased lymphocyte proliferation resulted in mice exposed to 

10 ppm for up to 8 weeks (Sharma and Gehring 1979). Exposures of 10–1,000 ppm resulted in increases 

and decreases in various relative and absolute organ weights (Sharma and Gehring 1979), including the 

liver (Bi et al. 1985; Sokal et al. 1980; Torkelson et al. 1961). Adverse histopathological changes in the 

liver of rats and mice exposed to 2,000–3,000 ppm have been observed in several other intermediateduration inhalation studies (Lester et al. 1963; Schaffner 1978; Sokal et al. 1980; Torkleson et al. 1961; 

Wisniewska-Knypl et al. 1980). Centrilobular degeneration and necrosis was observed in rabbits exposed 

to 200 ppm for 6 months (Torkleson et al. 1961). Fatty liver changes were also observed in two studies of 

rats exposed to 50 ppm for 10 months (Sokal et al. 1980; Wisniewska-Knypl et al. 1980). The lowest 

observed effect level was 10 ppm, which resulted in centrilobular hypertrophy in F1 female rats exposed 

for 19 weeks (Thornton et al. 2002). 

While effects were observed in both mice and rats exposed to 10 ppm, the rat study provided data for 

centrilobular hypertrophy in F1 offspring, a minimally adverse effect in a sensitive subpopulation 

(offspring) of the target organ (liver) that is sensitive to both inhalation and oral exposures. Further, the 

rat study provided data for a longer exposure period than the mouse study. Therefore, the study of 

Thornton et al. (2002) was chosen as the principal study for derivation of the intermediate-duration 

inhalation MRL, providing a critical effect level of 10 ppm as the LOAEL for centrilobular hypertrophy. 

In the Thornton et al. (2002) study, groups of 30 male and female Sprague-Dawley rats were exposed to 

0, 10, 100, or 1,100 ppm vinyl chloride, 6 hours/day for 10 weeks prior to mating and during a 3-week 

mating period. F0 females were exposed during gestation and lactation. Absolute and relative mean liver 

weights were significantly increased at all exposure levels in F0 males and in 100 and 1,100 ppm F1 

males. Slight centrilobular hypertrophy resulted in 1,100-ppm male and female F0 and F1 rats, 100 ppm 

male and female F0 and F1 rats, and in the 10 ppm F0 and F1 female rats. The incidence rate for 

centrilobular hypertrophy in the F1 females was statistically significant. 

An intermediate-duration inhalation MRL of 0.03 ppm was derived for vinyl chloride, based on a 

benchmark concentration of 5 ppm derived from the concentration-response data for hepatic centrilobular 
VINYL CHLORIDE 22 

2. RELEVANCE TO PUBLIC HEALTH 

hypertrophy in female Sprague-Dawley rats (Thornton et al. 2002). Using the Benchmark Dose Software 

(BMDS version 1.3.2), incidence data were fit to eight dichotomous models to derive the lower 

95% confidence limit (LEC10) of a 10% extra risk for hepatic centrilobular hypertrophy, which was 

selected as the benchmark response for the point of departure. Several models provided equivalent 

goodness-of-fit statistics. Therefore, the LEC10 value of 5 ppm, derived from the simplest model 

(Weibull), was selected as the point of departure for calculating an intermediate-duration inhalation MRL 

(see Appendix A for more detailed information on the application of Benchmark Dose Modeling in 

deriving the intermediate-duration inhalation MRL for vinyl chloride). The LEC10 of 5 ppm was 

duration-adjusted for intermittent exposure as follows: 

LEC10ADJ = 5 ppm x 6 hours / 24 hours = 1 ppm. 

The human equivalent concentration (LEC10HEC) was calculated using EPA (1994g) methodology for an 

extrarespiratory effect produced by a category 3 gas by multiplying the LEC10ADJ by the ratio of the 

blood:gas partition coefficients in animals and humans ([Hb/g]A / [Hb/g]H). The partition coefficient in rats 

is greater than that in humans. Therefore, a default value of 1 is used for the ratio, resulting in a LEC10HEC 

of 1 ppm. The intermediate-duration inhalation MRL of 0.03 ppm was derived by dividing the LEC10HEC 

of 1 ppm in rats by an uncertainty factor of 30 (3 for species extrapolation with a dosimetric adjustment 

and 10 for human variability). 

In the absence of exposure level data, the human data base did not provide a suitable LOAEL or NOAEL 

for derivation of a chronic-duration inhalation MRL. A NOAEL (10 ppm) and a LOAEL (100 ppm) were 

identified for testicular effects (increases in the number of degenerative seminiferous tubule changes) in a 

chronic-duration inhalation study (Bi et al. 1985). However, the results of the Thornton et al. (2002) 

study suggest that liver effects would occur at lower concentrations (10 ppm) than the reported testicular 

effects. Though several other chronic-duration studies did report carcinogenicity in rats chronically 

exposed to 5–250 ppm vinyl chloride (Drew et al. 1983; Lee et al. 1977a, 1978; Maltoni et al. 1981), they 

did not report the incidence of noncancerous or precancerous histopathological lesions in the any tissue. 

Therefore, no chronic-duration inhalation MRL was derived for vinyl chloride. 

Oral MRLs 

No studies of human adverse effects resulting from oral exposure to vinyl chloride were available. 

Therefore, animal studies were used for the derivation of MRLs. No acute- or intermediate-duration oral 
VINYL CHLORIDE 23 

2. RELEVANCE TO PUBLIC HEALTH 

MRLs were derived for vinyl chloride because of an absence of data on the effects of oral exposure to 

vinyl chloride for these duration categories. 

•	 An MRL of 0.003 mg/kg/day has been derived for chronic-duration oral exposure (≥365 days) to 

vinyl chloride. 

Chronic gavage doses of 30 mg/kg/day vinyl chloride in rats resulted in increased collagen deposition and 

skin thickness (Knight and Gibbons 1987). Decreased blood clotting time was observed in rats given 

17 mg/kg/day (Feron et al. 1981). Doses of 6 mg/kg/day in female rats resulted in extensive hepatic 

necrosis and 100% early mortality (Feron et al. 1981). A number of effects were observed in rats given 

1.7–1.8 mg/kg/day, including hepatocellular alterations (Feron et al. 1981), liver cell polymorphisms, and 

increased mortality (Til et al. 1983, 1991). The LOAEL of 1.7 mg/kg/day for liver cell polymorphism in 

both sexes and hepatic cysts in female rats was the lowest identified LOAEL and was associated with the 

lowest identified NOAEL for any chronic effect of 0.17 mg/kg/day. Liver cell polymorphism is not 

considered a precursor to carcinogenicity (Afzelius and Schoental 1967; Schoental and Magee 1957, 

1959) and represents an effect to the target organ that is sensitive to both inhalation and oral exposures of 

vinyl chloride. For these reasons, the study of Til et al. (1983, 1991) was chosen as the critical study and 

the NOAEL of 0.17 mg/kg/day was chosen as the critical effect level for derivation of the chronicduration oral MRL. 

In the study of Til et al. (1983, 1991), groups of 50 or 100 male and female Wistar rats were administered 

vinyl chloride in the daily diet at 0, 0.46, 4.6, or 46 ppm for 149 weeks. Using measurements of 

evaporative loss of vinyl chloride from the diet, the study authors calculated the average oral intake of the 

combined sexes during the daily feeding periods to be 0, 0.018, 0.17, and 1.7 mg/kg/day for the 0, 0.49, 

4.49, and 44.1ppm groups, respectively. Types and incidences of neoplastic and nonneoplastic liver 

lesions were determined at the end of the study. A LOAEL of 1.7 mg/kg/day was identified for 

significantly increased incidences of liver cell polymorphism in male and female rats and increased 

incidence of hepatic cysts in female rats. The NOAEL for nonneoplastic liver effects is 0.17 mg/kg/day. 

Other histopathologic lesions, described as hepatic foci of cellular alteration, were observed at all dose 

levels in female rats and in high-dose male rats, but were not used to derive an MRL because they are 

considered to be preneoplastic lesions. 

This MRL of 0.003 mg/kg/day was based on a NOAEL of 0.17 mg/kg/day for noncancerous liver effects 

(i.e., liver cell polymorphism) in female Wistar rats (Til et al. 1983, 1991) and application of the 

physiologically based pharmacokinetic (PBPK) model (Clewell et al. 2001; EPA 2000). Source code and 
VINYL CHLORIDE 24 

2. RELEVANCE TO PUBLIC HEALTH 

parameter values for running the rat and human models in Advance Continuous Simulation Language 

(ACSL) were transcribed from Appendix C of EPA (2000). Exposures in the Til et al. (1983, 1991) rat 

dietary exposure study were simulated in rats as 4-hour oral exposures with the NOAEL dose for liver 

effects of 0.17 mg/kg/day. The total amount of vinyl chloride metabolized in 24 hours per liter of liver 

volume was the rat internal dose metric used to determine the human oral dose that would result in an 

equivalent human internal dose. One kilogram of liver was assumed to have an approximate volume of 

1 L. The human model was run iteratively, until the model converged with the internal dose estimate for 

the rat (3.16 mg/L liver). The human dose was assumed to be uniformly distributed over a 24-hour 

period. The resulting human oral dose of 0.09 mg/kg/day, associated with the rat NOAEL of 

0.17 mg/kg/day (Til et al. 1983, 1991), served as the basis for the chronic-duration oral MRL for vinyl 

chloride. The chronic-duration oral MRL of 0.003 mg/kg/day was derived by dividing the PBPKmodeled equivalent human NOAEL of 0.09 mg/kg/day for liver cell polymorphisms by an uncertainty 

factor of 30 (3 for species extrapolation with a dosimetric adjustment and 10 for human variability). 

More detailed information regarding the application of the PBPK model in deriving the chronic-duration 

oral MRL for vinyl chloride is provided in Appendix A. 
VINYL CHLORIDE 25 

3. HEALTH EFFECTS 

3.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of vinyl chloride. It 

contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. 

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals and others address the needs of persons living or working near 

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by adverse health effect (death, systemic, immunological, neurological, 

reproductive, developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of 

three exposure periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or 

more). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in 

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress 

or death). "Less serious" effects are those that are not expected to produce significant dysfunction or 

death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a 

considerable amount of judgment may be required in establishing whether an end point should be 

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the 

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between 
VINYL CHLORIDE 26 

3. HEALTH EFFECTS 

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is 

considered to be important because it helps the users of the profiles to identify levels of exposure at which 

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not 

the effects vary with dose and/or duration, and place into perspective the possible significance of these 

adverse effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans 

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of vinyl chloride 

are indicated in Tables 3-1 and 3-2 and Figures 3-1 and 3-2. Because cancer effects could occur at lower 

exposure levels, Figures 3-1 and 3-2 also shows a range for the upper bound of estimated excess risks, 

ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10-4 to 10-7), as developed by EPA. 

Estimates of exposure levels posing minimal risk to humans (MRLs) have been made for vinyl chloride. 

An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an 

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are 

derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive 

health effect(s) for a specific duration within a given route of exposure. MRLs are based on 

noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for 

acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. 

Although methods have been established to derive MRLs (Barnes and Dourson 1988; EPA 1990), 

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional 

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an 

example, acute inhalation MRLs may not be protective for health effects that are delayed in development 

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic 

bronchitis. As these kinds of health effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. It should be noted that MRLs are also 
VINYL CHLORIDE 27 

3. HEALTH EFFECTS 

not protective in the case of altered health status caused by exposure to cigarette smoking or excessive 

alcohol consumption (i.e., altered lung and liver function). 

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in 

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

3.2.1 Inhalation Exposure 

3.2.1.1 Death 

A report by Danziger (1960) described the deaths of two vinyl chloride workers. In one case, a worker 

exposed to high concentrations of vinyl chloride emitted from an open valve was found dead. In another 

case, a worker responsible for cleaning a polymerization tank was found dead in the tank. Autopsies 

performed on these men showed congestion of the internal organs, particularly the lungs and kidneys, and 

failure of the blood to clot. Circumstances surrounding the deaths suggested that the deaths were due to 

breathing very high levels of vinyl chloride. 

No increase in mortality was observed in 1,100 workers exposed to vinyl chloride compared to the same 

number of controls in a 7-year prospective cohort study of (Laplanche et al. 1992). At the time of the 

study interview, 36% of the 1,100 workers were currently being exposed to vinyl chloride, and 64% had 

been exposed in the past (Laplanche et al. 1987, 1992). 

Brief exposures to concentrations of vinyl chloride ranging from 100,000 to 400,000 ppm have been 

shown to be fatal in experimental animals such as rats (Lester et al. 1963; Mastromatteo et al. 1960; 

Prodan et al. 1975), guinea pigs (Mastromatteo et al. 1960; Patty et al. 1930; Prodan et al. 1975), mice 

(Mastromatteo et al. 1960; Prodan et al. 1975), and rabbits (Prodan et al. 1975). At these concentrations, 

deaths occurred within 30–60 minutes. Male mice exposed to 30,000 ppm vinyl chloride 6 hours/day for 

5 days, in a dominant lethal study showed an increased mortality rate (Anderson et al. 1976). An 

increased mortality rate was also observed at much lower concentrations in maternal mice in a 

developmental toxicity study (John et al. 1977, 1981). In this study, maternal mice had an increased 

incidence of deaths following exposure to 500 ppm for 10 days during gestation. 

Decreased longevity was observed in intermediate-duration studies (Adkins et al. 1986; Drew et al. 1983; 

Feron et al. 1979a; Hong et al. 1981; Lee et al. 1978) and chronic-duration studies (Drew et al. 1983; 
VINYL CHLORIDE 28 

3. HEALTH EFFECTS 

Feron et al. 1979a; Viola 1970). A treatment-related increase in the mortality rate was observed in mice 

exposed to 500 ppm of vinyl chloride for 6 hours/day, 5 days/week, for 6 months (Adkins et al. 1986). In 

mice and rats maintained for 12 months following a 6-month, 6 hour/day, 5 day/week exposure regime, 

decreased longevity was observed at concentrations as low as 50 ppm; however, statistical analyses of the 

data were not available to verify the significance of the decrease (Hong et al. 1981). Substantial increases 

in the mortality rate of mice and rats exposed to 250 ppm vinyl chloride for 12 months were observed by 

Lee et al. (1977a, 1978). In addition, small increases in mortality of mice and rats during the 12-month 

exposure period were observed at 50 ppm in these reports; however, the statistical significance of these 

increases was not reported. 

The influence of the age on survival of female animals exposed to vinyl chloride was examined by Drew 

et al. (1983). In female hamsters exposed to 200 ppm, two strains of female mice exposed to 50 ppm, and 

female rats exposed to 100 ppm for 12 months, a higher death rate was observed when 2-month-old 

animals were exposed than when 8- or 14-month-old animals were exposed. Similar trends were 

observed when hamsters and mice were exposed to these concentrations for 6 months. The treatmentrelated deaths in this study may be due to the induction of vinyl chloride-induced carcinogenesis. These 

results demonstrate the importance of the latency period for cancer and associated mortality. Animals 

that were exposed at a younger age had a longer post-exposure period for the development of tumors. It 

is difficult to assess the sensitivity of younger animals to cancer mortality in this study because the same 

exposure concentrations were used for each age group. These results do not necessarily indicate that 

young people are more susceptible to the lethal effects of vinyl chloride, since animals that were exposed 

later in life may have died of age-related causes prior to the expression of the lethal effects. This study 

was limited in that only one dose of vinyl chloride was tested in each species. 

All reliable LOAEL values for death in each species and duration category are recorded in Table 3-1 and 

plotted in Figure 3-1. 

3.2.1.2 Systemic Effects 

The highest NOAEL values and all reliable LOAEL values for each study with a systemic end point in 

each species and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 
14

300000

612

146625

310

30000

300

500

17

200000

611

107525

20

300000

008

100000

613

224825

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation 

Exposure/ 

Duration/ 

a

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) 

ACUTE EXPOSURE Death 

1 Rat 

(NS) 

30 min 

System 

NOAEL 

(ppm) 

Less Serious 

(ppm) 

LOAEL 

Serious 

(ppm) 

300000 (5/5 died) 

Reference Chemical Form 

Mastromatteo et al. 196

2 Rat 

(NS) 

1x 2 hr 146625 (7/30 died) Prodan et al. 1975 

3 Mouse 

(CD-1) 

5 d 6 hr/d 30000 M (11/20 died) Anderson et al. 1976 

4 Mouse 

(CF-1) 

10 d 7 hr/d Gd6-15 

500 F (5/29 died) John et al. 1977, 1981 

5 Mouse 

(NS) 

30 min 200000 (1/5 died) Mastromatteo et al. 196

6 Mouse 

(NS) 

1x 2 hr 107525 (15/61 died) Prodan et al. 1975 

7 Gn Pig 

(NS) 

30 min 300000 (1/5 died) Mastromatteo et al. 196

8 Gn Pig 

(NS) 

up to 8 hr 100000 (death) Patty et al. 1930 

9 Gn Pig 

(NS) 

1x 2 hr 224825 (1/6 died) Prodan et al. 1975 
614

224825

226

50000

100000

16

100000

100000 200000200000 300000

224

50000

96

50000

607

1100

19

100000

200000 300000

100000

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (ppm) (ppm) (ppm) Chemical Form 

10 Rabbit 

(NS) 

Systemic 

11 Rat 

(Holtzman) 

1x 2 hr 1, 5 d 6 hr/d Hepatic 50000 M 

224825 

100000 M (hepatocellular 

vacuolization, increased 

AKT and SDH) 

(1/4 died) Prodan et al. 1975 

Jaeger et al. 1974 

12 Rat 

(NS) 

30 min Resp 100000 (lung hyperemia) Mastromatteo et al. 196

Hepatic Renal 

100000 200000 

200000 300000 

(fatty infiltration changes) (renal congestion) 

13 Rat 

(Holtzman) 

1, 5 d 6 hr/d Hepatic 50000 M Reynolds et al. 1975a 

14 Rat 

(NS) 

1 d 6 hr/d Hepatic 50000 M Reynolds et al. 1975b 

15 Rat 

(SpragueDawley) 

4 hr/d Gd 6-19 Bd Wt 1100 F Thornton et al. 2002 

16 Mouse 

(NS) 

30 min Resp 100000 (lung hyperemia) Mastromatteo et al. 196

Hepatic Renal 

200000 300000 

100000 

(liver congestion) 

(degenerative tubular 

epithelium) 
22

100000

400000200000 300000400000400000

335

400000

152

4000 8000

185

50000

303

500

225

50000 100000

154

50000

15

100000

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (ppm) (ppm) (ppm) Chemical Form 

17 Gn Pig 

(NS) 

30 min Resp 100000 (slight pulmonary 

hyperemia) 

Mastromatteo et al. 196

Cardio 400000 Hepatic Endocr 

200000 400000 

300000 (fatty degeneration) 

Immuno/ Lymphoret 

18 Gn Pig 

(NS) 

30 min 

Neurological 

19 Human 3 d 

2 x/d 5 min 

Ocular 400000 

400000 

4000 8000 (dizziness) 

Mastromatteo et al. 196Lester et al. 1963 

20 Rat 

(Fischer- 344) 

1 hr 50000 Hehir et al. 1981 

21 Rat 

(Fischer- 344) 

2 wk 5 d/wk 1 hr/d 

500 Hehir et al. 1981 

22 Rat 

(Holtzman) 

1, 5 d 6 hr/d 50000 M 100000 M (anesthesia) Jaeger et al. 1974 

23 Rat 

(Sherman) 

2 hr 50000 (moderate intoxication) Lester et al. 1963 

24 Rat 

(NS) 

30 min 100000 (narcosis) Mastromatteo et al. 196
187

5000 50000

18

100000

21

100000

009

10000 25000

608

1100

242

30000

223

2500

606

1100

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

a

Key to Species 

Figure (Strain) 

25 Mouse 

(ICR) 

26 Mouse 

(NS) 

27 Gn Pig 

(NS) 

28 Gn Pig 

(NS) 

Reproductive 

29 Rat 

(SpragueDawley) 

30 Mouse 

(CD-1) 

Developmental 

31 Rat 

(SpragueDawley) 

32 Rat 

(SpragueDawley) 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) Serious (ppm) 

1 hr 5000 50000 (ataxia) 30 min 100000 (narcosis) 30 min 100000 (tremor, loss of 

consciousness) 

up to 8 hr 10000 25000 (narcosis) 16 wk (M) 19 wk (F) 2 gen 4 hr/d 

1100 

5 d 6 hr/d 30000 M 10 d 7 hr/d Gd6-15 

2500 F (ureter dilation) 

4 hr/d Gd 6-19 1100 

Reference Chemical Form 

Hehir et al. 1981 Mastromatteo et al. 196Mastromatteo et al. 196Patty et al. 1930 Thornton et al. 2002 Anderson et al. 1976 John et al. 1977, 1981 Thornton et al. 2002 
222

50 500

221

500

188

5000

140

50

42

500500

138

50

237

10

100

100

3000

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a 

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (ppm) (ppm) (ppm) Chemical Form 

33 Mouse 

(CF-1) 

10 d 7 hr/d Gd6-15 

b

50 F 500 F 

34 Rabbit 

(New Zealand) 

Cancer 

35 Mouse 

(ICR) 

13 d 7 hr/d Gd6-18 1 hr 

500 F 

INTERMEDIATE EXPOSURE Death 

36 Rat 

(CD) 

1-10 mo 5 d/wk 6 hr/d 

37 Mouse 

(A/J) 

6 mo 5 d/wk 6 hr/d 

38 Mouse 

(CD-1) 

Systemic 

39 Rat 

(Wistar) 

1-6 mo 5 d/wk 6 hr/d 3 mo 6 d/wk 6 hr/d 

Cardio 10 M 100 M 

Renal 100 M 3000 M 

(delayed ossification) John et al. 1977, 1981 

(delayed ossification) John et al. 1977, 1981 

5000 (CEL: bronchioalveolar 

adenoma) 

Hehir et al. 1981 

50 (17/26 died) Hong et al. 1981 

500 M (37/70 died) 500 F (23/70 died) 

Adkins et al. 1986 

50 (15/16 died) Hong et al. 1981 

(increased relative heart 

weight) 

Bi et al. 1985 

(increased relative kidney 

weight) 
245

1010

157

5000050000

5000050000 50000

158

2000020000

20000

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a 

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (ppm) (ppm) (ppm) Chemical Form 

40 Rat 

(Wistar) 

6 mo 6 d/wk 6 hr/d 

Cardio 

Hepatic 

10 M 

10 M 

41 Rat 

(Sherman) 

19 d 8 hr/d Hemato 

Hepatic 

50000 

50000 

42 Rat 

(Sherman) 

92 d 5 d/wk 8 hr/d 

Renal Dermal 

Hemato 

Hepatic 

50000 

50000 F 50000 M 

20000 

20000 

Renal 20000 

(increased relative heart Bi et al. 1985 

weight) 

(increased relative liver 

weight) 

(decreased white blood Lester et al. 1963 

cells) 

(hepatocellular 

hypertrophy, large irregular vacuoles, compression of sinusoids, elevated relative liver weight) 

(thin coats, scaly tails) 

(decreased white blood Lester et al. 1963 

cells) 

(moderate hepatocellular 

hypertrophy, fine to medium vacuoles, compression of sinusoids) 
24

20000

50

50 500

50

609

10

1100

128

200

100

200200

002

50

43 44 45 

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (ppm) (ppm) (ppm) Chemical Form 

Rat 10 mo (Wistar) 5 d/wk Musc/skel 20000 M Sokal et al. 1980 5 hr/d 

Hepatic 50 M (fatty changes) Renal 50 M 500 M (increased kidney weight) Bd Wt 50 M (10% decrease in body 

weight) 

Rat 16 wk (M) c(Sprague- 19 wk (F) Hepatic 10 F (centrilobular hypertrophy Thornton et al. 2002 Dawley) 2 gen in F1 female rats) 4 hr/d 

Bd Wt 1100 

Rat 6 mo Hemato 200 Torkelson et al. 1961 (NS) 5 d/wk 0.5-7 hr/d 

Hepatic 100 (increased relative liver 

weight) 

Renal 200 Bd Wt 200 

Rat 10 mo (Wistar) 5 d/wk Hepatic 50 M (fatty changes) Wisniewska- Knypl et a

5 hr/d 

46 
75

2500

204

1000

1000

10001000

143

2500

131

100

200

200200

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

a

Key to Species 

Figure (Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System NOAEL (ppm) Less Serious (ppm) 

LOAEL 

Serious 

(ppm) 

Reference Chemical Form 

47 Mouse 

(NS) 

1-6 mo 5 d/wk 5 hr/d 

Hepatic 2500 M (hyperplasia of 

hepatocytes and activated sinusoidal cells) 

Schaffner 1978 

48 Mouse 

(CD-1) 

8 wk 5 d/wk 6 hr/d 

Hemato 1000 M Sharma and Gehring 19

Hepatic Renal Bd Wt 

1000 M 1000 M 

1000 M (decreased liver weight) 

49 Mouse 

(CD-1) 

5-6 mo 5 d/wk 5 hr/d 

Resp 2500 M (proliferation and 

hypertrophy of bronchial epithelium; hypersecretion of mucin; hyperplasia of alveolar epithelium) 

Suzuki 1978, 1981 

50 Rabbit 

(NS) 

6 mo 5 d/wk 7 hr/d 

Hepatic 100 200 (centrilobular 

degeneration and necrosis) 

Torkelson et al. 1961 

Renal 200 Bd Wt 200 
309

100

3000

313

10

315

50

203

10

306

50

236

10

100

241

50 250

52 53 

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (ppm) (ppm) (ppm) Chemical Form 

Immuno/ Lymphoret 

51 Rat 3 mo 

6 d/wk 100 M 3000 M (increased spleen Bi et al. 1985 (Wistar) 6 hr/d weight) 

Rat 6 mo (Wistar) 6 d/wk 10 M (increased spleen Bi et al. 1985 6 hr/d weight) Rat 10 mo (Wistar) 5 d/wk 50 M (increased spleen Sokal et al. 1980 5 hr/d weight) 

54 Mouse 

(CD-1) 

2-8 wk 5 d/wk 6 hr/d 

10 M (increased spontaneous 

lymphocyte proliferation) 

Sharma and Gehring 19

Neurological 

55 Rat 

(Fischer- 344) 

20 wk 5 d/wk 1 hr/d 

Reproductive 

56 Rat 

(Wistar) 

3, 6 mo 6 d/wk 6 hr/d 

50 10 M 100 M (decreased testes 

weight) 

Hehir et al. 1981 Bi et al. 1985 

57 Rat 

(CD) 

11 wk 5 d/wk 6 hr/d 

50 M 250 M (reduced male fertility) Short et al. 1977 
23

50

500

112

100

603

500

141

250

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ 

Duration/ 

Key to

a 

Species Frequency 

Figure (Strain) (Route) System NOAEL (ppm) 

LOAEL 

Less Serious Serious Reference 

(ppm) (ppm) Chemical Form 

58 Rat 10 mo 

(Wistar) 5 d/wk 5 hr/d 50 M 500 M (spermatogenic epithelial Sokal et al. 1980 necrosis)

Cancer 

59 Rat 6 mo 

(Fischer- 344) 5 d/wk 6 hr/d 100 F (CEL: hepatic Drew et al. 1983 hemangiosarcoma, hepatocellular

carcinoma, neoplasticnodules; mammaryfibroadenoma)

60 Rat 33 d 

(Sprague- 6 d/wk Dawley) 8 hr/d 

61 Rat 6 or 10 mo 

(CD) 5 d/wk 6 hr/d 

500 M 

250 

(CEL: hepatocellular Froment et al. 1994carcinoma,angiosarcoma of theliver, benigncholangioma,nephroblastoma,angiomyoma, leukemia,Zymbal gland carcinoma,pituitary adenoma,mammary carcinoma andfibroma.

(CEL: liver Hong et al. 1981hemangiosarcoma,neoplastic nodules)
610

1100

43

50

116

50

120

50

139

50

215

50

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

a

Key to Species 

Figure (Strain) 

62 Rat 

(SpragueDawley) 

63 Mouse 

(A/J) 

64 Mouse 

(CD-1) 

65 Mouse 

(B6C3F1) 

66 Mouse 

(CD-1) 

67 Mouse 

(Swiss) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (ppm) (ppm) (ppm) Chemical Form 

16 wk (M) 19 wk (F) 2 gen 4 hr/d 6 mo 5 d/wk 6 hr/d 6 mo 5 d/wk 6 hr/d 6 mo 5 d/wk 6 hr/d 1, 3, 6 mo 5 d/wk 6 hr/d 30 wk 5 d/wk 4 hr/d 

1100 F (CEL: foci of Thornton et al. 2002 

hepatocellular alterations considered to be pre-neoplastic) 

50 (CEL: pulmonary Adkins et al. 1986 

adenoma) 

50 F (CEL: hemangiosarcoma Drew et al. 1983 

of skin, peritoneum; mammary gland carcinoma; lung carcinoma) 

50 F (CEL: hemangiosarcoma Drew et al. 1983 

of subcutis, peritoneum; mammary gland carcinoma) 

50 F (CEL: mammary gland Hong et al. 1981 

adenocarcinoma/carcinom 

50 (CEL: liver angiosarcoma Maltoni et al. 1981 

and angioma) 
94

100

124

200

216

500

230

100 300010 10010

100

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ 

Duration/ 

Key to

a 

Species Frequency 

Figure (Strain) (Route) 

LOAEL 

NOAEL Less Serious Serious Reference 

System (ppm) (ppm) (ppm) Chemical Form 

68 Mouse 

(CD-1) 

69 Hamster 

(Golden Syrian) 

70 Hamster 

(Golden Syrian) 

4 wk 5 d/wk 6 hr/d 6 mo 5 d/wk 6 hr/d 30 wk 5 d/wk 4 hr/d 

CHRONIC EXPOSURE Systemic 

71 Rat 12 mo 

(Wistar) 6 d/wk 6 hr/d 

100 M (CEL: lung alveogenic 

tumors) 

Suzuki 1983 

200 F (CEL: liver 

hemangiosarcoma; skin hemangiosarcoma, spleen hemangiosarcoma; mammary gland carcinoma) 

Drew et al. 1983 

500 M (CEL: liver 

angiosarcoma) 

Maltoni et al. 1981 

Hepatic 100 M 3000 M (increased liver weight) Bi et al. 1985 

Renal 10 M 100 M (increased kidney weight) Bd Wt 10 M 100 M (14% decrease in body 

weight) 
228

10

100

229

100

114

100

627

50

26

250

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a 

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (ppm) (ppm) (ppm) Chemical Form 

Reproductive 

72 Rat 

(Wistar) 

Cancer 

73 Rat 

(Wistar) 

74 Rat 

(Fischer- 344) 

75 Rat 

(albino) 

76 Rat 

(CD) 

12 mo 6 d/wk 6 hr/d 

10 M 100 M (degenerative 

seminiferous tubule changes) 

12 mo 6 d/wk 6 hr/d 

100 M 

12, 18, 24 mo 5 d/wk 6 hr/d 

100 F 

6 hr/d 5 d/wk 26 or 52 wk 

50 

1-12 mo 5 d/wk 6 hr/d 

250 F 

(CEL: liver 

angiosarcoma; lung angiosarcoma) 

(CEL: hepatic 

hemangiosarcoma, hepatocellular carcinoma, neoplastic nodules; mammary gland fibroadenoma and adenocarcinoma) 

(CEL: lung, kidney, 

abdominal hemangiosarcoma) 

(CEL: hepatic 

hemangiosarcoma) 

Bi et al. 1985 Bi et al. 1985 Drew et al. 1983 Holmberg et al. 1976 Lee et al. 1978 
207

5

118

50

122

50

334

5050

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ 

Duration/ 

Key to

a 

Species Frequency 

Figure (Strain) (Route) System NOAEL (ppm) 

LOAEL 

Less Serious Serious Reference 

(ppm) (ppm) Chemical Form 

77 Rat 

(SpragueDawley) 

52 wk 5 d/wk 4 hr/d 

5 F (CEL: mammary gland 

carcinoma) 

Maltoni et al. 1981 

78 Mouse 

(Swiss CD-1) 

12, 18 mo 5 d/wk 6 hr/d 

50 F (CEL: lung; 

hemangiosarcoma of peritoneum, subcutis; mammary gland carcinoma) 

Drew et al. 1983 

79 Mouse 

(B6C3F1) 

12 mo 5 d/wk 6 hr/d 

50 F (CEL: hemangiosarcoma 

of peritoneum, subcutis; mammary gland carcinoma) 

Drew et al. 1983 

80 Mouse 

(CD-1) 

1-12 mo 5 d/wk 6 hr/d 

50 F (CEL: mammary gland 

adenoma and adenocarcinoma) 

Lee et al. 1977a, 1978 

50 (CEL: hepatic 

hemangiosarcoma; bronchiolo-alveolar adenoma; malignant lymphoma) 
110

200

Table 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a 

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (ppm) (ppm) (ppm) Chemical Form 

81 Hamster 

(Golden Syrian) 

12, 18, 24 mo 5 d/wk 6 hr/d 

200 F (CEL: liver 

hemangiosarcoma; skin carcinoma, 

Drew et al. 1983 

hemangiosarcoma; spleen hemangiosarcoma; mammary gland carcinoma; stomach adenoma) 

a Numbers correspond to entries in Figure 3-1. b Used to derive an acute-duration inhalation Minimal Risk Level (MRL) of 0.5 ppm. A NOAEL was adjusted for intermittent exposure and converted to a Human EqConcentration (HEC) before applying uncertainty factors. The MRL was obtained by dividing the NOAEL-HEC by an uncertainty factor of 30 (3 for extrapolation from humans using a dosimetric adjustment, and 10 for human variability). c Used to derive an intermediate-duration inhalation MRL of 0.03 ppm. LEC10 converted to an HEC and adjusted for intermittent exposure before applying uncertaMRL was obtained by dividing the LEC10-HEC by an uncertainty factor of 30 (3 for extrapolation from animals to humans using a dosimetric adjustment, and 10 for AKT = alpha-ketoglutarate transaminase; B - both; Bd Wt = body weight; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); derm = dermal; Endocr = eFemale; Gd = gestational day; Gn pig = guinea pig; hemato = hematological; hr = hour(s); Immuno = immunological; LOAEL = lowest-observed-adverse-effect leveminute(s); mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respiratory; SDH = sorbitol dehydrweek(s); x = time(s) 
Death Respiratory Cardiovascular Hepatic Renal 

Figure 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation 

Acute (≤14 days) 

Systemic 

ppm 

1E+6 

7g 1r 17g 12r 

17g 16m 

5m 10h 9g 17g 16m 12r 12r 2r 

100000 8g 6m 17g 16m 12r 11r 12r 16m

11r 13r 14r 

3m 

10000 

1000 

4m 

100 

10 

1 

0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans q-Cow a-Sheep g-Guinea Pig 
Ocular Body Immuno/Lymphor Neurological Reproductive Developmental C

Weight 

Figure 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued)

Acute (≤14 days) 

Systemic 

ppm 

1E+6 

17g 18g 

100000 27g 26m 22r 24r 

25m 20r 22r 23r 

30m 28g 

10000 28g 19 

25m 35

19 

31r 

15r 29r 32r 

21r 33m 

1000 

34h 

100 

33m 

10 

1 

*Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer endpoint. 0.1 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans q-Cow a-Sheep g-Guinea Pig 
0.01

0.1

1

10

100

1000

10000

100000

Death

37m 37m

38m 36r

Respiratory

49m

Cardiovascular

39r

39r

40r

Hematological

48m

41r

42r

45r

Musculoskeletal

43r

Hepatic

47m

48m

40r

41r

42r

43r

44r

45r

46r

50h

50h

Renal

48m

39r

39r

41r

42r

43r

43r

45r 50h

ppm

Figure 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Systemic

VINYL CHLORIDE

 3. HEALTH EFFECTS

46
0.01

0.1

1

10

100

1000

10000

100000

Neurological

55r

Reproductive

56r

56r

57r

57r

58r

58r

Cancer *

69s

70s

63m 64m 65m 66m 67m

68m 59r

60r

61r

62r

ppm

Figure 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continued)

Intermediate (15-364 days)

c-Cat

d-Dog

r-Rat

p-Pig

q-Cow

 -Humans

k-Monkey

m-Mouse

h-Rabbit

a-Sheep

f-Ferret

j-Pigeon

e-Gerbil

s-Hamster

g-Guinea Pig

n-Mink

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

 LOAEL, Less Serious-Animals

 NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

 LOAEL, Less Serious-Humans

 NOAEL - Humans

 LD50/LC50

 Minimal Risk Level

 for effects

 other than

 Cancer

Dermal

41r 41r

Body Weight

48m

43r

44r

45r 50h

Immuno/Lymphor

54m

51r

51r

52r

53r

Systemic

*Doses represent the lowest dose tested per study that produced a tumorigenic

response and do not imply the existence of a threshold for the cancer endpoint.

VINYL CHLORIDE

 3. HEALTH EFFECTS

47
Hepatic Renal Body Weight Reproductive Cancer * 

Figure 3-1 Levels of Significant Exposure to Vinyl Chloride - Inhalation (continue

Chronic (≥365 days) 

Systemic 

ppm 

10000 

71r 

1000 

76r 

81s 

73r 74r 

78m 

100 71r 71r 71r 72r 

79m 80m 80m 75r 

10 71r 71r 72r 

77r 

1 

0.1 

0.01 10-4 

0.001 10-5 

0.0001 10-6 

1E-5 10-7 

*Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer endpoint. 1E-6 

c-Cat -Humans f-Ferret n-Mink Cancer Effect Level-Animals Cancer Effect Level-Humans d-Dog k-Monkey j-Pigeon o-Other LOAEL, More Serious-Animals LOAEL, More Serious-Humans r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans p-Pig h-Rabbit s-Hamster NOAEL - Animals NOAEL - Humans q-Cow a-Sheep g-Guinea Pig 
VINYL CHLORIDE 49 

3. HEALTH EFFECTS 

Respiratory Effects. Limited information is available on the acute adverse effects from inhalation of 

vinyl chloride by humans. Autopsy findings from a man who died after being overcome by vinyl chloride 

revealed the irritating nature of a high-level inhalation exposure. The lungs were found to be intensely 

hyperemic, and some desquamation of the alveolar epithelium had occurred (Danziger 1960). Reports 

regarding respiratory effects in workers who are occupationally exposed to vinyl chloride are 

contradictory. Several epidemiologic studies found no increased incidence of respiratory disease among 

vinyl chloride workers (Gamble et al. 1976; Laplanche et al. 1987, 1992; NIOSH 1977). However, 

adverse respiratory effects were reported in several epidemiologic surveys and case reports, with these 

effects including increased incidence of emphysema (Suciu et al. 1975; Wong et al. 1991), decreased 

respiratory volume and vital capacity, respiratory insufficiency (Suciu et al. 1975), decreased respiratory 

oxygen and carbon dioxide transfer (Lloyd et al. 1984), pulmonary fibrosis of the linear type (Suciu et al. 

1975), abnormal chest x-rays (Lilis et al. 1975, 1976), and dyspnea (Walker 1976). Interpretation of 

many of these results is confounded by the inclusion of smokers among those exposed to vinyl chloride 

and the concurrent exposure of many vinyl chloride workers to PVC resin dust, which is known to 

produce respiratory lesions (Mastrangelo et al. 1979). 

Brief inhalation of high concentrations of vinyl chloride produced respiratory inflammation in a variety of 

animals. A 30-minute exposure of guinea pigs, mice, and rats to 100,000 ppm of vinyl chloride produced 

hyperemia in all three species (Mastromatteo et al. 1960). Exposure to higher concentrations 

(200,000 ppm and 300,000 ppm) produced increased congestion, edema, and at the highest 

concentrations, pulmonary hemorrhages in all three species (Mastromatteo et al. 1960). Tracheal 

epithelium was also absent in one guinea pig exposed to 400,000 ppm for 30 minutes (Mastromatteo et al. 

1960). Edema and congestion of the lungs of rats were also observed following a 2-hour exposure to 

150,000 ppm (Lester et al. 1963). 

Histopathologic examination of mice exposed to 2,500 ppm vinyl chloride 5 hours/day, 5 days/week for 

5–6 months revealed proliferation and hypertrophy of the bronchiolar epithelium, hyperplasia of the 

alveolar epithelium, hypersecretion of mucin (Suzuki 1978, 1980, 1981), increased endoplasmic 

reticulum and free ribosomes in Clara cells, and mobilization of alveolar macrophages (Suzuki 1980). 

These changes were observed irrespective of the recovery period (2 or 37 days), indicating that they were 

not readily reversible. However, these studies were limited by the small number of animals tested and the 

absence of a statistical analysis. 
VINYL CHLORIDE 50 

3. HEALTH EFFECTS 

Chronic exposure of rats to 5,000 ppm 7 hours/day, 5 days/week for 12 months produced hyperplasia of 

the olfactory epithelium, increased cellularity of the interalveolar septa of the lungs, and an increased 

incidence of pulmonary hemorrhage (Feron and Kroes 1979). Interstitial pneumonia and hemorrhagic 

lungs were observed in rats exposed to 30,000 ppm of vinyl chloride 4 hours/day, 5 days/week for 

12 months (Viola et al. 1971). However, neither of these studies reported the statistical significance of 

these findings. 

Cardiovascular Effects. Occupational exposure to vinyl chloride has been associated with the 

development of Raynaud's phenomenon, a condition in which the fingers blanch and become numb with 

discomfort upon exposure to the cold. It has also been reported in a worker exposed once to a vinyl 

chloride leak (Ostlere et al. 1992). Although only a small percentage of vinyl chloride workers develop 

Raynaud's phenomenon (Laplanche et al. 1987, 1992; Lilis et al. 1975; Marsteller et al. 1975; Suciu et al. 

1963, 1975; Veltman et al. 1975; Walker 1976), the incidence is significantly higher than in unexposed 

workers (Laplanche et al. 1987, 1992). Investigation of the peripheral circulation of workers afflicted 

with Raynaud's phenomenon has revealed thickening of the walls of the digital arteries (Harris and 

Adams 1967), narrowing of the arterial lumen (Veltman et al. 1975), vascular occlusions (Walker 1976), 

arterial occlusions (Preston et al. 1976; Veltman et al. 1975), tortuosity (Preston et al. 1976), 

hypervascularity (Preston et al. 1976), inflammatory infiltration of the arterioles (Magnavita et al. 1986), 

deposition of immune products along the vascular endothelium (Ward 1976), vasomotor impairment 

(Suciu et al. 1963), and impaired capillary microcirculation (Magnavita et al. 1986; Maricq et al. 1976). 

Three reports indicate that upon removal from exposure, Raynaud's phenomenon gradually disappears 

(Freudiger et al. 1988; Suciu et al. 1963, 1975). For further discussion of Raynaud's phenomenon, see 

Immunological/Lymphoreticular Effects (Section 3.2.1.3). 

Splenomegaly, with evidence of portal hypertension (dilated peritoneal veins and esophageal varices), has 

been reported by investigators studying the effects of vinyl chloride exposure (Marsteller et al. 1975). In 

addition, hypertension among vinyl chloride workers (NIOSH 1977; Suciu et al. 1975) and significantly 

increased mortality rate due to cardiovascular and cerebrovascular disease (Byren et al. 1976) have been 

reported. An association between vinyl chloride exposure and arterial hypertension was observed in an 

occupational worker study. Conclusive evidence was not provided for an association of vinyl chloride 

with coronary heart disease (Kotseva 1996). 

Investigators studying the anesthetic properties of vinyl chloride in dogs have observed that doses 

producing anesthesia (100,000 ppm, Oster et al. 1947; 150,000–900,000 ppm, Carr et al. 1949) also 
VINYL CHLORIDE 51 

3. HEALTH EFFECTS 

produced cardiac arrhythmias. Arrhythmias were characterized by intermittent tachycardia, 

extraventricular systoles, vagal beats, ventricular fibrillation, and atrioventricular block. However, the 

statistical significance of these effects was not reported. At high concentrations (>30,000 ppm), vinyl 

chloride was been shown to sensitize the heart to epinephrine, resulting in cardiac arrhythmias in dogs 

(Clark and Tinston 1973). No histopathological changes in the heart were noted in guinea pigs exposed to 

400,000 ppm of vinyl chloride for 30 minutes (Mastromatteo et al. 1960). 

A study by Bi et al. (1985) demonstrated an increase in the relative heart weight at concentrations of vinyl 

chloride as low as 10 ppm when administered to male rats 6 hours/day, 6 days/week for 6 months. Heart 

weight was also increased after 3 months in rats exposed to 100 ppm under this regimen (Bi et al. 1985). 

Chronic exposure of rats to 5,000 ppm vinyl chloride 7 hours/day, 5 days/week for 1 year resulted in 

increases in areas of myodegeneration in the heart and thickening of the walls of arteries (Feron and 

Kroes 1979). However, the statistical significance of this effect was not reported. Exposure of rats to 

30,000 ppm of vinyl chloride 4 hours/day, 5 days/week for 1 year also produced thickening of the walls of 

small arterial vessels. The thickening was characterized by a proliferation of the endothelium. In some 

vessels, the thickening was severe enough to cause blockage of the lumen (Viola 1970). 

Gastrointestinal Effects. Approximately 32% of the vinyl chloride workers examined by Lilis et al. 

(1975) reported a history of "gastritis, ulcers (gastric and duodenal), and upper gastrointestinal bleeding." 

Because these subjects were not compared to workers who had not been exposed to vinyl chloride, the 

significance of these findings is unknown. Other symptoms reported by vinyl chloride workers included 

nausea, abdominal distension, and heartburn. Loss of appetite and nausea have been reported in 

Singapore workers exposed to 1–21 ppm vinyl chloride (Ho et al. 1991). However, these workers were 

selected on the basis of liver dysfunction. 

No studies were located regarding gastrointestinal effects in animals following inhalation exposure to 

vinyl chloride. 

Hematological Effects. Blood tests performed at autopsy of two workers whose deaths were 

believed to be due to exposure to extremely high levels of vinyl chloride revealed that blood clotting did 

not occur (Danziger 1960). Slight-to-severe thrombocytopenia in workers occupationally exposed to 

vinyl chloride was reported in several studies (Marsteller et al. 1975; Micu et al. 1985; Veltman et al. 

1975), but Lilis et al. (1975) found no increased incidence of thrombocytopenia in vinyl chloride workers. 

A prospective study of female workers exposed to vinyl chloride at levels ranging from 0.2 to 130.7 ppm 
VINYL CHLORIDE 52 

3. HEALTH EFFECTS 

showed that the exposed workers had a significantly lower number of platelets than the nonexposed 

controls during the early part of their pregnancies (weeks 8–10) but that this effect abated by the end of 

the pregnancy (34–38 weeks) following a period free from exposure (Bao et al. 1988). Splenomegaly was 

reported in a number of studies (Ho et al. 1991; Marsteller et al. 1975; Popper and Thomas 1975; Suciu et 

al. 1963; Veltman et al. 1975). Thrombocytopenia was found in patients who both did and did not present 

with splenomegaly (Veltman et al. 1975). Increased levels of two plasma proteins (α1- and α2-globulin) 

were reported in studies examining the effects of occupational exposure to vinyl chloride (Harris and 

Adams 1967; Suciu et al. 1975). 

A brief (30-minute) exposure of guinea pigs to 400,000 ppm vinyl chloride resulted in a failure of the 

blood to clot in the animals that died during the exposure (Mastromatteo et al. 1960). Mice that were 

exposed to 5,000 ppm (4 hours/day for 6 days) or 10,000 ppm (4 hours/day for 5 days) showed an 

increased emergence of basophilic stippled erythrocytes (Kudo et al. 1990). This effect was also noted in 

mice that were exposed for 10 weeks to 50 ppm intermittently (4 hours/day for 4–5 days/week,) or to 30– 

40 ppm continuously for 62 days (Kudo et al. 1990). Exposure of dogs and rats to 200 ppm for 

7 hours/day, 5 days/week, for 6 months had no effect on hematologic values (Torkelson et al. 1961). 

Also, an 8-week exposure of mice to 1,000 ppm for 6 hours/day, 5 days/week had no effect on 

erythrocyte or leukocyte counts (Sharma and Gehring 1979). Exposure of rats to either 50,000 ppm for 

8 hours/day for 19 consecutive days or 20,000 ppm for 8 hours/day, 5 days/week for 92 days resulted in a 

decrease in white blood cells (Lester et al. 1963). Exposure of rats to 5,000 ppm vinyl chloride for 

7 hours/day, 5 days/week for 1 year produced increased hematopoiesis in the spleen (Feron and Kroes 

1979). The statistical significance of these results was not reported. Blood clotting time was decreased in 

rats exposed to 5,000 ppm for7 hours/day for 1 year, but the statistical significance of these effects was 

not reported (Feron et al. 1979a). 

Musculoskeletal Effects. Acroosteolysis, or resorption of the terminal phalanges of the finger, was 

observed in a small percentage of workers occupationally exposed to vinyl chloride (Dinman et al. 1971; 

Lilis et al. 1975; Marsteller et al. 1975; Sakabe 1975; Veltman et al. 1975; Wilson et al. 1967). Bone 

lesions were most often confined to the terminal phalanges of the fingers, but in a few cases the bones of 

the toes (Harris and Adams 1967), feet (Preston et al. 1976), sacroiliac joint (Harris and Adams 1967), 

and arms, legs, pelvis, and mandible (Preston et al. 1976) were also involved. Development of 

acroosteolysis was most often preceded by Raynaud's phenomenon (Dinman et al. 1971; Freudiger et al. 

1988; Harris and Adams 1967; Magnavita et al. 1986; Markowitz et al. 1972; Preston et al. 1976; Sakabe 

1975; Veltman et al. 1975; Wilson et al. 1967). In two reports, bone resorption was observed to progress 
VINYL CHLORIDE 53 

3. HEALTH EFFECTS 

despite discontinuation of exposure (Markowitz et al. 1972; Preston et al. 1976). However, in two other 

reports, improvement was observed after exposure ceased (Veltman et al. 1975; Wilson et al. 1967). Joint 

pain was also reported by Lilis et al. (1975). 

Although Sokal et al. (1980) found no alterations in the bones of male rats exposed to 20,000 ppm for 

5 hours/day, 5 days/week for 10 months, Viola (1970) observed skeletal changes (i.e., osteochondroma) 

in the bones of rats exposed to 30,000 ppm for 4 hours/day, 5 days/week for 12 months. The statistical 

significance of these effects was not reported and only one exposure level was tested. 

Hepatic Effects. Throughout the early years of the use of vinyl chloride, only a minimal degree of 

functional hepatic abnormalities were detected in workers. However, when it became apparent in the 

early 1970s that angiosarcoma of the liver was associated with long-term vinyl chloride exposure, an 

intensive effort was initiated by a number of investigators to characterize the hepatic effects of vinyl 

chloride. These studies revealed characteristic hepatic lesions produced by vinyl chloride exposure (Berk 

et al. 1975; Falk et al. 1974; Gedigke et al. 1975; Ho et al. 1991; Jones and Smith 1982; Lilis et al. 1975; 

Liss et al. 1985; Marsteller et al. 1975; NIOSH 1977; Popper and Thomas 1975; Suciu et al. 1975; 

Tamburro et al. 1984; Vihko et al. 1984). The incidence and severity of the effects correlated well with 

the duration of exposure (Gedigke et al. 1975; Lilis et al. 1975; NIOSH 1977). 

Routine, noninvasive techniques revealed hepatomegaly in a limited number of workers (14–37%) (Ho et 

al. 1991; Lilis et al. 1975; Marsteller et al. 1975; NIOSH 1977; Suciu et al. 1963, 1975). However, when 

peritoneoscopy was performed or biopsies were obtained from exposed workers, Marsteller et al. (1975) 

found a much higher prevalence of hepatic abnormalities. Only 37% of the workers studied by Marsteller 

et al. (1975) were diagnosed with hepatomegaly, but peritoneoscopy revealed a 50% incidence of granular 

changes in the liver surface and an 86% incidence of capsular fibrosis with increased numbers of capsular 

vessels. Histopathological examination of the biopsied tissue from these workers revealed an 80% 

incidence of collagenization of the sinusoidal walls, a 90% incidence of proliferation of cells lining the 

sinusoids, a 30% incidence of septal fibrosis, and degeneration of hepatocytes (incidence not specified). 

A number of other investigators observed similar changes in liver tissues obtained from workers exposed 

to vinyl chloride (Falk et al. 1974; Gedigke et al. 1975; Popper and Thomas 1975; Tamburro et al. 1984). 

Based on these observations, a profile of vinyl chloride-induced liver damage was compiled and includes 

the following features: hypertrophy and hyperplasia of hepatocytes, activation and hyperplasia of 

sinusoidal lining cells, fibrosis of the portal tracts and the septa and intralobular perisinusoidal regions, 

sinusoidal dilation, and focal areas of hepatocellular degeneration. This pattern of changes was observed 
VINYL CHLORIDE 54 

3. HEALTH EFFECTS 

to be highly unusual and was similar to the hepatic changes produced by arsenic (Gedigke et al. 1975). In 

addition, the degenerative changes in hepatocytes appeared to be less severe when biopsy material was 

obtained from workers who had not been exposed to vinyl chloride recently. However, sinusoidal 

changes were not influenced by the length of time since the last exposure (Gedigke et al. 1975). 

One possible reason that the hepatotoxic effects of vinyl chloride went undetected for many years was the 

lack of sensitivity of standard biochemical liver function tests to detect the liver injury produced by vinyl 

chloride (Berk et al. 1975; Marsteller et al. 1975; Tamburro et al. 1984; Vihko et al. 1984). For example, 

the values obtained in several standard biochemical liver function tests (activities of serum alkaline 

phosphatase, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase) from 

workers with biopsy evidence of vinyl chloride-associated liver damage were not significantly higher than 

those from unexposed controls (Liss et al. 1985). Gamma-glutamyltransferase levels were significantly 

higher in workers exposed to vinyl chloride at TWA exposure concentrations of >10 ppm compared to 

workers exposed to lower exposure concentrations (Du et al. 1995). Workers exposed to lower levels of 

vinyl chloride had gamma-glutamyltransferase levels that were within the normal range (Hensyl 1990). 

Abnormal liver function (i.e., increased alkaline phosphatase, alanine aminotransferase, or 

gamma-glutamyltransferase) was demonstrated in workers exposed to high concentrations of vinyl 

chloride (1–20 ppm) (Ho et al. 1991; Lilis et al.1975) and workers who experienced a combined exposure 

to vinyl chloride and ethylene dichloride (Cheng et al. 1999). In the mixed exposure situation, altered 

liver function may be related to the effect of each component or the interactive effect of the mixture. 

Serum bile acids (Berk et al. 1975; Liss et al. 1985) and/or indocyanine green clearance (Liss et al. 1985; 

Tamburro et al. 1984) correlated with liver injury. Furthermore, investigators have shown that levels of 

chenodeoxycholic acid (a serum bile acid) in asymptomatic vinyl chloride workers were elevated when 

compared to the 95% interval of values from a healthy reference population (Vihko et al. 1984). The 

serum hyaluronic acid concentration was demonstrated to be elevated in workers with angiosarcoma of 

the liver, while other liver function tests were normal (McClain et al. 2002). 

