vvEPA
United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-078
October 1980
Ambient
Water Quality
Criteria for
Vinyl Chloride
Do not weed. This document
should be retained in the EPA
Region 5 Library Collection.
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AMBIENT WATER QUALITY CRITERIA FOR
VINYL CHLORIDE
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
Protection Agency
Seerborn Street
60804
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
, STsSKCtf 8? ASSET
ii
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Jerry F. Stara (author)
ECAO-Cin
U.S. Environmental Protection Agency
Debdas Mukerjee (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Paul Berger, ODW
U.S. Environmental Protection Agency
Karen Blackburn, HERL-Cin
U.S. Environmental Protection Agency
Patrick Durkin
Syracuse Research Corporation
Terence M. Grady, ECAO-Cin
U.S. Environmental Protection Agency
Rolf Hartung
University of Michigan
Rudolph J. Jaeger
New York University Medical Center
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.J. Quesnell, C. Russom, B. Gardiner.
*CAG Participating Members: Elizabeth L. Anderson, Larry Anderson, Ralph Arnicar,
Steven Bayard, David L. Bayliss, Chao W. Chen, John R. Fowle III, Bernard Haberman,
Charalingayya Hiremath, Chang S. Lao, Robert McGaughy, Jeffrey Rosenblatt,
Dharm V. Singh, and Todd W. Thorslund.
John H. Gentile, ERL-Narragansett
U.S. Environmental Protection Agency
Dinko Kello
Yugoslav Academy of Sciences and
Arts for Medical Research and
Occupational Health
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Robert E. McGaughy, CAG
U.S. Environmental Protection Agency
Martha Radike
University of Cincinnati
James R. Withey
National Health and Welfare., Canada
Roy E. Albert, CAG
U.S. Environmental Protection Agency
IV
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TABLE OF CONTENTS
Page
Introduction A-l
Aquatic Life Toxicology 3-1
Effects B-l
Summary B-l
Criteria B-l
References B-2
Mammalian Toxicology and Human Health Effects C-l
Introduction C-l
Exposure C-3
Ingestion from Water C-3
Ingestion from Food C-5
Inhalation C-8
Dermal C-10
Pharmacokinetics C-10
Absorption C-10
Distribution C-l2
Metabolism C-l4
Excretion C-l7
Effects C-l7
Acute, Subacute and Chronic Toxicity C-l7
Synergism and/or Antagonism C-21
Teratogenicity C-22
Mutagenicity C-23
Carcinogenicity C-25
Criteria Formulation C-50
Existing Guidelines and Standards C-50
Special Groups at Risk C-60
Basis and Derivation of Criterion C-60
References C-63
Appendix C-81
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CRITERIA DOCUMENT
VINYL CHLORIDE
CRITERIA
Aquatic Life
No freshwater organisms have been tested with vinyl chloride and no
statement can be made concerning acute or chronic toxicity.
No saltwater organisms have been tested with vinyl chloride and no
statement can be made concerning acute or chronic toxicity.
Human Health
For the maximum protection of human health from the potential carcino-
genic effects due to exposure of vinyl chloride through ingestion of contam-
inated water and contaminated aquatic organisms, the ambient water concen-
trations should be zero based on the non-threshold assumption for this chem-
ical. However, zero level may not be attainable at the present time.
Therefore, the levels which may result in incremental increase of cancer
—5 —6 —7
risk over the lifetime are estimated at 10 , 10" , and 10 . The
corresponding recommended criteria are 20 ug/1, 2.0 ug/1, and 0.2 ug/1,
respectively. If the above estimates are made for consumption of aauatic
organisms only, exluding consumption of water, the levels are 5,246. ug/1,
525 ug/1, and 52.5 ug/1, respectively.
VI
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INTRODUCTION
Vinyl chloride has been used for over 40 years in producing polyvinyl
chloride (PVC) which in turn is the most widely used material in the manu-
facture of plastics throughout the world. Of the estimated 18 billion
pounds of vinyl chloride produced worldwide in 1972, about 25 percent was
manufactured in the United States (Berk, et al. 1976). Production of vinyl
chloride in the United States reached slightly over 5 billion pounds in 1978
(U.S. Int. Trade Comm.). Production of vinyl chloride has risen nearly 14
percent annually between 1968 and 1973 as evidenced by the broad dependence
of nearly every branch of industry and commercial activity upon products and
components fabricated from polyvinyl chloride (U.S. EPA, 1974).
Vinyl chloride and polyvinyl chloride are used in the manufacture of
numerous products in building and construction, the automotive industry, for
electrical wire insulation and cables, piping, industrial and household
equipment, packaging for food products, medical supplies, and is depended
upon heavily by the rubber, paper and glass industries (Maltoni, 1976).
Polyvinyl chloride and vinyl chloride copolymers are distributed and pro-
cessed in a variety of forms including dry resins, plastisol (dispersions in
plasticizers), organosol (dispersions in plasticizers plus volatile sol-
vent), and latex (colloidal dispersion in water). Latexes are used to coat
or impregnant paper, fabric, or leather (Falk, et al. 1974).
As of 1974, approximately 15 plants synthesized the vinyl chloride mono-
mer, 43 facilities were engaged in the polymerization of PVC and over 7,500
plants fabricated products from PVC. About 1,500 workers were employed in
monomer synthesis and an additional 5,000 in polymerization operations
A-l
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(Falk, et al. 1974). As many as 350,000 workers were estimated to be asso-
ciated with fabrication plants (U.S. EPA, 1974). By 1976, it was estimated
that nearly one million persons were associated with manufacturing goods
derived from PVC (Maltoni, 1976).
Vinyl chloride (CHgCHCl; molecular weight 62.5) is a highly flammable
chloroolefinic hydrocarbon which emits a sweet or pleasant odor and has a
vapor density slightly more than twice that of air (Weast, 1972; Braker and
Mossmein, 1971). It has a boiling point of -13.9eC and a melting point of
-153.8'C. Its solubility in water at 28°C is 0.11 g/lOOg water and it is
soluble in alcohol and very soluble in ether and carbon tetrachloride
(Weast, 1972). Vinyl chloride is volatile and readily passes from solution
into the gas phase under most laboratory and ecological conditions. Many
salts such as soluble silver and copper salts, ferrous chloride, platinous
chloride, iridium dichloride, and mercurous chloride to name a few, have the
ability to form complexes with vinyl chloride which results in its increased
solubility in water (U.S. EPA, 1975). Conversely, alkali metal salts such
as sodium or potassium chloride may decrease the solubility of vinyl chlo-
ride in ionic strengths of the aqueous solution (Fox, 1978). Therefore, the
amounts of vinyl chloride in water could be influenced significantly by the
presence of salts (U.S. EPA, 1975).
Vinyl chloride introduced into aquatic systems will most probably be
auickly transferred to the atmosphere through volatilization. In fact, re-
sults from model simulations indicate that vinyl chloride should not remain
in an aauatic ecosystem under most natural conditions. Once in the tropo-
sphere, vinyl chloride reacts at an extremely rapid rate with hydroxyl radi-
cals, exhibiting a half-life on the order of a few hours with the subsequent
formation of hydrogen chloride or formyl chloride as possible products.
A-2
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Formyl chloride, if formed, is reported to decompose thermally at ambient
temperatures with a half-life of about 20 minutes, yielding carbon monoxide
and hydrogen chloride. As a result, vinyl chloride in the troposphere
should be decomposed within a day or two of release.
Based on the information found, it does not appear that oxidation hy-
drolysis, biodegradation or sorption, are important fate processes for vinyl
chloride in the aauatic environment (U.S. EPA, 1979).
A-3
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REFERENCES
Berk, et al. 1976. Vinyl chloride-associated liver disease. Ann. Int.
Med. 84.
Braker, W. and A.L. Mossmein. 1971. Matheson Gas Data Book. 5th ed.
Matheson Gas Products, East Rutherford, New Jersey.
