VINYL CHLORIDE
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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ATSDR/TP-88/25
TOXICOLOGICAL PROFILE FOR
VINYL CHLORIDE
Date Published — August 1989
Prepared by:
Syracuse Research Corporation
under Contract No. 68-C8-0004
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. 1857-B026-A1
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DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substance* and Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund)
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans."
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
iii
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Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
Ut«*u-
James 0. Mason, M.D. , Dr. P.M.
Assistant Surgeon General
Administrator, ATSDR
iv
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CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xL
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS VINYL CHLORIDE? 1
1.2 HOW MIGHT I BE EXPOSED TO VINYL CHLORIDE? 1
1.3 HOW DOES VINYL CHLORIDE GET INTO MY BODY? 2
1.4 HOW CAN VINYL CHLORIDE AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO VINYL CHLORIDE? 2
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 3
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH? 3
2. HEALTH EFFECTS SUMMARY 7
2.1 INTRODUCTION 7
2.2 LEVELS OF SIGNIFICANT EXPOSURE 8
2.2.1 Key Studies and Graphical Presentations 8
2.2.1.1 Inhalation 8
2.2.1.2 Oral 15
2.2.1.3 Dermal 15
2.2.2 Biological Monitoring as a Measure of
Exposure and Effects 15
2.2.3 Environmental Levels as Indicators of
Exposure and Effects 16
2.2.3.1 Levels found in the environment 16
2.2.3.2 Human exposure potential 18
2. 3 ADEQUACY OF DATABASE 19
2.3.1 Introduction 19
2.3.2 Health Effect End Points 19
2.3.2.1 Introduction and graphic summary 19
2.3.2.2 Descriptions of highlights of graphs .... 22
2.3.2.3 Summary of relevant ongoing research .... 23
2.3.3 Other Information Needed for Human
Health Assessment 23
2.3.3.1 Pharmacokinetics and mechanisms of
action 23
2.3.3.2 Monitoring of human biological samples .. 24
2.3.3.3 Environmental considerations 24
3. CHEMICAL AND PHYSICAL INFORMATION 25
3.1 CHEMICAL IDENTITY 25
3.2 PHYSICAL AND CHEMICAL PROPERTIES 25
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Concents
4 . TOXICOLOGICAL DATA
4 . 1 OVERVIEW
4 . 2 TOXICOKINETICS
4.2.1 Absorption
4.2.1.1 Inhalation
4.2.1.2 Oral
4.2.1.3 Dermal
4.2.2 Distribution
4.2.2.1 Inhalation
4.2.2.2 Oral
4.2.2.3 Dermal
4.2.3 Metabolism
4.2.3.1 Inhalation
4.2.3.2 Oral
4.2.3.3 Dermal
4.2.4 Excretion
4.2.4.1 Inhalation
4.2.4.2 Oral
4.2.4.3 Dermal
4.2.4.4 Parenteral
4 . 3 TOXICITY
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Inhalation
4.3.1.2 Oral
4.3.1.3 Dermal
4.3.2 Systemic/Target Organ Toxicity
4.3.2.1 Hepatotoxicity
4.3.2.2 Nervous system effects
4.3.2.3 Other systemic effects
4.3.3 Developmental Toxicity
4.3.3.1 Inhalation
4.3.3.2 Oral
4.3.3.3 Dermal
4.3.3.4 General discussion
4.3.4 Reproductive Toxicity
4.3.4.1 Inhalation
4.3.4.2 Oral
4.3.4.3 Dermal
4.3.4.4 General discussion
4 . 3 . 5 Genotoxicity
4 , V 5 . 1 Human
4.3.5.2 Nonhuman
4 . 3 . 5 . 3 General discussion
4.3.6 Carcinogeniclty
4.3.6.1 Inhalation
4.3.6.2 Oral
4.3.6.3 Dermal
4.3.6.4 General discussion
4.4 INTERACTIONS WITH OTHER CHEMICALS
5 . MANUFACTURE. IMPORT. USE, AND DISPOSAL
5 . 1 OVERVIEW
5 . 2 PRODUCTION
5 . 3 IMPORT
29
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vi
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Concent*
5.4 USES
5 . 5 DISPOSAL
.................. 64
6 . ENVIRONMENTAL FATE ...................... 65
6 . 1 OVERVIEW .............................. .................. 65
6 . 2 RELEASES TO THE ENVIRONMENT ........ . .................... 65
6 . 3 ENVIRONMENTAL FATE .......... .................. 65
'''''''''''''''''"
6-3-2 Water
6-3.3 Soil
66
7. POTENTIAL FOR HUMAN EXPOSURE ... 6g
7 . 1 OVERVIEW ....................... '.'.'.'.'.'.'.'.'.'.'.'.'.'. ........... 69
7 . 2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ......... 69
7-2. i Air ....................................... ;;;;;;; 69
7.2.2 Water ............... 70
7.2.3 Soil ................ ................... 71
7.2.4 Other ................ ................... 7{
7 . 3 OCCUPATIONAL EXPOSURES ....... ....................... 72
7.4 POPULATIONS AT HIGH RISK ................ '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'. 72
8 . ANALYTICAL METHODS .................... 7,
8 . 1 ENVIRONMENTAL MEDIA ............ '.'. ....................... 73
8 . 2 BIOMEDICAL SAMPLES .............. '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'. 73
9. REGULATORY AND ADVISORY STATUS ........ 79
9 . 1 INTERNATIONAL .......... .................. 79
9 . 2 NATIONAL ........................ '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.' 79
9.2.1 Regulations ....................... ,.[. ........... 79
9.2.1.1 Air ................. '.', .................. 79
9.2.1.2 Water ......................... '.'.'.'.'.'.'.'.'.'. 79
9.2.1.3 Food ................................ 79
9.2.1.4 Other ......................... ''." ...... gO
9.2.2 Advisory Guidance .................. '. ............. 80
9.2.2.1 Air ................................. ;;;; 80
9.2.2.2 Water ................................. 80
9.2.3 Data Analysis ....................... '.'.'.'.'.'.'.'.'.'.'.'.'. 80
9.2.3.1 Reference doses (RfDs) .................. 80
9.2.3.2 Carcinogenic potency .................. 81
9.3 STATE ................. ..... . ..... . ................ ;;;;; JJ
10. REFERENCES [[[ 83
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LIST OF FIGURES
1.1 Health effects from breathing vinyl chloride 4
1.2 Health effects from ingesting vinyl chloride 5
2.1 Effects of vinyl chloride--inhalation exposure 9
2.2 Effects of vinyl chloride--oral exposure 10
2.3 Levels of significant exposure for vinyl chloride--
inhalation 11
2.4 Levels of significant exposure for vinyl chloride--oral 12
2.5 Urinary output of thiodiglycolic acid from volunteers
12 h after exposure to vinyl chloride in air for 12 h 17
2.6 Availability of information on health effects of
vinyl chloride (human data) 20
2.7 Availability of information on health effects of
vinyl chloride (animal data) 21
4.1 Proposed metabolic pathways for vinyl chloride 33
ix
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LIST OF TABLES
3 . 1 Chemical identity of vinyl chloride .......................... 26
3.2 Physical and chemical properties of vinyl chloride .......... 27
4.1 Excretion of radioactivity in rats exposed to ^C- vinyl
chloride in air for 6 h ..................................... 16
4.2 Percent of administered dose of radioactivity excreted 72 h
following a single oral dose of 14C- vinyl chloride
in rats [[[ 38
4.3 Experimental protocol for animal exposure to vinyl chloride .. 41
4.4 Genotoxicity of vinyl chloride in vivo ...................... 52
4.5 Genotoxicity of vinyl chloride in vitro ...................... 54
4.6 Tumor incidence in male and female Sprague-Dawley
rats exposed by inhalation to vinyl chloride
4 h/day, 5 days/week for 52 weeks ............................ 57
4.7 Tumor incidence in Uistar rats orally exposed to
vinyl chloride ............................................... 59
8.1 Analytical methods for the quantification of vinyl chloride .. 75
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS VINYL CHLORIDE?
Vinyl chloride is a colorless gas with a mild, sweet odor. It is a
man-made chemical that does not occur naturally in the environment Most
of the vinyl chloride produced in the United States is used to make
polyvinyl chloride (PVC). This material is used to manufacture a variety
of plastic and vinyl products including pipes, wire and cable coatings,
packaging materials, furniture and automobile upholstery, wall
coverings, housewares, and automotive parts. Much smaller amounts of
vinyl chloride are used as a cooling gas and in the manufacture of other
compounds.
1.2 HOW MIGHT I BE EXPOSED TO VINYL CHLORIDE?
Humans are exposed to vinyl chloride from environmental and
occupational sources. Vinyl chloride has been found in at least 133 of
1.177 hazardous waste sites on the National Priorities List (NPL). Vinyl
chloride is mainly released into the air and discharged in wastewater
from the plastics industries (primarily vinyl chloride and PVC
manufacturers). Most of the vinyl chloride that enters the environment
eventually ends up in air where it gradually breaks down into less
harmful substances. The levels of vinyl chloride found in the
environment are usually more than a thousand times lower than levels
found in occupational settings. Outdoor levels in the environment are
usually expressed in terms of parts of vinyl chloride present in a
billion parts of air or water (ppb). Outdoor levels of vinyl chloride
result from the discharge of exhaust gases from factories that
manufacture or process vinyl chloride, or evaporation from areas where
chemical wastes are stored. Highest outdoor levels have been measured in
air near vinyl chloride factories or over chemical waste storage areas
Tests published in 1976 suggest that the air inside new cars may contain
levels of vinyl chloride higher than expected for that location, because
vinyl chloride may seep into the air from the new plastic parts. Levels
of vinyl chloride are expected to drop rapidly, however, when doors or
windows are opened or when the heater or air conditioner is operated.
Vinyl chloride that enters drinking water comes from factories that
release wastes containing it into rivers and lakes and from its seepage
into underground water in areas where chemical wastes containing it are
stored. Small amounts of vinyl chloride can enter the drinking water
from contact with polyvinyl chloride pipes. In the past, higher than
expected amounts were present in foods packaged in plastic that
contained vinyl chloride. Currently, the U.S. Food and Drug
Administration (FDA) limits the amount of vinyl chloride allowed in
packaging materials that contact food in order to limit the intake of
vinyl chloride.
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2 Section 1
Vinyl chloride manufacturing or processing factories may have
indoor levels of vinyl chloride that are much higher than those from
outdoor sources. Levels expressed in terms of parts of vinyl chloride
per million parts of air (ppm) have been measured in vinyl chloride
manufacturing plants.
1.3 HOV DOES VINYL CHLORIDE GET INTO XT BODY?
The most likely way that vinyl chloride can enter your body is if
you breathe air containing it. This path of exposure is of concern for
persons employed in vinyl chloride manufacturing or processing, for
people living in communities where vinyl chloride plants are located,
and for individuals living near hazardous waste disposal sites. Vinyl
chloride can also enter your body if you eat food or drink water
containing it. Passage of vinyl chloride through the skin is not likely
to be an important pathway.
1.4 HOV CAN VINYL CHLORIDE AFFECT MY HEALTH?
Short-term exposures to very high levels of vinyl chloride in air
can cause dizziness, stumbling and lack of muscle coordination,
headache, unconsciousness, and death. Long-term exposure to lower but
unmeasured amounts in factories where vinyl chloride is made or
processed has caused "vinyl chloride disease." This disease is
characterized by severe damage to the liver, effects on the lungs, poor
circulation in the fingers, changes in the bones at the end of the
fingers, thickening of the skin, and changes in the blood. An increased
risk of developing cancer of the liver and possibly several other
tissues has been linked with breathing air in factories containing vinyl
chloride. Studies designed to determine if the low levels of vinyl
chloride measured in outside air, drinking water, or food could cause
harmful effects in humans have not been performed.
Some of the health effects observed in humans have also been seen
in laboratory animals. Effects on the nervous system of animals have
occurred after short-term exposure to very high levels of vinyl chloride
in air. Effects on the liver developed in animals after short-term
exposure to high levels and after longer-term exposure to lower levels
of vinyl chloride. Kidney effects also occurred after exposure to high
levels. Laboratory animals developed cancer in several tissues after
eating food or breathing air that contained vinyl chloride. Effects on
the testes were seen in male rats that breathed air containing vinyl
chloride, but information is not sufficient to determine whether humans
exposed to vinyl chloride develop effects on the testes.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO VINYL CHLORIDE?
Vinyl chloride can be measured in urine and body tissues, but the
tests cannot be used to determine what levels of vinyl chloride you were
exposed to. Measuring the amount of the major breakdown product of vinyl
chloride in the urine may give some indication of recent exposure;
however, people differ in the quantity of excretion of this breakdown
product. Neither of these tests is routinely available at your doctor's
office. The laboratory tests commonly used by doctors to evaluate liver
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Public HeaLch Seacement 3
damage and liver function are usually not helpful for determining if
liver damage from vinyl chloride exposure has occurred.
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
The graphs on the following pages show the link between exposure to
vinyl chloride and known health effects. In the first set of graphs
labeled "Health effects from breathing vinyl chloride" (Fig. 1.1),
exposure is expressed in parts of vinyl chloride per million parts of
air (ppm). In the second set of graphs, the same relationship is shown
for the known "Health effects from ingesting vinyl chloride" (Fig. 1.2).
Exposures are expressed in milligrams of vinyl chloride per kilogram of
body weight per day (mg/kg/day). In both graphs, effects in animals are
shown on the left, effects in humans on the right.
The first column, labeled "Short-term exposure," refers to effects
associated with exposure durations of 14 days or less. The column
labeled "Long-term exposure" refers to exposures lasting longer than 14
days. The levels marked on the graphs as "Minimal risk for effects othej
than cancer" are estimates based on information obtained from laboratory
animals and, therefore, are subject to the uncertainties involved in
using animal data to predict effects in humans.
Vinyl chloride is regarded worldwide as a chemical that causes
cancer in humans, but exposure levels necessary to cause cancer in
humans are not known. The Environmental Protection Agency (EPA),
therefore, used available data in animals to estimate that breathing air
containing 1 ppm vinyl chloride every day for 70 years may place as many
as 1,100 persons in a population of 10,000 (or 1,100,000 persons in a
population of 10,000,000) at risk of developing cancer. Eating food
containing 1 ppm vinyl chloride every day for 70 years may place as many
as 644 persons in a population of 10,000 (or 644,000 persons in a
population of 10,000,000) at risk of developing cancer. Similarly,
drinking water containing 1 ppm vinyl chloride every day for 70 years
may place as many as 657 persons in a population of 10,000 (or 657,000
persons in a population of 10,000,000) at risk of developing cancer. It
should be noted that these risk values are plausible upper-limit
estimates based on information obtained from animal studies. Actual risk
levels are unlikely to be higher and may be lower.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
EPA stated that community drinking water systems that regularly
serve the same 25 persons for at least 8 months of the year must limit
vinyl chloride in the drinking water to 2 j*g/L (2 ppb) , starting
January 9, 1989. In order to limit intake of vinyl chloride in food to
levels considered to be safe, the Food and Drug Administration (FDA)
recently changed its regulations regarding the vinyl chloride content of
various plastics that contact food and carry water used in food
processing, and of plastics that are used in food packaging. Limits
range from 5 to 50 ppm, depending on the nature of the plastic and its
use.
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Section 1
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
CONC. IN
AR
(ppm)
EFFECTS
IN
HUMANS
EFFECTS
IN
ANIMALS
CONC. IN
AIR
(ppm)
EFFECTS
IN
HUMANS
10.000
10.000
EFFECTS ON
BRAIN FUNCTION
EFFECTS -
DEATH.—
LIVER
EFFECTS
,1.000
1.000
100
100
TESTICULAR
EFFECTS
10
REDUCED
LIFE SPAN-
LIVER 1Q
EFFECTS- °
1.0
1.0
0.1
0.1
QUANTITATIVE DATA
WERE NOT
AVAILABLE
Fit. 1.1. HnJdi effect! tnm
ffayl
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Public Health Statement
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
DOSE
(mg/kg/day)
EFFECTS
IN
HUMANS
EFFECTS
IN
ANIMALS
OOSE
(mg/kg/day)
EFFECTS
IN
HUMANS
1.000
DEATH-
1.000
QUANTITATIVE
DATA WERE
NOT AVAILABLE
100
100
10
EFFECTS ON
BLOOD
10
1 0
10
DECREASED LIFE
SPAN AND LIVER
EFFECTS
01
01
0.01
001
0.001
0.001
• MINIMAL RISK
LEVEL FOR
EFFECTS
OTHER THAN
CANCER
Fig. 1.2. Health effects from ingesting vinyl chloride.
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6 Section 1
In order to control the handling of vinyl chloride, EPA has named
the chemical as a hazardous component of solid waste. If quantities
greater than 1 pound are released to the environment, the National
Response Center of the Federal Government must be notified immediately.
The Occupational Safety and Health Administration (OSHA)
regulations state that a worker must not be exposed to a concentration
of vinyl chloride in air that exceeds 1 ppm over any 8-hour work period
in a 40-hour workweek and that the concentration must not exceed 5 ppm
for more than 15 minutes. The National Institute for Occupational Safety
and Health (NIOSH) recommends that workers exposed to any measurable
amount of vinyl chloride wear an air-supplied respirator. EPA has
determined that factories must limit the release of vinyl chloride in
air to 10 ppm.
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2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to vinyl chloride. The purpose of this section is to
present levels of significant exposure for vinyl chloride based on key
toxicological studies, epidemiological investigations, and environmental
exposure data. The information presented in this section is critically
evaluated and discussed in Sect. 4, Toxicological Data, and Sect. 7,
Potential for Human Exposure.
This Health Effects Summary section comprises two major parts
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of vinyl chloride and (2) a
summarized depiction of significant exposure levels associated with
various adverse health effects. This section also includes information
on the levels of vinyl chloride that have been monitored in human fluids
and tissues and information about levels of vinyl chloride found in
environmental media and their association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt clinical findings in exposed
persons or with the identification of persons with the potential to
develop such disease may be interested in levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health officials
and project managers concerned with response actions at Superfund sites
may want information on levels of exposure associated with more subtle
effects in humans or animals (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse -Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels, MRL) are of interest
to health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies on exposure to vinyl chloride in the scientific literature and
displays these data in three-dimensional graphs consistent with the
format in Sect. 2.2. The purpose of this section is to suggest where
there might be insufficient information to establish levels of
significant human exposure. These areas will be considered by the Agency
for Toxic Substances and Disease Registry (ATSDR). EPA, and the National
Toxicology Program (NTP) of the U.S. Public Health Service in order to
develop a research agenda for vinyl chloride.
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8 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of exposure--
inhalation, ingestion, and dermal--and then by toxicological end points
that are categorized into six general areas--lethality, systemic/target
organ toxicity, developmental toxicity, reproductive toxicity, genetic
toxicity, and carcinogenicity. The data are discussed in terms of three
exposure periods--acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type is
a "thermometer" graph. It provides a graphical summary of the human and
animal toxicological end points (and levels of exposure) for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing NOAELs and
LOAELs reflect the actual doses (levels of exposure) used in the key
studies. No adjustments for exposure duration or intermittent exposure
protocol were made.
Adjustments reflectii 3 the uncertainty of extrapolating animal data
to man, intraspecies variations, and differences between experimental vs
actual human exposure conditions were considered when estimates of
levels posing minimal risk to human health were made for noncancer end
points. These minimal risk levels were derived for the most sensitive
noncancer end point for each exposure duration by applying uncertainty
factors. These levels are shown on the graphs as a broken line starting
from the actual dose (level of exposure) and ending with a concave-
curved line at its terminus. Although methods have been established to
derive these minimal risk levels (Barnes et al. 1987), shortcomings
exist in the techniques that reduce confidence in the projected
estimates. Also shown on the graphs under the cancer end point are low-
level risks (10"^ to 10'7) reported by EPA. In addition, the actual dose
(level of exposure) associated with the tumor incidence is plotted.
2.2.1 Key Studies and Graphical Presentations
Dose-response-duration data for the toxicity and carcinogenicity of
vinyl chloride are displayed in two types of graphs. These "data are
derived from the key studies described in the following sections. The
"thermometer" graphs in Figs. 2.1 and 2.2 plot exposure levels vs NOAELs
and LOAELs for various effects and durations of inhalation and oral
exposures, respectively. The graphs of levels of significant exposure in
Figs. 2.3 and 2.4 plot end-point-specific NOAELs and LOAELs and minimal
levels of risk for acute (<14 days), intermediate (15-364 days), and
chronic (>365 days) duration for inhalation and oral exposures,
respectively.