A recent IARC update of a multi-center cohort study demonstrated an increase in mortality from liver 

cirrhosis in workers exposed to moderate to high concentrations of vinyl chloride (Ward et al. 2001). 

Morbidity associated with liver cirrhosis was also reported to be elevated among vinyl chloride workers 

(Du and Wang 1998). Alcohol intake was not evaluated as a critical confounding factor in these studies. 

Mastrangelo et al (2004) evaluated the possible interaction between alcohol consumption, hepatitis 

infection, and liver cirrhosis in a large cohort of vinyl chloride workers. Vinyl chloride was suggested to 

be an independent risk factor for liver cirrhosis with a synergistic interaction described for alcohol 
VINYL CHLORIDE 55 

3. HEALTH EFFECTS 

consumption and an additive interaction observed for hepatitis infection. Liver ultrasonography 

illustrated an increase in the incidence of periportal fibrosis in vinyl chloride workers (Maroni et al. 

2003). Portal fibrosis and portal hypertension were considered to contribute to mortality in several cases 

(Lee et al. 1996; Lelbach 1996). 

Brief exposure of animals to extremely high concentrations of vinyl chloride has been shown to produce 

hepatic damage. For example, acute exposure (30 minutes) of guinea pigs and mice to 300,000 ppm of 

vinyl chloride produced liver congestion or severe fatty degeneration while 200,000 ppm caused fatty 

infiltration in rats (Mastromatteo et al. 1960). Exposure to 100,000 ppm for 6 hours produced 

centrilobular vacuolization and increased alanine serum α-ketoglutarate transaminase activity in rats 

(Jaeger et al. 1974). However, exposure of rats to 50,000 ppm for 6 hours produced no observable effects 

on the liver (Reynolds et al. 1975a, 1975b). In contrast, a single-concentration study in which pregnant 

rats were continuously exposed to 1,500 ppm for 7–9 days during either the first or second trimester of 

pregnancy resulted in an increase in the liver-to-body-weight ratio (Ungvary et al. 1978). Interestingly, a 

single 1-hour exposure of mice to 500, 5,000, or 50,000 ppm of vinyl chloride, followed by an 18-month 

observation period, resulted in an increased incidence of hepatocellular hypertrophy in these animals at 

terminal sacrifice (Hehir et al. 1981). The hypertrophy was not dose dependent; thus, the significance of 

this effect is uncertain. 

In studies with longer durations of exposure, lower concentrations of vinyl chloride have produced 

hepatic toxicity. Symptoms of hepatotoxicity that have been observed in rats have included 

hepatocellular degeneration (Sokal et al. 1980; Torkelson et al. 1961; Wisniewska-Knypl et al. 1980), 

swelling of hepatocytes with compression of sinusoids (Lester et al. 1963), dilation of the rough 

endoplasmic reticulum (Du et al. 1979), proliferation (Sokal et al. 1980) or hypertrophy (Thornton et al. 

2002; Wisniewska-Knypl et al. 1980) of smooth endoplasmic reticulum, changes in metabolic enzyme 

activities (Du et al. 1979; Wisniewska-Knypl et al. 1980), proliferation of reticulocytes (Sokal et al. 

1980), and an increased liver-to-body-weight ratio (Bi et al. 1985; Lester et al. 1963; Sokal et al. 1980; 

Thornton et al. 2002; Torkelson et al. 1961). For example, exposure of rats to 500 ppm for 7 hours/day, 

5 days/week for 4.5 months resulted in an increase in liver-to-body-weight ratio and granular 

degeneration (Torkelson et al. 1961). An increased liver-to-body-weight ratio was also found in rats 

exposed to 100 ppm vinyl chloride for 7 hours/day, 5 days/week for 6 months (Torkelson et al. 1961). 

Relative liver weight was decreased in mice exposed to 1,000 ppm vinyl chloride for 6 hours/day, 

5 days/week for 8 weeks (Sharma and Gehring 1979). The liver-to-body-weight ratio was shown to be 

increased in male rats exposed to 3,000 ppm, but not 100 ppm, vinyl chloride for 6 hours/day, 
VINYL CHLORIDE 56 

3. HEALTH EFFECTS 

5 days/week for 12 months (Bi et al. 1985). Significantly increased liver-to-body-weight ratio was also 

observed in rats exposed to concentrations of vinyl chloride as low as 10 ppm for 6 hours/day, 

6 days/week for 6 months (Bi et al. 1985). Exposure of rats to 500 ppm for 5 hours/day, 5 days/week for 

10 months produced swelling of hepatocytes and proliferation of reticuloendothelial cells, increased liver 

weight, and cellular degeneration; at 50 ppm, small lipid droplets and proliferation of smooth 

endoplasmic reticulum were noted (Sokal et al. 1980). Histopathological examination of rats exposed to 

either 50,000 ppm vinyl chloride for 8 hours/day for 19 consecutive days or 20,000 ppm vinyl chloride 

for 8 hours/day, 5 days/week, for 92 days showed hepatocellular hypertrophy, vacuolization, and 

sinusoidal compression (Lester et al. 1963). Mice exposed to 2,500 ppm vinyl chloride 5 hours/day, 

5 days/week for up to 6 months showed histopathological changes in the liver that included hyperplasia of 

hepatocytes and activated sinusoidal cells (Schaffner 1978). Centrilobular necrosis and degeneration 

were noted in rabbits exposed to 200 ppm vinyl chloride 7 hours/day, 5 days/week for 6 months but not at 

100 ppm vinyl chloride in this regimen (Torkelson et al. 1961). Also, exposure of rats to 50 ppm for 

5 hours/day, 5 days/week for 10 months produced fatty degeneration and proliferation of the smooth 

endoplasmic reticulum (Wisniewska-Knypl et al. 1980). Liver effects were observed in a 2-generation 

reproductive toxicity study where rats were exposed to 0, 10, 100, or 1,100 ppm vinyl chloride 

(6 hours/day for a 10-week premating period and a 3-week mating period) (Thornton et al. 2002). 

Absolute and relative mean liver weights were significantly increased at all exposure levels in F0 males 

and in 100- and 1,100-ppm F1 males. Centrilobular hypertrophy, considered to be a minimal adverse 

effect, was noted in the livers of all 1,100-ppm male and female F0 and F1 rats, most 100-ppm male and 

female F0 and F1 rats, and in 2/30 and 6/30 of the 10-ppm F0 male and F1 female rats, respectively. 

Centrilobular hypertrophy was not noted in the 30 female rats of the control group. Histopathological 

alterations occurring at 100 and 1,100 ppm included centrilobular hypertrophy and acidophilic, 

basophilic, and clear cell foci. Based on this study, an intermediate-duration MRL of 0.03 ppm was 

derived from a benchmark dose of 5 ppm as described in the footnote in Table 3-1. 

The NOAELs for liver effects in a number of species following a 6-month exposure to vinyl chloride 

indicated that mice and rats were the most sensitive (NOAEL=50 ppm), rabbits were the next most 

sensitive (NOAEL=100 ppm), and dogs and guinea pigs were the least sensitive (NOAEL>200 ppm) 

(Torkelson et al. 1961). 

Popper et al. (1981) compared histopathological findings from sections of liver from mice and rats 

exposed by Maltoni and LeFemine (1975) with the liver biopsy material obtained from vinyl chloride 

workers. Hyperplasia and hypertrophy of hepatocytes and/or sinusoidal cells, with areas of sinusoidal 
VINYL CHLORIDE 57 

3. HEALTH EFFECTS 

dilation, were observed in both humans and rodents. The major difference between the species was the 

greater degree of fibrosis, seen as reticulin deposition and collagen formation, in the livers of humans. 

Also, inflammatory cells were present in the livers of humans but not rodents. 

Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to 

vinyl chloride. 

Acute exposure of mice and rats to 300,000 ppm of vinyl chloride for 30 minutes resulted in kidney 

congestion (Mastromatteo et al. 1960). Also, the kidneys of one mouse out of five exposed to either 

100,000 or 200,000 ppm of vinyl chloride for 30 minutes showed degenerative changes (Mastromatteo et 

al. 1960). Exposure of rats to 50,000 ppm for 8 hours/day for 19 consecutive days or 20,000 ppm for 

8 hours/day, 5 days/week for 92 days produced no adverse effects on the kidneys (Lester et al. 1963). 

However, exposures of male rats to 3,000 ppm for 6 hours/day, 6 days/week, for 3 months produced an 

increase in the kidneys-to-body-weight ratio (Bi et al. 1985). After a 6-month observation period, there 

was also an increased kidneys-to-body-weight ratio noted in the male rats exposed to 100 ppm vinyl 

chloride for 6 hours/day, 6 days/week for 12 months; no effect was noted at 10 ppm (Bi et al. 1985). 

Relative kidney weights were increased in male rats exposed to 500 ppm vinyl chloride for 5 hours/day, 

5 days/week, for 10 months, although no histopathological changes in the kidney were noted (Sokal et al. 

1980). No changes in kidney weights were reported when mice were exposed to 1,000 ppm vinyl 

chloride 6 hours/day, 5 days/week for 8 weeks (Sharma and Gehring 1979). Urinalysis values were 

within normal limits in rats and rabbits exposed to 200 ppm vinyl chloride for up to 7 hours/day, 

5 days/week, for 6 months (Torkelson et al. 1961). One year of exposure to 5,000 ppm vinyl chloride for 

7 hours/day, 5 days/week produced an increase in the kidneys-to-body-weight ratio (Feron et al. 1979a) 

and tubular nephrosis in rats (Feron and Kroes 1979). However, the statistical significance of these 

findings was not reported in the study. 

Endocrine Effects. A study of workers exposed to vinyl chloride in PVC manufacturing plants 

reported that most workers who presented with scleroderma were shown to have thyroid insufficiency 

(Suciu et al. 1963). 

No histopathological effects on the adrenals were reported in guinea pigs exposed to 400,000 ppm for 

30 minutes (Mastromatteo et al. 1960). Rats exposed to 30,000 ppm vinyl chloride 4 hours/day, 

5 days/week for 12 months were found to have colloid goiter and markedly increased numbers of 

perifollicular cells (Viola 1970). 
VINYL CHLORIDE 58 

3. HEALTH EFFECTS 

Dermal Effects. Occupational exposure to vinyl chloride was observed to produce scleroderma-like 

skin changes on the hands of a small percentage of exposed workers (Freudiger et al. 1988; Lilis et al. 

1975; Marsteller et al. 1975; Suciu et al. 1963, 1975; Veltman et al. 1975; Walker 1976). The skin 

changes were characterized by a thickening of the skin (Lilis et al. 1975; Markowitz et al. 1972; Ostlere et 

al. 1992; Preston et al. 1976; Veltman et al. 1975; Walker 1976), decreased elasticity (Lilis et al. 1975), 

and edema (Lilis et al. 1975; Suciu et al. 1975) and were almost exclusively observed in exposed 

individuals who also suffered from Raynaud's phenomenon. Skin biopsies revealed increased collagen 

bundles in the subepidermal layer of the skin (Harris and Adams 1967; Markowitz et al. 1972; Ostlere et 

al. 1992; Veltman et al. 1975). Biochemical analyses by Jayson et al. (1976) demonstrated that a high 

rate of collagen synthesis was taking place in the affected skin. Most often the skin changes were 

confined to the hands and wrists, but Jayson et al. (1976) reported scleroderma-like skin changes on the 

hands, arms, chest, and face of one afflicted worker. 

Skin changes were observed in rats exposed to 30,000 ppm for 12 months (Viola 1970). The skin of the 

paws of the exposed rats showed areas of hyperkeratosis, thickening of the epidermis, edema, collagen 

dissociation, and fragmentation of the elastic reticulum. Interpretation of these results is limited by the 

absence of a statistical analysis and insufficient information on the treatment of control animals. Lester et 

al. (1963) reported that male rats exposed to 50,000 ppm vinyl chloride 8 hours/day for 19 days had thin 

coats and scaly tails, while females exposed to the same concentration showed no effects. For further 

information regarding scleroderma-like responses to vinyl chloride exposure, see Immunological and 

Lymphoreticular Effects (Section 3.2.1.3). 

Ocular Effects. Ocular effects that have been reported after inhalation exposure are believed to have 

resulted from direct contact of the vinyl chloride gas with the eyes and are discussed under Dermal 

Exposure (Section 3.2.3.2). No studies were located regarding ocular effects in humans that were related 

solely to the inhalation of vinyl chloride. No histopathological changes were noted in the eyes of guinea 

pigs exposed to 400,000 ppm vinyl chloride for 30 minutes (Mastromatteo et al. 1960). 

Body Weight Effects. Several studies have reported that workers intoxicated by vinyl chloride 

experienced anorexia (Suciu et al. 1963, 1975). 

No effects on body weight were noted in ICR mice exposed to either 10,000 ppm vinyl chloride 

4 hours/day for 5 days or to 5,000 ppm vinyl chloride 4 hours/day for 6 days (Kudo et al. 1990). No 
VINYL CHLORIDE 59 

3. HEALTH EFFECTS 

consistent or dose-related differences in body weight were noted between control rats and rats exposed to 

up to 50,000 ppm for 1 hour or rats exposed to 500 ppm 5 days/week, for 2 weeks (Hehir et al. 1981). 

However, statistical analysis was not performed. No changes in body weight gain were noted in rats or 

rabbits exposed to 200 ppm vinyl chloride 7 hours/day, 5 days/week for 6 months (Torkelson et al. 1961) 

or in mice exposed to 1,000 ppm vinyl chloride 6 hours/day, 5 days/week for 8 weeks (Sharma and 

Gehring 1979). Significant decreases were found in the body weight of rats exposed to 100 ppm vinyl 

chloride 6 hours/day, 6 days/week for 12 months; these changes were not observed at 10 ppm (Bi et al. 

1985). Significant decreases were also noted in mean body weights of rats exposed to 5,000 ppm vinyl 

chloride 7 hours/day, 5 days/week for 4–52 weeks but these data were not quantified (Feron et al. 1979a). 

This study was limited since only one concentration was tested. Body weight was decreased 10% in male 

rats exposed to 50 ppm vinyl chloride 5 hours/day, 5 days/week for 10 months (Sokal et al. 1980). 

Maternal body weight gain was significantly decreased in mice exposed to 500 ppm for 7 hours/day 

during gestation days (Gd) 6–15 (John et al. 1977). 

3.2.1.3 Immunological and Lymphoreticular Effects 

A number of studies have examined the immunologic profiles of workers occupationally exposed to vinyl 

chloride. Male workers exposed to vinyl chloride for an average of 8 years, with concentrations ranging 

from 1 to 300 ppm during sampling periods, were found to have significantly increased percentages of 

lymphocytes compared to controls (Fucic et al. 1995, 1997, 1998). Additionally, 75 out of these 

100 workers showed disturbances of mitotic activity in these cells. A statistically significant increase in 

circulating immune complexes in workers exposed to vinyl chloride was observed when compared to 

levels in unexposed workers (Bogdanikowa and Zawilska 1984). The increase in circulating immune 

complexes was greatest in women and in those with duties involving exposure to relatively higher levels 

of vinyl chloride. Compared to controls, immunoglobulin G (IgG) levels were significantly increased in 

women exposed to the high levels of vinyl chloride in the same study. 

Studies of workers who have developed "vinyl chloride disease," a syndrome consisting of Raynaud's 

phenomenon, acroosteolysis, joint and muscle pain, enhanced collagen deposition, stiffness of the hands, 

and scleroderma-like skin changes, indicate that this disease may have an immunologic basis. Sera 

obtained from patients with varying degrees of severity of symptoms of vinyl chloride disease 

demonstrate a close correlation between the disease severity and the extent of the immunologic 

abnormality (Grainger et al. 1980; Langauer-Lewowicka et al. 1976; Ward 1976), although these 
VINYL CHLORIDE 60 

3. HEALTH EFFECTS 

symptoms have been reported without immunological findings (Black et al. 1986; Ostlere et al. 1992). 

The most frequent immunologic finding in workers with vinyl chloride disease is an increase in 

circulating immune complexes or cryoglobulinemia. In workers with the most severe clinical signs, there 

also are an increased incidence of B-cell proliferation, hyperimmunoglobulinemia (Ward 1976), 

cryoglobulinemia (Grainger et al. 1980), and complement activation (Grainger et al. 1980; Ward 1976). 

Evidence of a structurally altered IgG has been obtained, and it has been proposed that vinyl chloride (or 

a metabolite) binds to IgG (Grainger et al. 1980). 

Based on the similarity of vinyl chloride disease and systemic sclerosis, which may be a genetically 

linked autoimmune disease, Black et al. (1983, 1986) examined the human lymphocyte antigen (HLA) 

phenotypes of patients with vinyl chloride disease. Many autoimmune diseases show statistically 

significant associations with certain HLA alleles. These authors found that when compared to unexposed 

controls or asymptomatic controls, workers with vinyl chloride disease had a significantly greater 

incidence of possessing the HLA-DR5 allele. Furthermore, among those with the disease, the severity of 

the symptoms was significantly related to the possession of the HLA-DR3 and B8 alleles. These authors 

concluded that susceptibility was increased in the presence of HLA-DR5 or a gene in linkage 

disequilibrium with it, and progression was favored by HLA-DR3 and B8 phenotypes. Immune system 

dysfunction has also been linked to a case of polymyositis (i.e., muscle fiber necrosis and atrophy) in an 

exposed worker, with involvement of antibodies to histidyl-t-RNA synthetase (Jo-1) (Serratrice et al. 

2001). 

Splenomegaly was reported in a number of studies (Ho et al. 1991; Marsteller et al. 1975; Popper and 

Thomas 1975; Suciu et al. 1963; Veltman et al. 1975). No histopathological changes were noted in the 

spleen or lymph nodes of guinea pigs exposed to 400,000 ppm vinyl chloride for 30 minutes 

(Mastromatteo et al. 1960). An increase in the relative spleen weight was observed in rats exposed to 

50 ppm for 5 hours/day, 5 days/week for 10 months (Sokal et al. 1980). Although no dose response was 

evident, increased relative spleen weight was also reported by Bi et al. (1985) when rats were exposed to 

either 10 ppm for 6 hours/day, 6 days/week for 6 months or 3,000 ppm for 6 hours/day, 6 days/week for 

3 months. This effect was not observed at 100 ppm in the 3-month study (Bi et al. 1985). 

The immunologic effects of vinyl chloride have been examined in mice (Sharma and Gehring 1979). 

Lymphocytes isolated from the spleens of mice exposed to concentrations as low as 10 ppm vinyl 

chloride 6 hours/day, 5 days/week for 4 weeks had increased spontaneous and lectin-stimulated 
VINYL CHLORIDE 61 

3. HEALTH EFFECTS 

transformation. This increase was not observed when lymphocytes from unexposed mice were cultured 

in the presence of vinyl chloride. 

The highest NOAEL value and all reliable LOAEL values for immunological effects in guinea pigs, mice, 

and rats exposed in acute- and intermediate-duration studies are recorded in Table 3-1 and plotted in 

Figure 3-1. For further information on Raynaud's phenomenon and scleroderma-like responses to vinyl 

chloride, see Cardiovascular and Dermal Effects (Section 3.2.1.2). 

3.2.1.4 Neurological Effects 

Vinyl chloride was once considered for use as an inhalation anesthetic (ACGIH 2003). Investigators 

studying the effects of vinyl chloride exposure frequently report central nervous system symptoms that 

are consistent with the anesthetic properties of vinyl chloride. The most commonly reported central 

nervous system effects are ataxia or dizziness (Ho et al. 1991; Langauer-Lewowicka et al. 1983; Lilis et 

al. 1975; Marsteller et al. 1975; Spirtas et al. 1975; Suciu et al. 1963, 1975; Veltman et al. 1975), 

drowsiness or fatigue (Langauer-Lewowicka et al. 1983; Spirtas et al. 1975; Suciu et al. 1963, 1975; 

Walker 1976), loss of consciousness (NIOSH 1977), and/or headache (Langauer-Lewowicka et al. 1983; 

Lilis et al. 1975; Marsteller et al. 1975; NIOSH 1977; Spirtas et al. 1975; Suciu et al. 1963, 1975; 

Veltman et al. 1975). Other central nervous system effects that have been reported by vinyl chloride 

workers include euphoria and irritability (Suciu et al. 1963, 1975), visual and/or hearing disturbances 

(Marsteller et al. 1975), nausea (Marsteller et al. 1975; Spirtas et al. 1975), memory loss (LangauerLewowicka et al. 1983; Suciu et al. 1963, 1975), and nervousness and sleep disturbances (LangauerLewowicka et al. 1983; Suciu et al. 1963). Central nervous system tests revealed pyramidal signs and 

cerebellar disturbances in some exposed subjects (Langauer-Lewowicka et al. 1983); however, reliable 

estimates of exposure levels producing these effects were not available. 

Exposure of volunteers to known levels of vinyl chloride has provided some indication of the levels of 

vinyl chloride associated with the effects noted above. Volunteers exposed to 25,000 ppm vinyl chloride 

for 3 minutes, in a single-exposure study, reported experiencing dizziness, disorientation, and burning 

sensations in the feet during exposure (Patty et al. 1930). Recovery from these effects was rapid upon 

termination of exposure, but the subjects developed headaches. Exposure of volunteers to concentrations 

of vinyl chloride ranging from 4,000 to 20,000 ppm for 5 minutes twice a day in periods separated by 

6 hours on 3 consecutive days was studied by Lester et al. (1963). No effects were noted at 4,000 ppm. 
VINYL CHLORIDE 62 

3. HEALTH EFFECTS 

However, at 8,000 ppm one of six subjects reported feeling dizzy. The incidence of dizziness increased at 

higher concentrations. Nausea was experienced at higher concentrations, and recovery from all effects 

was rapid upon termination of exposure. Headaches developed following exposure to 20,000 ppm. 

Indications of an exposure-related peripheral neuropathy have been observed in a number of the 

occupational studies. A peripheral neuropathy, most severe in hands and feet, was diagnosed in 70% of 

the vinyl chloride workers examined in a study by Perticoni et al. (1986). The peripheral neuropathy was 

manifested as denervation-related fasciculations and fibrillations and increased duration and amplitude of 

motor unit potentials (indicating collateral sprouting). Similar effects were observed by Magnavita et al. 

(1986) in a case study of a vinyl chloride worker. Other peripheral nervous system symptoms have been 

reported by a number of investigators studying the effects of occupational exposure to vinyl chloride. 

The symptom most frequently reported was tingling (paresthesia) in the extremities (Lilis et al. 1975; 

Sakabe 1975; Spirtas et al. 1975; Suciu et al. 1963, 1975; Veltman et al. 1975; Walker 1976). Additional 

peripheral nervous system symptoms included numbness in the fingers (Lilis et al. 1975; Sakabe 1975), 

weakness (Langauer-Lewowicka et al. 1983; Suciu et al. 1963, 1975), depressed reflexes (NIOSH 1977), 

warmth in the extremities (Suciu et al. 1963, 1975), and pain in the fingers (Sakabe 1975). It is unclear 

whether some of these symptoms are associated with tissue anoxia due to vascular insufficiency, or 

whether they represent the direct toxic effects of vinyl chloride on peripheral nerves. 

Acute exposure of a number of species to high levels of vinyl chloride has provided additional 

information on the characteristics of the central nervous system effects that are produced. Exposure of 

guinea pigs to 10,000 ppm for 8 hours (Patty et al. 1930) was observed to be without effects. Exposure to 

25,000 ppm resulted in ataxia, which developed into unconsciousness during the 8-hour exposure. As the 

concentration was increased, the development of unconsciousness was more rapid. At 100,000 ppm, 

Mastromatteo et al. (1960) observed the development of unconsciousness within 30 minutes. Mice 

experienced similar signs at approximately equivalent exposure levels. At 5,000 ppm, vinyl chloride was 

without effect during a 1-hour exposure. Exposure to 50,000 ppm produced ataxia and twitching (Hehir 

et al. 1981), and at 100,000 ppm for 30 minutes, unconsciousness was produced, proceeded by increased 

motor activity, incoordination, twitching, and tremors (Mastromatteo et al. 1960). Similar effects in rats 

were observed by Lester et al. (1963), Jaeger et al. (1974), and Mastromatteo et al. (1960). In contrast, in 

two reports using rats, exposure to 50,000 ppm for either 1 or 6 hours was without effect (Hehir et al. 

1981; Jaeger et al. 1974). No effects were noted in rats exposed to 500 ppm vinyl chloride for 2 weeks 

(1 hour/day, 5 days/week) or in rats exposed to 50 ppm for 20 weeks (1 hour/day, 5 days/week) (Hehir et 
VINYL CHLORIDE 63 

3. HEALTH EFFECTS 

al. 1981). In addition, tolerance developed to the intoxicating effects of exposure to 50,000 ppm vinyl 

chloride after five or six 8-hour exposures (Lester et al. 1963). 

Chronic exposure of rats to high levels of vinyl chloride has produced damage to nervous tissue. Rats 

exposed to 30,000 ppm for 4 hours/day, 5 days/week for 12 months in a single-concentration study were 

soporific during exposures (Viola 1970; Viola et al. 1971). Following 10 months of exposure, the rats 

had decreased responses to external stimuli and disturbed equilibrium. Histopathological examination 

revealed diffuse degeneration of gray and white matter. Cerebellar degeneration in the Purkinje cell layer 

was pronounced. Also, peripheral nerve endings were surrounded and infiltrated with fibrous tissue 

(Viola 1970; Viola et al. 1971). Nonneoplastic lesions in the brain were not noted in rats exposed to 

5,000 ppm for 7 hours/day, 5 days/week for 12 months in a single-concentration study by Feron and 

Kroes (1979). 

The highest NOAEL values and all reliable LOAEL values for neurological effects in each species from 

acute- or intermediate-duration studies are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.5 Reproductive Effects 

A number of case reports of workers occupationally exposed to vinyl chloride suggest that sexual 

performance may be affected by vinyl chloride. However, these studies are limited by the lack of 

quantification of exposure levels and possible concomitant exposures to other chemicals. Sexual 

impotence was reported by 24% of the workers examined by Suciu et al. (1975). Approximately 20% of 

the workers examined by Veltman et al. (1975) complained of potency troubles. A loss of libido in 35% 

and impotence and decreased androgen secretion in 8% of workers exposed at least once to very high 

levels of vinyl chloride were also reported by Walker (1976). 

In retrospective and prospective studies by Bao et al. (1988), increased incidence and severity of elevated 

blood pressure and edema during pregnancy (preeclampsia) were found in female workers exposed to 

vinyl chloride when compared to unexposed workers. Company records indicated that exposure levels 

ranged from 3.9 to 89.3 ppm during the retrospective study and from 0.2 to 130.7 ppm during the 

prospective study. More detailed information regarding the exposure levels was not presented. 
VINYL CHLORIDE 64 

3. HEALTH EFFECTS 

A 2-generation reproductive toxicity study was conducted in rats exposed to vinyl chloride via inhalation 

(Thornton et al. 2002). Male and female Sprague-Dawley rats were exposed to 0, 10, 100, or 1,100 ppm 

vinyl chloride 6 hours/day for a 10-week premating period and a 3-week mating period. No adverse 

effects were noted in reproductive capability over the two generations at any dose. No effects were seen 

in body weight, feed consumption, ability to reproduce, gestation index or length, or pre- and 

postweaning developmental landmarks. Sperm counts, motility, and morphology were also unaffected by 

vinyl chloride exposure. Changes in liver weights and/or histopathological alterations were seen in F0 and 

F1 generation male and female rats. For further information regarding the liver toxicity of vinyl chloride, 

see Section 3.2.1.2. 

Two dominant lethal studies examined the reproductive performance of exposed male rats. A brief 

exposure (5 days, 6 hours/day) of mice to concentrations of vinyl chloride as high as 30,000 ppm had no 

effect on male fertility or pre- or postimplantation loss (Anderson et al. 1976). In contrast, exposure of 

male rats to concentrations as low as 250 ppm for 6 hours/day, 5 days/week for 11 weeks produced a 

decrease in the ratio of pregnant to mated females, indicating a decrease in male fertility; this effect was 

not observed at 50 ppm (Short et al. 1977). These results are supported by two studies using rats in which 

adverse effects of vinyl chloride on the testes were observed (Bi et al. 1985; Sokal et al. 1980). Exposure 

of rats to 100 ppm for 6 hours/day, 6 days/week for 12 months produced a significant increase in the 

incidence of damage to the seminiferous tubules and depletion of spermatocytes (Bi et al. 1985). At the 

6-month interim sacrifice, a significant decrease in testicular weight was also observed at 100 ppm. No 

effect on male reproductive organs was observed in this study at 10 ppm. Several methodological 

limitations have been identified for this study. Temperature and humidity conditions in the inhalation 

chambers were not maintained within the normal range. Inhalation chamber volume and air flow were 

also not held constant across dose groups. A significant increase in damage to the spermatogenic 

epithelium and disorders of spermatogenesis were found with exposure to 500 ppm vinyl chloride for 

5 hours/day, 5 days/week for 10 months, but was not observed after exposure to 50 ppm vinyl chloride 

(Sokal et al. 1980). Temperature and relative humidity values were not reported for this study. No 

significant change in testicular weight was found in rats exposed to 500 ppm for 7 hours/day, 5 days/week 

for 4.5 months or in dogs, rabbits, or guinea pigs exposed to 200 ppm for 7 hours/day, 5 days/week for 

6 months (Torkelson et al. 1961). However, the quality of this study is limited because of the small 

number of animals tested. Exposures involved up to 10 rats or guinea pigs of each gender, three rabbits 

of each sex, and one dog of each sex. No histopathological data on the testes of these animals were 

presented. 
VINYL CHLORIDE 65 

3. HEALTH EFFECTS 

The highest NOAEL values and all reliable LOAEL values for reproductive effects in each species and 

duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.1.6 Developmental Effects 

Although evidence has been presented indicating that members of communities with nearby vinyl 

chloride polymerization facilities have significantly greater incidences of some forms of developmental 

toxicity, these studies failed to demonstrate a statistically significant correlation between the 

developmental toxicity and either parental occupation or proximity to the facility (Edmonds et al. 1978; 

Infante 1976; Rosenman et al. 1989; Theriault et al. 1983). 

The pregnancy outcome of wives of workers employed at a vinyl chloride polymerization facility was 

compared to the pregnancy outcome of wives of a control group made up of unexposed rubber workers 

and PVC fabricators believed to be exposed to "very low" levels of vinyl chloride (Infante et al. 1976a, 

1976b). Pregnancy outcomes were determined based on the responses given by fathers on a 

questionnaire. Infante et al. (1976a, 1976b) and NIOSH (1977) reported a significant excess of fetal loss 

in the group whose husbands had been exposed to vinyl chloride. The greatest difference occurred in 

wives of men under 30 years of age, where fetal loss was 5.3% for controls and 20.0% for exposed 

workers. However, this study has been severely criticized based on the conduct of the study and method 

of statistical analysis used (Hatch et al. 1981; Stallones 1987). Furthermore, Hatch et al. (1981) and 

Stallones (1987) concluded that the study failed to demonstrate an association of parental exposure to 

vinyl chloride with increased fetal loss. 

Additional work by Infante (1976) and Infante et al. (1976b) examined the occurrence of congenital 

malformations among populations exposed to emissions from PVC polymerization facilities. A 

statistically significant increase in birth defects was observed in three cities in which polymerization 

facilities were located when compared to statewide and countywide averages. The greatest increases 

were noted in malformations of the central nervous system, upper alimentary tract, and genital organs and 

in the incidence of club foot. However, this study has also been criticized based on the conduct and 

analyses used (Hatch et al. 1981; Stallones 1987). These authors concluded that the study failed to 

demonstrate an association between exposure to emissions and the prevalence of birth defects. 

Furthermore, another study that examined the incidence of malformations in one of the cities studied by 

Infante (1976) concluded that, although the city had statistically increased incidences of congenital 
VINYL CHLORIDE 66 

3. HEALTH EFFECTS 

malformations, no correlation existed with parental proximity to the polymerization plant or with parental 

employment at the plant (Edmonds et al. 1975). In fact, more parents of control infants worked at the 

plant or lived closer to the plant than parents of infants with central nervous system malformations. 

Additional studies have also examined the prevalence of congenital malformations in populations exposed 

to emissions from polymerization facilities (Edmonds et al. 1978; Rosenman et al. 1989; Theriault et al. 

1983). The incidence of central nervous system defects in a West Virginia county with a polymerization 

plant was compared to incidences in other regions in the United States with no known exposure to vinyl 

chloride (Edmonds et al. 1978). Although the rate of central nervous system defects in the West Virginia 

county exceeded that in control areas, no correlation was noted between the increased central nervous 

system defects and parental occupation or potential exposure based on proximity to the plant or prevailing 

wind patterns. 

A significantly greater prevalence of birth defects was found in residents of a town with a polymerization 

facility than in three matched towns without potential for exposure to vinyl chloride (Theriault et al. 

1983). The most commonly reported defects included those of the musculoskeletal, alimentary, 

urogenital, and central nervous systems. The incidences were observed to fluctuate with seasonal changes 

in emissions. However, no correlations were found between the presence of defects and proximity of the 

residence to the plant or parental occupation. Also, other industrial emissions could not be eliminated as 

potential sources of the increased incidence of congenital malformations observed and additional 

confounding factors such as nutritional status, smoking, and alcohol and other drug use were not 

eliminated. 

No significant increases in birth defects were observed in a community with two polymerization facilities, 

but odds ratios for central nervous system defects were found to correlate with the amount of emissions 

from the individual facilities and with the distance of the residences of affected parents from the facilities 

(Rosenman et al. 1989). However, this study was limited by the small sample size. 

Pregnancy outcomes of mothers occupationally exposed to vinyl chloride for >1 year were compared to 

those of pregnant workers not exposed to vinyl chloride in retrospective and prospective studies (Bao et 

al. 1988). Company records indicated that exposure levels ranged from 3.9 to 89.3 ppm during the 

retrospective study and from 0.2 to 130.7 ppm during the prospective study. More detailed information 

regarding the exposure levels was not presented. The study authors concluded that exposure to vinyl 
VINYL CHLORIDE 67 

3. HEALTH EFFECTS 

chloride did not correlate with changes in sex ratio, birth weight or height, perinatal mortality, or the 

incidence of congenital abnormalities. 

A number of inhalation studies have examined the effects of vinyl chloride exposure on pregnancy 

outcome in animals. Results of these studies indicate that vinyl chloride produces adverse developmental 

effects at concentrations that are also toxic to maternal animals. John et al. (1977, 1981) exposed rats and 

rabbits to 0, 500, or 2,500 ppm and mice to 0, 50, or 500 ppm throughout the period of organogenesis. 

Separate control groups were used for each of the mice exposure concentrations. Mice were most 

sensitive to the effects of vinyl chloride. In mice exposed to 500 ppm, maternal toxicity was evidenced 

by decreased food consumption, decreased body weight gain, and increased mortality rate (John et al. 

1977, 1981). Delayed ossification was noted in fetuses at 500 ppm. The only significant fetal effect 

observed at 50 ppm was an increase in crown-rump length. The biological significance of this effect is 

unknown. Based on this NOAEL of 50 ppm, an acute-duration MRL of 0.5 ppm was calculated as 

described in the footnote in Table 3-1. In rats, 500 ppm produced decreased maternal weight gain and 

fetal weight, increased crown-rump length, and vertebral lumbar spurs. Increasing the exposure level to 

2,500 ppm was not associated with a dose-dependent increase in these effects. The only effects observed 

at 2,500 ppm were decreased maternal food consumption and, in fetuses, an increased incidence of dilated 

ureters. In rabbits exposed to 500 ppm, maternal animals had decreased food consumption, and fetal 

animals had delayed ossification. These effects were not observed in rabbits at 2,500 ppm. However, the 

number of animals that were tested at 2,500 ppm was much lower than at 500 ppm (5 versus 20); thus, no 

conclusions may be drawn as to the dose response of these effects. 

An embryo-fetal developmental toxicity study was conducted in rats exposed to vinyl chloride via 

inhalation (Thornton et al. 2002). Female Sprague-Dawley rats were exposed to 0, 10, 100, or 1,100 ppm 

vinyl chloride 6 hours/day on Gd 6–19. No adverse effects were noted in embryo-fetal developmental 

parameters including uterine implantation, fetal gender distribution, fetal body weight, and fetal 

malformations and variations. Vinyl chloride produced a decrease in maternal body weight gain at all 

exposure levels; however, no changes were observed in feed consumption, clinical signs, or postmortem 

gross findings. Maternal liver and kidney weights were increased relative to total body weight. 

Exposure of rats to either 0 or 1,500 ppm of vinyl chloride during the first, second, or third trimester of 

pregnancy was examined (Ungvary et al. 1978). In maternal animals, an increased liver-to-body weight 

ratio was observed in those exposed during the first and second trimesters, but no histopathologic 

alterations were found. A significant increase in resorptions was observed in animals exposed during the 
VINYL CHLORIDE 68 

3. HEALTH EFFECTS 

first trimester of pregnancy. Two central nervous system malformations (microphthalmia and 

anophthalmia) were observed in exposed fetuses but not in controls, but the incidence of these 

malformations did not reach statistical significance. This study is limited in that only a single 

concentration of vinyl chloride was tested, precluding conclusions as to the dose-response relationship of 

the effects observed. 

The effects of exposure of rats to vinyl chloride throughout gestation were examined by Mirkova et al. 

(1978) and Sal'nikova and Kotsovskaya (1980). An unspecified number of pregnant rats were exposed to 

0, 1.9, or 13.9 ppm for 4 hours/day for the 21 days of gestation. Fetuses were examined for abnormalities 

just prior to the end of gestation, and offspring were examined at 6 months postparturition (Sal'nikova and 

Kotsovskaya 1980). At 13.9 ppm, a decrease in maternal erythrocyte count was observed. At 1.9 and 

13.9 ppm, fetuses had an increased incidence of hemorrhages, and at 13.9 ppm, increased edema. 

However, the affected organs were not specified. Rats examined at 6 months, following in utero 

exposure to 1.9 ppm, were found to have decreased hemoglobin and leukocytes and decreased organ 

weights (males: liver, kidneys, spleen; females: lung, liver). In addition to these effects, exposure to 

13.9 ppm in utero resulted in an increased hexanol sleep time and a decreased ability of the rats to orient 

themselves. 

Continuous exposure of an unspecified number of rats throughout gestation to 2.4 ppm of vinyl chloride 

resulted in decreased fetal weight and increased early postimplantation loss, hematomas, and 

hydrocephaly with intracerebral hematoma. Weanling rats had hepatotoxic effects including decreased 

bile enzyme activity, decreased bile secretion, and decreased cholic acid content,. No histological data on 

the livers of pups, or information regarding maternal health, or statistical analyses of the data were 

presented (Mirkova et al. 1978). Also, both this study and the report by Sal'nikova and Kotsovskaya 

(1980) failed to provide information on the number of animals in each test group. 

The developmental toxicity of vinyl chloride was examined using a whole embryo culture system (Zhao 

et al. 1996). Vinyl chloride induced embryo growth retardation, but was not shown to be teratogenic in 

the rat in vitro whole embryo culture system. 

The highest NOAEL value and all reliable LOAEL values for developmental effects in mice, rats, and/or 

rabbits in acute-duration studies are recorded in Table 3-1 and plotted in Figure 3-1. 
VINYL CHLORIDE 69 

3. HEALTH EFFECTS 

3.2.1.7 Cancer 

A recent review pooled the analyses of worker cohorts from 56 vinyl chloride plants in North America 

and Europe (Bosetti et al. 2003). This analysis includes over 22,000 workers and represents the most 

comprehensive data on occupational risks of vinyl chloride exposure. An elevated risk of liver cancer 

mortality was observed. While differences between the two cohorts were observed for excess soft tissue 

sarcoma and brain cancer, no significant excess for these effects were seen in the pooled data. Deaths 

from lung and laryngeal cancer were lower than expected, and no excess cancer risk was observed for 

lymphoid and hematopoietic system cancers. The most compelling evidence for the carcinogenic 

potential of vinyl chloride in humans comes from the cluster of reports of greater than expected 

incidences of angiosarcoma of the liver in workers occupationally exposed to vinyl chloride (Byren et al. 

1976; Creech and Johnson 1974; Forman et al. 1985; Fox and Collier 1977; Infante et al. 1976b; Jones et 

al. 1988; Laplanche et al. 1992; Lee et al. 1996; Monson et al. 1975; Pirastu et al. 1990; Rinsky et al. 

1988; Simonato et al. 1991; Teta et al. 1990; Theriault and Allard 1981; Waxweiler et al. 1976; Weber et 

al. 1981; Wong et al. 1991; Wu et al. 1989). Angiosarcoma of the liver is considered to be a very rare 

type of cancer (25–30 cases/year in the United States) (Heath et al. 1975). However, approximately 

30 years after the introduction of vinyl chloride for use in the industrial production of PVC, it became 

apparent that workers exposed to high levels of vinyl chloride had an unusually high incidence of this 

type of tumor. Investigators identified an increased likelihood of developing hepatic angiosarcoma 

among those exposed to the highest levels of vinyl chloride and those exposed to vinyl chloride for the 

longest duration (Fortwengler et al. 1999; Fox and Collier 1977; Infante et al. 1976b; Jones et al. 1988; 

Rinsky et al. 1988; Weber et al. 1981; Wong et al. 1991; Wu et al. 1989). Angiosarcoma of the liver was 

not found in residents living in the vicinity of vinyl chloride sites, unless they were also exposed to high 

concentrations of vinyl chloride in the workplace (Elliott and Kleinschmidt 1997). Based on this 

information, vinyl chloride is considered to be a carcinogen in humans (EPA 1994c; IARC 1987). 

Histopathological examination of liver tissue from humans with hepatic angiosarcoma has led to the 

hypothesis that angiosarcoma develops as a result of hyperplastic changes in sinusoidal cells. Areas of 

transition to angiosarcoma contained greatly increased numbers of sinusoidal cells with greatly expanded 

sinusoidal spaces. Also, hepatic cells were replaced by fibrous tissue forming trabeculae. These areas 

also showed infiltration of angiosarcoma cells. In fully developed angiosarcoma, multiple areas with 

nodules of angiosarcoma cells were noted, the centers of which exhibited hemorrhagic necrosis (Popper et 

al. 1981). A recent case report suggests that vinyl chloride can also produce malignant hemangiopericytoma in the liver, which is a vascular tumor similar to angiosarcoma (Hozo et al. 1997, 2000). 
VINYL CHLORIDE 70 

3. HEALTH EFFECTS 

Other liver tumors, including hepatocellular carcinoma and cholangiocellular carcinoma, have also been 

associated with occupational exposure to vinyl chloride (Cheng et al. 1999; Du and Wang 1998; Lelbach 

1996; Saurin et al. 1997; Ward et al. 2001; Weihrauch et al. 2000; Wong et al. 2002a, 2003a). A metaanalysis of eight independent studies confirms an increased risk of hepatocellular carcinoma for 

occupational workers exposed to vinyl chloride (Boffetta et al. 2003). The risk of developing liver cancer 

appears elevated in those with a history of Hepatitis B viral infection (Du and Wang 1998; Wong et al. 

2003a). Mastrangelo et al (2004) evaluated the possible interaction between alcohol consumption, 

hepatitis infection and hepatocellular carcinoma in a large cohort of vinyl chloride workers. Vinyl 

chloride was suggested to be an independent risk factor for hepatocellular carcinoma with a synergistic 

interaction described for alcohol consumption and an additive interaction observed for hepatitis infection. 

Lewis (2003) reports the continuing occurrence of angiosarcoma of the liver in retirees from a PVC 

production plant in Louisville, Kentucky. This ongoing incidence is reported primarily for those workers 

employed prior to 1960, suggesting that those exposed to the highest concentrations of vinyl chloride 

remain at risk for developing cancer for the remainder of their lives. The reported latency period for 

workers diagnosed prior to 1975 was 12–28 years, while those diagnosed after 1975 showed a latency of 

27–47 years. 

Other cancers that have shown a statistically significant increase in mortality rate among vinyl chloride 

workers, in at least some studies, include cancer of the brain and central nervous system, the lung and 

respiratory tract, connective and other soft tissues, and the lymphatic/hematopoietic system. With regard 

to cancer of the brain and central nervous system, Cooper (1981), Waxweiler et al. (1976), and Wong et 

al. (1991) reported statistically significant increases; Monson et al. (1975) reported an increase in central 

nervous system cancer mortality in a proportional mortality study; Byren et al. (1976), Simonato et al. 

(1991), and Tabershaw and Gaffey (1974) reported increases that were not statistically significant; and 

Fox and Collier (1977), Jones et al. (1988), Thomas et al. (1987), and Wu et al. (1989) found no increase 

in cancer of the central nervous system among workers occupationally exposed to vinyl chloride. It 

should be noted that the Cooper (1981), Tabershaw and Gaffey (1974), and Wong et al. (1991) studies 

were all based on the same cohort from a Chemical Manufacturers Association (CMA) study (Wong and 

Whorton 1993). Workers in the studies by Waxweiler et al. (1976) and Wu et al. (1989) were also 

employed at the same plants used for the CMA study (Wong and Whorton 1993). At least one analysis of 

epidemiological studies exposed certain weaknesses in the data that support a causal link between vinyl 

chloride and brain cancer (Doll 1988). 
VINYL CHLORIDE 71 

3. HEALTH EFFECTS 

Follow up mortality studies at polymer production plants indicate that liver cancer mortality remained 

elevated while brain cancer mortality was markedly reduced (as compared to earlier studies). It should be 

noted that increased brain cancer incidence was not associated with vinyl chloride exposure in these later 

studies (Lewis 2001; Lewis and Rempala 2003; Lewis et al. 2003; Mundt et al. 2000). In a meta-analysis 

of eight independent studies, no statistically significant increase in brain cancer mortality was observed 

(Boffetta et al. 2003). An IARC update of a European multi-center cohort study was also negative for 

brain cancer (Ward et al. 2001). 

An association between respiratory tract cancer and vinyl chloride exposure has not been consistently 

observed. A significant increase in cancer of the respiratory tract was reported by Belli et al. (1987), 

Infante et al. (1976b), and Waxweiler et al. (1976), and also by Monson et al. (1975) in a proportional 

mortality study. Although smoking history was not considered in these studies, Waxweiler et al. (1976) 

noted that the types of respiratory tract cancer most frequently recorded were large-cell undifferentiated 

carcinoma or adenocarcinoma, which are two lung cancer types not usually associated with smoking, but 

may be due to concomitant exposure. Increased risk of lung cancer was also associated with exposure to 

high concentrations of polyvinyl chloride dust particles (Mastrangelo et al. 2002). Respiratory tract 

cancer was not reported as elevated in studies by Buffler et al. (1979), Cheng et al. (1999), Cooper 

(1981), Fox and Collier (1977), Jones et al. (1988), Mundt et al. (2000), Scelo et al. (2004), Simonato et 

al. (1991), Wong et al. (1991, 2002a), and Wu et al. (1989). Similarly, a meta-analysis of eight 

independent studies (Boffetta et al. 2003) and an IARC update of a multi-center cohort study did not 

demonstrate excess mortality from lung cancer (Ward et al. 2001). 

A significant increase in cancers of connective and other soft tissues was observed in a recent follow up 

mortality study (Mundt et al. 2000) and in a meta-analysis of eight independent studies (Boffetta et al. 

2003). Rhomberg (1998) also suggests that vinyl chloride can induce soft tissue sarcoma outside of the 

liver; however, an IARC update of a multi-center cohort study was negative for soft tissue sarcoma (Ward 

et al. 2001). A meta-analysis of five occupational exposure studies additionally suggests a weak 

association between vinyl chloride exposure and pancreatic cancer (Ojajarvi et al. 2001). 

A statistically significant increase in cancers of the lymphatic/hematopoietic system was reported by 

Rinsky et al. (1988), Smulevich et al. (1988), Weber et al. (1981), and Wong et al. (2002a). Monson et al. 

(1975) also reported an increase in their proportional mortality study. However, no statistically 

significant increase in these types of cancer was reported by Infante et al. (1976b), Jones et al. (1988), 

Mundt et al. (2000), or Wong et al. (1991). In a meta-analysis of eight independent studies, the mortality 
VINYL CHLORIDE 72 

3. HEALTH EFFECTS 

data for cancers of the lymphatic/hematopoietic system were highly variable. A strong association was 

not observed between vinyl chloride exposure and lymphatic/hematopoietic system cancers; however, a 

negative conclusion was considered premature (Boffetta et al. 2003). 

An increased incidence of malignant melanoma among vinyl chloride workers has been reported (Heldaas 

et al. 1984, 1987), but the significance of this finding has been disputed (ten Berge 1987). A follow up to 

the original Heldaas (1984, 1987) studies reported only one additional case of melanoma between 1985 

and 1993, weakening the proposed association between vinyl chloride exposure and the development of 

malignant melanoma (Langard et al. 2000). 

Few studies directly address the incidence of cancer in women occupationally exposed to vinyl chloride. 

However, one study found that women employed in the production of vinyl chloride and PVC had a 

significantly greater chance of developing leukemia or lymphomas (Smulevich et al. 1988). Furthermore, 

the subgroup of women who were exposed to the highest levels of vinyl chloride had increased incidences 

of stomach cancer and the highest incidences of leukemia and lymphoma. No significant increase in any 

type of cancer was observed in exposed males in this report, irrespective of the level of exposure. 

The human epidemiology data demonstrate a clear association between vinyl chloride exposure and liver 

cancer (i.e., angiosarcoma and hepatocellular carcinoma). Although other cancers have been previously 

reported for vinyl chloride workers (i.e., respiratory tract cancer, brain cancer), recent follow-up studies 

do not demonstrate a consistent association between vinyl chloride exposure and tumor formation in these 

organ systems (Boffetta et al. 2003; Lewis 2001; Lewis and Rempala 2003; Lewis et al. 2003; Mundt et 

al. 2000; Ward et al. 2001). 

Studies in several animal species support the conclusion that vinyl chloride is carcinogenic. A large 

series of experiments was performed by Maltoni et al. (1981) using rats (Sprague-Dawley and Wistar), 

mice, and hamsters. All animals were chamber exposed; controls were chamber exposed to air only. The 

test material was >99.9% pure. A complete gross and histopathological examination of every animal was 

performed. However, extremely limited histopathological data were presented and cancer incidences 

were presented only in summary tables. Also, survival of control animals was poor in some of the 

experiments. Furthermore, statistical analyses, where present, appear to be based on a compilation of data 

from several individual studies. In one group of studies, Maltoni et al. (1981) exposed Sprague-Dawley 

rats to vinyl chloride for 52 weeks at concentrations ranging from 1 to 30,000 ppm. Animals were 

examined at the time of their spontaneous death. Statistically significant increases were noted in the 
VINYL CHLORIDE 73 

3. HEALTH EFFECTS 

incidence of mammary gland carcinomas, Zymbal gland carcinomas, nephroblastoma, and liver 

angiosarcoma. Exposure of Swiss mice to 50 ppm vinyl chloride for 4 hours/day, 5 days/week for 

30 weeks also appeared to increase the incidence of liver angiosarcoma and angioma (Maltoni et al. 

1981). Maltoni et al. (1981) also reported that decreasing the duration of exposure decreased the 

incidence of vinyl chloride-related tumors (nephroblastomas, liver angiosarcomas, Zymbal gland 

carcinomas, and to some extent, neuroblastomas), but statistics were not presented to support these 

conclusions. 

Some variation in the target organs that developed tumors was observed when different species were 

exposed to vinyl chloride (Maltoni et al. 1981). Whereas angiosarcomas of the liver were reported to 

occur in rats, mice, and hamsters, mammary gland carcinomas were found only in rats and mice; Zymbal 

gland carcinomas, neuroblastomas, and nephroblastomas were found only in rats; lung tumors were found 

only in mice; and melanomas, acoustical duct epithelial tumors, and leukemias were found only in 

hamsters. 

Other inhalation experiments support the carcinogenicity of vinyl chloride. Rats and mice exposed to 0, 

50, 250, or 1,000 ppm for 6 hours/day, 5 days/week for 6 months (Hong et al. 1981) or up to 12 months 

(Lee et al. 1977a, 1978) had a significantly increased incidence of hemangiosarcoma of the liver at 

≥250 ppm. Increases in bronchio-alveolar adenoma of the lung and mammary gland tumors 

(adenocarcinomas, squamous and anaplastic cell carcinomas) were also observed in mice at ≥50 ppm, 

although it is unclear whether the increases in these tumor types are statistically significant (Lee et al. 

1977a, 1978). Mice exposed to 50 or 500 ppm vinyl chloride for 6 hours/day, 5 days/week for 6 months 

or 1 year had an increased incidence of lung adenoma, as well as hemangiosarcoma of fat tissue in 

various organs (Holmberg et al. 1976). Only one liver hemangiosarcoma was noted. Male rats exposed 

to concentrations as low as 100 ppm for 6 hours/day, 6 days/week, for 12 months had significantly 

increased incidence of cancer, including angiosarcoma of the liver and lung, when sacrificed at 18 months 

(Bi et al. 1985). Rats exposed to 30,000 ppm vinyl chloride 4 hours/day, 5 days/week, for 12 months had 

an increased incidence of epidermoid carcinoma of the skin, adenocarcinoma of the lungs, and 

osteochondroma in the bones (Viola et al. 1971), and rats exposed to 5,000 ppm for 52 weeks had primary 

tumors in the brain, lung, Zymbal gland, and nasal cavity (Feron and Kroes 1979). However, these 

studies (Feron and Kroes 1979; Viola et al. 1971) are limited by the absence of statistical analysis of the 

data. A concentration-dependent increase in tumor formation (alveologenic adenomas of the lung, 

angiosarcomas of the liver, and adenosquamous carcinoma of the mammary gland) was observed in mice 

exposed to 0, 50, 200, or 2,500 ppm vinyl chloride in a study performed for the Manufacturing Chemists 
VINYL CHLORIDE 74 

3. HEALTH EFFECTS 

Association (Keplinger et al. 1975). However, no statistics were presented to support these conclusions. 

Furthermore, an audit of data performed for the Manufacturing Chemists Association (CMA 1979) 

indicated that mishandling of the tissues precluded making statements regarding the relationship of 

tumors other than angiosarcoma of the liver to vinyl chloride exposure. Female mice exposed to 50 ppm 

vinyl chloride showed increased incidence of hemangiosarcoma of the subcutis and peritoneum as well as 

tumors of the lung and mammary gland (Drew et al. 1983), i.e., hemangiosarcoma of the skin, spleen, or 

liver and mammary gland carcinomas. 

In a preliminary study with a limited number of animals, alveogenic lung tumors developed in 26 of 

27 mice exposed to 2,500 or 6,000 ppm for 5–6 months (Suzuki 1978). A concentration-related increase 

in the incidence of alveogenic tumors was observed in a study in which a greater number of mice were 

exposed to 0–600 ppm for 4 weeks and then observed for up to 40 weeks postexposure (Suzuki 1983). 