Falk, H., et al. 1974. Hepatic disease among workers at a vinyl chloride
polymerization plant. Jour. Am. Med. Assoc. 230: 59.
Fox, C.R. 1978. Plant uses prove phenol recovery with resins. Hydrocarbon
Proc. November, 269.
Maltoni, C. 1976. Carcinogenicity of vinyl chloride: Current results.
Experimental evidence. Proc. 6th Int. Symp. Biological Characterization of
Human Tumours, Copenhagen May 13-15, 1975. Vol. 3. Biological characteri-
zation of human tumours, 1976. American Elsevier Publishing Co., Inc. New
York.
U.S. EPA. 1974. Preliminary assessment of the environmental problems asso-
ciated with vinyl chloride and polyvinyl chloride. EPA 560/4-74-001. Off.
Toxic Subst., U.S. Environ. Prot. Agency, Washington, D.C.
U.S. EPA. 1975. A scientific and technical assessment report on vinyl
chloride and polyvinyl chloride. EPA-600/6-75-004. Off. Res. Dev., U.S.
Environ. Prot. Agency, Washington, D.C.
A-4
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U.S. EPA. 1979. Water-related environmental fate of 129 priority pollut-
ants. EPA 68-01-3852. U.S. Environ. Prot. Agency, Washington, D.C.
U.S. International Trade Commission. 1978. Synthetic organic chemicals.
U.S. Production and Sales 1977. Publ. 920. U.S. Government Printing Of-
fice, Washington, D.C.
Weast, R.C., (ed.) 1972. Handbook of Chemistry and Physics. CRC Press,
Cleveland, Ohio.
A-5
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Aquatic Life Toxicology*
EFFECTS
Few data are available for freshwater or saltwater organisms and vinyl
chloride. One paper by Brown, et al. (1977) described an acute test using
northern pike, but the description of test methods was incomplete and the
control organism procedures were quite different from those for the exposed
organisms. No difference could be detected between bacterial growth in cul-
tures of five bacterial populations and in test cultures containing up to
900,000 yg/1, indicating that vinyl chloride was not toxic to bacteria at
these concentrations (Hill, et al. 1976).
Summary
No appropriate acute or chronic data are available for any freshwater or
saltwater organisms and vinyl chloride.
CRITERIA
No freshwater organisms have been tested with vinyl chloride, and no
statement can be made concerning acute or chronic toxicity.
No saltwater organisms have been tested with vinyl chloride, and no
statement can be made concerning acute or chronic toxicity.
*The reader is referred to the Guidelines for Deriving Water Quality Crite-
ria for the Protection of Aquatic Life and Its Uses in order to better un-
derstand the following discussion and recommendation.
B-l
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REFERENCES
Brown, E.R., et al. 1977. Chemical pollutants in relation to diseases in
fish. Ann. N. Y. Acad. Sci. 298: 535.
Hill, J., IV, et al. 1976. Dynamic behavior of vinyl chloride in aquatic
ecosystems. EPA-600/3-76-001. U.S. Environ. Prot. Agency.
B-2
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Mammalian Toxicology and Human Health Effects
INTRODUCTION
Sufficient evidence has been accumulated in recent years
implicating vinyl chloride as a human and animal carcinogen. The
first four human cases of liver angiosarcoma in workers employed by
a vinyl chloride plant were reported by Creech and Johnson in 1974.
The first experimental data on the carcinogenic effects of vinyl
chloride in rats were published by Viola, et al. in 1971; a compre-
hensive report on dose-effect relationship of vinyl chloride in
experimental animals by Maltoni, et al. followed in 1974. These
initial reports spurred a series of retrospective epidemiologic
investigations of workers in the vinyl chloride industry (Creech
and Johnson, 1974; Baxter, et al. 1977; Infante, et al. 1976b;
Brady, et al. 1977) and supportive experimental studies in animals.
The large amount of published literature was summarized in several
comprehensive reviews; of note are the two volumes compiled by the
New York Academy of Sciences in 1975 and 1976, a review in the Pro-
ceedings of the Royal Society of Medicine (1976) and the U.S. EPA
Scientific and Technical Assessment Report (STAR) on Vinyl Chloride
and Polyvinyl Chloride (1975a).
The purpose of this report is to briefly summarize the pub-
lished reviews and reports including more recently published data
with special attention to research studies concerned with the ex-
tent of human exposure to vinyl chloride contaminated public water
supplies. Unfortunately, toxicologic or epidemiologic data on this
issue are not available, since vinyl chloride appears to escape in
gaseous phase from surface waters; only one report was located
C-l
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indicating the presence of small amounts of vinyl chloride in water
supplies of two cities. There is scanty information available on
the carcinogenic effects of vinyl chloride due to ingestion of
vinyl chloride-contaminated olive oil (Maltoni, 1976).
There is no evidence that vinyl chloride exists in nature per
se. A study by Hoffman, et al. (1976) does suggest that vinyl chlo-
ride may be released as a combustion product from organic material
where inorganic chloride was originally present. Vinyl chloride is
synthesized as chlorinated olefinic hydrocarbon monomer derived
from petrochemical feedstock and chlorine. In 1974, the U.S. pro-
duction of PVC was over 4 billion pounds. Emissions from these
sources, therefore, present the primary risk of vinyl chloride
exposure for workers employed in these industries and populations
living in their vicinity; however, additional exposure, even though
it is thought to be minimal, can occur via ingestion of contaminat-
ed food and water, and through the skin. Vinyl chloride levels
from detectable to high have been found in drinking water, bever-
ages, food, cosmetics, and other consumer products. Aerosol prod-
ucts containing vinyl chloride as a propellent have been discontin-
ued. Municipal incinerators may be an additional source of vinyl
chloride emissions. Experimental data by Boettner, et al. (1973)
have demonstrated that vinyl chloride monomer may be released under
certain combustion conditions from some samples of PVC. It is not
clear whether this vinyl chloride represents untrapped vinyl chlo-
ride monomer in the PVC mixture that was being tested. There are
other data (Close, et al. 1977) which indicate that polyvinyl chlo-
ride (PVC) does not usually depolymerize into vinyl chloride mono-
C-2
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mer even under a variety of conditions. Whether these particular
processes can occur in municipal incinerators is uncertain at this
time. Insufficient published data are available on exposure levels
of persons living in the vicinity of PVC fabricating plants, or on
the release of the monomer from various plastic products. Yet, all
of these are additional potential sources of population exposure.
EXPOSURE
Ingestion from Water
Small amounts of vinyl chloride may be present in public water
supplies as a result of vinyl chloride industrial wastewater dis-
charges. Levels of vinyl chloride in wastewater effluents vary
considerably depending on the extent of in-plant treatment of waste
water. Vinyl chloride in samples of wastewater from seven areas
(representing 12 PVC-vinyl chloride plants) ranged from 0.05 ppm to
20 ppm (U.S. EPA, 1974) . More typically, levels of 2 to 3 ppm were
found. In these studies, values represent vinyl chloride concen-
trations in three 24-hour composite wastewater samples. The low
solubility (0.11 gms/100 gms water) (Weast, 1978) and high volatil-
ity of vinyl chloride in water limit the amount present in a given
volume; however, the presence of other agents, such as salts, in-
creases the solubility of vinyl chloride. However, it may be spec-
ulated that other materials such as fumates, surfactants, and par-
ticulates may extend the residence time of vinyl chloride in water
and therefore increase its effective concentration for a given
exposure situation via water route (U.S. EPA, 1975a).
Polyvinyl chloride pipe used in water distribution systems
provides another source of low levels of vinyl chloride in drinking
C-3
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water. The U.S. EPA's Water Supply Research Division studied five
water distribution systems which used PVC pipes (Dressman and
McFarren, 1978). Sites chosen were representative of extremes in
climatic conditions and of variable age, length, and size of pipe.