2.2.1.1 Inhalation
Lethality and decreased longevity. Acute occupational exposure to
high unspecified concentrations of vinyl chloride has caused death in
humans (ACGIH 1986a) probably due to narcosis. Guinea pigs exposed to
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Health Effects Summary 9
HUMANS
(ppm)
1.000.000 ^»
100.000
10000
1000
100
1 000000 r—
• RABBIT LCW 2 h CONTINUOUS
- • GUINEA PW NAflCOSS AND OEATM. 30-MMN CONTINUXIS
• DOGS. ANESTHESIA
• MATS. INTOXICATION 2 h. CONTINUOUS
• GUINEA PIG. ATAX1A. 2 MM
100000 -
10.000
• RAT RENAL TOXKITY ANEMM. 12 MONTHS. INTERMITTENT
O RABBT. DEVELOPMENTAL TOXIOTV. 13 DAYS. INTERMTrTENT
^*RAT. DEVELOPMENTAL TOXICfTV 7-6 DAYS. INTERMrTTENT
°J» MOUSE. ACUTE LETHALITY. HEPATOTOJOCITY t DAYS INTERMTrTENT
I* MOUSE. BODY WEIGHT LOSS. • MONTHS. MTERMTTENT
O RAT DEVELOPMENTAL TOXKITY. 10 DAYS. MTERMnTENT
(O MOUSE. ACUTE LETHALITY. MTERMnTENT
\O MOUSE. BODY WEIGHT LOSS 12 MONTHS. MTERMnTENT
• RAT.HEPATOTOXICrTY 6 MONTHS. INTERMTrTENT
• RAT REDUCED BODY WEIGHT TESDCULAP EFFECTS. 12 MONTHS. INTEPMTTENT
6 MOUSE. DEVELOPMENTAL TOXICrTY. 10 DAYS. INTEHMrTTENT
• RAT. MOUSE. REDUCED SURVIVAL, S-12 MONTHS. INTERMnTENT
• RAT. HEPATOTOXXaTY. 12 MONTHS. INTERMnTENT
• RAT. UVER CANCER 52 WEEKS. WTERMTTENT
• HAMSTER. MOUSE. UVER CANCER. 30 WEEKS. INTERMTTENT
MOUSE. LUMP CANCER 4 WEEKS. INTERMTTTENT
RAT. HEPATOTOXtOTY a MONTHS. INTERMnTENT
RAT. REDUCED BODY WEIGHT TESTCULAR EFFECTS. 12 MONTHS. INTERMTTTENT
1.000
100
* CNS EFFECTS
L- A GENOTOXICITY
• LOAELFORANMALS
O NOAELFORANUMLS
A LOAEL FOR HUMANS
A NOAEL FOR HUMANS
Flf.2.1. Effeett of
-------
10 Section 2
ANIMALS
(mg/kg/day)
1000 r—
100
10
01 I—
RAT. LD,o
RAT. HEPATOXOCITY. 13 WEEKS
HUMANS
O RAT. HEPATOTOXICITY. 13 WEEKS
• RAT. HEMATOLOGIC EFFECTS. LIFETIME
O RAT. HEMATOLOGIC EFFECTS. LIFETIME
• RAT. CANCER. LIFETIME
• RAT. DECREASED SURVIVAL. HEPATOTOXICITY. LIFETIME
O RAT. DECREASED SURVIVAL. HEPATOTOTXICITY. LIFETIME
• LOAEL
O NOAEL
QUANTITATIVE DATA
WERE NOT AVAILABLE
Fig. 2.2. Effects of vinyl chloride—oral exposure.
-------
Health Effects Summary 11
ACUTE
(SI 4 DAYS)
INTERMEDIATE
(15-364 DAYS)
CHRONIC
12365 DAYS)
DEVELOP TARGET TARGET REPRO DECREASED TARGET
LETHALITY MENTAL ORGAN LETHALITY ORGAN DUCTION LONGEVITY ORGAN CANCER
ippm)
1 000.000 r
100.000
•g
• d(CNS)
• r (CNS)
10000
A (CNS)
1 000
100
10
1 0
0 1
001
r
Or
• m(LIVER)
r(TESTIS)
'(LIVER) •' s
ff (LIVER) 6
Vl/
0001
00001
000001 -
0 000001
10-* -,
to-' J
ESTIMATED
UPPER BOUND
HUMAN
CANCER
RISK LEVELS
h RABBIT
g GUINEA PIG
0 DOG
r RAT
m MOUSE
S HAMSTER
A LOAEL FOR HUMANS
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
!
LOAEL AND NOAEL
IN THE SAME SPECIES
I MINIMAL RISK LEVEL
I FOR EFFECTS OTHER
I THAN CANCER
Fig. 2.3. Levels of significant exposure for vinyl chloride—inhalation.
-------
12 Section 2
ACUTE INTERMEDIATE CHRONIC
(SI 4 DAYS) ( 1 5-384 DAYS) (2365 DAYS)
DEVELOP- TARGET TARGET REPRO- DECREASED
LETHALITY MENTAL ORGAN LETHALITY ORGAN DICTION LONGEVITY
(mgfkgftjiy)
1 000
100
10
1
0 1
001
0001
00001
0 00001
0 000001
0000001
~
• r (LIVER)
'
• r
O
-
_
-
TARGET
ORGAN CANCER
• r(HEMAT)
• r(UVER) *'
-•
w
10-*-,
ESTIMATED
UPPER BOUND
HUMAN
10-»- CANCER
RISK LEVELS
<-
r RAT •LOAEL • LOAEL AND NOAEL i MINIMAL RISK LEVEL
ONOAEL A IN THE SAME SPECIES i FOR EFFECTS IN
THE SAME SPECIES
Fig. 2.4. Leveb of significant exposure for rinyl chloride—oral.
-------
Health Effects Summary 13
100,000 ppm died vichin 30 minutes as a result of central nervous system
(CNS) depression (Patty et al. 1930). Levels plotted as LOAELs on the
graphs in Figs. 2.1 and 2.3 include a 2-h LC5Q of 230,800 ppm in rabbits
(EPA 198Sa), a level of 100,000 ppm that was lethal in guinea pigs after
30 to 60 min (Patty et al. 1930), a level of 1,000 ppm that decreased
survival in mice exposed intermittently for 5 days (Lee et al. 1977a),
and a level of SO ppm that decreased survival in rats and mice exposed
intermittently for 6 to 12 months (Lee et al. 1977a, Hong et al. 1981).
Systemic/target organ toxicity. Humans occupationally exposed to
high levels of vinyl chloride have suffered from a syndrome called vinyl
chloride disease, which displays manifold signs of toxicity involving
the liver, CNS, and peripheral circulation and nerves. Exposures have
not been quantified, however, and thresholds for this syndrome have not
been identified. Important target organs in animals are the liver and
CNS. CNS effects generally follow acute exposure to high levels (see
Figs. 2.1 and 2.3), such as 8,000 ppm associated with CNS effects in
humans (Lester et al. 1963), 70,000 ppm associated with anesthesia in
dogs (Oster et al. 1947), and 50,000 ppm associated with intoxication in
rats (Lester et al. 1963). CNS effects involving occupational exposure
have been reported, but exposures have not been quantified (Dinceva et
al. 1985, Perticoni et al. 1986, Halama et al. 1985).
The liver appears to be the most sensitive organ in humans and
animals. Acute hepatotoxicity was observed in mice dying after
intermittent exposure to 1,000 ppm for 5 to 9 days (Lee et al. 1977a)
(see Figs. 2.1 and 2.3). In rats, exposures of intermediate (6 months)
duration to 10 ppm were a LOAEL for liver effects (Bi et al. 1985) (see
Figs. 2.1 and 2.3). A chronic LOAEL for liver effects in rats was
observed at 50 ppm in a chronic (12 months) experiment (Lee et al.
1977a) (see Figs. 2.1 and 2.3). However, since this was the lowest
concentration tested, a chronic NOAEL could not be determined. After
12-month exposure, 100 ppm was a LOAEL and 10 ppm was a NOAEL for
reduced terminal body weights in rats (Bi et al. 1985) (Fig. 2.1).
Minimal risk levels are not estimated in Fig. 2.3 based on liver
toxicity at the acute level of 1,000 ppm, because this level was a frank
effect level, and a NOAEL or LOAEL was not identified. A minimal risk
level of 0.005 ppm for intermediate exposure is based on the LOAEL for
liver effects observed in rats exposed intermittently to 10 ppm for
6 months (Bi et al. 1985). Data were not sufficient to estimate a
minimal risk level for chronic exposure.
Developmental toxicity. Several epidemiology studies (Infante et
al. 1976; Vaxweiler et al. 1977; Theriault et al. 1983; Edmonds et al.
1975, 1978) and evaluations of these studies (Hatch et al. 1981,
Stallones 1987, Downs et al. 1977, The Vinyl Institute 1987) have
investigated the effects of vinyl chloride exposure on the incidence of
fetal loss and birth defects. No solid association has been found.
Animal data identify a NOAEL for developmental toxicity in rabbits
exposed intermittently to 2,500 ppm on days 6 to 18 of gestation (John
et al. 1977). The same study identifies intermittent exposure of mice at
50 ppm on days 6 to 15 of gestation as a NOAEL. A NOAEL for rats of
1,500 ppm exposed Intermittently on 10 days of gestation was identified
from a study by Ungvary et al. (1978). The animal data are depicted in
Figs. 2.1 and 2.3.
-------
14 Section 2
Two studies indicating subtle effects at unusually low exposure
levels (Mirkova et al. 1978, Sal'nikova and Kitsovskaya 1980) were
insufficiently reported and judged to be inadequate for critical
evaluation.
Reproductive toxlcity. Two occupational studies associated effects
on sexual and endocrinological function in men and women and on
gynecological health in women with exposure to vinyl chloride (Makarov
1984, Makarov et al. 1984). Although exposure levels were estimated, the
reports were inadequately reported for critical evaluation, and the data
from these studies are not plotted on the graphs. In a 1-year study in
rats, intermittent exposure to 100 ppm was a LOAEL for testicular
effects and 10 ppm was a NOAEL (see Figs. 2.1 and 2.3) (Bi et al.,
1985). In an earlier study, Torkelson et al. (1961) observed no effects
on relative testicular weight in rats exposed intermittently to 500 ppm
for 4.5 months or in dogs, rabbits, or guinea pigs exposed
intermittently to 200 ppm for 6 months. The quality of this study was
limited, however, because small numbers of animals were used.
Genotoxicity. Several studies reviewed in Sect. 4.3.5.1 on
genotoxicity in humans suggest that vinyl chloride causes chromosomal
aberrations in lymphocytes in occupationally exposed workers. The key
study (Hansteen et al. 1978) identified a NOAEL of 1 ppm for this
effect. Positive results were obtained in microorganisms in nonhuman
systems, in the recessive lethal test in Drosophila and in other
mammalian test systems (see Section 4.3.5.2 on genotoxicity in animals).
Carcinogenicity. Several epidemiology studies, many of which have
been reviewed by EPA (1985b), associated occupational exposure to vinyl
chloride with cancers of the liver and possibly of the brain.
Concentrations of vinyl chloride in the workroom air were not measured.
In the key studies used by EPA (1985b) to derive an inhalation potency
factor (Haltoni et al. 1980, 1981), rats were exposed intermittently to
1 to 30,000 ppm for 52 weeks, and mice and hamsters were exposed to 50
to 30,000 ppm for 30 weeks followed by an observation period. Estimation
of carcinogenic potency was based on the incidence of liver
angiosarcomas in rats. A statistically significant increase in tumor
incidence was observed in all three species at i50 ppm. Several other
inhalation studies, reviewed in Sect. 4.3.6, Carcinogenicity, support
the Carcinogenicity of inhalation exposure to vinyl chloride-. Studies by
Suzuki (1981, 1983) appear to define intermittent exposure of mice to
10 ppm as a level associated with increased incidence of lung cancer.
Mice were exposed for 4 weeks followed by a 41-week observation period.
The concentration of 50 ppm associated with cancer in rats and hamsters
and the concentration of 10 ppm associated with lung cancer in mice are
depicted in Figs. 2.1 and 2.3.
From the incidence of liver angiosarcomas in rats of both sexes in
the Maltoni et al. (1980, 1981) experiments, and based upon the absorbed
doses of vinyl chloride, an upper bound q.* of 2.95 x 10'^ (mg/kg/day)'1
was estimated by EPA (1985b). Assuming humans breathe 20 m3/day, absorb
50% of inhaled vinyl chloride, and weigh 70 kg each, estimated
concentrations associated with cancer risks of 10'4, 10'5, 10'6, and
lO'7 are 9 x 10'4, 9 x 10'5, 9 x 10'6, and 9 x 10'7 ppm, respectively
(see Fig. 2.3).
-------
Health Effects Summary 15
2.2.1.2 Oral
Lethality and decreased longevity. Oral lethality data are Limited
to an LD50 in rats of 500 mg/kg (Sax 1984) , and an effect level of
1.3 mg/kg/day and a .NOAEL of 0.13 mgAg/day in a lifetime dietary study
in rats (Til et al. 1983) (see Figs. 2.2 and 2.4).
Systemic/target organ tozicity. Oral toxicity data were not
located for humans. The liver appears to be the critical target organs
for animals orally exposed to vinyl chloride. In a 13-week gavage study
in rats, 300 mgAg/day was a LOAEL and 30 mgAg/day was a NOAEL for
hepatotoxicity (Feron et al. 1975) (see Figs. 2.2 and 2.4). A minimal
risk level of 0.30 mgAg/day is estimated for intermittent oral exposure
based on the NOAEL of 30 mgAg/day (see Fig. 2.4). In a lifetime dietary
study in rats (Til et al. 1983), a LOAEL of 1.3 mgAg/day and a NOAEL of
0.13 mgAg/day for hepatotoxicity were identified (see Figs. 2.2 and
2.4). A minimal risk level for chronic oral exposure is estimated from
the NOAEL of 0.13 mgAg/day for hepatotoxicity because this dose is also
a NOAEL for decreased longevity. The minimal risk level is -0.0013
mgAg/day (see Fig. 2.4). Other effects observed in a lifetime dietary
study in rats by Feron et al. (1981) include mild hematological changes
at >14.1 mgAg/day, but not at 5.0 mgAg/day. These data are depicted in
Fig. 2.2, but have no bearing on critical evaluation.
Developmental tozicity. Data were not located regarding
developmental toxicity in orally exposed humans or animals.
Reproductive tozicity. Data were not located regarding
reproductive toxicity in orally exposed humans or animals.
Genotozicity. See Sect. 2.2.1.1 on genotoxicity associated with
inhalation exposure.
Carcinogenicity. Data were not located regarding cancer in orally
exposed humans. In the key lifetime dietary study in rats (Feron et al.
1981) used by EPA (1985a, 1987a) to derive a potency estimate for oral
exposure, rats were fed diets that provided vinyl chloride at doses of
1.8, 5.6, or 17.0 mgAg/day for lifetime. An increased incidence of
neoplastic nodules of the liver and/or hepatocellular carcinoma,
statistically significant, was observed at >1.8 mgAg/day in females and
at >5.6 mgAg/day in males. The lower dose is depicted in Fig. 2.4 as
the lowest dose in animals associated with cancer. EPA (1985a, 1987a)
estimated the upper-bound cancer potency at 2.3 (mgAg/day)'1 based on
the combined incidence of liver and lung tumors in both sexes of rats.
Doses associated with excess cancer risks of 10*^, 10'5, 10'6, and 10'7
are plotted in Fig. 2.4.
2.2.1.3 Dermal
Pertinent data regarding toxicity in humans or animals dermally
exposed to vinyl chloride were not located in the available literature.
2.2.2 Biological Monitoring as a Measure of Exposure and Effects
Biological monitoring for exposure to vinyl chloride has had
limited success. In an early study, Baretta et al. (1969) attempted to
correlate postexposure concentrations of vinyl chloride in exhaled air
-------
16 Section 2
with exposure levels. Although there was a very close relationship
between exposure levels >SO ppm and levels in expired air, the method
does not appear to be useful at exposure concentrations <50 ppm. Methods
have been devised to quantify vinyl chloride in urine (van Sittert and
de Jong 1985) and tissue (Zuccato et al. 1979), but metabolism occurs so
quickly that quantification of levels of unchanged compound in urine is
not likely to reflect exposure levels, particularly at low
concentrations.
More recently, biological monitoring has focused on correlating
urinary levels of thiodiglycolic acid, the major urinary metabolite of
vinyl chloride (Green and Hathway 1977), with exposure levels in the air
(Heger et al. 1982). The results, presented in Fig. 2.5, suggest a
reasonable correlation between exposure concentration and urinary output
of thiodiglycolic acid. In reviewing these data, however, Tarkowski
(1984) noted that a great deal of individual variation occurred, and the
correlation was not strong enough to render this method reliable at
exposure concentrations of <5 ppm. Tarkowski (1984) concluded that no
reliable method exists for biological monitoring of exposure to vinyl
chloride.
As indicated in Sect. 4.3.2.1, Hepatotoxicity, liver disease is
probably the most common adverse effect associated with exposure to
vinyl chloride. Generally, routinely performed biochemical screening and
liver function screening tests have not been useful in monitoring the
presence, severity, or progress of vinyl chloride disease (Lee et al.
1977b, Lilis et al. 1975). More recently, Doss et al. (1984) measured
total urinary porphyrins and secondary urinary coproporphyrin in several
patients with liver disease resulting from exposure to vinyl chloride.
These investigators observed a correlation between slightly to
moderately elevated total urinary porphyrin and the early stages of
toxic liver disease. Particularly noted was a marked elevation in
urinary coproporphyrin. In cases of chronic liver disease, total urinary
porphyrin was markedly elevated to 3 to 6 times the upper normal limit,
but coproporphyrin appeared to be elevated relatively less than was
observed for acute toxicity. The investigators observed that elevated
urinary coproporphyrin is a common clinical pathological finding in
vinyl-chloride-related liver disease and may be useful in monitoring
chronic exposure and progress of the clinical case, althoughvother liver
toxins and an inherited defect can also result in elevated urinary
porphyrin.
2.2.3 Environmental Levels a* Indicators of Exposure and Effects
2.2.3.1 Levels found in the environment
Levels of vinyl chloride in environmental media are typically low
and, generally, are not likely to result in significant human exposure.
The most important medium for human exposure is air. Atmospheric levels
in most places are usually below the level of detection (Stephens et al.
1986; Grimsrud and Rasmussen 1975a,b; Markov et al. 1984; Wallace et al.
1984; EPA 1985b). Levels from trace to 8.8 mg/m3 (3.4 ppm) have been
found near vinyl chloride production plants (Gordon and Keeks 1977,
Pellizzarl et al. 1979, IARC 1979, EPA 1985b), and levels have ranged
from undetectable to 30.8 Mg/m3 (0.012 ppm) over landfills (Stephens et
-------
Health Effects Suaaary
17
11
10
9
3 8
E
I*
I 4
1 3
2
1 h
0
•I
6 8 10 12 14 16 18 20 22 24
CONCENTRATION IN AIR (ppm)
Fig. 2.5. Urinary output of thiodiglycolic acid from volunteers 12 h after exposure to vinyl
chloride in air for 12 a. Source: Tarkowski 1984.
-------
18 Section 2
al. 1986, Baker and Mackay 1985). Vinyl chloride in air over landfills
may originate from the disposal of vinyl chloride containing wastes or
from the degradation of trichloroethylene, tetrachloroethylene, or
1,1,1-trichloroethane (HSDB 1987, Wilson and Wilson 1985, Smith and
Dragun 1984). It is unlikely that levels in ambient air would result in
significant exposure.
Several epidemiological studies associated occupational exposure
with adverse health effects, including cancer; however, these studies
(see Sect. 4, Toxicological Data) did not quantify exposure. A NIOSH
survey of three vinyl chloride manufacturing plants reported a time-
weighted average concentration of 0.18 to 69 mg/m3 (0.07 to 27 ppm) in
workplace air (Fishbein 1979). Concentrations in some plants were as
high as 100 to 800 mg/m3 (39 to 315 ppm) (Fishbein 1979). There seems
little doubt that occupational exposure remains the most important
source of exposure to vinyl chloride.
Levels in drinking water as high as 10 /ig/L have been detected
(Dyksen and Hess 1982, HSDB 1987), but most monitoring studies have
reported no detectable vinyl chloride in drinking water (HSDB 1987,
Coniglio et al. 1980). Data were not located regarding the monitoring of
vinyl chloride in soil, but exposure from contact with contaminated soil
is likely to be negligible because dermal absorption is not considered
significant (Hefner et al. 1975a).
In the past, vinyl chloride had been detected in various foods as a
result of migration from polyvinyl chloride food wrappings and
containers (EPA 1985b). Currently, the FDA regulates the concentration
of vinyl chloride monomer in polymers that contact food in order to
restrict intake of vinyl chloride to safe levels.
2.2.3.2 Human exposure potential
Monitoring data indicate that people living in the vicinity of
vinyl chloride, PVC, or vinyl chloride copolymer manufacturers, or
hazardous waste sites that contain vinyl chloride, would be exposed to
this compound through inhalation of contaminated air, whereas people not
living near these sources would be exposed to negligible levels.
Locations of large industrial sources include, but are not limited to:
Plaquemine, Louisiana; Houston, Texas; Lake Charles, Louisiana; Calvert
City, Kentucky; Point Comfort. Texas; Oklahoma City, Oklahoma; Baton
Rouge, Louisiana; Delaware City, Delaware; Pensacola, Florida; and
Aberdeen, Massachusetts (CMR 1986a,b). The greatest likelihood for human
inhalation exposure to vinyl chloride is occupational. NIOSH estimated
that 27,000 workers are definitely exposed to vinyl chloride and as many
as 2.2 million workers may probably be exposed (Sittig 1985).
The level of vinyl chloride in drinking water is expected to be
highest in areas where the raw water supplies are contaminated with
vinyl chloride. The most probable source of surface water contamination
is wastewater from vinyl chloride, PVC, and vinyl chloride copolymer
manufacturers. The most probable sources of groundwater contamination
are landfills. It has been shown that use of PVC pipes may result in
leaching of vinyl chloride monomer into drinking water supplies;
however, the concentrations in drinking water that occur from these
pipes are below those expected to cause adverse health effects.
-------
Health Effaces Summary 19
2.3 ADEQUACY OF DATABASE
2.3.1 Introduction
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of
significant human exposure for the substance and the
associated acute, subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and
chronic health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans."