The lowest concentration at which multiple foci tumors were observed was 100 ppm (Suzuki 1983.) A 

significant increase in the incidence of pulmonary adenomas was reported in mice exposed to 50 ppm, 

6 hours/day, 5 days/week for 6 months (Adkins et al. 1986). An increase in bronchio-alveolar adenoma 

was observed in a lifespan study in mice that were exposed to 50 ppm for 100 1-hour exposures, 500 ppm 

for 10 1-hour exposures, or 5,000 ppm for a single 1-hour exposure (Hehir et al. 1981). The statistical 

significance of these observations was not reported. 

Some data suggest that exposure of animals early in their lives may increase the likelihood of developing 

tumors due to the latency period for vinyl chloride-induced cancer (Drew et al. 1983). Early life exposure 

may also affect the type of tumor that develops (Maltoni et al. 1981). When hamsters, mice, and rats 

were exposed to vinyl chloride for periods of 6–24 months starting at various times after weaning, the 

incidence of tumors such as hemangiosarcoma of the liver, skin, and spleen, and angiosarcoma of the 

stomach was greater when animals were exposed for 12 months immediately after weaning than if 

animals were held for 12 months and then exposed for the next 12 months (Drew et al. 1983). Mammary 

gland carcinoma was also significantly increased when 2- or 8-month-old hamsters, but not 14- or 

20-month-old hamsters, were exposed to 200 ppm vinyl chloride for 6 months (Drew et al. 1983). 

Fibroadenoma of the mammary gland was also increased in female rats exposed to 100 ppm of vinyl 

chloride for 6 hours/day, 5 days/week, over 6–24 months (Drew et al. 1983). Also, when pregnant rats 

were exposed to 6,000 ppm vinyl chloride from gestation day 12 through 18, the incidence of mammary 

gland carcinomas, Zymbal gland carcinomas, and forestomach epithelial tumors was reported to be 

greater in transplacentally exposed animals than in maternal animals (Maltoni et al. 1981). At 

10,000 ppm in this study, nephroblastomas were increased in transplacentally exposed animals compared 
VINYL CHLORIDE 75 

3. HEALTH EFFECTS 

to maternal animals (Maltoni et al. 1981). No control group was used, however, and no statistics were 

presented to support the conclusions. Maltoni and Cotti (1988) also exposed pregnant rats to 2,500 ppm 

vinyl chloride starting on Gd 12 and continued to expose both maternal animals and offspring for a total 

of 76 weeks. Hepatocarcinoma, hepatic angiosarcoma, and neuroblastoma were increased in treated 

animals compared to controls. The incidence of hepatocarcinoma was reported to be much higher in 

offspring than in maternal animals. In contrast, the incidence and latency period of neuroblastomas and 

hepatic angiosarcomas was similar between offspring and parents. However, no statistics were presented 

to support these conclusions. 

Many of the tumors that were observed in the Drew et al. (1983) and Maltoni et al. (1981) studies were 

also observed in a study performed by Froment et al. (1994). In this study, Sprague-Dawley pups were 

exposed to 500 ppm vinyl chloride 8 hours/day, 6 days/week, on postpartum days 3–28. After weaning, 

22 animals/gender were exposed for an additional 2 weeks, for a total exposure duration of 33 days. Rats 

were observed daily until death or development of tumors, and the surviving rats were sacrificed at 

19 months. All livers from exposed animals that appeared normal at gross examination were found to 

contain multiple nodular hyperplastic foci of hepatocytes. Liver tumors that were found in exposed 

animals included angiosarcomas, hepatocellar carcinomas, and benign cholangiomas. Other tumors found 

included pulmonary angiosarcoma (probably metastatic), nephroblastoma, abdominal angiomyoma, 

leukemia, Zymbal gland carcinoma, pituitary adenoma, mammary carcinoma, and mammary fibroma. 

Tumor incidence was not reported in control animals. Only one concentration (500 ppm) of vinyl 

chloride was used because the purpose of the study was to examine the genotoxicity of vinyl chloride in 

liver tumors produced by exposure. 

In general, the available evidence from inhalation studies in animals supports the finding in humans; that 

vinyl chloride is a carcinogen by this route of exposure. Based on these and other findings, the National 

Toxicology Program of the Department of Health and Human Services has determined vinyl chloride to 

be a known human carcinogen (DHHS 2002). In addition, IARC has concluded that sufficient evidence 

for carcinogenicity in humans and animals exists and has placed vinyl chloride in carcinogenicity 

category 1 (i.e., carcinogenic to humans) (IARC 1987). EPA also has concluded that sufficient evidence 

of carcinogenicity exists in humans and animals and has classified vinyl chloride according to its 1986 

classification scheme as a Group A or known human carcinogen (EPA 1994c). EPA’s current weight-ofevidence characterization for vinyl chloride concludes that vinyl chloride is a known human carcinogen 

by the inhalation route of exposure, based on human epidemiological data. By analogy, vinyl chloride is 

carcinogenic by the oral route because of positive animal bioassay data as well as pharmacokinetic data 
VINYL CHLORIDE 76 

3. HEALTH EFFECTS 

allowing dose extrapolation across routes. Vinyl chloride is also considered highly likely to be 

carcinogenic by the dermal route because it is well absorbed and acts systemically (EPA 2000); however, 

animal data suggest that dermal absorption of vinyl chloride gas is not likely to be significant (Hefner et 

al. 1975a). Because the epidemiological evidence does not provide sufficient exposure and incidence data 

to quantify risk based solely on human data, EPA cancer potency factors for inhalation and oral exposure 

have been calculated based on animal studies. An inhalation unit risk of 8.8x10-6 per ug/m3

 for 

continuous lifetime exposure from birth was estimated by EPA (2000) based on the incidence of liver 

tumors observed in rats in the inhalation study by Maltoni et al. (1981). An inhalation unit risk of 

4.4x10-6 per ug/m3.for continuous lifetime exposure during adulthood was also estimated by EPA (2000). 

Air concentrations associated with excess cancer risks of 10-4, 10-5, 10-6, and 10-7 are 9.0x10-3, 9.0x10-4, 

9.0x10-5, and 9.0x10-6 ppm, respectively, and are plotted in Figure 3-1. These risks were calculated using 

physiologically based pharmacokinetic (PBPK) modeling, which is discussed in further detail in 

Section 3.4. The lowest concentrations tested that produced a tumorigenic response CEL for each species 

and duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.2 Oral Exposure 

All dosages of vinyl chloride administered in the diet are reported as mg/kg (body weight)/day unless 

otherwise specified. 

3.2.2.1 Death 

No studies were located regarding lethal effects in humans following oral exposure to vinyl chloride. 

No studies were located regarding acute or intermediate lethal effects of vinyl chloride in animals. 

However, decreased longevity has been observed in rats as a result of chronic ingestion of vinyl chloride. 

Significant increases in mortality were observed by Feron et al. (1981) when Wistar rats were allowed to 

consume vinyl chloride doses as low as 5.6 mg/kg/day in the diet for 4 hours/day over a 2-year period. 

Also, the effects of consumption of vinyl chloride during a lifespan study in Wistar rats lasting almost 

3 years (149 weeks) were examined by Til et al. (1983, 1991). These authors found a decreased survival 

rate at a vinyl chloride dosage of 1.7 mg/kg/day. In both of these studies, vinyl chloride was administered 

by incorporating PVC resin that was high in vinyl chloride content into the diet. In the Til et al. (1991) 

study, the diets of the control animals contained 1% PVC powder that did not contain residual vinyl 
VINYL CHLORIDE 77 

3. HEALTH EFFECTS 

chloride. Vaporization of vinyl chloride from the diets was limited by presenting feed containing the 

vinyl chloride to the rats for only a 4-hour period. 

All reliable LOAEL values for death in rats following chronic exposure are recorded in Table 3-2 and 

plotted in Figure 3-2. 

3.2.2.2 Systemic Effects 

The highest NOAEL values and all reliable LOAEL values for hematological, hepatic, dermal, and body 

weight effects in rats following chronic oral exposure are recorded in Table 3-2 and plotted in Figure 3-2. 

No studies were located regarding adverse respiratory, cardiovascular, gastrointestinal, musculoskeletal, 

renal, endocrine, or ocular effects in humans or animals following oral exposure to vinyl chloride. 

Hematological Effects. No studies were located regarding adverse hematological effects in humans 

after oral exposure to vinyl chloride. 

Rats fed 17 mg/kg/day for 2 years showed decreased clotting time of the blood, which was not observed 

at 5.6 mg/kg/day (Feron et al. 1981). No changes in thrombocyte count or prothrombin times were noted 

in Wistar rats fed diets containing low concentrations of vinyl chloride in PVC resin (1.7 mg/kg/day) for 

149 weeks (Til et al. 1983, 1991). 

Hepatic Effects. No studies were located regarding adverse hepatic effects in humans after oral 

exposure to vinyl chloride. 

Chronic exposure of rats to vinyl chloride in their feed for 149 weeks produced an increase in the 

incidence of several types of microscopic liver lesions in male and female rats. Neoplastic and 

preneoplastic lesions in the liver included several types of foci of cellular alteration (i.e., clear-cell, 

basophilic, eosinophilic, or mixed), neoplastic nodules, hepatocellular carcinoma, and angiosarcoma. 

Other liver lesions associated with vinyl chloride exposure included liver-cell polymorphism and hepatic 

cysts. The high-dose group in male and female rats (1.7 mg/kg/day) represents a LOAEL for noncancer 

liver effects in this study (i.e, liver cell polymorphism, hepatic cysts) (Til et al. 1983, 1991). The human 

equivalent dose derived from a NOAEL of 0.17 mg/kg/day identified in this study was used as the basis 
70

5.6

162

1.7

72

5.6 17

1.8 17

5.6

90

30

164

1.70.17 1.71.7

4 5 

Table 3-2 Levels of Significant Exposure to Vinyl Chloride - Oral 

a

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) 

CHRONIC EXPOSURE Death 

System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

1 Rat 

(Wistar) 

2 yr 5 d/wk 4 hr/d (F) 

5.6 (100% died) Feron et al. 1981 

2 Rat 

(Wistar) 

149 wk 4 hr/d (F) 

1.7 (increased mortality) Til et al. 1983, 1991 

Systemic 

3 Rat 

(Wistar) 

2 yr 5 d/wk 4 hr/d (F) 

Hemato 5.6 17 (decreased clotting time) Feron et al. 1981 

Hepatic 1.8 (cellular alteration) 17 M extensive necrosis 

b

5.6 F (extensive necrosis) 

Rat 2 yr Dermal 30 (increased skin Knight and Gibbons 198(Wistar) 1 x/d thickness, collagen) (GO) Rat 149 wk (Wistar) 4 hr/d Hemato 1.7 Til et al. 1983, 1991 

(F) 

c

Hepatic 0.17 F 1.7 F (liver cell polymorphism) Bd Wt 1.7 
71

5.61.8

213

5016.65

214

0.3

Table 3-2 Levels of Significant Exposure to Vinyl Chloride - Oral (continued) 

a

Key to Species 

Figure (Strain) 

Cancer 

6 Rat 

(Wistar) 

7 Rat 

(SpragueDawley) 

8 Rat 

(SpragueDawley) 

Exposure/ LOAEL 

Duration/ 

Frequency NOAEL Less Serious Serious Reference (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

2 yr 5 d/wk 4 hr/d (F), (GO) 52 wk 5 x/wk (GO) 52 wk 5 x/wk (GO) 

5.6 M (CEL: angiosarcoma of Feron et al. 1981 

lung; neoplastic nodules of liver, hepatic angiosarcoma) 

b

1.8 F (CEL: neoplastic nodules 

of liver) 

50 M (CEL: liver Maltoni et al. 1981 

angiosarcoma) 

b

16.65 F (CEL: liver 

angiosarcoma) 

0.3 (CEL: liver Maltoni et al. 1981 

angiosarcoma, hepatoma) 
163

1.71.70.0181.7

Table 3-2 Levels of Significant Exposure to Vinyl Chloride - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

Key to

a 

Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

9 Rat 

(Wistar) 

149 wk 4 hr/d (F) 

1.7 M (CEL: hepatocellular 

carcinoma) 

Til et al. 1983, 1991 

1.7 F (CEL: neoplastic nodules 

of liver) 

b

0.018 F (CEL: basophilic foci 

considered to be pre-neoplastic lesions) 

1.7 (CEL: hepatic 

angiosarcoma) 

a Numbers correspond to entries in Figure 3-2. b Differences in levels of health effects and cancer effects between male and females are not indicated in Figure 3-2. Where such differences exist, only the levels most sensitive gender are presented. c Used to derive an chronic-duration Minimal Risk Level (MRL) of 0.002 mg/kg/day; dose divided by an uncertainty factor of 100 (10 for extrapolation from animals tfor human variability). B - both; Bd Wt = body weight; CEL = cancer effect level; d = day(s); derm = dermal; (F) = feed; F = Female; (GO) = gavage in oil; hemato = hematological; hr = holowest-observed-adverse-effect level; M = male; NOAEL = no-observed-adverse-effect level; wk = week(s); x = time(s); yr = year(s) 
Death Hematological Hepatic Dermal Body Weight Cancer * 

Figure 3-2 Levels of Significant Exposure to Vinyl Chloride - Oral 

Chronic (≥365 days) 

Systemic 

mg/kg/day 

100 

4r 

3r 7r
 

10
 

1r 3r 2r 5r 3r 5r 5r 6r 9r 9r
 

1
 

8r 

5r 

0.1 

9r 

0.01 

0.001 

10-4 0.0001 10-5 

1E-5 

10-6 
 1E-6 


*Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer endpoint. 10-7 1E-7 

c-Cat -Humans f-Ferret n-Mink d-Dog k-Monkey j-Pigeon o-Other Cancer Effect Level-Animals Cancer Effect Level-Humans 

LOAEL, More Serious-Animals LOAEL, More Serious-Humans 

r-Rat m-Mouse e-Gerbil LOAEL, Less Serious-Animals LOAEL, Less Serious-Humans p-Pig h-Rabbit s-Hamster q-Cow a-Sheep g-Guinea Pig NOAEL - Animals 

 NOAEL - Humans 
VINYL CHLORIDE 82 

3. HEALTH EFFECTS 

for a chronic oral MRL of 0.003 mg/kg/day. Chronic oral exposure of rats fed vinyl chloride daily during 

a 4-hour period for 2 years also resulted in areas of hepatocellular alteration at concentrations as low as 

1.8 mg/kg/day (Feron et al. 1981). In this study, areas of necrosis were observed in the liver of female 

rats fed 5.6 mg/kg/day and male rats fed 17 mg/kg/day (Feron et al. 1981). Increased incidence of hepatic 

cysts were found in female rats fed 1.7 mg/kg/day and clear or basophilic areas of cellular alteration were 

found in male rats fed 1.7 mg/kg/day in the Til et al. (1983, 1991) studies. 

Dermal Effects. No studies were located regarding adverse dermal effects in humans after oral 

exposure to vinyl chloride. 

Daily administration of 30 mg/kg of vinyl chloride to rats by gavage for 2 years produced increased 

thickness, moisture content, and collagen content of the skin. Newly synthesized intermolecular and 

intramolecular collagen crosslinks were also significantly increased (Knight and Gibbons 1987). 

Body Weight Effects. No studies were located regarding adverse body weight effects in humans 

after oral exposure to vinyl chloride. 

No changes in body weight were noted in Wistar rats fed 1.7 mg/kg/day vinyl chloride mixed with PVC 

powder in the diet for 149 weeks (Til et al. 1983, 1991). 

No studies were located regarding the following health effects in humans or animals after oral exposure to 

vinyl chloride: 

3.2.2.3 Immunological and Lymphoreticular Effects 

3.2.2.4 Neurological Effects 

3.2.2.5 Reproductive Effects 

3.2.2.6 Developmental Effects 

3.2.2.7 Cancer 

No studies were located regarding cancer in humans following oral exposure to vinyl chloride. 
VINYL CHLORIDE 83 

3. HEALTH EFFECTS 

Four studies were located that examined the carcinogenic potential of vinyl chloride in animals when 

administered by the oral route. In two of these studies in Wistar rats, conducted for 149 weeks, vinyl 

chloride was added to the diet by incorporating PVC powder containing a high level of the monomer 

(Feron et al. 1981; Til et al. 1983, 1991). To limit volatilization of vinyl chloride from the diet, the rats 

were allowed access to the diet for only 4 hours/day. The actual intake of vinyl chloride in these reports 

was calculated by taking into consideration both the food consumption and the rate of vinyl chloride 

evaporation. Statistically significant increases in hepatic angiosarcoma of the liver were observed in the 

2-year study by Feron et al. (1981) at 5.6 mg/kg/day in males and 17 mg/kg/day in females. In the same 

study, statistically significant increases in neoplastic nodules of the liver were also observed at a 

concentration of 5.6 mg/kg/day in males but as low as 1.8 mg/kg/day in females (Feron et al. 1981). 

Also, in the 149-week study by Til et al. (1983, 1991), statistically significant increases in hepatocellular 

carcinoma were observed in males at 1.7 mg/kg/day and hepatic neoplastic nodules in females at 

1.7 mg/kg/day. A few animals exposed to 1.7 mg/kg/day in this study developed hepatic angiosarcoma. 

An increased incidence of Zymbal gland tumors was also observed in the study by Feron et al. (1981). 

Although the increase was not statistically significant, the tumors were considered to be treatment related 

based on the historical rarity of this type of tumor. 

Two studies were located in which vinyl chloride was administered to Sprague-Dawley rats by gavage for 

52 weeks. In one of these studies, a statistically significant increase in the incidence of hepatic 

angiosarcomas was observed at doses as low as 16.65 mg/kg/day in females and 50 mg/kg/day in males. 

Zymbal gland tumors at 16.65 and 50 mg/kg/day, even though not statistically significant, were 

considered to be treatment related because of the rarity of this type of tumor (Maltoni et al. 1981). Lower 

doses of vinyl chloride were also tested in a similar study in which hepatic angiosarcomas were observed 

at doses as low as 0.3 mg/kg/day and Zymbal gland tumors at 1 mg/kg/day. Although neither of these 

findings reached statistical significance, the tumors were considered to be treatment related because of the 

historically rare observation of these tumor types in the colony (Maltoni et al. 1981). 

Based on the evidence of carcinogenicity in animals after oral exposure, it would be prudent to consider 

the potential for carcinogenic effects in humans by this route as well. The National Toxicology Program 

of the Department of Health and Human Services has determined vinyl chloride to be a known human 

carcinogen (DHHS 2002). In addition, IARC has concluded that sufficient evidence for carcinogenicity 

in humans and animals exists and has placed vinyl chloride in carcinogenicity category 1 (i.e., 

carcinogenic to humans) (IARC 1987). EPA also has concluded that sufficient evidence of 

carcinogenicity exists in humans and animals and has classified vinyl chloride according to its 1986 
VINYL CHLORIDE 84 

3. HEALTH EFFECTS 

classification scheme as a Group A or known human carcinogen (EPA 1994c). EPA’s current weight-ofevidence characterization for vinyl chloride concludes that vinyl chloride is a known human carcinogen 

by the inhalation route of exposure, based on human epidemiological data. By analogy, vinyl chloride is 

considered carcinogenic by the oral route because of positive animal bioassay data as well as 

pharmacokinetic data allowing dose extrapolation across routes. By inference, vinyl chloride is also 

considered highly likely to be carcinogenic by the dermal route because it acts systemically (EPA 2000). 

Because the epidemiological evidence does not provide sufficient exposure and incidence data to quantify 

risk based solely on human data, EPA cancer potency factors for inhalation and oral exposure have been 

calculated based on animal studies. An oral slope factor for continuous lifetime exposure from birth was 

estimated by EPA (2000) to be 1.5 per mg/kg/day based on the incidence of liver tumors in rats in the 

study by Feron et al. (1981). An oral slope factor of 7.5x10-1 per mg/kg/day for continuous lifetime 

exposure during adulthood was also estimated by EPA (2000). Oral doses associated with excess cancer 

risks of 10-4, 10-5, and 10-6 are 1.33x10-4, 1.33x10-5, 1.33x10-6, and 1.33x10-7 mg/kg/day, respectively, and 

are plotted in Figure 3-2. These risks were calculated using PBPK modeling, which is discussed in 

further detail in Section 3.4. The lowest doses tested that produced a tumorigenic response (CEL) in rats 

chronically exposed to vinyl chloride by the oral route are recorded in Table 3-2 and plotted in Figure 3-2. 

3.2.3 Dermal Exposure 

Dermal exposure to vinyl chloride may occur by skin contact with either gaseous or liquid vinyl chloride. 

Negligible amounts of gaseous vinyl chloride are absorbed through the skin (see also Section 3.4 

regarding absorption by the dermal route). However, dermal exposure can also occur by direct contact of 

gaseous vinyl chloride with the eyes. Only studies that specifically relate to dermal contact of liquid vinyl 

chloride or adverse ocular effects occurring with inhalation exposure to gaseous vinyl chloride are 

discussed below. 

3.2.3.1 Death 

No studies were located regarding lethal effects in humans or animals after dermal exposure to vinyl 

chloride. 
VINYL CHLORIDE 85 

3. HEALTH EFFECTS 

3.2.3.2 Systemic Effects 

No studies were located regarding adverse respiratory, cardiovascular, gastrointestinal, hematological, 

musculoskeletal, hepatic, renal, or endocrine effects in humans or animals after dermal exposure to vinyl 

chloride. 

Dermal Effects. Vinyl chloride exists as a liquid when stored under pressure. However, when it is 

released from pressurized containers, it rapidly vaporizes into gas. Thus, the adverse dermal effects 

observed after exposure to vinyl chloride are not unique to vinyl chloride but can be expected as a result 

of a rapidly evaporating liquid on the skin. The effects are due to tissue freezing rather than direct 

toxicity of vinyl chloride. A man who had liquid vinyl chloride sprayed on his hands developed second 

degree burns. At first, the man reported that his hands felt numb. Within a short period, the hands had 

developed marked erythema and edema (Harris 1953). 

No studies were located regarding adverse dermal effects in animals after dermal exposure to vinyl 

chloride. 

Ocular Effects. Local burns on the conjunctiva and cornea were observed in a man who died after 

exposure to an unknown quantity of vinyl chloride escaping from an open valve (Danziger 1960). 

No adverse ocular effects were noted in guinea pigs exposed for 30 minutes to up to 400,000 ppm vinyl 

chloride in inhalation chambers (Mastromatteo et al. 1960). 

3.2.3.3 Immunological and Lymphoreticular Effects 

No studies were located regarding adverse immunological and lymphoreticular effects in humans or 

animals following dermal exposure to vinyl chloride. 

3.2.3.4 Neurological Effects 

A man who had liquid vinyl chloride sprayed on his hands initially reported that his hands felt numb 

(Harris 1953). 
VINYL CHLORIDE 86 

3. HEALTH EFFECTS 

No studies were located regarding adverse neurological effects in animals after dermal exposure to vinyl 

chloride. 

No studies were located regarding the following adverse health effects in humans or animals after dermal 

exposure to vinyl chloride: 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

3.3 GENOTOXICITY 

Vinyl chloride has been shown to be mutagenic and clastogenic in both in vivo and in vitro test systems. 

Tables 3-3 and 3-4 list the key in vivo and in vitro genotoxicity studies for vinyl chloride. 

Genotoxicity studies of vinyl chloride in humans include a large number of assays for chromosomal 

aberrations in the cultured lymphocytes of occupationally exposed workers. Studies completed through 

the mid-1980s generally found a statistically significant increase in the frequency of chromosomal 

aberrations, usually of the chromatid type (i.e., affecting only one of the two strands formed upon 

deoxyribonuclei c acid [DNA] replication), but also including some chromosomal-type defects such as 

inversions, rings, and translocations, which affect the entire chromosome (Anderson et al. 1981; 

Anderson 1999, 2000; Fleig et al. 1978; Fucic et al. 1990; Heath et al. 1977). An increase in 

chromosomal aberrations was also observed following an accidental environmental exposure to vinyl 

chloride (Becker et al. 2001; Huttner and Nikolova 1998; Huttner et al. 1998, 1999). Workers exposed to 

vinyl chloride for an average of 15 years were shown to have elevated levels of micronuclei and 

chromosomal aberrations when compared to the unexposed controls (Garaj-Vrhovac et al. 1990). An 

increase in chromosome aberrations and micronuclei was correlated with the air concentration of vinyl 

chloride at a plastics plant and the excretion of thiodyglycolic acid in the urine of exposed workers 

(Vaglenov et al. 1999). Micronuclei counts were also increased in a group of 52 workers exposed to vinyl 

chloride levels of 1.3–16.7 ppm compared to those of controls, but these increases were not observed in 

workers exposed to 0.3–7.3 ppm (Sinues et al. 1991). Micronuclei were also increased in lymphocytes 

from 19 workers exposed to 50 ppm vinyl chloride for approximately 15 years (Fucic et al. 1990). 
VINYL CHLORIDE 87 

3. HEALTH EFFECTS 

Table 3-3. Genotoxicity of Vinyl Chloride In Vivo 

Species (test system) End point Results Reference 

Mouse Dominant lethal – Anderson et al. 1976 

Micronuclei + Richardson et al. 1983 

Rat Dominant lethal – Short et al. 1977 

– Anderson et al. 1976 

– Purchase et al. 1975 

 Chromosomal aberration + Anderson and Richardson 1981 

Hamster Chromosomal aberration + Fleig et al. 1978 

Human lymphocyte Sister chromatid exchange – Hansteen et al. 1978 

+ Kucerova et al. 1979 

+ Sinués et al. 1991 

+ Fucic et al. 1990a 

+ Fucic et al. 1992 

+ Fucic et al. 1995 

+ Fucic et al. 1996a 

+ Fucic et al. 1996b 

+ Zhao et al. 1994 

DNA damage + Awara et al. 1998 

+ Du et al. 1995 

Micronuclei + Fucic et al. 1990a 

+ Garaj-Vrhovac et al. 1990 

+ Sinués et al. 1991 

+ Vaglenov et al. 1999 

Chromosomal aberration + Hansteen et al. 1978 

+ Heath et al. 1977 

+ Kucerova et al. 1979 

_ Picciano et al. 1977 

+ Purchase et al. 1978 

+ Ducatman et al. 1975 

+ Anderson 1980, 1981 

+ Fleig et al. 1978 

+ Fucic et al. 1990a, 1990b 

+ Fucic et al. 1995 

+ Fucic et al. 1996a 
VINYL CHLORIDE 88 

3. HEALTH EFFECTS 

Table 3-3. Genotoxicity of Vinyl Chloride In Vivo 

Species (test system) End point Results Reference 

+ Fucic et al. 1996b 

Human lymphocyte (cont.) Chromosomal aberration + Funes-Cravioto et al. 1975 

+ Hrivnak et al. 1990 

+ Garaj-Vrhovac et al. 1990 

+ Anderson, 1999 

+ Becker et al. 2001 

+ Huttner et al. 1998 

+ Huttner et al. 1999 

+ Huttner and Nikolova 1998 

+ Fucic et al. 1992 

+ Vaglenov et al. 1999 

Rat DNA alkylation + Laib et al. 1989 

+ Green and Hathway 1978 

+ Gwinner et al. 1983 

+ Singer et al. 1987 

+ Bolt et al. 1986 

+ Ciroussel et al. 1990 

+ Eberle et al. 1989 

Mouse DNA alkylation + Osterman-Golkar et al. 1977 

DNA damage + Walles et al. 1988 

Rat DNA adduct + Fedtke et al. 1990 

+ Ciroussel et al. 1990 

+ Swenberg et al. 1992 

+ Bolt et al. 1986 

+ Morinello et al. 2002a, 2002b 

+ Eberle et al. 1989 

– = negative result; + = positive result; DNA = deoxyribonucleic acid 
VINYL CHLORIDE 89 

3. HEALTH EFFECTS 

Table 3-4. Genotoxicity of Vinyl Chloride In Vitro 

Result 

Without 

Species (test system) End point With activation activation Reference 

Salmonella typhimurium Reverse mutation 	 + – Rannug et al. 1974 

+ + Bartsch et al. 1975, 

1976 

+ + Andrews et al. 1976 

+ + Simmon et al. 1977 

Not tested – Elmore et al. 1976 

+ + Poncelet et al. 1980 

+ + De Meester et al. 1980 

+ + Victorin and Stahlberg 

1988a 

+ 	 Not tested McCann et al. 1975 

+ + Rannug et al. 1976 

TA100, TA1535 Base-pair substitution + + duPont 1992a, 1992b 

+ Not tested Malaveille et al. 1975 

TA98, TA1537, TA1538 Frameshift mutation – – 

Escherichia coli Not applicable + Jacobsen et al. 1989 

Saccharomyces Not tested – Shahin 1976 

cerevisiae 

Gene conversion + Not tested Loprieno et al. 1976 

Schizosaccharomyces Forward mutation + – Loprieno et al. 1977 

pombe 

+ Not tested Loprieno et al. 1976 

D7RAD yeast Gene conversion + _ Ekardt et al. 1981 

Chinese hamster ovary Not applicable + Huberman et al. 1975 

cells 

+ 	 Not tested Drevon et al. 1978 

+ – duPont 1992c 

Bacillus subtilis Rec-repair Not tested – Elmore et al. 1976 

Rat liver microsomes RNA alkylation Not applicable + Laib and Bolt 1977 

QT6 (avian cells) Inhibition of DNA Not applicable + Kandala et al. 1990 

synthesis 

– = negative result; + = positive result; DNA = deoxyribonucleic acid; RNA = ribonucleic acid 
VINYL CHLORIDE 90 

3. HEALTH EFFECTS 

Increased sister chromatid exchanges have also been reported in occupationally exposed workers (Fucic 

et al. 1990, 1992, 1995; Kucerova et al. 1979; Sinues et al. 1991; Zhao et al. 1996). Sister chromatid 

exchange frequencies were significantly increased compared to those of the controls at 0.003–7.3 ppm 

vinyl chloride (Sinues et al. 1991). A positive correlation between frequency of chromosomal aberrations 

and length of exposure and history of exposure to excursion levels (up to 2,000 ppm) was reported by 

Purchase et al. (1978), who examined a cohort of 57 vinyl chloride workers, 19 on-site controls, and five 

off-site controls. The exposures for this cohort ranged from 1,000 ppm between 1945 and 1955 to 5 ppm 

since 1975. These authors also reported an effect on chromosomal aberrations from smoking. Smoking 

and the presence of an aldehyde dehydrogenase 2 genotype was associated with an increase in the 

frequency of sister chromatid exchange in vinyl chloride workers (Wong et al. 1998). DNA damage in 

lymphocytes of plastic industry workers was also demonstrated by a single-cell gel electrophoresis 

technique. A correlation was observed between the severity of DNA damage and the duration of 

exposure (Awara et al. 1998). DNA single strand breaks present in human lymphocytes from exposed 

workers were quickly repaired following cessation of exposure (Du et al. 1995). Induction of singlestrand breaks in liver DNA was also observed in mice after inhalation of vinyl chloride (Walles et al. 

1988). 

The reversibility of chromosome damage has been reported for several populations of workers following 

a cessation or reduction of exposure to vinyl chloride. The increase of chromosome aberrations observed 

in workers exposed to 50 ppm returned to normal within 42 months after exposure levels had been 

reduced to <5 ppm (Anderson et al. 1980). Another study demonstrated a statistically significant increase 

in aberrations in workers exposed to concentrations of approximately 25 ppm. Following a reduction in 

exposure to 1 ppm, vinyl chloride chromosomal aberrations had returned to control values (Hansteen et 

al. 1978). A 9-year follow-up study of an occupationally exposed population demonstrated a decrease in 

chromosome aberrations and sister chromatid exchange frequencies over time, corresponding to a 

decrease in vinyl chloride air concentrations at the plant (Fucic et al. 1996a, 1996b). 

The reversibility of clastogenic effects was not seen in another study of 12 current and 3 retired plastics 

industry workers who had been exposed to vinyl chloride while employed for 1.5–35 years (Fucic et al. 

1992). Sister chromatid exchange frequencies were significantly higher in workers exposed to 

concentrations up to 2,000 ppm than in the controls. These findings showed no significant decrease in 

sister chromatid exchange frequencies from 8 days to 10 years after exposure (Fucic et al. 1992). 
VINYL CHLORIDE 91 

3. HEALTH EFFECTS 

Other papers on human subjects have focused on specific mechanisms involved in the clastogenic effects 

of vinyl chloride. A cohort of 67 workers exposed to approximately 5 ppm for an average of 15 years 

was reported to have a nonrandom distribution of chromatid and bichromatid breaks (Fucic et al. 1990b). 

The most frequently affected areas of the genome were the terminal segments of the A, B, and C group 

chromosomes, suggesting that vinyl chloride or its metabolites interact more frequently with specific sites 

along the chromosome than would be expected. The study authors presented no correlation with 

particular fragile sites (gene sequences more prone to breakage than normal) or oncogene locations 

known to occur at these terminal segments. The implication is that the carcinogenicity of vinyl chloride 

could be at least partially explained by its nonrandom interaction with particular genes. These workers 

were also periodically exposed to 2,000 ppm for short periods. No specific information was given as to 

the frequency or duration of these events. 

Male workers (n=20) who had been employed for 2–14 years at a vinyl chloride polymerization plant 

exposed to concentrations of vinyl chloride of 1 ppm (with occasional peaks of 300 ppm) underwent 

cytogenetic testing (Fucic et al. 1995). The test results were compared to those from 20 unexposed 

control men. Exposed individuals had higher percentages of chromosome aberrations, primarily 

chromatid breaks. Sister chromatid exchange frequencies were also increased in exposed workers (4– 

22 per cell) compared to controls (4–7 per cell). Significant changes in mitotic activity were noted among 

exposed workers; values for second mitosis were lower than controls and values for third mitosis were 

higher than controls (Fucic et al. 1995, 1997). Chromosome aberrations were not increased in workers 

exposed to <5 ppm vinyl chloride; however, the average exposure duration for this study was <1 year 

(Picciano et al. 1977). 

Genetic polymorphisms of metabolic and DNA repair genes have been associated with the sister 

chromatid exchange frequency in exposed workers (Wong et al. 2003b). Metabolic genotypes for 

CYP2E1, aldehyde dehydrogenase 2 (ALDH2) and the DNA repair genotype for x-ray repair cross 

complementing group1 (XRCC1) were associated with an increased risk of DNA damage in humans. 

Animal studies of rats and mice exposed via inhalation to vinyl chloride have concentrated on identifying 

the direct effects of vinyl chloride and its metabolites on DNA. Vinyl chloride is metabolized by mixed 

function oxidases (MFO) to form an epoxide intermediate, 2-chloroethylene oxide, which spontaneously 

rearranges to form 2-chloroacetaldehyde. Reactive metabolites of vinyl chloride can be transported 

intercellularly from parenchymal cells to the nonparenchymal cells (Kuchenmeister et al. 1996). Many 

studies have characterized the mutation profile associated with DNA adducts formed by the reactive 
VINYL CHLORIDE 92 

3. HEALTH EFFECTS 

metabolites of vinyl chloride (Akasaka et al. 1997; Chiang et al. 1997; Dosanjh et al. 1994; Guichard et 

al. 1996; Matsuda et al. 1995; Pandya and Moriya 1996; Zhang et al. 1995; Zielinski and Hergenhahn 

2000;). Four primary mutagenic DNA adducts are formed by the reactive metabolites of vinyl chloride. 

These are cyclic etheno-adducts that include 1,N6

-ethenoadenine, 3,N4-ethenocytosine, N2,3-ethenoguanine, and 1,N2

-ethenoguanine. These adducts can induce base-pair (i.e., purine-to-purine or 

pyrimidine-to-pyrimidine exchange) transitions during transcription (Cullinan et al. 1997; Oesch and 

Doerjer, 1982; Pandya and Moriya 1996; Singer et al. 1987, 1996). 1,N6

-Ethenoadenine adducts have 

been demonstrated to trap topoisomerase I, affecting DNA replication and transcription (Pourquier et al. 

1998). DNA crosslinks can also be formed because chloracetaldehyde is bifunctional (Singer 1994). The 

adduct 7-(2’-oxoethyl)guanine is also extensively formed in mammalian liver (Laib et al. 1981); however, 

it is quickly recognized and removed by DNA repair mechanisms. Etheno-adducts are less abundant, but 

more persistent because they are poorly repaired (Brandt-Rauf et al. 2000b; Whysner et al. 1996). 

The identification of the etheno-nucleosides has been reported following inhalation exposure to vinyl 

chloride in rats (Bolt et al. 1986; Ciroussel et al. 1990; Eberle et al. 1989; Fedtke et al. 1990; Morinello et 

al. 2002a, 2002b; Swenberg et al. 1992). Immature rats exposed in vivo formed 6 times more of this 

nucleoside adduct, which correlated with the age-related sensitivity to carcinogenesis in these animals 

(Ciroussel et al. 1990). This age-related sensitivity to DNA adduct formation was also noted in an 

inhalation study of lactating rats and their 10-day-old pups exposed 4 hours/day, for 5 days to 600 ppm of 

vinyl chloride (Fedtke et al. 1990). Concentrations of two adducts found in the liver of the pups were 

4-fold higher than those found in the liver of the dams. Increased alkylation of liver DNA and increased 

cell proliferation were reported by Laib et al. (1989) following exposure to 600 ppm vinyl chloride for 

6 hours. Young rats were apparently more susceptible to the effects of vinyl chloride, but only three male 

adults and two female adults were used for comparison. The concentration of ethenoguanine adducts was 

2–3-fold greater in weanling rats as compared to adult rats exposed at the same dose for the time period 

(0, 10, 100, or 1,100 ppm, 6 hours/day for 5 days) (Morinello et al. 2002a). Rats exposed to 2,000 ppm 

vinyl chloride for 8 hours/day, 5 days/week, for 3 weeks beginning at 7 days of age demonstrated 

hepatocellular ATPase-deficient foci and alkylation of liver DNA (Gwinner et al. 1983). A study in rats 

exposed to 1,100 ppm vinyl chloride for 6 hours/day, 5 days/week for 1 or 4 weeks demonstrated that 

ethenoguanine adducts are not formed in the adult rat brain (Morinello et al. 2002b). This differential 

induction of DNA adducts (brain vs. liver) may relate to the direct effect of reactive intermediates at the 

site of metabolite generation. 
VINYL CHLORIDE 93 

3. HEALTH EFFECTS 

The role of etheno-adducts in the carcinogenesis of vinyl chloride has been recently reviewed (Albertini 

et al. 2003; Barbin 1998, 1999, 2000; Kielhorn et al. 2000; Laib 1986; Nivard and Vogel 1999; Whysner 

et al. 1996). Both 2-chloroethylene oxide and 2-chloroacetaldehyde can react with DNA nucleotide 

bases; however, 2-chloroethylene oxide is a more potent mutagen and may be the ultimate carcinogenic 

metabolite of vinyl chloride (Chiang et al. 1997). Etheno-adducts generate mainly base pair substitution 

mutations. Mutations in specific genes (i.e., ras oncogenes, p53 tumor suppressor gene) have been 

identified in vinyl chloride-induced liver tumors in rats and humans and are discussed in further detail 

below. Exocylic DNA adducts are excised from the DNA by glycosylase enzymes that contribute to 

genetic stability (Laval and Saparbaev 2001). The four primary cyclic adducts formed in DNA by the 

vinyl chloride metabolite chloroacetaldehyde are released by human glycosylase enzymes (Dosanjh et al. 

1994; Singer and Hang 1999). The expression of the DNA repair enzyme N-methylpurineDNA-glycosylase was shown to be deficient in nonparenchymal cells of the rat liver, which are the target 

cells for vinyl chloride-induced angiosarcoma (Holt et al. 2000; Swenberg et al. 1999). However, there 

was no difference observed in the formation of ethenoguanine adducts in hepatocytes and 

nonparenchymal cells immediately following vinyl chloride exposure (Morinello et al. 2002a). Together, 

these data suggest that cellular differences in DNA repair capacity may play a role in vinyl chlorideinduced carcinogenesis. It is important to note that endogenously formed etheno-adducts are also present 

in humans and laboratory animals due to a reaction between DNA and lipid peroxidation by-products. 

This background incidence of etheno-adducts should be taken into account when evaluating exposure to 

chemicals like vinyl chloride (Albertini et al. 2003; Bartsch and Nair 2000; Gonzalez-Reche et al. 2002; 

Swenberg et al. 2000; Watson et al. 1999; Yang et al. 2000; Zielinski and Hergenhahn 2001). 

It has been suggested that members of the ras gene family, including Ha-ras, Ki-ras, and N-ras, are 

responsible for the control of cell proliferation and differentiation (Froment et al. 1994). DNA adducts 

formed by vinyl chloride metabolites can produce point mutations in these genes. Mutations of the 

Ki-ras-2 gene has been found in hepatic angiosarcomas of workers exposed to high levels of vinyl 

chloride; this specific gene was shown to be activated by a GC-AT transition at codons 12 and 13 

(Brandt-Rauf et al. 1995; Marion et al. 1991; Weihrauch et al. 2002). Similar mutations of Ki-ras-2 have 

been found in hepatocellular carcinomas of workers exposed to vinyl chloride (Weihrauch et al. 2001a, 

2001b). Hypermethylation of the p16 gene was also associated with Ki-ras-2 mutation in hepatocellular 

carcinomas from exposed workers (Weinhrauch 2001b). 

Mutation of the Ki-ras-2 gene results in the expression of a mutant p21 protein. This mutant oncoprotein 

was detected in serum samples taken from vinyl chloride workers with angiosarcoma of the liver (DeVivo 
VINYL CHLORIDE 94 

3. HEALTH EFFECTS 

et al. 1994; Marion 1998). Mutant p21 protein was also detected in the serum or plasma of exposed 

workers without liver tumors and a relationship between the frequency of the mutant protein in serum and 

the intensity of vinyl chloride exposure was demonstrated in several studies (Brandt-Rauf et al. 1995; 

DeVivo et al. 1994; Li et al. 1998; Luo et al. 1998, 2003; Marion 1998). 

Rat liver tumors induced by exposure to 500 ppm vinyl chloride were examined for mutations of the 

Ha-ras, Ki-ras, and N-ras genes (Boivin-Angele et al. 2000; Froment et al. 1994; Marion and BoivinAngele 1999). In contrast with the studies in humans, Ki-ras gene mutation does not occur in rats or mice 

with angiosarcoma of the liver induced by vinyl chloride exposure. Rats with hepatocellular carcinoma 

demonstrated a AT–TA transversion of base 2 of codon 61 of the Ha-ras gene. This mutation was not 

detected in rodent angiosarcoma of the liver suggesting that there might be cell-specific factors that affect 

the ras gene. Other mutations in codons 13 and 36 of the N-ras A gene were found in two out of five of 

the liver angiosarcomas examined (Froment et al. 1994). These studies suggest differing molecular 

mechanisms of carcinogenesis in humans and rodents. 

The p53 tumor suppressor gene is mutated in a variety of human cancers (Staib et al. 2003; Trivers et al. 

1995). A study was performed to examine the p53 tumor suppressor genes and the murine double min2 (MDM2) proto-oncogenes from tumors of five vinyl chloride workers; four with angiosarcoma of the 

liver and one with hepatocellular carcinoma (Hollstein et al. 1994). The p53 tumor suppressor gene was 

being tested for mutation, while the MDM2 proto-oncogene was being tested for amplification. No 

amplification of the MDM2 gene was detected; however, adenosine-to-thymidine missense mutations 

were found in exons 5–8 (codons 249 and 255) of the p53 gene in two of the angiosarcoma cases. In 

another study, tumors (angiosarcoma of the liver) from three of six vinyl chloride workers also had 

adenosine-to-thymidine missense mutations in the p53 gene (codons 249, 255, and 179) (Trivers et al. 

1995). Data from a study of angiosarcoma of the liver resulting from endogenous or unknown sources 

(i.e., no vinyl chloride exposure) indicated that p53 mutations were uncommon, providing support for the 

specificity of p53 mutations with vinyl chloride exposure in cases of angiosarcoma of the liver (Soini et 

al. 1995). The p53 gene mutation pattern in rat liver tumors (angiosarcoma and hepatocellular carcinoma) 

was shown to be similar to that observed in human tumors from vinyl chloride-exposed workers (Barbin 

et al. 1997; Marion and Boivin-Angele 1999). Mutations of the p53 gene were found in hepatocellular 

carcinomas from workers exposed to vinyl chloride; however, no correlation with vinyl chloride exposure 

occurred and the mutation pattern was thought to reflect endogenous mechanisms rather that chemical 

mutagenesis (Weihrauch et al. 2000). A p53 mutation at codon 179 was detected in myofibroblast-type 

cells isolated from a liver tumor in an exposed worker (Boivin et al. 1997). Ki-ras mutations were not 
VINYL CHLORIDE 95 

3. HEALTH EFFECTS 

observed in these cells. Vinyl chloride mutations of the p53 gene produce conformational effects in the 

expressed p53 protein that affect its function (Chen et al. 1999). 

Mutant p53 protein and/or anti-p53 antibodies have been detected in the serum and plasma of vinyl 

chloride-exposed workers (Luo et al. 1999; Marion 1998; Smith et al. 1998; Trivers et al. 1995). A 

relationship between the frequency of the mutant protein or p53 antibodies in serum/plasma and the 

intensity of vinyl chloride exposure was demonstrated in these studies. Polymorphisms of the genes for 

vinyl chloride metabolism (CYP2E1) and DNA repair (x-ray cross-complementing group 1) are 

associated with a greater risk of p53 gene mutation and over-expression of p53 mutant protein (Li et al. 

2003; Wong et al. 2002b). 

Rat studies suggest that gap junctional intercellular communication mediated by connexin 37 is disturbed 

in angiosarcoma of the liver; however, mutation of the connexin 37 gene is considered rare (Saito et al. 

1997). The incidence of hypoxanthine-guanine-phosphoribosyl-transferase (HPRT) mutants was not 

consistently elevated in workers exposed to vinyl chloride (Huttner and Holzapfel 1996; Liber et al. 

1999). HPRT mutants were also not increased in humans accidentally exposed to vinyl chloride (Becker 

et al. 2001). 

Vinyl chloride has not been shown to be positive for dominant lethal effects in rats exposed to up to 

30,000 ppm, for 6 hours/day for 5 days (Anderson et al. 1976; Purchase et al. 1975; Short et al. 1977). 

The studies showed no evidence of pre- or postimplantation loss among the untreated females mated to 

the exposed males. These results indicate that no germinal mutations were produced by these acute 

exposures. Vinyl chloride induces somatic and sex-linked recessive lethal mutations in Drosophila, but 

does not induce dominant lethal mutations (Ballering et al. 1996; Giri 1995; Magnusson and Ramel et al. 

1978). 

Vinyl chloride is mutagenic in S. typhimurium (Andrews et al. 1976; Bartsch et al. 1975, 1976; de 

Meester et al. 1980; Elmore et al. 1976; Malaveille et al. 1975; Poncelet et al. 1980; Simmon et al. 1977), 

but only in strains reverted by base-pair substitution by alkylating agents rather than by frameshift 

mutations (Bartsch et al. 1976; duPont 1992a, 1992b). Metabolic activation is necessary for any 

mutagenic activity in this system (Rannug et al. 1974) or for a maximal response (Simmon et al. 1977). 

In addition, vinyl chloride is mutagenic in the gaseous phase, but not when it is dissolved in water 

(Poncelet et al. 1980). The negative findings for vinyl chloride dissolved in water are most likely due to 
VINYL CHLORIDE 96 

3. HEALTH EFFECTS 

methodological problems associated with rapid evaporation and therefore do not reflect a lack of 

mutagenic potential. 

Concentrations of vinyl chloride tested in vitro range from 0.275% (Shahin 1976) to 40% (duPont 1992a). 

Shahin (1976) reported negative results for 0.275 and 0.55% vinyl chloride in Saccharomyces cerevisiae. 

In S. typhimurium, a doubling of revertants has been reported to occur at about 5% vinyl chloride 

(Victorin and Stahlberg 1988a). Vinyl chloride was found to be mutagenic in Chinese hamster ovary 

cells and yeast (Drevon et al. 1978; duPont 1992c; Eckardt et al. 1981; Loprieno et al. 1976). A 5-hour 

exposure to 4,600 ppm vinyl chloride did not cause mutatgenicity in the mammalian spot test (Peter and 

Ungvary 1980). Workers exposed to vinyl chloride have been shown to have increased chromosomal 

aberrations, micronucleic counts, and sister chromatid exchange frequencies (Anderson et al. 1980; Fucic 

et al. 1992, 1995, 1997; Garaj-Vrhovac et al. 1990; Kucerova et al. 1979; Sinues et al. 1991; Zhao et al. 

1996). 

There is evidence that in S. typhimurium, E. coli, and B. subtilis, it is the oxidation of vinyl chloride to the 

reactive intermediates 2-chloroethylene oxide and 2-chloroacetaldehyde that is responsible for the 

mutagenicity of vinyl chloride (Bartsch et al. 1976, 1979; Hussain and Osterman-Golkar, 1976; Jacobsen 

et al. 1989; Laumbach et al. 1977; McCann et al. 1975; Rannug et al. 1976). The S-9 fraction from 

surgically obtained human liver specimens was shown to metabolize vinyl chloride to electrophiles that 

were mutagenic to S. typhimurium TA1530 (Sabadie et al. 1980). Mutagenicity assays were performed 

by exposing the plates containing S. typhimurium and 150 μL human S-9 fraction to a gaseous mixture of 

20% vinyl chloride in air for 4 hours. Vinyl chloride was removed after the exposure. The vinyl chloride 

concentration in the aqueous phase of the plates was 4x10-3 M. Incubation was continued for an 

additional 48 hours. When compared with the number of revertants per plate resulting from identically 

prepared S-9 fractions from female strain BD IV rats, human S-9 fractions induced mutations (and 

presumably metabolism to a reactive electrophile) to an average 84% of the extent mediated by rat S-9. 

However, a 9-fold individual variation was observed. 

Chloroacetaldehyde appears to be less genotoxic in yeast and Chinese hamster V79 cells than 

2-chloroethylene oxide (Huberman et al. 1975; Loprieno et al. 1977) and has been shown to inhibit DNA 

synthesis in avian cells (Kandala et al. 1990). However, 2-chloroacetaldehyde has been shown to react 

directly with single-stranded DNA, which then produced base changes and subsequent reversion in E. coli 

when the DNA was inserted via phage (Jacobsen et al. 1989). Recent data have also shown 
VINYL CHLORIDE 97 

3. HEALTH EFFECTS 

2-chloroacetaldehyde to be mutagenic in human fibroblast cells using shuttle vectors (Matsuda et al. 

1995). 

3.4 TOXICOKINETICS 

Vinyl chloride is volatile and exposure occurs largely by inhalation. Studies in humans and animals have 

shown that vinyl chloride is readily absorbed through the lungs (Krajewski et al. 1980; Withey, 1976). 

Animal studies demonstrate that vinyl chloride is rapidly and almost completely absorbed from the 

gastrointestinal tract after oral exposure (Watanabe et al. 1976a; Withey 1976). A single study in 

monkeys, suggests that dermal absorption of vinyl chloride gas is not likely to be significant (Hefner et al. 

1975a). No studies were located that reported the absorption of vinyl chloride in humans after oral or 

dermal exposure. 

Animal studies indicate that the distribution of vinyl chloride is rapid and widespread; however, storage in 

the body is limited because of rapid metabolism and excretion. Metabolites of vinyl chloride have been 

found in the liver, kidney, spleen, skin, and brain, but tissue concentrations do not increase following 

repeated exposure (Bolt et al. 1976a; Butcher et al. 1977; Duprat et al., 1977; Watanabe 1978a, 1976b). 

Vinyl chloride has been shown to cross the placenta after inhalation exposure (Ungvary et al. 1978). No 

studies were located that reported tissue distribution after inhalation, oral, or dermal exposure to vinyl 

chloride in humans or after dermal exposure in animals. Vinyl chloride distribution may be affected by 

differences in gender, age, and nutritional status. 

Vinyl chloride metabolism in humans is attributed to the cytochrome P-450 monooxygenases in the liver 

(Ivanetich et al. 1977; Sabadie et al. 1980; Salmon 1976). The proposed metabolic pathways for vinyl 

chloride are shown in Figure 3-3. Data obtained in rats indicate that metabolic pathways are consistent 

for both inhalation and oral exposure (Bartsch et al., 1976, 1979; Green and Hathway 1975, 1977; 

Hathway 1977; Watanabe and Gehring 1976; Watanabe et al. 1976a). Metabolism occurs via the 

oxidation of vinyl chloride by mixed function oxidases (MFO) to form an epoxide intermediate, 

2-chloroethylene oxide, which spontaneously rearranges to form 2-chloroacetaldehyde. Intermediates are 

detoxified primarily via glutathione conjugation and conjugates are excreted in urine as substituted 

cysteine derivatives. Metabolism has been shown to follow Michaelis-Menten kinetics in rats, with 

enzyme saturation near 100 ppm in air or between 1 and 100 mg/kg/day for a single gavage dose (Hefner 

et al. 1975b; Watanabe et al. 1976a). Macromolecular binding has been attributed to the reactive 

intermediate 2-chloroethylene oxide, which binds to DNA and RNA (ribonucleic acid), and its reaction 
VINYL CHLORIDE 98 

3. HEALTH EFFECTS 

Figure 3-3. Proposed Metabolic Pathways for Vinyl Chloride* 

O mixed function oxidase

 ClHC=CH2 H2C CH 

vinyl chloride Cl 

2-chloroethylene oxide 

(1-chlorooxirane) 

 ClH2C-CHO + glutathione 

2-chloroacetaldehyde 

G-S-CH2-CHO aldehyde 

dehydrogenase S-formylmethyl

 glutathione 

 ClH2C-CHOOH 

2-chloroacetic acid** 

+ glutathione cys-S-CH2-CHO

 S-formylmethyl 

cysteine** G-S-CH2-COOH 

S-carboxymethyl glutathione

 cys-S-CH2-CH2OH 

S-(2-hydroxyethyl)-cysteine 

 cys-S-CH2-COOH 

S-carboxymethyl cysteine

 NH3 

ammonia N-Ac-cys-S-CH2-CH2OH 

(transamination) 

N-acetyl-S-(2-hydroxyethyl) cysteine** 

CO2
 

carbon dioxide
 

(oxidative decarboxylation)

 HOOC-CH2-S-CH2-COOH 

thiodiglycolic acid (thiodiacetic acid)** 

*Derived from Bolt et al. (1980); Cogliano and Parker (1992); Hefner et al. (1975b); Park et al. (1993); and Plugge 

and Safe (1977). 