Low concentrations of vinyl chloride were detected in three of the
five water supply systems. Water from the most recently installed
and the longest pipe system had the highest vinyl chloride concen-
tration (1.4 ug/1). Traces of vinyl chloride (0.03 and 0.06 ug/1)
were still present in the other two systems (which were the old-
est) , about nine years after installation.
The National Sanitation Foundation (NSF) annually issues a
list of PVC pipe and fittings conforming to standard No 14. Those
manufactured in 1977-78 and listed will be low in residual monomer.
A level of 10 ppm or less of residual monomer in finished pipe and
fittings was adopted as a voluntary standard in February, 1977.
Three times a year NSF field personnel collect test samples. More
than 95 percent of these samples conformed to the standard in 1977.
However, in testing samples of water supplies in several cities,
vinyl chloride (5.6 yg/1 and 0.27 yg/1) was detected in the water
supply of at least two American cities (U.S. EPA, 1975b).
Although the vinyl chloride concentrations in public water
supplies tested so far are below the minimum levels associated with
reported carcinogenic or other toxic responses, confirmation stud-
ies with experimental animals are in progress. For example, inves-
tigations are being conducted by Professor Cesare Maltoni of Bolog-
na, Italy, to determine the incidence and type of cancer produced
by ingestion of low doses of vinyl chloride, including 1.0, 0.3,
C-4
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and 0.03 mg/kg/day. Because of the long latency of the carcinogen-
ic response, the results of these investigations will not be avail-
able for some time (Maltoni, 1976).
The environmental fate of vinyl chloride was evaluated in a
closed model aquatic ecosystem by Lu, et al. in 1977. Five organ-
isms, including algae and fish, bioaccumulated small amounts of
vinyl chloride and/or metabolites of vinyl chloride. The low tis-
sue values observed in fish as a result of the three day exposure
suggest that vinyl chloride is not biomagnified to any great
degree.
Ingestion from Food
Small quantities of vinyl chloride are ingested by humans
since the entrained monomer migrates into foods packaged in PVC
wrappings and containers (U.S. EPA, 1975a). The solubility of vinyl
chloride in foods packaged in water is low (0.11 g/100 g water);
however, the monomer is soluble in alcohols and mineral oil. In
1973, prior to the recognition of the carcinogenicity of vinyl
chloride in man, the U.S. Treasury Department banned the use of
vinyl chloride polymers for packaging alcoholic beverages as a
result of studies indicating that levels up to 20 mg/kg were pres-
ent in liquors so packaged [International Agency for Research on
Cancer (IARC) , 1974]. The reason for this action was that vinyl
chloride migration into the liquor resulted in a discoloration and
unpleasant taste. The Food and Drug Administration analyzed a num-
ber of PVC packaged products for vinyl chloride content in 1974.
Concentrations ranged from "not detectable" to 9,000 ppb. Vegeta-
ble oils and apple cider contained the highest concentration.
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Table 1 presents some levels of vinyl chloride found in foods and
beverages in 1975.
Withey and Collins (1976) have developed a statistical model
for use in equating oral dose levels of vinyl chloride to inhala-
tion exposure levels in rats, using vinyl chloride blood level time
curves. For example, the authors concluded that "if the total
daily liquid intake contained 20 ppm vinyl chloride, then the area
generated under the blood level time curve for rats would be equiv-
alent to an inhalation exposure of about 2 ppm for 24 hours."
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus, the per capita
ingestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average per-
cent lipids of consumed fish and shellfish, and a steady-state BCF
for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
the same species to estimate that the weighted average percent lie-
ids for consumed freshwater and estuarine fish and shellfish is 3.0
percent.
C-6
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TABLE 1
Levels of Vinyl Chloride in Alcoholic
Beverages, Peanut Oil, and Vinegars
Contained in PVC Bottles
Sample
Alcoholic
beverages
Gin
Martini
Beaujolais
Cognac
Sherry
Vegetable oil
Peanut
Vinegars
Apple cider
Malt
Malt
Malt
Salad
Red wine
Type
of PVC
Bottle
Ae
A
B
C
D
H
E
E
F
G
G
G
No. Of
Samples
4
4
4
4
6
10
13
4
7
1
2
1
Range
ug/ml
0.21-0.65
0.86-1.60
0.15-0.84
0.025
0.38-0.98
u
0.3-3.29°
0.56-8.40
0.16-2.28
0,C 1.5d
0C
oc
0C
Av. ,
Vig/ml
0.44
0.37
0.60
-
0.66
K
2.16°
3.49
1.86
— m
w
M
—
Analyzed on column A, average of duplicate injections
Values expressed as ppm
•*
'No vinyl chloride detected, detection limit 0.01
Single positive, six negative
"Letters designate manufacturing brands of PVC
'Source: Williams and Miles, 1975
C-7
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No measured steady-state BCF is available for vinyl chloride,
but the equation "Log BCF = (0.85 Log P) - 0.70" can be used
(Veith, et al. 1979) to estimate the BCF for aquatic organisms that
contain about 7.6 percent lipids (Veith, 1980) from the octanol-
water partition coefficient (P) . Since no measured log P value
could be found, a log P value of 1.38 was calculated for vinyl chlo-
ride using the method described in Hansch and Leo (1979). Thus,
the steady-state bioconcentration factor for vinyl chloride is
estimated to be 2.97. An adjustment factor of 3.0/7.6 = 0.395 can
be used to adjust the estimated BCF from the 7.6 percent lipids on
which the equation is based to the 3.0 percent lipids that is the
weighted average for consumed fish and shellfish. Thus, the
weighted average bioconcentration factor for vinyl chloride and the
edible portion of all freshwater and estuarine aquatic organisms
consumed by Americans is calculated to be 2.97 x 0.395 = 1.17.
Inhalation
Inhalation of vinyl chloride is the principal route of expo-
sure to people working in or living near vinyl chloride industries.
Vinyl chloride boils at -13.9°C and is a gas at normal atmospheric
temperature and pressure. The odor is usually described as sweet
or pleasant and those familiar with the odor may first detect it at
1,200 to 2,000 ppm.
Because of its narcotic properties (Patty, et al. 1930) , vinyl
chloride was considered for use as an anesthetic agent, but reports
in 1947 of cardiac arrythmias in dogs following its inhalation
resulted in vinyl chloride being dropped from consideration as an
anesthetic (Oster, et al. 1947).
C-8
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Relatively little attention was given in the past to monitor-
ing vinyl chloride in the air of workplaces because toxicologic
data at the time indicated there was little hazard. The earliest
reports of hepatoxicity in vinyl chloride workers were noted by
Tribukh, et al. (1949); however, the effects were attributed to
plasticizers added in the manufacturing process. In these studies,
the observed concentrations of vinyl chloride ranged from 1 to 470
ppm.
Some data are available concerning airborne vinyl chloride in
the workplace prior to 1974. In Russia, Pilatova and Gronsberg
(1957) observed concentrations of 8 to 16,000 ppm with average
exposures ranging from 20 to 300 ppm. Although monitoring of the
workplace for vinyl chloride levels was not a common practice in
the U.S. prior to 1950, Dow Chemical Co. initiated monitoring about
that time. Exposures were generally below 500 ppm; however, peak
concentrations of 4,000 ppm were recorded (Ott, et al. 1975).
After 1960, Dow Chemical Co. was successful in reducing exposures
to workers to about 25 ppm even though levels up to 500 ppm still
occurred. After vinyl chloride-induced angiosarcoma of the liver
was reported in workers and animals (Creech and Johnson, 1974;
Viola, et al. 1971; Maltoni and Lefemine, 1974b) inhalation expo-
sures dropped drastically.
Inhalation of vinyl chloride by the general population occurs
in the vicinity of vinyl chloride and PVC industries (Nelson, et
al. 1975). This problem currently is receiving increased atten-
tion. Prior to 1974, vinyl chloride was widely used as a propel-
lant for many commercially available products such as pesticides,
C-9
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deodorants, hair sprays, et cetera. Consumers repeatedly using
such products in closed rooms were undoubtedly exposed to moderate-
ly high concentrations.