This section identifies gaps in current knowledge relevant to
developing levels of significant exposure for vinyl chloride. Such gaps
are identified for certain health effect end points (lethality,
systemic/target organ toxicity, developmental toxicity, reproductive
toxicity. and carcinogenicity) reviewed in Sect. 2.2 of this profile in
developing levels of significant exposure for vinyl chloride, and for
other areas, such as human biological monitoring and mechanisms of
toxicity. The present section briefly summarizes the availability of
existing human and animal data, identifies data gaps, and summarizes
research in progress that may fill such gaps.
Specific research programs for obtaining data needed to develop
levels of significant exposure for vinyl chloride will be developed by
ATSDR, NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs. 2.6 and 2.7, respectively.
The bars of full height indicate that there are data to meet at
least one of the following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no-effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or "probable human carcinogen" by both EPA
and the International Agency for Research on Cancer (IARC)
-------
HUMAN DATA
SUFFICIENT
INFORMATION*
ro
o
(t
n
§
V SOME
^INFORMATION
NO
INFORMATION
OHAL
INHALATION
DERMAL
HTMAIITT ACUTI IMTCMMEMATI CHNOMC DCVELOPMCNTAL Mraooucnw CAMCINOOCNKITV
L / TOXICfTV TOUCITY
•rsientc TOKICITT
Sufficient rtormation exials to meet at least one o( the criteria for cancer or noocancer and point*.
Fif. 2.6. Availability of informmioo on bealik effects of vfaiyl cUoride (bunun fata).
-------
ANIMAL DATA
SUFFICIENT
INFORMATION*
J
SOME
INFORMATION
NO
INFORMATION
ORAL
INHALATION
DERMAL
LETHALITY ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOOENICITr
/ / TOXICITV TOXICITV
SYSTEMIC TOIICITV
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points
Fig. 2.7. Availability of information on health effects of vinyl chloride (animal data).
it
I
n
in
(ft
-------
22 Section 2
(qualitative), and the data are sufficient to derive a cancer
potency factor (quantitative).
3. For animal carcinogenicity, a substance causes a statistically
significant number of tumors in at least one species, and the data
are sufficient to derive a cancer potency factor.
4. There are studies that show that the chemical does not cause this
health effect via this exposure route.
Bars of half height indicate that "some" information for the end
point exists, but does not meet any of these criteria.
The absence of a column indicates that no information exists for
that end point and route.
2.3.2.2 Description* of highlights of graphs
Figure 2.6 shows that human dose-response data for oral and dermal
exposure are lacking. Data are available that associate high inhalation
levels of vinyl chloride with mortality in acute occupational exposure,
but exposure levels were not quantified; therefore, the graphs indicate
"some" but not "adequate" data. Data were not located for acute or
intermediate inhalation exposure to vinyl chloride. Many epidemiological
studies and case studies have characterized the syndrome known as vinyl
chloride disease in occupationally exposed humans (see paragraph on
vinyl chloride disease from inhalation exposure, human, in Sect.
4.3.2.3). Several epidemiology studies have investigated the effects of
vinyl chloride exposure on the incidence of fetal loss and birth
defects. No solid association was found, and the date are considered
"inadequate" for developmental toxicity in humans. Two studies suggest
that occupational exposure interferes with normal sexual activity and
compromises gynecological health (Hakarov 1984, Makarov et al. 1984).
These data are inadequately reported for critical evaluation, and,
consequently, the graph for reproductive toxicity indicates "some" data.
Although vinyl chloride is clearly a human carcinogen based on
occupational data (see Sect. 4.3.6.1 on carcinogenicity from inhalation
exposure, human), exposures were not quantified, and the data are
classified as "some."
The lack of dermal data is not problematical since dermal
absorption of vinyl chloride vapor is expected to be insignificant
compared with inhalation absorption (Hefner et al. 1975a). Although
there is a lack of oral data in humans, data in relevant animal models
are sufficient to estimate significant levels of exposure for
intermediate and chronic oral exposure. Deficiencies in the human
inhalation toxicity data are somewhat more noteworthy because animal
data are sufficient for estimating a minimal risk level for intermediate
duration but not for chronic inhalation exposure.
From Fig. 2.7 it is apparent that the database for inhalation
exposure in animals is more extensive than for humans. Inhalation data
for acute lethality, intermediate duration toxicity, developmental
toxicity, and carcinogenicity are sufficient for critical evaluation and
are defined as "adequate." Inhalation data for chronic systemic toxicity
are inadequate for defining a range of toxicity and, therefore, are
graphically depicted as "some."
-------
Health Effects Summary 23
The oral database is more nearly complete. Data "adequate" for risk
assessment are available for intermediate and chronic toxicity and
carcinogenicity. However, acute lethality data, limited to an LD50 in
rats (Sax 1984), were judged to be "some." Data were lacking for acute
systemic, developmental, and reproductive toxicity. Since oral exposure
is possible, the data gap regarding developmental and reproductive
toxicity should be filled.
2.3.2.3 Summary of relevant ongoing research
Peter Foiles at the American Health Foundation in New York City
will conduct a study sponsored by the National Cancer Institute to
develop monoclonal antibodies that will aid in the detection of cyclic
DNA adducts in humans exposed to environmental carcinogens. The study
may contribute to our knowledge of adducts that are formed in humans
from vinyl chloride exposure and the role these adducts play in human
carcinogenesis (NTIS 1987).
Peter Guengerich at the Department of Biochemistry at Vanderbilt
University in Nashville, Tennessee, will investigate the bioactivation
and covalent binding of metabolites of vinyl halides, including vinyl
chloride. This work, sponsored by the National Institute of
Environmental Health Sciences, may contribute to our understanding of
the impact of specific enzymes in the liver and other organs to the
toxification and detoxification-of vinyl chloride (NTIS 1987).
D.P. Brown at NIOSH in Cincinnati, Ohio, is updating cohort
mortality studies on several chemicals and mixtures, including vinyl
chloride. It is hoped that the updated studies may provide sufficient
statistical analyses to provide more definitive information regarding
the association of vinyl chloride with various types of cancer (NTIS
1987).
J.R. Giacin at Michigan State University has been investigating the
migration of monomers in plastics into food stimulants. This project,
sponsored by the U.S. Department of Agriculture, may allow more accurate
estimation of the exposure of the population to vinyl chloride from
foods packaged in plastic (NTIS 1987).
According to Dow Chemical Co. (1988), an update of the Fox and
Collier (1977) British study of occupational exposure^ to vinyl chloride
is imminent.
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Pharmacokinetics and mechanisms of action
The pharmacokinetics of vinyl chloride in humans exposed by
inhalation is relatively well understood, but little is known of oral
and dermal pharmacokinetics. The gap in human pharmacokinetlc knowledge
is not a concern because the pharmacokinetics of oral vinyl chloride in
relevant animal models is well understood, and dermal exposure is not
likely to be significant. Metabolism to an epoxide and an aldehyde
provides reactive intermediates thought to be responsible for the
carcinogenicity and probably the hepatotoxicity of the compound in
-------
24 Section 2
animals and humans. Further understanding of the mechanism of action on
other systems, such as the CNS, could be gained.
2.3.3.2 Monitoring of human biological camples
The most practical biological monitoring procedure appears to be
quantification of urinary output of thiodiglycolic acid, the predominant
urinary metabolite of vinyl chloride (Heger et al. 1982). Individual
variation, however, renders this method unreliable at exposure
concentrations
-------
25
3. CHEMICAL AMD PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
Data pertaining to the chemical identity of vinyl chloride are
listed in Table 3.1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
The physical and chemical properties of vinyl chloride are
presented in Table 3.2.
-------
26 Section 3
Table 3.1. Chemical identity of rinyl chloride
Parameter
Value
References
Chemical name
Synonyms and trade names
Chemical formula
Wiswesser line notation
Chemical structure
Identification numbers
CAS Registry No.
NIOSH RTECS No.
EPA Hazardous Waste No.
OHM-TADS No.
DOT/UN/NA/IMCO Shipping No.
STCC No.
Hazardous Substances Data Bank No.
National Cancer Institute No.
Chloroethene
Vinyl chloride,
chloroethylene,
ethylene monochloride,
monochloroethylene,
VC, VCM, vinyl
C monomer
C2HjCl
G1U1
SANSS 1987
SANSS 1987
H
\
Cl
C = C
H
\
H
75-01-4
KU962SOOO
U043
7216947
1086
49 057 92
169
None available
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSD&1987
HSDB 1987
-------
Chemical and Physical Information 27
Table 3.2. Physical and chemical properties of vinyl chloride
Property
Molecular weight
Color
Physical state
Odor
Odor threshold
Water
Air
Melting point
Boiling point
Autoigmtion temperature
Solubility
Water
Value
62.5
Colorless
Gas
Mild, sweet
3 4 ppm (w/v)
3.000 ppm (v/v)
-153 8°C
-134°C
472°C
2.763 mg/L at 25°C
References
Cowfer and Magistro 1983
Cowfer and Magistro 1983
Cowfer and Magistro 1983
Verschueren 1983
A moo re and Hautula 1983
Amoore and Hautula 1983
Cowfer and Magistro 1983
Cowfer and Magistro 1983
Cowfer and Magistro 1983
EPA 1985b
Organic solvents
Density, g/cm3
Vapor density (air = 1)
Log octanol-water
partition coefficients
Vapor pressure
Henry's law constant
Refractive index
Flashpoint
Flammability limits
Conversion factors
ppm (v/v) to mg/m1
in air
mg/m1 to ppm (v/v)
in air
1.100 mg/L at 25°C
Soluble in hydrocarbons,
oil, alcohol, chlorinated
solvents, and most common
organic liquids
0.969 (-14.2°C)
2.15
1.36
2,660 mm Hg at 25°C
1.2 (atm-m3)/mol at 10°C
1.3700 at 20° C
— 77.75 (open cup)
4-22 vol %
ppm (v/v) = 2.60 mg/m3
mg/m3 — 0.39 ppm (v/v)
Cowfer and Magistro 1983
Cowfer and Magistro 1983
Cowfer and Magistro 1983
Verschueren 1983
EPA 1987b
Verschueren 1983
EPA I985b
EPA 1985b
Cowfer and Magistro 1983
Cowfer and Magistro 1983
-------
29
4. TOZICOLOGICAL DATA
4.1 OVERVIEW
Much of the data summarized in this section is reviewed in two
recent EPA documents (EPA 1985a,b). Respiratory and gastrointestinal
absorption of vinyl chloride appears to be rapid. In one briefly
reported study it was estimated that humans retain -42% of vinyl
chloride inhaled at concentrations of 3 to 24 ppm. Animal studies
suggest that gastrointestinal absorption is nearly complete. Dermal
absorption of vinyl chloride vapors is not likely to result in toxicity.
Distribution of absorbed vinyl chloride may be widespread, with highest
levels of parent compound located in fat; but metabolism and excretion
occur so rapidly that highest levels of excretory products are located
in the liver and kidney, the primary organs of metabolism and excretion.
Regardless of the route of administration, inhalation or oral,
metabolism proceeds via oxidation and subsequent conjugation with
sulfhydryl groups. An important oxidative pathway involves mixed-
function oxidase and results in reactive electrophilic intermediates,
2-chloroethylene oxide and 2-chloroacetaldehyde, which bind to liver
macromolecules and may be responsible for the toxicity and oncogenicity
associated with vinyl chloride. Excretion of polar metabolites is
predominantly through the urine; when metabolic pathways are saturated,
substantial amounts of unmetabolized vinyl chloride are exhaled.
At sublethal doses, the liver is the primary target organ for
carcinogenic and noncarcinogenie effects of vinyl chloride in humans and
animals. The significant feature of the toxicity of vinyl chloride is
its carcinogenicity. In occupationally exposed humans and in animals
exposed orally or by inhalation, an increased incidence of liver and
brain tumors, and possibly other types of tumors, can be attributed to
vinyl chloride. Other symptoms in occupationally exposed humans are
collectively termed "vinyl chloride disease," and include
acroosteolysis, circulatory disturbance in the extremities, Raynaud
syndrome, scleroderma, hematological effects, and effects on the lungs,
as well as effects on the liver. No counterpart of the human disease has
been produced in experimental animals.
In occupationally exposed humans, vinyl chloride is genotoxic. This
effect is associated with an increase in chromosomal aberrations in
peripheral lymphocytes, and it appears to be reversible when exposures
are reduced to Si ppm. Vinyl chloride is mutagenic in a number of
microbial and other test systems. Electrophilic metabolites of vinyl
chloride, 2-chloroethylene oxide and 2-chloroacetaldehyde, have been
shown to bind to macromolecules. 2-Chloroethylene oxide forms adducts
with DNA. These mechanisms may explain the toxicity and carcinogenicity
of vinyl chloride.
-------
30 Section 4
4.2 TOXICOKINETICS
4.2.1 Absorption
4.2.1.1 Inhalation
Human. Krajewski et al. (1980) exposed young male volunteers to
vinyl chloride monomer concentrations of 7.5 to 60 mg/m3 (3 to 24 ppm)
by gas mask for 6 h. The authors did not report whether steady state had
been achieved, and the data were inadequate to determine this point.
Retention was estimated by measuring the difference between inhaled and
exhaled concentrations. Retention reached a maximum within 15 min and
declined rapidly after 30 min of exposure, after which it increased to a
relatively constant value. An average retention of 42% was estimated.
Although the results varied among the individuals tested, the percentage
retained appeared to be independent of the concentration inhaled.
Animal. Animal data, while demonstrating that inhalation
absorption of vinyl chloride occurs readily and rapidly, are not
sufficient to quantitatively determine the proportion of an inhaled dose
that is absorbed. Withey (1976) determined that peak blood levels
occurred at 30 min in rats exposed head only to 7,000 ppm. Bolt et al.
(1977) placed rats that had been pretreated with 6-nitro-l,2,3-
benzothiadiazole to completely block the metabolism of vinyl chloride in
a closed chamber containing 0.4 to 0.5 ppm 14C-vinyl chloride.
Radioactivity in the chamber air declined only for the first 15 min of
exposure, indicating that equilibrium between atmospheric and tissue
levels of radioactivity had occurred, suggesting rapid uptake by the
tissues of the rats.
4.2.1.2 Oral
Human. Data regarding the oral absorption of vinyl chloride by
humans were not located.
Animal. Several studies in rats indicate that vinyl chloride is
rapidly and probably completely absorbed from the gastrointestinal
tract. Withey (1976) administered single 10 mL (44 to 92 mg/kg) oral
doses of vinyl chloride in aqueous solution and observed that blood
levels of vinyl chloride peaked in 10 to 20 min. Vatanabe et al. (1976a)
administered single gavage doses of 0.05, 1, and 100 mgAg 14C-vinyl
chloride in corn oil and measured the amount of radioactivity excreted
in expired air, urine, and feces, as well as the amount retained in the
carcass, at 72 h. The fraction of the administered dose recovered in the
feces, roughly indicative of the proportion unabsorbed, ranged from
0.47 to 2.39%, suggesting that absorption was nearly complete. Total
recovery, however, ranged from 82.3 to 91.3%, suggesting substantial
loss of radioactivity. Feron et al. (1981) provided rats with diets
containing nominally 20, 60, or 200 ppm vinyl chloride monomer (from
powdered polyvinyl chloride containing a high level of the monomer) for
4 h and measured the fecal excretion of vinyl chloride over 23 h from
the start of the feeding period. Fecal excretion accounted for 8, 10,
and 17% of the vinyl chloride present in the low, middle, and high
diets, respectively. The investigators hypothesized that the vinyl
chloride recovered from the feces was encapsulated by polyvinyl chloride
-------
Toxicological Data 31
and was not available to the rats for absorption, and that absorption of
available vinyl chloride was virtually complete.
4.2.1.3 Dermal
Human. Data regarding the dermal absorption of vinyl chloride by
humans were not located.
Animal. Animal data suggest that dermal absorption of vinyl
chloride gas is not likely to be Significant. Hefner et al. (1975a)
placed all but the heads of two anesthetized rhesus monkeys in chambers
containing 800 or 7,000 ppm 14C-vinyl chloride for 2.5 or 2 h,
respectively, to measure the uptake of radioactivity. On the basis of
vinyl chloride measured in expired air and radioactivity measured in
selected tissues, the investigators estimated dermal absorption of 0.031
and 0.023% of the available vinyl chloride at 800 and 7,000 ppm,
respectively. The investigators concluded that dermal absorption was far
less significant than inhalation absorption.
4.2.2 Distribution
4.2.2.1 Inhalation
Human. Data regarding the distribution of vinyl chloride in the
tissues of humans exposed by inhalation were not located.
Animal. Data from rat studies suggest that the distribution of
Inhaled vinyl chloride is rapid and widespread but depends on
metabolism. Buchter et al. (1977) exposed rats to 14C-vinyl chloride to
determine tissue distribution of radioactivity. In rats pretreated with
6-nitro-l,2,3-benzothiadiazole to block metabolism of vinyl chloride,
the highest levels of radioactivity were located in the fat, with lesser
amounts in the blood, liver, kidney, muscle, and spleen. When metabolism
was not blocked, the highest levels of radioactive metabolites were
located in the liver and kidney. At 10 mln after a 5-min exposure of
rats to 20,000 ppm ^C-vlnyl chloride, Duprat et al. (1977) detected
radioactivity in the liver, bile duct, digestive tract, and kidney. At
3 h after the exposure described above, radioactivity was also detected
in the urinary tract, salivary and lacrlmal glands, thymus, and skin.
Immediately after a 5-h exposure to 14C-vinyl chloride, at 50 ppm, tissue
levels of radioactivity, expressed as percent incorporated per gram of
tissue, were highest In the kidney (2.13%) and liver (1.86%), with lower
levels In the spleen (0.73%) and brain (0.17%) (Bolt et al. 1976a).
Watanabe et al. (1976b) exposed rats to 10 or 100 ppm 14C-vlnyl chloride
for 6 h and measured radioactivity in tissues 72 h later. In order of
decreasing concentration, radioactivity (present as nonvolatile
metabolites) was detected in the liver, kidney, skin, lung, muscle
carcass, plasma, and fat.
4.2.2.2 Oral
Human. Data regarding the tissue distribution of vinyl chloride in
orally exposed humans were not located.
Animal. Watanabe et al. (1976a) measured the level of
radioactivity present as nonvolatile metabolites in tissues of rats 72 h
-------
32 Section 4
after single 0.05 to 100-mg/kg gavage doses of 14C-vinyl chloride In
corn oil. Highest levels occurred in the liver, -2 to 5 tines higher
than in the other tissues examined (skin, plasma, nuscle, lung, fat, and
carcass).
4.2.2.3 Dermal
Data regarding the distribution of vinyl chloride following dermal
exposure of humans or experimental animals were not located.
4.2.3 Metabolism
4.2.3.1 Inhalation
Human. In the only human data located, Sabadie et al. (1980)
examined the ability of aryl hydrocarbon hydroxylase in the S-9 fraction
from surgically obtained liver specimens to metabolize vinyl chloride to
electrophiles mutagenic to Salmonella cyphiaurium TA1530. The number of
revertants per plate were compared with that resulting from identically
prepared S-9 fractions from female strain BD IV rats. Human S-9
fractions induced mutations (and presumably metabolism to a reactive
electrophile) to an average 84% of the extent mediated by rat S-9, but a
ninefold individual variation was observed.
Animal. Hefner et al. (197Sb) exposed rats to vinyl chloride in a
closed chamber at concentrations of -SO to 1,000 ppm for 52.5 to
356.3 min. Additional rats pretreated with ethanol (to inhibit alcohol
dehydrogenase activity) or SKF 525-A (to inhibit microsomal oxidase
activity) were similarly exposed. Metabolism, estimated by measuring the
rate of disappearance of vinyl chloride from the closed system, appeared
to follow first-order kinetics with a half-life of 86 min at <100 ppm.
At >220 ppm, metabolism was slowed to a half-life of 261 min, suggesting
saturation of the pathway predominant at <100 ppm. Pretreatment with
ethanol depressed the rate of metabolism >83% at <100 ppm but <47% at
>1,000 ppm. Pretreatment with SKF 525-A, however, had no effect at
<100 ppm but depressed metabolism 19% at >1,000 ppm. The authors
postulated three alternative pathways for metabolism, as depicted in
Fig. 4.1. At low concentrations, sequential oxidation to 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, probably because 2-chloroacetaldehyde conjugated rapidly with
ubiquitous sulfhydryl groups. When the alcohol dehydrogenase pathway
became saturated, 2-chloroethanol may have been oxidized by catalase in
the presence of hydrogen peroxide (H202) to a peroxide, which may have
undergone subsequent dehydration to form 2-chloroacetaldehyde. An
alternative pathway may have involved oxidation by mixed-function
oxidase to form a highly reactive epoxide Intermediate, 2-chloroethylene
oxide, which spontaneously rearranged to form 2-chloroacetaldehyde.
Hefner et al. (1975b) reported urinary excretion of polar metabolites
and 2-chloroacetic acid by rats exposed by inhalation.
Other animal data expand the hypotheses of Hefner et al. (1975b).
Hultmark et al. (1979) used an in vitro technique to determine that
metabolism was NADPH-dependent, located in the microsomal fraction of
-------
Toxlcologlcal Data 33
CIMC • CH n
VNYL CHLORDE
I
CIH2C - CH2OH
2-CHLOROETHANOL
MIXED FUNCTION
OXIDASE
H2O2
CATALASE
ALCOHOL
DEHYDROGENASE
O
/\
^ H2C - CH
Cl
2-CHLOROETHYLENE OXIDE
CIH2C - CH2OOH
2-CHLOROETHYL-
HYOROPEROXIDE
CIH2C - CHO
2-CHLOROACETALDEHYDE
CIH2C - COOH
2-CHLOROACETIC AGO
Flf.4.1.
•etebdk ptfkwiyi for riayi
-------
34 Section 4
the liver, and probably involved mixed-function oxidase. Bolt et al.