**Excreted in urine. 
VINYL CHLORIDE 99 

3. HEALTH EFFECTS 

product, 2-chloroacetaldehyde, which binds to protein molecules (Barbin et al., 1975; Guengerich and 

Watanabe 1979; Guengerich et al. 1979, 1981; Kappus et al. 1976; Watanabe et al. 1978a, 1978b). No 

studies were located regarding vinyl chloride metabolism in humans after oral or dermal exposure or in 

animals after dermal exposure. It should be noted that the toxicokinetics of vinyl chloride could be 

affected by compromised liver function or exposure to alcohol and other drugs and chemicals. 

Animal studies have demonstrated that the primary route of excretion is dose-dependent (Watanabe and 

Gehring 1976; Watanabe et al. 1978a, 1976b). Vinyl chloride metabolites are excreted primarily in the 

urine following oral or inhalation exposure to low doses. At higher doses where metabolic saturation has 

been exceeded, vinyl chloride is exhaled as the parent compound. This was also demonstrated in humans 

exposed by inhalation, where exhalation of vinyl chloride was a minor pathway of elimination at low 

concentrations (Krajewski et al. 1980). No studies were located regarding excretion in humans after oral 

or dermal exposure to vinyl chloride. After dermal exposure in monkeys, most of the little vinyl chloride 

absorbed was excreted in exhaled air (Hefner et al. 1975a). 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

Inhalation absorption of vinyl chloride is rapid in humans. Young adult male volunteers were exposed to 

vinyl chloride concentrations of 2.9, 5.1, 11.7, or 23.5 ppm by gas mask for 6 hours (Krajewski et 

al. 1980). Retention was estimated by measuring the difference between inhaled and exhaled 

concentrations. An average retention of 42% was estimated. Although the results varied among the 

individuals tested, the percentage retained was independent of the concentration inhaled. Since retention 

did not change with increasing vinyl chloride concentrations, it appears that saturation of the major 

pathway of overall metabolism did not occur in this exposure regimen. 

Animal data demonstrate that the inhalation absorption of vinyl chloride occurs readily and rapidly. 

PBPK models that have been developed to provide quantitative estimates of uptake are discussed in 

Section 3.4.5. Peak blood levels occurred at 30 minutes in rats exposed (head only) to 7,000 ppm 

(Withey 1976). On removal from the vinyl chloride atmosphere, blood levels fell rapidly. After 2 hours, 

concentrations were barely detectable. 
VINYL CHLORIDE 100 

3. HEALTH EFFECTS 

3.4.1.2 Oral Exposure 

No studies were located regarding absorption in humans after oral exposure to vinyl chloride. 

Several studies in rats indicate that vinyl chloride is rapidly and virtually completely absorbed from the 

gastrointestinal tract. Peak blood levels of vinyl chloride were observed within 10–20 minutes after 

dosing in rats administered single oral doses (44–92 mg/kg) of vinyl chloride in aqueous solution (Withey 

1976). Peak blood levels varied from 6 to >40 μg/mL. Data from another study in which rats were 

administered single gavage doses of 0.05, 1, and 100 mg/kg vinyl chloride labelled with radioactive 

carbon (14C-vinyl chloride) (in corn oil) suggested that almost complete absorption of vinyl chloride 

occurred (Watanabe et al. 1976a). The fraction of the administered dose recovered in the feces, roughly 

indicative of the proportion unabsorbed, ranged from 0.47 to 2.39%; total recovery ranged from 82.3 to 

91.3%. Loss of radioactivity might be attributed either to experimental error or to incomplete sampling of 

the carcass. Fecal excretion was measured in rats fed 0, 1.8, 5.6, and 17.0 mg/kg/day of vinyl chloride 

monomer (from powdered PVC containing a high level of the monomer) (Feron et al. 1981). Fecal 

excretion accounted for 8, 10, and 17% of the vinyl chloride present in the low-, middle-, and high-dose 

groups, respectively. The investigators hypothesized that the vinyl chloride recovered from the feces was 

encapsulated by PVC and was not available to the rats for absorption, and that absorption of available 

vinyl chloride was virtually complete. 

3.4.1.3 Dermal Exposure 

No studies were located regarding absorption in humans after dermal exposure to vinyl chloride. 

Animal data suggest that dermal absorption of vinyl chloride gas is not likely to be significant. Dermal 

absorption was measured in two rhesus monkeys that received full body (except head) exposure to vinyl 

chloride gas. It was estimated that 0.031 and 0.023% of the total available vinyl chloride was absorbed at 

800 and 7,000 ppm, respectively, after a 2–2.5-hour exposure (Hefner et al. 1975a). The investigators 

concluded that, after short-term exposure to high concentrations, dermal absorption was far less 

significant than inhalation absorption. No information is available regarding dermal absorption of vinyl 

chloride from liquid or solid mediums. 
VINYL CHLORIDE 101 

3. HEALTH EFFECTS 

3.4.2 Distribution 

Representative vinyl chloride partition coefficients for humans, rats, mice, and hamsters can be found in 

Table 3-5. These partition coefficients were obtained for use in PBPK models. They were estimated 

using a vial equilibration technique (Air Force 1990b). Further details about how the values were 

obtained, including the number of experiments completed and whether the errors shown are standard 

deviations or standard errors, were not provided. In general, concentrations of vinyl chloride found in fat 

are higher than would be found in other tissues. Partition coefficients for vinyl chloride range from 10 to 

20 (fat/air) and from 1 to 3 (muscle/air, blood/air, and liver/air). In animal studies, females have shown 

greater partitioning from air to fat than males. 

Tissue/blood partition coefficients in male Sprague-Dawley rats, measured using a vial equilibration 

method, have been reported as 10±3 for fat/blood, 0.4±0.2 for muscle/blood, 0.7±0.3 for liver/blood, and 

0.7±0.4 for kidney/blood (Barton et al. 1995). 

3.4.2.1 Inhalation Exposure 

No studies were located regarding tissue distribution in humans after inhalation of vinyl chloride. 

Data from rat studies suggest that the distribution of inhaled vinyl chloride is rapid and widespread, but 

storage of vinyl chloride in the body is limited by rapid metabolism and excretion. In rats exposed to 

14C-vinyl chloride and pretreated with 6-nitro-1,2,3-benzothiadiazole to block metabolism of vinyl 

chloride by microsomal cytochrome P-450 oxidation pathways, the highest levels of radiolabel were 

located in the fat, with lesser amounts in the blood, liver, kidney, muscle, and spleen. When metabolism 

was not blocked, the highest levels of radiolabelled metabolites were located in the liver and kidney 

(Buchter et al. 1977). Immediately after a 5-hour exposure to 14C-vinyl chloride at 50 ppm, tissue levels 

of 14C-activity, expressed as the percentage 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). 

Radioactivity in tissue was measured in rats 72 hours after exposure to 10 or 1,000 ppm 14C-vinyl 

chloride for 6 hours. In order of decreasing concentration for rats exposed to 10 ppm, 14C-labeled 

compounds (expressed as percentage), present as nonvolatile metabolites, were measured in the liver 

(0.14), kidney (0.08), skin (0.07), lung (0.07), muscle (0.05), carcass (0.05), plasma (0.05), and fat (0.03). 

For rats exposed to 1,000 ppm, radiolabel (expressed as percentage) was measured in the liver (0.15), skin 
VINYL CHLORIDE 102 

3. HEALTH EFFECTS 

Table 3-5. Vinyl Chloride Partition Coefficients 

Partition coefficient 

Species 

Rat 

Strain 

CDBRa 

Sex 

M 

F 

Blood/air 

1.8±0.22 

2.1±0.44 

Liver/air 

3.0±0.41 

1.7±0.43 

Muscle/air 

2.2±0.70 

1.3±0.25 

Fat/air 

14.6±0.92 

19.2±0.96

 F-344a M 

F 

1.6±0.33 

1.6±0.11 

2.0±2.0 

2.1±0.17 

2.1±0.40 

2.4±0.46 

11.8±0.81 

21.1±1.3 

 Wistar

a M 

F 

2.1±0.31 

1.6±0.07 

2.7±0.56 

1.5±0.28 

2.7±0.58 

1.6±0.22 

10.2±1.6 

22.3±0.54

 SpragueDawleyb 

M 2.4±0.5 – – – 

Mouse B6C3F1 

a M 

F 

2.8±0.22 

2.6±0.14 

– 

– 

– 

– 

– 

– 

 CD-1a M 

F 

2.3±0.07 

2.4±0.16 

– 

– 

– 

– 

– 

– 

Hamster Golden Syriana M 

F 

2.7±0.15 

2.2±0.47 

3.4±0.36 

1.3±0.28 

2.6±0.46 

2.0±0.28 

14.3±5.3 

21.1±2.0 

Humanc NA NR 1.16 – – – 

a

Air Force 1990b; values determined using vial equilibration method. b

Barton et al. 1995 

c

EPA 1987g 

– = no data; F = female; M = male; NA = not applicable; NR = not reported 
VINYL CHLORIDE 103 

3. HEALTH EFFECTS 

(0.12), kidney (0.06), carcass (0.05), lung (0.05), muscle (0.04), fat (not detected), and plasma (not 

detected) (Watanabe et al. 1976b). There was no difference in the routes or rate of excretion between 

repeated-dose versus single-dose exposure of rats to 5,000 ppm of 14C-vinyl chloride (Watanabe et 

al. 1978a). The concentration of radiolabel detected in tissues 72 hours after exposure revealed no 

statistically significant difference between rats exposed once or repeatedly to vinyl chloride. Percentages 

of radioactivity after 72 hours measured in tissues are as follows (for single and repeated doses, 

respectively): liver (0.12 and 0.16), kidney (0.06 and 0.07), skin (0.05 and 0.08), carcass (0.03 and 0.04), 

and fat (not detected and not detected). 

Placental transfer of vinyl chloride can occur rapidly in rats. Female rats exposed to approximately 0, 

2,000, 7,000, or 13,000 ppm vinyl chloride for 2.5 hours on Gd 18 showed high concentrations of vinyl 

chloride in maternal and fetal blood and amniotic fluid (Ungvary et al. 1978). Vinyl chloride 

concentrations in maternal blood were 19.02, 32.40, and 48.43 μg/mL, respectively, while fetal blood 

concentrations were 12.80, 22.67, and 30.52 μg/mL, respectively. Vinyl chloride concentrations in 

amniotic fluid were 0, 4.27, 4.93, and 13.50 μg/mL, at 2,000, 7,000, and 13,000 ppm vinyl chloride, 

respectively (Ungvary et al. 1978). 

3.4.2.2 Oral Exposure 

No studies were located regarding tissue distribution in humans after oral exposure to vinyl chloride. 

The level of 14C-nonvolatile metabolites was measured in tissues of rats 72 hours after single gavage 

doses (0.05–100 mg/kg) of 14C-vinyl chloride in corn oil (Watanabe et al. 1976a). The highest levels of 

radioactivity for each dose level occurred in the liver. These levels were 2–5 times higher than in the 

other tissues examined (skin, plasma, muscle, lung, fat, and carcass). 

3.4.2.3 Dermal Exposure 

No studies were located regarding tissue distribution for humans or animals after dermal exposure to 

vinyl chloride. 
VINYL CHLORIDE 104 

3. HEALTH EFFECTS 

3.4.3 Metabolism 

3.4.3.1 Inhalation Exposure 

Metabolism can be quantitatively estimated from gas uptake experiments in which, after initial absorption 

of vinyl chloride, continued absorption is largely attributed to metabolism. Krajewski et al. (1980) 

exposed young men to vinyl chloride at concentrations of 2.9, 5.1, 11.7, and 23.5 ppm by gas mask for 

6 hours. Retention was independent of the inhaled concentration and did not change with increasing vinyl 

chloride concentrations, suggesting that saturation of the major metabolic pathway did not occur over this 

exposure range. 

The major metabolic pathway of vinyl chloride involves oxidation by mixed-function oxidases to form a 

highly reactive epoxide intermediate, 2-chloroethylene oxide, which spontaneously rearranges to form 

2-chloroacetaldehyde (Guengerich et al. 1979, 1981; Gwinner et al. 1983; Laib 1982). These 

intermediates are detoxified mainly through conjugation with glutathione catalyzed by glutathione 

S-transferase. The conjugated products are excreted in urine as substituted cysteine derivatives and 

include thiodiglycolic acid, S-formylmethylcysteine, and N-acetyl-S-(2-hydroxyethyl) cysteine (Bolt et al. 

1980; Hefner et al. 1975b). Urinary metabolites identified in rats exposed by inhalation include polar 

compounds at low exposure concentrations (Hefner et al. 1975b; Watanabe et al. 1976b) and 

2-chloroacetic acid at high exposure concentrations (Hefner et al. 1975b). 

Early work on the metabolism of vinyl chloride in animals indicated that metabolism is a dose-dependent, 

saturable process. Rats were exposed to vinyl chloride in a closed chamber at concentrations of about 50– 

1,000 ppm for 52.5–356.3 minutes (Hefner et al. 1975b). Additional rats pretreated with ethanol (to 

inhibit alcohol dehydrogenase activity) or SKF 525-A (to inhibit microsomal oxidase activity) were 

similarly exposed. Metabolism, estimated by measuring the rate of disappearance of vinyl chloride from 

the closed system, followed first-order kinetics with a half-life of 86 minutes at <100 ppm. At >220 ppm, 

metabolism was slowed to a half-life of 261 minutes, suggesting saturation of the pathway predominant at 

100 ppm. Pretreatment with ethanol depressed the rate of metabolism by approximately 83% at 

<100 ppm but by approximately 47% at >1,000 ppm. Pretreatment with SKF 525-A, however, had no 

effect at <100 ppm but depressed metabolism by 19% at >1,000 ppm. The study authors postulated 

alternative pathways for vinyl chloride metabolism. They suggested that at low concentrations sequential 

oxidation to 2-chloroethanol, 2-chloroacetaldehyde, and 2-chloroacetic acid involving alcohol 

dehydrogenase (inhibited by pretreatment with ethanol) appeared to be the predominant pathway. Little 

2-chloroacetic acid was formed, however, possibly because 2-chloroacetaldehyde conjugated rapidly with 
VINYL CHLORIDE 105 

3. HEALTH EFFECTS 

ubiquitous sulfhydryl groups. The authors further speculated that when the alcohol dehydrogenase 

pathway became saturated, 2-chloroethanol could be oxidized by catalase in the presence of hydrogen 

peroxide (H2O2) to a peroxide, which could undergo subsequent dehydration to form 2-chloroacetaldehyde. However, it appears that the only support for this proposed metabolism of vinyl chloride 

by alcohol dehydrogenase comes from studies demonstrating metabolic inhibition by alcohol. This is not 

recognized as a direct pathway for metabolism of vinyl chloride in modern PBPK modeling studies. It is 

possible that ethanol exerts its effects by inhibiting specific P-450 enzymes involved in the metabolic 

activation of vinyl chloride. 

Isolated rat liver cells converted 14C-vinyl chloride into nonvolatile metabolites (Hultmark et al. 1979). 

Using this in vitro technique, it was determined that metabolism was NADPH-dependent, located in the 

microsomal fraction of the liver, and probably involved an MFO. Pretreatment with 6-nitro-1,2,3-benzothiadiazole, an inhibitor of some microsomal cytochrome P-450 oxidation pathways, was sufficient to 

totally block the metabolism of vinyl chloride in rats exposed to 0.45 ppm in a closed system for 5 hours 

(Bolt et al. 1977). This observation suggests that metabolism of vinyl chloride proceeds primarily 

through an MFO pathway with likely production of an epoxide intermediate. 

Inhalation exposure to high concentrations of vinyl chloride has also been associated with a reduction in 

the liver nonprotein sulfhydryl concentration in the rat (Barton et al. 1995). These results are consistent 

with conjugation of the metabolites of vinyl chloride with limited reserves of glutathione and/or cysteine 

(Bolt et al. 1976b; Hefner et al. 1975b; Jedrychowski et al. 1984; Watanabe et al. 1978b). 

Saturation of metabolic pathways was observed in rats and monkeys that were exposed in a closed system 

to 14C-vinyl chloride (Bolt et al. 1977; Buchter et al. 1980; Filser and Bolt 1979). In Wistar rats, 

metabolic saturation was determined to occur at approximately 250 ppm, and a metabolic rate (Vmax) of 

110 μmol/hour/kg was estimated (Bolt et al. 1977; Filser and Bolt 1979). Kinetic constants of 

58 μmol/hour/kg for Vmax and 1 μM for the Km in male Sprague-Dawley rats have also been reported 

(Barton et al. 1995). In an experiment using rhesus monkeys, metabolic saturation occurred at 200 ppm, 

with a Vmax of 50 μmol/hour/kg (Buchter et al. 1980). The Vmax of 50 μmol/hour/kg that was estimated 

using rhesus monkeys was suggested as a closer approximation of metabolism in humans than the value 

of 110 μmol/hour/kg estimated for rats by Filser and Bolt (1979). 

Kinetic constants for vinyl chloride metabolism have also been derived from in vitro studies in rat liver 

microsomes (El Ghissassi et al. 1998). Vinyl chloride metabolism to reactive species followed Michaelis­
VINYL CHLORIDE 106 

3. HEALTH EFFECTS 

Menton kinetics with a Km of 7.42 μM and a Vmax of 4,674 pmol/mg protein/minute. Inhibitor studies 

using chemical and immunological inhibitors demonstrate that vinyl chloride is metabolized primarily by 

CYP2E1. 

Several investigators have observed the binding of nonvolatile metabolites of 14C-vinyl chloride to liver 

macromolecules in vitro and in rats exposed by inhalation (Guengerich and Watanabe 1979; Guengerich 

et al. 1979, 1981; Kappus et al. 1976; Watanabe et al. 1978a, 1978b). In single-exposure experiments at 

different concentrations, the extent of macromolecular binding increased proportionately to the amount of 

vinyl chloride metabolized and disproportionately to the exposure concentration (Watanabe et al. 1978b). 

The extent of macromolecular binding was increased by repeated exposure to vinyl chloride (Watanabe et 

al. 1978a) and by pretreatment with phenobarbital (Guengerich and Watanabe 1979). Macromolecular 

binding has been attributed to the reactive intermediate 2-chloroethylene oxide, which has been shown to 

bind to DNA and RNA, and to its rearrangement product, 2-chloroacetaldehyde, which has been shown to 

bind to protein molecules (Guengerich and Watanabe 1979; Guengerich et al. 1979, 1981; Kappus et al. 

1976; Watanabe et al. 1978a, 1978b). 

3.4.3.2 Oral Exposure 

No studies were located regarding metabolism in humans after oral exposure to vinyl chloride. 

Urinary metabolites identified from rats ingesting 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 include N-acetyl-S-(2-hydroxyethyl)cysteine, 

2-chloroacetic acid, and thiodiglycolic acid (Green and Hathway 1975, 1977; Watanabe and Gehring 

1976; Watanabe et al. 1976a). Metabolic saturation appears to occur with a single gavage dose of 

between 1 and 100 mg/kg/day (Watanabe et al. 1976a). 

3.4.3.3 Dermal Exposure 

No studies were located regarding metabolism in humans or animals after dermal exposure to vinyl 

chloride. 
VINYL CHLORIDE 107 

3. HEALTH EFFECTS 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

Human data suggest that exhalation of unmetabolized vinyl chloride is not an important pathway of 

elimination at low exposure concentrations. The mean concentration in expired air for humans exposed 

for 6 hours to air containing 2.9–23.5 ppm ranged from 0.21 to 1.11 ppm, representing from 7.23 to 

4.73% of the inhaled amounts, respectively (Krajewski et al. 1980). 

Animal studies indicate that the importance of exhalation of vinyl chloride as a major route of excretion 

varies with the exposure concentration. The mode of excretion of vinyl chloride and its metabolites 

following inhalation exposure of animals to different concentrations reflects the saturation of metabolic 

pathways. The cumulative excretion of radioactivity over a 72-hour postexposure period was measured in 

rats exposed to 10–1,000 ppm (Watanabe and Gehring 1976; Watanabe et al. 1976b) or 5,000 ppm 

(Watanabe et al. 1978a) 14C-vinyl chloride for 6 hours. Radioactivity expired as carbon dioxide or vinyl 

chloride, excreted in the urine and feces, and retained in the carcass was expressed as a percentage of the 

total radioactivity recovered. The results suggest that metabolism was nearly complete at 10 ppm because 

less than 2% of the recovered radioactivity occurred as unchanged parent compound. The predominant 

route for excretion of radioactive metabolites was through the urine, accounting for about 70% of the 

recovered radioactivity. Metabolism became saturated at 1,000 ppm, since unchanged vinyl chloride 

increased to 12.3% and urinary radioactivity decreased to 56.3%. At 5,000 ppm, more than half the 

recovered radioactivity appeared as unchanged vinyl chloride in expired air, and urinary excretion 

accounted for about 27% of the recovered activity. Generally, there was little change in the proportion of 

recovered radioactivity excreted in the feces or exhaled as carbon dioxide. The percentage of the 

radioactivity retained in the carcass and tissues appeared to be somewhat decreased at 5,000 ppm 

compared with 10 and 1,000 ppm, suggesting preferential retention of metabolites rather than unchanged 

vinyl chloride. It should be noted that the trend of a greater percentage of vinyl chloride being exhaled at 

higher concentrations in animals is the opposite of what was observed in humans in Krajewski et al. 

(1980). In humans, a higher percentage of unmetabolized vinyl chloride was found in expired air at lower 

concentrations (Krajewski et al. 1980). However, it is possible that a reversal of this trend would occur in 

humans if concentrations were increased to those used in the animal studies or to concentrations closer to 

the Km for human metabolism. 

Pulmonary excretion of unaltered vinyl chloride in rats followed first-order kinetics regardless of 

exposure concentrations, with half-lives of 20.4, 22.4, and 30 minutes following 6-hour exposures at 10, 
VINYL CHLORIDE 108 

3. HEALTH EFFECTS 

1,000, and 5,000 ppm, respectively. The urinary excretion of radioactivity was biphasic, with the second 

or slow phase accounting for less than 3% of the total urinary excretion. Estimated half-lives for the rapid 

(first-order) phase were 4.6, 4.1, and 4.5 hours, at 10, 1,000, and 5,000 ppm, respectively. Urinary 

metabolites included N-acetyl-S- (2-hydroxyethyl)cysteine, thiodiglycolic acid, and possibly 

S-(2-hydroxyethyl)cysteine (Watanabe et al. 1976b). Identification of these metabolites of vinyl chloride 

in the urine indicates that vinyl chloride is transformed in the body to a reactive metabolite, which is then 

detoxified by reaction with glutathione (GSH, gamma-glutamylcysteinylglycine). Subsequently the 

glutamic acid and glycine moieties of the tripeptide are cleaved, and the cysteine conjugate of the reactive 

metabolite of vinyl chloride is either acetylated or further oxidized and excreted. Thiodiglycolic acid is 

the major metabolite of vinyl chloride detected in the urine of exposed workers (Cheng et al. 2001). 

Urinary thiodiglycolic acid levels were correlated with vinyl chloride levels in air at concentrations 

>5 ppm. 

3.4.4.2 Oral Exposure 

No studies were located regarding excretion in humans after oral exposure to vinyl chloride. 

Single oral doses of 14C-vinyl chloride (0.05, 0.25, 1.0, 20, 100, and 450 mg/kg) were administered to 

rats, and the excretion of radioactivity was monitored over a 72-hour period (Green and Hathway 1975; 

Watanabe and Gehring 1976; Watanabe et al. 1976a). A striking increase in exhalation of unchanged 

vinyl chloride and compensatory decreases in urinary and fecal excretion of radioactivity and exhalation 

of carbon dioxide were observed at >20 mg/kg, suggesting that metabolic saturation had occurred at that 

dosage. At less than 1.0 mg/kg, the predominant route of elimination was urinary excretion of polar 

metabolites. 

Exhalation of unchanged vinyl chloride was generally complete within 3–4 hours, but excretion of 

metabolites continued for days (Green and Hathway 1975). Pulmonary excretion of vinyl chloride 

appeared to be monophasic at less than 1.0 mg/kg, with a half-life of about 55–58 minutes (Watanabe et 

al. 1976a). At 100 mg/kg, pulmonary excretion of vinyl chloride was biphasic, with half-lives of 14.4 and 

40.8 minutes for the rapid and slower phases, respectively. Urinary excretion of radioactivity was 

biphasic, with the rapid phase accounting for more than 97% of total urinary radioactivity and having 

half-lives of 4.5–4.6 hours for dosages of 0.05–100 mg/kg. 
VINYL CHLORIDE 109 

3. HEALTH EFFECTS 

Metabolites identified in the urine of orally treated rats were consistent with the formation of 

2-chloroethylene oxide and 2-chloroacetaldehyde (Green and Hathway 1977; Watanabe et al. 1976a), as 

postulated for metabolism following inhalation exposure. The major metabolites were identified as 

thiodiglycolic acid and N-acetyl-S-(2-hydroxyethyl)cysteine (Watanabe et al. 1976a). 

N-Acetyl-S-(2-chloroethyl)cysteine and S-(2-chloroethyl)cysteine have also been identified as having 

smaller amounts of radiolabelled urea, glutamic acid, and 2-chloroacetic acid (Green and Hathway 1975). 

3.4.4.3 Dermal Exposure 

No studies were located regarding excretion in humans after dermal exposure to vinyl chloride. 

When two rhesus monkeys received whole-body (except head) exposure to vinyl chloride gas (800 and 

7,000 ppm) for 2–2.5 hours, although very little vinyl chloride was absorbed, most was excreted in 

expired air (Hefner et al. 1975a). The percentages of absorbed vinyl chloride that were exhaled were 

0.028 and 0.014% at 700 and 8,000 ppm, respectively (Hefner et al. 1975a). 

3.4.4.4 Other Routes of Exposure 

The elimination of radioactivity following intraperitoneal administration of 14C-vinyl chloride to rats 

resembles the pattern observed following inhalation or oral administration. Following an intraperitoneal 

dose of 0.25 mg/kg, exhalation of unchanged vinyl chloride, exhalation of carbon dioxide, and urinary 

and fecal excretion of radioactivity accounted for 43.2, 11.0, 43.1, and 1.8% of the administered dose, 

respectively (Green and Hathway 1975). At 450 mg/kg, exhaled vinyl chloride increased to 96.2% of the 

administered dose, carbon dioxide decreased to 0.7%, urinary radioactivity decreased to 2.6%, and fecal 

radioactivity decreased to 0.1%. 

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 

14C-vinyl chloride to rats and recovered 80% of the dose within 2 minutes and 99% within 1 hour as 

unchanged compound in expired air. 
VINYL CHLORIDE 110 

3. HEALTH EFFECTS 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 
VINYL CHLORIDE 111 

3. HEALTH EFFECTS 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-4 shows a conceptualized representation of a PBPK model. 

If PBPK models for vinyl chloride exist, the overall results and individual models are discussed in this 

section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species 

extrapolations. 

PBPK models are available for vinyl chloride. The overall results and individual models are discussed in 

this section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species 

extrapolations. 

Summary of PBPK/PD Models 

Models have been developed to predict the metabolism and distribution of vinyl chloride. EPA (1987g) 

developed a PBPK model to estimate the metabolized dose of vinyl chloride coupled to a multistage 

model to estimate cancer risk in animals. This PBPK model consists of four compartments, the liver, fat, 

highly perfused tissue, and poorly perfused tissue. All metabolism was assumed to occur in the liver by 

one saturable pathway (Michaelis-Menten kinetics) and by a first-order metabolism pathway. The 

physiologic parameters used were values from an EPA draft "Reference Physiologic Parameters in 

Pharmacokinetic Modeling" by Dr. Curtis Travis of the Oak Ridge National Laboratory. 

The dose delivery of the vinyl chloride model developed by EPA (1987g) was further validated by the Air 

Force (1990b) study with additional vinyl chloride metabolism studies in rats. At low concentrations, this 

model fit in vivo data in rats by Gehring et al. (1978) well, but at concentrations above 25 ppm, the model 

predicted a greater amount of vinyl chloride metabolism than observed. The Air Force (1990b) then 

made modifications in the model to improve the fit with actual data. In the first modification, both vinyl 
VINYL CHLORIDE 112 

3. HEALTH EFFECTS 

Figure 3-4. Conceptual Representation of a Physiologically Based 
 

Pharmacokinetic (PBPK) Model for a 
 

Hypothetical Chemical Substance 
 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax Km 

Ingestion 

Inhaled chemical Exhaled chemical 

GI 

Tract 

Feces 

Urine

 Chemicals in air 

contacting skin 

Source: adapted from Krishnan et al. 1994 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 
VINYL CHLORIDE 113 

3. HEALTH EFFECTS 

chloride and the epoxide metabolite were assumed to react with glutathione. This model had difficulty 

predicting glutathione depletion at high doses; for example, it predicted glutathione depletions higher than 

observed at 4,600–5,800 ppm vinyl chloride. The second alternative model, in which only the product of 

the first-order metabolism was assumed to react with glutathione, also predicted glutathione depletions 

higher than observed at high concentrations. To improve the model, the investigators suggested the 

addition of a low-affinity glutathione pathway. 

Using data obtained from Wright-Patterson Air Force Base, the Air Force (1990b) extended the first 

glutathione conjugation model, developed in rats, to different strains of rats, mice, and hamsters. Vinyl 

chloride gas uptake experiments were completed in which animals were exposed to various 

concentrations of vinyl chloride in closed chambers for up to 6 hours, and the disappearance of vinyl 

chloride was monitored. The glutathione content of the animals was also measured immediately after 

exposure. Using data from these studies and the physiologic parameters shown in Table 3-6, the 

investigators estimated metabolic parameters for vinyl chloride and the rate constant for the conjugation 

of vinyl chloride with glutathione (Table 3-7). Using the metabolic parameters determined from the gas 

uptake experiments, the model predictions showed good agreement with the actual data for all the strains 

tested. It does not appear that the investigators further validated the model with data from studies other 

than those used to determine the metabolic parameters. This model was not used to estimate metabolized 

doses for humans because the investigators indicated that human data to estimate all the required 

parameters were not available. They suggested that allometry may have to be used to estimate some of 

the parameters for humans. 

Clewell et al. (1995) used PBPK modeling coupled with a linearized multistage model to predict human 

cancer risk. The model again had four compartments as described for the EPA (1987g) study, and the 

same EPA physiologic parameters were used. Partition coefficients were from in vitro experiments and 

are shown in Table 3-4. Metabolism was modeled by two saturable pathways: one high affinity, low 

capacity (P450 2E1), and one low affinity, high capacity (2C11/6 and 1A1/2). The metabolic parameters 

used were not provided, but they were estimated from the Air Force (1990b) model. This model assumed 

that the metabolites (chloroethylene oxide and chloroacetaldehyde) were further degraded to carbon 

dioxide, or reacted with glutathione, or reacted with DNA. The parameters (not stated) for reactions of 

the metabolites were estimated from vinylidene chloride data (D'Souza and Andersen 1988) using 

appropriate allometric scaling. Based on this PBPK model and a linearized multistage model using liver 

angiosarcoma data from animal studies, the human risk estimates for lifetime exposure to 1 ppb vinyl 

chloride ranged from 1.1 to 15.7/million persons (Clewell et al. 1995). Based on the incidence of liver 
VINYL CHLORIDE 114 

3. HEALTH EFFECTS 

Table 3-6. Physiological Parameters Used to Estimate Parameters from Vinyl 
 

Chloride Gas Uptake Experimentsa
 

Parameter Rats Mice Hamsters 

Ventilation rate (L/hour/body weight0.74) 14 23–25b 13 

Total cardiac output (L/hour/body weight0.74) 14 23–25b 13 

Blood flow to the liver (fraction of total cardiac output) 0.25 0.24 0.24 

Blood flow to highly perfused tissue (fraction of total cardiac output) 0.51 0.52 0.52 

Blood flow to fat (fraction of total cardiac output) 0.09c

 0.05 0.09 

Blood flow to poorly perfused tissue (fraction of total cardiac output) 0.15c

 0.20 0.15 

Volume of tissue (L/body weight) 0.04 0.04 0.04 

Volume of highly perfused tissue (L/body weight) 0.04 0.05 0.05 

Volume of fat tissue (L/body weight) 0.07–0.1d

 0.04 0.07 

Volume of poorly perfused tissue (L/body weight) 0.72–0.75d

 0.78 0.75 

a

Air Force 1990b; units of body weight were not provided. 
 b

Ventilation rates and total cardiac outputs were 23 for male B6C3F1 mice, 25 for female B6C3F1 mice, 28 for female 
 

CD-1 mice, and 35 for male CD-1 mice. 
 c

Male Wistar rats blood flow to fat = 0.08 and blood flow to slowly perfused tissue = 0.16. 
 d

Female F-344 and female Wistar rats had volume of fat tissue = 0.07 and volume of slowly perfused tissue = 0.75; 
 

male F-344 and female Wistar rats had volume of fat tissue = 0.08 and volume of slowly perfused tissue = 0.74; 
 

male Wistar rats and male CDBR rats had volume of fat tissue = 0.1 and volume of slowly perfused tissue = 0.72. 
 
VINYL CHLORIDE 115 

3. HEALTH EFFECTS 

Table 3-7. Estimates of Metabolic Parameters Obtained from Gas Uptake 
 

Experiments 
 

Species Strain Sex 

Vmax/body weight0.7 

(mg/hour/body 

weight0.7) 

Kfc 

(body weight

0.3/ 

hour) 

Kgsc 

(body weight

0.3/hour/μmol/L 

GSH) 

Rat CDBR M 2.5 0.63 ND 

F 2.47 1.0 0.000241 

 F-344 M 3.17 1.08 0.000249 

F 2.95 1.03 0.000227 

 Wistar M 3.11 0.45 0.000093 

F 2.97 1.55 0.00040 

Mouse B6C3F1 M 5.89 5.5 0.000827 

F 5.53 8.93 0.00167 

CD-1 M 6.99 5.1 0.000563 

F 5.54 6.62 0.000809 

Hamster Golden M 4.94 1.67 ND 

Syrian 

F 4.76 2.06 0.000330 

Source: Air Force 1990b 

F = female; GSH = glutathione; Kfc = first order of epoxide formation; Kgsc = rate constant for conjugation of vinyl 

chloride with glutathione; M = male; ND = not determined; Vmax = maximum velocity of reaction 
VINYL CHLORIDE 116 

3. HEALTH EFFECTS 

angiosarcoma in human epidemiological studies, the risk estimates for lifetime exposure to 1 ppb vinyl 

chloride were 0.4–4.22/million persons. Clewell et al. (1995) indicated that the risk estimates in the 

occupational exposure range using PBPK modeling are about 30–50 times lower than estimates using 

external dose calculations based on the linearized multistage model. 

Reitz et al. (1996) also developed a PBPK model that coupled measures of delivered dose in rats to a 

linearized multistage model to predict the incidence of hepatic angiosarcoma in mice and humans. The 

model incorporated four compartments—fat, muscle, rapidly perfused tissues, and liver. Physiological 

parameters in the model were based on similar ones used in an earlier multispecies PBPK model 

developed for methylene chloride. Partition coefficients were estimated by vial equilibration techniques 

similar to those described in the Air Force (1990b) study. Metabolic rate constants were obtained from in 

vivo gas uptake experiments performed at Wright-Patterson Air Force Base. 

Based on the PBPK-based procedure utilized by Reitz et al. (1996), the predicted human risk estimates 

ranged from about 200 cases/100,000 (for workers employed 10 years at a plant where the TWA was 

50 ppm) to almost 4,000 cases/100,000 in workers employed for 20 years in a plant where the TWA was 

2,000 ppm. The predictions of human risk were compared with the data reported by Simonato et al. 

(1991). The predictions of angiosarcoma incidence in humans were almost an order of magnitude higher 

than actually observed in exposed human populations, and were more than two orders of magnitude lower 

than risk estimations that did not utilize pharmacokinetic data. 

Clewell et al. (2001) futher refined the PBPK model for vinyl chloride and this model was applied by the 

EPA to develop quantitative toxicity values for vinyl chloride (i.e., reference dose [RfD], reference 

concentration [RfC], inhalation unit risk, oral slope factor) (EPA 2000). The model had four 

compartments and metabolism was modeled by two saturable pathways: one high affinity, low capacity 

(P450 2E1), and one low affinity, high capacity (2C11/6 and 1A1/2). A description of glutathione 

kinetics was also included in the model. Cancer risk estimates in the occupational exposure range 

calculated using the PBPK model were consistent with risk estimates from epidemiological studies and 

were approximately 80-fold lower than cancer risk estimates from animal studies without PBPK 

modeling. The inhalation portion of the PBPK model is well documented with experimental inhalation 

data sufficient to ensure a high degree of confidence in the derived dose metrics. Less confidence is 

associated with the oral dose metrics due to the limited experimental data available (EPA 2000). 
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The Clewell et al. (2001) model was also recently applied to evaluate the potential impact of age- and 

gender-specific pharmacokinetic differences on the dosimetry of vinyl chloride (Clewell et al. 2004). The 

rate of metabolite production per volume of liver was estimated to rise rapidly from birth until about 

age 16, after which it remains relatively constant before rising again late in life. Other factors that may 

affect vinyl chloride toxicity at early life stages include the presence of fetal P450s and the level of 

glutathione transferase. 

The PBPK model described in Clewell et al. (2001) and EPA (2000) was used to derive the chronicduration oral MRL. The chronic oral MRL for vinyl chloride is based on the same critical effect as that 

used by EPA (2000) to derive the RfD for vinyl chloride (i.e., the NOAEL for liver cell polymorphism in 

the oral rat study of Til et al. 1983, 1991). Source code and parameter values for running the rat and 

human models in Advance Continuous Simulation Language (ACSL) were transcribed from Appendix C 

of EPA (2000). Exposures in the Til et al. (1983, 1991) rat dietary study were simulated as 4-hour oral 

exposures with the NOAEL dose for liver effects of 0.17 mg/kg/day. A 4-hour feeding period was used 

in the study due to the rapid evaporative loss of vinyl chloride from the food. The total amount of vinyl 

chloride metabolized in 24 hours per liter of liver volume was the rat internal dose metric that was used in 

determining the human dose that would result in an equivalent human dose metric. One kilogram of liver 

was assumed to have an approximate volume of 1 L. Dose metrics reflect the cumulative amount of vinyl 

chloride metabolized over the 24-hour period. The human model was run iteratively, until the model 

converged with the internal dose estimate for the rat (3.16 mg/L liver). The human dose was assumed to 

be uniformly distributed over a 24-hour period with the resulting human equivalent dose of 

0.09 mg/kg/day. Therefore, the human equivalent dose of 0.09 mg/kg/day, associated with the rat 

NOAEL of 0.17 mg/kg/day (Til et al. 1983, 1991), served as the basis for the chronic-duration oral MRL 

for vinyl chloride. A total uncertainty factor of 30 (3 for extrapolating from animals to humans using a 

dose metric conversion and 10 for human variability) was applied to yield the chronic-duration oral MRL 

of 0.003 mg/kg/day (see Appendix A for more detailed information regarding the application of the PBPK 

modeling in deriving the chronic-duration oral MRL for vinyl chloride). 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Absorption. Vinyl chloride appears to be rapidly and completely absorbed following inhalation and 

oral exposure (Bolt et al. 1977; Krajewski et al. 1980; Watanabe et al. 1976a; Withey 1976). 
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Distribution. Distribution of vinyl chloride in the body is rapid and widespread. Storage is limited by 

rapid metabolism and excretion (Bolt et al. 1976a). 

Metabolism. Vinyl chloride is metabolized by mixed function oxidases (MFO) to form an epoxide 

intermediate, 2-chloroethylene oxide, which spontaneously rearranges to form 2-chloroacetaldehyde. 

Reactive metabolites of vinyl chloride are detoxified by a reaction with glutathione. The glutamic acid 

and glycine moieties of the tripeptide are cleaved, and the cysteine conjugate of the reactive metabolite is 

either acetylated or further oxidized and excreted. 

Excretion. The primary route of excretion of metabolites of vinyl chloride is through urine. Urinary 

metabolites that have been identified include N-acetyl-S-(2-hydroxyethyl)cysteine, thiodiglycolic acid, 

and possibly S-(2-hydroxyethyl)cysteine (Watanabe et al. 1976b). Exhalation of unmetabolized vinyl 

chloride is not an important pathway of elimination by humans after exposure to low concentrations. The 

importance of exhalation of vinyl chloride varies with the exposure concentration. At low exposure 

concentrations, little vinyl chloride is excreted unchanged in exhaled air. However, vinyl chloride can be 

excreted unchanged in exhaled air if metabolic pathways become saturated at high exposure 

concentrations (Green and Hathway 1975; Watanabe and Gehring 1976; Watanabe et al. 1976a, 1978a). 

3.5.2 Mechanisms of Toxicity 

The mechanisms of toxicity for noncancer effects of vinyl chloride have not been completely elucidated. 

Vinyl chloride disease exhibits many of the characteristics of autoimmune diseases (Raynaud's 

phenomenon and scleroderma). B-cell proliferation, hyperimmunoglobulinemia, and complement 

activation, as well as increased circulating immune complexes or cryoglobulinemia, have been noted in 

affected workers, indicating stimulation of immune response (Bogdanikowa and Zawilska 1984; Grainger 

et al. 1980; Ward 1976). Mechanisms for the vascular changes, such as those occurring with Raynaud's 

phenomenon, have been proposed by Grainger et al. (1980) and Ward (1976). According to these 

mechanisms, a reactive vinyl chloride intermediate metabolite, such as 2-chloroethylene oxide or 

2-chloroacetaldehyde, binds to a protein such as IgG. The altered protein initiates an immune response, 

with deposition of immune products along the vascular endothelium. Circulating immune complexes are 

proposed to precipitate in response to exposure to the cold, and these precipitates are proposed to produce 

blockage of the small vessels. Resorptive bone changes in the fingers, also characteristic of vinyl chloride 

disease, may be due to activation of osteoclast secondary to vascular insufficiency in the finger tips, but 
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this mechanism has not been conclusively demonstrated. Scleroderma is an autoimmune disease of 

unknown etiology. It is characterized clinically by cutaneous and visceral fibrosis and can range from 

limited skin involvement to extensive cutaneous sclerosis with internal organ changes. It has been 

proposed that fetal cells may be involved in the pathogenesis of scleroderma. An increase in the number 

of microchimeric cells of fetal origin was reportedly associated with dermal fibrosis in mice injected with 

vinyl chloride (Christner et al. 2001). 

It has been hypothesized that cardiac arrhythmia reported after vinyl chloride exposure may result from 

sensitization of the heart to circulatory catecholamines, as occurs with other halogenated hydrocarbons. 

This was demonstrated in a dog study where the EC50 for cardiac sensitization was determined to be 

50,000 ppm (Clark and Tinston 1973). Cardiac sensitization by halogenated hydrocarbons generally 

occurs at very high air concentrations (0.5–90%) (Brock et al. 2003). Therefore, it appears unlikely that 

persons exposed to low levels of vinyl chloride will experience these effects. 

Peripheral nervous system symptoms such as paresthesia, numbness, weakness, warmth in the 

extremities, and pain in the fingers have been reported after vinyl chloride exposure (LangauerLewowicka et al. 1983; NIOSH 1977; Suciu et al. 1963, 1975). It is not known whether these effects 

represent direct adverse effects of vinyl chloride on peripheral nerves or whether they are associated with 

tissue anoxia due to vascular insufficiency. 

Vinyl chloride is a known human and animal carcinogen. It has been associated with both an increased 

incidence of hepatic angiosarcomas and hepatotoxicity. The mechanism for these liver effects has been 

studied to some extent. Vinyl chloride is metabolized by MFO to form an epoxide intermediate, 

2-chloroethylene oxide, which spontaneously rearranges to form 2-chloroacetaldehyde. Reactive 

metabolites of vinyl chloride can be transported intercellularly from parenchymal cells to the 

nonparenchymal cells (Kuchenmeister et al. 1996). Many studies have characterized the mutation profile 

associated with DNA adducts formed by the reactive metabolites of vinyl chloride (Akasaka et al. 1997; 

Chiang et al. 1997; Dosanjh et al. 1994; Guichard et al. 1996; Matsuda et al. 1995; Pandya and Moriya 

1996; Zhang et al. 1995; Zielinski and Hergenhahn 2000). Four primary DNA adducts are formed by the 

reactive metabolites of vinyl chloride. These are cyclic etheno-adducts that include 1,N6

-ethenoadenine, 

3,N4

-ethenocytosine, N2,3-ethenoguanine, and 1,N2-ethenoguanine. These adducts can produce base-pair 

(i.e., purine-to-purine or pyrimidine-to-pyrimidine exchange) transitions during transcription (Cullinan et 

al. 1997; Pandya and Moriya 1996; Singer et al. 1987, 1996). DNA crosslinks can also be formed 

because chloracetaldehyde is bifunctional (Singer 1994). 
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The role of etheno-adducts in the carcinogenesis of vinyl chloride has been recently reviewed (Albertini 

et al. 2003, Barbin 1998, 2000; Kielhorn et al. 2000; Laib 1986; Whysner et al. 1996). 2-Chloroethylene 

oxide and 2-chloroacetaldehyde can both react with DNA nucleotide bases; however, 2-chloroethylene 

oxide is a more potent mutagen and may be the ultimate carcinogenic metabolite of vinyl chloride 

(Chiang et al. 1997). Etheno-adducts generate mainly base pair substitiution mutations. Mutations in 

specific genes (i.e., ras oncogenes, p53 tumor suppressor gene) have been identified in vinyl chlorideinduced liver tumors in rats and humans and are discussed in further detail in Section 3.3. 

The mechanisms for clastogenic effects of vinyl chloride exposure were examined by Fucic et al. (1990). 

Since chromatid and bichromatid breaks most frequently occurred in the terminal A, B, and C group 

chromosomes, these investigators suggested that vinyl chloride or its metabolites might interact with 

specific sites along the chromosome. This implies that the carcinogenicity induced by vinyl chloride can 

be explained in part by its nonrandom interaction with particular genes. 

Liver toxicity has been demonstrated in workers exposed vinyl chloride (Berk et al. 1975; Falk et al. 

1974; Gedigke et al. 1975; Ho et al. 1991; Jones and Smith 1982; Lilis et al. 1975; Liss et al. 1985; 

Marsteller et al. 1975; NIOSH 1977; Popper and Thomas 1975; Suciu et al. 1975; Tamburro et al. 1984; 

Vihko et al. 1984). The mechanism for liver toxicity is thought to be related to the production of reactive 

metabolites that covalently bind to liver proteins, resulting in cellular toxicity (Kappas et al. 1975). The 

intermediary metabolites, 2-chloroethylene oxide and 2-chloroacetaldehyde, bind to macromolecules in 

the body. 2-Chloroethylene oxide is believed to bind primarily to DNA and RNA, whereas 

2-chloroacetaldehyde binds primarily to proteins (Bolt 1986; Guengerich and Watanabe 1979; 

Guengerich et al. 1979, 1981; Kappus et al. 1976; Watanabe et al. 1978a, 1978b). 

3.5.3 Animal-to-Human Extrapolations 

Limited information is available regarding the toxicokinetic differences between species. Toxicokinetic 

data in humans are limited (Krajewski et al. 1980; Sabadie et al. 1980), but a primate study suggested that 

metabolism may saturate at lower concentrations in primates than in rats (Buchter et al. 1980), which is 

suggestive of a lower saturation point in humans. Exposure concentrations greater than about 300– 

400 ppm in the primate study showed saturation characteristics (Buchter et al. 1980). PBPK models have 

been developed to predict the metabolism and distribution of vinyl chloride in laboratory animals and 

humans (see Section 3.4.5). The most recent PBPK model for vinyl chloride (Clewell et al. 2001) was 
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applied by the EPA to develop quantitative toxicity values for vinyl chloride (i.e., RfD, RfC, inhalation 

unit risk, oral slope factor) (EPA 2000). The model had four compartments and metabolism was modeled 

by two saturable pathways: one high affinity, low capacity (P450 2E1), and one low affinity, high 

capacity (2C11/6 and 1A1/2). A description of glutathione kinetics was also included in the model. 

Cancer risk estimates calculated using the PBPK model were consistent with risk estimates from 

epidemiological studies. 

Correlation of toxic effects between humans and animals with regard to respiratory, cardiovascular, 

hematological, hepatic, dermal, immunological, neurological, reproductive, and cancer effects has been 

noted. Renal effects, including increased relative kidney weight and an increase in severity of tubular 

nephrosis, have been reported in several rat studies (Bi et al. 1985; Feron and Kroes 1979; Feron et al. 

1979a), but no evidence of renal effects has been shown in humans. Thus, it is unclear whether the renal 

effects reported in rats represent a lesion that can be attributed to vinyl chloride exposure that is unique to 

rats or whether the effects represent an increase in severity of a naturally occurring lesion. From the 

limited data available, however, it does not appear that the rat is the most appropriate species for use in 

studies of renal toxicity. 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects produced by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 
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in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may produce toxicities 

that are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in 

altering, for example, metabolic, sexual, immune, and neurobehavioral functions. Such chemicals are 

also thought to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis 

(Berger 1994; Giwercman et al. 1993; Hoel et al. 1992). 

Vinyl chloride has not been classified as an endocrine modulator; however, adverse reproductive and 

developmental effects have been reported in human and laboratory animal studies. Effects on the thyroid 

gland have also been reported. 

A number of case studies of male workers occupationally exposed to vinyl chloride report sexual 

impotence, loss of libido, and decreased androgen secretion (Suciu et al. 1975; Veltman et al. 1975; 

Walker 1976). Preeclampsia (i.e., elevated blood pressure and edema during pregnancy) was reported in 

female workers exposed to vinyl chloride (Bao et al. 1988). Animal studies indicate that exposure to 

vinyl chloride can result in a decrease in testicular function (Bi et al. 1985; Sokal et al. 1980); however, 

these effect appears to be due to direct toxicity at the target organ and are not related to a hormonemediated mechanism of action. 

Reproductive capability was not affected in a 2-generation inhalation reproductive toxicity study in rats 

(Thornton et al. 2002). No effects were seen in body weight, feed consumption, ability to reproduce, 

gestation index or length, or pre- and postweaning developmental landmarks. Sperm counts, motility, and 

morphology were also unaffected by vinyl chloride exposure. Changes were observed in liver weights 

and/or histopathological alterations in the liver of F0 and F1 generation male and female rats. No effect 

was observed on male fertility or pre- or postimplantation loss in mice following an acute exposure to 

vinyl chloride (i.e., 30,000 ppm, 6 hours/day, 5 days/week) (Anderson et al. 1976). In contrast, exposure 

of male rats to concentrations as low as 250 ppm for 6 hours/day, 5 days/week for 11 weeks produced a 

decrease in the ratio of pregnant to mated females, indicating a decrease in male fertility; this effect was 

not observed at 50 ppm (Short et al. 1977). 
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Although evidence has been presented indicating that members of communities with nearby vinyl 

chloride polymerization facilities have significantly greater incidences of some forms of developmental 

toxicity, these studies failed to demonstrate a statistically significant correlation between the 

developmental toxicity and either parental occupation or proximity to the facility (Edmonds et al. 1978; 

Infante et al. 1976b; Rosenman et al. 1989; Theriault et al. 1983). Vinyl chloride did not correlate with 

changes in gender ratio, birth weight or height, perinatal mortality, or the incidence of congenital 

abnormalities in mothers occupationally exposed to vinyl chloride for more than 1 year (Bao et al. 1988). 

There are inconsistencies in the developmental toxicity database for the vinyl chloride. In general, vinyl 

chloride produced minor developmental effects in laboratory animals (i.e., delayed ossification) only at 

concentrations that were significantly toxic to maternal animals. Maternal toxicity was evident in mice, 

rats, and rabbits exposed throughout the period of organogenesis. Adverse fetal effects included delayed 

ossification (all species), increased crown-rump length (mice and rats), and vertebral lumbar spurs (rats). 

Mice were the most sensitive species investigated (John et al. 1977, 1981). Ungvary et al. (1978) 

reported a significant increase in resorptions in rats exposed to vinyl chloride during the first trimester of 

pregnancy. Increased liver-to-body weight ratios were observed in maternal animals exposed during the 

first and second trimesters, but no histopathologic alterations were found. Continuous exposure of rats to 

vinyl chloride throughout gestation resulted in decreased fetal weight and increased early 

postimplantation loss, hematomas, and hydrocephaly with intracerebral hematoma. Weanling rats 

displayed hepatotoxic effects including decreased bile enzyme activity, decreased bile secretion, 

decreased cholic acid content, and increased hexobarbital sleep time. No histological data on the livers of 

pups, or information regarding maternal health were presented (Mirkova et al. 1978). 

In contrast with previous studies, no adverse effects were reported in an embryo-fetal developmental 

toxicity study conducted in rats exposed to similar concentrations of vinyl chloride via inhalation 

(Thornton et al. 2002). Embryo-fetal developmental parameters including uterine implantation, fetal 

gender distribution, fetal body weight, and fetal malformations and variations were not affected by vinyl 

chloride exposure. Vinyl chloride produced a slight decrease in maternal body weight gain at all 

exposure levels; however, no changes were observed in feed consumption, clinical signs, or postmortem 

gross findings. Maternal liver and kidney weights were increased relative to total body weight. 
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The developmental toxicity of vinyl chloride was examined using an in vitro whole embryo culture 

system (Zhao et al. 1996). Vinyl chloride induced embryo growth retardation, but was not shown to be 

teratogenic in the rat in vitro whole embryo culture system. 

A study of workers exposed to vinyl chloride in PVC manufacturing plants reported that most workers 

who presented with scleroderma were shown to have thyroid insufficiency (Suciu et al. 1963). No 

histopathological effects on the adrenals were reported in guinea pigs exposed to 400,000 ppm for 

30 minutes (Mastromatteo et al. 1960). Rats exposed to 30,000 ppm vinyl chloride 5 days/week, 

4 hours/day for 12 months, were found to have colloid goiter and markedly increased numbers of 

perifollicular cells (Viola 1970). 

3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential adverse health effects from exposures during the period from conception 

to maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure and the nature of their response to toxicants. Exposures of children are discussed 

in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to adverse health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 
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and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 

tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

No studies were located that specifically address the effects of vinyl chloride in children. The effects that 

have been reported to occur in humans come almost exclusively from studies of workers exposed to high 

concentrations of vinyl chloride by inhalation. Although the effects observed in human adults could also 

be observed in children, it is important to note that occupational exposure concentrations are likely to be 

much greater than environmental levels to which children might be exposed. The toxicological effects 

reported in adult vinyl chloride workers include cardiovascular, gastric, hematologic, musculoskeletal, 

hepatic, endocrine, dermal, ocular, immunologic, neurologic, and reproductive effects as well as cancer 

and death. 

Some epidemiologic studies (Infante 1976; Infante et al. 1976a, 1976b; NIOSH 1977) have suggested an 

association between birth defects and vinyl chloride exposure of the parents of affected children. 
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However, the design and analysis of these studies has been criticized (Hatch et al. 1981; Stallones 1987). 