Dermal
Absorption of vinyl chloride through the skin is minor. Cal-
culations based on the percutaneous absorption of vinyl chloride by
Rhesus monkeys (Hefner, et al. 1975b) , indicate that a 6-foot, 90
kg man exposed to 7,000 ppm (dermal) for two hours would absorb the
equivalent of a 0.2 ppm, 8-hour inhalation exposure. Therefore,
significant percutaneous absorption would not be expected to occur
upon exposures to low concentrations of 1 or 5 ppm.
PHARMACOKINETICS
Absorption
Vinyl chloride is rapidly absorbed through the lungs and
enters the blood stream (Duprat, et al. 1977). In rats inhaling
20,000 ppm C vinyl chloride for five minutes, 14C was found in
the liver, bile duct, digestive lumen, and kidneys 10 minutes from
the beginning of the inhalation exposure. The amount and distribu-
tion of vinyl chloride and its metabolites increased up to three
hours post-exposure and in addition to sites of deposition observed
10 minutes from initiation of exposure, C activity was found in
the urinary tract, salivary, harder and lacrimal glands, skin, and
thymus. Watanabe, et al. (1976b) and Bolt, et al. (1977) also ob-
served the rapid uptake and equilibration of atmospheric vinyl
chloride with rats via the inhalation route.
The fate and absorption of vinyl chloride following oral
administration is consistent with observations derived from inhala-
C-10
-------
tion studies (Watanabe, et al. 1976a) . Watanabe, et al. (1977)
compared the fate of vinyl chloride in rats following repeated ver-
sus single inhalation exposures and found that the routes and rates
of excretion were the same for both groups. The activity of micro-
somal enzymes was essentially the same in rats exposed once, re-
peatedly, and in control rats. Covalent bonding to hepatic macro-
molecules was greater in repeatedly exposed rats than in those
given a single exposure. The hepatic nonprotein sulfhydryl concen-
tration of the repeatedly exposed rats was greater than that of the
single exposure rats (79 and 37 percent of control, respectively);
the authors concluded that "...repeated exposure to vinyl chloride
does not induce its biotransformation. However, the increase in
hepatic macromolecular binding indicates that repeated exposure
augments the reaction of electrophilic metabolites with macromole-
cules, and this may be expected to enhance potential toxicity in-
cluding carcinogenicity."
Using male Wistar rats, Withey (1976) determined that vinyl
chloride migrates rapidly from the gastrointestinal tract to the
blood following gastric intubation of aqueous solutions of vinyl
chloride (22.6 to 28.2 mg per animal) or gastric intubation of a
vegetable oil solution of vinyl chloride (12.55 or 25.1 mg per ani-
mal) . The nature of the vehicle had little or no effect on the
rates of uptake or elimination kinetics. After a 5-hour inhalation
exposure at approximately 7,000 ppm, blood levels of vinyl chloride
decreased rapidly.
C-ll
-------
Distribution
The liver of rats (Table 2) retains the greatest percentage of
vinyl chloride and/or metabolites of vinyl chloride 72 hours after
single oral administration of 0.05, 1.0, or 100 mg/kg of the 14C-
labeled compound (Watanabe, et al. 1976a).
Ten minutes after the initiation of a 5-minute 10,000 ppm
inhalation exposure to 14C-vinyl chloride, 14C activity is found in
the liver, bile duct, stomach, and kidneys of rats (Duprat, et al.
1977).
Bolt, et al. (1976) studied the tissue disposition of 14C-
vinyl chloride in rats. Immediately after exposure by inhalation
of 50 ppm vinyl chloride for five hours in a closed system, the per-
cent incorporated as C-radioactivity per g tissue was highest for
kidney (2.13), liver (1.86), and spleen (0.73). Forty-eight hours
after the beginning of exposure, labeled material could still be
detected in these tissues.
Metabolism
Detoxification of vinyl chloride takes place primarily in the
liver by oxidation to polar compounds which can be conjugated to
glutathione and/or cysteine (Hefner, et al. 1975a). These cova-
lently bound metabolites are then excreted in the urine.
Vinyl chloride is metabolized extensively by rats in vivo and
the metabolic pathway appears to be saturable (Watanabe, et al.
1976a,b; Bolt, et al. 1977; Hefner, et al. 1975a). These investi-
gators postulate that the primary metabolic pathway involves alco-
hol dehydrogenase because ingested ethanol or pyrazole inhibits the
uptake of vinyl chloride. In rats this primary pathway appears to
C-12
-------
TABLE 2
14,
Percentage of the Administered C Activity per Gram of
Tissue After Administration of ( C) Vinyl Chloride3
Dose (mg/kg)
Q
1
I-1
00
Tissue
Liver
Skin
Carcass
Plasma
Muscle
Lung
Fat
0
0
0
0
0
0
0
0
.172
.070
.027
.041
.028
.050
.030
.05
± °
± °
± °
± °
± °
± °
± °
.025b
.023
.007
.004
.003
.003
.004
0
0
0
0
0
0
0
1.0
.182 + i
.076 + i
.046 +
.053 +
.031 +
.061 +
.045 +
0.005
0.010
0.002
0.007
0.003
0.003
0.008
0
0
0
0
0
0
100
.029 +
.010 ±
.007 ±
NDC
.006 +
.011 +
.006 +
0.002
0.002
0.001
0.001
0.001
0.001
*Source: Watanabe, et al. 1976a
aRemaining in the body after 72 hr
Mean + SE, five rats per dose
°Not detectable above background
-------
be saturated by exposures to concentrations exceeding 220 to 250
ppm. In rats exposed to higher concentrations, metabolism of vinyl
chloride is postulated to occur via a secondary pathway involving
epoxidation and/or peroxidation. Present data indicate that vinyl
chloride is metabolized to an activated carcinogen electrophile
(Van Duuren, 1975; Montesano and Bartsch, 1976; Kappus, et al.
1976) and is capable of covalently reacting with nucleophilic
groups or cellular macromolecules.
There is ample evidence that the mixed function oxidase (MFO)
system may be involved in the metabolism of vinyl chloride. Pre-
treatment of rats with phenobarbital, which induces the MFO system,
also enhances liver toxicity of vinyl chloride (Jaeger, et al.
1974). Rat liver microsomes catalyze the covalent binding of vinyl
chloride metabolites to protein and nucleic acids (Kappus, et al.
1975; 1976); chloroethylene oxide is thought to be the primary
microsomal metabolite capable of alkylating these cellular macro-
molecules (Laib and Bolt, 1977). Hathway (1977) reports in vitro
depurination of calf thymus DNA by chloroacetaldehyde is identical
to that observed in hepatocyte DNA following administration of
vinyl chloride to rats iji vivo.
Excretion
14
Excretion of C activity within 72 hours following a single
14
oral dose of C-labeled vinyl chloride is shown in Table 3.
Administration of vinyl chloride by inhalation produced almost
identical results (Watanabe, et al. 1976b). Two or three major
metabolites are identified as indicated in Table 4; again, the
route of administration has no effect.
C-14
-------
o
I
M
Ul
TABLE 3
Percentage of Administered 14C Activity Recovered Following
a*
A Single Oral Dose of Vinyl Chloride
Dose (mg/kg)
Expired:
As VC
As C02
Urine
Feces
Carcass and tissues
Cage washc
Total recovery
1
8
68
2
10
91
0.
.43
.96
.34
.39
.13
.25
05
+ 0
± °
± °
± °
± !
0
± 2
1.0
.13b
.59
.54
.52
.93
.47
2.
13.
59.
2.
11.
0.
88.