(1977) reported that pretreataent with 6-nitro-1.2,3-benzothiadiazole
was sufficient to totally block metabolism of vinyl chloride in rats
exposed to -0.45 ppm in a closed system for 5 h. Bolt et al. (1977) and
Bolt (1986) interpreted this observation to strongly suggest that
metabolism of vinyl chloride proceeds primarily through a mixed-function
oxidase pathway with likely production of an epoxide intermediate,
because 6-nitro-l,2,3-benzothiadiazole is known to inhibit some
microsomal cytochrome P-450 oxidation pathways. Bolt et al. (1977) and
Filser and Bolt (1979) exposed rats in a closed system to 100 or
1.000 ppm 14C-vinyl chloride. By measuring the disappearance of
radioactivity with time, they determined 250 ppm to be the threshold at
which saturation of metabolic pathways occurs. A metabolic rate (Vmax)
of 110 jimol/h/kg was estimated for rats. In a similar experiment in
rhesus monkeys, metabolic saturation was observed to occur at 200 ppm,
with a Vmax of SO /jmol/hAg (Buchter et al. 1980). The Vmax of
SO pmol/h/kg was suggested as a closer approximation of metabolism in
humans than the value of 110 pmol/h/kg estimated for rats by Filser and
Bolt (1979).
Inhalation exposure has been associated with reduction in liver
nonprotein sulfhydryl concentration in the rat (Hefner et al. 1975b,
Bolt et al. 1976b) , particularly at exposure concentrations >100 ppm
(Watanabe et al. 1978a, Jedrychowski et al. 1984). Urinary metabolites
identified in rats exposed by inhalation include polar compounds
resulting from conjugation with sulfhydryl groups at low exposure
concentrations (Vatanabe et al. 1976b, Hefner et al. 1975b) and
2-chloroacetic acid at high exposure concentrations (Hefner et al.
1975b).
Several investigators have observed the binding of nonvolatile
metabolites of 14C-vinyl chloride to liver macromolecules in vitro and
in rats exposed by inhalation (Kappus et al. 1976; Guengerich and
Watanabe 1979; Guengerich et al. 1979, 1981; Vatanabe et al. 1978a,b).
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 (Vatanabe et al. 1978a). The extent of macromolecular
binding was increased by repeated exposure to vinyl chloride (Vatanabe
et al. 1978b) and by pretreatment with phenobarbltal (Guengerich and
Vatanabe 1979). Macromolecular binding has been attributed to the
reactive intermediate 2-chloroethylene oxide, which may bind to DNA and
RNA, and to its rearrangement product, 2-chloroacetaldehyde, which may
bind to protein molecules (Guengerich et al. 1979, 1981; Guengerich and
Vatanabe 1979; Vatanabe et al. 1978a,b; Kappus et al. 1976; Bolt 1986).
4.2.3.2 Oral
Human. Data regarding the metabolism of vinyl chloride by orally
exposed humans were not located.
Animal. Urinary metabolites identified from rats orally exposed to
14C-vinyl chloride are consistent with the metabolic pathways postulated
for inhalation exposure, in particular with the formation of
2-chloroethylene oxide and 2-chloroacetaldehyde. Metabolites identified
-------
Toxicologlcal Data 35
include N-acetyl-S-(2-hydroxyethyl)cysteine, N-acetyl-S-(2-
chloroethyDcysteine, 2-chloroacetic acid, thlodlglycolic acid, and
glutamic acid (Watanabe et ml. 1976a; Vatanabe and Gehrlng 1976; Green
and Hathway 1975, 1977). Metabolic saturation appears to occur with a
single gavage dbse'of >1 and <100 mgAg/day (Watanabe et ml. 1976a).
4.2.3.3 Dermal
Data regarding metabolism In humans or animals dermally exposed to
vinyl chloride were not located.
4.2.4 Excretion
4.2.4.1 Inhalation
Human. Human data suggest that exhalation of unmetabollzed vinyl
chloride Is not an Important pathway of elimination at low exposure
concentrations Krajewski et ml. (1980) exposed humans to air containing
7.5 to 60 mg/mj for 6 h and measured the mean concentration in expired
air for 30 min at termination of exposure. Mean concentrations in
expired air ranged f i jm undetectable to 2.84 mg/m3, representing up to
3.60 to 4.73% of the inhaled concentration.
In a study available as a brief abstract, Shu et ml. (1986)
reported that urinary concentration of thiodlglycolic acid increased
with Increasing air concentration of vinyl chloride in an occupational
setting. Urinary concentrations of thiodiglycolic acid peaked within
20 h. The investigators suggested that daily urinary output of
thiodiglycolic acid might be a satisfactory biological index of exposure
to vinyl chloride.
Animal. The mode of excretion of vinyl chloride and its
metabolites following inhalation exposure of animals to different
concentrations reflects the saturation of metabolic pathways at low
concentrations discussed in Sect. 4.2.3.1, in the subsection on
metabolism in animals after inhalation exposure. The cumulative
excretion of radioactivity over a 72-h postexposure period was measured
in rats exposed to 10 or 1,000 ppm (Watanabe and Gehring 1976, Watanabe
et ml. 1976b) or 5,000 ppm (Watanabe et ml. 1978b) 14C-vinyl chloride
for 6 h. Radioactivity expired as C02 or vinyl chloride, excreted In the
urine and feces, and retained in the carcass was expressed as a
percentage of the total radioactivity recovered. The results presented
in Table 4.1 suggest that metabolism was nearly complete at 10 ppm,
because <2% of the recovered radioactivity occurred as unchanged parent
compound. The predominant route for excretion of radioactive metabolites
was through the urine, accounting for -70% of the recovered
radioactivity. Metabolism appeared to be saturated at 1,000 ppm, since
unchanged vinyl chloride increased to 12.3% and urinary radioactivity
decreased to 56.3%. At 5,000 ppa, more than half the recovered
radioactivity appeared as unchanged vinyl chloride, and urinary
excretion accounted for -27% of the recovered activity. Generally, there
was little change in the proportion of recovered radioactivity excreted
in the feces or exhaled as C02. The percentage of the radioactivity
retained in the carcass and tissues appeared to be somewhat decreased at
-------
36 Section
Table 4.1. Excretion of radioactivity in rats exposed to
"C-vinyl chloride in air for 6 h
Radioactivity expressed as percent
of total recovered
Expired vinyl chloride
Expired CO2
Urine
Feces
Carcass and tissues
10
1.61
12.09
67.97
4.45
13.84
Exposure concentration (ppm)
1.000
12.26
12.30
56.29
4.21
14.48
5,000
54.5
8.0
27.1
3.2
7.3
Source: Watanabe and Gehring 1976; Watanabe et al. 1976b, 1978b.
-------
Toxicologlcal Data 37
5,000 ppm conpared with 10 and 1,000 ppn, suggesting preferential
retention of metabolites rather than unchanged vinyl chloride.
Pulmonary excretion of unaltered vinyl chloride appeared to follow
first-order kinetics-regardless of exposure concentrations, with half-
lives of 20.4, 22.4, and 30 min at 10, 1,000, and 5,000 ppm. The urinary
excretion of radioactivity was biphasic, with the second or slow phase
accounting for <3% of the total urinary excretion. Half-lives for the
rapid (first-order) phase were estimated at 4.6, 4.1, and 4.5 h,
respectively. Urinary metabolites included N-acetyl-S-(2-
hydroxyethyl)cysteine, thiodiglycolic acid, and possibly S-(2-
hydroxye thy1)cys te ine.
4.2.4.2 Oral
Human. Data regarding the excretion of vinyl chloride by orally
exposed humans were not located.
Animal. In experiments in the United States (Vatanabe et al.
1976a, Vatanabe and Gehring 1976) and Great Britain (Green and Hathway
1975), which studied the similarities of pharmacokinetics following
inhalation and oral exposure, single oral doses of ^C-vinyl chloride
were administered to rats, and the excretion of radioactivity was
monitored over a 72-h period. Details are presented in Table 4.2. A
striking increase in exhalation of unchanged vinyl chloride and
compensatory decreases in urinary and fecal excretion of radioactivity
and exhalation of C02 were observed at 220 mg/kg, suggesting that
metabolic saturation had occurred at that dosage. At £l.O mg/kg, the
predominant route of elimination was urinary excretion of polar
metabolites.
Exhalation of unchanged vinyl chloride was generally complete
within 3 to 4 h, but excretion of metabolites continued for days (Green
and Hathway 1975). Pulmonary excretion of vinyl chloride appeared to be
monophasic at 97% of total urinary radioactivity
and having half-lives of 4.5 to 4.6 h for dosages of 0.05 to 100 mg/kg-
Metabolites identified in the urine of orally treated rats were
consistent with the formation of 2-chloroethylene oxide and 2-
chloroacetaldehyde (Vatanabe et al. 1976a, Green and Hathway 1977), as
postulated for metabolism following inhalation exposure. The major
metabolite was Identified as thiodiglycolic acid; nearly equivalent
amounts of N-acetyl-S-(2-hydroxyethyl)cysteine were identified (Vatanabe
et al. 1976a, Green and Hathway 1975). Smaller amounts of radlolabeled
S-(2-chloroethyl)cysteine, urea, glutamlc acid, and 2-chloroacetic acid
were also identified (Green and Hathvay 1975).
4.2.4.3 Dermal
Data regarding the metabolism of vinyl chloride following dermal
exposure of humans or animals were not located.
-------
38 Section 4
Table 4.2. Percent of administered dose of radioactivity
excreted 72 h following a single oral dose
of 14C-vinyl chloride in rats
Dose (nig/ kg)
Expired
As vinyl chloride
AsCO2
Urine
Feces
Carcass
Total
0.05"
1.43
8.96
68.34
2.39
10.13
91.25
0.25*
37
135
75.1
4.6
NRf
96.9
1.0"
2.13
13.26
59.30
2.20
11.10
88.83
20-
41.6
4.8
22.6
1.0
11.0
81.0
100s
66.64
2.52
10.84
0.47
1.83
82.30
450*
91.9
0.7
5.4
0.7
NR
98.7
" Watanabe and Gehnng 1976. Watanabe et al. 1976a.
*Green and Hathaway 1975.
fNot reported.
-------
Toxicologies! Data 39
4.2.4.4 Parenteral
Human. Data regarding the metabolism of parenterally administered
vinyl chloride in humans were not located.
Animal. The elimination of radioactivity following intraperitoneal
administration of ^C-vinyl chloride to rats resembles the pattern
observed following inhalation and oral administration. Following an
intraperitoneal dose of 0.25 mg/kg, exhalation of unchanged vinyl
chloride, exhalation of C02, and urinary and fecal excretion of
radioactivity accounted for 43.2, 11.0, 43.1, and 1.8% of the
administered dose, respectively (Green and Hathway 1975). At 450 mg/kg,
exhaled vinyl chloride increased to 96.2% of the administered dose, CO2
decreased to 0.7%, urinary radioactivity decreased to 2.6%, and fecal
radioactivity remained unchanged.
Small doses administered intravenously were eliminated very rapidly
and almost entirely by exhalation of unchanged vinyl chloride. Green and
Hathway (1975) administered a 0.25-mg/kg intravenous dose of 14C-vinyl
chloride to rats and recovered 80% of the dose within 2 min and 99%
within 1 h as unchanged compound from expired air.
4.3 TOXICITY
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Inhalation
Human. ACGIH (1986a) and EPA (1985a) reviewed early reports of
acute toxicity at high levels resulting in lethality among
occupationally exposed workers. Deaths appeared to be due to narcosis.
Exposure levels were not reported, and an LCLO cannot be identified.
Animal. Patty et al. (1930) reported that narcosis and death
occurred within 30 to 60 min in guinea pigs exposed to 10% vinyl
chloride (100,000 ppm). EPA (1985a) reviewed a number of acute studies
in animals and reported 2-h LC50 values ranging from 117,500 ppm for
mice to 230,800 ppm for rabbits. Mastromatteo et al. (1960) exposed
rats, mice, and guinea pigs (five per sex per group) to 10, 20, 30, or
40% (guinea pigs only) vinyl chloride in air (100,000, 200,000, 300,000,
or 400,000 ppm) for 30 min. One guinea pig exposed to 40% died; all
mice, rats, and one guinea pig exposed to 30% died; one mouse but no
rats or guinea pigs exposed to 20% died.
Long-term studies in rats and mice associate intermittent exposure
to 50 ppm with decreased longevity. Lee et al. (1977a, 1978) exposed
rats and mice (36 per sex per species) to 0, 50, 250, or 1,000 ppm, 6
h/day, 5 days/week for up to 12 months. Acute lethality associated with
toxic hepatitis and tubular necrosis of the renal cortex occurred in
mice after 5 to 9 days at 1,000 ppm. Shortened life span attributed to
nonearcinogenic effects of vinyl chloride occurred in all exposed groups
of both species. In a subsequent study. Hong et al. (1981) exposed mice
(8 to 28 per sex per group) and rats (4 to 16 per sex per group) to 0,
50, 250, or 1,000 ppm, 6 h/day, 5 days/week for up to 6 months (mice) or
10 months (rats), followed by a 12-month observation period. A decrease
in longevity related to concentration and duration of exposure was
-------
40 Section 4
observed in both species at all exposure concentrations, which was
attributed to a combination of systemic toxicity and tumor development.
4.3.1.2 Oral
Human. Data regarding reduced longevity in humans orally exposed
to vinyl chloride were not located.
Animal. Sax (1984) reported an oral LD50 in rats of 500 mg/kg- The
key lifetime oral study is that submitted by Til et al. (1983), in which
male and female Uistar rats were fed diets containing polyvinyl chloride
with a high level of the monomer. Dietary intakes of vinyl chloride
monomer were estimated at 0, 0.014, 0.13, and 1.3 mg/kg/day. Groups
consisted of 100 rats per sex except for the high group, which contained
SO rats per sex. Mortality was slightly but significantly increased in
high-group rats, starting at 68 weeks of treatment. No effects on
longevity were observed at <0.13 mg/kg/day, which is considered the
NOAEL for decreased survival.-
An earlier lifetime study in rats from this laboratory (Feron et
al. 1981) supports the NOAEL for reduced survival of 0.13 mg/kg/day.
In chis experiment, diets containing polyvinyl chloride with high
levels of vinyl chloride monomer provided intakes of 0, 1.7, 5.0, or
14.1 mg/kg/day. A marked and statistically significant increase in
mortality occurred at >5.0 mg/kg/day. Females at 1.7 mg/kg/day had-a
slight but not statistically significant increase in mortality.
4.3.1.3 Dermal
Data regarding lethality or reduced longevity in dermally exposed
humans or animals were not located in the available literature.
4.3.2 Systemic/Target Organ Toxicity
4.3.2.1 Hepatotoxicity
Inhalation, human. Several epidemiologic studies have associated
occupational exposure with impaired liver function and/or biochemical or
histological evidence of liver damage (Berk 1976, Buchancova et al.
1985, Gedigk et al. 1975, Marsteller et al. 1975, Popper and Thomas
1975, Doss et al. 1984, Lilis et al. 1975, Tamburro 1984, Taaburro et
al. 1984). Several of these studies have been reviewed by EPA (1985a,b).
Thresholds for hepatotoxicity cannot be identified, because data
regarding exposure concentrations and duration were not available.
Negative results, however, were reported in liver status screening
studies in 422 exposed and 202 control workers in one large vinyl
chloride manufacturing and polymerization plant (Lee et al. 1977).
Inhalation, animal. In the Lee et al. (1977a) study described in
Sect. 4.3.1.1, in the subsection on lethality and decreased longevity in
animals after inhalation exposure, acute hepatotoxicity was observed in
mice dying after intermittent exposure to 1,000 ppm vinyl chloride for
5 to 9 days.
In an intermediate-length animal inhalation study (Torkelson et al.
1961), several species were exposed Intermittently for up to 6 months,
as detailed in Table 4.3. Air-exposed controls were maintained.
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roxicologlcal Data 41
Table 4.3. Experimental protocol for animal exposure to rinyl chloride
Number of
animals/group
Species
Rats
Guinea pigs
Rabbits
Dogs
Males
10
20-24
5
10
10-12
3
1
Females
10
24
0
0
8-12
3
1
Dose of
vinyl chloride
(ppm)
500
50, 100, or 200
100 or 200
50
50, 100, or 200
50, 100, or 200
50. 100, or 200
Exposure
schedule"
(hours/day)
7
7
0.5, 1,2, or 4
1. 2. or 4
7
7
7
Exposure
duration
(months)
4.5
6
6
6
6
6
6
"All animals were exposed 5 days/week.
Source: Torkelson et al. 1961.
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42 Section 4
Parameters of liver toxicicy evaluated included gross and
histopathologic examination, measurement of relative organ weights, and
determination of serum levels of enzymes associated with liver damage.
Biochemical parameters of liver status were within normal limits at all
exposure concentrations, but histopathologic lesions occurred in rats
exposed to 500 ppm and in rabbits exposed to 200 ppm. Elevated relative
liver weights appeared to be the most sensitive indicator of
hepatotoxicicy and were observed in rats at 100 ppm, 7 h/day, but not at
50 ppm by the same schedule. In a study designed primarily to evaluate
effects on the testis (see Sect. 4.3.4.1, in the subsection on
reproductive toxicity in animals after inhalation exposure), Bi et al.
(1985) reported a concentration*related and significant elevation in
relative liver weight in rats exposed to 10, 100, or 3,000 ppm, 6 h/day,
6 days/week for 6 months. The 10-ppm concentration is considered a LOAEL
for liver effects in intermediate-length exposures. The longer-term
study by Lee et al. (1977a) in which rats and mice were exposed to 0,
50, 250, or 1,000 ppm, 6 h/day, 5 days/week for up to 12 months (Sect.
4.3.1.1, in the subsection on lethality and decreased longevity in
animals after inhalation exposure) failed to identify a NOAEL for
hepatotoxicity. Lee et al. (1977a) observed no adverse effects on
biochemical parameters of rats or mice exposed to 3250 ppm. Several
mitotic figures, indicating increased rate of cell division, were
observed in the livers of rats exposed to 50 or 1,000 ppm at 8 to
9 months, and increased rate of DNA synthesis was observed at 50 ppm.
Since the liver is a known target organ for the toxicity and
oncogenicity of vinyl chloride, these effects are judged to be
potentially adverse, and 50 ppm is considered an effect level in this
s tudy.
Feron et al. (1979a) exposed rats to 0 or 5,000 ppm, 7 h/day,
5 days/week for 4, 13, 26, or 52 weeks and observed histopathologic
alteration of the liver after 13 weeks and ultrastructural alteration
after only 4 weeks of exposure.
Oral, human. Data were not located regarding hepatotoxicity in
orally exposed humans.
Oral, animal. A gavage study in rats identifies 30 mg/kg as a
NOAEL and 100 mg/kg as a LOAEL for liver effects in an intermediate-
length study. Feron et al. (1975) administered vinyl chloride in soybean
oil by gavage to groups of 15 rats per sex at 0, 30, 100, or 300 mg/kg.
6 days/week for 13 weeks. Parameters of liver toxicity evaluated
included serum biochemistry, relative liver weight, and histopathologic
and histochemical examination at all dosages and electron microscopy at
0 and 300 mg/kg. No effects were observed at 30 mg/kg, equivalent to
26 mg/kg/day. Reduced blood sugar and slightly altered hepatocytes were
observed at 100 and 300 mg/kg. A dose-related increase in relative liver
weight was observed and became statistically significant only at
300 mg/kg. Hypertrophic rough endoplasmic reticulum was observed at
300 mgAg.
The key long-term oral study that defines thresholds for
hepatotoxicity was reported by Til et al. (1983) and was described in
Sect. 4.3.1.2, in the subsection on lethality and decreased longevity in
animals after inhalation exposure. Diets provided daily dosages of 0,
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Toxicological Data 43
0 014, 0.13, or 1.3 mgAg/day to rats for their lifetime. There were no
effects on general appearance, behavior, food consumption, body weight
or limited hematologic and biochemical parameters. Relative organ
weights were not evaluated. Noncarcinogenic adverse histopathologic
effects were confined to the liver and consisted of hepatocellular
alteration and hepatic cysts in both sexes at 1.3 mg/kg/day An
increased incidence of basophilic foci were observed in both sexes at
1.3 mgAg/day and only in females in the two lower dosage groups
Lacking a dose-related increase in the incidence of basophilic foci and
histopathological evidence of adverse effects at 0.13 mgAg/day such as
were observed at the higher dosage, basophilic foci in the liver of rats
of one sex may be considered a nonadverse, although compound-related
™Ie?C' d°Sage of °'13 »8Ag/day, therefore, may be considered a'
NOAEL, and 1.3 mgAg/day may be considered a LOAEL for hepatotoxicity.
An earlier lifetime study from this laboratory supports the NOAEL
for hepatotoxicity of 0.13 mgAg/day. Feron et al. (1981) fed diets
containing polyvinyl chloride with high levels of vinyl chloride monomer
to rats that provided intakes of 0, 1.7, 5.0, or 14.1 mgAg/day An
increased incidence cf several histopathologic lesions, some of which
were probably preneoplastic, were observed in the livers of rats from
all treated groups.
Dermal. Data regarding hepatotoxicity associated with dermal
exposure of humans or animals to vinyl chloride were not located.