Some inhalation studies with animals have suggested that vinyl chloride is a developmental toxicant (i.e., 

produces delayed ossification) at doses that also produce maternal toxicity (John et al. 1977, 1981; 

Mirkova et al. 1978; Sal'nikova and Kotsovskaya 1980; Ungvary et al. 1978). However, no adverse 

effects on embryo-fetal development were noted in a recent inhalation study in rats conducted using 

similar concentrations of vinyl chloride (Thornton et al. 2002). 

Carcinogenicity studies with animals indicate that some of the adverse health effects of vinyl chloride are 

dependent on the age of the animal at the time of the exposure. Thus, higher death rates were observed 

when 2-month-old female hamsters, mice, and rats (equivalent to adolescent humans) were exposed to 

vinyl chloride in the air for 12 months than when 8- or 14-month-old animals were exposed (Drew et al. 

1983). Lifetime cancer risk was also dependent on the age of the animals at the time of exposure to vinyl 

chloride. The incidence of hemangiosarcoma of the liver, skin, and spleen, and angiosarcoma of the 

stomach was greater in animals exposed by inhalation for 12 months starting immediately after weaning 

than in animals that were 1 year older at the time of exposure (Drew et al. 1983). The incidence of 

mammary gland carcinoma was higher in 2- or 8-month-old hamsters exposed to 200 ppm vinyl chloride 

for 6 months than in 14- or 20-month-old hamsters exposed to the same concentration and for the same 

duration (Drew et al. 1983). These results demonstrate the importance of the latency period for vinyl 

chloride-induced carcinogenesis. Animals that were exposed at a younger age had a longer post-exposure 

period for the development of tumors. It is difficult to assess the sensitivity of younger animals to cancer 

in this study because the same exposure concentrations were used for each age group. Exposures were 

most effective in producing cancer when started early in life (Drew et al. 1983). 

Maltoni et al. (1981) evaluated the effect of vinyl chloride dosing on liver carcinogenicity in SpragueDawley rats. Rats were exposed to 0, 6,000, or 10,000 ppm vinyl chloride for 100 hours, beginning either 

at 1 day or at 13 weeks of age. The incidence of angiosarcoma of the liver in newborn rats exposed for 

only 5 weeks was higher than the incidence observed in rats exposed for 52 weeks beginning at 13 weeks. 

Hepatoma incidence was approximately 50% in newborn rats exposed for 5 weeks, but did not occur in 

rats exposed for 52 weeks after maturity. The increased tumor incidence combined with the production 

additional tumor types (i.e., angiosarcomas and hepatomas) suggest that newborn rats may be more 

sensitive to vinyl-chloride induced carcinogenicity. 

An age-related increase in DNA adduct formation was noted in an inhalation study of lactating rats and 

their 10-day-old pups exposed to 600 ppm of vinyl chloride, 4 hours/day for 5 days (Fedtke et al. 1990). 
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Concentrations of two adducts found in liver of pups were 4-fold higher than those found in liver of 

dams; however, pups were exposed to contaminated breast milk in addition to air concentrations vinyl 

chloride. In another study, immature rats exposed to vinyl chloride formed 6 times more ethenonucleosides compared with adults (Ciroussel et al. 1990). The concentration of ethenoguanine adducts 

was 2–3-fold greater in weanling rats as compared to adult rats exposed at the same dose for the time 

period (0, 10, 100, or 1,100 ppm, 6 hours/day for 5 days) (Morinello et al. 2002a). 

Vinyl chloride induced preneoplastic foci in newborn rats, but not in mature rats (Laib et al. 1985). A 

study with newborn male or female Wistar rats exposed to 2,000 ppm vinyl chloride indicated that the 

induction of preneoplastic hepatocellular lesions in rats by vinyl chloride is restricted to an early stage in 

the life of the animals. The early-life stage sensitivity to the induction of tumors in animals exposed to 

vinyl chloride appears to be related to the induction by vinyl chloride of hepatic adenosine-5’-triphosphatase (ATPase) deficient enzyme altered foci, which are putative precursors of hepatocellular 

carcinoma. 

Taken together, the studies cited above suggest an early life stage sensitivity to vinyl chloride 

carcinogenicity (Cogliano et al. 1996). EPA has recommended an adjustment of the cancer risk estimates 

to account for early life-stage sensitivity to vinyl chloride (EPA 2000; Ginsberg 2003). 

No studies were located that specifically address the toxicokinetics of vinyl chloride in children; however, 

the toxicokinetic behavior of vinyl chloride in children is expected to be similar to that in adults. An 

evaluation of pharmacokinetic differences across life stages suggests that the largest difference in 

pharmacokinetics occurs during the perinatal period (Gentry et al. 2003). The most important factor 

appears to be the potential for decreased clearance due to immature metabolic enzymes systems; however, 

an analysis of CYP2E1 levels during development suggests that protein levels and enzyme activity in 

children between 1 and 10 years old are comparable to adults (EPA 2001). This enzyme is not expressed 

in the embryonic liver, but rapidly increases during the first 24 hours after birth. Young children appear 

capable of metabolizing vinyl chloride to reactive intermediates that form DNA adducts that lead to 

cancer. A PBPK model was also recently applied to evaluate the potential impact of age- and genderspecific pharmacokinetic differences on the dosimetry of vinyl chloride (Clewell et al. 2004). The rate of 

metabolite production per volume of liver was estimated to rise rapidly from birth until about age 16, after 

which it remains relatively constant before rising again late in life. The data on CYP2E1 levels in the 

developing organism suggests that early life stage sensitivity to vinyl chloride-induced cancer is not 

solely due to an increase in the production of reactive intermediates via this isozyme. Fetal CYP isoforms 
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may play a role in metabolism of vinyl chloride to reactive intermediates in the fetus and neonate. 

Glutathione conjugation may also differ in the developing organism. DNA repair capacity and other 

pharmacodynamic factors may also be associated with an early life stage susceptibility to cancer. 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers 

as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic 

substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target 

molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The 

preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in 

readily obtainable body fluid(s) or excreta. However, several factors can confound the use and 

interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures 

from more than one source. The substance being measured may be a metabolite of another xenobiotic 

substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic 

compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental 

conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the 

body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous 

substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as 

copper, zinc, and selenium). Biomarkers of exposure to vinyl chloride are discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects 

produced by vinyl chloride are discussed in Section 3.8.2. 
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A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, “Populations That Are Unusually Susceptible”. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to Vinyl Chloride 

Exposure to vinyl chloride may be monitored to some extent by the identification and quantitation of a 

number of parameters. For example, following acute exposure to moderate-to-high levels, vinyl chloride 

can be measured in expired air. The expiration of vinyl chloride follows first-order kinetics; therefore, 

this parameter may be directly correlated with exposure levels (Baretta et al. 1969). This measure may 

provide the most direct evidence of vinyl chloride exposure. However, measurement of exposure by this 

technique is limited by the rapidity of excretion of vinyl chloride in expired air. The half-life of vinyl 

chloride in expired air has been determined to be between 20 and 30 minutes following an inhalation 

exposure and to be approximately 60 minutes following oral dosing (Watanabe and Gehring 1976; 

Watanabe et al. 1976b, 1978a, 1978b). Thus, testing must be initiated as soon as possible following 

termination of exposure. Furthermore, measurement of vinyl chloride in expired air has limited utility for 

low-level exposures (<50 ppm) because of competition with absorption and rapid metabolic processes 

(Baretta et al. 1969). In addition, it provides no information on the duration of exposure. 

Thiodiglycolic acid is a major metabolite of vinyl chloride that is excreted in the urine. Measurement of 

thiodiglycolic acid in urine has been used to monitor workers occupationally exposed to vinyl chloride 

(Cheng et al. 2001; Müller et al. 1979). However, although this metabolite is used to estimate levels of 

exposure, the amount of thiodiglycolic acid in the urine varies according to individual metabolic 

idiosyncracies. Also, metabolism of vinyl chloride to thiodiglycolic acid is a saturable process. 

Therefore, when exposure exceeds a certain level, the excretion of vinyl chloride as thiodiglycolic acid 

will plateau (Watanabe and Gehring 1976). Furthermore, the rate of metabolism of vinyl chloride to 

thiodiglycolic acid may be influenced by the presence of liver disease, ethanol, or certain other substances 

such as barbiturates (Hefner et al. 1975b) (also see Section 3.4). Similar to the measurement of vinyl 

chloride in expired air, the measurement of thiodiglycolic acid must take place shortly after exposure 

because of the rapidity of its excretion. The half-life for excretion of thiodiglycolic acid following an 

acute exposure is between 4 and 5 hours (Watanabe and Gehring 1976; Watanabe et al. 1978a, 1978b). 

Cheng et al. (2001) suggests that urinary thiodiglycolic acid levels should not be measured at the end of a 
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work shift, but are best detected at the beginning of the following work day. Finally, excretion of 

thiodiglycolic acid is not unique to exposure to vinyl chloride. For example, thiodiglycolic acid may be 

excreted in the urine as the result of exposure to vinylidene chloride, ethylene oxide, or 2,2-dichloroethylether (Norpoth et al. 1986; Pettit 1986). Also, infants delivered prematurely have been found to have 

high levels of urinary thiodiglycolic acid. A correlation was observed between the thiodiglycolic acid 

levels and the number of weeks that the infant was born prematurely. The origin of this thiodiglycolic 

acid is unknown, but is not believed to be associated with vinyl chloride exposure (Pettit 1986). 

The intermediary metabolites, 2-chloroethylene oxide and 2-chloroacetaldehyde, bind to macromolecules 

in the body. 2-Chloroethylene oxide is believed to bind primarily to DNA and RNA, whereas 

2-chloroacetaldehyde binds primarily to proteins (Bolt 1986; Guengerich and Watanabe 1979; 

Guengerich et al. 1979, 1981; Kappus et al. 1976; Watanabe et al. 1978a, 1978b). Two of the DNA 

adducts that are formed are 1,N6

-etheno-adenosine and 3,N4-ethenocytidine. Monoclonal antibodies for 

these DNA adducts have been isolated and used in enzyme-linked immunosorbent assays (ELISA) to 

quantify these ethenoderivatives in biological samples (Eberle et al. 1989; Young and Santella 1988). 

Measurement of DNA adducts may be useful in estimating vinyl chloride exposure. However, this 

technique is of limited value for quantifying levels of exposure because formation of these products will 

be influenced by variability in vinyl chloride metabolism. Also, their persistence in tissues will be 

influenced by the rate of DNA metabolism and repair. Furthermore, the DNA adducts, for which 

monoclonal antibodies have been isolated, are also formed as a result of exposure to vinyl bromide, ethyl 

carbamate, acrylonitrile, 2-cyanoethylene, and 1,2-dichloroethane (Bolt et al. 1986; Svensson and 

Osterman-Golkar 1986). See Section 3.4 for additional information on the kinetics of vinyl chloride. 

Ethenoguanine adducts have been quantified in human urine using high performance liquid 

chromatography and tandem mass spectrometry (Gonzalez-Reche et al. 2002). Etheno-adducts are 

removed from DNA through base excision repair and excreted in the urine where they can be measured 

using this technique. This method would also include the measurement of endogenously formed ethenoadducts; thus, it is critical to determine the background level of urinary adducts in a control population. 

Vinyl chloride-induced genetic alterations have been identified in the Ki-ras oncogene and the p53 tumor 

suppressor gene, and oncoproteins and p53 antibodies have been detected in the serum of cancer patients 

with angiosarcoma (see Section 3.3). Immunological techniques have been used to detect the presence of 

Asp13p21 (oncoprotein for mutation of the Ki-ras gene), p53 mutant protein, and p53 antibodies in the 

serum of exposed workers (Brandt-Rauf et al. 2000a, 2000b; Marion 1998). Statistical analyses suggest a 
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relationship between vinyl chloride exposure and the presence of these serum biomarkers; however, the 

predictive value of these biomarkers for development of cancer is not known. 

The micronucleus assay, performed using peripheral lymphocytes of 32 vinyl chloride workers, was used 

to indicate the time elapsed since the last vinyl chloride exposure occurred (Fucic et al. 1994, 1997). The 

study showed a decrease in the frequency of micronuclei and mitotic activity in proportion to the length 

of the interval after the last vinyl chloride exposure. For the group with 10 years of employment, the 

percentage of micronuclei decreased from 12.82 when exposure occurred on the day of blood sampling to 

3.16 when the last exposure occurred 90 days before blood sampling (Fucic et al. 1994). Similar changes 

were noted when the mean duration of employment was 5 years. However, this use of the micronucleus 

assay must take into account the total duration of exposure. Micronucleus frequency was shown to be 

several times higher in binucleated lymphocytes as compared to mononuclear lymphocytes in 25 workers 

exposed to vinyl chloride for an average of 10 years (Fucic et al. 2004). 

Exposure to vinyl chloride may also be estimated to some extent by the presence of certain symptoms 

known to be closely associated with vinyl chloride exposure. The exposure may have occurred even if 

the symptoms were not found upon examination, but their presence could be indicative of exposure. For 

example, a syndrome known as vinyl chloride disease has been identified in workers occupationally 

exposed to vinyl chloride. This syndrome includes Raynaud's phenomenon, acroosteolysis of the distal 

phalanges of the fingers, and scleroderma-like changes in the hands and forearms (also see Section 3.2). 

Although this syndrome resembles systemic sclerosis, a differential diagnosis may be made based on the 

absence of antinuclear antibodies from the blood of those afflicted with vinyl chloride disease (Black et 

al. 1983, 1986). The occurrence of vinyl chloride disease in highly exposed worker populations is about 

3%, and susceptibility appears to be genetically related (Black et al. 1983, 1986). Symptoms of vinyl 

chloride disease are unlikely to occur in hazardous waste site conditions because of predicted low levels 

of exposure. Absence of these symptoms would not eliminate the possibility of exposure, but their 

presence may be a good indicator of exposure. 

Angiosarcoma of the liver has been identified in workers occupationally exposed to vinyl chloride. This 

type of tumor is extremely rare in the general population (Heath et al. 1975); therefore, its diagnosis may 

indicate vinyl chloride exposure. However, other causes of angiosarcoma such as exposure to arsenicals 

and Thorotrast (thorium dioxide; formerly used in arteriography) should be considered as possible 

causative factors, if present, before correlating hepatic angiosarcoma with vinyl chloride exposure 

(Gedigke et al. 1975; Marsteller et al. 1975). Their elimination may depend upon such factors as the 
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magnitude of the vinyl chloride exposure and the frequency of the other causes of angiosarcoma in the 

population. 

3.8.2 Biomarkers Used to Characterize Effects Caused by Vinyl Chloride 

The realization that angiosarcoma of the liver is associated with vinyl chloride exposure prompted several 

investigators to try to identify assays that could be used to monitor those individuals considered to be at 

risk. Standard serum assays designed to detect the presence of hepatic enzymes in the blood were found 

to be of limited value in monitoring the progression of vinyl chloride-induced hepatic changes (Berk et al. 

1975; Liss et al. 1985; Vihko et al. 1984). This may be because of the extent of hepatic damage produced 

by vinyl chloride and the late development of necrotic areas in the disease process (Popper et al. 1981). 

In contrast, studies indicate that clearance type assays, which measure liver function, are more sensitive 

indicators of the hepatic damage resulting from vinyl chloride exposure. These assays include the 

indocyanine clearance test, measurement of serum bile acids, and measurement of serum hyaluronic acid 

concentration (Berk et al. 1975; Liss et al. 1985; McClain et al. 2002; Vihko et al. 1984). 

Liver biopsy may provide the most accurate identification of vinyl chloride-associated liver damage (Liss 

et al. 1985). This is because of the characteristic pattern of hepatic histopathology associated with vinyl 

chloride-induced damage (Popper et al. 1981). However, liver biopsy is an invasive procedure with 

attendant risks and, therefore, may not be justified. 

Individual exposure to vinyl chloride has been linked to angiosarcoma and benign angiomatous lesions 

based on the monitoring of serum found to be positive for the presence of the mutant protein 

Asp 13 c-Ki-ras p21, which was not present in control individuals (DeVivo et al. 1994). Additionally, 

this protein was found in the serum of 49% of exposed workers who had no apparent liver lesions. It may 

be possible to utilize the presence of this mutant protein for the early detection of angiosarcoma of the 

liver. 

Use of enzyme-linked immunoassay (EIA) to detect anti-p53 antibodies in serum of individuals exposed 

to vinyl chloride may provide an early method of screening for angiosarcoma of the liver (Trivers et al. 

1995). Detection of serum anti-p53 antibodies has occurred in some, but not all, individuals exposed to 

vinyl chloride who later developed angiosarcoma of the liver (Trivers et al. 1995). However, not all 

individuals who developed angiosarcoma of the liver tested positive for anti-p53 antibodies. Also, antip53 antibodies are not specific to angiosarcoma of the liver but can be detected in the sera of patients with 
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other types of cancers such as leukemia; childhood lymphoma; breast, lung, and colon cancer; and 

hepatocellular carcinoma. 

The symptoms and signs associated with vinyl chloride disease (Raynaud's phenomenon, sclerodermalike skin changes, and acroosteolysis) are similar to those observed in systemic sclerosis. Vinyl chloride 

disease may be differentiated from systemic sclerosis by the absence of antinuclear antibodies in the 

blood and association of vinyl chloride disease with vinyl chloride exposure (Black et al. 1983, 1986). 

Raynaud's phenomenon is an early symptom of vinyl chloride disease. However, cyanosis and blanching 

of fingers with exposure to cold may be the result of a number of other conditions such as connective 

tissue disorders, mechanical arterial obstruction, hyperviscosity of the blood, or exposure to drugs, 

chemicals, or vibrating tools (Freudiger et al. 1988). Thus, other potential causes must be eliminated 

before this syndrome can be used to identify vinyl chloride disease. The symptoms associated with vinyl 

chloride disease have been attributed to vinyl chloride-induced changes in the microvasculature (Grainger 

et al. 1980). Capillary abnormalities in the hands may be detected using wide-field capillary microscopy 

and have been proposed to represent an early manifestation of the effects of vinyl chloride (Maricq et al. 

1976). Also, immunofluorescent examination of biopsy material from the skin may be used to identify 

circulating immune complexes and their deposition on the vascular endothelium (Ward 1976). 

Chromosomal aberrations found in lymphocytes may be indicative of the genotoxic effects of vinyl 

chloride (Anderson 2000; Anderson et al. 1980; Ducatman et al. 1975; Fucic et al. 1990a, 1990b, 1992; 

Funes-Cravioto et al. 1975; Garaj-Vrhovac et al. 1990; Hansteen et al. 1978; Hrivnak et al. 1990; 

Kucerova et al. 1979; Purchase et al. 1978; Sinues et al. 1991). However, any of a number of genotoxic 

substances can produce chromosomal aberrations. Also, de Jong et al. (1988) have found that variability 

in the control population may obscure the observation of chromosomal aberrations in persons exposed to 

low levels of vinyl chloride. G-banding analysis appeared to provide a more sensitive indication of 

chromosomal alteration than sister chromatid exchanges (Zhao et al. 1996). DNA damage in 

lymphocytes can be directly assessed using a single-cell gel electrophoresis technique. The severity of 

the damage may correlate with the duration of exposure (Awara et al. 1998). The DNA adducts produced 

by the reactive intermediary metabolites of vinyl chloride, including 1,N6

-ethenoadenosine and 

3,N4

-ethenocytidine, may be more specific indicators of vinyl chloride's genotoxic potential. 
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3. HEALTH EFFECTS 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

A number of studies have been performed that examine the effect of agents intended to alter the 

metabolism of vinyl chloride on its toxicity. For example, the effects of phenobarbital pretreatment on 

vinyl chloride-induced hepatotoxicity have been examined by Jaeger et al. (1974, 1977), Jedrychowski et 

al. (1985), and Reynolds et al. (1975a, 1975b). Pretreatment of rats with phenobarbital for 7 days prior to 

a 4-hour vinyl chloride exposure produced an increase in microsomal cytochrome P-450 activity 

(Reynolds et al. 1975b) and enhanced hepatotoxicity (Jaeger et al. 1974, 1977; Jedrychowski et al. 1985; 

Reynolds et al. 1975a, 1975b). In these studies, in the absence of the phenobarbital pretreatment, a single 

exposure to approximately 50,000 ppm had no detectable adverse effect on the livers of exposed rats. 

However, following phenobarbital pretreatment, 50,000 ppm of vinyl chloride produced increased serum 

activity of hepatic enzymes (Jaeger et al. 1977; Jedrychowski et al. 1985), areas of hepatic necrosis 

(Reynolds et al. 1975a), or both (Jaeger et al. 1974; Reynolds et al. 1975b). 

Another agent known to increase MFO activity, Aroclor 1254, was also tested for its ability to enhance 

vinyl chloride-induced hepatotoxicity (Conolly and Jaeger 1979; Conolly et al. 1978; Jaeger et al. 1977; 

Reynolds et al. 1975b). Pretreatment of rats with Aroclor 1254 for several days prior to exposure to vinyl 

chloride resulted in an increase in serum activity of hepatic enzymes (Conolly and Jaeger 1979; Conolly 

et al. 1978; Jaeger et al. 1977; Reynolds et al. 1975b) and areas of hepatic necrosis (Conolly et al. 1978; 

Reynolds et al. 1975b). 

Additional support for a role for MFO in the enhanced toxicity of vinyl chloride was obtained using 

SKF525A, an MFO inhibitor. If SKF525A was administered following phenobarbital pretreatment and 

before vinyl chloride exposure, it blocked the ability of phenobarbital pretreatment to enhance vinyl 

chloride-induced hepatotoxicity (Jaeger et al. 1977). 

The role of glutathione conjugation in vinyl chloride-induced toxicity was also examined (Conolly and 

Jaeger 1979; Jaeger et al. 1977). The investigators hypothesized that depletion of glutathione might 

enhance the toxicity of vinyl chloride by preventing the excretion of toxic intermediary metabolites. 

However, diethylmaleate, an agent known to deplete hepatic glutathione levels, had no effect on the 

toxicity produced by vinyl chloride following pretreatment with either phenobarbital (Jaeger et al. 1977) 

or Aroclor 1254 (Conolly and Jaeger 1979). Trichloropropene oxide (TCPO), another agent known to 

deplete hepatic glutathione, produced enhancement of the hepatic toxicity produced by Aroclor 1254 

pretreatment and vinyl chloride exposure but only when the animals had been fasted prior to vinyl 
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3. HEALTH EFFECTS 

chloride exposure (Conolly and Jaeger 1979). The study authors hypothesized that the enhancement of 

vinyl chloride toxicity was a result of the ability of TCPO to inhibit epoxide hydrase rather than its ability 

to deplete glutathione levels. The lack of the effect of glutathione depletion indicates that the glutathione 

pathway is not very important at normal levels of exposure. 

Although the depletion of cellular glutathione levels did not appear to enhance vinyl chloride toxicity, 

treatment with cysteine, the rate-limiting precursor in hepatic glutathione synthesis, increased hepatic 

glutathione levels and provided partial protection against the toxic effects produced by Aroclor 1254 and 

vinyl chloride (Conolly and Jaeger 1979). 

The effects of the interaction of ethanol with vinyl chloride on development were tested by John et al. 

(1977). In this study, animals were exposed to vinyl chloride in the presence and absence of 15% ethanol 

in the drinking water during pregnancy. Ethanol produced a decrease in maternal food consumption and 

maternal weight gain in mice, rats, and rabbits and enhanced incidence of skeletal abnormalities in mice, 

and to a lesser extent, in rats. Interpretation of these results is clouded by the absence of an ethanolexposed control group and the current recognition of the adverse effects of ethanol on pregnancy 

outcome. 

In the experiment by Radike et al. (1981), ethanol-consuming rats exposed to vinyl chloride for a year had 

an enhanced incidence of hepatic angiosarcomas, hepatomas, and lymphosarcomas, earlier onset of the 

tumors, and an enhanced death rate. The incidence of vinyl chloride-induced angiosarcomas was 

potentiated by ethanol, whereas the increased incidences of hepatoma and lymphosarcomas by ethanol 

were additive in nature. 

The effects of smoking on chromosomal aberrations in vinyl chloride-exposed workers was examined by 

Hrivnak et al. (1990), who found no effect of smoking in 43 workers exposed for an average of 11.2 years 

to levels of vinyl chloride ranging from 0.8 to 16 ppm. Most cytogenetic studies of the effects of smoking 

in humans have reported no effect on chromosomal aberrations, although the sister chromatid exchange 

frequency is usually elevated (Wong et al. 1998). 

A study that examined the interaction between vinyl chloride and trichloroethylene using both inhalation 

exposures of rats and pharmacokinetic modeling found that trichloroethylene exposure inhibited vinyl 

chloride in a competitive manner (Barton et al. 1995). This interaction was observed only at high 
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concentrations (both chemicals >10 ppm), and the study authors concluded that the interaction is not 

likely to be important for environmental exposures. 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to vinyl chloride than will most 

persons exposed to the same level of vinyl chloride in the environment. Reasons may include genetic 

makeup, age, gender, health and nutritional status, physiological status (e.g., pregnancy), and exposure to 

other toxic substances (e.g., cigarette smoke). These parameters result in reduced detoxification or 

excretion of vinyl chloride or compromised function of organs affected by vinyl chloride. Populations 

who are at greater risk due to their unusually high exposure to vinyl chloride are discussed in Section 6.7, 

Populations With Potentially High Exposures. 

Data suggest that the following subsets of the human population may be unusually susceptible to the toxic 

effects of vinyl chloride: fetuses; infants; young children; people with liver disease, irregular heart 

rhythms, impaired peripheral circulation, or systemic sclerosis; people with exposure to organochlorine 

pesticides; and people consuming ethanol or barbiturates or taking Antabuse for alcoholism. Also, 

persons who possess the HLA-DR5, HLA-DR3, and B8 alleles may be at increased risk. 

Vinyl chloride can cross the placenta and enter the blood of the fetus (Ungvary et al. 1978). Studies by 

Drew et al. (1983), John et al. (1977, 1981), and Maltoni et al. (1981) have shown that animals exposed 

by inhalation prior to adolescence or during pregnancy may have a greater death rate and increased 

likelihood of developing cancer than adult animals exposed for similar periods. This may relate to the 

length of the induction period of hepatic angiosarcoma rather than to an increased susceptibility of the 

young, per se. It is also possible that there are explanations for these findings. Cogliano and Parker 

(1992) suggested that in the multistage model of carcinogenesis, carcinogens that induce an initial 

transition early in the life of an animal would be more effective since there would be a longer period of 

time remaining in the lifespan for completion of the remaining transitions. Their empirical model of the 

effect of age at exposure on the development of cancer suggests that there is an age-sensitive period of 

exposure to vinyl chloride. 

Vinyl chloride is metabolized in the liver in a multistep process. The intermediary metabolites of vinyl 

chloride, 2-chloroethylene oxide and 2-chloroacetaldehyde, have been suggested to be responsible for 

some of the adverse effects produced by vinyl chloride. Thus, activation of the enzyme system 
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responsible for production of these toxic metabolites would be expected to increase the toxicity of vinyl 

chloride exposures. 2-Chloroethylene oxide is formed by action of the MFO system associated with 

cytochrome P-450. The barbiturate, phenobarbital, and the pesticide extender, Aroclor 1254, increased 

MFO activity and have been shown to greatly increase the hepatotoxicity of vinyl chloride (Conolly and 

Jaeger 1979; Conolly et al. 1978; Jaeger et al. 1974, 1977; Jedrychowski et al. 1985; Reynolds et al. 

1975a, 1975b). Thus, persons taking barbiturates or who might be exposed to organochlorine pesticides 

that are known to induce microsomal enzymes (such as Aroclor 1254) would be expected to be at 

increased risk for developing vinyl chloride-induced hepatotoxicity. 

Genetic polymorphisms related to vinyl chloride metabolism and DNA repair may increase the 

susceptibility of individuals to liver toxicity and cancer. CYP2E1 and glutathione S-transferase genotypes 

were associated with abnormal liver function, “vinyl chloride disease”, and the incidence of angiosarcoma 

in exposed workers (El Ghissassi et al. 1995; Green et al. 2000; Huang et al. 1997). Genotypes for 

CYP2E1, the DNA repair gene, x-ray repair cross-complementing group 1 (XRCC1), and aldehyde 

dehydrogenase 2 (ALDH2) have been associated with increased sister chromatid exchange frequency and 

increased expression of p53 mutant protein and anti-p53 antibody in exposed workers (Li et al. 2003; 

Wong et al. 1998, 2002b, 2003b). The risk of developing liver cancer also appears elevated in those with 

a history of Hepatitis B viral infection (Du and Wang 1998; Wong et al. 2003b). 

Radike et al. (1981) demonstrated that ethanol-consuming rats exposed to vinyl chloride had an increased 

incidence of cancer and an earlier death rate than animals exposed to vinyl chloride in the absence of 

ethanol. 

Some persons consume the agent, Antabuse, to curb the desire for alcohol. In its role as a therapeutic 

agent, Antabuse blocks aldehyde dehydrogenase and causes a build-up of acetaldehyde, which is emetic, 

in the body when alcohol is consumed. If persons taking Antabuse are exposed to vinyl chloride, the 

alternative metabolic pathway for vinyl chloride metabolism will be blocked, causing more vinyl chloride 

to be metabolized to the toxic metabolite, 2-chloroethylene oxide. Thus, these persons may be at 

increased risk for hepatotoxicity, cancer, and death at an early age. 

Very high levels of vinyl chloride have been demonstrated to cause cardiac arrhythmias in dogs (Carr et 

al. 1949; Oster et al. 1947). Persons with a propensity to develop cardiac arrhythmias because of heart 

disease or damage may be at an increased risk of having heart beat irregularities when exposed to high 

concentrations of vinyl chloride. 
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Vinyl chloride has been shown to produce decreased circulation in the hands and fingers of some people. 

Persons with impaired circulation due to some other cause such as connective tissue disorders, systemic 

sclerosis, hyperviscosity of the blood, or use of vibrating tools, may experience more severe impairment 

of the circulation. 

Work by Black et al. (1983, 1986) has shown that persons with the HLA allele HLA-DR5 may have an 

increased likelihood of developing vinyl chloride disease, and those with the alleles HLA-DR3 and B8 

may have an increased severity of the disease. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to vinyl chloride. However, because some of the treatments discussed may be experimental and 

unproven, this section should not be used as a guide for treatment of exposures to vinyl chloride. When 

specific exposures have occurred, poison control centers and medical toxicologists should be consulted 

for medical advice. The following texts provide specific information about treatment following exposures 

to vinyl chloride: 

Bronstein AC, Currance PL, eds. 1988. Emergency care for hazardous materials exposure. St. Louis, 

MO: CV Mosby Company, 143-144. 

Haddad LM, Winchester JF, eds. 1990. Clinical management of poisoning and overdose. Philadelphia, 

PA: W.B. Saunders Company, 516, 1209, 1214, 1224, 1227-1229. 

Stutz DR, Ulin S, eds. 1992. Hazardous materials injuries. A handbook for pre-hospital care. 3rd ed. 

Beltsville, MD: Bradford Communications Corporation, 286-287. 

3.11.1 Reducing Peak Absorption Following Exposure 

Limited information from humans and results from animal studies indicate that vinyl chloride is rapidly 

and virtually completely absorbed following inhalation and oral exposure, but animal studies suggest that 

dermal absorption of vinyl chloride gas is not likely to be significant (see Section 3.3.1). Efforts to 

reduce absorption following acute exposure to vinyl chloride should focus on removing the individual 

from the site of exposure and decontaminating exposed areas of the body. Vinyl chloride gas is relatively 

dense and accumulates at ground level. Therefore, the subject should be moved from low-lying areas. 
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3. HEALTH EFFECTS 

Contaminated skin may be washed with soap and water; however, this will most likely not prevent tissue 

damage produced by frostbite from the cooling caused by the rapid evaporation of vinyl chloride from the 

skin. It is suggested that eyes exposed to vinyl chloride be copiously irrigated with water or normal saline 

(Bronstein and Currance 1988; Haddad and Winchester 1990; Stutz and Ulin 1992). Because of its 

volatility, it is unlikely that vinyl chloride would be ingested unless it had been dissolved in a solvent. If 

such ingestion of vinyl chloride occurs, it is suggested that water or milk be administered for dilution if 

the patient can swallow, has a good gag reflex, and is not drooling (Bronstein and Currance 1988; Stutz 

and Ulin 1992). In addition, gastric lavage and administration of activated charcoal have been suggested 

as a means to reduce absorption of vinyl chloride. Induction of emesis is contraindicated (Bronstein and 

Currance 1988; Haddad and Winchester 1990; Stutz and Ulin 1992). 

3.11.2 Reducing Body Burden 

Because of its rapid metabolism and excretion, vinyl chloride does not tend to accumulate in the body. 

As discussed in Section 3.4.3, the metabolism of vinyl chloride is a dose-dependent, saturable process. 

Vinyl chloride is oxidized primarily by the microsomal MFO system (cytochrome P-450) to a reactive 

epoxide intermediate (2-chloroethylene oxide), which can rearrange to 2-chloroacetaldehyde or conjugate 

with glutathione to form S-formylmethyl glutathione. At exposure concentrations below about 1,000 ppm 

in air, very little vinyl chloride is excreted unchanged in the exhaled air. However, when metabolic 

saturation occurs at high exposure concentrations (approximately 1,000 ppm following inhalation 

exposure in rats [Watanabe and Gehring 1976; Watanabe et al. 1976b] and approximately 20 mg/kg 

following oral administration to rats [Green and Hathway 1975; Watanabe and Gehring 1976; Watanabe 

et al. 1976a]), vinyl chloride is excreted unchanged in expired air. Therefore, a possible means to 

enhance the elimination of vinyl chloride without allowing its biotransformation to toxic intermediates is 

to saturate this oxidative pathway by administration of substances known to be metabolized via this route. 

Saturation of the P-450 system may occur with drugs such as phenytoin or dicumerol (Goodman and 

Gilman 1980). However, the effectiveness of these agents in blocking the P-450 metabolism of vinyl 

chloride has not been tested, and it is unclear whether toxic doses would be necessary to overcome the 

relative affinities of the enzymes for vinyl chloride versus these agents. In addition, the potential toxicity 

of any side products of these substances would need to be considered in any protocol. Several agents 

induce activity of the microsomal enzymes and could potentially increase the toxicity of vinyl chloride. 

Administration of such substances would be contraindicated. 
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3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

Following acute, high-level exposure, vinyl chloride behaves as an anesthetic and produces central 

nervous system and respiratory depression (see Sections 3.2.1.4). Therefore, basic life support measures, 

such as supplemental oxygen and cardiopulmonary resuscitation, are suggested in such instances 

(Bronstein and Currance 1988; Haddad and Winchester 1990; Stutz and Ulin 1992). In addition, like 

other halogenated hydrocarbons, vinyl chloride may sensitize the heart to the effects of circulating 

catecholamines. Therefore, the patient's cardiac rhythm should be monitored, and the use of 

isoproterenol, epinephrine, or other sympathomimetic drugs should be avoided (Haddad and Winchester 

1990). 

Vinyl chloride is a known human and animal carcinogen; long-term exposure to this compound is 

associated with an increased incidence of hepatic angiosarcomas (see Section 3.2.1.7). Vinyl chloride is 

also hepatotoxic. The mechanism by which vinyl chloride induces its carcinogenic and toxic effect on the 

liver has been well studied. A reactive epoxide intermediate of vinyl chloride, 2-chloroethylene oxide, 

interacts directly with DNA and RNA producing cyclic etheno-adducts that include 1,N6

-ethenoadenine, 

3,N4

-ethenocytosine, N2,3-ethenoguanine, and 1,N2-ethenoguanine. This alkylation results in highly 

efficient base-pair substitution, leading to neoplastic transformation (see Section 3.5.2). As discussed 

above, this epoxide intermediate is formed when vinyl chloride is oxidized by the P-450 isoenzymes. 

Interference with this metabolic pathway, therefore, could reduce the toxic and carcinogenic effects of 

vinyl chloride by reducing the amount of epoxide produced. A number of drugs, such a cobaltous 

chloride, SKF-535-A, and 6-nitro-1,2,3-benzothioadiazole, have been reported to inhibit P-450 enzymes. 

Pretreatment with 6-nitro-1,2,3-benzothioadiazole completely blocked the metabolism of vinyl chloride in 

rats exposed to 0.45 ppm in a closed system for 5 hours (Bolt et al. 1977). P-450 metabolism also results 

in products that can be more readily eliminated than can the parent compound. Hence, any side products 

of the drugs and their potential to increase the biological half-life of vinyl chloride would also need to be 

considered in any protocol. In fact, a study by Buchter et al. (1977) showed that substantial 

unmetabolized vinyl chloride accumulated in fatty tissue when 6-nitro-1,2,3-benzothioadiazole was used 

to block P-450 metabolism. The study did not examine the fate of vinyl chloride in fatty tissue after 

P-450 metabolism was reactivated, but it is likely that vinyl chloride would leave the fat slowly and be 

metabolized. Thus, while P-450 metabolism would probably reduce the generation of toxic metabolites in 

the short term, it is unclear whether the generation of toxic metabolites could be completely avoided. 

Further research to determine which isozymes are involved in the metabolism to the reactive 

intermediates, as well as which isozymes are involved in enhancing the elimination of vinyl chloride, 
VINYL CHLORIDE 141 

3. HEALTH EFFECTS 

could lead to the development of strategies to selectively inhibit specific isozymes and thus reduce the 

toxic effects of vinyl chloride. 

Because vinyl chloride is detoxified by conjugation with glutathione and/or cysteine (see discussion 

above and Section 3.4.3), ensuring sufficient glutathione stores in the body (e.g., by treatment with 

N-acetyl cysteine) may reduce the possibility of toxic effects following acute exposure to vinyl chloride. 

Vinyl chloride disease has been reported in a small percentage of workers exposed to this compound. 

One of the symptoms of this condition is Raynaud's phenomenon (blanching, numbness, and discomfort 

of the fingers upon exposure to cold). Studies of these individuals demonstrated that vinyl chloride may 

produce blockage of the blood vessels supplying the hand, hypervascularity, and a thickening of the blood 

vessel walls (Harris and Adams 1967; Preston et al. 1976; Veltman et al. 1975; Walker 1976). Several 

investigators have suggested that the mechanism for vinyl chloride disease may be an autoimmune 

response similar to systemic sclerosis. Grainger et al. (1980) and Ward (1976) proposed that a reactive 

vinyl chloride intermediate metabolite, such as 2-chloroethylene oxide or 2-chloroacetaldehyde, binds to a 

protein such as IgG. The altered protein initiates an immune response, with deposition of immune 

products along the vascular endothelium. Cold temperatures could produce the precipitation of these 

immune complexes resulting in blockage of the blood vessels. Another characteristic of vinyl chloride 

disease is acroosteolysis, in which the terminal phalanges of the fingers are resorbed. This condition has 

been noted predominantly in workers who first had Raynaud's phenomenon (Dinman et al. 1971; 

Freudiger et al. 1988; Harris and Adams 1967; Magnavita et al. 1986; Markowitz et al. 1972; Preston et 

al. 1976; Sakabe 1975; Veltman et al. 1975; Wilson et al. 1967). The resorptive bone changes may be 

due to activation of osteoclasts secondary to vascular insufficiency in the finger tips, but this remains to 

be demonstrated conclusively. Other manifestations of vinyl chloride disease include joint and muscle 

pain, enhanced collagen deposition, stiffness of the hands, and scleroderma-like skin changes. Increased 

levels of circulating immune complexes and immunoglobulins have been observed in vinyl chloride 

workers, suggesting a stimulatory effect of vinyl chloride on the immune system (Bogdanikowa and 

Zawilska 1984). A correlation between the severity of the symptoms of vinyl chloride disease and the 

magnitude of the immune response was observed (Grainger et al. 1980; Langauer-Lewowicka et al. 1976; 

Ward 1976). Research on the genetic characteristics of workers with this disease has demonstrated that 

the susceptibility to vinyl chloride disease was increased in the presence of the HLA-DR5 allele or a gene 

in linkage disequilibrium with it, and progression of the disease to its more severe forms was favored by 

HLA-DR3 and B8 (Black et al. 1983, 1986). If vinyl chloride disease is mediated by an immune 

mechanism in individuals with a genetic predisposition, then the effects of this disease may be mitigated 
VINYL CHLORIDE 142 

3. HEALTH EFFECTS 

by administration of drugs used to treat other similar autoimmune diseases (e.g., azathioprine, 

cyclophosphamide, and prednisone). However, the toxicity associated with the use of these drugs must 

also be considered. 

3.12 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the adverse health effects of vinyl chloride is available. Where adequate 

information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is 

required to ensure the initiation of a program of research designed to determine the adverse health effects 

(and techniques for developing methods to determine such adverse health effects) of vinyl chloride. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 Existing Information on Adverse Health Effects of Vinyl Chloride 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

vinyl chloride are summarized in Figure 3-5. The purpose of this figure is to illustrate the existing 

information concerning the adverse health effects of vinyl chloride. Each dot in the figure indicates that 

one or more studies provide information associated with that particular effect. The dot does not 

necessarily imply anything about the quality of the study or studies, nor should missing information in 

this figure be interpreted as a “data need”. A data need, as defined in ATSDR’s Decision Guide for 

Identifying Substance-Specific Data Needs Related to Toxicological Profiles (Agency for Toxic 

Substances and Disease Registry 1989), is substance-specific information necessary to conduct 

comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any 

substance-specific information missing from the scientific literature. 
VINYL CHLORIDE 143 

3. HEALTH EFFECTS 

Figure 3-5. Existing Information on Health Effects of Vinyl Chloride 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Inhalation 

Oral 

Dermal 

Human 

Death

Acute 

Intermediate 

Chronic 

Immunologic/Lymphoretic 

Neurologic 

Reproductive 

Developmental 

Genotoxic 

Cancer 

Systemic 

Inhalation 

Oral 

Dermal 

Animal 

Existing Studies 
VINYL CHLORIDE 144 

3. HEALTH EFFECTS 

Virtually all of the literature regarding adverse health effects in humans comes from studies of workers 

exposed to vinyl chloride during the production of PVC. Case reports and cohort studies describe some 

acute health effects and a wide range of long-term health effects. The predominant mode of exposure in 

these studies is via inhalation. These studies are limited by the lack of reliable data on individual 

exposure levels. No studies were found regarding the adverse health effects of oral exposure. One case 

report examined the effects of dermal exposure to liquid vinyl chloride, but exposure by this route is not 

expected to contribute significantly to producing adverse health effects because of the limited absorption 

of vinyl chloride through the skin. 

A large number of studies examining the adverse health effects of inhaled vinyl chloride in animals were 

reviewed. As can be seen in Figure 3-5, no information is available on acute adverse systemic effects, 

immunologic, neurologic, reproductive, developmental, or genotoxic effects of exposure of animals by 

the oral route. One study examined the effects of dermal/ocular exposure to vinyl chloride gas, but 

toxicokinetic studies indicate that this route is not an important means of exposure. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. Populations in areas that contain hazardous waste sites may be exposed 

to vinyl chloride for brief periods. Exposure most likely would occur by inhalation, but relatively brief 

oral and dermal exposures are also possible. There are acute inhalation exposure data in humans and 

animals that indicate that the central nervous system is a major target organ of vinyl chloride toxicity. 

Symptoms of central nervous system depression ranging from dizziness and drowsiness to loss of 

consciousness have been observed in humans and animals as a result of brief exposure to very high levels 

of vinyl chloride (Hehir et al. 1981; Jaeger et al. 1974; Lester et al. 1963; Mastromatteo et al. 1960; Patty 

et al. 1930). A threshold for central nervous system effects appears to be approximately 8,000 ppm 

(Lester et al. 1963). Extremely high concentrations of vinyl chloride produce respiratory irritation and 

death in humans and animals by the inhalation route (Danziger 1960; Lester et al. 1963; Mastromatteo et 

al. 1960; Patty et al. 1930). Based on studies in animals, the threshold for these effects appears to be in 

the range of 100,000–400,000 ppm (Lester et al. 1963; Mastromatteo et al. 1960; Patty et al. 1930). 

However, increased rate of death was noted in pregnant mice at 500 ppm (John et al. 1977, 1981). 

Extremely high concentrations of vinyl chloride produced cardiac arrhythmias in dogs exposed by the 

inhalation route (Carr et al. 1949; Oster et al. 1947). Although no threshold was reported for these 

effects, concentrations of this magnitude would not likely be encountered by humans. Pharmacokinetic 

data indicate that similar end points might be expected if sufficiently high doses could be consumed by 
VINYL CHLORIDE 145 

3. HEALTH EFFECTS 

the oral route. However, the solubility characteristics of vinyl chloride in aqueous media (1,100– 

2,763 mg/L at 25 °C) (Cowfer and Magistro 1983; EPA 1985b) indicate that achieving concentrations of 

vinyl chloride in excess of 5,000 ppm may be extremely difficult. Animal studies indicate that acute 

inhalation exposures to vinyl chloride can produce developmental effects at concentrations that also cause 

significant maternal toxicity (John et al. 1977, 1981; Ungvary et al. 1978). Concentrations of 500 ppm 

were observed to produce delayed ossification in the fetus and decreased food consumption, body weight 

gain, and increased rate of mortality in maternal mice (John et al. 1977, 1981). The NOAEL (50 ppm) in 

this study was used to derive an acute-duration inhalation MRL. Animal studies examining the 

developmental, neurological, and systemic effects of the highest doses achievable in drinking water 

would be helpful for determining whether any effects would occur when vinyl chloride-contaminated 

groundwater or food products are consumed. One report described severe frostbite with second degree 

burns on the hands of a man resulting from the rapid evaporation of spilled liquid vinyl chloride (Harris 

1953). A toxicokinetic study using two monkeys indicates that absorption of vinyl chloride by the dermal 

route is exceedingly small (Hefner et al. 1975a); thus, studies examining the effects of acute-duration 

dermal exposure do not seem warranted. However, if further toxicokinetics studies contradict these 

findings, acute-duration dermal exposure studies in animals may be valuable. 

A report was located regarding adverse hepatic and respiratory effects observed 18 months following a 

single 1-hour inhalation exposure to vinyl chloride (Hehir et al. 1981). However, limitations in the study 

diminished its reliability. Because of the implications of adverse chronic effects from acute exposure, 

confirmation of these results in another study would be valuable. 

Intermediate-Duration Exposure. No studies in humans specifically address intermediate-duration 

effects by any route. Most epidemiological studies of occupationally exposed persons have concentrated 

on persons who have been employed over several years. A study with reliable quantification of exposure 

levels that examined the effects experienced by vinyl chloride workers in their first year of exposure 

would be helpful for predicting the effects that might be observed in populations exposed to hazardous 

waste sites for similar periods of time. However, at current low levels of exposure in the workplace, it 

may be difficult to demonstrate effects. There is a large database describing the effects of intermediateduration inhalation exposures in animals (Adkins et al. 1986; Bi et al. 1985; Drew et al. 1983; Du et al. 

1979; Feron et al. 1979a, 1979b; Hong et al. 1981; Lee et al. 1978; Lester et al. 1963; Maltoni et al. 1981; 

Mirkova et al. 1978; Sal'nikova and Kotsovskaya 1980; Schaffner 1978; Sharma and Gehring 1979; Short 

et al. 1977; Sokal et al. 1980; Suzuki 1978, 1981; Thornton et al. 2002; Torkelson et al. 1961; 

Wisniewska-Knypl et al. 1980). Animals exposed to vinyl chloride for more than 2 weeks and less than a 
VINYL CHLORIDE 146 

3. HEALTH EFFECTS 

year have experienced effects on the liver, kidneys, lungs, and blood (Bi et al. 1985; Du et al. 1979; Feron 

et al. 1979a, 1979b; Lester et al. 1963; Sal'nikova and Kotsovskaya 1980; Schaffner 1978; Sokal et al. 

1980; Torkelson et al. 1961; Wisniewska-Knypl et al. 1980). Data were sufficient to determine an 

intermediate-duration inhalation MRL based on adverse liver effects in rats. The MRL was based on a 

NOAEL of 15 ppm for hepatic centrilobular hypertrophy (Thornton et al. 2002). Extremely limited 

information was available regarding oral intermediate-duration effects. One chronic study presented 

interim sacrifice data that identified relative weight and histopathological changes in the liver (Feron et al. 

1981). However, only a single-dose group was compared to controls, precluding determination of the 

dose-response of the effects observed. Thus, no MRL for oral intermediate-duration exposures could be 

determined. Additional studies examining the effects of oral exposure to vinyl chloride would be helpful 

for evaluating relevant biomarkers of exposure and effects in humans consuming contaminated drinking 

water or foods (see Section 3.8). As noted above, absorption of vinyl chloride through the skin is not 

expected to be significant (Hefner et al. 1975a); thus, additional dermal exposure studies do not seem 

warranted. However, if further toxicokinetics studies contradict these findings, other intermediateduration dermal exposure studies may be valuable. 

Chronic-Duration Exposure and Cancer. A large number of studies of workers exposed to vinyl 

chloride have identified a wide range of target organs that may be affected by chronic-duration inhalation 

of vinyl chloride (Bao et al. 1988; Bencko et al. 1988; Berk et al. 1975; Black et al. 1983, 1986; 

Bogdanikowa and Zawilska 1984; Brugnami et al. 1988; Byren et al. 1976; Creech and Johnson 1974; 

Dinman et al. 1971; Falk et al. 1974; Freudiger et al. 1988; Fucic et al. 1995; Gedigke et al. 1975; 

Grainger et al. 1980; Harris and Adams 1967; Jayson et al. 1976; Jones and Smith 1982; LangauerLewowicka et al. 1976; Laplanche et al. 1987; Lee et al. 1977b; Lilis et al. 1975; Liss et al. 1985; Lloyd et 

al. 1984; Magnavita et al. 1986; Maricq et al. 1976; Markowitz et al. 1972; Marsteller et al. 1975; Micu et 

al. 1985; Miller 1975; NIOSH 1977; Perticoni et al. 1986; Popper and Thomas 1975; Popper et al. 1981; 

Preston et al. 1976; Sakabe 1975; Spirtas et al. 1975; Suciu et al. 1963, 1975; Tamburro et al. 1984; 

Veltman et al. 1975; Vihko et al. 1984; Walker 1976; Ward 1976; Wilson et al. 1967; Wong et al. 1991). 

The target organs include the liver, lungs, blood, immune system, cardiovascular system, skin, bones, 

nervous system, and the reproductive organs. These studies are severely limited in that individual 

exposure levels have not been documented. In general, studies in animals provide supportive evidence 

for these effects and give indications of the exposure levels that may be associated with them (Bi et al. 

1985; Feron and Kroes 1979; Feron et al. 1979a, 1979b; Lee et al. 1981; Thornton et al. 2002; Viola 

1970; Viola et al. 1971). 
VINYL CHLORIDE 147 

3. HEALTH EFFECTS 

No information was available regarding chronic-duration oral exposure in humans. However, studies in 

animals indicate that the liver, blood, and skin are target organs for oral exposure to vinyl chloride (Feron 

et al. 1981; Knight and Gibbons 1987; Til et al. 1983, 1991). A chronic-duration oral MRL of 

0.003 mg/kg/day was derived from a human equivalent NOAEL of 0.09 mg/kg/day based on liver cell 

polymorphism in rats (Til et al. 1983, 1991). 

No information was available regarding effects of chronic-duration dermal exposure in humans or 

animals, but absorption of vinyl chloride gas through the skin was not significant in an acute-duration 

exposure study in monkeys (Hefner et al. 1975a). However, only two animals were used, and this was the 

only study located that examined toxicokinetics after dermal exposure. No information is available 

regarding dermal absorption of vinyl chloride from liquid or solid media (i.e., water, soil). Dermal 

exposure from these media is expected to be minimal; however, a study confirming this assumption 

would be useful. If further toxicokinetic studies demonstrate significant dermal absorption of vinyl 

chloride, then other intermediate-duration dermal exposure studies may be needed. 

There is sufficient evidence to indicate that vinyl chloride is carcinogenic to humans (Belli et al. 1987; 

Boffetta et al. 2003; Brugnami et al. 1988; Byren et al. 1976; Cheng et al. 1999; Chung and Keh 1987; 

Cooper 1981; Creech and Johnson 1974; Davies et al. 1990; Du and Wang 1998; Fitzgerald and Griffiths 

1987; Fox and Collier 1977; Gelin et al. 1989; Geryk and Zudova 1986; Hagmar et al. 1990; Heldass et 

al. 1987; Infante et al. 1976b; Jones et al. 1988; Lelbach 1996; Lewis 2001; Lewis and Rempala 2003; 

Lewis et al. 2003; Monson et al. 1975; Mundt et al. 2000; Ojajarvi et al. 2001; Pirastu et al. 1990; 

Rhomberg 1998; Rinsky et al. 1988; Saurin et al. 1997; Simonato et al. 1991; Smulevich et al. 1988; Teta 

et al. 1990; Ward et al. 2001; Waxweiler et al. 1981; Weber et al. 1981; Weihrauch et al. 2000; 

Williamson and Ramsden 1988; Wong et al. 1991, 2002a, 2002b, 2003a, 2003b; Wu et al. 1989) and 

animals (Bi et al. 1985; Drew et al. 1983; Feron and Kroes 1979; Feron et al. 1979a; Froment et al. 1994; 

Lee et al. 1978; Maltoni et al. 1981; Viola et al. 1971) exposed via inhalation, and in animals exposed via 

the oral route (Feron et al. 1979a; Maltoni et al. 1981; Til et al. 1983, 1991). The mechanism for 

carcinogenicity appears to be associated with the formation of reactive intermediates that bind to DNA. 

Genotoxicity. There are substantial data on clastogenesis in humans exposed to vinyl chloride that 

indicate that this chemical acts as a potent genotoxicant (Anderson 2000; Anderson et al. 1980; Awara et 

al. 1998; Becker et al. 2001; Ducatman et al. 1975; Fucic et al. 1990a, 1990b, 1992, 1995; Funes-Cravioto 

et al. 1975; Hansteen et al. 1978; Hrivnak et al. 1990; Huttner and Nikolova 1998; Huttner et al. 1998, 

1999; Kucerova et al. 1979; Marion et al. 1991; Purchase et al. 1978; Sinues et al. 1991; Wong et al. 
VINYL CHLORIDE 148 

3. HEALTH EFFECTS 

1998; Zhao et al. 1996). The reversibility of chromosome damage has been reported for several 

populations of workers following a cessation or reduction of exposure to vinyl chloride (Anderson et al. 

1980; Fucic et al. 1996a, 1996b; Hansteen et al. 1978). Findings in humans are supported by both animal 

studies and in vitro studies that show positive genotoxicity in a variety of microbial organisms, cultured 

cell lines, and isolated nucleic acid assays (Anderson and Richardson 1981; Andrews et al. 1976; Bartsch 

1976; Bartsch et al. 1976; Bolt et al. 1986; Ciroussel et al. 1990; de Meester et al. 1980; Eberle et al. 