13
26
30
20
10
84
83
+
+
+
+
+
+
+
100
0.22
0.47
2.75
0.39
0.47
0.45
1.98
66
2
10
0
1
82
.64 +
.52 +
.84 +
.47 +
.83 +
0
.30 +
0.67
0.13
0.95
0.06
0.14
0.43
*Source: Watanabe, et al. 1976a
Percentage of dose excreted over 72 hr. Only the C activity associated with the
expired VC can be attributed to VC per se
Mean + SE five rats per dose
GDistilled water wash of metabolism cage at termination of the study
-------
TABLE 4
Separation of C-containing Urinary Metabolites from
Rats Given Vinyl Chloride3
o
Dose (mg/kg)
Compound 0.05(4)b 1.0(5)b
N-acetyl-S-(2-
hydroxyethyl) -cysteine 30.4 + 2.0 36.2 + 3.9
Thiodiglycolic acid 25.6 + 1.9 23.7 + 1.1
Unidentified 38.6 + 2.9 34.5 + 4.6
Total 94.6 94.4
100(5)b
29.1 + 2.0
25.4 + 0.9
36.6 + 2.0
91.1
*Source: Watanabe, et al. 1976a
aMetabolites were separated and quantitated by high pressure liquid chromatography.
Values are expressed as percentage of total urinary radioactivity.
Number in parentheses = Number of animals per dose
G
Mean
SE
-------
Green and Hathway (1975) measured the excretion of 250 yg C-
vinyl chloride per kg body weight administered to rats by intra-
gastric, intravenous (femoral vein), or intraperitoneal routes.
Rats given 14C-vinyl chloride by the intragastric route (250 yg/kg
in corn oil) exhaled 3.7 percent of this dose as vinyl chloride 24
hours post exposure, 12.6 percent as C02, 71.5 percent labeled
material in the urine, and 2.8 percent in the feces. Intravenous
injections of 250 yg/kg in n-(B-hydroxethyl) lactamide resulted in
99 percent exhaled as vinyl chloride, 0.1 percent C02, 0.5 percent
of the label excreted in the urine, and 0.1 in the feces.
Intraperitoneal injection of 250 ug/kg resulted in 43.2 per-
cent of the dose exhaled as vinyl chloride, 10.3 percent as C02,
41.5 percent in the urine, and 4.8 percent in the feces. At a larg-
er dose, (450 yg/kg) 92 to 96 percent was exhaled as vinyl chloride
following intragastric and intraperitoneal routes, respectively.
EFFECTS
Acute, Subacute, and Chronic Toxicity
Acute toxicity tests with vinyl chloride were carried out by
Patty, et al. (1930) of the Bureau of Mines, Department of Com-
merce. Single exposure of guinea pigs to vinyl chloride gas, 10
percent in air, resulted in narcosis and death within 30 to 60
minutes. Lower concentrations resulted in ataxia and narcosis.
Pathological findings at necropsy were congestion and edema of the
lungs and hyperemia of the kidneys and liver. A number of investi-
gators have made similar observations when examining the acute
inhalation toxicity of vinyl chloride in mice, rats, guinea pigs,
rabbits, cats, dogs (Peoples and Leake, 1933; Lester, et al. 1963;
C-17
-------
Mastromatteo, et al. 1961; Haley, 1975; Prodan, et al. 1975). In
animal studies, LE>50S at two hours ranged from 117,500 ppm for mice
to 230,800 ppm for rabbits. Deaths of two Canadian workers were
reported in 1960 (Danziger, 1960) following acute exposures to
vinyl chloride gas. At autopsy, there was congestion of the liver,
spleen, and kidneys.
The earliest reports of vinyl chloride-associated liver abnor-
malities were from the USSR (Tribukh, et al. 1949), although the
effects were attributed to vinyl chloride and plasticizer resin.
In 1957 the USSR set upper limits of industrial exposures to vinyl
chloride at 400 ppm. As referenced by Marsteller and Lebach
(1975) , reports from Romania in 1963 and 1967 described vinyl, chlo-
ride-associated Raynaud's syndrome, dermatitis, scleroderma, thy-
roid insufficiency, and hepatomegaly. Cordier, et al. (1966) were
the first to describe acro-osteolysis of the distal phalanges com-
bined with a Raynaud-like symptomatology. Subsequently, other
cases were reported in the literature. The first cases in the U.S.
of occupational vinyl chloride-associated acro-osteolysis were
reported by Wilson, et al. 1967. These reports prompted studies of
chronic toxicity (Viola, 1970), and to further observations of
vinyl chloride-induced neoplasia in rats (Viola, et al. 1971).
Exposure of workers to high concentrations of vinyl chloride
produces conditions of euphoria and intoxication. Irritation of
the respiratory tract is followed by chronic bronchitis and workers
complained of headache, irritability, poor memory, tingling, and
weight loss (Suciu, et al. 1975).
C-18
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There are numerous clinical indications that chronic exposure
to vinyl chloride is toxic to humans. Tribukh, et al. (1949) re-
ported hepatitis-like liver changes although the effects were
attributed to vinyl chloride and plasticizer resin. Angioneurosis
of a spastic character was reported by Filatova, et al. in 1958.
Raynaud's syndrome, scleroderma-like skin changes, lytic lesions of
the terminal phalanges in hands and feet, and pseudoclubbing of the
fingers have been reported in many workers in the U.S. and Europe.
This latter condition has been termed occupational acro-osteolysis.
Cases of this new occupational disease have been reported from
around the world (Wilson, et al. 1967; Dinman, et al. 1971; Wedry-
chowiez, 1976; Harris and Adams, 1967).
Examination by wide-field capillary microscopy of the hands of
PVC workers demonstrated capillary abnormalities in a high percent-
age of exposed men. This noninvasive technique may be useful as a
mass-screening procedure in the early detection and prevention of
vinyl chloride-associated diseases (Maricq, et al. 1976).
Other long-term effects include functional disturbances of the
central nervous sytem with adrenergic sensory polyneuritis (Smir-
nova and Granik, 1970); thrombocytopenia, splenomegaly, liver mal-
function with marked fibrosis in the portal areas, and pulmonary
insufficiency with restrictive changes in the lungs (Lange, et al.
1974) .
In 1972, Kramer and Mutchler studied workers exposed to vinyl
chloride and correlated clinical parameters with environmental
exposure. Ninety-eight workers were studied who had been exposed
to vinyl chloride up to 25 years. Tests indicated there were
C-19
-------
slight changes in physiologic and clinical laboratory parameters
suggesting some impairment of liver function.
Increased urinary excretion of monochloroacetic acid has been
correlated with an increase in the concentration of inhaled vinyl
chloride (Grigorescu and Tiba, 1966). One-year exposure to vinyl
chloride caused a decrease in blood catalase activity and an in-
crease in peroxidase, indophenoloxidase, and glutathione (Gabor, et
al. 1964).
In humans exposed to vinyl chloride, serum levels of gamma-
glutamic transpeptidase (GGTP) appear to be the best clinical para-
meter for detecting liver abnormalities and reflecting the extent
of liver lesions by the degree of elevation. Alkaline phosphatase,
serum glutamic pyruvic transaminase, serum glutamic oxaloacetic
transaminase, lactic dehydrogenase, and bilirubin levels were also
increased in many cases. Location of the liver lesions affected
the elevation of specific enzymes found in the plasma. (Makk, et
al. 1976).
Ward, et al. (1976) provided data which suggest that vinyl
chloride disease is an immune complex disorder. Immunological and
immuno-chemical investigations of workers with the syndrome showed
the presence of circulating immune complexes in 19 of 28 patients.
Abnormalities were also detected in some workers exposed to vinyl
chloride who had few or no overt clinical signs. Studies are in
progress to investigate all the exposed workers in one factory and
also workers in other related industrial plants.
C-20
-------
Synergism and/or Antagonism
Hefner, et al. (1975a) inhibited the metabolism of vinyl chlo-
ride by administering to rats 320 mg/kg of pyrazole one hour prior
to inhalation of the gas. Pyrazole is an inhibitor of alcohol
dehydrogenase, xanthine oxidase, and other enzymes (Carter and
Isselbacher, 1972). Pretreatment of rats with ethanol (5 mg/kg, 95
percent) also inhibited vinyl chloride metabolism.