General discussion. Symptoms and signs of liver disease associated
with occupational exposure to vinyl chloride include pain or discomfort
in the right-hand upper quadrant of the abdomen, hepatomegaly
splenomegaly, portal hypertension, thrombocytopenia, esophageal varices
and evidence of fibrosis and cirrhosis; however, these observations are'
not pathognomonic for vinyl-chloride-induced liver disease (Lilis et al
1975, Popper and Thomas 1975, Lee et al. 1977b). Severity of the
clinical picture appeared to correlate positively with duration of
exposure (Lilis et al. 1975). Biochemical screening and liver function
tests generally have not been useful to monitor the presence or progress
of the disease (Lee et al. 1977b, Lilis et al. 1975), although recently,
Doss et al. (1984) noted that increased urinary porphyrin and
coproporphyrin occurred consistently in cases of liver disease induced
by vinyl chloride and other industrial hepatotoxins.
A number of investigators have noted that metabolites of vinyl
chloride bind covalently to hepatocellular macromolecules and may be
important in the mechanism of carcinogenesis (Bolt et al. 1976b Bolt
1986 Kappus et al. 1976, Watanabe et al. 1978a, Watanabe and Gehring
1976). A mechanism for noncarcinogenic liver effects has not been
postulated; however, since many of the lesions observed in the livers of
yjj^-chloride-exposed rats are considered preneoplastic (Feron et al.
1981), it seems reasonable to suspect that macromolecular binding of
reactive intermediates may be involved in noncarcinogenic toxicity
Support is derived from the data of Jaeger et al. (1977), who observed
that mixed-function oxidase inducers Aroclor 1254 and phenobarbital
potentiate the acute hepatotoxicity in rats exposed to vinyl chloride by
inhalation. Pretreatment with SKF 525-A. a nixed-function oxidase
inhibitor, prevented vinyl-chloride-induced toxicity
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44 Section 4
It should be noted that Che oral NOAEL for hepatotoxicIty in a
chronic study (Til et al. 1983) was far below the NOAEL in a subchronlc
study (Feron et al. 1975). At least for oral exposure, the duration of
exposure appears to be of major Importance.
4.3.2.2 Nervous system effects
Inhalation, human. Vinyl chloride was once considered for use as
an inhalation anesthetic (ACGIH 1986a). Acute exposures to 0.8 to 2.0%
vinyl chloride (8,000 to 20,000 ppm) have been associated with
dizziness, giddiness, euphoria, ataxia, headache, and narcosis
(Nicholson et al. 1975, Lester et al. 1963). Recent data from the
foreign literature suggest that subtle signs of neurotoxicity may be
associated with occupational exposure. Mild distal axonal neuropathy was
reported in the legs of 45/64 exposed vinyl chloride workers, which was
suggestive to the investigators of a dying-back syndrome (Perticoni et
al. 1986). Halama et al. (1985) associated neurologic and psychiatric
disease with occupational exposure. Dinceva et al. (1985) reported
electroencephalogram (EEC) changes that they thought were indicative of
early evidence of neurotoxicity in workers exposed to vinyl chloride in
combination with other organic solvents. Exposure levels were not
reported by these authors.
Inhalation, animal. Oster et al. (1947) anesthetized dogs with -7
to 50% (70,000 to 500,000 ppm) vinyl chloride and concluded that its use
as an anesthetic was unsuitable because of cardiac and muscular effects.
Lester et al. (1963) exposed rats to concentrations ranging from 5 to
15% (50,000 to 150,000 ppm) for up to 2 h to evaluate CNS effects.
Moderate intoxication was observed at 5%, loss of reflexes was observed
at 5 to 10%, and deep surgical anesthesia was reached at 15%. Patty et
al. (1930) produced ataxia and narcosis in guinea pigs exposed to 2.5 to
5% (25,000 to 50,000 ppm) vinyl chloride for 2 to 5 min. Nervous system
effects and histopathologic lesions in the brain were not reported in
mice exposed to 50 ppm 6 h/day, 5 days/week for up to 12 months (Lee et
al. 1977a) or in rats exposed to 5,000 ppm 7 h/day, 5 days/week for
12 months (Feron and Kroes 1979).
Oral. Neurological effects have not been reported in orally
exposed humans or in rats treated by gavage with vinyl chloride in soya
bean oil at 300 mg/kg, 6 days/week for 13 weeks (Feron et al. 1975) or
at 300 mg/kg, 5 days/week for 84 weeks (Feron et al. 1981).
Dermal. Neurologic effects in dentally exposed humans or animals
have not been reported.
General discussion. CNS effects appear to be a manifestation of
acute inhalation exposure to high levels of vinyl chloride in humans and
animals (Nicholson et al. 1975, Lester et al. 1963) that may result in
death, at least in animals (Lester et al. 1963, Mastromatteo et al.
1960). Recent human data provide some evidence that chronic exposure to
vinyl chloride may result in neurologic or psychiatric effects
(Perticoni et al. 1986, Dinceva et al. 1985, Halama et al. 1985).
Further investigation is needed. Neurologic signs or effects on the
brain have not been reported in chronic inhalation studies in rats and
mice (Lee et al. 1977a; Feron and Kroes 1979; Feron et al. 1975, 1981).
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lexicological Data 45
4.3.2.3 Other systemic effects
Vinyl chloride disease froa inhalation exposure, human. Vinyl
chloride disease is the name given to the total clinical syndrome
associated with^occupational exposure. It includes a syndrome known as
acroosteolysis or dissolution of the ends of the distal phalanges of the
hands, circulatory disturbance in the extremities. Raynaud syndrome,
scleroderma, hematologic effects, and effects on the lungs, as well as
the liver effects previously discussed (Halama et al. 1985, Sakabe 1975,
Lilis et al. 1975, Markowitz et al. 1972, Wilson et al. 1967, Dinman et
al. 1971, Preston et al. 1976). In addition, Micu et al. (1985) reported
obscure effects of unknown toxicological significance on enzyme levels
of leukocytes and thrombocytes of exposed workers. Other investigators
have reported elevated levels of circulating IgG (Bogdanikowa and
Zawilska 1984) or immune complexes (Ward 1976) as part of the syndrome,
but the biological significance of these effects is not clear.
Vinyl chloride disease from inhalation exposure, animal. Lee et
al. (1977a, 1978) exposed rats and mice to vinyl chloride at 0, 50, 250,
or 1,000 ppm 6 h/day, 5 days/week for up to 12 months, as described in
Sect. 4.3.2.1, in the subsection on hepatotoxicity in animals after
inhalation exposure. Parameters of toxicity evaluated included general
appearance, feed consumption, body weight, hematology, clinical
chemistry, macrophage counts of pulmonary washings, cytogenic
examination of bone marrow cultures, senographic radiography of the long
bones of the limbs, gross necropsy, selected organ weights, and
histopathologic examination of a comprehensive set of organs and
tissues. Abnormalities observed in the mice included body weight loss at
1,000 ppm after 8 months of normal growth and elevated pulmonary
macrophage count in mice from all exposure groups that had
bronchoalveolar adenoma. Because of its association with lung tumors, an
elevated pulmonary macrophage count in mice in this study is not
considered a noncarcinogenic toxic effect. Rats exposed to 1,000 ppm had
reduced body weights compared with controls. Other noncarcinogenic
adverse effects were not observed in rats.
Bi et al. (1985) exposed rats to 10, 100, or 1,000 ppm 6 h/day,
6 days/week for 12 months to evaluate effects on the testis (see Sect.
4.3.4.1, in the subsection on reproductive toxicity in animals after
inhalation exposure). At termination of exposure, a concentration-
related decrease in body weights was evident and became statistically
significant at 100 ppm. Effects on body weight were not reported by
Torkelson et al. (1961) in rats (n S 12) exposed for 7 h/day,
5 days/week to 500 ppm for 4.5 months or to 200 ppm for 6 months, or in
dogs (n - 1), guinea pigs (n - 10). or rabbits (n - 3) exposed to
200 ppm by the same schedule. The value of this study is jeopardized by
small animal group sizes.
In a series of studies on rats exposed to 0 or 5,000 ppm 7 h/day,
5 days/week for 1 year, adverse effects not previously discussed
included slightly reduced growth, hematologic evidence of anemia,
decreased blood clotting time, and minor biochemical alterations of
uncertain biological significance (Feron et al. 1979a,b; Feron and Kroes
1979). Effects on the kidney were noted and included elevated relative
kidney weights, slightly increased blood urea nitrogen (BUN), altered
-------
46 Section 4
urinalysis parameters, and increased intensity of progressive nephrosis,
all compared with controls. Other noncarcinogenic lesions seen in
treated rats included mild alterations of the Zymbal glands and lungs,
increased splenic hematopoiesis, degeneration of the myocardium and
thickening of the walls of the arteries, and hyperplasia of the
olfactory epithelium.
Vinyl chloride disease from oral exposure, human. Data regarding
effects of vinyl chloride in orally exposed humans were not located.
Vinyl chloride disease from oral exposure, animal. In a 13-week
study described in Sect. 4.3.2.1, in the subsection on hepatotoxicity in
animals after oral exposure, Feron et al. (1975) treated rats with vinyl
chloride at 0, 30, 100, or 300 mg/kg 6 days/week. Parameters of toxicity
not previously discussed included general appearance and behavior, body
weight, food consumption, hematology, selected blood chemistry and
urinalysis tests, gross appearance on necropsy, relative weights of
major organs, and histopathologic appearance of a wide range of organs
and tissues. Minor hematologic and biochemical changes were observed but
were not considered to be adverse. Decreased relative adrenal weight was
observed in males at 300 mgAg but was not considered toxicologically
significant. No adverse response was reported in other organs or
tissues.
In a lifetime study also described in Sect. 4.3.2.1, in the
subsection on hepatoxicity in animals after oral exposure, Feron et al.
(1981) fed rats diets that provided 0, 1.7, 5.0, or 14.1 mg/kg/day vinyl
chloride. An additional group was treated by gavage with 300 mg/kg
5 days/week. Parameters of toxicity evaluated included general
appearance and behavior, body weight, food consumption, hematology,
blood chemistry, urinalysis, gross appearance at necropsy, and
histopathologic examination of a wide range of tissues from controls and
the two higher-dose groups, with a more limited histopathologic
examination of low-dose rats. Lethargy and poor condition were reported
at 25.0 mg/kg/day, apparently in rats that developed tumors.
Noncarcinogenic effects included reduced blood clotting time and
increased splenic hematopoiesis at 214.1 but not at 5.0 mg/kg/day.
Vinyl chloride disease from dermal exposure. Data regarding toxic
effects of vinyl chloride in dermally exposed humans or animals were not
located.
Vinyl chloride disease, general discussion. Vinyl chloride disease
in humans appears to involve a large number of organ systems and
tissues, including the liver, as discussed in Sect. 4.3.2.3, in the
subsection on vinyl chloride disease in humans after inhalation exposure
(Halama et al. 1985, Sekabe 1975, Lilis et al. 1975, Harkowitz et al.
1972, Wilson et al. 1967, Dinman et al. 1971, Preston et al. 1976). It
is not possible to determine the critical effect in humans (the effect
that occurs at the lowest exposure) because quantitative human exposure
data were not provided. Animals exposed orally or by inhalation manifest
cancerous and noncancerous liver effects similar to those seen in
humans, but other effects seen in humans, such as acroosteolysis,
Raynaud syndrome, and scleroderma, have not been reproduced in animals,
even at very high exposures. Liver effects appear to be the critical end
-------
Toxicologies! Data 47
point In animals; therefore, animals are probably a satisfactory model
for noncancerous end points of toxicity in humans.
4.3.3 Developmental Toxicity
• -
4.3.3.1 Inhalation
Human. Epidemiological data associate increased fetal loss with
occupational exposure to vinyl chloride, although exposure data were not
quantified. Using a questionnaire, Infante et al. (1976) and Waxweiler
et al. (1977) studied the outcome of pregnancies of wives of 95 vinyl
chloride workers and a control group of 158 unexposed rubber workers and
polyvinyl chloride fabricators exposed to "very low" levels of vinyl
chloride monomer. Data were obtained for the exposed cohort regarding
pregnancies that occurred before and during employment in a vinyl-
chloride-contaminated atmosphere. The most significant observation was
that "age adjusted" fetal loss occurred in 8.8% of the pregnancies of
wives of controls and in 15.8% of the pregnancies of wives of exposed
workers. The most significant difference occurred in wives of men under
age 30, where fetal 1>ss was 5.3% for controls and 20.0% for exposed
workers. Published (Hatch et al. 1981, Stallones et al. 1987) and
unpublished (The Vinyl Institute 1987, Downs et al. 1977) evaluations
severely criticize the conduct and statistical analysis of the Infante
et al. (1976) study. These evaluations concluded that the study in fact
showed no association of paternal occupational exposure to vinyl
chloride with increased fetal loss and that the study actually lacked
the statistical power to do so.
In a preliminary investigation of the potential for vinyl chloride
exposure to increase the occurrence of congenital malformations, Infante
(1976) compared the number of malformations per 1,000 live births in
three Ohio cities where polyvinyl chloride production plants were
located (index cities) with the incidence in the state as a whole and
with the incidence in other parts of the counties in which the index
cities were located. The incidence of malformations was greater in the
three index cities by either comparison, and the difference was
statistically significant. Greatest increases were noted in
malformations of the CNS, upper alimentary tract, and genital organs,
and in the incidence of clubfoot. Published (Hatch et al. 1981,
Stallones et al. 1987) and unpublished (The Vinyl Institute 1987, Downs
et al. 1977) evaluations severely criticize the conduct and statistical
analysis of the Infante et al. (1976) study. These evaluations concluded
that the study in fact showed no association between living in a region
with a vinyl chloride factory and an increased incidence of birth
defects.
An additional study of one of the Ohio cities revealed no
association with parental occupation and no evidence that parents of
malformed infants lived closer to the local polyvinyl chloride plant
than did a randomly selected group of parents who delivered normal
infants (Edmonds et al. 1975). Edmonds et al. (1975) concluded that
there was no association of birth defects with exposure to vinyl
chloride.
-------
48 Section 4
Theriault et al. (1983) investigated the incidence of birth defects
in residents of a Canadian town where there is a vinyl chloride
polymerization plant. The incidence of birth defects was significantly
greater in the index town than in any or all of three matched towns with
no potential exposure to vinyl chloride. The most commonly reported
defects involved the musculoskeletal, cardiovascular, central nervous,
and urogenital systems. The incidence rate peaked in March and was
lowest in September for the index town, but no seasonal effect was
observed in the comparison communities. The lowest incidence rate
followed the time of lowest estimated ambient atmospheric levels of
vinyl chloride by 8 months. In comparisons between parents of deformed
infants and control parents in the index town, no correlations were
noted with proximity of residence to the vinyl chloride plant or with
parental occupation. Furthermore, there were several industries in the
index town that emitted pollutants into the atmosphere. The
investigators concluded that the available data did not substantiate an
association between atmospheric vinyl chloride and an increased
incidence of birth defects.
Edmonds et al. (1978) compared the incidence rates of CNS defects
in a West Virginia county in which a polyvinyl chloride polymerization
plant was located with those for other regions in the United States with
no exposure to vinyl chloride. The incidence rates of the index county
exceeded those of control areas by a factor of 1.5 to 2. By comparing
data from parents of deformed infants with randomly chosen matched
controls living in the index county, no correlation was noted for
parental occupation, for proximity to the polyvinyl chloride plant, or
for patterns of wind direction and air pollution. Furthermore, one major
and several smaller chemical plants were located in the area.
Animal. Inhalation experiments in animals have not associated
vinyl chloride with developmental toxicity at concentrations below those
associated with maternal toxicity. John et al. (1977) exposed groups of
30 to 40 pregnant CF1 mice, 20 to 35 Sprague-Dawley rats, and 15 to 20
New Zealand white rabbits to vinyl chloride at 0 or 500 ppm 7 h/day on
gestation days 6 to 15 for rats and mice and 6 to 18 for rabbits.
Additional groups of mice were similarly exposed to 50 ppm, and
additional groups of rats and rabbits were similarly exposed to
2,500 ppm. Parameters of maternal and developmental toxicity.were
evaluated; both the fetus and litter were evaluated. In mice, maternal
effects were restricted to 500 ppm and included increased mortality,
reduced body weight, and reduced absolute, but not relative, liver
weight. Fetotoxicity, manifested as Increased fetal resorption,
decreased fetal body weight, reduced litter size, and retarded cranial
and stemebral ossification, was observed only at 500 ppm. There was no
evidence of a teratogenic effect in mice at either concentration.
Maternal effects in rats at 500 ppm, but not at 2,500 ppm, were
restricted to reduced body weight gain. Maternal effects in rats at
2,500 ppm were death of one rat, elevated absolute and relative liver
weights, and reduced food consumption. Reduced fetal body weight and an
increase in the incidence of lumbar spurs were observed at 500 but not
2,500 ppm and are not considered signs of chemical*related fetotoxicity.
The incidence of dilated ureters, however, was increased at 2,500 ppm
-------
lexicological Data 49
and may represent a chemical-Induced effect. Signs of maternal or
developmental toxicity were not observed in rabbits at either 500 or
2,500 ppm.
Ungvary et al. (1978) exposed groups of pregnant CFY rats
continuously to -1,500 ppm on gestation days 8 to 14 or 14 to 21 in a
study that identified a NOAEL for developmental toxicity in rats.
Controls consisted of groups of rats that were chamber exposed to air
only on gestation days 8 to 14 or 14 to 21. An additional control group
consisted of unexposed rats that were not subjected to the chamber.
Groups contained 14 to 28 litters, and the litter was a unit of
comparison for fetal effects. Maternal toxicity was manifested by
increased relative liver weight in dams exposed on gestation days 8 to
14 and slightly reduced body weight gain in dans exposed on days 14 to
21. There was no evidence of fetal toxicity or teratogenicity. In
another part of this study, rats were exposed as described above on
gestation days 1 to 9 and simultaneously injected subcutaneously with
physiologic saline. Compared with air-exposed controls treated with
physiologic saline, these rats had significantly increased relative
liver weights and fetal wastage, and a slight but not statistically
significant increase in the percentage of fetuses with body weights
<3.3 g. The investigators also observed one fetus with anophthalmia and
one with microphthalmia in rats exposed during days 1 to 9, as well as a
tendency for increased fetal wastage in rats exposed on days 8 to 14.
They suggested that the developmental toxicity of vinyl chloride should
be tested by continuous exposure throughout the period of organogenesis.
In a Bulgarian study, Mirkova et al. (1978) exposed pregnant rats
to 0 or 6.15 mg/m3 (2.4 ppm) continuously throughout gestation.
Fetotoxic effects included early postimplantation fetal loss, reduced
fetal body weights, retarded ossification, and fetal hematomas.
Teratogenic effects included anomalies of the brain. In offspring from
rats allowed to deliver, liver function at 1 month of age was
compromised, as indicated by increased hexobarbital sleeping time.
In a Russian study, Sal'nikova and Kotsovskaya (1980) exposed
pregnant rats to 0, 4.8, or 35.5 mg/m3 (0, 1.9, or 13.9 ppm) 4 h/day
throughout gestation. Maternal effects included decreased RBC count and
decreased urinary excretion of hippuric acid at 13.9 ppm. Fetal
hemorrhages were reported at both exposure levels, and fetal edema was
reported at 35.5 mg/m3. In offspring of rats allowed to deliver,
behavioral changes were reported at 35.5 mg/m3, and liver effects,
hematologic and biochemical effects, and altered relative organ weights
were reported in both groups.
4.3.3.2 Oral
Data regarding developmental toxicity in orally exposed humans or
animals were not located.
4.3.3.3 Dei
Data regarding developmental toxicity in dentally exposed humans or
animals were not located.
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SO Section 4
4.3.3.4 General discussion
Early epidemiologic data suggested an association between paternal
occupational exposure to yiny.1 chloride and fetal loss (Infante et al.
1976, Uaxveiler et al. 1977) and between parental residence in a region
with a vinyl chloride plant and an increased incidence of birth defects
(Infante et al. 1976). Subsequent evaluations of this study (Hatch et
al. 1981, Stallones et al. 1987, Downs et al. 1977, The Vinyl Institute
1987) severely criticize its conduct and statistical analysis and
seriously question its ability to detect the end points reported. Other
studies (Edmonds et al. 1975, 1978; Theriault et al. 1983) found no
association between parental residence in a region with a vinyl chloride
plant and the incidence of birth defects. Developmental toxicity was not
observed in animals exposed for 7- to 12-day periods during
organogenesis at levels below those also associated with severe maternal
toxicity (John et al. 1977, Ungvary et al. 1978). Ungvary et al. (1978),
however, noted evidence of developmental toxicity in rats exposed in the
first trimester compared with rats exposed later in gestation and
suggested that valid testing should involve exposure during the entire
gestation period. A Bulgarian study reported both fetotoxicity and
teratogenicity in rats exposed continuously to a low concentration
throughout gestation (Mirkova et al. 1978). The protocol and results
were incompletely reported; hence, the study cannot be properly
evaluated. Reporting problems also preclude proper evaluation of a
Russian study (Sal'nikova and Kotsovskaya 1980) that reported
developmental toxicity in rats intermittently exposed to low levels
throughout gestation. These studies, however, underscore the need for
further testing, using continuous exposure at low levels throughout
gestation.
4.3.4 Reproductive Toxicity
4.3.4.1 Inhalation
Human. Russian studies examined sexual function and hormone levels
in men (Makarov 1984) and sexual function and gynecological health in
women (Makarov et al. 1984) occupationally exposed to vinyl chloride and
in unexposed control groups. Sexual function was evaluated by
questionnaire, hormone levels were measured, and women were given
gynecological examinations. Exposures were reported as low. not
exceeding 1 maximum allowable concentration (MAC) (30 mg/m3 or -12 ppm);
average, in the range of 1 to 5 MAC (12 to 60 ppm); or significant,
exceeding 5 MAC (60 ppm). An exposure- and duration-related decline in
sexual function was reported in exposed men and women. Ovarian
dysfunction, benign uterine growths, and prolapsed genital organs were
reported in 77% of exposed women.