1989; Froment et al. 1994; Green and Hathway 1978; Gwinner et al. 1983; Hansteen et al. 1978; 

Huberman et al. 1975; Jacobsen et al. 1989; Kandala et al. 1990; Laib and Bolt 1977; Laib et al. 1989; 

Loprieno et al. 1977; McCann et al. 1975; Osterman-Golkar et al. 1977; Poncelet et al. 1980; Rannug et 

al. 1974, 1976; Simmon et al. 1977; Singer et al. 1987; Victorin and Stahlberg 1988a; Walles et al. 1988). 

The role of etheno-adducts in the carcinogenesis of vinyl chloride has been extensively studied (Albertini 

et al. 2003, Barbin 1998, 1999, 2000; Kielhorn et al. 2000; Nivard and Vogel 1999; Whysner et al. 1996). 

Both 2-chloroethylene oxide and 2-chloroacetaldehyde can react with DNA nucleotide bases; however, 

2-chloroethylene oxide is a more potent mutagen and may be the ultimate carcinogenic metabolite of 

vinyl chloride (Chiang et al. 1997). Etheno-adducts generate mainly base pair substitution mutations. 

Mutations in specific genes (i.e., ras oncogenes, p53 tumor suppressor gene) have been identified in vinyl 

chloride-induced liver tumors in rats and humans (Barbin et al. 1997; Brandt-Rauf et al. 1995; Hollstein et 

al. 1994; Marion and Boivin-Angele 1999; Marion et al. 1991; Trivers et al. 1995; Weihrauch et al. 2002). 

Immunological techniques have been used to detect the presence of Asp13p21 (oncoprotein for mutation 

of the Ki-ras gene), p53 mutant protein, and p53 antibodies in the serum of exposed workers (BrandtRauf et al. 2000a, 2000b; Marion 1998). Statistical analyses suggest a relationship between vinyl 

chloride exposure and the presence of these serum biomarkers; however, the predictive value of these 

biomarkers for development of cancer is not known. Further mechanistic research would be helpful in 

identifying the specific gene mutations responsible for vinyl chloride-induced liver cancer. 

Reproductive Toxicity. Data from a number of epidemiological studies provide suggestive evidence 

of adverse effects on male and female reproductive function. Sexual impotence and decreased androgen 

levels were found in men exposed occupationally to vinyl chloride (Suciu et al. 1975; Veltman et al. 

1975; Walker 1976). In women exposed to vinyl chloride, menstrual disturbances and an increased 

incidence of elevated blood pressure and edema during pregnancy (preeclampsia) were observed (Bao et 

al. 1988). Animal studies indicate that exposure to vinyl chloride can result in a decrease in testicular 

weight, damage to the seminiferous tubules, and depletion of spermatocytes (Bi et al. 1985). A 

significant increase in damage to the spermatogenic epithelium and disorders of spermatogenesis were 

also observed (Sokal et al. 1980). Reproductive capability was not affected in a 2-generation inhalation 
VINYL CHLORIDE 149 

3. HEALTH EFFECTS 

reproductive toxicity study in rats (Thornton et al. 2002). No effects were seen in body weight, feed 

consumption, ability to reproduce, gestation index or length, or pre- and postweaning developmental 

landmarks. Sperm counts, motility, and morphology were also unaffected by vinyl chloride exposure. 

Animal models of preeclampsia could be tested to determine the mechanism by which vinyl chloride 

might produce this effect. Well-designed and well-conducted epidemiological studies examining such 

changes would also be helpful. No data are available on the possible reproductive toxicity resulting from 

oral exposure to vinyl chloride. Oral studies that use drinking water as the vehicle of administration 

would be particularly useful because contaminated groundwater is a potentially significant source of 

human exposure. However, such studies would be technically difficult to perform due to the volatility of 

vinyl chloride and its low solubility in water. The PBPK model would be useful for assessing 

reproductive toxicity resulting from oral exposure to vinyl chloride. 

Developmental Toxicity. The epidemiological studies that have addressed developmental toxicity in 

offspring of humans who have been exposed to vinyl chloride are controversial. Although some of these 

purport to show a significant association between birth defects and vinyl chloride exposure (Infante 1976; 

Infante et al. 1976a, 1976b; NIOSH 1977), their design and analysis have been severely criticized (Hatch 

et al. 1981; Stallones 1987). At this time, there are insufficient human data to provide a definitive answer 

to this question. A well-designed and well-conducted epidemiological study examining potential 

developmental end points would be helpful. There are also inconsistencies in the developmental toxicity 

data for vinyl chloride in laboratory animals. In general, vinyl chloride produced minor adverse 

developmental effects only at concentrations that were significantly toxic to maternal animals. 

Concentrations of 500 ppm were observed to produce delayed ossification in the fetus and decreased food 

consumption, body weight gain, and mortality in maternal mice (John et al. 1977, 1981). In contrast, no 

adverse effects were reported in an embryo-fetal developmental toxicity study conducted in rats exposed 

to vinyl chloride via inhalation (Thornton et al. 2002). Embryo-fetal developmental parameters including 

uterine implantation, fetal gender distribution, fetal body weight, and fetal malformations and variations 

were not affected by vinyl chloride exposure. Vinyl chloride produced a decrease in maternal body 

weight gain at all exposure levels; however, no changes were observed in feed consumption, clinical 

signs, or postmortem gross findings. Maternal liver and kidney weights were increased relative to total 

body weight. It would be helpful to determine whether pregnancy increases the susceptibility to vinyl 

chloride in the mother. There are no data for oral exposures. Because of this deficiency, oral studies 

examining a range of developmental end points would be useful in assessing the possibility of these 

effects in humans. However, such studies would be technically difficult to perform due to the volatility of 
VINYL CHLORIDE 150 

3. HEALTH EFFECTS 

vinyl chloride and its low solubility in water. The PBPK model would be a useful tool in such risk 

assessment. 

Immunotoxicity. Studies of workers occupationally exposed to vinyl chloride suggest that the 

immune system may be activated by vinyl chloride (Bogdanikowa and Zawilska 1984). Some data 

suggest that reactive intermediates may bind to proteins in the body, sufficiently altering them so that they 

become antigenic (Grainger et al. 1980). In some instances, an autoimmune-like syndrome develops. 

The likelihood of this may be associated with the possession by individuals of specific genetic 

determinants (HLA alleles) (Black et al. 1983, 1986). Because of the low incidence of the autoimmune 

response in humans, the immunotoxicity may be best further studied in one of the strains of mice known 

to have a propensity for developing autoimmune diseases. Also, additional epidemiological studies 

examining the immune response of exposed populations may be helpful. 

Neurotoxicity. A number of studies in humans (Lester et al. 1963; Patty et al. 1930) and animals 

(Hehir et al. 1981; Jaeger et al. 1974; Lester et al. 1963; Mastromatteo et al. 1960; Patty et al. 1930) 

demonstrate that vinyl chloride is a central nervous system depressant following brief high-level 

inhalation exposures. Two studies in animals have also found degenerative effects in central nervous 

system tissue following chronic inhalation exposure to high levels of vinyl chloride (Viola 1970; Viola et 

al. 1971). It is unknown whether these degenerative changes might also occur at lower doses; thus, a 

study examining the effects of a range of lower doses would be informative. In addition, relatively recent 

studies present suggestive evidence that vinyl chloride may also produce peripheral nerve damage in 

humans exposed chronically via inhalation (Langauer-Lewowicka et al. 1976; Magnavita et al. 1986; 

Perticoni et al. 1986; Sakabe 1975; Walker 1976). Animal studies examining histopathological and 

electrophysiological end points in peripheral nerves would be helpful for assessing what doses may be 

associated with this effect. Epidemiological studies examining exposed populations for subclinical 

peripheral nerve damage would also be helpful. 

Epidemiological and Human Dosimetry Studies. Virtually all of the data on effects in humans 

following inhalation exposure to vinyl chloride come from epidemiological studies of workers exposed 

during the production of PVC (Belli et al. 1987; Boffetta et al. 2003; Brugnami et al. 1988; Byren et al. 

1976; Cheng et al. 1999; Chung and Keh 1987; Cooper 1981; Creech and Johnson 1974; Davies et al. 

1990; Du and Wang 1998; Fitzgerald and Griffiths 1987; Fox and Collier 1977; Gelin et al. 1989; Geryk 

and Zudova 1986; Hagmar et al. 1990; Heldass et al. 1987; Infante et al. 1976b; Jones et al. 1988; 

Lelbach 1996; Lewis 2001; Lewis and Rempala 2003; Lewis et al. 2003; Monson et al. 1975; Mundt et al. 
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3. HEALTH EFFECTS 

2000; Ojajarvi et al. 2001; Pirastu et al. 1990; Rhomberg 1998; Rinsky et al. 1988; Saurin et al. 1997; 

Simonato et al. 1991; Smulevich et al. 1988; Teta et al. 1990; Ward et al. 2001; Waxweiler et al. 1981; 

Weber et al. 1981; Weihrauch et al. 2000; Williamson and Ramsden 1988; Wong et al. 2002a, 2002b, 

2003a, 2003b, 1991; Wu et al. 1989). These studies are limited by the absence of information on 

individual exposure levels. Also, in North America and Western Europe, only limited numbers of 

females have been studied. 

For the most part, studies examining the carcinogenic potential of vinyl chloride have been adequate to 

distinguish an increased incidence of the rare cancer, angiosarcoma (Byren et al. 1976; Creech and 

Johnson 1974; Fox and Collier 1977; Infante et al. 1976b; Jones et al. 1988; Monson et al. 1975; Pirastu 

et al. 1990; Rinsky et al. 1988; Teta et al. 1990; Waxweiler et al. 1976; Weber et al. 1981; Wong et al. 

1991; Wu et al. 1989). However, many studies have used cohorts that are too small to detect smaller 

increases in other types of cancer (respiratory, central nervous system, lymphatic, or hematopoietic). 

Epidemiological studies designed to investigate reproductive and developmental effects of vinyl chloride 

have not been useful, in part because of a poor choice of statistical analysis, inadequate controls, lack of 

effects due to current low levels of exposure, or failure to take into account nutritional status and other 

chemical exposures. Additional cohort studies of these end points would be useful for examining these 

effects in humans. 

Clastogenic effects have been used as a dosimeter for exposures to radioactive substances, and work has 

been done to use this approach for chemical exposures as well. More data on quantified exposures and 

well-controlled cytogenetic studies would be useful in developing a method for monitoring populations 

living near hazardous waste sites. 

Biomarkers of Exposure and Effect. 

Exposure. Several potential biomarkers for exposure to vinyl chloride have been identified. Vinyl 

chloride measured in expired air is an adequate indicator of recent, moderate-to-high-level exposure 

(Baretta et al. 1969). However, for low-level exposures or exposures that occur over 1–2 hours prior to 

the time of measurement, this biomarker is not useful. Thiodiglycolic acid, a major urinary metabolite of 

vinyl chloride, has been used to monitor workers occupationally exposed to vinyl chloride (Müller et al. 

1979). However, this biomarker is rapidly excreted, and therefore, the period of its utility is limited 

(Watanabe and Gehring 1976; Watanabe et al. 1979b). Also, thiodiglycolic acid is not specific for vinyl 
VINYL CHLORIDE 152 

3. HEALTH EFFECTS 

chloride; it may also be produced as a result of the metabolism of 1,1-dichloroethene, ethylene oxide, or 

2,2-dichloroethylether (Norpoth et al. 1986; Pettit 1986). 

The DNA adducts 1,N6

-ethenoadenosine and 3,N4-ethenocytidine may be used to indicate vinyl chloride 

exposure, although studies correlating the levels of these adducts with exposure levels are still lacking. 

These products remain in the body longer than free vinyl chloride or thiodiglycolic acid, thereby 

increasing the period after exposure that a potential exposure may be detected (Bolt 1986; Guengerich 

and Watanabe 1979; Guengerich et al. 1979, 1981; Kappus et al. 1976; Watanabe et al. 1987a, 1987b). 

However, the presence of these adducts cannot indicate how long it has been since exposure occurred. In 

addition, these adducts are formed as the result of binding of the intermediary metabolites with nucleic 

acids, and other compounds producing the same intermediary metabolites will also produce these adducts. 

For example, these adducts have been identified as a result of exposure to vinyl bromide, ethyl carbamate, 

acrylonitrile, 2-cyanoethylene, and 1,2-dichloroethane (Bolt et al. 1986; Svensson and Osterman-Golkar 

1986). Studies attempting to identify a metabolite more specific to vinyl chloride may be helpful in 

developing a biomarker that may be used to facilitate future medical surveillance, which can lead to early 

detection and possible treatment. 

Vinyl chloride-induced genetic alterations have been identified in the Ki-ras oncogene and the p53 tumor 

suppressor gene, and oncoproteins and p53 antibodies have been detected in the serum of cancer patients 

with angiosarcoma (see Section 3.3). Immunological techniques have been used to detect the presence of 

Asp13p21 (oncoprotein for mutation of the Ki-ras gene), p53 mutant protein, and p53 antibodies in the 

serum of exposed workers (Brandt-Rauf et al. 2000a, 2000b; Marion 1998). Statistical analyses suggest a 

relationship between vinyl chloride exposure and the presence of these serum biomarkers; however, the 

predictive value of these biomarkers for development of cancer is not known. 

Effect. With regard to biomarkers of effect of vinyl chloride exposure, numerous indicators have been 

examined. The central nervous system depression associated with brief high-level exposures is easily 

determined by observation. The hepatic changes that may develop during longer term exposures are 

difficult to detect by standard biochemical liver function tests (Berk et al. 1975; Du et al. 1995; Liss et al. 

1985; Vihko et al. 1984). In contrast, tests of clearance such as the indocyanine clearance test or 

measurement of serum bile acid levels are more specific and sensitive indicators of vinyl chloride-induced 

liver damage (Berk et al. 1975; Liss et al. 1985; Vihko et al. 1984). Angiosarcoma of the liver is a rare 

tumor type that has been shown to result from vinyl chloride exposure. However, other agents are known 

to produce angiosarcoma of the liver, such as arsenic and Thorotrast® (Gedigke et al. 1975; Marsteller et 
VINYL CHLORIDE 153 

3. HEALTH EFFECTS 

al. 1975). Enzyme-linked immunoassay (EIA) has been used to detect anti-p53 antibodies in the serum of 

some individuals with angiosarcoma of the liver before clinical diagnosis of this lesion was made (Trivers 

et al. 1995). However, not all individuals who develop angiosarcoma of the liver test positive for anti-p53 

antibodies; in addition, anti-p53 bodies are not specific only to angiosarcoma of the liver. Further 

investigation into the ability of this assay to predict individuals at increased risk for developing 

angiosarcoma of the liver would be useful. Measurement of chromosomal aberrations may indicate the 

genotoxic effects of vinyl chloride (Anderson et al. 1980; Ducatman et al. 1975; Fucic et al. 1990a, 

1990b). However, these aberrations do not specifically indicate vinyl chloride-induced damage. Also, 

DNA adducts may signal the potential to develop genotoxic effects. Further work identifying the 

correlation between specific adducts and genotoxic effects would be useful. The cyanosis and blanching 

of the fingers in response to exposure to the cold may be an early indicator for the development of vinyl 

chloride disease. However, other conditions also known to produce these symptoms include connective 

tissue disorders, mechanical arterial obstruction, hyperviscosity of the blood, and exposure to drugs, 

chemicals, or vibrating tools (Black et al. 1983, 1986; Freudiger et al. 1988). The presence of basophilic 

stippled erythrocytes has been reported after inhalation exposure of mice to vinyl chloride (Kudo et al. 

1990). Further study would be necessary to determine whether this parameter could be used as a 

biomarker of effect in humans. 

Absorption, Distribution, Metabolism, and Excretion. There are few data on humans for all 

toxicokinetic parameters across all exposure routes (Krajewski et al. 1980; Sabadie et al. 1980). There 

are a number of animal studies describing the absorption, distribution, metabolism, and excretion of vinyl 

chloride administered via the oral route (Feron et al. 1981; Green and Hathway 1978; Watanabe and 

Gehring 1976; Watanabe et al. 1987a, 1987b; Withey 1976) and the inhalation route (Bolt et al. 1976a, 

1977; Buchter et al. 1977, 1980; Filser and Bolt 1979; Guengerich and Watanabe 1979; Hefner et al. 

1975b; Jedrychowski et al. 1984, 1985; Ungvary et al. 1978; Watanabe and Gehring 1976; Watanabe et 

al. 1978a, 1978b; Withey 1976) but few describing the toxicokinetics of vinyl chloride administered via 

the dermal route. One study in monkeys found an extremely limited absorption of vinyl chloride across 

the skin (Hefner et al. 1975a). However, only two animals were used, and this was the only study located 

that examined toxicokinetics after dermal exposure. No information is available regarding dermal 

absorption of vinyl chloride from liquid or solid media (i.e., water, soil). Dermal exposure from these 

media is expected to be minimal; however, a study confirming this assumption would be useful. 

Furthermore, the intermediary metabolites of vinyl chloride appear to be responsible for many of the toxic 

effects observed. Therefore, information regarding differences in the metabolic pattern according to 
VINYL CHLORIDE 154 

3. HEALTH EFFECTS 

gender, age, nutritional status, and species and correlations to differences in health effects would also be 

useful. 

Comparative Toxicokinetics. The absorption, distribution, metabolism, and excretion of vinyl 

chloride have been studied in animals (Bolt et al. 1976a, 1977; Buchter et al. 1977, 1980; Feron et al. 

1981; Filser and Bolt 1979; Green and Hathway 1975; Guengerich and Watanabe 1979; Hefner et al. 

1975b; Jedrychowski et al. 1984, 1985; Ungvary et al. 1978; Watanabe and Gehring 1976; Watanabe et 

al. 1976a, 1976b, 1978a, 1978b; Withey 1976), but information on toxicokinetics in humans is extremely 

limited (Krajewski et al. 1980; Sabadie et al. 1980). Human and animal data indicate that similar target 

organs (liver, central nervous system) for the toxic effects of vinyl chloride exist, suggesting some 

similarities of kinetics. Limited information is available regarding interspecies differences in kinetics. 

Most toxicokinetic studies have been conducted using rats (Bolt et al. 1976a, 1977; Buchter et al. 1977; 

Feron et al. 1981; Filser and Bolt 1979; Green and Hathway 1975; Guengerich and Watanabe 1979; 

Hefner et al. 1975b; Jedrychowski et al. 1984, 1985; Ungvary et al. 1978; Watanabe and Gehring 1976; 

Watanabe et al. 1976a, 1976b, 1978a, 1978b; Withey 1976), but one study in primates indicates that 

metabolism may saturate at lower concentrations in primates than rats (Buchter et al. 1980). This may 

suggest a lower saturation point in humans also. Modeling studies might continue to provide information 

on the toxicokinetics of vinyl chloride in humans. 

Methods for Reducing Toxic Effects. Vinyl chloride appears to be rapidly and completely 

absorbed following inhalation and oral exposure (Bolt et al. 1977; Krajewski et al. 1980; Watanabe et al. 

1976a; Withey 1976). Methods used to reduce absorption immediately after exposure include removal 

from the source of exposure, cleansing contaminated body parts, and in cases of ingestion, speeding the 

removal of unabsorbed material from the gastrointestinal tract (Bronstein and Currance 1988; Haddad and 

Winchester 1990; Stutz and Ulin 1992). No information was located regarding the mechanism of 

absorption. Additional experiments examining the mechanism of absorption and potential means of 

interfering with that mechanism would be useful. Distribution of vinyl chloride in the body is rapid and 

widespread, but storage is limited by rapid metabolism and excretion (Bolt et al. 1976a; Buchter et al. 

1977; Watanabe et al. 1976a, 1976b, 1978a). The toxicity of vinyl chloride has been attributed to the 

formation of reactive epoxide metabolites. No information was located regarding removal of these toxic 

metabolites from the body once they have been formed, but information from toxicokinetic studies 

suggest that vinyl chloride metabolism to toxic metabolites may be reduced. Saturation of the metabolic 

pathways for vinyl chloride can result in the clearance of unmetabolized vinyl chloride in exhaled air 

(Green and Hathway 1975; Watanabe and Gehring 1976; Watanabe et al. 1976a, 1976b, 1978a). Studies 
VINYL CHLORIDE 155 

3. HEALTH EFFECTS 

examining the effectiveness and endogenous toxicity of the agents used to block the metabolic pathways 

(cobaltous chloride, SKF-535-A, 6-nitro-1,2,3-benzothiadiazole) would provide useful information. 

Another strategy for reducing the formation of toxic metabolites includes increasing the pool of 

glutathione for use in metabolism to nontoxic metabolites. Studies examining the effectiveness of this 

procedure would also be helpful. Vinyl chloride disease may be mediated by an autoimmune mechanism 

(Grainger et al. 1980; Ward 1976). Further studies continuing to examine the role of autoimmune 

responses in vinyl chloride disease, the genetic factors resulting in greater susceptibility to the disease, 

and the effectiveness of drugs that block immune responses in reducing the symptoms of vinyl chloride 

disease would also provide valuable information. 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 

No studies were located that specifically address the effects of vinyl chloride in children. Some 

epidemiologic studies (Infante 1976; Infante et al. 1976a, 1976b; NIOSH 1977) have suggested an 

association between birth defects and vinyl chloride exposure of the parents of affected children. 

However, the design and analysis of these studies has been criticized (Hatch et al. 1981; Stallones 1987). 

Some inhalation studies with animals have suggested that vinyl chloride is a developmental toxicant (i.e., 

produces delayed ossification), but only at doses that produce significant maternal toxicity (John et al. 

1977, 1981; Mirkova et al. 1978; Sal'nikova and Kotsovskaya 1980; Ungvary et al. 1978). No adverse 

effects on embryo-fetal development were noted in a recent inhalation study in rats conducted using 

similar concentrations of vinyl chloride (Thornton et al. 2002). There is no evidence that vinyl chloride 

has hormone-like effects. However, a developmental neurotoxicity study in rats in which pups are tested 

at various ages after being exposed in utero would be informative. 

Carcinogenicity studies with animals suggest that younger animals may be more sensitive to the toxicity 

and carcinogenicity of vinyl chloride (Laib et al. 1985; Maltoni et al. 1981). An age-related sensitivity to 

DNA adduct formation was noted in rats (Ciroussel et al. 1990; Fedtke et al. 1990; Morinello et al. 

2002a). Further mechanistic research may be useful in establishing the mechanism of early life stage 

sensitivity in laboratory animals and determining whether it is anticipated to be relevant to humans. 

No studies were located that specifically address the toxicokinetics of vinyl chloride in children; however, 

the toxicokinetic behavior of vinyl chloride in children is expected to be similar to that in adults. Young 
VINYL CHLORIDE 156 

3. HEALTH EFFECTS 

children appear capable of metabolizing vinyl chloride to reactive intermediates that form DNA adducts 

that lead to cancer. The data on CYP2E1 levels in the developing organism suggest that early life stage 

sensitivity to vinyl chloride-induced cancer is not solely due to an increase in the production of reactive 

intermediates via this isozyme. Fetal CYP isoforms may play a role in metabolism of vinyl chloride to 

reactive intermediates in the fetus and neonate. Glutathione conjugation may also differ in the developing 

organism. DNA repair capacity and other pharmacodynamic factors may also be associated with an early 

life stage susceptibility to cancer. Further information on the toxicokinetics and toxicodynamics of vinyl 

chloride and metabolites during pregnancy, lactation, and early childhood would be useful. The 

biomarkers of exposure and effects used in occupational worker populations should be evaluated for their 

relevance to human exposure at all age levels following acute or chronic exposure to vinyl chloride. 

There are no data on the interaction of vinyl chloride with other chemicals in children. The information 

available indicates that methods to reduce peak absorption of vinyl chloride are applicable to children. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

The following ongoing studies concerning the adverse health effects associated with vinyl chloride have 

been identified in the Federal Research in Progress (FEDRIP 2005) database. 

Dr. P.W. Brandt-Rauf at Columbia University proposes to investigate whether genetic polymorphisms in 

vinyl chloride-metabolizing enzymes are also related to the more specific biomarkers of mutagenic 

damage (mutant ras-p21 and/or mutant p53) in vinyl chloride-exposed workers. Restriction fragment 

length polymorphism techniques will be used to analyze DNA from sub-groups of vinyl chloride-exposed 

workers. It is anticipated that workers with genetic polymorphisms will be more likely to have the 

biomarkers of mutagenic damage than similarly exposed workers without the polymorphisms and thus 

will be more likely to suffer from the subsequent carcinogenic and other health effects of vinyl chloride 

exposure. If this proves to be correct, then such special populations at risk could be targeted for more 

stringent interventions to help prevent the occurrence of vinyl chloride-related occupational diseases. 

This research is sponsored by the National Institute for Occupational Safety and Health. 

Dr. W.K. Kaufman at the University of North Carolina at Chapel Hill will investigate the role of DNA 

repair in the formation of hprt mutations in vinyl chloride-exposed workers. A subfraction of people 
VINYL CHLORIDE 157 

3. HEALTH EFFECTS 

exposed to vinyl chloride in the workplace expressed high frequencies of hprt mutations in blood 

lymphocytes. The possible existence of a DNA repair defect in sensitive workers will be evaluated by 

studying chlorethylene oxide-induced genotoxicity in lymphoblastoid lines derived from sensitive and 

resistant people. This project will employ a functional assay for DNA repair capacity in peripheral 

lymphocytes that measures rejoining of radiation-induced chromatid breaks. This research is supported 

by the National Institute of Environmental Health Sciences (NIEHS). 

Dr. G.E. Kisby at the Oregon Health Sciences University proposes experiments to examine the 

relationship between the formation of etheno base DNA adducts of chloroacetaldehyde and neurotoxicity 

or mutations. Neuronal and astrocyte cell cultures will be developed from different brain regions (e.g., 

cortex, hippocampus, midbrain, cerebellum) of DNA repair proficient and deficient mice (i.e., 

k N-methylpurine DNA glycosylase Aag). These cell lines will be examined for acute and delayed 

chloroacetaldehyde-induced neurotoxicity. Separate sets of astrocyte cell cultures will be developed from 

hprt heterozygous-deficient mice and examined to determine the spectrum of chloroacetaldehyde-induced 

mutations. Findings from these studies are expected to provide important information about the 

neurotoxic and mutagenic mechanisms of vinyl chloride. This research is sponsored by the NIEHS. 

Dr. K.D. Thrall at the Oregon Health Sciences University will investigate the influence of route of 

exposure on the total body burden and internal target tissue dosimetry of vinyl chloride and other 

chemicals. Exposure assessment studies will be conducted with human volunteers using a novel real-time 

breath analysis system to determine the uptake of contaminants from tap water by each of three routes: 

inhalation, ingestion, and dermal contact. These data will be coupled with PBPK modeling to determine 

uptake kinetics and brain dosimetry. This research is sponsored by the NIEHS. 
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3. HEALTH EFFECTS 

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VINYL CHLORIDE 159 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

Information regarding the chemical identity of vinyl chloride is located in Table 4-1. This information 

includes synonyms, chemical formula and structure, and identification numbers. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

Information regarding the physical and chemical properties of vinyl chloride is located in Table 4-2. 
VINYL CHLORIDE 160 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of Vinyl Chloride 

Characteristic Information Reference 

Chemical name Vinyl chloride HSDB 2005 

Synonym(s) Chloroethene; chloroethylene; 1-chloroethylene; 

ethylene monochloride; monovinyl chloride; 

monochloroethene; monochloroethylene; 

MVCs; Trovidur; VC; VCM; vinyl chloride 

monomer 

Fire 1986; HSDB 2005 

Registered trade name(s) No data 

Chemical formula C2H3Cl HSDB 2005 

Chemical structure H H HSDB 2005 

CC 
 

H Cl 

Identification numbers: 

CAS registry 75-01-4 HSDB 2005 

 NIOSH/RTECS KU9625000 HSDB 2005 

EPA hazardous waste U043 HSDB 2005 

 OHM/TADS 7216947 HSDB 2005 

 DOT/UN/NA/IMCO 1086 HSDB 2005 

shipping 

HSDB 169 HSDB 2005 

NCI No data HSDB 2005 

CAS = Chemical Abstract Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substance Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for 

Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; 

RTECS = Registry of Toxic Effects of Chemical Substances 
VINYL CHLORIDE 161 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of Vinyl Chloride 

Property Information Reference 

Molecular weight 62.5 Lewis 1996 

Color Colorless Budavari 1989 

Physical state Gas Budavari 1989 

Melting point -153.8 °C Budavari 1989 

Boiling point -13.37 °C Budavari 1989 

Density: 

at -14.2 °C 0.969 g/cm3 Cowfer and Magistro 1983 

at 15 °C 0.9195 g/cm3

 Lewis 1996 

at 20 °C 0.9106 g/cm3

 NIOSH 1986 

Vapor density 2.16 Fire 1986 

Odor Sweet HSDB 1996 

Odor threshold: 

Water 3.4 ppm Amoore and Hautala 1983 

Air 3,000 ppm Amoore and Hautala 1983 

Solubility: 

Water at 25 °C 2,763 mg/L EPA 1985b 

1,100 mg/L Cowfer and Magistro 1983 

Organic solvent(s) Soluble in hydrocarbons, oil, alcohol, Cowfer and Magistro 1983 

chlorinated solvents, and most common 

organic liquids 

Partition coefficients: 

 Log Kow 1.36 NIOSH 1986

 Log Koc 1.99 Lyman et al. 1982 

Vapor pressure: 

at 20 °C 2,530 mmHg Budavari 1989 

at 25 °C 2,600 mmHg Lewis 1996 

Henry’s law constant: 

10.3 °C 0.0147 (atm-m3

)/mol Gossett 1987 

17.5 °C 0.0193 (atm-m3

)/mol Gossett 1987 

24.8 °C 0.0278 (atm-m3

)/mol Gossett 1987 

34.6 °C 0.0358 (atm-m3

)/mol Gossett 1987 

Autoignition temperature 472 °C Lewis 1996 

Flashpoint -78 °C (closed cup) Budavari 1989 

Flammability limits 3.6–33 volume % NIOSH 1986 

Conversion factors: 

ppm to mg/m3

 in air 1 ppm=2.6 mg/m3 NIOSH 1990

 mg/m3

 to ppm in air 1 mg/m3=0.38 ppm NIOSH 1990 

Explosive limits 4–22 volume % Lewis 1996 
VINYL CHLORIDE 162 

4. CHEMICAL AND PHYSICAL INFORMATION 

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VINYL CHLORIDE 163 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

Vinyl chloride was first produced commercially in the 1930s by reacting hydrogen chloride with 

acetylene. Currently, vinyl chloride is produced commercially by the chlorination of ethylene through 

one of two processes, direct chlorination or oxychlorination. Direct chlorination reacts ethylene with 

chlorine to produce 1,2-dichloroethane. Similarly, oxychlorination produces 1,2-dichloroethane, but this 

is accomplished by reacting ethylene with dry hydrogen chloride and oxygen. After both processes, the 

1,2-dichloroethane is subjected to high pressures (2.5–3.0 megapascals) and temperatures (550–550 °C). 

This causes the 1,2-dichloroethane to undergo pyrolysis, or thermal cracking, which forms the vinyl 

chloride monomer and hydrogen chloride. The vinyl chloride monomer is then isolated (Cowfer and 

Magistro 1985). The technical-grade product is available in 99.9% purity (HSDB 2005). Efforts are 

being made to minimize by-product formation (hydrocarbons, chlorinated hydrocarbons, and unreacted 

material) in 1,2-dichloroethane pyrolysis (Cowfer and Magistro 1985). 

Table 5-1 summarizes the facilities in the United States that either manufacture or process vinyl chloride. 

This information was obtained from the Toxic Release Inventory (TRI03 2005), and also lists the 

maximum amounts of vinyl chloride that are present at these sites and the end uses of vinyl chloride. 

Table 5-2 lists the facilities that solely manufacture vinyl chloride for commercial purposes and their 

production capacities. In 2001, the global demand for vinyl chloride was 14.89 billion pounds; in 2002, 

demand was 15.94 billion pounds; and in 2006, it is estimated that demand for vinyl chloride will be 

17.8 billion pounds (CMR 2003). Demand for vinyl chloride monomer is almost entirely dependent upon 

the consumption of polyvinyl chloride (PVC) materials. Demand is expected to increase globally at a rate 

of approximately 3.5% annually due to increasing demand in Asia, while demand in the United States is 

expected to increase by about 2.8% annually (CMR 2003). 

5.2 IMPORT/EXPORT 

Imports of vinyl chloride totaled 29 million pounds (13.17 million kilograms) in 1994 and 164 million 

pounds in 1991 (CPS 1993; NTD 1995). Imports have been steadily declining from a high of 302 million 

pounds in 1989, prior to which they had been increasing (CPS 1993). Currently, the amounts of vinyl 
VINYL CHLORIDE 164 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-1. Facilities that Produce, Process, or Use Vinyl Chloride 

Number Minimum Maximum 

of amount on site amount on site 

Statea facilities in poundsb in poundsb Activities and usesc 

AL 2 1,000 999,999 2, 3, 6, 7 

AR 3 1,000 999,999 6, 12 

CA 8 100 9,999,999 2, 3, 6, 7, 8, 9, 10, 12 

DE 6 10,000 99,999,999 2, 3, 6, 11, 12 

FL 2 100,000 9,999,999 6 

GA 3 1,000 999,999 6, 7, 8 

IL 5 1,000 49,999,999 6, 8, 11 

IN 4 0 99,999 1, 7, 8, 13 

KS 8 100 99,999 1, 2, 3, 5, 6, 10, 12, 13 

KY 10 1,000 49,999,999 1, 2, 3, 4, 6, 12, 14 

LA 37 100 10,000,000,000 1, 2, 3, 4, 5, 6, 11, 12, 13 

MI 8 1,000 9,999,999 2, 3, 6, 12 

MO 5 1,000 9,999,999 1, 2, 3, 5, 6, 8, 11 

MS 4 1,000,000 999,999,999 6 

NC 7 0 999,999 1, 5, 6, 8, 11 

NE 1 10,000 99,999 12 

NJ 11 1,000 49,999,999 6, 7, 8, 12 

NY 2 10,000 999,999 6, 8 

OH 10 0 9,999,999 2, 3, 6, 7, 8, 11, 12 

OK 1 1,000,000 9,999,999 6 

PA 2 1,000,000 9,999,999 3, 6, 8 

SC 2 10,000 9,999,999 8, 12 

TX 43 0 499,999,999 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14 

UT 1 1,000 9,999 12 

VA 4 1,000 999,999 1, 7, 12, 13 

WI 1 10,000 99,999 7 

a

Post office state abbreviations used b

Amounts on site reported by facilities in each state c

Activities/Uses: 

1. Produce 

2. Import 

3. Onsite use/processing 

4. Sale/Distribution 

5. Byproduct 

6. Impurity 

7. Reactant 

8. Formulation Component 

9. Article Component 

10. Repackaging 

11. Chemical Processing Aid 

12. Manufacturing Aid 

13. Ancillary/Other Uses 

14. Process Impurity 

Source: TRI03 2005 (Data are from 2003) 
VINYL CHLORIDE 165 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

Table 5-2. U.S. Production Capacity of Vinyl Chloride 

U.S. Producer Location Capacity (millions pounds per year) 

Dow Chemicals Oyster Creek, Texas; Freeport, Texas 2,700 

Dow Chemicals Plaquemine, Louisiana 1,500 

Formosa Plastics Baton Rouge, Louisiana 980 

Formosa Plastics Point Comfort, Texas 1,235 

Geismar Vinyls Geismar, Louisiana 650 

Georgia Gulf Lake Charles, Louisiana 1,000 

Georgia Gulf Plaquemine, Louisiana 1,600 

Oxy Mar Ingleside, Texas 2,300 

Oxy Vinyls Deer Park, Texas 1,300 

Oxy Vinyls La Porte, Texas 2,400 

PHH Monomers Lake Charles, Louisiana 1,300 

Westlake Monomers Calvert City, Kentucky 1,200 

U.S. total capacity: 18,165 million pounds 

Source: CMR 2003 
VINYL CHLORIDE 166 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

chloride imported into the United States are negligible (CMR 2003). Exports of vinyl chloride were 

1.65 billion pounds (0.75 billion kilograms) in 1992 and 2.10 billion pounds (0.95 billion kilograms) in 

1994 (NTD 1995). Recent estimates have shown a slight decrease in U.S. export volumes. In 2001, 

exports of vinyl chloride totaled 1.89 billion pounds and in 2002, exports were 1.43 billion pounds (CMR 

2003). 

5.3 USE 

Vinyl chloride is an important industrial chemical because of its wide variety of end-use products and the 

low cost of producing polymers from it. Approximately 98% of all vinyl chloride produced is used to 

manufacture PVC materials (CMR 2003). These PVC materials are widely used in automotive parts, 

packaging products, pipes, construction materials, furniture, and a variety of other products (Cowfer and 

Magistro 1985). Other miscellaneous uses, which account for about 2% of the vinyl chloride that is 

produced annually, include the production of 1,1,1-trichloroethane and copolymers with vinyl acetate, 

vinyl sterate, and vinylidene chloride (CMR 2003). 

Vinyl chloride has been used in the past as a refrigerant, as an extraction solvent for heat-sensitive 

materials, and in the production of chloroacetaldehyde and methyl chloroform (IARC 1979). In the 

United States, limited quantities of vinyl chloride were used as an aerosol propellant and as an ingredient 

of drug and cosmetic products; however, these practices were banned by the EPA in 1974 (HSDB 2005; 

IARC 1979). 

5.4 DISPOSAL 

Since vinyl chloride has been identified by EPA as a hazardous material, its disposal is regulated under 

the Federal Resource Conservation and Recovery Act (RCRA) (EPA 1993d). The transportation of 

hazardous materials for disposal is regulated by the Department of Transportation in compliance with this 

act (DOT 1993). The recommended method of disposal is total destruction by incineration. The 

temperature of the incinerator must be sufficient to ensure the complete combustion of the vinyl chloride 

in order to prevent the formation of phosgene. The recommended temperature range for incineration is 

450–1,600 °C, with residence times of seconds for gases and liquids, and hours for solids (HSDB 2005). 

If in solution, the vinyl chloride product may need to be adsorbed onto a combustible material prior to 

incineration. Recommended materials include vermiculite, sawdust, or a sand-soda ash mixture (90/10) 
VINYL CHLORIDE 167 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

covered with wood and paper (OHM/TADS 1985). The vinyl chloride can also be dissolved in a 

flammable solvent prior to incineration. An acid scrubber should be used in conjunction with the 

incinerator in order to remove any hydrogen chloride that is produced by the combustion process (HSDB 

2005; OHM/TADS 1985). Alternatively, chemical destruction may be used, especially with small 

quantities. From 1 to 2 days is generally sufficient for complete destruction (HSDB 2005). 

Aqueous byproduct solutions from the production of vinyl chloride are usually steam-stripped to remove 

volatile organic compounds, neutralized, and then treated in an activated sludge system to remove 

nonvolatile organic compounds remaining in the waste water (Cowfer and Magistro 1983). 
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5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

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VINYL CHLORIDE 169 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

Vinyl chloride has been identified in at least 622 of the 1,662 hazardous waste sites that have been 

proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 2005). However, the number 

of sites evaluated for vinyl chloride is not known. The frequency of these sites can be seen in Figure 6-1. 

Of these sites, all are located within the continental United States with the exception of one site located in 

the Virgin Islands and one site in the Commonwealth of Puerto Rico (not shown). 

Vinyl chloride is used almost exclusively in the United States by the plastics industry for the production 

of polyvinyl chloride (PVC) and several copolymers. Much of the vinyl chloride produced at 

manufacturing facilities gets converted to PVC and vinyl chloride derived copolymers on-site. Nearly all 

vinyl chloride shipped to facilities off-site is also converted to PVC or PVC copolymers. In many cases, 

vinyl chloride is transported by pipeline directly to the plant producing the polymer. The physical form of 

vinyl chloride is a neat liquid (99.9% minimum purity) stored or transported under pressure (OECD 

2001). 

Anthropogenic sources are responsible for all of the vinyl chloride found in the environment. Most of the 

vinyl chloride released to the environment eventually escapes to the atmosphere. Lesser amounts are 

released to groundwater. Vinyl chloride has been detected in the ambient air in the vicinity of vinyl 

chloride and PVC manufacturing plants and hazardous waste sites. The compound has also leached into 

groundwater from spills, landfills, and industrial sources; it can also enter groundwater after being 

produced by the bacterial degradation of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane 

(Smith and Dragun 1984). 

Effluents and emissions from vinyl chloride and PVC manufacturers are responsible for most of the vinyl 

chloride released to the environment. In the vicinity of hazardous waste sites, a significant source of 

vinyl chloride may originate from the bacterial degradation of chlorinated solvents such as 

trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane, rather than industrial sources. When 

released to the atmosphere, vinyl chloride is expected to be removed by reaction with photochemically 

generated hydroxyl radicals (half-life=1–2 days). Reaction products include hydrochloric acid, 
VINYL CHLORIDE 170 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with Vinyl Chloride Contamination 

Frequency of 

NPL Sites 

1-2 

3-7 

8-14 

15-26 

Derived from HazDat 2005	 27-47 

48-54 
VINYL CHLORIDE 171 

6. POTENTIAL FOR HUMAN EXPOSURE 

formaldehyde, formyl chloride, acetylene, chloroacetaldehyde, chloroacetylchloranil, and chloroethylene 

epoxide. In photochemical smog, the half-life of vinyl chloride is reduced to a few hours. When released 

to water, volatilization is expected to be the primary environmental fate process. In waters containing 

photosensitizers, such as humic materials, sensitized photodegradation may also be important. Sensitized 

photodegradation may occur when a molecule other than the compound of interest absorbs light, 

promoting it to an excited state; a transfer of energy occurs between the excited state of the photosensitizer and the compound of interest, which involves no direct absorption of photons by that particular 

compound. When released to soil, vinyl chloride either volatilizes rapidly from soil surfaces or leaches 

readily through soil, ultimately entering groundwater. 

Segments of the general population living in the vicinity of emission sources are exposed to vinyl 

chloride by inhalation of contaminated air. Average daily intake of vinyl chloride by inhalation for these 

people ranges from trace amounts to 2,100 μg/day. The average daily intake of vinyl chloride by 

inhalation is expected to be very low for the remainder of the population. The majority of the general 

population is not expected to be exposed to vinyl chloride through ingestion of drinking water. The 

average daily intake of vinyl chloride through the diet is essentially zero. Workers, particularly those 

employees at vinyl chloride and PVC manufacturing facilities, are exposed to vinyl chloride mainly by 

inhalation, although minor absorption through the skin possible. Workers involved in the handling and 

and processing of PVC resins are exposed to lower levels of vinyl chloride than employees at vinyl 

chloride and PVC manufacturing facilities since fabricated products contain only minute quantities of 

vinyl chloride present as residual monomer. The National Occupational Exposure Survey (NOES), 

conducted by NIOSH from 1981 to 1983, estimated that 81,314 workers (28,398 of these are females) 

employed at 3,711 plant sites were potentially exposed to vinyl chloride (NOES 1990). This survey does 

not differentiate between exposures to persons working in vinyl chloride and PVC manufacturing 

facilities and those persons employed in trades that fabricate end products where the level of exposure is 

expected to be lower. Since the early 1970s, improvements in manufacturing facilities, engineering 

controls, and workplace practices have substantially reduced workplace exposures in the United States 

and most other industrialized countries that manufacture vinyl chloride and produce or fabricate PVC 

products. 
VINYL CHLORIDE 172 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.2 RELEASES TO THE ENVIRONMENT 

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ 10 or more full-time 

employees; if their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 

1081, and 1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the 

purpose of generating electricity for distribution in commerce), 4931 (limited to facilities that combust 

coal and/or oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to 

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 2005). 

6.2.1 Air 

Estimated releases of 587,677 pounds of vinyl chloride to the atmosphere from 52 domestic 

manufacturing and processing facilities in 2003, accounted for about 85% of the estimated total 

environmental releases from facilities required to report to the TRI (TRI03 2005). These releases are 

summarized in Table 6-1. 

The major source of vinyl chloride releases to the environment is believed to be emissions and effluents 

from plastic industries, primarily vinyl chloride and PVC manufacturers. Worldwide emissions of vinyl 

chloride into the atmosphere during 1982 totaled approximately 400 million pounds (Hartmans et al. 

1985). Another emission source is tobacco smoke, which has been found to contain 5.6–28 ng vinyl 

chloride per cigarette (Hoffman et al. 1976). The combustion of coal and the incineration of municipal 

waste may also release small quantities of vinyl chloride to the atmosphere (Dempsey 1993; Miller et al. 

1994). 

The EPA National Toxics Inventory (NTI) estimated that in 1996, 1,650 tons of vinyl chloride 

(3.3 million pounds) were released to the atmosphere in the contiguous United States (plus Puerto Rico 

and the Virgin Islands) (EPA 2005). The NTI includes more facilities than the TRI because of TRI 
VINYL CHLORIDE 173 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Releases to the Environment from Facilities that Produce, Process, or 
 

Use Vinyl Chloridea
 

Reported amounts released in pounds per yearb 

Total release 

Statec RFd Aire Water

f

 UIg Landh Otheri On-sitej

 Off-sitek 

On- and offsite 

AL 1 2,427 No data 0 0 0 2,427 0 2,427 

AR 2 109 No data 0 0 0 109 0 109 

DE 2 84,092 1 0 5 0 84,093 5 84,098 

IL 2 57,025 5 0 5 0 57,030 5 57,035 

IN 1 0 No data 0 0 0 0 0 0 

KS 1 0 No data 38 0 0 38 0 38 

KY 6 44,481 7 0 7 28 44,488 35 44,523 

LA 10 140,614 3 80,116 18 45 220,735 61 220,796 

MI 2 3,534 0 0 0 0 3,534 0 3,534 

MO 1 100 0 0 0 0 100 0 100 

MS 1 30,272 No data 0 0 0 30,272 0 30,272 

NC 1 17 No data 0 0 0 17 0 17 

NJ 3 32,484 64 0 71 0 32,548 71 32,619 

OH 4 267 5 0 24,250 1,260 272 25,510 25,782 

OK 1 4,235 No data 0 0 0 4,235 0 4,235 

PA 1 73,241 0 0 0 0 73,241 0 73,241 

TX 11 114,629 267 0 8 87 114,904 87 114,991 

UT 1 1 No data 0 0 0 1 0 1 

VA 1 149 No data 0 0 0 149 0 149 

Total 52 587,677 352 80,154 24,364 1,420 668,193 25,775 693,967 

a

The TRI data should be used with caution since only certain types of facilities are required to report. This is not an 
 

exhaustive list. Data are rounded to nearest whole number.
 b

Data in TRI are maximum amounts released by each facility.
 c

Post office state abbreviations are used. 
 d

Number of reporting facilities.
 e

The sum of fugitive and point source releases are included in releases to air by a given facility. 
 f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs)
 

(metal and metal compounds).
 g

Class I wells, Class II-V wells, and underground injection. 
 h

Resource Conservation and Recovery Act (RCRA) subtitle C landfills; other on-site landfills, land treatment, surface 
 

impoundments, other land disposal, other landfills. 
 i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for 
 

disposal, unknown 
 j

The sum of all releases of the chemical to air, land, water, and underground injection wells. 
 k

Total amount of chemical transferred off-site, including to POTWs. 
 

RF = reporting facilities; UI = underground injection 

Source: TRI03 2005 (Data are from 2003) 
VINYL CHLORIDE 174 

6. POTENTIAL FOR HUMAN EXPOSURE 

reporting thresholds and the limitations in the types of facilities required to report to TRI. The NTI is 

compiled primarily using state and local agency and tribal toxic air pollutant emission inventories. The 

emissions organized by state are summarized in Table 6-2. Vinyl chloride was detected in the air at 63 of 

the 1,662 current or former EPA NPL hazardous waste sites (HazDat 2005). Vinyl chloride detected at 

these hazardous waste sites may not necessarily arise from industrial sources. The bacterial degradation 

of chlorinated solvents such as trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane can 

produce vinyl chloride as a degradation product, and this may be the origin of vinyl chloride at these sites 

(Smith and Dragun 1984). 

6.2.2 Water 

Estimated releases of 352 pounds of vinyl chloride to surface water from 52 domestic manufacturing and 

processing facilities in 2003, accounted for <1% of the estimated total environmental releases from 

facilities required to report to the TRI (TRI03 2005). These releases are summarized in Table 6-1. 

Vinyl chloride released in waste water from the plastics industries is expected to volatilize fairly rapidly 

(on the order of hours to days) into the atmosphere. Anaerobic reductive dehalogenation of trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane also releases vinyl chloride into groundwater at 

hazardous waste sites (Smith and Dragun 1984) or other locations where the proper conditions are found 

in the subterranean strata. Vinyl chloride was detected in groundwater at 538 of the 1,662 current or 

former EPA NPL hazardous waste sites, and in surface water at 110 of the 1,662 current or former EPA 

NPL hazardous waste sites (HazDat 2005). Since vinyl chloride possesses high mobility in soils, it 

leaches into groundwater from spills, landfills, and industrial sources that may release it to soil (TRI03 

2005). According to data collected from the analysis of leachates and monitoring wells at sites where 

groundwater was contaminated by municipal solid waste landfill leachate, vinyl chloride was present in 

both the leachates and the groundwater samples (Sabel and Clark 1984). Vinyl chloride has been found in 

groundwater at other landfills also (Agency for Toxic Substances and Disease Registry 1995a, 1995b). 

6.2.3 Soil 

Estimated releases of 24,364 pounds of vinyl chloride to soils from 52 domestic manufacturing and 

processing facilities in 2003, accounted for about 3.5% of the estimated total environmental releases from 

facilities required to report to the TRI (TRI03 2005). In addition, 80,154 pounds of vinyl chloride, 
VINYL CHLORIDE 175 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Emissions of Vinyl Chloride Organized by State in 1996 

State Emissions (pounds/year) Emission density (pounds/year/square mile) 

Alabama 19,300 0.38 

Arizona 26,200 0.23 

Arkansas 7,220 0.14 

California 568,000 3.64 

Colorado 70,200 0.67 

Connecticut 3,080 0.63 

Delaware 155,800 78.40 

Washington, DC 2 0.03 

Florida 31,400 0.57 

Georgia 26,400 0.45 

Idaho 3,460 0.04 

Illinois 176,400 3.16 

Indiana 26,000 0.72 

Iowa 7,120 0.13 

Kansas 7,860 0.10 

Kentucky 80,200 2.00 

Louisiana 158,600 3.54 

Maine 480 0.02 

Maryland 8,100 0.84 

Massachusetts 86,000 10.78 

Michigan 124,000 2.20 

Mississippi 36,600 0.77 

Missouri 14,540 0.21 

Montana 1,768 0.01 

Nebraska 4,120 0.05 

Nevada 7,260 0.07 

New Hampshire 3,080 0.34 

New Jersey 63,200 8.36 

New Mexico 10,680 0.09 

New York 248,000 5.20 

North Carolina 26,800 0.55 

North Dakota 2,760 0.04 

Ohio 43,000 1.04 

Oklahoma 6,640 0.10 

Oregon 12,000 0.13 

Pennsylvania 246,000 5.46 

Rhode Island 2,820 3.14 

South Carolina 11,160 0.37 

South Dakota 1,280 0.02 

Tennessee 19,940 0.48 
VINYL CHLORIDE 176 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-2. Emissions of Vinyl Chloride Organized by State in 1996 

State Emissions (pounds/year) Emission density (pounds/year/square mile) 

Texas 846,000 3.22 

Utah 6,060 0.07 

Vermont 1,038 0.11 

Virginia 23,400 0.59 

Washington 11,460 0.17 

West Virginia 13,600 0.56 

Wisconsin 9,320 0.17 

Wyoming 1,292 0.01 

Puerto Rico 2,480 0.72 

Virgin Islands 1 0.01 

Source: National Toxics Inventory (NTI) 
VINYL CHLORIDE 177 

6. POTENTIAL FOR HUMAN EXPOSURE 

amounting to about 11.5% of the total released was injected underground. These releases are summarized 

in Table 6-1. 

Vinyl chloride can either enter the soil from leachates at hazardous waste sites or enter the ground via 

underground injection. Release through either of these mechanisms is, however, only a small fraction of 

the total environmental discharge (TRI03 2005). Vinyl chloride was detected in soil at 160 of the 

1,662 current or former EPA NPL hazardous waste sites, and in sediment at 47 of the 1,662 current or 

former EPA NPL hazardous waste sites (HazDat 2005). The bacterial degradation of chlorinated solvents 

such as trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane can produce vinyl chloride as a 

degradation product, and this may be a significant source of vinyl chloride at these sites (Smith and 

Dragun 1984). 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

Based on a vapor pressure of 2,660 mmHg at 25 °C, essentially all vinyl chloride in the atmosphere is 

expected to exist solely as a gas (Eisenreich et al. 1981; Verschueren 1983). Consequently, removal from 

the atmosphere by dry deposition is not expected to be an important fate process. 

The primary transport process for vinyl chloride from natural water systems is volatilization into the 

atmosphere. The Henry's law constant of vinyl chloride has been measured as 0.0278 atm-m3

/mol at 

24.8 °C (Gossett 1987), which suggests that vinyl chloride should partition rapidly to the atmosphere. 

The half-life for vinyl chloride volatilization from a typical pond, river, and lake has been estimated to be 

43.3, 8.7, and 34.7 hours, respectively. These values are based on an experimentally determined 

reaeration rate ratio of approximately 2 and assumed oxygen reaeration rates of 0.008, 0.04, and 0.01 per 

hour for a typical pond, river, and lake, respectively (EPA 1982a). Predicted half-lives should be 

considered rough estimates since the presence of various salts in natural water systems may affect the 

volatility of vinyl chloride significantly (EPA 1979d). Many salts have the ability to form complexes 

with vinyl chloride and can increase its water solubility; therefore, the presence of salts in natural waters 

may significantly influence the amount of vinyl chloride remaining in the water (EPA 1979d). The halflife of vinyl chloride in bodies of water is also affected by depth and turbidity. 
VINYL CHLORIDE 178 

6. POTENTIAL FOR HUMAN EXPOSURE 

The relatively high vapor pressure of vinyl chloride indicates that the compound volatilizes quite rapidly 

from dry soil surfaces (Verschueren 1983). The effective half-life (due to volatilization and degradation) 

of vinyl chloride incorporated 10 cm deep in dry soil is predicted to be 12 hours (Jury et al. 1984). Vinyl 

chloride is soluble in water and thus can leach through the soil and enter groundwater before evaporation 

can occur (Cowfer and Magistro 1983). 

Experimental data regarding adsorption of vinyl chloride to soil were not located. Based on the 

regression equations given by Lyman et al. (1982), Sabljic (1984), and Kenaga and Goring (1980), the 

soil organic carbon adsorption coefficient (Koc) for vinyl chloride was estimated to range from 14 to 131. 

These Koc values suggest a very low sorption tendency, meaning that this compound would be highly 

mobile in soil. Thus, vinyl chloride has the potential to leach into groundwater. 