A study of the effects of ingested ethanol (5 percent in water
ad libitum) on the induction of liver tumors in Sprague-Dawley rats
by year-long vinyl chloride inhalation indicates that chronic
ingestion of alcohol increases the incidence of liver tumors and
tumors in other sites (Radike, 1977b). The first animals treated
with 5 percent ethanol and 600 ppm vinyl chloride died of angio-
sarcoma of the liver in 39 weeks; the first treated with vinyl
chloride died due to liver tumor proliferation in 53 weeks.
Jaeger (1975) conducted experiments to determine the interac-
tion between vinylidene chloride (1,1-DCE) and vinyl chloride. In
this experiment the effects of 4-hour exposures to 200 ppm of
vinylidine chloride and 1,000 ppm vinyl chloride were less than if
1,1-DCE was given alone. Simultaneous 4-hour exposures to 200 ppm
vinylidene chloride and 1,000 ppm vinyl chloride indicated that
vinyl chloride prevented injury caused in rats by the administra-
tion of 1,1-DCE alone. Injury was indicated by an elevation in
serum alanine o<^ketoglutarate transaminase. These two monomers
are used together in the production of vinyl copolymers and expo-
sure to both agents was reported by Kramer and Mutchler (1972).
C-21
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Teratogenicity
Animal studies using three species (mice, rats, and rabbits)
indicate that inhalation of vinyl chloride does not induce gross
teratogenic abnormalities in offspring of mothers exposed seven
hours daily to concentrations ranging from 50 to 2,500 ppm (John,
et al. 1977); however, statistically significant excess occur-
rences of minor skeletal abnormalities were noted (Wilcoxon,
p^O.05). Mice and rats were exposed on days 6 through 15 and rab-
bits on days 6 through 18 of gestation. At high concentrations
there was evidence of increased fetal death in all three species.
Radike, et al. (1977a) also did not observe gross abnormalities in
the offspring of rats exposed four hours daily on the 9th to the
21st day of gestation by inhalation to 600 or 6,000 ppm vinyl chlo-
ride; minor skeletal abnormalities did occur in excess.
As to the teratogenic effects, human females are generally not
exposed to high concentrations of vinyl chloride; the question
arises whether low environmental levels may cause congenital mal-
formations. There are reports of high rates of congenital defects
in three small communities in which vinyl chloride polymerization
plants are located. Significantly greater numbers of malformations
of the central nervous system, upper alimentary tract, genital
organs, and feet were reported (Infante, 1976; Infante, et al.
1976; Edmonds, et al. 1975). Results of these studies are not com-
pletely unequivocal and further studies are needed. Overall, the
evidence suggests that exposure of pregnant women to vinyl chloride
at appreciable levels should be avoided.
C-22
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Mutagenicity
Vinyl chloride is mutagenic in a number of biological systems.
The mutagenic action of vinyl chloride appears to be dependent upon
its metabolic conversion into chemically reactive metabolites
(e.g., chloroethylene oxide, 2-chloroacetaldehyde). The mutagenic
effects of vinyl chloride have been demonstrated in: (1) metabol-
ic ally activated systems using Salmonella typhimurium (Bartsch, et
al. 1975; Bartsch and Montesano, 1975; McCann, et al. 1975; Elmore,
et al. 1976; Rannug, et al. 1974; Garro, et al. 1976) developed by
Ames, et al. (1973) in which the genetic indicator organisms revert
to histidine prototrophy by base-pair substitutions, or frameshift
mutations; (2) Escherichia coli K12 bioauxotrophic strain with back
mutation to arginine"1" (Greim, et al. 1975) ; (3) several species of
yeast inducing forward mutations and gene conversions at specific
loci (Loprieno, et al. 1976, 1977); (4) in germ cells of Drosophila
(Verbugt, 1977); and (5) Chinese hamster V79 cells (Huberman, et
al. 1975) .
The mutagenic activity of inhaled vinyl chloride (3,000,
10,000, or 30,000 ppm for six hours a day for five days) was as-
sessed in fertile male CD-I mice in the dominant lethal assay
(Anderson, et al. 1976). At these high concentrations vinyl chlo-
ride was not mutagenic as judged by scoring of post-implantation
fetal deaths, pre-implantation egg losses and reduction in fertili-
ty. Positive control tests indicated that the dominant lethal
effect was expressed in the CD-I mice used in these experiments.
In relation to man, several investigators have observed a sig-
nificantly higher incidence of chromosomal aberrations in the
C-23
-------
lymphocytes of workers chronically exposed to high levels of vinyl
chloride (Ducatman, et al. 1975; Purchase, et al. 1975; Funes-
Cravioto, et al. 1975). Most of the damage involved gross changes
such as fragmentations or rearrangements.
Picciano, et al. (1977) have reported no statistically signif-
icant differences in chromatid and chromosome aberrations or pro-
portion of abnormal cells in a group of 209 vinyl chloride-exposed
workers. These workers were exposed for periods ranging from 1 to
332 months (x = 48.5 mo.) to time-weighted average levels of vinyl
chloride ranging from 0.3 to 15.2 ppm. Killian, et al. (1975) have
also reported a lack of evidence for excess chromosome breakage in
a population of vinyl chloride-exposed workers.
On the other hand, Ducatman, et al. (1975) and Purchase, et
al. (1975) have reported increased incidence of chromosomal break-
age among their cohorts of vinyl chloride-exposed workers popula-
tions.
Heath, et al. (1977) examined cytogenetic effects in three
groups of industrial workers: PVC polymerization workers (presumed
high exposure), PVC processing workers (presumed low exposure) and
rubber and tire manufacture workers (presumed negligible exposure).
Chromosome breakage in all three groups was significantly greater
than in nonindustrial controls and overall breakage levels were
similar in all three groups. These data suggest that other agents
in addition to vinyl chloride may cause cytogenetic damage in work-
ers employed in similar occupations.
Waxweiler, et al. (1977) reported cytogenetic studies of vinyl
chloride workers, plastics workers, and rubber workers. Vinyl
C-24
-------
chloride workers had a slightly higher rate of chromosome breakage
than rubber workers and the plastics workers showed the highest
rates of breakage. None of the differences between the industrial
groups studied was significant; however, all of the industrial
groups had higher chromosome breakage rates than nonindustrial con-
trols. Additionally, a significant increase in fetal loss rate was
found in wives of workers relative to their husbands' exposure to
vinyl chloride.
Carcinogenicity
Inhalation-Animal Studies: (Viola, et al. 1971) reported the
carcinogenic response of male rats (Ar/IRE Wistar strain) exposed
to vinyl chloride by inhalation (Table 5) . After the year-long
exposure, animals were killed at 20-day intervals. Skin tumors
were first noted at approximately 10 months; tumors in the lungs
and bones were observed at about 11 months.
Maltoni, in a series of reports starting in 1973, confirmed
the carcinogenicity of inhaled vinyl chloride in experimental ani-
mals and listed several types of neoplasms including angiosarcoma
of the liver. Confirmation of observations made in animal models
came in 1974 with the report of vinyl chloride-associated angiosar-
coma of the liver in vinyl chloride polymerization workers at the
B.F. Goodrich plant in Louisville, Kentucky (Creech and Johnson,
1974). By December, 1975, similar reports came from 11 different
countries culminating in 64 known cases (according to the latest
compilation by Spirtas and Kaminski, 1978).