Animal. Bi et al. (1985) exposed groups of 75 adult male Vistar
rats to 0, 10, 100, or 3,000 ppm, 6 h/day, 6 days/week for up to 12
months to evaluate effects on the testes. Relative testicular weight,
evaluated only after 6 months of exposure, was significantly reduced at
100 and 3,000 ppm. Histopathological examination revealed a
concentration-related increase in the incidence of testicular
degeneration significant at 100 ppm. In an earlier study, Torkelson et
al. (1961) observed no effects on relative testicular weight in rats
-------
Toxicological Data 51
exposed to 500 ppm 7 h/day, 5 days/week for 4.5 months, or in dogs,
rabbits, or guinea pigs exposed to 200 ppm 7 h/day, 5 days/week for
6 months. The quality of this study was limited, however, because of the
small numbers of animals tested. Exposures involved up to 12 rats/sex
and 12 guinea pigs/sex, 3 rabbits/sex, and 1 dog/sex.
4.3.A.2 Oral
Data regarding the reproductive effects of vinyl chloride in orally
exposed humans or animals were not found in the literature.
4.3.4.3 Dermal
Data regarding the reproductive effects of vinyl chloride in
dermally exposed humans or animals were not found.
4.3.4.4 General discussion
Data regarding the reproductive effects of exposure to vinyl
chloride are limited. Human data associating occupational exposure with
reduced sexual function in both sexes and impaired gynecological health
in women (Makarov 1984, Makarov et al. 1984) are not adequately reported
for proper evaluation; therefore, such data cannot be used to identify
thresholds. Whereas animal data do associate exposure to vinyl chloride
with testicular effects, sexual performance and fertility were not
tested.
4.3.5 Genotoxic ity
4.3.5.1 Human
Genotoxicity studies of vinyl chloride in humans include a large
number of chromosomal aberration tests in the peripheral lymphocytes of
occupationally exposed workers (Table 4.4). These tests (Ducatman et al
1975, Funes-Cravioto et al. 1975, Purchase et al. 1978, Hansteen et al
1978, Kucerova et al. 1979, Katsova and Pavlenko 1985), with the
exception of a less rigorously performed and reported Dow Chemical
Company study (Kilian et al. 1975), generally suggest a mutagenic role
for vinyl chloride. The key study in this group is Hansteen et al.
(1978), in which blood from 37 exposed workers and from 16 to 32
unexposed controls was examined twice at intervals of'2 to 2.5 years.
Exposure levels during the time of first sampling were measured at
25 ppm, and there was a statistically significant increase in the
percent of peripheral lymphocytes with chromosomal aberrations. When
these workers were subsequently reexamined, exposure levels had dropped
to 1 ppm. and there were no statistical differences between exposed and
controls in the percentage of chromosomal aberrations.
Anderson et al. (1980) observed an increase in lymphocytes with
chromosomal aberrations in another cohort at exposure levels estimated
at 50 ppm. The incidence of aberrations was returning to normal,
however, when the cohort was resampled after exposure levels had been
reduced to <5 ppm. In a Russian paper (Katsova and Pavlenko 1985),
0.1 mg/m^ (-0.04 ppm) was suggested as a no-effect level for chromosomal
-------
52 Section 4
Table 4.4. Genotoxicity of vinyl chloride in vivo
End point
Species/test system
Result
References
Recessive lethal
Dominant lethal
Sex chromosome loss
Chromosomal translocation
Chromosomal aberration
Sister chromatid exchange
Chromosomal aberration
Chromosomal aberration
Micronucleus test
RNA alkylation"
DNA alkylation
DNA alkylation
Drosophila melanogaster
D. melanogaster
Mouse
D. melanogaster
D. melanogaster
Rat
Mouse
Human lymphocyte
Human lymphocyte
Human lymphocyte
Human lymphocyte
Human lymphocyte
Human lymphocyte
Human lymphocyte
Human lymphocyte
Human lymphocyte
Mouse
Rat
Rat
Mouse
Rat
Verburgt and Vogel 1977
Verburgt and Vogel 1977
Purchase et al. 197S.
Anderson et al. 1976
Verburgt and Vogel 1977
Verburgt and Vogel 1977
Anderson and Richardson 1981
Walles and Holmberg 1984
Hansteen et al. 1978
Hansteen et al. 1978
Kucerova et al. 1979
Kucerova et al. 1979
Purchase et al. 197S, 1978
Ducatman et al. 1975
Funes-Cravioto et al. 197S
Katsova and Pavlenko 198S
Kilian et al. 197S
Jenssen and Ramel 1980
Laib and Bolt 1977
Laib et al. 198S
Osterman-Golkar et al. 1977
Green and Hathway 1978
"Although RNA alkylation is not a genotoxic effect, the results of this test are supportive evi-
dence that vinyl chloride metabolites interact with nucleic acids.
-------
Toxicological Dae a. 53
aberrations. The study was insufficiently reported to allow critical
evaluation, however, and the NOAEL from the Hansteen et al. (1978) study
is accepted.
4.3.5.2 Nonhuman
It is beyond the scope of this document to evaluate all data
regarding the mutagenicity of vinyl chloride in nonhuman systems.
Representative data, largely taken from a recent EPA (1985b) review, are
presented in Tables 4.4 and 4.5.
Vinyl chloride is mutagenic in Salmonella typhimurium (Rannug et
al. 1974; Bartsch et al. 1975, 1976; Andrews et al. 1976; Simmon et al.
1977; Elmore et al. 1976; Poncelet et al. 1980; de Meester et al. 1980).
but only in strains reverted by base-pair substitution by alkylating
agents rather than by frameshift mutations (Bartsch et al. 1976).
Metabolic activation may be necessary for any mutagenic activity in this
system (Rannug et al. 1974) or for a maximal response (Simmon et al.
1977). Results in other microbial systems were mixed. Vinyl chloride was
positive for recessive lethal effects but negative for dominant lethal
effects, chromosomal translocation, and sex chromosome loss in
Drosophila melanogaster (Verburgt and Vogel 1977). The investigators
suggested that the negative results in the dominant lethal test may
indicate that metabolites capable of causing chromosomal damage did not
reach the germ cells. Negative results were obtained for the dominant
lethal test in mice (Purchase et al. 1975, Anderson et al. 1976).
Positive results were obtained in mutation and cell transformation
tests and in chromosomal aberration tests in in vivo and in vitro
mammalian systems (Styles 1977, Drevon and Kuroki 1979. Jenssen and
Ramel 1980, Walles and Holmberg 1984, Laib and Bolt 1977, Laib et al.
1985, Anderson and Richardson 1981). Positive results were also reported
for DNA alkylation tests in rats (Green and Hathway 1978) and mice
(Osterman-Golkar et al. 1977) and for RNA alkylation in rat liver
microsomes (Laib and Bolt 1977).
4.3.5.3 General discussion
Evidence strongly implicates the oxidation of vinyl chloride to the
reactive intermediates 2-chloroethylene oxide and 2-chloroacetaldehyde
as being responsible for mutagenicity in the systems discussed above.
Reports indicate that 2-chloroethylene oxide and 2-chloroacetaldehyde
are manyfold more active in S. typhLmuriun than the parent compound or
other oxidation products of vinyl chloride such as 2-chloroethanol or
chloroacetic acid (Rannug et al. 1976, Bartsch 1976, McCann et al.
1975). 2-Chloroethylene oxide has also been shown to be responsible for
base-pair substitutions in EscherichLa coii (Barbin et al. 1985a), to be
highly mutagenic in gene mutation and gene conversion tests in yeasts
(Loprieno et al. 1977), and to induce mutations in Chinese hamster V79
cells (Huberman et al. 1975). In vitro testing has shown that
2-chloroethylene oxide is capable of alkylating DNA to form
7-(2-oxoethyl)guanine as the principal adduct (Barbin et al. 1985b).
This adduct has not been shown to cause errors in DNA replication in an
in vitro test with E. colL DNA polymerase I, and the role of DNA
alkylation in mutagenesis is unclear.
-------
54 Section 4
TtNe4J. GcMtoxkhy of Tiayl chloridt hi rhro
End point
Result
Species/test system
Without
activation
With
activation
References
Reverse mutation
Salmonella typhimurium
S typhimunum
S. typhimunum
S. typhimunum
S. typhimurium
S. typhimurium
NT"
Rannug et aL 1974
Bansch et al. 197S. 1976
Andrews et aL 1976
Simmon et al. 1977
Elmore et aL 1976
Poncelet et aL 1980.
de Meester et aL 1980
Forward or reverse
mutation
Reverse mutation
Forward mutation
Rec-repair
Forward mutation
Cell transformation
RNA alkylationc
Eichenchia coli —
Saccharomycts ctrevisiae —
Schizosaccharomyces pombt —
Bacillus subtills -
Chinese hamster cell V79 +
Neonatal hamster kidney cells +
Rat liver microtomes +
+
NT
•f-
NT
NA»
NA
NA
Gram et aL 197S
Shahin 1976
Lopneno et aL 1977
Elmore et aL 1976
Drevon and Kuroki 1979
Styles 1977
Laib and Bolt 1977
"Not tested.
"Not applicable.
"Although RNA alkylation is not a genotoxic effect, the results of this test are supportive evidence that
vmyl chloride metabolites interact with nucleic acids.
-------
Toxicological Data 55
4.3.6 Carcinogenicity
4.3.6.1 Inhalation
Human. Several reports (Tabershav and Gaffey 1974, Monson et al.
1975. Waxweiler et al. 1976, Nicholson et al. 1975, Heath et al. 1975,
Lills et al. 1975, Popper and Thomas 1975, Bryen et al. 1976, Fox and
Collier 1977, Heldaas et al. 1984, Geryk and Zudova 1986) associate
human cancer with occupational exposure to vinyl chloride. The most
recent review of the human data is that of EPA (1985b). Since none of
the human studies quantify exposures sufficiently for quantitative risk
assessment, no single report is chosen as a key study. In a review of
these data, IARC (1979) concluded that the human data constitute
"sufficient" evidence for the carcinogenicity of the compound EPA
(1985b) classified vinyl chloride in I ARC Group 1; subsequently, EPA
(1987b) placed this compound in Carcinogen Assessment Group A. Both
classifications reflect the designation of vinyl chloride as a known
human carcinogen.
The incidence of liver cancer, in particular angiosarcoma, provides
the most convincing e/idence for the carcinogenicity of vinyl chloride
because the expected background level (25 to 30 cases per year in the
United States) is extremely low (Heath et al. 1975). Most of the
epidemiologic studies cited above reported a higher observed/expected
ratio for liver cancer than for cancers of any other site. Other cancers
associated with vinyl chloride exposure include tumors of the brain
and CNS, the lung and respiratory tract, the digestive tract, and the
lymphocytic/hematopoietic system, although statistical significance was
not necessarily reached (Monson et al. 1975, Waxweiler et al. 1976,
Bryen et al. 1976). Fox and Collier (1977), however, concluded that
there is no evidence that cancers other than those of the liver are
associated with exposure to vinyl chloride. More recent and larger
unpublished epidemiology studies (Wong et al. 1986, Doll 1987), however.
while supporting the association of exposure with liver and brain
cancer, report no association between exposure and increased risk from
lung and respiratory cancer, lymphocytic/hematopoietic cancer, or
melanoma. Heldaas et al. (1984) also reported an unusual number of cases
of malignant melanoma of the skin in exposed workers.
Generally, prolonged exposure (employment) increased the risk of
cancer, particularly if intermittent high exposures have occurred (Bryen
et al. 1976, Heath et al. 1975). Tabershaw and Gaffey (1974) noted that
an increased risk of malignancy correlated with an increased "exposure
index," an interplay of level and duration of exposure. Fox and Collier
(1977), however, reported little correlation with duration of exposure
Animal. The key animal inhalation studies of carcinogenicity are
the series of experiments by Maltoni et al. (1980, 1981) in Sprague-
Dawley rats, Swiss mice, and golden hamsters. A report of interim
results was published earlier (Maltoni and Lefemine 1975). All animals
were chamber exposed; controls were chamber exposed to air only. The
test material was >99.9% pure. A complete gross and histopathological
examination of every animal was performed. Mice and hamsters were
exposed to vinyl chloride concentrations of 50 to 10,000 ppm for
30 weeks, followed by an observation period of 51 weeks (mice) or
-------
56 Section 4
79 weeks (hamsters). Exposure levels and results from the most
comprehensive and longest term experiments in rats are presented in
Table 4.6. The investigators noted that increased incidence of tumors
occurred at 250 ppm in all species tested. All species shoved an
increase in the incidence of liver angiosarcoma. In addition to the
tumor types presented in Table 4.6, the authors associated extra hepatic
angiosarcomas, hepatomas, Zymbal gland carcinomas, and neuroblastomas in
rats with exposure to vinyl chloride.
Other inhalation experiments support the carcinogenicity of vinyl
chloride. Rats, mice, and hamsters vere exposed to 50 to 2,500 ppm vinyl
chloride for 9 or 12 months (Keplinger et al. 1975, MCA 1980). All
species developed liver angiosarcomas in a concentration-related manner
at >50 ppm, the lowest level tested. Metastases to lymph nodes or lung
vere common. Rats also developed Zymbal gland tumors at >50 ppm and
brain tumors at 2200 ppm, and mice developed lung tumors at 250 ppm.
Viola et al. (1971) exposed rats to 3% vinyl chloride (30.000 ppm) for
12 months and observed primary tumors of the skin, lungs, and bones.
Feron and Kroes (1979) exposed rats to 0 or 5,000 ppm for 52 veeks and
observed primary tumors in treated rats in the brain, lung, Zymbal
gland, and nasal cavity. Lee et al. (1977a, 1978) exposed rats and mice
to 0, 50, 250, or 1,000 ppm, 6 h/day, 5 days/veek for up to 12 months;
subsequently, they observed an increased incidence of hemangiosarcoma of
the liver in rats at >250 ppm, as veil as bronchoalveolar adenoma of the
lung, mammary tumors, and hemangiosarcoma of the liver and other organs
in mice at 250 ppm. In a later study from the same laboratory, Hong et
al. (1981) exposed rats and mice to 0, 50, 250, or 1,000 ppm, 6 h/day,
5 days/veek for up to 6 months, folloved by a 12-month observation
period. Tumor types attributed to vinyl chloride exposure in rats vere
those observed by Lee et al. (1977a, 1978), in addition to
bronchoalveolar lung tumors at 2250 ppm and mammary tumors at all
exposure concentrations.
Suzuki (1978, 1981, 1983) also observed lung tumors as a primary
carcinogenic response of mice to vinyl chloride. Lung tumors developed
in 26 of 27 mice exposed to 2,500 or 6,000 ppm for 5 to 6 months (Suzuki
1978). Concentration-related increased incidences of lung tumors vere
observed in studies in which mice vere exposed to 0 to 100 or 0 to
600 ppm for 4 weeks and then observed for up to 41 weeks postexposure
(Suzuki 1981, 1983). It appeared that 10 ppm was a level associated with
an increased incidence of lung tumors in mice in these studies. Hehir et
al. (1981) reported an increased incidence of lung tumors in mice given
single 1-h exposures to 5,000 or 50,000 ppm.
Inhalation data in three species suggest that age at exposure has
an effect on carcinogenic response. Drew et al. (1983) exposed rats,
mice, and hamsters to concentrations of 50 to 200 ppm for periods of
6 to 24 months. Exposures vere started at 0, 6, 12, or 18 months after
weaning. All three species had a maximal ohcogenic response when exposed
during the first 12 months of life. Exposures begun after a 12-month
holding period did not produce a carcinogenic response. Maltoni et al.
(1983) and Cotti et al. (1983) exposed rats in utero from gestation day
12 and after birth to 1 year of age to 2,500 ppm and observed very high
incidences of liver and brain tumors. Liver angiosarcoma, with an
average latency period of 50 weeks, developed in 32 of 56 males and in
-------
Toxlcological Data 57
Table 4.6. Tumor incidence in male and female Sprague-Dawley
rats exposed by inhalation to vinyl chloride
4 h/day, 5 days/week for 52 weeks
Exposure level
(ppm)
0
1
5
10
25
SO
100
ISO
200
250
500
2,500
6,000
10,000
30,000
Duration of
study
(weeks)
135-147
147
147
147
147
135
143
143
143
135
135
135
135
135
68
Incidence of liver
angiosarcoma
0/363
0/118
0/119
1/119
5/120
1/60
1/120
6/119
12/120
3/59
6/60
13/60
13/59
7/60
18/60
Incidence of kidney
nephroblastoma
0/363
0/118
0/119
0/119
1/120
1/60
10/120
11/119
7/120
5/59
6/60
6/60
5/59
5/60
NR«
"Not reported.
Source: Maltoni et al. 1980, 1981.
-------
58 Section 4
38 of 55 females. Brain tumors, with an average latency of 48 weeks,
developed in 27 of 57 males and in 28 of 57 females. Lower incidences of
tumors developed in rats exposed for only 7 days in utero. Maltoni et
al. (1980, 1981) exposed rats to 6,000 or 10,000 ppm in utero on days
12 to 18 of gestation a'nd continued to observe them for 115 weeks. In 54
high-dose progeny, there were 3 with Zymbal gland carcinoma, 2 with
angiosarcoma, and 1 with nephroblastoma of the brain. In 32 low-dose
progeny, 1 developed Zymbal gland carcinoma and 2 had angiosarcoma.
Radike et al. (1988) exposed pregnant Sprague-Dawley rats to vinyl
chloride at 600 ppm 5 h/day on gestation days 9-21. An additional group
was also exposed through the lactation period. The occurrence of
angiosarcoma in offspring of dams exposed during gestation confirms the
transplacental carcinogenicity of vinyl chloride. Additional exposure
during lactation greatly increased the incidence of liver tumors.
4.3.6.2 Oral
Human. Data regarding the carcinogenicity of vinyl chloride in
orally exposed humans were not found.
Animal. Cancer types observed in orally treated rats resemble
those observed from inhalation exposure. In the key oral study, Feron et
al. (1981) exposed groups of Uistar rats to vinyl chloride in the diet
by incorporating polyvinyl chloride (FVC) powder containing a high level
of the monomer. Diets were fed 4 h/day, and food consumption and body
weights were monitored. Volatilization of vinyl chloride from the diet
was estimated, and dosages of vinyl chloride available to the rats were
also estimated. In addition, one group received vinyl chloride by gavage
5 days/week. Pertinent data are summarized in Table 4.7. Exposure was
for the lifetime of the rats. Treatment of the 300-mg/kg gavage group
was terminated at 84 weeks because of high mortality. The liver tumor
incidence data presented in Table 4.7 suggest that angiosarcomas
predominated at high dosages but chat hepatocellular carcinomas
predominated at low dosages. In addition to tumors of the liver and
lung, the investigators attributed exposure to the development of extra
hepatic abdominal angiosarcomas and Zymbal gland tumors. They also noted
some evidence that exposure enhanced the development of abdominal
mesotheliomas and adenocarcinomas of the mammary gland.
Other oral studies indicate that the type of tumor observed may
depend on the dosage given. Maltoni (1977) treated rats by gavage at
16.7 or 50 mg/kg/day for 52 weeks followed by an 84-week observation
period. An Increased incidence of liver angiosarcomas and kidney
nephroblastomas was attributed to vinyl chloride. Zymbal gland
carcinomas may also have been the result of exposure to vinyl chloride.
Til et al. (1983), in a lifetime study, administered vinyl chloride in
the diet (from PVC containing a high level of of the monomer) to rats at
dosages of 0.014 to 1.3 mg/kg/day. Males at 1.3 mg/kg/day had a small
but significantly increased incidence of hepatocellular carcinoma.
Females at 1.3 mg/kg/day had a significantly increased incidence of
hepatic neoplastic nodules, along with a suggestive but not significant
increase in hepatocellular carcinoma. Tumorigenic effects were not seen
at lower doses.
-------
Toxlcological Data 59
Table 4.7. Tumor Incidence io Wlsur rats orally exposed to
rtnyl chloride"
Dose*
Sex (mg/kg/day)
F 300
F 170
F 56
F 18
F 00
M 300
M 170
M 5.6
M 18
M 0.0
Duration of
treatment
(weeks) Vehicle/ method
84 Soybean oil/
gavage
143 PVC/diet
143 PVC/diet
143 PVC/diet
NA' Untreated diet
only
84 Soybean oil/
gavage
143 PVC/diet
143 PVC/diet
143 PVC/diet
NA Untreated diet
only
Target
organ
Liver
Lung
Liver
Lung
Liver
Lung
Liver
Lung
Liver
Lung
Liver
Lung
Liver
Lung
Liver
Lung
Liver
Lung
Liver
Lung
Tumor type
Neoplastic nodule
Hepatocellular carcinoma
Angtosarcoma
Angiosarcoma
Neoplastic nodule
Hepatocellular carcinoma
Angiosarcoma
Angiosarcoma
Neoplastic nodule
Hepatocellular carcinoma
Angiosarcoma
Angiosarcoma
Neoplastic nodule
Hepatocellular carcinoma
Angiosarcoma
Angiosarcoma
Neoplastic nodule
Hepatocellular carcinoma
Angiosarcoma
Angiosarcoma
Neoplastic nodule
Hepatocellular carcinoma
Angiosarcoma
Angiosarcoma
Neoplastic nodule
Hepatocellular carcinoma
Angiosarcoma
Angiosarcoma
Neoplastic nodule
Hepatocellular carcinoma
Angiosarcoma
Angiosarcoma
Neoplastic nodule
Hepatocellular carcinoma
Angiosarcoma
Angiosarcoma
Neoplastic nodule
Hepatocellular carcinoma
Angiosarcoma
Angiosarcoma
Tumor incidence
(f> value)
2/54
0/54
29/54
23/54
44/57 (/><0 001 f
29/57 (/><0 001 )c
9/57 (/><0 001 f
5/57(/»<005)<0 001 )f
8/59 (/><0 001 )c
27/59 (P<0 001 )c
19/59 (/»<0 01 )c
7/56(/»
-------
60 Section 4
4.3.6.3 Dermal
Data regarding the carclnogenlclty of vinyl chloride In dermally
exposed humans or animals were not found.