Vinyl chloride is soluble in most common organic solvents (Cowfer and Magistro 1983). In situations 

where organic solvents exist in relatively high concentrations (e.g., landfills, hazardous waste sites), 

cosolvation of vinyl chloride could have the effect of reducing its volatility, thus causing it to have even 

greater mobility than indicated by estimated Koc values. 

Vinyl chloride's small octanol/water partition coefficient (log Kow=1.23) indicates that the potential for 

bioconcentration in aquatic organisms is low (EPA 1982a). Using a log Kow of 1.23 and a regression 

derived equation (Meylan et al. 1999), the bioconcentration factor (BCF) for vinyl chloride is estimated 

as 3. Freitag et al. (1985) measured BCFs in algae, fish, and activated sludge. The BCFs for algae, fish, 

and activated sludge were 40, <10, and 1,100, respectively. The very low value for fish, in comparison to 

the algae and activated sludge, may suggest a detoxification process in more highly developed organisms 

such as fish. Lu et al. (1977) examined the bioaccumulation of 14C-vinyl chloride in a closed model 

aquatic ecosystem over a 3-day period. The high volatility of vinyl chloride minimized any potential 

bioaccumulation. Relatively low tissue concentrations found in fish suggested that vinyl chloride is not 

biomagnified in aquatic food chains to any substantial degree. 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

Reaction of gaseous vinyl chloride with photochemically generated hydroxyl radicals is predicted to be 

the primary degradation mechanism for this compound in the atmosphere (Cox et al. 1974; Howard 1976; 
VINYL CHLORIDE 179 

6. POTENTIAL FOR HUMAN EXPOSURE 

Perry et al. 1977). The rate constant for this reaction has been measured as 6.96x10-12 cm3/molec-second 

(Kwok and Atkinson 1994). This rate constant corresponds to an atmospheric half-life of about 18 hours 

assuming a hydroxyl radical concentration of 1.5x106 molecules/cm3

. Products of this reaction are 

hydrochloric acid, formaldehyde, formyl chloride, carbon monoxide, carbon dioxide, chloroacetaldehyde, 

acetylene, chloroethylene epoxide, chloroacetylchloranil, and water (Müller and Korte 1977; Woldbaek 

and Klaboe 1978). Under conditions of photochemical smog, the half-life of vinyl chloride would be 

reduced to a few hours (Carassiti et al. 1977). Reaction with ozone, nitrate radicals and direct photolysis 

are less important degradation mechanisms of vinyl chloride in the atmosphere (EPA 1976a, 1985c; 

Zhang et al. 1983). Vinyl chloride in the gas phase does not absorb light of wavelengths above 220 nm 

(EPA 1976a). Since atmospheric ozone blocks almost all sunlight with wavelengths <295 nm, direct 

photolysis is likely to occur very slowly, if at all, in the atmosphere (EPA 1976a). 

6.3.2.2 Water 

The primary removal process for vinyl chloride from surface waters is volatilization into the atmosphere. 

Vinyl chloride in water does not absorb ultraviolet radiation above 218 nm; therefore, direct photolysis in 

the aquatic environment is expected to occur very slowly, if at all (EPA 1976a). In sunlit surface waters 

containing photosensitizers, such as humic materials, photodegradation may be more rapid. If so, in some 

waters, sensitized photodegradation may be an important removal mechanism (EPA 1976a). Vinyl 

chloride decomposed rapidly when irradiated with ultraviolet light in the presence of acetone, a high 

energy triplet sensitizer, or hydrogen peroxide, a free radical source (EPA 1976a). 

The hydrolytic half-life of vinyl chloride has been estimated to be <10 years at 25 °C (EPA 1976a). Since 

the volatilization rate of vinyl chloride is much more rapid than the predicted rate of hydrolysis, 

hydrolysis is not a significant aquatic fate (EPA 1976a, 1979d). Vinyl chloride is not oxidized chemically 

by reaction with photochemically generated molecular oxygen in natural water systems (EPA 1976a). 

Experiments carried out at 20 mg/L vinyl chloride in water saturated with molecular oxygen at elevated 

temperatures showed that, after 12 hours at 85 °C, no degradation of vinyl chloride was observed. At 

temperatures and oxygen concentrations in natural waters, therefore, vinyl chloride is not expected to 

degrade by molecular oxygen at a significant rate (EPA 1976a). 

EPA (1977) observed no change in the biochemical oxygen demand in raw sewage seed (used as a 

microbial inoculum) and raw sewage seed plus vinyl chloride at 20 °C over a 25-day period. The study 
VINYL CHLORIDE 180 

6. POTENTIAL FOR HUMAN EXPOSURE 

authors interpreted this to mean that no biodegradation of vinyl chloride occurred. However, more recent 

data has shown that vinyl chloride can undergo microbial degradation under aerobic conditions. 

Rhodococcus sp. strains SM-1 and Wrink, which were isolated from a trichloroethylene-degrading 

bacterial mixture, and Rhodococcus rhodochrous ATCC 21197 were shown to degrade >99.9% of vinyl 

chloride within 7 days (Malachowsky et al. 1994). No significant differences in the amount of vinyl 

chloride degraded were found among the three organisms. The majority (66–83%) of the labeled carbon 

was metabolized to carbon dioxide (CO2). 

Vinyl chloride (1 ppm) was rapidly degraded under aerobic conditions in a laboratory study that used soilwater microcosms from aquifer material without the addition of other nutrients, such as nitrogen and 

phosphorus (Davis and Carpenter 1990). About 25% of the vinyl chloride was degraded after 1 week and 

more than 99% was degraded after 108 days. Sixty-five percent of labeled vinyl chloride was recovered 

as 14CO2 after 108 days, demonstrating the extent of the mineralization. 

Rhodococcus sp. Strain SM-1, a member of the order Actinomycetales, obtained from a trichloroethylenedegrading consortium was found to mineralize vinyl chloride to CO2 by using propane as an energy 

source during growth experiments or cell suspension experiments (Phelps et al. 1991). Vinyl chloride 

concentrations decreased by more than 90%; growth cultures and cell suspensions incorporated about 

10% of the transformed vinyl chloride into biomass (Phelps et al. 1991). Mycobacterium vaccae JOB5 

degraded 100% of vinyl chloride in a 2-hour incubation (Wackett et al. 1989). 

Degradation of vinyl chloride generally occurs slowly in anaerobic groundwater and sediment; however, 

under methanogenic or Fe(III) reducing conditions anaerobic degradation occurs more rapidly. Vinyl 

chloride was mineralized approximately 34% in 84 hours in anaerobic aquifer microcosms supplemented 

with Fe(III) and held under Fe(III) reducing conditions (Bradley and Chapelle 1996). 

6.3.2.3 Sediment and Soil 

Most vinyl chloride present on soil surfaces will volatilize to the atmosphere. Vinyl chloride is also 

mobile in soil and susceptible to leaching (Lyman et al. 1982). The presence of other organic solvents, 

such as those found at hazardous waste sites, may affect the mobility of the substance in the soil (Cowfer 

and Magistro 1983). Photodegradation on the surface of soils is possible since sensitized 
VINYL CHLORIDE 181 

6. POTENTIAL FOR HUMAN EXPOSURE 

photodegradation in water occurs; however, this is not expected to be an important environmental fate 

process for vinyl chloride in most soils and sediment. 

Several laboratory studies have indicated that both aerobic and anaerobic biodegradation of vinyl chloride 

can occur in soils and aquifer materials via a number of mechanisms (Barrio-Lage et al. 1990; Castro et 

al. 1992a, 1992b; Davis and Carpenter 1990), although these degradation processes were generally slow. 

More recently, Nelson et al. (1993) investigated methanotrophic degradation of vinyl chloride using a 

laboratory-scale, methanotrophic, attached-film, expanded-bed bioreactor. They found that this technique 

is an efficient way to degrade vinyl chloride, with the removal efficiency >90%. Under methanotrophic 

conditions, vinyl chloride was mineralized between 5 and 44% over 37 days using creek bed sediment 

microcosms obtained from a naval station near Jacksonville, Florida (Bradley and Chapelle 1997). 

Slightly higher mineralization rates were observed under Fe(III) reducing conditions. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to vinyl chloride depends in part on the reliability 

of supporting analytical data from environmental samples and biological specimens. Concentrations of 

vinyl chloride in unpolluted atmospheres and in pristine surface waters are often so low as to be near the 

limits of current analytical methods. In reviewing data on vinyl chloride levels monitored or estimated in 

the environment, it should also be noted that the amount of chemical identified analytically is not 

necessarily equivalent to the amount that is bioavailable. The analytical methods available for monitoring 

vinyl chloride in a variety of environmental media are detailed in Chapter 7. 

6.4.1 Air 

Air in rural/remote and urban/suburban areas of the United States typically contains very low or no 

detectable amounts of vinyl chloride (EPA 1982f; Grimsrud and Rasmussen 1975a, 1975b; Harkov et al. 

1984; Pratt et al. 2000; Stephens et al. 1986; Wallace et al. 1984). The mean concentration of vinyl 

chloride from 3,650 samples monitored in the state of Minnesota over an 8-year study period (1991– 

1998) was 0.01 μg/m3

 (0.0038 ppb), with a maximum observed value of 1.77 μg/m3 (0.672 ppb) (Pratt et 

al. 2000). Sampling was performed at 25 different sites across the state with sampling sites chosen to 

measure concentrations of pollutants near specific point sources, or to collect baseline data near the 

Minneapolis-St. Paul area. Vinyl chloride levels in urban air were summarized in the EPA 1997 Urban 
VINYL CHLORIDE 182 

6. POTENTIAL FOR HUMAN EXPOSURE 

Air Toxics Monitoring Program, a study designed to characterize the magnitude and composition of 

potentially toxic air pollution in, or near, urban areas (EPA 1999). These data are summarized in 

Table 6-3. In general, few detections of vinyl chloride were observed in most of the cities sampled, and 

when positive detections were measured, the levels were below 1 ppb (EPA 1999). 

Limited monitoring data indicate that in areas near vinyl chloride and PVC manufacturing facilities, the 

concentration of vinyl chloride in air typically ranges from trace levels to 105 μg/m3

 (40 ppb) (EPA 

1979a, 1982f; Gordon and Meeks 1977) but have been shown to exceed 2,600 μg/m3

 (1,000 ppb) 

(Fishbein 1979). More recent monitoring data sampled at the fenceline of vinyl chloride production 

facilities suggest that levels around these sites are in the low ppb range. Vinyl chloride levels ranged 

from below the detection limits of 0.16 μg/m3

 (0.06 ppb) to approximately 90 μg/m3 (34 ppb) at one site, 

and were <0.16 μg/m3

 (0.06 ppb) to 26 μg/m3 (10 ppb) at a second facility (OECD 2001). 

Elevated levels of vinyl chloride may also be found in the vicinity of hazardous waste sites and municipal 

landfills. Concentrations ranging from below detection limits to 5–8 μg/m3

 (2–3 ppb) have been 

measured in the air above some landfills (Baker and Mackay 1985; Stephens et al. 1986). Homes near 

one hazardous waste site in southern California were found to contain levels as high as 1,040 μg/m3 

(400 ppb) (Stephens et al. 1986) and homes near another site contained between 1 and 9 ppb (Miller and 

Beizer 1985). Gaseous emissions from 20 Class II (nontoxic) landfills in southern California were 

analyzed for vinyl chloride (Wood and Porter 1987). Vinyl chloride was found in emissions from 85% of 

the landfills tested, and concentrations >2,600 μg/m3

 (1 ppm) were detected in more than half of the 

landfill emissions. The concentrations of vinyl chloride measured in this study ranged from 0.624 to 

114.4 mg/m3

 (240–44,100 ppb). Based on their observations, the study authors concluded that the 

presence of vinyl chloride at these landfills was due to either illegal disposal or in situ generation by the 

degradation of chlorinated solvents by bacteria and other microbes (Wood and Porter 1987). Ambient air 

monitoring data downwind from the Eastview Road Landfill located in Guelph, Ontario indicated the 

presence of vinyl chloride at low levels. Concentrations ranging from 0.0023 to 0.042 μg/m3

 (0.0009– 

0.016 ppb) were observed downwind from this facility during sampling conducted in May and June 1993 

(Chadder 1994). 
VINYL CHLORIDE 183 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-3. Vinyl Chloride Levels in Ambient Urban Air 

Prevalence of vinyl Range of concentrations Central tendency and variability of 

chloride in air (ppb) measured concentrations 

Number Percent of 

of non- positive Arithmetic Geometric 

detects detections Lowest Highest Median mean mean SD CV 

Baton Rouge, Louisiana 

20 33 ND 0.52 0.03 0.07 0.05 0.10 1.39 

Garyville, Louisiana 
 

29 3 ND 0.21 0.03 0.04 0.03 0.03 0.83 
 

Hahnville, Louisiana 
 

32 3 ND 0.11 0.03 0.03 0.03 0.01 0.41 
 

Brattleboro, Vermont 
 

31 0 ND ND – – – – – 
 

Burlington, Vermont 
 

31 0 ND ND – – – – – 
 

Rutland, Vermont 
 

30 0 ND ND – – – – – 
 

Underhill, Vermont 
 

31 0 ND ND – – – – – 
 

Winooski, Vermont 
 

10 0 ND ND – – – – – 
 

Camden, New Jersey
 

31 0 ND ND – – – – – 
 

El Paso, Texas
 

30 0 ND ND – – – – – 
 

North Little Rock, Arkansas
 

32 0 ND ND – – – – – 
 

Texarkana, Arkansas 
 

30 0 ND ND – – – – – 
 

CV = coefficient of variance; ND = not detected; SD = standard deviation 

Source: EPA 1999 
VINYL CHLORIDE 184 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.2 Water 

Vinyl chloride has been detected at varying concentrations in surface water, groundwater, and drinking 

water throughout the United States. Concentrations of vinyl chloride in drinking water wells and surface 

water in New York State were found to be 50 μg/L (0.05 ppm) and 10 μg/L (0.01 ppm), respectively 

(Burmaster 1982). Monitoring studies in nine states have identified concentrations as high as 380 μg/L 

(0.38 ppm) in groundwater (Dyksen and Hess 1982). Vinyl chloride levels ranged from below the 

detection limit (0.64 μg/L) to 55.6 μg/L (3.35 μg/L mean value) in river water sampled near vinyl chloride 

and PVC manufacturing facilities in Osaka, Japan (Yamamoto et al. 2001). 

Levels of vinyl chloride in groundwater in the United States were determined during the 1982 EPA 

Groundwater Supply Survey (Westrick et al. 1984). Water supplies from 945 sites throughout the United 

States were studied. Vinyl chloride was positively identified in only 0.74% of the 945 groundwater 

supplies (detection limit 0.001 ppm). It was reported that 0.5% of 186 random sample sites and 3.8% of 

158 nonrandom sample sites contained detectable levels of vinyl chloride. The maximum concentrations 

at the random and nonrandom sites were 1.1 μg/L (0.0011 ppm) and 8.4 μg/L (0.0084 ppm), respectively 

(Westrick et al. 1984). Approximately half of the samples were taken from a random list of water 

systems, which were subdivided into two sets of systems—those serving fewer than 10,000 people and 

those serving more than 10,000 people. The nonrandom samples were taken from systems selected by the 

states, using groundwater sources that were likely to include volatile organic compounds in drinking 

water (Westrick et al. 1984). Other studies have reported the occurrence of vinyl chloride in groundwater 

samples collected throughout the United States at levels at or below 380 μg/L (0.38 ppm) (Cotruvo 1985; 

EPA 1982f; Goodenkauf and Atkinson 1986; Stuart 1983). In a study of three landfills located in Orange 

County, Florida, vinyl chloride was detected in water samples obtained at four out of nine wells with 

average concentrations ranging from 2.0 to 26.5 μg/L (Hallbourg et al. 1992). In a survey of 30 industrial 

sites located in Taiwan, vinyl chloride was detected in six groundwater wells at concentrations of 

100,000 (1993 sampling period) and 22,000 μg/L (1994 sampling period) (Kuo et al. 2000). 

6.4.3 Sediment and Soil 

Monitoring data for vinyl chloride in soil were not located in the available literature. 
VINYL CHLORIDE 185 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.4.4 Other Environmental Media 

In the past, vinyl chloride had been detected in various foods and bottled drinking water as a result of 

migration from PVC food wrappings and containers (Benfenati et al. 1991; Gilbert et al. 1980). Vinyl 

chloride has been found in vinegar at levels up to 98,000 μg/L (98 ppm), in edible oils at 300–1,800 μg/L 

(0.3–1.8 ppm), and in alcoholic beverages at 0.0–8,400 μg/L (0.0–8.4 ppm) when these foods were 

packaged and stored in PVC containers (Williams 1976; Williams and Miles 1975). At present, the Food 

and Drug Administration (FDA) regulates the use of PVC polymers in food packaging materials and the 

amount of residual monomer in polymers and as a result, significant reduction in the levels of vinyl 

chloride in food samples has been achieved since the early 1970s (WHO 1999). In 1986, FDA 

determined that thick-walled PVC food packaging (i.e., bottles and blister packages) was safe provided 

that the polymer contained <10 ppb vinyl chloride (McNeal et al. 2003). Since the late 1970s, 

modifications to the vinyl chloride and PVC manufacturing and production processes have greatly 

reduced the amount of residual vinyl chloride monomer in food packaging and other PVC related items. 

To determine whether the residual vinyl chloride levels in PVC containing food packages in current use 

are <10 ppb, a survey and analysis of PVC containing food packages was recently conducted (McNeal et 

al. 2003). The results showed that vinyl chloride levels found in the packages ranged from none detected 

(<1 ppb) to about 275 ppb. The package containing 275 ppb residual vinyl chloride was not a food 

contact material (McNeal et al. 2003). Data regarding the residual vinyl chloride monomer levels in food 

packaging items was summarized by Borrelli et al. (2004) and are presented in Tables 6-4 and 6-5. In 

general, most food packaging items contain nondetectable or minute quantities of residual vinyl chloride 

and most food products do not contain levels above the analytical detection limits. Dietary exposure to 

vinyl chloride from PVC packages used for food has been calculated by several agencies, and based upon 

estimated average intakes in the United Kingdom and the United States, an exposure of 

<0.0004 μg/kg/day was estimated for the late 1970s and early 1980s (WHO 1999). 

In a modeling study using liquid chromatography to simulate migration conditions of vinyl chloride from 

PVC in actual food packaging and storage, it was shown that at the very low concentrations (<1 ppm) of 

residual vinyl chloride monomer in PVC packaging material, "essentially zero" migration of the vinyl 

chloride monomer into foods occurs (Kontominas et al. 1985). Vinyl chloride levels were determined in 

Italian drinking water bottled in PVC; levels ranged from 13 to 83 parts per trillion (ppt) (mean, 48 ppt) 

(Benfenati et al. 1991). It was also determined that there was a progressive migration of vinyl chloride 

from the bottle to the water, which occurred at a rate of 1 ng/L/day (Benfenati et al. 1991). Vinyl chloride 
VINYL CHLORIDE 186 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-4. Residual Vinyl Chloride Monomer in Food and Nonfood 
 

Packaging Items from Store Shelves 
 

Package item Residual vinyl chloride monomer (ppb) 

Food packaging 

1-Gallon water jug A 4.7 

1-Gallon water jug B 5 

Mouthwash bottle 3.3 

Non-dairy creamer jar <2 

PVC meat wrap A <2 

PVC meat wrap B <2 

Saran® wrap <2 

Canola oil jug 1.7 

Vegetable oil jug 2.9 

Olive oil jug 2.4 

Olive oil bottles (n=3) 28.3 

Nonfood packaging 

PVC plumbing blister 135.4 

PVC cell phone blister 3.9 

Source: Borrelli et al. 2004 
VINYL CHLORIDE 187 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-5. Residual Vinyl Chloride Monomer in Food Products 

Food item Residual vinyl chloride monomer (ppb) 

Olive oil A ND 

Turkish olive oil B 0.6 

Vegetable oil A ND 

Vegetable oil B ND 

Mouth wash ND 

Source: Borrelli et al. 2004 
VINYL CHLORIDE 188 

6. POTENTIAL FOR HUMAN EXPOSURE 

was also detected in bottled water from Saudi Arabia packaged in PVC bottles; however, the levels were 

≤0.6 ppb (Fayad et al. 1997). 

Vinyl chloride has been detected in municipal drinking water supplies. A study by EPA (1982f) 

estimated that 12 of 11,202 public water supplies that used surface water as their primary source had 

levels of vinyl chloride between 1.0 μg/L (0.001 ppm) and 5.0 μg/L (0.005 ppm); none had levels above 

5 μg/L (0.005 ppm). Another study found that drinking water that ran through PVC pipes contained vinyl 

chloride at 1.4 μg/L (0.0014 ppm), whereas water that ran through a PVC system 9 years older contained 

0.03–0.06 μg/L (0.03–0.06 ppb) (Dressman and McFarren 1978). The amount of vinyl chloride migrating 

from rigid PVC water pipes into drinking water was directly proportional to the residual level of vinyl 

chloride in the pipe itself. In 2000, the National Sanitation Foundation (NSF), at the request of the Vinyl 

Institute, conducted a study on the levels of residual vinyl chloride monomer found in PVC pipe and 

fittings (Borelli et al. 2004). This report concluded that 86% of the PVC pipes and 88% of the fittings 

had no detectable levels (detection limit of 0.1 mg/kg) of residual vinyl chloride monomer. The average 

residual vinyl chloride monomer level for all samples (non-detects were counted as zero) were 

0.007 mg/kg for PVC pipes, and 0.03 mg/kg for fittings (Borelli et al. 2004). Under certain test 

conditions, vinyl chloride in drinking water reacts with chlorine and is converted to chloroacetaldehyde 

and chloroacetic acid (Ando and Sayato 1984). Information concerning the effect of this reaction on 

drinking water supplies that are treated with chlorine and the extent of this reaction was not stated. 

During an EPA study, detectable levels of vinyl chloride were found in indoor air samples taken from two 

of seven new 1975 model cars. Levels of vinyl chloride in indoor air in the two cars ranged from 0.4 to 

1.2 ppm (EPA 1976b). Ventilation of the car interiors led to the dissipation of vinyl chloride. The cars 

involved in the study had a high ratio of plastic to interior volume and were expected to provide worstcase concentrations for vinyl chloride in interior car air (EPA 1976b). Because of the limited nature of 

these data and the fact that this study is somewhat dated, no conclusions can be drawn regarding levels of 

vinyl chloride monomer in interior air of cars currently being produced. 

Vinyl chloride has been detected in tobacco smoke. Cigarette smoke and smoke from small cigars has 

been found to contain 5.6–27 ng vinyl chloride per cigarette (Hoffman et al. 1976). The study authors 

suggested that the inorganic chloride concentrations in the tobacco determine the amount of vinyl chloride 

formed upon combustion of tobacco and released into the smoke (Hoffman et al. 1976). 
VINYL CHLORIDE 189 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

Inhalation of ambient or workplace air containing vinyl chloride is the most likely route of exposure for 

the general population. Typical values for the average daily intake of vinyl chloride by inhalation in 

urban/suburban and rural/remote areas not near emission sources are very small, since only trace levels of 

vinyl chloride are usually found in ambient air. Assuming that the average adult intake of air is 

20 m3

/day, the average daily intake of vinyl chloride by people living in the vicinity of emission sources 

has been estimated to range from trace amounts to 2,100 μg (EPA 1979a, 1982f; Gordon and Meeks 

1977). The majority of drinking water supplies in the United States do not contain detectable levels of 

vinyl chloride (EPA 1982f; Westrik et al. 1984). Based on this conclusion, it is estimated that the average 

daily intake of vinyl chloride by ingestion of drinking water for most people in the United States is 

essentially zero (at or below 0.028 μg/kg/day [EPA 1982f]). Estimates provided by EPA (1985b) indicate 

that 0.9% of the U.S. population is exposed to levels of vinyl chloride in drinking water ≥1 μg/L, and 

0.3% of the population is exposed to levels >5 μg/L. 

NOES conducted by NIOSH from 1981 to 1983 estimated that 81,314 workers employed at 3,711 plant 

sites were potentially exposed to vinyl chloride in the United States (NOES 1990). The NOES database 

does not contain information on the frequency, concentration, or duration of exposure; the survey 

provides only estimates of workers potentially exposed to chemicals in the workplace. Employees 

involved in the handling and and processing of PVC resins are exposed to lower levels of vinyl chloride 

than employees at vinyl chloride and PVC manufacturing facilities since finished products contain only 

minute quantities of vinyl chloride present as residual monomer. Exposure is believed to occur primarily 

through inhalation with some minor absorption through the skin (Hefner et al. 1975a). Upon exposure to 

800 or 7,000 ppm of vinyl chloride vapor over a 2–2.5-hour period, 0.023–0.031% was absorbed 

dermally by monkeys (Hefner et al. 1975a). The authors concluded that significant percutaneous 

absorption is not likely to occur at relatively low concentrations (1–5 ppm) that might be encountered in 

the workplace. Workers who are involved in welding applications that use PVC pipes or other PVC 

materials may be exposed to higher levels of vinyl chloride from subsequent fumes. Airborne vinyl 

chloride levels of less than the detection limit of 0.05 ppm (0.13 mg/m3

) to 0.1 ppm (0.26 mg/m3) were 

observed during the thermal welding of PVC pipes (Williamson and Kavanaugh 1987). Table 6-6 

summarizes the level of vinyl chloride observed in five PVC manufacturing facilities located in Taiwan, 

and Table 6-7 provides the time-weighted average (TWA) exposure to workers performing various job 

tasks (Du et al. 1996). Tank suppliers, cleaners, and PVC relievers were observed to have the highest 

TWA exposure since they more often came into direct contact with vinyl chloride in these job functions. 
VINYL CHLORIDE 190 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-6. Vinyl Chloride Levels in Five Polyvinyl Chloride 
 

Manufacturing Facilities Located in Taiwan 
 

Number of Mean Median 

Sample site samples (mg/m3

) (mg/m3) Range (mg/m3

) 

Outside reaction tank 4 296.30 86.25 6.19–1009.32 

Reaction tank farm 18 13.60 9.97 0.18–110.59 

Vinyl chloride recovery 9 9.25 5.46 0.85–33.39 

Vinyl chloride shipping 3 5.98 7.38 0.85–9.71 

Vinyl chloride storage tanks 6 4.97 3.03 0.60–14.25 

Stripper 12 3.86 1.68 <LOD–18.62 

Waste water treatment 7 3.37 3.32 0.83–6.73 

Drier 11 2.62 1.55 <LOD–7.17 

Control room (inside) 6 2.15 1.48 0.57–5.13 

Control room (inside) 7 1.71 0.91 0.18–4.07 

Polyvinyl chloride warehouse 17 1.66 1.79 <LOD–5.96 

Factory perimeter 3 1.66 0.85 <LOD–3.34 

Additive preparation 6 1.61 0.78 0.57–4.07 

Administrative office 4 0.65 0.67 <LOD–1.27 

Plastic pallet making area 1 <LOD <LOD <LOD 

LOD = limit of detection (0.1259 mg/m3

) 

Source: Du et al. 1996 
VINYL CHLORIDE 191 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-7. Time-Weighted Average Exposure to Workers in Polyvinyl 
 

Chloride Manufacturing Facilities Located in Taiwan
 

Number of Mean Median 

Job description samples (mg/m3) (mg/m3) Range (mg/m3) 

Tank supplier 9 659.67 23.70 5.70–3,677.8 

Polyvinyl chloride reliever 10 153.07 47.92 1.04–825.69 

Tank cleaner

a

 14 95.57 69.15 0.36–341.88 

Vinyl chloride unloading 2 12.56 12.56 10.23–14.97 

Safety/health specialist 4 12.04 1.74 1.19–22.87 

Foreman 4 9.04 6.89 1.84–20.59 

Stripper operator 3 4.51 3.37 2.33–7.82 

Vinyl chloride recovery 5 4.38 4.48 0.88–5.93 

Control room operator 8 4.01 3.47 1.04–10.02 

Field supervisor 6 3.42 3.47 1.19–7.95 

General office personnel 4 3.34 2.56 <LOD–8.18 

Maintenance 3 2.69 1.76 0.85–5.49 

Dryer operator 6 1.84 1.48 <LOD–4.25 

Bagger and trucker 5 0.93 1.09 <LOD–1.58 

Gatekeeper 2 0.93 0.93 <LOD–1.86 

a

Tank cleaner exposure measured on a short term task lasting 15–40 minutes. 
 

LOD = limit of detection (0.1259 mg/m3) 
 

Source: Du et al. 1996 
 
VINYL CHLORIDE 192 

6. POTENTIAL FOR HUMAN EXPOSURE 

These workplace levels likely exceed current levels observed in the United States due to strict regulations 

imposed governing workplace exposure to vinyl chloride over the past 30 years. In the United States, 

vinyl chloride is an Occupational Safety and Health Administration (OSHA) regulated substance. Current 

OSHA regulations impose a permissible exposure limit (PEL) of 1.0 ppm (2.6 mg/m3

) averaged over an 

8-hour period or a short-term exposure of no more than 5 ppm over a 15-minute period (Cowfer and 

Gorensek 1997). Where concentrations cannot be lowered below the PEL of 1.0 ppm, employers must 

create an area with controlled access and a respirator program conforming to OSHA standards. 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Children are likely to be exposed to vinyl chloride via the same pathways that affect non-occupationally 

exposed adults; namely inhalation of ambient air and ingestion of food items or drinking water that may 

contain low levels of vinyl chloride. Children’s plastic products such as bath toys, squeeze toys, and dolls 

are often made from PVC. Chewing or sucking on these toys has the potential to release any 

unpolymerized vinyl chloride from the object; however, no quantitative data exists regarding this 

potential exposure route and it is unlikely that there are significant levels of vinyl chloride in PVC-based 

toys. Vinyl chloride has not been detected in samples of human maternal adipose tissue, maternal blood, 

cord blood, or breast milk. No body burden studies that quantitatively or qualitatively identified vinyl 

chloride in children were located. 
VINYL CHLORIDE 193 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Individuals located near or downwind of production facilities, hazardous waste disposal sites, and 

landfills may be exposed to atmospheric levels of vinyl chloride higher than ambient background levels. 

Concentrations around 5–8 μg/m3

 (0.002–0.003 ppm) have been measured in the air above some landfills 

(Baker and Mackay 1985; Stephens et al. 1986). Homes near one hazardous waste site in southern 

California were found to contain levels as high as 1,040 μg/m3

 (0.4 ppm) of vinyl chloride (Stephens et al. 

1986) and homes near another site contained levels between 2.6 and 23.4 μg/m3

 (0.001–0.009 ppm) 

(Miller and Beizer 1985). These concentrations are several times greater than ambient air levels that are 

generally <1 μg/m3

 (Pratt et al. 2000). For specific levels associated with health effects, see Section 3.4. 

Individuals living near hazardous waste sites and landfills may also be exposed to vinyl chloride in their 

drinking water. Workers involved in the production or use of vinyl chloride are likely to be exposed to 

levels greater than the levels that the general public is exposed to (see Section 6.5). 

Cigarette smoke and smoke from small cigars have been found to contain vinyl chloride at levels of 5.6– 

27 ng per cigarette (Hoffman et al. 1976). Therefore, people who smoke heavily may be potentially 

exposed to higher levels of vinyl chloride than nonsmokers. 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the adverse health effects of vinyl chloride is available. Where adequate 

information is not available, ATSDR, in conjunction with NTP, is required to ensure the initiation of a 

program of research designed to determine the adverse health effects (and techniques for developing 

methods to determine such health effects) of vinyl chloride. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 
VINYL CHLORIDE 194 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of vinyl chloride are 

sufficiently well characterized to permit estimation of its environmental fate (Amoore and Hautala 1983; 

Cowfer and Magistro 1983; EPA 1985b; Fire 1986; HSDB 2005; IARC 1979; Lewis 1996; Lyman et al. 

1982). 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency Planning 

and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit 

substance release and off-site transfer information to the EPA. The Toxics Release Inventory (TRI03 

2005), which contains this information for 2003, became available in May of 2005. This database will be 

updated yearly and should provide a list of industrial production facilities and emissions. 

Vinyl chloride is released primarily to the atmosphere via emissions from vinyl chloride and PVC 

manufacturing facilities (Hartmans et al. 1985; SRI 1990a, 1990b, 1993, 1994; TRI03 2005). The risk of 

exposure to vinyl chloride is highest for workers in the plastics industry and populations living near 

industrial areas or hazardous waste sites. Current production, use, and manufacturing methods are well 

described in the literature (Cowfer and Magistro 1985; HSDB 1996; IARC 1979; SRI 1990a, 1990b, 

1993, 1994; TRI03 2005; USITC 1994). More current information on releases and disposal methods 

might assist in estimating potential exposures to vinyl chloride, particularly for populations living near 

hazardous waste sites. 

Environmental Fate. Vinyl chloride primarily partitions to the air where it is degraded relatively 

quickly by photochemically produced hydroxyl radicals (Kwok and Atkinson 1994). It is removed from 

surface water and soils mainly by volatilization and photodegradation (EPA 1976a). Biodegradation and 

hydrolysis also occur (Barrio-Lage et al. 1990; Castro et al. 1992a, 1992b; Davis and Carpenter 1990; 

EPA 1976a), but these reactions are generally slow as compared to the volatilization rate. More 

information regarding the transformation and degradation in soil and water would be helpful in defining 

the potential pathways for human exposure. 

Bioavailability from Environmental Media. Vinyl chloride can be absorbed following inhalation 

(Bolt et al. 1977; Krajewski et al. 1980; Withey 1976), oral (Feron et al. 1981; Watanabe et al. 1976a; 

Withey 1976), and to a much lesser extent, dermal exposure (Hefner et al. 1975a). These routes of 

exposure may be of concern to humans because of the potential of vinyl chloride to contaminate air 
VINYL CHLORIDE 195 

6. POTENTIAL FOR HUMAN EXPOSURE 

(Baker and MacKay 1985; EPA 1979a; Fishbein 1979; Gordon and Meeks 1977; Stephens et al. 1986; 

Wood and Porter 1987), water (Burmaster 1982; Cotruvo 1985; Dyksen and Hess 1982; Goodenkauf and 

Atkinson 1986; Stuart 1983; Westrick et al. 1984), and food (Gilbert et al. 1980; Williams 1976; Williams 

and Miles 1975). Information regarding the bioavailability from ingestion and dermal contact of 

contaminated soils would be helpful, particularly for populations living near hazardous waste sites, 

although vinyl chloride is not believed to be considerably absorbed through skin. 

Food Chain Bioaccumulation. Vinyl chloride can bioconcentrate to a limited extent in aquatic 

organisms (EPA 1982a; Freitag et al. 1985). Biomagnification of vinyl chloride in terrestrial and aquatic 

food chains does not appear to be important because of its high volatility and the fact that it is readily 

metabolized by higher-trophic-level organisms (Freitag et al. 1985; Lu et al. 1977). No data were located 

regarding biomagnification in terrestrial foodchains. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of vinyl 

chloride in contaminated media at hazardous waste sites are needed so that the information obtained on 

levels of vinyl chloride in the environment can be used in combination with the known body burden of 

vinyl chloride to assess the potential risk of adverse health effects in populations living in the vicinity of 

hazardous waste sites. 

Vinyl chloride has been detected in air (Baker and Mackay 1985; EPA 1979a; Fishbein 1979; Gordon and 

Meeks 1977; Stephens et al. 1986; Wood and Porter 1987), water (Burmaster 1982; Cotruvo 1985; 

Dyksen and Hess 1982; Goodenkauf and Atkinson 1986; Stuart 1983; Westrick et al. 1984), sediment 

(Wang et al. 1985), and food (Gilbert et al. 1980; Williams 1976; Williams and Miles 1975). Intake data 

for the general population from the various media are available (EPA 1979a, 1985b; Gordon and Meeks 

1977; Westrick et al. 1984). Data on levels of vinyl chloride in soils are needed. Site-specific data on 

concentrations of vinyl chloride in air, soil, and water would be helpful in estimating the risk of exposure 

for populations living in the vicinity of hazardous waste sites. Also, current data on the extent of release 

(if any) of vinyl chloride from PVC pipes and from car interiors are needed to estimate the risk of 

exposure of the general population. 

Exposure Levels in Humans. Vinyl chloride has been detected in exhaled breath of humans 

(Baretta et al. 1969; Conkle et al. 1975), but no other body burden studies are available. More 

information on exposure levels for populations living in the vicinity of hazardous waste sites would be 

helpful. This information is necessary for assessing the need to conduct health studies on these 
VINYL CHLORIDE 196 

6. POTENTIAL FOR HUMAN EXPOSURE 

populations. It is noted that it is difficult to directly analyze for vinyl chloride in humans, which may 

limit the practicality of conducting these tests. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. No data exist regarding the levels of vinyl chloride in children. Children 

are exposed to vinyl chloride by the same pathways that affect adults; inhalation of ambient air and the 

ingestion of foods or drinking water. It would be useful to determine if there exists any free 

unpolymerized vinyl chloride that can be extracted from PVC children’s toys. Child health data needs 

relating to susceptibility are discussed in Section 3.12.2, Identification of Data Needs: Children’s 

Susceptibility. 

Exposure Registries. No exposure registries for vinyl chloride were located. This substance is not 

currently one of the compounds for which a subregistry has been established in the National Exposure 

Registry. The substance will be considered in the future when chemical selection is made for 

subregistries to be established. The information that is amassed in the National Exposure Registry 

facilitates the epidemiological research needed to assess adverse health outcomes that may be related to 

exposure to this substance. 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2005) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. 

Josse Fabien and Zhou Rongnong of the University of Marquette (Milwaukee, Wisconsin) are attempting 

to characterize and design polymer-coated chemical sensors for the direct, rapid, in-situ monitoring of 

vinyl chloride and other hazardous constituents in water. Karla Thrall (Oregon Health and Science 

University) is studying the potential for human exposure to vinyl chloride and other VOC near Superfund 

sites. Exposure assessment studies will be conducted with volunteers using a novel real-time breath 

analysis system to determine the uptake of any of the nine potential contaminants of study from tap water 

by each of three routes: inhalation, ingestion, and dermal contact. 
VINYL CHLORIDE 197 

7. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring vinyl chloride, its metabolites, and other biomarkers of exposure and effect 

to vinyl chloride. The intent is not to provide an exhaustive list of analytical methods. Rather, the 

intention is to identify well-established methods that are used as the standard methods of analysis. Many 

of the analytical methods used for environmental samples are the methods approved by federal agencies 

and organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). 

Other methods presented in this chapter are those that are approved by groups such as the Association of 

Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). 

Additionally, analytical methods are included that modify previously used methods to obtain lower 

detection limits and/or to improve accuracy and precision. 

7.1 BIOLOGICAL MATERIALS 

The analytical method used to analyze for the presence of vinyl chloride in biological samples is 

separation by gas chromatography (GC) combined with detection by mass spectrometry (MS), flame 

ionization detector (FID), or electron capture detector (ECD). Vinyl chloride and/or its metabolite, 

thiodiglycolic acid, have been detected in breath, urine, blood, and tissues. Breath samples can be 

concentrated by cryogenic trapping. The two methods most commonly used to prepare liquid and solid 

samples are concentration by a purge-and-trap technique or headspace analysis. Concentration not only 

increases the sensitivity but, also in certain instances, may decrease the sample separation time prior to 

quantitation. Details of commonly used analytical methods for several types of biological samples are 

presented in Table 7-1. 

Vinyl chloride was determined in exhaled air by concentration with a multistage cryogenic trapping 

system followed by thermal desorption using GC/FID, GC/ECD, and GC/MS (Conkle et al. 1975). 

Sensitivity is in the low-ppb range. The authors of this study noted that the reproducibility of the 

subject/sampling system was inconclusive; a larger experimental population is needed for its 

demonstration. The quantitative data reflected considerable scatter, apparently indicating the variability 

of the biological system and the trace amounts of the compound. The additional requirement for longterm coupling (30–60 minutes) of the sampling system to the subject probably limits the method to 

industrial health applications, with relatively robust subjects (Conkle et al. 1975). Baretta et al. (1969) 
VINYL CHLORIDE 198 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining Vinyl Chloride in 
 

Biological Samples 
 

Sample 

Sample Analytical detection Percent 

matrix Preparation method method limit recovery Reference 

Breath Breath collected in pipets 

lined with Saran®

 film; 

GC/FID NR NR Baretta et al. 1969 

direct injection into gas 

chromatograph 

Breath Cyrogenic trapping of GC/FID, NR NR Conkle et al. 1975 

expired air; thermal GC/ECD, and 

desorption into gas GC/MS 

chromatograph 

Urine Acidified and desiccated GC/MS 50 ng/mL NR Müller et al. 1979 

overnight; add methanol; 

derivatize with 

diazamethane; add ionexchange resin 

Urine Internal standard added to GC/FID, GC/MS 10 mg/L NR Draminski and 

urine; acidification and Trojanowska 1981 

ethyl acetate extraction; 

evaporation of solvent; 

addition of 

N-trimethylsilyldiethylamine in pyridine (1:1); 

injection into gas 

chromatograph 

Blood and Extraction in ethanol-water GC/FID 5 ng/mL 75–79% Zuccato et al. 1979 

tissues mixture; incubation, blood 

injection into gas 

chromatograph 

Tissue preparation also 30 ng/g 76–92% 

includes freezing and tissue 

homogenization before the 

extraction procedure 

GC/ECD = gas chromatography/electron capture detector; GC/FID = gas chromatography/flame ionization detector; 

GC/MS = gas chromatography/mass spectrometry; NR = not reported 
VINYL CHLORIDE 199 

7. ANALYTICAL METHODS 

monitored exposure to vinyl chloride by breath analysis. The breath samples were collected in pipets 

with plastic caps lined with six layers of Saran film identical to that used for the construction of Saran air 

sampling bags. Aliquots were drawn from the pipets and injected directly into a gas chromatograph 

equipped with FID. One limitation of this method is its reduced ability to detect vinyl chloride when air 

concentrations in the workplace are below 50 ppm. 

Vinyl chloride has been measured in rat blood and tissues using headspace GC/FID (Zuccato et al. 1979). 

In headspace analysis, the gaseous layer above the sample is injected into the gas chromatograph. Sample 

preparation steps for rat blood and tissues involve extraction in an ethanol-water mixture, incubation, and 

direct injection into the gas chromatograph. Sample preparation for tissues includes an extra step 

involving freezing and homogenization before the extraction procedure. The recovery ranged from about 

75 to 92%. The method is sensitive to 5 ng/mL vinyl chloride in blood and 30 ng/g in tissues. 

Müller et al. (1979) employed GC/MS as a selective biomonitoring method for the quantitative 

measurement of thiodiglycolic acid, a urinary metabolite of vinyl chloride. They reported a sensitivity of 

50 ng/mL. Precision was generally good. These investigators noted that some thiodiglycolic acid has 

been found in supposedly unexposed subjects. Therefore, exposure to low levels of vinyl chloride could 

be masked by background metabolic levels within normal limits. This may limit the application of 

biological monitoring for the measurement of vinyl chloride following low-level exposure (Müller et al. 

1979; van Sittert and de Jong 1985). In a study by Jedrychowski et al. (1984), urinary excretion of 

thiodiglycolic acid was determined using GC/FID. The urine was extracted twice with ethyl acetate prior 

to analysis. No recovery data were given for this method. 

7.2 ENVIRONMENTAL SAMPLES 

Analysis of environmental samples is similar to that of biological samples. The most common methods 

used to detect vinyl chloride in environmental samples are GC/MS, GC/ECD, and GC/FID. 

Concentration of samples is usually done by sorption on solid sorbent for air and by the purge-and-trap 

method for liquid and solid matrices. Alternatively, headspace above liquid and solid samples may be 

analyzed without preconcentration. Details of commonly used analytical methods for several types of 

environmental samples are presented in Table 7-2. 
VINYL CHLORIDE 200 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Vinyl Chloride in 
 

Environmental Samples 
 

Sample 

Analytical detection Percent 

Sample matrix Preparation method method limit recovery Reference 

Occupational air Vinyl chloride in air 

adsorbed in activated 

GC/FID 0.04 μg per 94% at 1– 

sample 64 mg/m3 

NIOSH 1994a 

carbon trap and desorbed (0.00039– 

by carbon disulfide 0.025 ppb) 

Ambient indoor Air containing vinyl chloride GC/FID 5 ppb NR 	 IARC 1978 

and outdoor air passed through activated 

carbon trap and desorbed 

by dichloromethane or 

carbon 

Air Adsorption onTenax®

-GC 

or SKC®

 Carbon, then 

GC/MS 0.33 ppb NR 	 Krost et al. 

1982 

thermal desorption 

Air Air prefiltered by Na2S2O3­ GC/FID, 0.005 ppb NR Harkov et al. 

treated glass fiber filter was GC/MS, 1983, 1984 

passed through spherocarb GC/ECF 

adsorbent cartridge and 

thermally desorbed 

Automobile Exhaust samples contained GC/FID 0.02 ppm NR 	 Hasanen et al. 

exhaust in aluminized plastic bags 1979 

Air Trapped in cold Tenax®

-GC GC/FID NR 89.6% at Ives 1975 

trap; thermal desorption 6 ppb; 100% 

at 60 ppb 

Air Sample collected in GC/ECD 0.01 ppb NR 	 Harsch et al. 

pressurized canister is 1979; 

passed through a freezeout Rasmussen et 

loop and subsequently al. 1977 

heated 

Air Sample collected in GC/FID 0.4 ppb NR 	 McMurray and 

polyester-coated plastic Tarr 1978 

bags concentrated by 

freezeout and subsequently 

heated 

Drinking water Samples collected in serum GC/HSD, NR NR Dressman and 

reaction bottles; purge and GC/MS McFarren 1978 

trap technique 

Tenax®

-GC; thermal 

Drinking water Purge and trap in 

and waste water 

GC/HSD, 

GC/MS (EPA 

0.18 ppb 

(HSD) 

102% at 0.8– 

32.3 ppb 

APHA 1985; 

EPA 1982d 

desorption Methods 601 

and 624) 
VINYL CHLORIDE 201 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Vinyl Chloride in 
 

Environmental Samples 
 

Sample 

Analytical detection Percent 

Sample matrix Preparation method method limit recovery Reference 

Groundwater, Purge at 45 °C and trap in 

liquid and solid Tenax®

-GC; thermal 

matrices desorption 

Water Purge into CarbosieveTM S 

III; desorption with CS2 and 

bromine derivation 

Drinking water 	 Purge and trap in 

Tenax®

-GC; thermal 

desorption 

Migration of 	 Small section put in water 

monomer into	 in sealed serum vial for a 

drinking water 	 number of days at 20 °C; 

from PVC pipes	 solution directly injected 

into gas chromatograph 

Water 	 Sample ins sealed vial is 

equilibrated at constant 

temperature; headspace 

gas injected into gas 

chromatograph 

Landfill gas 	 Gas from landfill sites 

sampled by PTFE tubing 

inside drive-in piezometers 

was adsorbed in Tenax®

­

GC or Porapak®

, a sorbent; 

trapped sample desorbed 

and concentrated in liquid 

N2-cooled loop and flash 

desorbed 

Sediment and 	 Homogeneous sample 

oyster 	 mixed with water and vinyl 

chloride purged into a 

closed loop injected into 

gas chromatograph 

Landfill gas 	 Sample collected in 2-L 

evacuated glass bulb; gas 

directly injected into gas 

chromatograph 

GC/HSD (EPA 

Method 8010) 

GC/ECD 

GC/Hall 

detector, 

GC/PID (EPA 

Methods 502.2 

and 524.2) 

GC/FID 

GC/FID 

GC/MS 

GC/ECD 

GC/FID 

0.18 ppb 	 102% at EPA 1982e 

0.82– 

32.3 ppb 

0.0004 ppb 98.9% at 	 Wittsiepe et al. 

0.00625– 1993 

62.5 ppb 

0.04 ppb 100–119% at Reding 1987 

(Hall 5–10 ppb 

detector); 

0.02 ppb 

(PID) 

NR NR Ando and 

Sayato 1984 

<1 ppb 	 NR IARC 1978 

0.04–	 NR Young and 

0.8 ppm 	 Parker 1984 

2 ng/g NR Wang et al. 
 

(sediment); 1985 
 

4 ng/g 
 

(oyster) 
 

NR NR 	 Wood and 

Porter 1987 
VINYL CHLORIDE 202 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining Vinyl Chloride in 
 

Environmental Samples 
 

Sample 

Analytical detection Percent 

Sample matrix Preparation method method limit recovery Reference 

Food (orange Sample sealed in vials and GC/FID NR NR Chudy and 

drink, wine, olive equilibrated at 40 °C for Crosby 1977 

oil) 2 hours; injected into gas 

chromatograph 

Foodstuffs 	 Sample sealed in vials and GC/FID 1–5 ppb NR IARC 1978 

equilibrated at 40 °C for a 

minimum of 2 hours; 

headspace gas injected 

into gas chromatograph 

CS2 = carbon disulfide; EPA = Environmental Protection Agency; GC/ECD = gas chromatography/electron capture 

detector; GC/FID = gas chromatography/flame ionization detector; GC/HSD = gas chromatography/halogen specific 

detector; GC/MS = gas chromatography/mass spectrometry; GC/PID = gas chromatography/photoionization 

detector; HSD = halogen specific detector; N2 = nitrogen; Na2S2O3 = sodium thiosulfate; NR = not reported; 

PID = photoionization detector; PTFE = polytetrafluorethylene; PVC = polyvinyl chloride 
VINYL CHLORIDE 203 

7. ANALYTICAL METHODS 

The primary method of analyzing vinyl chloride in air is GC combined with either MS, ECD, or FID. Air 

samples are usually pumped through a sample collection column with Tenax-GC, coconut activated 

charcoal, or spherocarb (a carbon molecular sieve material) as the most common adsorbents. Several 

authors have noted that Tenax-GC displays poor retention for vinyl chloride when the compound is 

present in the very low-ppb range (Bozzelli and Kebbekus 1979; Krost et al. 1982; McMurry and Tarr 

1978). Vinyl chloride is thermally desorbed from the collection column and concentrated on a cryogenic 

trapping column located on the gas chromatograph. Vapors are heat-released from the trapping column 

directly to the gas chromatograph (Bozzelli and Kabbekus 1979; Krost et al. 1982). Grab samples of air 

can also be obtained and preconcentrated on a cryogenic column (Rasmussen et al. 1977). The limit of 

detection for GC/MS and GC/ECD is in the sub-ppb range (Bozzelli and Kebbekus 1979; Harsch et al. 

1979; Krost et al. 1982; Rasmussen et al. 1977). Accuracy is generally good (Bozzelli and Kebbekus 

1979). With careful technique, precision is adequate, ranging from 5 to 20% (Bozzelli and Kebbekus 

1979; McMurray and Tarr 1978). 

Trace amounts of vinyl chloride in air and water were detected employing GC/ECD after derivatization to 

1,2-dibromochloroethane (Wittisiepe et al. 1990, 1993). Air samples were taken by drawing a known 

volume directly through an ice-cooled adsorption tube. Water samples were purged with an inert gas 

before being drawn through the adsorption tube. The tubes were eluted with carbon disulfide, and the 

vinyl chloride was derivatized with bromine water to form 1,2-dibromochloroethane. This derivatization 

technique is used for enhancement of sensitivity with GC/ECD. The derivative was determined by 

capillary GC with ECD. The detection limits for air and water samples are 50 ng/m3

 and 0.4 ng/L 

(0.4 parts per trillion), respectively. Results from recovery experiments with dosed water indicated that 

accuracy was good. 

Vinyl chloride can be detected in drinking water, groundwater, waste water, and leachate from solid 

waste. Analysis of vinyl chloride is done by purge-and-trap or headspace GC. The primary analytical 

method is separation by GC combined with MS, ECD, FID, Hall's electrolytic conductivity detector 

(HECD), or another type of halogen specific detector (HSD). In most methods, vinyl chloride is liberated 

from the liquid matrix by purging with an inert gas and concentrated by trapping on a suitable solid 

sorbent. Vinyl chloride is thermally desorbed and backflushed onto the column of the gas chromatograph 

with an inert gas. Detection of vinyl chloride is generally achieved using HECD, HSD, or MS (APHA 

1985; EPA 1982d, 1982e; IARC 1978; Reding 1987). The limit of detection is in the sub-ppb range for 

halogen specific detectors (APHA 1985; EPA 1982d, 1982e) and in the low-ppb range for MS (EPA 
VINYL CHLORIDE 204 

7. ANALYTICAL METHODS 

1982d). Accuracy is >98% and precision ranges from 11 to 25% for GC/HECD and GC/MS (EPA 

1982d). 

EPA has made improvements in methods for measuring volatile organic chemicals. The major change is 

the use of smaller sample volumes allowed by increased use of capillary gas chromatographic columns. 

Capillary columns provide better resolution, minimum detection limits, and less column bleed than 

packed columns (Reding 1987). 

Vinyl chloride has been measured in sediment using GC/ECD with sensitivity in the low-ppb range. 

Accuracy and precision data were not provided in the report (Wang et al. 1985). No information on 

analysis of vinyl chloride in soil was located. GC/HSD of headspace gases is the EPA-recommended 

method for solid matrices with sensitivity in the sub-ppb range. Accuracy (101.9%) is good and precision 

(11.4%) is adequate (EPA 1982d). Vinyl chloride levels in food have been determined using GC/FID. 

GC analysis by headspaces gases is a common method for testing foods, with sensitivity in the low-ppb 

range (IARC 1978). 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the adverse health effects of vinyl chloride is available. Where adequate 

information is not available, ATSDR, in conjunction with NTP, is required to ensure the initiation of a 

program of research designed to determine the adverse health effects (and techniques for developing 

methods to determine such adverse health effects) of vinyl chloride. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 
VINYL CHLORIDE 205 

7. ANALYTICAL METHODS 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Methods are available for measuring vinyl chloride and/or its metabolite, thiodiglycolic acid, 

in breath, urine, blood, and tissue (Baretta et al. 1969; Conkle et al. 1975; Draminski and Trojanowska 

1981; Müller et al. 1979; Zuccato et al. 1979). These methods are sensitive for measuring levels at which 

adverse health effects might occur, and for measuring higher background levels that might be found in 

specific populations known to be exposed to elevated levels of vinyl chloride (e.g., workers in the plastics 

industry and individuals living in the vicinity of hazardous waste sites). Measurement of urinary 

thiodiglycolic acid can be used as an indicator of vinyl chloride intake as long as individual variability in 

metabolism (due to such factors as liver disease, use of drugs, and alcohol intake) can be accounted for 

(Hefner et al. 1975b; Müller et al. 1979). Exposure to vinyl chloride at concentrations below 1–5 ppm 

could be masked by background metabolic levels of thiodiglycolic acid within normal limits (Müller et al. 

1979). Also, the formation of thiodiglycolic acid is not unique to vinyl chloride exposure (Norpoth et al. 

1986; Pettit 1986). The methods are generally reliable, although increased precision for most methods 

would increase reliability. Background levels for the general population are ill defined (EPA 1985b). 