Caputo, et al. (1974) exposed larger numbers of male and
female rats (A and IRE Wistar strain) by inhalation to various con-
C-25
-------
o
t!>
TABLE 5
Oncogenic Effects of Inhaled Vinyl Chloride*
Cone. VC (ppm)
4 hrs/day,
5 days/wk
12 months
30,000
No treatment
Number
Rats
26
25
Skin
Epidermoid
Carcinomas
17
-
Lung
Adenocarcinomas
& Squamous Cell
Carcinomas
6
—
Bones
Osteochondroma
5
—
Total
25
"~
*Source: Viola, et al. 1971
-------
centrations of vinyl chloride. Carcinomas and sarcomas were ob-
served in all groups except those exposed to 50 ppm (Table 6) .
Tumors appeared between eight and 13 months from the beginning of
the inhalation treatment. These investigators also exposed rabbits
by inhalation to 10,000 ppm vinyl chloride for 15 months (Table 6)
and reported incidence of lung and skin carcinomas.
Maltoni and Lefemine (1974a,b; 1975) reported a series of
experiments concerning the effects of inhalation exposure on rats,
mice, and hamsters to vinyl chloride at concentrations ranging from
50 to 10,000 ppm for varying periods of time. Animals were ob-
served for their lifetime. Angiosarcomas in the liver occurred in
all three species as well as tumors at several other sites. The
following tables summarize some of their findings (Tables 7-11).
Male hamsters and male and female rats and mice were used in these
experiments. A differential response of the sexes was not re-
ported.
The most recent publication of Maltoni's ongoing experiments
(1976) does not report average latent periods or the total number
of animals with tumors per treatment group. For this reason, both
Maltoni and Lefemine's (1975) and Maltoni's (1976) data are includ-
ed in both reports.
Experiments which are not yet completed (Maltoni, 1976) in-
clude: (1) inhalation exposure of male and female Sprague-Dawley
rats to concentrations of 200, 150, and 100 ppm for 52 weeks (Table
12); (2) inhalation exposure of male and female Sprague-Dawley rats
lasting only 17 weeks, observed at last report UP to 114 weeks
(data not included) (preliminary results indicate that a 17 week
C-27
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TABLE 6
Incidence of Tumors in Rats and Rabbits Exposed to
Vinyl Chloride by Inhalation*
Cone. VC (ppm)
4 hrs/day,
5 days/wk
12 months
— "~
20,000
10,000
O
K> 5,000
00 '
2,000
500
50
No treatment
15 months
10,000
No treatment
Number of
Animals
Rats
150
200
200
200
150
200
200
Rabbits
40
20
Liver
Angiosar comas
Cholangiomas
31
16
12
10
4
-
—
Lung
Adeno-
Alveolar
Carcinomas
21
16
4
8
—
— "
f.
_ — , „, • —
Skin
Squamous Cell
Carcinoma
Acanthoma
67
34
20
6
3
12
— — —
Other
7
8
2
6
-
*Source: Caputo, et al. 1974
-------
TABLE 7
Incidence of Tumors in Sprague-Dawley Rats Exposed 4 hts/day, 5 days/wk, 52 weeks
By Inhalation to Various Concentrations of Vinyl Chloride: Results after 135 weeks*
Cone. VC
(ppm)
10,000
^ 6,000
v£ 2,500
500
250
50
No treatment
Number
Total
69
72
74
67
67
64
68
of Animals
Corrected
61
60
59
59
59
59
58
Liver
Angio
sarcomas
9
13
13
7
4
1
Average
Latency
(wk)
64
70
78
81
79
135
Kidnev
Nephro
blastemas
5
4
6
4
6
1
Average
Latency
(wk)
59
65
74
83
80
135
Average
Carcinomas Latency
(wk)
16 50
7 62
2 33
4 79
-
-
Other
25
19
18
11
9
12
10
Total
Number of
Rats with
One or
More Tumors
38
31
32
22
16
10
6
*Source: Maltoni and Lefemine, 1975
-------
TABLE 8
Incidence of Tumors in Swiss Mice Inhaling Vinyl Chloride 4 hrs/day, 5 days/wk,
30 weeks: Results after 41 weeks*
o
1
oo
o
Cone. VC
(ppm)
10,000
6,000
2,500
500
250
50
No treatment
Number
Total
60
60
60
60
60
60
150
of Animals
Corrected
50
54
53
58
58
57
141
Pulmonary
Tumors
Liver
Angiosarcomas
4
2
4
4
3
-
NO.
27
22
12
16
11
1
Average
(wks)
34
33
35
34
34
39
Mammary
Carcinomas
No.
9
8
4
2
6
7
-
Average
(wks)
28
33
32
33
30
35
—
Other
9
5
3
2
1
4
"
Total Number
One or
More Tumors
28
27
13
17
15
8
1
*Source: Maltoni and Lefemine, 1975
-------
TABLE 9
Incidence of Tumors in Swiss Mice Inhaling Vinyl Chloride 4 hrs/day,
5 days/wk, 30 weeks: Results after 81 weeks*
Number of Animals with Tumors
Cone. VC
(ppm)
10,000
6,000
n 2,500
U)
i- 500
250
50
No treatment
Number of Animals
(Male and Female)
60
60
60
60
60
60
150
Liver
Angiosar comas
8
5
11
11
11
1
-
Pulmonary
Tumors
35
38
30
38
33
2
8
Other
26
24
25
26
35
25
1
*Source: Maltoni, 1976
-------
TABLE 10
Incidence of Tumors in Golden Hamsters Inhaling Vinyl Chloride 4 hrs/day,
5 days/wk, 30 weeks: Results after 48 weeksa
o
1
OJ
Ni
Cone. VC
(ppm)
10,000
6,000
2,500
500
250
50
No treatment
Number
Total
35
32
33
33
32
33
70
of Animals
Liver
Survivors Angiosarcomas
19
21
19
23 lb
18
23
49
Other
3
8
5
4
2
5
2
Total Number of
Animals with One
or more Tumors
3
5
4
4
2
5
2
aSource: Maltoni and Lefemine, 1975
bMore than 18 weeks post-exposure
-------
TABLE 11
Incidence of Tumors in Golden Hamsters Inhaling Vinyl Chloride 4 hrs/day,
5 days/wk, 30 weeks: Results after 76 weeks3
U)
OJ
Cone. VC
(ppm)
10,000
6,000
2,500
500
250
50
No treatment
Number
Total
35
32
33
33
32
33
70
of Animals
Survivors
1
3
4
4
4
5
14
Liver Tumors
Angiosarcoma
Angiomas
Hepatomas
-
3
4
2b
-
-
-
Other
13
10
10
8
4
10
4
Source: Maltoni, 1976
Angiosarcomas
-------
TABLE 12
Incidence of Tumors in Sprague-Dawley Rats Exposed 4 hrs/day, 5 days/week,
52 weeks by Inhalation to Vinyl Chloride; Results after 89 weeks*
n
Cone. VC
(ppm)
200
150
100
3 treatment
Number
Total
120
120
120
185
of Animals
Survivors
41
45
49
76
Liver
Angiosarcoma
7
3
1
Nephro Zymbal Gland
Blastemas Carcinomas
2
4
8 1
1
Angiosarcomas
Other Sites
1
1
1
*Source: Maltoni, 1976
-------
exposure produces the same kinds of lesions observed following a
52-week exposure) ; (3) 52-week exposure of male Wistar rats ob-
served for 88 weeks with preliminary results in general confirming
results with Sprague-Dawley rats; and (4) exposure of newborn rats
by inhalation to high concentrations of vinyl chloride for five
weeks results after 48 weeks, indicating that angiosarcomas in the
liver and hepatomas had developed.
Maltoni (1976) also observed four subcutaneous angiosarcomas,
four Zymbal's gland carcinomas, and one nephroblastoma in 66 off-
spring of 60 Sprague-Dawley rats exposed by inhalation 4 hrs/day to
10,000 or 6,000 ppm vinyl chloride from the 12th to the 18th day of
gestation (21-day gestation). At the time of Maltoni's publication
(1976), 20 offspring were living at 115 weeks' post-exposure.