4.3.6.4 General discussion
The data reviewed Indicate that there is some similarity in cancer
types In experimentally exposed animals and occupationally exposed
humans. The human data present the strongest statistical case for
associating occupational exposure with liver angiosarcoma (Monson et al
1975, Waxweiler et al. 1976, Bryen et al. 1976, Fox and Collier 1977) '
The incidence of cancer of the brain, lung, and digestive tract
although not always statistically significant, is suggestive of'a vinyl
foi!r ?,?C,2«P' M°re reCent lar*er ""P^l^hed studies (Wong et al.
1986, Doll 1987) associate vinyl chloride exposure with liver
angiosarcoma and possibly with tumors of the brain, but not with tumors
of the lung or digestive tract. The substantial amount of animal data
also presents the strongest association for liver angiosarcoma (Maltoni
et al. 1980, 1981; MCA 1980; Feron and Kroes 1979). Statistically
significant increases have also been observed for lung cancer In mice
(Lee et al. 1978; Hong et al. 1981; Suzuki 1978, 1981, 1983) and
biologically significant increases have been reported for brain cancer
in rats (Feron and Kroes 1979; MCA 1980; Maltoni et al. 1980, 1981)
Animal data suggest that both the young and the prenatal organism are
™eptlble C° ^"y1'chloride-induced cancer (Maltoni et al. 1980, 1981
1983; Drew et al. 1983; Radike et al. 1988).
v, ,_,It ls «enerally «8«ed that oxidation to 2-chloroethylene oxide, a
highly electrophlllc Intermediate, is responsible for the mutagenlcity
of vinyl chloride (Gwinner et al. 1983. Valno 1978). In vitro testing
has shown 2-chloroethylene oxide capable of alkylating DNA to form
7-(2-oxoethyl)guanlne as the principal adduce (Barbln et al. 1985b)
This adduct has not been shown to be Involved In genetic miscoding and
the role of DNA alkylation in carcinogenesis Is unclear.
4.4 INTERACTIONS WITH OTHER CHEMICALS
A series of investigations describes the interactions of vinyl
chloride with various other compounds, which clarifies the role of
metabolism In the toxlelty of this compound. In all studies, the acute
toxiclty to the liver of rats exposed by inhalation to high
concentrations, as manifested by serua levels of enzymes indicative of
liver damage and the hlstopathologlcal appearance of the liver, was the
end point evaluated. In the first study (Jaeger et al. 1974),
pretreatnent of rats with phenobarbltal resulted in liver damage as
measured by biochemical and histopathological parameters. Liver damage
was not detected In nonpretreated rats. The investigators suggested that
phenobarbital had Induced the mixed-function oxidase (MPO) system to
enhance metabolism of vinyl chloride to a toxic Intermediate. In
subsequent experiments (Reynolds et al. 1975, Conolly et al. 1978),
pretreatment with the polychlorinated biphenyl (PCB) mixture Aroclor
1254 was also observed to cause acute exposure to vinyl chloride to
result In hepatotoxiclty. The same mechanism, induction of hepatic MPO,
-------
Toxicological Daca 61
was suggested to result In oxidation of vinyl chloride to the epoxide,
2-chloroethylene oxide.
Conolly and Jaeger (1978, 1979) Investigated the effect of
chemicals that regulate xenobiotic metabolism on vinyl-chloride-induced
hepatotoxicity. Trichloropropene oxide (TCPO), which depletes
glutathione and inhibits epoxide hydrase conversion of an epoxide co ics
corresponding less-toxic alcohol, was found to enhance the toxic icy of
vinyl chloride in fasted PCB-pretreated rats, but not in fed pretreated
rats. Since nonprotein sulfhydryl concentrations in the liver in
TCPO-treated rats did not differ from those in control rats, the
investigators suggested that the enhanced toxicity in TCPO-treated rats
resulted from inhibition of epoxide hydrase rather than from glutathione
depletion. The lack of effect in fed rats was Judged to underscore the
importance of epoxide hydrase in the detoxification of epoxide in
glutathione-depleted rats.
In other parts of these same studies, cysteine, the rate-limiting
precursor of glutathione, was able to block depletion of nonprotein
sulfhydryl in the liver and thus reduce the intensity of liver toxicity
in PCB-pretreated, vinyl-chloride-exposed rats. Treatment of fed rats
with diethylmaleate, another glutathione depleting agent, reduced liver
nonprotein sulfhydryl to levels attained in fasted rats, but did not
increase hepatotoxicity.
Several studies evaluated the interaction of ethanol with vinyl
chloride, because ethanol has been shown to slow metabolism of vinyl
chloride in rats. Radike et al. (1988) provided drinking water
containing 5% ethanol to pregnant rats exposed concurrently to vinyl
chloride in the air on days 9-21 of gestation in a perinatal
carcinogenesis study. The occurrence of angiosarcoma of the liver, lung,
and muscle confirmed the transplacental oncogenicity of vinyl chloride.
Exposure to ethanol had no apparent effect on the incidence of
angiosarcoma. John et al. (1977) exposed rats, mice, and rabbits to 15%
ethanol in drinking water concurrently with vinyl chloride in air during
organogenesis. The investigators stated that ethanol exacerbated some of
the fetal and maternal effects of vinyl chloride. The most striking
effects of ethanol were a marked reduction in food intake, ranging from
33% (mice) to 83% (rabbits) compared with animals exposed to vinyl
chloride alone, and a commensurate reduction in maternal body weight
gain.
-------
63
5. MANUFACTURE. IMPORT, USE, AND DISPOSAL
5.1 OVERVIEW
Vinyl chloride is produced at 11 locations in the United States.
During 1986, 8.439 billion Ib of this chemical were produced in the
United States. It is produced by thermal cracking of ethylene
dichloride. Vinyl chloride is used almost exclusively in the United
States for the production of polyvinyl chloride (PVC) and several
copolymers. These compounds yield a wide range of end-use products which
are used by industries and consumers.
5.2 PRODUCTION
Domestic production of vinyl chloride during 1986 was 8.439 billion
Ib (USITC, 1987). This required essentially all of the available
production capacity in 1986. In 1985, 7.8 billion Ib of vinyl chloride
was produced in the United States (C&EN 1987).
Manufacturers and sites of production are as follows (SRI 1988):
Borden Chemical in Geismar, Louisiana; Dow Chemical in Oyster Creek,
Texas, and Plaquemine, Louisiana; Formosa Plastics in Baton Rouge,
Louisiana, and Point Comfort, Texas; Georgia-Gulf in Plaquemine,
Louisiana; BF Goodrich in Calvert City, Kentucky, and La Porte, Texas;
PPG Industries in Lake Charles, Louisiana; Occidental Chemical in Deer
Park, Texas; and Vista Chemical in Lake Charles, Louisiana.
Vinyl chloride is produced commercially by thermal cracking of
ethylene dichloride (EDC). EDC used in this process is made by either
direct chlorination of ethylene using liquid chlorine, or
oxychlorination of ethylene using dry hydrochloric acid and oxygen
(Cowfer and Magistro 1985). Vinyl chloride is usually supplied as a
liquid under pressure (IARC 1979). The technical grade product is
available in 99.9% purity (Sax and Lewis 1987).
5.3 IMPORT
Imports of vinyl chloride were -200 million Ib in 1987 (C&EN 1987).
5.4 USES
The use pattern for vinyl chloride is as follows (CMR 1986a):
polyvinyl chloride (PVC), 85%; exports, 13%; and other, mostly copolymer
use, 2%. This use pattern indicates that vinyl chloride monomer is used
almost exclusively in the United States by the plastics industry. Very
small amounts are used as a refrigerant gas and as an intermediate in
the production of chlorinated compounds (Curry and Rich 1980, Gosselin
et al. 1984, IARC 1979). Limited quantities of vinyl chloride were used
in the United States as an aerosol propellant and as an ingredient of
-------
64 Seccion 5
drug and cosmetic products; however, these practices have been
discontinued (EPA 1985b).
Vinyl chloride is industrially important because of its inherent
flame retardant properties, its wide variety of end-use products, and
the low cost of producing polymers from vinyl chloride (Cowfer and
Magistro 1985). Principal end-use products include: PVC pipes, wire and
cable coatings, packaging materials, furniture and automobile
upholstery, wall coverings, housewares, and automotive parts and
accessories; vinyl chloride-vinyl acetate copolymer floor coverings,
phonographic records, and flexible film; vinyl chloride-acrylonitrile
battery cell separators; and vinyl chloride-vinylidine chloride
copolymer food packaging film (Curry and Rich 1980, Salkind and Pearlman
1978, Farkas 1980).
5.5 DISPOSAL
EPA requires that persons who generate, transport, treat, store, or
dispose of this compound comply with regulations of the Federal Resource
Conservation and Recovery Act (RCRA). The recommended method of
disposal, reported by Sittig (1985), involves the incineration of this
chemical after mixing it with another combustible fuel. Care should be
taken to ensure that complete combustion has taken place in order to
avoid formation of phosgene. An acid scrubber is required to remove HC1.
In addition to this method, other disposal techniques have been
developed for the recovery of vinyl chloride from PVC latexes (Sittig
1985).
-------
65
6. ENVIRONMENTAL FATE
6.1 OVERVIEW
Information regarding the environmental fate and transport of vinyl
chloride is limited. Effluents and emissions from vinyl chloride and PVC
manufacturers are responsible for the majority of vinyl chloride
released to the environment. When released to the atmosphere vinyl
chloride is expected to be removed by reaction with photochemically
generated hydroxyl radicals (half-life - 1.2 to 1.8 days). Reaction
products include HC1, formaldehyde, formyl chloride, acetylene
chloroacetaldehyde, chloroacetylchloranil, and chloroethylene 'in
photochemical smog situations, vinyl chloride has a half-life of 3 to
7 h. When released to water, volatilization is expected to be the
primary fate process (half-life - 8.7 to 43.3 h). In waters containing
photosensitizers, such as humic materials, sensitized photodegradation
may also be important. When released to soil, vinyl chloride will either
volatilize rapidly from soil surfaces or leach readily through soil
ultimately entering groundwater.
6.2 RELEASES TO THE ENVIRONMENT
The major source of release of vinyl chloride to the environment is
believed to be emissions and effluents from plastic industries
(primarily vinyl chloride and PVC manufacturers). Vinyl chloride
released in wastewater is expected to volatilize fairly rapidly (on the
order of hours to days) into the atmosphere. Other sources of release
include disposal of vinyl chloride wastes in landfills, incomplete
combustion of PVC, tobacco smoke, spills, and biodegradation of
itoiahl™t?£ienef tetrachl°™«thylene, and 1,1.1-trichloroethane (IARC
1979, HSDB 1987, Vakeman and Johnson 1978, Wilson and Wilson 1985 Smith
and Dragun 1984). EPA estimated that prior to 1975, 110 million kg/year
of vinyl chloride escaped into the atmosphere from PVC production
facilities In the United States (IARC 1979). Worldwide emissions of
vinyl chloride into the atmosphere during 1982 was -400 million Ib
(Hartnans et al. 1985).
6.3 ENVIRONMENTAL FATE
6.3.1 Air
Based on a vapor pressure of 2,660 ma Hg at 25'C, essentially all
vinyl chloride in the atmosphere is expected to exist in vapor form
(Verschueren 1983, Eisenreich et al. 1981). Consequently, removal from
the atmosphere by dry deposition is not expected to be an important fate
process. Vinyl chloride has a relatively high partition coefficient
between air and water (H - 50), which suggests that significant amounts
-------
66 Section 6
of vinyl chloride would not be removed from the atmosphere by vet
deposition (EPA 1985b).
Reaction of vinyl chloride vapor with photochemically generated
hydroxyl radicals is predicted to be the primary degradation mechanism
for this compound in the atmosphere. The half-life for this reaction in
the typical atmosphere has been -1.5 to 1.8 days (EPA 1985b). Products
of this reaction are HC1, formaldehyde, formyl chloride, carbon
monoxide, carbon dioxide, chloroacetaldehyde, acetylene, chloroethylene,
chloroacetylchloranil, and H20 (EPA 1985b). In photochemical smog
situations, the reaction half-life of vinyl chloride is predicted to
range between 3 and 7 h (HSDB 1987). Reaction with ozone (half-life -
4.2 to 33 days), reaction with oxygen atoms [0(3P>] (half-life - 373 to
532 days), and direct photolysis are relatively insignificant
degradation mechanisms in the atmosphere (EPA 1985b).
6.3.2 Water
The primary loss process for vinyl chloride in natural water
systems is volatilization into the atmosphere. The half-life for vinyl
chloride volatilization from a typical pond, river, and lake has been
estimated to be 43.3, 8.7, and 34.7 h, respectively. These values are
based on an experimentally determined reaeration rate ratio of -2 and
assumed oxygen reaeration rates of 0.008, 0.04, and 0.01 hour"1 for a
typical pond, river, and lake, respectively (EPA 1985b). Predicted
half-lives should be considered rough estimates since the presence of
various salts in natural water systems may affect the volatility of
vinyl chloride significantly (EPA 1985b). In waters containing
photosensitizers, such as humic materials, photodegradation may be
fairly rapid. This suggests that in some waters sensitized
photodegradation would also be a significant removal mechanism (HSDB
1987, EPA 1985b).
Chemical hydrolysis of vinyl chloride does not appear to be
environmentally important. The hydrolytic half-life for vinyl chloride
has been estimated to be <10 years (EPA 1985b). Vinyl chloride is not
expected to oxidize chemically by reaction with photochemically
generated hydroxyl radicals, molecular oxygen, or alkyl peroxy radicals
in natural water systems. Limited available data on the biodegradation
of vinyl chloride indicate that this compound is resistant to microbial
degradation under aerobic conditions (EPA 1985b). Vinyl chloride is not
expected to adsorb significantly to suspended solids and sediments in
water or bioaccumulate significantly in aquatic organisms (HSDB 1987).
6.3.3 Soil
The relatively high vapor pressure of vinyl chloride (2,660 mm Hg
.at 25°C) indicates that this compound should volatilize quite rapidly
from dry soil surface. The effective half-life (due to volatilization)
of vinyl chloride placed 10 cm deep in dry soil is predicted to be 12 h
(EPA 1985b). Evaporation from moist soil surfaces is also expected to be
significant since this compound does not adsorb strongly to soil and
appears to volatilize fairly rapidly from water.
-------
Environmental Face 67
Experimental data regarding adsorption of vinyl chloride to soil
were not located. Based on the regression equations given by Lyman et
al. (1982) and Sablj ic (1984), the soil adsorption coefficient (Koc) for
vinyl chloride has been estimated to range between 17 and 131. These KOC
values suggest that this compound would be highly mobile in soil. Thus,
vinyl chloride has the potential to leach into groundwater.
Vinyl chloride is soluble in most common organic solvents (Cowfer
and Magistro 1983). In situations where organic contaminants exist in
relatively high concentrations (e.g., landfills, hazardous waste sites),
cosolvation of vinyl chloride could have the effect of reducing its
volatility, thus causing it to have even greater mobility than indicated
by its estimated
Based on data in aquatic media, chemical reaction of vinyl chloride
in soil does not appear to be a significant fate process, and it appears
that vinyl chloride would be resistant to biodegradation under aerobic
conditions.
-------
69
7. POTENTIAL FOR HUMAN EXPOSURE
7.1 OVERVIEW
Anthropogenic sources are responsible for all of Che vinyl chloride
found in Che environment. Vinyl chloride has been found in at least 133
of 1,177 hazardous wasCe sices on Che National Priorities List (View
data base 1989). Mosc of Che vinyl chloride released to the environment
will eventually locate in the atmosphere while much smaller amounts will
eventually locate in groundwater. Vinyl chloride has been detected in
the ambient air in the vicinicy of vinyl chloride and PVC manufacturing
planes and hazardous waste sites. Vinyl chloride is expected to leach
into groundwater from spills, landfills, and industrial sources.
Segments of Che general populaCion living in Che vicinicy of
emission sources are exposed Co 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 pg/day. The average
daily intake of vinyl chloride by inhalation is expected to be
essentially zero for the remainder of the population. However, short-
term inhalation exposure to elevated levels may occur during use of new
cars. This is due to volatilization of vinyl chloride from vinyl
polymers within the car interior.
The majority of Che general population is not expected to be
exposed to vinyl chloride through ingesCion of drinking water. However,
people who have PVC water pipes that have not been treated adequately to
remove vinyl chloride monomer may ingest -0.06 to 2.8 jig/day of vinyl
chloride from drinking water. The average daily intake of vinyl chloride
through diet is predicted to be essentially zero.
NIOSH estimated that 27,000 workers are definitely exposed to vinyl
chloride and that workers probably exposed may be as many as
2.2 million. Intake is expected to occur primarily through inhalation
and less importantly by absorption through skin. Workplace air in some
PVC manufacturing plants was found to contain 100 to 800 mg/m3 (39 to
312 ppm) vinyl chloride with peak concentrations of up to 87,300 mg/m3
(34,000 ppm). A NIOSH survey of three vinyl chloride manufacturers
reported a time-weighted-average exposure of 0.18 to 70 mg/m3 (0.07 to
27 ppm) vinyl chloride in workplace air.
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
7.2.1 Air
Air in rural/remote and urban/suburban areas of the United States
typically contain no detectable amount of vinyl chloride (Stephens et
al. 1986; Grimsrud and Rasmussen 1975a,b; Harkov et al. 1984; Wallace et
al. 1984; EPA 1985b). Limited monitoring data indicate that in areas
-------
70 Section 7
near vinyl chloride and polyvinyl chloride manufacturers, Che
concentration of vinyl chloride in air typically ranges from trace
levels to -105 pg/m3 (Gordon and Meeks 1977, Pellizzari et al. 1979,
IARC 1979, EPA 1985b), but may exceed 2.600 pg/m3 (1 ppm) (Fishbein
1979). Elevated levels of vinyl chloride may also be found in the
vicinity of hazardous waste landfills. Concentrations ranging from below
detection limits to 5 to 8 pg/m3 (0.002 to 0.003 ppm) have been
monitored in the air above some landfills (Stephens et al. 1986, Baker
and Mackay 1985). Homes near a hazardous waste site in Southern
California were found to contain levels as high as 1,040 pg/m3 (0.4 ppm)
(Stephens et al. 1986).
Typical values for the average daily intake of vinyl chloride by
inhalation in urban/suburban and rural/remote areas have been estimated
to be essentially zero. Assuming that the average intake of air is
20 m3/day, the average daily intake of vinyl chloride by people living
in source-dominated areas has been estimated to range from trace amounts
to 2,100 pg/day.
7.2.2 Water
Vinyl chloride has been detected at varying concentrations in
surface, ground, and drinking waters throughout the United States (EPA
1985b). Concentrations as high as 9.8 pg/L in surface water, 380 Mg/L in
groundwater, and 10 Mg/L in drinking, water have been reported (Dyksen
and Hess 1982, HSDB 1987). There was no report in the literature of
vinyl chloride being detected in sediment.
The level of vinyl chloride in groundwater in the United States was
determined during the 1982 EPA Groundwater Supply Survey. Water supplies
from 945 sites geographically located throughout the United States were
studied. Results indicate that vinyl chloride was positively identified
in only 0.74% of groundwater supplies (detection limit 1 pg/L). The
maximum concentration detected was 8.4 pg/L (Vestrick et al. 1984).
Other studies have also reported the occurrence of vinyl chloride in
groundwater throughout the United States at levels at or below 380 pg/L
(Cotruvo 1985, Goodenkauf and Atkinson 1986, Page 1981, Coniglio et al.
1980, Stuart 1983).
The concentration of vinyl chloride in finished drinking waters in
the United States was studied during the 1976-1977 EPA National Organics
Monitoring Survey (NOMS). Only 2 samples out of 113 contained detectable
levels (>0.1 pg/L), and these averaged 0.14 pg/L (HSDB 1987). Results of
other studies also indicate that the majority of drinking water supplies
in the United States contain no detectable levels of vinyl chloride
(HSDB 1987, Coniglio et al. 1980). Based on these studies, it is assumed
that the average daily intake of vinyl chloride by ingestion of drinking
water for most persons in the United States would be essentially zero.
Estimates provided in EPA (1985a) indicate that 0.9% of the United
States population is exposed to levels of vinyl chloride in drinking
water il.O pg/L and 0.3% of the population is exposed to levels >5 pg/L.
-------
Potential for Human Exposure 71
7.2.3 Soil
Monitoring data for vinyl chloride in soil were not located in the
available literature.
7.2.4 Other
In the past, vinyl chloride had been detected in various foods as a
result of migration from polyvinyl chloride food wrappings and
containers (EPA 1985b). Vinyl chloride has been found in vinegar at
levels up to 9.4 ppm, in edible oils at 0.15 to 14.8 ppm, and in butter
at 0.05 ppm when these foods were packaged and stored in PVC containers
(IARC 1979). At present, the Food and Drug Administration (FDA)
regulates use of vinyl chloride polymers available for use in production
of articles intended to contact food. These articles include food-
packaging materials, coatings, plastisols, gaskets, and parts for food-
processing (see Sect. 9, Regulatory and Advisory Status). A recent study
on the migration of vinyl chloride from PVC under conditions closely
simulating actual food packaging and storage revealed that at very low
concentrations of vinyl chloride in PVC packaging material, there was
essentially zero migration of vinyl chloride (Kontominas et al. 1985).