Further research on the relationship between low-level exposure and levels of vinyl chloride in biological 

media would be helpful in assessing the risks and adverse health effects of chronic, low-level exposure. 

Effect. Existing methods are sensitive for measuring levels of vinyl chloride and its metabolite, 

thiodiglycolic acid, in individuals affected by exposure to very high levels of vinyl chloride (Baretta et al. 

1969; Conkle et al. 1975; Draminski and Trojanowska 1981; Müller et al. 1979; Zuccato et al. 1979). 

Also, methods are available to detect DNA adducts produced by the reaction of vinyl chloride metabolites 

with DNA (Eberle et al. 1989; Young and Santella 1988). These DNA adducts are specific indicators of 

vinyl chloride's genotoxic potential. These methods, however, are not sufficiently sensitive to determine 

the genotoxic effects resulting from low-level exposure. Correlations between levels detected in 

biological tissues and fluids and specific observed effects for lower levels of exposure have not been 

established. Additional research in this area would allow better assessment of existing methods and 

would help in defining areas in which improvements are needed. 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Existing methods for determining vinyl chloride in air (Harkov et al. 1983, 1984; Harsch et al. 

1979; Hasanen et al. 1979; IARC 1978; Ives 1975; Krost et al. 1982; McMurry and Tarr 1978; NIOSH 
VINYL CHLORIDE 206 

7. ANALYTICAL METHODS 

1994a; Rasmussen et al. 1977) and water (Ando and Sayato 1984; APHA 1985; Dressman and McFarren 

1978; EPA 1982d, 1982e; IARC 1978; Reding 1987), the media of most concern for human exposure, are 

sensitive, reproducible, and reliable for measuring background levels in the environment. Research 

investigating the relationship between levels measured in air and water and observed adverse health 

effects could increase our confidence in existing methods and/or indicate where improvements are 

needed. Methods specifically relating to the analysis of vinyl chloride in soils were not located. EPA 

does, however, have sensitive and reliable methods for determining the concentration of vinyl chloride in 

soil matrices (EPA 1982e), which include contaminated soils. 

7.3.2 Ongoing Studies 

Eltron Research Incorporated (Principal Investigator, Thomas Ross) is developing a direct-reading 

personal monitor for detecting vinyl chloride in workplace air (FEDRIP 2005). 
VINYL CHLORIDE 207 

8. REGULATIONS AND ADVISORIES 
 

The international, national, and state regulations and guidelines regarding vinyl chloride in air, water, and 

other media are summarized in Table 8-1. 

ATSDR has derived three MRL values for vinyl chloride. An acute-duration inhalation MRL of 0.5 ppm 

was derived for vinyl chloride based on a NOAEL for developmental effects for mice (John et al. 1977, 

1981). An intermediate-duration inhalation MRL of 0.03 ppm was derived for vinyl chloride based on a 

LOAEL of 10 ppm for increased incidences of hepatic centrilobular hypertrophy in rats (Thornton et al. 

2002). A chronic-duration oral MRL of 0.003 mg/kg/day was derived for vinyl chloride based on a 

human equivalent NOAEL of 0.09 mg/kg/day for liver cell polymorphism in rats (Til et al. 1983, 1991). 

EPA (IRIS 2004) has derived an RfD of 0.003 mg/kg/day for vinyl chloride, based on a NOAEL for liver 

cell polymorphism in rats administered vinyl chloride in the diet for a lifetime (Til et al. 1983, 1991). 

EPA (IRIS 2004) has derived an RfC of 0.1 mg/m3

 (0.04 ppm) for vinyl chloride, based on route-to-route 

extrapolation (using PBPK modeling) from a NOAEL for liver cell polymorphism in rats administered 

vinyl chloride in the diet for a lifetime (Til et al. 1983, 1991). 

The FDA is responsible for regulating vinyl chloride as an indirect food additive. With regard to 

components of coatings, paper, and paperboard, the FDA states that when vinyl chloride is copolymerized 

with certain other substances, it is a safe food-contact surface. The amount of vinyl chloride content 

permitted varies depending on the nature of the polymer and its use (FDA 1994). 
VINYL CHLORIDE 208 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Vinyl Chloride 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification Group 1a

 IARC 1987 

WHO Drinking water guideline 0.3 μg/Lb

 WHO 2000 

Air quality guideline (10-6 cancer risk) 1 μg/m3

 WHO 2000 

NATIONAL 

Regulations and Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA) 1 ppm ACGIH 2003 

EPA Hazardous air pollutant EPA 2004k 

42USC7412 

Regulated toxic substances pursuant to 10,000 poundsc

 EPA 2004a 

Section 112(r) of the Clean Air Act and 40CFR68.130 

threshold quantities for accidental release 

prevention 

NIOSH REL (10-hour TWA) Potential occupational NIOSH 2004 

carcinogen 

IDLH No data 

OSHA PEL for general industry OSHA 2004a 

8-hour TWA 1 ppm 29CFR1910.1017 

15-minute TWA 5 ppm 

PEL for construction industry OSHA 2004c 

8-hour TWA 1 ppm 29CFR1926.1117 

15-minute TWA 5 ppm 

PEL for shipyard industry OSHA 2004b 

8-hour TWA 1 ppm 29CFR1915.1017 

15-minute TWA 5 ppm 

b. Water 

Drinking water standards 0.002 mg/L EPA 2004j 

40CFR141.32 

Drinking water standards and health EPA 2004c 

advisories 

1-Day HA for a 10-kg child 3.0 mg/L 

10-Day HA for a 10-kg child 3.0 mg/L 

DWEL 

10-4 Cancer risk 

0.1 mg/L 

0.002 mg/L 

MCL 0.002 mg/L EPA 2004i 

40CFR141.61 

MCLG Zero EPA 2004g 

40CFR141.50 

c. Food 

FDA Bottled water 0.002 mg/L FDA 2003a 

21CFR165.110 
VINYL CHLORIDE 209 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Vinyl Chloride 

Agency Description 	 Information Reference 

NATIONAL (cont.) 

FDA Drug products withdrawn or removed from 

the market for reasons of safety or 

effectiveness 

Indirect food additive for use only as a 

component of adhesives 

d. Other 

 ACGIH Carcinogenicity classification 

EPA Carcinogenicity classification 

Oral slope factor 

Continuous lifetime exposure during 

adulthood 

Continuous lifetime exposure from 

birth 

Drinking water unit risk 

Continuous lifetime exposure during 

adulthood 

Continuous lifetime exposure from 

birth 

Inhalation unit risk 

Continuous lifetime exposure during 

adulthood 

Continuous lifetime exposure from 

birth 

Hazardous waste identification 

RfC 

RfD 

Superfund; community right-to-know; toxic 

chemical release reporting; effective date 

Superfund; designated as a hazardous 

substance pursuant to Section 307(a) of the 

Clean Water Act, Section 112 of the Clean 

Air Act, and Section 3001 of RCRA 

Reportable quantity 

Unlisted hazardous waste; characteristic 

of toxicity; RCRA waste number 

NTP Carcinogenicity classification 

STATE 

a. Air 

California 	 Ambient air quality standard (24-hour 
 

averaging time)g
 

All aerosol drug 

products containing 

vinyl chloride 

A1d 

Group Ae,f 

7.2x10-1 (mg/kg/day)-1 

1.4 (mg/kg/day)

-1 

2.1x10-5 (μg/L)-1 

4.2x10-5 (μg/L)-1 

4.4x10-6 (mg/m3

)

-1 

8.8x10-6 (mg/m3

)

-1 

U043 

1x10-1 mg/m3 

3x10-3 mg/kg/day 

01/01/1987 

1 pound 

D043 

Known to be a human 

carcinogen 

0.01 ppm 

FDA 2003c 

21CFR216.24 

 FDA 2003b 

21CFR175.105 

 ACGIH 2003 

IRIS 2005 

EPA 2004d 

40CFR261, 

Appendix VIII 

EPA 2004m 

40CFR372.65 

 EPA 2004b 

40CFR302.4 

NTP 2005 

CalEPA 2005 
VINYL CHLORIDE 210 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to Vinyl Chloride 

Agency Description 	 Information Reference 

STATE (cont.) 

b. Water 

California Public health goal 0.05 μg/L CalEPA 2000 

Drinking water guidelines and standards HSDB 2005 

 Arizona 0.015 μg/L 

California 0.5 μg/L 

 Connecticut 2.0 μg/L 

 Florida 1.0 μg/L 

Maine 0.2 μg/L 

 Minnesota 0.2 μg/L 

 New Jersey 2.0 μg/L 

 Wisconsin 0.2 μg/L 

c. Food 

No data 

d. Other 

No data 

a

Group 1: Carcinogenic to humans. b

For substances that are considered to be carcinogenic, the guideline value is the concentration in drinking water 

associated with an upper-bound excess lifetime cancer risk of 10-5 (one additional cancer per 100,000 of the 

population ingesting drinking-water containing the substance at the guideline value for 70 years). Concentrations 

associated with upper-bound estimated excess lifetime cancer risks of 10-4 and 10-6 can be calculated by multiplying 

and dividing, respectively, the guideline value by 10. c

Vinyl chloride: Mandated for listing by Congress and it is a flammable gas. d

Group A1: Confirmed human carcinogen. e

Group A: Human carcinogen; according to EPA Risk Assessment Guidelines (EPA 1986). f

Vinyl chloride is a known human carcinogen by the inhalation route of exposure, based on human epidemiological 

data, and by analogy the oral route because of positive animal bioassay data as well as pharmacokinetic data 

allowing dose extrapolation across routes. Vinyl chloride is also considered highly likely to be carcinogenic by the 

dermal route because it is well absorbed and acts systemically (EPA 1996). 

g

The Air Resources Board has identified vinyl chloride as 'toxic air contaminants' with no threshold level of exposure 

for adverse health effects determined. These actions allow for the implementation of control measures at levels below 

the ambient concentrations specified for these pollutants. 

ACGIH = American Conference of Governmental Industrial Hygienists; CFR = Code of Federal Regulations; 

DWEL = drinking water equivalent level; EPA = Environmental Protection Agency; FDA = Food and Drug 

Administration; HA = Health Advisory; HSDB = Hazardous Substances Data Bank; IARC = International Agency for 

Research on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information System; 

MCL = maximum contaminant level; MCLG = maximum contaminant level goal; NIOSH = National Institute for 

Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health 

Administration; PEL = permissible exposure limit; RCRA = Resource Conservation and Recovery Act; 

RfC = reference concentration; RfD = reference dose; STEL = short-term exposure limit; TLV = threshold limit values; 

TWA = time-weighted average; USC = United States Codes; WHO = World Health Organization 
_______________________ 

VINYL CHLORIDE 211 

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VINYL CHLORIDE 267 

10. GLOSSARY 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 
VINYL CHLORIDE 268 

10. GLOSSARY 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

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. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (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. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 
VINYL CHLORIDE 269 

10. GLOSSARY 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—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 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 
VINYL CHLORIDE 270 

10. GLOSSARY 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of greater than 1 is considered to indicate greater risk of disease in the 

exposed group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 
VINYL CHLORIDE 271 

10. GLOSSARY 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3

 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

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 no-observed-adverse-effect level 

(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 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 
VINYL CHLORIDE 272 

10. GLOSSARY 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio greater than 1 indicates greater risk of disease in the exposed 

group compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 
VINYL CHLORIDE 273 

10. GLOSSARY 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 
VINYL CHLORIDE 274 

10. GLOSSARY 

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VINYL CHLORIDE A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 
VINYL CHLORIDE A-2 

APPENDIX A 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Environmental Medicine, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. 

For additional information regarding MRLs, please contact the Division of Toxicology and 

Environmental Medicine, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, 

Mailstop F-32, Atlanta, Georgia 30333. 
VINYL CHLORIDE A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Vinyl Chloride 

CAS Number: 75-01-4 

Date: March 2006 

Profile Status: Final Draft Post-Public Comment 

Route: [X] Inhalation [ ] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 33 

Species: Mouse 

Minimal Risk Level: 0.5 [ ] mg/kg/day [X] ppm 

References: 

John JA, Smith FA, Leong BKJ, et al. 1977. The effects of maternally inhaled vinyl chloride on 

embryonal and fetal development in mice, rats, and rabbits. Toxicol Appl Pharmacol 39:497-513. 

John JA, Smith FA, Schwetz BA. 1981. Vinyl chloride: Inhalation teratology study in mice, rats, and 

rabbits. Environ Health Perspect 41:171-177. 

Experimental design: CF-1 mice were exposed to vinyl chloride at concentrations of 0, 50, or 500 ppm 

for 7 hours/day on gestational days 6–15 (John et al. 1977, 1981). Concurrent control groups were used, 

one for each dose level. Control groups were sham-exposed to filtered room air. Exposure was 

conducted in chambers of 3.7 m3

 volume under dynamic conditions. Animals were observed daily for 

clinical signs, and maternal body weights were determined several times during gestation. Animals were 

euthanized on gestational day 18 by carbon dioxide inhalation. Maternal liver weight was determined and 

uterine horns were examined. Fetuses were weighed, measured (crown-rump length), sexed, and 

subjected to gross and histopathological examinations. 

Effects noted in study and corresponding doses: No adverse maternal or fetal effects were noted at 

50 ppm, with the exception of a slight increase (p<0.05) in crown-rump length that was not observed at 

500 ppm. The 50-ppm exposure level is considered to be a NOAEL for maternal and developmental 

toxicity. At the LOAEL of 500 ppm, delayed ossification (p<0.05) was observed. An increase in 

resorptions at 500 ppm was considered to have been within historical control limits. Significant changes 

in percentage resorption, litter size, and fetal body weight would not have been observed at 500 ppm if 

comparison had been made to the other control group. There was frank maternal toxicity at 500 ppm 

(17% death). The limited number and spacing of dose group precludes the use of benchmark dose 

modeling for determination of the point-of-departure for the MRL. 

Dose and end point used for MRL derivation: 

[X] NOAEL [ ] LOAEL [ ] benchmark dose 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 3 for extrapolation from animals to humans with dosimetric adjustment 

[X] 10 for human variability 
VINYL CHLORIDE A-4 

APPENDIX A 

Was a conversion used from ppm in food or water to a mg/body weight dose? No. 

If so, explain: 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

The intermittent exposure duration of 7 hours/day was duration-adjusted (NOAELADJ) to continuous 

exposure according to the following equation: 

NOAELADJ = NOAEL (50 ppm) x 7 hours/24 hours per day = 15 ppm. 

Following EPA (1994g) methodology, the human equivalent concentration (NOAELHEC) for an 

extrarespiratory effect produced by a category 3 gas, such as vinyl chloride, is calculated by multiplying 

the duration-adjusted animal NOAEL by the ratio of the blood:gas partition coefficients in animals and 

humans ([Hb/g]A / [Hb/g]H). Since the partition coefficient in mice is greater than that in humans, as seen in 

Table 3-3, a default value of 1 is used for the ratio resulting in a NOAELHEC of 15 ppm. The acuteduration inhalation MRL of 0.5 ppm was derived by dividing the NOAELHEC of 15 ppm for 

developmental effects in female CF-1 mice by a factor of 30 (3 for species extrapolation using a 

dosimetric conversion and 10 for human variability). 

Other additional studies or pertinent information which lend support to this MRL: Delayed ossification 

(500 ppm, the lowest concentration tested) was the only developmental effect observed in a rabbit 

developmental study (John et al. 1977/ 1981). 

Agency Contact (Chemical Manager): G. Daniel Todd, Ph.D. 
VINYL CHLORIDE A-5 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Vinyl Chloride 

CAS Number: 75-01-4 

Date: March 2006 

Profile Status: Final Draft Post-Public Comment 

Route: [X] Inhalation [ ] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 44 

Species: Rat 

Minimal Risk Level: 0.03 [ ] mg/kg/day [X] ppm 

Reference: Thornton SR, Schroeder RE, Robison RL, et al. 2002. Embryo-fetal developmental and 

reproductive toxicology of vinyl chloride in rats. Toxicol Sci 68:207-219. 

Experimental design: Groups of male and female Sprague-Dawley rats (30/sex/group) were exposed to 

vinyl chloride vapor concentrations of 0, 10, 100, or 1,100 ppm, 6 hours/day for 10 weeks prior to mating 

and during a 3-week mating period. F0 males were exposed during the gestational period and sacrificed 

following the completion of parturition. F0 females were exposed during gestation and lactation (with the 

exception of a break in exposure from gestation day 21 through postnatal day 4 to allow for delivery of 

litters). All F0 rats were observed twice daily for clinical signs. Body weights and food consumption 

were monitored. F1 litters were examined for live and dead pups and on lactation day 4, litters were 

culled to eight pups (equal numbers of male and female pups where possible). All F0 female rats 

(including those that did not produce offspring) were sacrificed after the F1 rats had been weaned. 

Reproductive tissues, adrenal glands, brain, kidneys, liver, lungs, spleen, thymus, mammary glands, nasal 

tissues, pituitary, and trachea from each of the F0 rats were individually weighed and subjected to 

histopathologic examinations. At weaning, 15 male and female F1 rats/group were selected for gross and 

microscopic examinations. Other F1 rats were randomly selected to form groups of 30/sex/group, and 

these F1 rats were subjected to the same treatment as the F0 rats during the production of an F2 generation. 

At weaning, 15 male and female F2 rats/group were subjected to gross and microscopic examinations. 

Sperm parameters were assessed in 15 F0 and 15 F1 male rats of each exposure group. 

Effects noted in study and corresponding doses: Absolute and relative mean liver weights were 

significantly increased at all exposure levels in F0 males and in 100- and 1,100-ppm F1 males. Slight 

centrilobular hypertrophy, considered to be a minimal adverse effect, was noted in the livers of all 

1,100-ppm male and female F0 and F1 rats, most 100-ppm male and female F0 and F1 rats, and in 2/30 and 

6/30 of the 10-ppm F0 and F1 female rats, respectively (see Table A-1). No incidences of centrilobular 

hypertrophy were found in any of the control rats. Compared to an incidence of 0/30 for this lesion in 

controls, the incidence of 6/30 in the 10-ppm F1 female rats exceeded the level of statistical significance 

(p<0.05 according to Fisher’s Exact Test performed by ATSDR). 

Dose and end point used for MRL derivation: 

[ ] NOAEL [ ] LOAEL [X] LEC10 from benchmark dose modeling 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 3 for extrapolation from animals to humans with dosimetric adjustment 

[X] 10 for human variability 
VINYL CHLORIDE A-6 

APPENDIX A 

Was a conversion used from ppm in food or water to a mg/body weight dose? No. 

If so, explain: 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

The incidence data for centrilobular hypertrophy in the male and female F0 and F1 rats exposed to vinyl 

chloride by inhalation, 6 hours/day for 10 weeks prior to mating and during mating, gestation, and 

lactation (Thornton et al. 2002) are shown in Table A-1. 

Table A-1. Incidences of F0 And F1 Male and Female With Centrilobular 
 

Hypertrophy in the Liver Following Inhalation Exposure to Vinyl 
 

Chloride Vapors for 6 Hours/Day for 10 Weeks Prior to Mating 
 

and During Mating and Gestation (Males and Females) and 
 

Lactation (Females) 
 

Exposure concentration (ppm) 

0 10 100 1,100 

F0 males 0/30 0/30 15/30* 30/30* 

F0 females 0/30 2/30 26/30* 30/30* 

F1 males 0/30 0/30 19/30* 30/30* 

F1 females 0/30 6/30* 30/30* 30/30* 

*Statistically significantly (p<0.05) different from controls according to Fisher’s Exact Test performed by ATSDR. 

Source: Thornton et al. (2002) 

All dichotomous models in the Benchmark Dose Software (BMDS version 1.3.2) were fit to the incidence 

data for centrilobular hypertrophy in the liver of the F1 female rats, which had also been exposed via their 

mothers during pre- and post-natal development. The lower 95% confidence limit (LEC10) of a 10% extra 

risk (EC10) for hepatic centrilobular hypertrophy was selected as the benchmark response for the point of 

departure. The Quantal Quadratic model provided the best fit as assessed by a chi-square goodness-of-fit 

test and the Aikake’s Information Criteria (AIC) (Table A-2). Therefore, the LEC10 value of 5 ppm, 

derived from the Quantal Quadratic model, was selected as the point of departure for calculating an 

intermediate-duration inhalation MRL (see Table A-2 and Figure A-1). 
VINYL CHLORIDE A-7 

APPENDIX A 

Table A-2. Modeling Results for the Incidence of F1 Female Rats with 
 

Centrilobular Hypertrophy in the Liver Following Inhalation 
 

Exposure to Vinyl Chloride Vapors for 6 Hours/Day for 
 

10 Weeks Prior to Mating and During Mating, 
 

Gestation, and Lactation, and Exposed via 
 

their Mothers During Pre- and 
 

Postnatal Development 
 

EC10 LEC10 

Model (ppm) (ppm) χ

2

 p-value AIC 

Gammaa 7.78 3.15 1.00 34.02 

Logistic 8.75 6.15 1.00 32.05 

Log-logisticb

 9.12 5.22 1.00 34.02 

Multi-stagec

 6.35 3.44 undefined 36.02 

Probit 9.11 5.69 1.00 34.02 

Log-probitb

 8.56 5.09 1.00 34.02 

Quantal linear 3.03 2.05 0.53 35.28 

Quantal quadratic 6.87 5.08 1.00 32.02 

Weibulla

 6.68 3.03 1.00 34.02 

a

Restrict power >=1 b

Slope restricted to >1 c

Restrict betas >=0; Degree of polynomial=3 

Source: Thornton et al. (2002) 

Figure A-1. Benchmark Dose Model Results for the Incidence of Female F1 Rats 
 

with Centrilobular Hypertrophy Following Exposure to Vinyl Chloride 
 

by Inhalation, 6 Hours/Day for 10 Weeks Prior to Mating and During 
 

Mating, Gestation, and Lactation, and Exposed Via their Mothers 
 

During Pre- and Postnatal Development 
 

Quantal Quadratic Model with 0.95 Confidence Level 

1 

0.8 

0.6 

0.4 

0.2 

0 

0 200 400 600 800 1000 1200 

BMDLBMD 

Quantal Quadratic 

dose 

16:24 06/21 2004 

Fraction Affected 
VINYL CHLORIDE A-8 

APPENDIX A 

The intermittent exposure duration of 6 hours/day was duration-adjusted (LEC10ADJ) to continuous 

exposure according to the following equation: 

LEC10ADJ = LEC10 (5 ppm) x 6 hours/24 hours per day = 1.25 ppm; (rounded to 1.0 ppm). 

Following EPA (1994g) methodology, the human equivalent concentration (LEC10HEC) for an 

extrarespiratory effect produced by a category 3 gas, such as vinyl chloride, is calculated by multiplying 

the animal LEC10ADJ by the ratio of the blood:gas partition coefficients in animals and humans [(Hb/g)A / 

Hb/g)H]. Since the partition coefficient in mice is greater than that in humans, as seen in Table 3-3, a 

default value of 1 is used for the ratio and the animal LEC10ADJ is equivalent to the LEC10HEC. Several 

physiologically-based pharmacokinetic (PBPK) models are available for vinyl chloride; however, none of 

these models included an evaluation of exposure during mating, gestation, or lactation. Therefore, PBPK 

models could not be used to calculate a LEC10HEC from the Thornton et al. (2002) study. The 

intermediate-duration inhalation MRL of 0.03 ppm was derived by dividing the LEC10HEC of 1.0 ppm for 

centrilobular hypertrophy in female Sprague-Dawley rats by a factor of 30 (3 for species extrapolation 

using a dosimetric conversion and 10 for human variability). 

Other additional studies or pertinent information which lend support to this MRL: Liver enlargement 

and/or histopathological changes have been noted in a number of intermediate-duration inhalation studies 

in animals (Bi et al. 1985; Lester et al. 1963; Schaffner 1978; Sokal et al. 1980; Torkelson et al. 1961; 

Wisniewska-Knypl et al. 1980). The studies by Thornton et al. (2002) and Bi et al. (1985) show these 

effects at a somewhat lower dosage. Additional support comes from a study citing immunostimulation in 

mice at 10 ppm (Sharma and Gehring 1979). 

Agency Contact (Chemical Manager): G. Daniel Todd, Ph.D. 
VINYL CHLORIDE A-9 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: Vinyl Chloride 

CAS Number: 75-01-4 

Date: March 2006 

Profile Status: Final Draft Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 5 

Species: Rat 

Minimal Risk Level: 0.003 [X] mg/kg/day [ ] ppm 

References: 

Til HP, Immel HR, Feron VJ. 1983. Lifespan oral carcinogenicity study of vinyl chloride in rats. Final 

report. Civo Institutes, TNO. Report No. V 93.285/291099. 

Til HP, Feron VJ, Immel HR. 1991. Lifetime (149-week) oral carcinogenicity study of vinyl chloride in 

rats. Food Chem Toxicol 29:713-718. 

Experimental design: Groups of Wistar rats (100/sex/group in controls and the two lowest exposure 

groups; 50/sex at the highest exposure level) were administered vinyl chloride in the daily diet at intended 

initial dietary concentrations of 0, 0.46, 4.6, or 46 ppm for 149 weeks. Due to rapid evaporative loss of 

vinyl chloride from the food, liquid vinyl chloride was mixed with polyvinyl chloride granules to produce 

a mixture in which vinyl chloride was effectively encapsulated in polyvinyl chloride granules (Feron et al. 

1975). The study authors trained the rats to a feeding schedule of 4 hours/day prior to the initiation of 

exposure to vinyl chloride in the diet. The authors noted that food consumption per hour was fairly 

constant during the 4-hour feeding period. Loss of vinyl chloride from food during the first hour, the 

second hour, and the final 2 hours was calculated. Periodic food intake measurements were made for the 

first hour, the second hour, and the final 2 hours. Based on these measurements, the study authors 

calculated the average oral intake of the combined sexes during the daily 4-hour feeding periods to be 0, 

0.018, 0.17, and 1.7 mg/kg/day for the 0-, 0.49-, 4.49-, and 44.1-ppm groups, respectively (see 

Table A-3). Measurements of vinyl chloride in the feces were made periodically at 1 hour prior to the 

feeding period, the end of the 4-hour feeding period, and 4 and 9 hours later. The study authors 

considered the vinyl chloride content in the feces to have remained encapsulated in the polyvinyl chloride 

granules and thus not to have been available for absorption from the gastrointestinal tract. The amount of 

vinyl chloride in the feces was subtracted from the calculated daily oral intake of vinyl chloride to arrive 

at what the study authors termed “actual oral exposure levels” of 0, 0.014, 0.13, and 1.3 mg/kg/day for the 

0-, 0.49-, 4.49-, and 44.1-ppm groups, respectively (see Table A-3). Results of toxicokinetic assessments 

for vinyl chloride indicate that, following absorption, vinyl chloride and its metabolites are not excreted in 

appreciable amounts in the feces. Types and incidences of neoplastic and nonneoplastic liver lesions 

were determined at the end of the study. 
VINYL CHLORIDE A-10 
 

APPENDIX A 
 

Table A-3. Exposure Levels and Oral Intake Values for Rats Exposed to Vinyl 
 

Chloride in the Diet for 149 Weeks 
 

Mean initial dietary 

level (ppm) 

Oral intake 

(mg/kg/day)a 

Adjusted oral intake 

(mg/kg/day)b 

Estimated absorbed 

dose (mg/kg/day)c 

0 0 0 0 

0.49 0.022 0.018 0.014 

4.49 0.21 0.17 0.13 

44.1 2.1 1.7 1.3 

a

Assuming no loss of vinyl chloride by evaporation from the diet. 
 b

Oral intake, adjusted for evaporative loss from the diet during the daily 4-hour feeding periods. 
 c

Oral intake of vinyl chloride (adjusted for evaporative loss and the amount excreted in the feces, which was 
 

considered to have remained encapsulated in the polyvinyl chloride granules and not to have been available for 
 

absorption). 
 

Source: Til et al. (1983, 1991) 

Effects noted in study and corresponding doses: The critical nonneoplastic effect was determined to be 

liver cell polymorphism, which was classified by severity (slight, moderate, severe). The incidences of 

this lesion are listed in Table A-4. 

Table A-4. Incidences of Male and Female Wistar Rats Exhibiting Slight, 
 

Moderate, or Severe Liver Cell Polymorphism Following Daily Oral 
 

Exposure to Vinyl Chloride in the Diet for 149 Weeks 
 

Oral intake (mg/kg/day) 

Males Females 

0 0.018 0.17 1.7 0 0.018 0.17 1.7 

Number of rats 99 99 99 49 98 100 96 49 

examined 

Slight 

Moderate 

27 

4 

23 

4 

26 

7 

19 

10a 

46 

14 

41 

13 

49 

8 

23 

15b 

Severe 1 1 1 3 2 3 4 9c 

a

Significantly different from controls according to Fisher’s exact test (p<0.001). b

Significantly different from controls according to Fisher’s exact test (p<0.05). c

Significantly different from controls according to Fisher’s exact test (p<0.0001). 

Source: Til et al. (1983, 1991) 

A LOAEL of 1.7 mg/kg/day was identified for statistically significantly increased incidences of liver cell 

polymorphism in male and female rats. The NOAEL for nonneoplastic liver effects is 0.17 mg/kg/day. 

An increase in the incidence of female rats with many hepatic cysts was also observed at the highest dose 

(1.7 mg/kg/day). Other histopathologic lesions, described as hepatic foci of cellular alteration, were 

observed at all dose levels in female rats and in high-dose male rats, but were not used to derive an MRL 

because they are considered to be preneoplastic lesions. MRLs are protective only for non-neoplastic 

effects and do not reflect cancer risk. 

The liver cell polymorphism incidences reported by Til et al. (1983, 1991) were also used as the basis of 

the RfD of 0.003 mg/kg/day for vinyl chloride derived by the U.S. EPA (EPA 2000). However, EPA 
VINYL CHLORIDE A-11 

APPENDIX A 

used the estimated absorbed dose of 0.13 mg/kg/day as the NOAEL, rather than the adjusted oral intake 

NOAEL of 0.17 mg/kg/day used by ATSDR. EPA (2000) applied the Clewell et al. (1995) PBPK model 

for vinyl chloride to the low-, mid-, and high-dose groups (estimated absorbed doses of 0.014, 0.13, and 

1.3 mg/kg/day, respectively) to generate dose metrics of 0.3, 3, and 30 mg vinyl chloride metabolites/L 

liver, respectively. The EPA (2000) rationale for using the total amount of metabolite generated divided 

by the volume of liver tissue as the dose metric for liver toxicity included evidence that vinyl chlorideinduced liver toxicity is related to the production of reactive intermediates and that binding to liver 

macromolecules correlates well with total metabolism (Watanabe et al. 1978). In EPA’s derivation of the 

RfD, it was assumed that all of the metabolism of vinyl chloride occurred in the liver. EPA (2000) 

simulated a continuous human exposure scenario (ingestion of 1 ppm of vinyl chloride in water or 

0.286 mg/kg/day, assuming consumption of 2 L water/day for a 70-kg person) using the Clewell et al. 

(1995) model, which resulted in a human internal dose metric of 1.01 mg metabolite/L liver. The ratio of 

the value for the human internal dose metric 1.01 mg metabolite/L liver) to the vinyl chloride intake of 

0.286 mg/kg/day in the simulated human exposure scenario (1.01 ÷ 0.286 = 35.31) was used by EPA 

(2000) to convert from the rat dose metric (3 mg metabolite/L liver) at the NOAEL (0.13 mg/kg/day 

estimated absorbed dose) to a human equivalent dose (i.e., the rat NOAEL of 0.13 mg/kg/day divided by 

35.31 equals a human equivalent dose of 0.09 mg/kg/day). EPA considered this approach to be adequate 

because vinyl chloride metabolism is linear in the dose range that includes the NOAEL of 0.13 mg/kg/day 

identified in the rat study of Til et al. (1983, 1991). 

EPA (2000) assessed the feasibility of using Benchmark Dose Modeling on incidence data for liver cell 

polymorphism in the study of Til et al. (1983, 1991). Incidence data for moderate and severe grades of 

liver cell polymorphism were combined for both sexes and summed to produce one control group and 

three exposure groups (moderate + severe incidences of liver cell polymorphism divided by the number of 

treated male and female rats at each dose level; 21/197 controls, 21/199 low-dose, 20/196 mid-dose, and 

37/98 high-dose rats). The resulting incidence data for each dose metric (0.3, 3, and 30 mg metabolite/L 

liver) were subjected to Benchmark Dose modeling in order to statistically identify a threshold response 

for vinyl chloride-induced effects. The resulting dose metric values are shown in Table A-5. 

Table A-5. LED10 Values Generated from Various Models to Liver Cell 
 

Polymorphism Incidence Data from Oral Exposure of Male and 
 

Female Rats to Vinyl Chloride in the Diet for 149 Weeks in the 
 

Study of Til et al. 1991 
 

Model LED10 (mg/L liver)a p-value 

Weibull (power≥1) 24.0 0.88 

Gammahit 21.4 0.88 

Quantal quadratic 13.8 0.96 

Logistic 12.9 0.47 

Multistage 11.8 0.79 

Probit 11.6 0.44 

Quantal linear 6.5 0.46 

NOAEL 3.00 (0.13 mg/kg/day) 

LOAEL 29.9 (1.3 mg/kg/day) 

a

LED10 is the lower 95% confidence limit of a 10% change in numbers exhibiting polymorphism evaluated as 

either moderate or severe. The NOAEL and LOAEL are shown for comparison. 

Source: EPA (2000) 

EPA (2000) noted that although all models provided adequate fit to the data, the liver cell polymorphism 

appeared to be only a high-dose phenomenon, the LED10 values ranged from 6.5 to 24.01 mg/L liver 
VINYL CHLORIDE A-12 

APPENDIX A 

(nearly a 4-fold range), and all modeled LED10 values were higher than the NOAEL of the study. EPA 

(2000) argued that there was no biological reason to choose the results of one model over another and that 

the dose-response characteristics present additional uncertainty due to the large gaps between dose levels. 

For these reasons, EPA (2000) chose to use the internal dose metric of 3 mg/L liver, corresponding to the 

rat NOAEL, rather than a benchmark LED10 value, to derive the RfD for vinyl chloride. EPA (2000) 

applied an uncertainty factor of 30 (3 for extrapolating from animals to humans using a dosimetric 

adjustment and 10 for intrahuman variability) to the HED of 0.09 mg/kg/day. 

Therefore, the RfD = 0.09 mg/kg/day ÷ 30 = 0.003 mg/kg/day. The chronic-duration oral MRL for vinyl 

chloride is based on the same critical effect as that used by EPA (2000) to derive the RfD for vinyl 

chloride (i.e., the NOAEL for liver cell polymorphism in the oral rat study of Til et al. 1983, 1991). 

However, the point of departure for the chronic-duration oral MRL was the NOAEL of 0.17 mg/kg/day 

(average ingested dose), rather than the estimated absorbed dose of 0.13 mg/kg/day used by EPA (2000), 

based on the assumption that all of the vinyl chloride that remained in the diet (after volatilization) was 

available for absorption. 

In deriving the MRL, the rat NOAEL of 0.17 mg/kg/day was converted to a human equivalent dose using 

the PBPK models described in Clewell et al. (2001) and EPA (2000) to extrapolate from rats to humans. 

Source code and parameter values for running the rat and human models in Advance Continuous 

Simulation Language (ACSL) were transcribed from Appendix C of EPA (2000). Parameter values used 

in the interspecies extrapolation are presented in Table A-6. Accuracy of the implementation of the 

model in ACSL (v. 11.8.4) was checked against observations reported in Gehring et al. (1978), also 

reported in Clewell et al. (2001) (results shown in Figure A-2). The total amount of vinyl chloride 

metabolized in 24 hours per L of liver volume was the rat internal dose metric that was used in 

determining the human dose that would result in an equivalent human dose metric. One kilogram of liver 

was assumed to have an approximate volume of 1 L. Exposures in the Til et al. (1983, 1991) rat dietary 

study were simulated as 4-hour oral exposures, for which, the average daily dose was equivalent to the 

NOAEL dose for liver effects (ADD, 0.17 mg/kg/day). This dose was uniformly distributed over a 

4-hour period (i.e., 0.0425 mg/kg/hour for 4 hours, followed by 16 hours at 0 mg/kg/hour). Dose metrics 

reflect the cumulative amount of vinyl chloride metabolized over the 24-hour period. 

Table A-6. Parameter Values for Rat and Human Models 

Model 

Parameter Definition Rat Human 

BW Body weight (kg) 0.377 (m) 70 

0.204 (f) 

VLC Liver volume (fraction of body) 0.05 0.026 

VFC Fat volume (fraction of body) 0.12 0.19 

VSC Slowly-perfused tissue volume (fraction of body) 0.75 0.63 

VRC Rapidly-perfused tissue volume (fraction of body) 0.05 0.064 

QCC Cardiac output (L/hr-kg body weight) 18.0 16.5 

QPC Alveolar ventilation rate (L/hr-kg body weight) 21.0 24.0 

QLC Liver blood flow (fraction of cardiac output) 0.25 0.26 

QFC Fat blood flow (fraction of cardiac output) 0.09 0.05 

QSC Slowly-perfused blood flow (fraction of cardiac output) 0.15 0.19 

QRC Rapidly-perfused blood flow (fraction of cardiac output) 0.51 0.5 

PB Blood:air partition coefficient 2.4 1.16 

PL Liver:blood partition coefficient 0.7 1.45 

PF Fat:blood partition coefficient 10.0 20.7 

PS Slowly-perfused partition coefficient 4.0 0.83 

PR Rapidly-perfused partition coefficient 0.7 1.45 
VINYL CHLORIDE A-13 

APPENDIX A 

Table A-6. Parameter Values for Rat and Human Models 

Model 

Parameter Definition Rat Human 

VMAX1C Maximum rate of oxidative metabolism 4.0 4.0 

(mg/hr-kg body weight) 

VMAX2C Maximum rate of oxidative metabolism 2.0 0.1 

(mg/hour-kg body weight) 

KM1 Michaelis-Menten coefficient for oxidative metabolism 0.1 0.1 

(mg/L) 

KM2 Michaelis-Menten coefficient for oxidative metabolism 10.0 10.0 

(mg/L) 

KCO2C Rate constant for formation of CO2 from oxidative 1.6 1.6 

metabolite (hour-1) 

KGSMC Rate constant for conjugation with GSH (hour

-1) 0.13 0.13 

KFEEC Rate constant for conjugation, not with GSH (hour-1) 35.0 35.0 

CGSZ Initial GSH concentration in liver (μmol/L) 5,800 5,800 

KBC Rate constant for GSH catabolism (hour-1) 0.12 0.12 

KS Coefficient controlling resynthesis of GSH (μmol/L) 2,000 2,000 

KZC Zero-order rate constant for resynthesis of GSH (μmol/hour) 28.5 28.5 

Ka Gastrointestinal absorption rate constant (hour

-1) 3.0 

Figure A-2. Predicted and Observed Relationship Between Air Exposure 
 

Concentration and Rate Metabolism of Vinyl Chloride in Rats* 
 

0 

2000 

4000 

6000 

8000 

10000 

12000 

1 10 100 1000 10000 

Exposure Concentration (ppm) 

Tot

al M

eta

bolize

d (

ug/

6hr) 

Gehring et al. 1978 

Model (BW=0.200) 

*Measurements of metabolites (non-volatile 14C in carcass) were made immediately following a 6-hour exposure to 

[

14C]vinyl chloride in air. Circles represent observations (±SD); the line shows the corresponding simulations. 
VINYL CHLORIDE A-14 

APPENDIX A 

The human model was run iteratively, varying the ADD, until the model converged with the internal dose 

estimate shown in row 1 in Table A-7 (rat, male). The value for the Km1 for oxidative metabolism in 

humans was assumed to be equal to the Km1 value for rats (0.1 mg/L) (EPA 2000). The human ADD 

was assumed to be uniformly distributed over a 24-hour period. The resulting HED was 0.09 mg/kg/day 

(see Table A-7). Additional simulations were performed assuming that the ADD was distributed over a 

12-hour period (to simulate exposure from drinking water or food during the day only). The resulting 

dose metrics were very similar to the 24-hour estimates (data not shown). 

Table A-7. Summary of Internal Dose Predictions and Corresponding Human 

and Rat Equivalent Doses 

BW Km1 ED EF1 EF2 ADD DM 

Species (kg) mg/L (week) (day/week) (hour/day) (mg/kg/day) (mg/L) 

Wistar rat 

Male 0.377 0.1 149 7 4 0.17 3.16 

Female 0.204 0.1 149 7 4 0.17 3.16 

Human 70 0.1 3,640 7 24 0.09 3.16 

ADD = average daily administered dose; BW = body weight; DM = dose metric equals the total amount of 

metabolite formed in 24 hours per L of liver; ED = exposure duration; EF = exposure frequency; Km1 = MichaelisMenten constant for oxidative metabolism 

ATSDR accepted the rationale used by EPA (2000) for not using Benchmark Dose modeling results for 

incidences of the critical effect (liver cell polymorphism in the oral rat study of Til et al. 1983, 1991) in 

the risk assessment. Therefore, the HED of 0.09 mg/kg/day, associated with the rat NOAEL of 

0.17 mg/kg/day (Til et al. 1983, 1991), served as the basis for the chronic-duration oral MRL for vinyl 

chloride. The chronic-duration oral MRL of 0.003 mg/kg/day was derived by dividing the PBPKmodeled equivalent human NOAEL of 0.09 mg/kg/day for liver cell polymorphisms by a factor of 

30 (3 for species extrapolation using a dosimetric conversion and 10 for human variability). 

Dose and end point used for MRL derivation: 

[X] NOAEL [ ] LOAEL 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 3 for extrapolation from animals to humans using a dose metric conversion 

[X] 10 for human variability 

Was a conversion used from ppm in food or water to a mg/body weight dose? No. 

If so, explain: 

If an inhalation study in animals, list the conversion factors used in determining human equivalent dose: 

N/A 
VINYL CHLORIDE A-15 

APPENDIX A 

Other additional studies or pertinent information which lend support to this MRL: This MRL is 

reinforced by a study by Feron et al. (1981) in which rats were fed diets containing PVC powder. 

Increased areas of cellular alteration (consisting of clear foci, basophilic foci, and eosinophilic foci) were 

observed in the liver of rats at an oral intake of vinyl chloride monomer of 1.8 mg/kg/day. 

Agency Contact (Chemical Manager): G. Daniel Todd, Ph.D. 
VINYL CHLORIDE A-16 
 

APPENDIX A 

This page is intentionally blank. 
VINYL CHLORIDE B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in non-technical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1.	 What effects are known to occur in humans? 

2. 	 What effects observed in animals are likely to be of concern to humans? 

3. 	 What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 
VINYL CHLORIDE B-2 

APPENDIX B 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 
VINYL CHLORIDE B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1) 	 Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2) Exposure Period. Three exposure periods—acute (less than 15 days), intermediate (15– 

364 days), and chronic (365 days or more)—are presented within each relevant route of exposure. 

In this example, an inhalation study of intermediate exposure duration is reported. For quick 

reference to health effects occurring from a known length of exposure, locate the applicable 

exposure period within the LSE table and figure. 

(3) Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4) 	 Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5) Species. The test species, whether animal or human, are identified in this column. Chapter 2,

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6) Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7) System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8) NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 
VINYL CHLORIDE B-4 

APPENDIX B 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 

(9) LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10) Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11) CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13) Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14) Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3

 or ppm and oral exposure is reported in 

mg/kg/day. 

(16) NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17) CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 
VINYL CHLORIDE B-5 

APPENDIX B 

(18)	 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)	 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 
SAMPLE 

1 → Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

Key to figurea 

Exposure frequency/ 

Species duration System 

NOAEL (ppm) 

LOAEL (effect) Less serious (ppm) 

Serious (ppm) 

Re

2 → INTERMEDIATE EXPOSURE 3 4 

5 6 7 8 9 10

→ Systemic ↓ ↓ ↓ ↓ ↓ ↓

18 Rat 13 wk Resp 3b 10 (hyperplasia) 

→ 5 d/wk Nit

6 hr/d 

CHRONIC EXPOSURE Cancer 11 

↓

38 Rat 18 mo 

5 d/wk 7 hr/d 

20 (CEL, multiple 

organs) 

Wo

39 Rat 89–104 wk 

5 d/wk 6 hr/d 

10 (CEL, lung tumors, 

nasal tumors) 

NT

40 Mouse 79–103 wk 

5 d/wk 6 hr/d 

10 (CEL, lung tumors, 

hemangiosarcomas) 

NT

12 → a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent ex

by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

VINYL CHLORIDE B-8 

APPENDIX B 

This page is intentionally blank. 
VINYL CHLORIDE C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD benchmark dose 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 

DOE Department of Energy 

DOL Department of Labor 

DOT Department of Transportation 
VINYL CHLORIDE C-2 

APPENDIX C 

DOT/UN/ Department of Transportation/United Nations/ 

NA/IMCO North America/International Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 
VINYL CHLORIDE C-3 

APPENDIX C 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 
VIN

YL CHLORIDE C-4 

APPENDIX C 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
VIN

YL CHLORIDE C-5 

APPENDIX C 

> greater than ≥ greater than or equal to 

= equal to 

< less than ≤ less than or equal to 

% percent α alpha β beta γ gamma δ delta μm micrometer μg microgram

* 

q1 cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 
VINYL CHLORIDE C-6 

APPENDIX C 

This page is intentionally blank. 
VINYL CHLORIDE D-1 

APPENDIX D. INDEX 
 

1,1,1-trichloroethane..........................................................................................................................176, 179, 185, 189 
 

2-chloroacetaldehyde...................................17, 19, 95, 96, 99, 100, 101, 103, 108, 110, 113, 124, 125, 126, 127, 137, 
 

...........................................................................................................................................................143, 146, 148, 156 
 

2-chloroethylene oxide ....................................... 17, 19, 94, 96, 99, 100, 101, 108, 110, 113, 124, 125, 126, 127, 137, 
 

...........................................................................................................................................143, 144, 146, 147, 148, 156 
 

absorbed dose ............................................................................................................................................................135 
 

acroosteolysis ..........................................................................................................................14, 53, 61, 138, 140, 148 
 

adenocarcinoma.....................................................................................................................................................72, 75 
 

adipose tissue.......................................................................................................................................................18, 206 
 

adrenals................................................................................................................................................................59, 130 
 

adsorbed.....................................................................................................................................................176, 215, 216 
 

adsorption ..........................................................................................................................................................190, 218 
 

aerobic ...............................................................................................................................................................192, 193 
 

alanine aminotransferase .............................................................................................................................................55 
 

ambient air...................................................................................................................6, 7, 13, 179, 203, 206, 207, 210
 

anaerobic............................................................................................................................................................192, 193 
 

angiosarcoma.................................................14, 15, 17, 18, 19, 54, 55, 70, 71, 74, 75, 76, 77, 79, 85, 96, 97, 98, 122,
 

........................................................................................................... 132, 133, 137, 138, 139, 143, 144, 159, 160, 161
 

aspartate aminotransferase...........................................................................................................................................55 
 

bioaccumulation ........................................................................................................................................................190 
 

bioavailability ............................................................................................................................................................209 
 

bioconcentration factor..............................................................................................................................................190 
 

biodegradation ...................................................................................................................................................192, 193 
 

biomarkers ................................................................................................. 135, 138, 154, 157, 160, 161, 164, 165, 212
 

blanching .............................................................................................................................................14, 140, 148, 161 
 

blood cell counts..........................................................................................................................................................21 
 

body weight effects..........................................................................................................................................60, 79, 84 
 

breast milk .........................................................................................................................................................133, 206 
 

cancer.....................................5, 6, 7, 14, 17, 18, 19, 26, 28, 70, 71, 72, 73, 74, 75, 76, 77, 84, 86, 115, 118, 123, 127,
 

................................................................................... 131, 132, 134, 137, 140, 143, 144, 157, 159, 160, 164, 223, 225 
 

carcinogen...................................................................................................... 6, 15, 71, 77, 85, 125, 147, 223, 224, 225
 

carcinogenic..........................................6, 16, 18, 19, 20, 25, 26, 70, 74, 77, 85, 96, 126, 147, 155, 156, 159, 165, 225
 

carcinogenicity .......................................................................... 16, 17, 19, 23, 75, 77, 85, 94, 126, 133, 134, 156, 164
 

carcinoma .......................................................................... 18, 71, 72, 74, 75, 76, 77, 79, 85, 96, 97, 98, 132, 133, 140 
 

cardiac arrhythmia ...............................................................................................................................52, 125, 145, 153 
 

cardiovascular..........................................................................................................................51, 79, 87, 127, 132, 155 
 

chromosomal aberrations.........................................................................................................88, 93, 99, 140, 142, 161
 

clearance......................................................................................................................................55, 134, 139, 161, 163 
 

CYP2E1...........................................................................................................................14, 94, 98, 110, 134, 144, 164 
 

death ...................................................................................................... 20, 25, 28, 74, 77, 78, 132, 142, 143, 144, 152
 

deoxyribonucleic acid (see DNA)..........................................................................................................................91, 92 
 

dermal effects ............................................................................................................................................59, 62, 84, 87 
 

dizziness ..................................................................................................................................................15, 62, 63, 152 
 

DNA (see deoxyribonucleic acid)................................... 14, 19, 88, 90, 91, 92, 93, 94, 95, 96, 98, 100, 101, 110, 122, 
 

....................................................................126, 127, 133, 134, 135, 137, 140, 144, 147, 156, 160, 161, 164, 165, 220 
 

DNA adducts ................................................................... 19, 95, 96, 126, 134, 135, 137, 140, 160, 161, 164, 165, 220 
 

endocrine ...............................................................................................................................................79, 87, 128, 132 
 

endocrine effects....................................................................................................................................................59, 87 
 

epoxide ................................................................ 94, 101, 108, 109, 118, 121, 124, 126, 142, 146, 147, 163, 182, 191 
 

erythema ......................................................................................................................................................................87 
 
VINYL CHLORIDE D-2 

APPENDIX D 

fetal resorption.............................................................................................................................................................20 
 

fetus...................................................................................................................................130, 134, 143, 153, 158, 164 
 

fibrosis.............................................................................................................................14, 15, 16, 17, 54, 56, 58, 125 
 

gastrointestinal effects .................................................................................................................................................52 
 

general population ................................................................................................... 4, 13, 135, 138, 182, 203, 209, 220
 

genotoxic .............................................................................................................................25, 100, 140, 152, 161, 220 
 

genotoxicity ...........................................................................................................................................77, 88, 156, 165 
 

groundwater..................................................................................... 3, 13, 153, 157, 179, 182, 185, 190, 192, 197, 218
 

growth retardation................................................................................................................................................70, 130 
 

half-life .............................................................................................. 108, 113, 135, 136, 147, 180, 182, 189, 190, 191
 

hematological effects.............................................................................................................................................52, 79 
 

hematopoietic ....................................................................................................................................18, 70, 72, 73, 159 
 

hepatic effects..................................................................................................................................................16, 54, 79 
 

hydrolysis ..........................................................................................................................................................191, 208 
 

hydroxyl radical...................................................................................................................................13, 180, 191, 208 
 

IgG...............................................................................................................................................................61, 125, 148 
 

immune system..........................................................................................................................................149, 155, 158 
 

immunological.....................................................................................................................20, 25, 61, 62, 87, 110, 127
 

immunological effects .................................................................................................................................................62 
 

Kow .....................................................................................................................................................................170, 190 
 

leukemia ........................................................................................................................................................73, 77, 140 
 

lymphatic .................................................................................................................................................18, 72, 73, 159 
 

lymphoreticular......................................................................................................................................................14, 87 
 

melanoma ..............................................................................................................................................................73, 75 
 

menstrual ...............................................................................................................................................................6, 157 
 

meta-analysis .............................................................................................................................................18, 71, 72, 73 
 

MFO (mixed function oxidases).............................................................. 14, 17, 94, 101, 109, 124, 126, 141, 144, 146 
 

micronuclei..........................................................................................................................................................89, 138 
 

milk............................................................................................................................................................................146 
 

mixed function oxidases (see MFO)........................................................................................14, 53, 94, 101, 124, 125 
 

narcosis........................................................................................................................................................................20 
 

neoplastic...............................................................................................................................15, 17, 18, 23, 79, 85, 147 
 

neurobehavioral .........................................................................................................................................................128 
 

ocular effects .............................................................................................................................................59, 79, 86, 87 
 

odds ratio .....................................................................................................................................................................68 
 

partition coefficients......................................................................................................................................21, 22, 105 
 

PBPK..............................................24, 86, 103, 105, 109, 114, 115, 116, 118, 122, 123, 127, 134, 157, 158, 166, 222 
 

pharmacodynamic......................................................................................................................................114, 134, 164 
 

pharmacokinetic....................................................................................... 16, 77, 86, 114, 115, 122, 123, 134, 142, 225 
 

pharmacokinetics...............................................................................................................................................131, 134 
 

photolysis...................................................................................................................................................................191 
 

physiologically based pharmacokinetic (PBPK) model.................................................................................24, 78, 117 
 

placenta..............................................................................................................................................................100, 143 
 

polyvinyl chloride (see PVC) ....................................................................................................2, 13, 72, 172, 179, 217
 

pulmonary fibrosis.......................................................................................................................................................50 
 

PVC (see polyvinyl chloride) ....................2, 3, 4, 6, 7, 10, 13, 16, 50, 59, 66, 67, 70, 71, 73, 78, 79, 84, 85, 104, 130, 
 

....................................152, 159, 172, 176, 179, 182, 183, 194, 197, 198, 200, 202, 203, 206, 208, 209, 210, 216, 217
 

rate constant.......................................................................................................................................118, 121, 122, 191 
 

renal effects .........................................................................................................................................................58, 127 
 

retention.....................................................................................................................................................103, 111, 218 
 

sarcoma............................................................................................................................................................18, 70, 73 
 

scleroderma........................................................................................................ 14, 59, 61, 62, 124, 130, 138, 140, 148
 

solubility............................................................................................................................................153, 157, 158, 189 
 

tetrachloroethylene ................................................................................................................................2, 179, 185, 189 
 

thrombocytopenia ........................................................................................................................................................52 
 

thyroid .........................................................................................................................................................59, 128, 130 
 
VINYL CHLORIDE D-3 

APPENDIX D 

toxicokinetic ................................................................................ 25, 103, 127, 134, 152, 153, 154, 155, 162, 163, 164 
 

tremors...................................................................................................................................................................15, 64 
 

trichloroethylene....................................................................................................................2, 142, 179, 185, 189, 192 
 

tumors............................................................ 16, 18, 19, 28, 71, 74, 75, 76, 77, 78, 85, 86, 96, 97, 126, 133, 142, 156
 

vapor pressure....................................................................................................................................................189, 190 
 

volatility.............................................................................................................................146, 157, 158, 189, 190, 209 
 

volatilization..................................................................................................................13, 85, 182, 189, 190, 191, 208
 

weanling ..............................................................................................................................................................95, 133 
 
VINYL CHLORIDE D-4 

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