It is reported that migration of vinyl chloride from rigid PVC
water pipes into drinking water occurs and that it is directly
proportional to the residual level of vinyl chloride in the pipe itself.
Under certain conditions, reaction with chlorine in the water may result
in the complete removal of vinyl chloride from drinking water (Fishbein
1979, Ando and Sayato 1984). During one study, it was found that
drinking water that ran through recently installed PVC pipes contained
vinyl chloride at 1.4 ng/'L, while water that ran through a 9-year-old
system contained 0.03 to 0.06 ftg/L (HSDB 1987). This is in agreement
with the conclusion of Berens and Daniels (1976) that PVC pipe
containing less than or equal to 1 ppm residual vinyl chloride monomer
would result in vinyl chloride concentrations of less than 2 pg/L under
any expected service conditions. This suggests that use of PVC pipe in
water distribution systems contributes to intake of vinyl chloride
through ingestion of contaminated drinking water. Assuming that the
average daily intake of water is 2 L, the average intake of vinyl
chloride from water contaminated with vinyl chloride from PVC pipes is
expected to range from 0.06 to 2.8 /jg/day.
During an EPA study, detectable levels of vinyl chloride monomer
(detection limit 0.05 ppm) were found in two out of seven new 1975 model
cars. Levels of vinyl chloride in these two cars ranged from 0.4 to
1.2 ppm. Ventilation of the car interiors led to the dissipation of
vinyl chloride. The cars involved in this study had a high ratio of
plastic to interior volume and were expected to provide worst-case
concentrations for vinyl chloride in interior car air since the source
of vinyl chloride was believed to be volatilization from vinyl plastics
(Hedley et al. 1976). Due to the limited nature of this data and the
fact that this study is somewhat dated, no conclusions could be drawn
regarding levels of vinyl chloride monomer in interior air of cars
currently being produced.
-------
72 Section 7
Vinyl chloride has been detected in tobacco smoke (EPA 1985b).
Cigarettes and little cigars have been found to contain 5.6 to 28 ng
vinyl chloride per cigarette (IARC 1979).
7.3 OCCUPATIONAL EXPOSURES
NIOSH estimates definite worker exposure to vinyl chloride to be
27,000 persons and probable worker exposure to be 2.2 million (Sittig
1985). This includes -5.000 workers employed in vinyl chloride
synthesis, 5,000 workers involved with polymerization processes, and as
many as 350,000 workers associated with fabrication plants. Exposure is
believed to occur primarily through inhalation and less frequently by
absorption through skin (Sittig 1985). In the past, concentrations of
vinyl chloride in workplace air in some plants producing PVC have been
reported to range from 100 to 800 mg/m3 (39 to 315 ppm) with peak
concentrations up to 87,300 mg/m3 (34,000 ppm) (IARC 1979). Currently,
the Occupational Safety and Health Administration (OSHA) sets standards
for occupational exposure to vinyl chloride (see Sect. 9, Regulatory and
Advisory Status). A recent NIOSH survey of three vinyl chloride plants
indicated that the time-weighted-average exposure to vinyl chloride
varied between 0.2 to 70 mg/m3 (0.07 to 27 ppm) (IARC 1979).
7.4 POPULATIONS AT HIGH RISK
Data were not located specifically regarding subpopulations
unusually sensitive to the effects of vinyl chloride. Individuals
located near or downwind of production facilities, hazardous waste
disposal sites, and landfills may potentially be exposed to higher
ambient atmospheric levels.
Workers involved in the production or polymerization of vinyl
chloride may constitute a group at risk because of the potential for
occupational exposure. Since the mid 1970s, however, atmospheric levels
in the workplace have often been reduced to £l ppm (Fishbein 1979,
Kilian et al. 1975, Hansteen et al. 1978).
Inhalation studies in animals demonstrated that exposure early in
life resulted in greater risk of developing cancer than did exposure
later in life (Drew et al. 1983). Although human studies that address
the effect of age on cancer risk were not located, the animal data
suggest that exposure during the younger years may result in increased
cancer risk. Other animal studies suggest that prenatal exposure may
increase cancer risk (Maltoni et al. 1980, 1981; Radike et al. 1988).
Although human data were not located, the animal data may suggest that
the prenatal exposure of humans to vinyl chloride may increase risk of
cancer.
Animal studies have demonstrated that pretreatment with xenobiotics
or drugs that induce mixed-function oxidase (MFO) potentiates the
hepatotoxicity of vinyl chloride (Jaeger et al. 1974, Reynolds et al.
1975, Conolly et al. 1978). Although human data were not located, the
animal data suggest that human exposure to environmental pollutants or
drugs that induce MFO may result in increased sensitivity to vinyl
chloride.
-------
73
8. ANALYTICAL METHODS
A variety of methods are available for the analysis of vinyl
chloride in environmental and biological matrices. The methods of choice
will depend on the nature of the sample matrix; the required precision,
accuracy, and detection limit; the cost of analysis; and the turnaround
time of the methodology. Preconcentration of samples may not only
increase the sensitivity but also, in certain instances, decrease the
time required for sample separation prior to quantification. The best
sensitivity and specificity for vinyl chloride quantification are
obtained with Hall detectors and photoionization detectors (Reding
1987). Mass spectrometry, although less sensitive than the most
sensitive detectors, is often used as a confirmatory tool for vinyl
chloride analysis. Details of analytical methodologies for vinyl
chloride are given in IARC (1978).
8.1 ENVIRONMENTAL MEDIA
Some of the more commonly used analytical methods for the
quantification of vinyl chloride are given in Table 8.1. Other methods
that are less sensitive (e.g., infrared analyzer and continuous
monitoring instruments) and less commonly used (e.g., semiconductor
devices) are given in IARC (1978). Details of sample collection, sample
preservation, sample pretreatment, and quantification methods are
provided in the cited references in Table 8.1.
8.2 BIOMEDICAL SAMPLES
The concentrations of vinyl chloride measured in environmental
samples may not reflect the concentration to which persons are exposed.
Proper biological monitoring not only can be used to support
environmental monitoring but also potentially may provide more accurate
data on exposure levels. The two biological media that have been used
most extensively as promising indicators of vinyl chloride exposure are
breath and urine. A close agreement has been found between postexposure
breath concentrations and the ambient vinyl chloride levels in both
environmental and industrial conditions (Baretta et al. 1969, Tarkowski
1984). However, problems with quantification of low concentrations of
vinyl chloride in exhaled air at ambient air levels of <50 ppm has led
to limited application of this method (Tarkowski 1984).
A reasonable correlation was noted between urinary output of
thiodiglycolic acid, the principal metabolite of vinyl chloride, and
ambient levels to which persons were exposed (Heger et al. 1982).
Measurement of urinary thiodiglycolic acid can be used as an indicator
of vinyl chloride intake only as long as individual variability in
metabolism due to such factors as liver disease, use of drugs, and
alcohol intake can be accounted for. Therefore, it appears that there
-------
74 Section 8
is no suitable biological medium that can be used as a reliable
indicator for vinyl chloride exposure (Tarkovski 1984). The commonly
used methods for the quantification of vinyl chloride in biological
media are given in Table 8.1.
-------
i ta Ite fHMMaUta of ttayl cUortfe
Sflninle nuirii
•Ttnr*«fMffiAfli*l mir
Ambieol indoor and
outdoor air
Air
Air
Air
Automobile cxhiuil
Air
Air
Air
Dnnking water and
wafUwater
Groundwaier. liquid.
and Mild malncei
Sfinpiy. preparation
••" T m r^ f ••—•
Vinyl cblonde in air abaorbed in
activated carbon trap and deaolved
byCSj
Air containing vinyl ehlorido patted
through activated carbon trap and
deaolved by dichloramethaae or carbon
diuilfide
Adtorption on Tenax GC : thermal
dctorption
Grab tampk collected in electro-
poliihcd flBJnlfnt ftff 1 cunt
Air premiered by Na2S2O3-
trcaled glaai fiber filter wai
paued through tpherocarb adtorbent
cartridge and thermally deaorbed
Eihauit tamplet taken into aluininized
plattic bagt
Trapped in cold Tenax-GC trap, thermal
deaorption
Sample collected in preuunzed canuter
it patted through a freezeout loop
and subsequently healed
Sample collected in polyester-coated
plastic bagt concentrated by frccwout
and lubatquenlly healed
Purge and trap in Tenax GC. thermal
deaorption
Purge at 45°C and trap in Tenax GC,
thermal desorpuon
Quantification method'
GC/FID
GC/FID
HRGC/MS
GC/MS at uibambient
temperature
HRGC/FID and HRGC/MS
HRGC/FID
GC/FID
GC/ECD
GC/FID
GC/HSD, GC/MS
(EPA Method No 601 and 624)
GC/HSD (EPA Method No-8010)
Detection
limit
0.8 ppb
rr**
4 ppb
033 ppb
0005 ppb
0005 ppb
20 ppb
rr
NR
001 ppb
0006 ppb
OISppb(HSD)
0 18 ppb
Accuracy/
% recovery
94% at
04-26 pom
NR*
NR
NR
NR
NR
79- 104 at
6-60 ppb
NR
NR
102% at
082-323
ppb
102% at
0 82-32 3
ppb
Rcfcrencca
NIOSH 1984
IARC 1978. Miller
and Beuer 1985
*
Krosl el al. 1982
Gnmtrud and
Rasmuaten I975a,b
Harkov el al.
1983. 1984
Hasttnen el al.
1979
Ivea 197$
RaiDiuuco el al.
1977. Hartch el
al 1979
McMurry and Tarr
1978
EPA I982a.
APHA I98S
EPA I982b
n
to
n
n
a-
o
ex
-------
Table 9.1 (eaatiancd)
Drinking water
Migration of
drinking water for
porynnyl pipoi
Water
Landfill gat
l™™
oyster
Food (orange drink,
wine, olive oil)
Breath
$Mmp|f» preparation
w w
Purge and trap in Tenax OC; thermal
Small MCtiofli put in water in tealed
Mmm vial for a number of dayi at 20°C;
tontion directly injected into a gat
Sample in eealed vial it equilibrated
gaiiajectediatoagafchroaiatograph
One hen landfill attee campled by PTFE
tubing inckfe drive-in pkaometen wai
abeorbed in Tenu OC aorbenl; trapped
liquid Nroooled loop aad flash deaorbed
gnt m ckaed loop injected into a gat
Sample eealed in viab and equilibrated
at 40*C for 2 b; headapace gat
Sample eealed in viab and equilibrated
at 40*C for a minimum of 2 h; headcpace
Cryogenic trapping of eioiied air. thermal
aeeorption mlo a gee chromatograpb
Detectioo
Quantififitkm method* limit
HRGC/Hall detector, HRGC/PID 0.04 ppb (Hall)
(EPA Method 502.2, 524.2) 0.02 (PID)
OC/HD NR
GC/HD <| ppb
OC/MS 0.04-0.8 ppm
OC/BCD 2 mA
teounent)
OC/FID NR
OC/HD I-S ppb
OC/HD. OC/ECD and OC/MS NR
Accuracy/
100-119 at
5-10 ppb
NR
NR
NR
NR
NR
NR
NR
Reding 1987
Ando and Seyalo
1984
IARC 1978
Young and Parker
1984
Cfaudy and Crotby
1977
IARC 1978
Cookie etaL
1975
Breath
Breath collected in Tedlar bag b
ooaceuralod by Ttanai OC
and thermally denrbed
OC/MS
PP>
77-110 Umana et aL 1985
o\
A
n
n
i-
§
-------
Table 8.1 (i
Sample matrix
Whole blood.
plasma, and serum
Blood, urine
Urine
Tissue (liver,
lung, kidney.
brain)
Tissue
"GC - Gas chromi
capture detector: USD
Not reported.
Detection
Sample preparation Quantification method limit
Sample equilibrated in a sealed vial at GC/ECD
65°C, headspace gas injected into a
gas chromatograph
Sample purged and trapped in Teoax GC, GC/MS
thermally desorbed
Sample solvent extracted, extract GC/MS or HRGC/MS
methylated, and cleaned by ion-exchange
resin
Homogenized samples mixed with ethanol- GC/FID
water mixture equilibrated in a sealed
vial at 70°C. headspace gas injected into
a gas chromatograph
Sample mixed with a proteolytic enzyme GC/ECD
incubated at 65eC. headspace gas
analyzed
•momnhv HRflC « hiah-Ksolulion aas chromaloaraobv. FID •• (lame
HUJ||I'I|JIIJF, nnW%* III0U •l^RFilil.WM 0*** *«««»*«««™»W^B««|»»»J, • ««^ •••••••
"™ halide-sensitive detector* PID •" photoiomzation detector.
NR
Screening
method
50ppb
(urinary
thiodiglycobc
acid)
30ppb
NR
lomzation detection, MS ~
Accuracy/
% recovery References
NR Ramsey and •
Hanagan 1982
1
NR Balkon and Leary
1979
NR van Sitlert and
deJong 1985.
MUUer ct al.
1979
75-92% Zuccato el al.
1979
NR Ramsey and
Flannagan 1982
mass spectrometry; BCD — electron
to
PT
o
to
n
3-
o
a
o
-------
79
9. REGULATORY AND ADVISORY STATUS
9.1 INTERNATIONAL
Advisory guidance issued by the World Health Organization (WHO) for
vinyl chloride was not located in the available literature.
9.2 NATIONAL
9.2.1 Regulations
9.2.1.1 Air
The Occupational Safety and Health Administration (OSHA 1983)
regulations for vinyl chloride state that a worker must not be exposed
to a concentration of >1 ppm over any 8-h period and that a worker must
not be exposed to >5 ppm for any period of time exceeding 15 minutes
Direct contact with liquid vinyl chloride is prohibited.
EPA (1982c) has established emission standards for vinyl chloride
released to the atmosphere by vinyl chloride and polyvinyl chloride
plants. Emissions are not to exceed 10 ppm.
9.2.1.2 Water
Pursuant to the Safe Drinking Water Act, EPA (1987c) promulgated a
maximum contaminant level (MCL) for vinyl chloride of 0.002 mg/L,
equivalent to an estimated cancer risk of 10'4. This regulation is to
become effective January 9, 1989. and is to apply to all community
drinking water systems that regularly serve the same 25 persons for at
least 8 months/year.
Vinyl chloride is regulated under the Clean Water Act Effluent
Guidelines for the following industrial point sources: steam electric.
asbestos industry, timber products processing, metal finishing, paving
and roofing, paint formulating, ink formulating, gum and wood, and
carbon black (EPA 1988).
9.2.1.3 Food
The Food and Drug Administration (FDA 1986) recently proposed to
amend its regulations regarding the vinyl chloride content of polymers
used in packaging materials or processing equipment for foods. Depending
on the nature of the polymer and Its use. proposed vinyl chloride
content may range from 5 to 50 ppm.
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80 Section 9
9.2.1.4 Other
EPA (1982d) has designated vinyl chloride as a hazardous
constituent of solid waste and requires that it be handled in accordance
with the regulations governing the same. EPA (19874) lists a reportable
quantity (RQ) for vinyl chloride of 1 Ib, but proposes that the RQ be
changed to 10 Ib. The RQ is the quantity that, if released to the
environment, must be reported immediately to the National Response
Center.
9.2.2 Advisory Guidance
9.2.2.1 Air
The American Conference of Governmental Industrial Hygienists
(ACGIH 1986b) recommends a Threshold Limit Value (TLV)-TWA for vinyl
chloride of 5 ppm and a Short-Term Exposure Limit (STEL) of 10 ppm with
the notation that the compound is a recognized human carcinogen. The
National Institute of Occupational Safety and Health (NIOSH 1975)
concluded that a TLV for vinyl chloride was inappropriate because of its
carcinogenicity. NIOSH (1975) recommended that any workers exposed to
vinyl chloride should wear an air-supplied respirator.
9.2.2.2 Water
An EPA (1980) study, based on an upper-bound human q.* of
1.74 x 10*2 (mg/kg/day)'1 calculated from the incidence of tumors in a
preliminary report of an inhalation study in rats (Maltoni and Lafemine
1975), estimated levels in ambient water of 20, 2, and 0.2 pg/L
associated with cancer risks of 10'5, 10'6, and 10'7, respectively,
assuming daily consumption of 2 L water and 6.5 g fish and shellfish.
For consumption of fish and shellfish alone, water concentrations of
5,246, 525, and 52.5 Mg/L correspond to cancer risk estimates of 10'5,
10'6, and 10'7, respectively. More recently, EPA (1985a, 1987b)
estimated that cancer risk levels of 10'*, 10'5, and 10'6 would result
from daily consumption of drinking water containing vinyl chloride at
1.5, 0.15, and 0.015 A*g/L. respectively, using an upper-bound limit q*
value of 2.3 (mg/kg/day)-1. L
EPA (1985a, 1987a) promulgated health advisories for vinyl chloride
in drinking water. A 10-day health advisory of 2.6 mg/L was based on a
NOAEL of 30 mg/kg/day in a 13-week gavage study by Feron et al. (1975).
Because data were not sufficient for derivation of a 1-day health
advisory, the 10-day health advisory was adopted as a conservative 1-day
health advisory. Longer term health advisories of 0.013 mg/L for a 10-kg
child and 0.046 mg/L for an adult were estimated from the NOAEL of
0.13 mg/kg/day in a lifetime dietary study in rats (Til et al. 1983).
9.2.3 Data Analysis
9.2.3.1 Reference doses (RfDs)
Reference doses for vinyl chloride have not been estimated by EPA.
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Regulatory and Advisory Status 81
9.2.3.2 Carcinogenic potency
Vinyl chloride has been classified in IARC Group 1 (IARC 1987) and
EPA Class A (EPA 1987a). By either classification scheme, the
designations have the same meaning, that evidence is sufficient to
consider vinyl chloride carcinogenic to humans. EPA has derived several
estimates of carcinogenic potency for vinyl chloride for both oral and
inhalation exposure. In an early estimate, EPA (1980) derived a q * for
human oral exposure of 1.74 x 10"2 (mg/kg/day)*^ based on preliminary
reports of the incidence of total tumors in rats of both sexes exposed
to vinyl chloride by inhalation at concentrations up to 10,000 ppm
(Maltoni and Lefemine 1975). A subsequent estimate of potency for oral
exposure is 2.3 (mg/kg/day)'*•, which appears in EPA (1987a) and
represents the most recent analysis. This estimate was based on the
incidence of lung and liver tumors in both sexes of rats exposed for
lifetime to diets that contained vinyl chloride (Feron et al. 1981).
The first estimate for carcinogenic potency by inhalation exposure.
2.5 x 10*2 (mg/kg/day)*1 derived in EPA (1984), was based on the same
preliminary inhalation data (Maltoni and Lefemine 1975) that was used as
the basis of the EPA (1980) oral estimate. A more recent estimate of
2.95 x 10*1 (mgAg/day)'1 (EPA 1985b) was based on the final report of
the incidence of liver angiosarcomas in male and female rats exposed for
up to 1 year to concentrations up to 30,000 ppm (Maltoni et al. 1980,
1981).
9.3 STATE
No state guidelines were available.
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33
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103
11. GLOSSARY
Acute Exposure--Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
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 time period.
Carcinogen--A chemical capable of inducing cancer.
Ceiling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure--Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
Frank Effect Level (FEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
EPA Health Advisory--An estimate of acceptable drinking water levels for
a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLE)--The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-Impair ing symptoms or irreversible
health effects.
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104 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxicity--The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro--Isolated from the living organism and artificially maintained,
as in a test tube.
In vivo--Occurring within the living organism.
Key Study--An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentration(LO) (LCLo)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentretion(50) (LCso)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose<50) (LDsO)--The dose of a chemical which has been calculated
to cause death in 50% of a defined experimental animal population.
Lowest-Observed-Advene-Effect Level (LOAEL)--The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
Lowest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
Malformations--Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level--An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen--A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
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Glossary 105
H«urotoxiclty--The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL)--That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
No-Observed-Effect Level (NOEL)--That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL)--An allowable exposure level in
workplace air averaged over an 8-h shift.
q^-The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The q * can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually Mg/L for water, me/kg/day for
food, and pg/tr* for air).
Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional Judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ)--The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are: (1) 1 lb
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Toxicity--The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations In sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system. e J
Short-Tern Exposure Limit (STEL)--The maximum concentration to which
workers can be exposed for up to 15 mln continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded
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106 Section 11
Target Organ Toxlcity--This term covers a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from those arising through a single limited exposure to those
assumed over a lifetime-of exposure to a chemical.
Teratogen--A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV)--A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TVA)--An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF)--A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population,
(2) the uncertainty in extrapolating animal data to the case of humans,
(3) the uncertainty in extrapolating from data obtained in a study that
is of less than lifetime exposure, and (4) the uncertainty in using
LOAEL data rather than NOAEL data. Usually each of these factors is set
equal to 10.
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107
APPENDIX: PEER REVIEW
A peer review panel was assembled for vinyl chloride. The panel
consisted of the following members: Dr. Richard Monson, Harvard
University, and Dr. Anthony Guarino, South Alabama University. These
experts collectively have knowledge of vinyl chloride's physical and
chemical properties, toxicokinetics, key health end points, mechanisms
of action, human and animal exposure, and quantification of risk to
humans. All reviewers were selected in conformity with the conditions
for peer review specified in the Superfund Amendments and
Reauthorization Act of 1986, Section 110.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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