Recent inhalation studies with albino CD-I mice and CD rats
(Charles River Breeding Lab) confirm the carcinogenicity of vinyl
chloride (Lee, et al. 1977). This study was designed to define
biochemical changes relating to histological and neoplastic le-
sions. For each species 360 animals were divided into five groups,
each consisting of 36 males and 36 females. Each group of both spe-
cies was exposed to 50, 250, or 1,000 ppm vinyl chloride for 6
hrs/day, 5 days/wk. Four animals of each species, sex, and expo-
sure level were terminated at the end of 1, 2, 3, 6, and 9 months
and the surviving animals terminated at 12 months. After 12
months, bronchioalveolar adenomas, mammary gland tumors, and angio-
sarcomas in the liver and other sites developed in mice exposed by
inhalation to 50, 250, or 1,000 ppm vinyl chloride. Rats exposed
to 250 or 1,000 ppm vinyl chloride developed angiosarcoma in the
liver, lungs, and other sites (Lee, et al. 1978).
C-35
-------
There is evidence that ingested alcohol makes rats more sus-
ceptible to the carcinogenic action of inhaled vinyl chloride
(Radike, et al. 1977b). Three hundred and twenty male Sprague-
Dawley rats were divided into four groups; two groups received 5
percent ethanol in water four weeks prior to vinyl chloride inhala-
tion (600 ppm 4 hrs/day, 5 days/wk, 12 months). The first death
from liver angiosarcoma in rats exposed to vinyl chloride was at 53
weeks from the first exposure; in rats ingesting 5 percent ethanol
and inhaling vinyl chloride the first death from angiosarcoma in
the liver was at 39 weeks from the first exposure. Cancerous
lesions were identified in only 13 rats (Table 13).
Maltoni, et al. (1975, Maltoni, 1976) claim that vinyl chlo-
ride is also carcinogenic via gastrointestinal ingestion. Vinyl
chloride dissolved in olive oil was administered by stomach tube
five times per week to 13-week-old Sprague-Dawley rats (40 males
and 40 females) in concentrations equivalent to 50.00, 16.65, and
3.33 mg/kg body weight (Table 14). After 50 weeks, one angiosarco-
ma of the liver was observed in one male animal in the group given
16.6 mg/kg. This is equivalent to 863 mg total over a 52-week peri-
od. One angiosarcoma of the thymus gland was observed in a female
animal receiving 50 mg/kg, which is equivalent to three times that
given to the male animal. This oral dosage is comparable to the
inhalation dose that induces both liver angiosarcomas and renal
nephroblastomas, i.e., 800 mg (Maltoni and Lefemine, 1975). The
data are preliminary in nature, since the study is not yet complet-
ed and/or reported. These studies are now in progress; they will
determine the incidence and type of cancer produced by ingestion of
C-36
-------
TABLE 13
Tumors in 13 Rats Exposed to Vinyl Chloride or to 5 Percent
Ethanol and Vinyl Chloride3
o
1
u>
-j
Group Treatment
600 ppm VCb
600 ppm VCb
5% Ethanol
Number of
Animals
with Tumors
6
7
Angio-
sarcoma
2
5
Liver
Hepatocellular
Carcinoma
1
2
Lung
Angiosarcoma
1
Kidney
Angiosarcoma
Fibrosarcoma
1 (each)
Source: Radike, et al. 1977b
4 hrs/day, 5 days/wk
-------
TABLE 14
Incidence of Tumors in Sprague-Dawley Rats Ingesting Vinyl Chloride in
Olive Oil: Results after 55 weeks*
o
1
u»
CD
Cone. VC
(mg/kg)
50.00
16.65
3.33
Olive Oil Alone
Number
Total
80
80
80
80
of Animals
Survivors
57
66
62
68
Liver
Ang iosarcomas
-
1
~
Ang iosarcomas
Other Sites
1
-
*Source: Maltoni, et al. 1975
-------
low doses of vinyl chloride, i.e., 1.0, 0.3, and 0.03 mg/kg/day
(Maltoni, 1976, 1980).
The primary effect associated with vinyl chloride exposure in
man is an increased risk of cancer in several organ systems includ-
ing angiosarcoma of the liver. Liver angiosarcoma is an extremely
rare liver cancer in humans with 26 cases reported annually in the
U.S. [National Cancer Institute (NCI), 1975]. Human data of carci-
nogenic effects of vinyl chloride have been obtained primarily from
cases of occupational exposures of workers. The latent period has
been estimated to be 15 to 20 years following onset of exposure;
however, recent case reports indicate a longer average latent peri-
od (Spirtas and Kaminski, 1978).
Epidemiological studies of vinyl chloride exposed workers have
primarily focused on cases of angiosarcoma of the liver. The basis
for this emphasis is clear; a primary problem in all epidemiologi-
cal investigations is the establishment of a cause/effect relation-
ship between a harmful agent and a population under study. Heman-
giosarcoma of the liver is a type of cancer rarely occurring in the
general population. Because of this rare occurrence of hemangio-
sarcoma in man, it is much easier to draw a casual relationship
between exposure to vinyl chloride and the development of this
tumor. The linking of vinyl chloride to other types of cancers
through epidemiological evidence is more tenuous.
The work of Maltoni, et al. (1974) among others was of primary
importance in focusing attention on the potential for liver angio-
sarcoma in workers exposed to vinyl chloride. He demonstrated
liver angiosarcoma as a specific lesion in rats following vinyl
C-39
-------
chloride inhalation exposures. Subsequently, the first four cases
of liver angiosarcoma in vinyl chloride exposed workers were re-
ported (Creech and Johnson, 1974).
Tabershaw/Cooper Associates (1974) conducted a mortality
study of vinyl chloride workers. Mortality calculations included
only those workers which could be traced in the followup study,
i.e., 7,129 of 8,384 workers. These individuals were from 33 dif-
ferent plants and all had been exposed to vinyl chloride for at
least one year. The mean employment duration for the group of
workers under study was 80 months (in contrast to 44 months for
those not located) , but the traced workers entered employment, about
10 years later. Among the 7,129 workers which were located there
were 854 with exposures of 20 years or longer and 1,640 exposed 15
or more years.
Compared to the general male U.S. population the overall mor-
tality rate was found to be lower, i.e., 75 percent that of expect-
ed rate. Specific causes of death were no greater than exoected
and no deaths seemed attributable to angiosarcoma. Standardized
mortality ratios (SMR) for malignant neoplasms in general increased
with increasing exposure level and/or duration. In the group iden-
tified as the high exposure group there were increases in liver
cancer (primarily angiosarcoma), respiratory system cancers, and
brain cancers. These differences were not statistically signifi-
cant (Tabershaw/Cooper Assoc., Inc. 1974; Tabershaw and Gaffey,
1974).
Ott, et al. (1975) have re-examined much of the mortality data
reported by Tabershaw and Gaffey (1974) and have included more
C-40
-------
clearly defined exposure levels and followup of former company
employees. The basic findings remain unchanged: no increase over
expected in malignant neoplasms was found in the low exposure group
(time-weighted average from 10 to 100 ppm) and an increase in
deaths due to malignant neoplasms was observed in the high exposure
group (time-weighted average was greater than 200 ppm) .
Dow Chemical Co. (Holder, 1974) conducted a mortality study of
594 workers exposed to vinyl chloride between 1942 and 1960. Work-
ers were assigned to exposure groups based on the highest level of
exposure for at least one month (low group - time-weighted average
less than 25 ppm vinyl chloride, intermediate - time-weighted aver-
age 25 to 200 ppm; high - time-weighted average 200 to 300 ppm) .
Also included in the high group were workers from the intermediate
group frequently exposed to 1,000 ppm for short time periods.
Total mortality was 91 percent of expected among the vinyl
chloride exposed workers. No deaths due to liver cancer were re-
ported and only a total of 13 cases of neoplasms were reported as
opposed to 15.4 expected. However, nine of these malignancies
occurred in the high exposure group as compared to 5.1 expected
(due to small number of deaths, this difference was not tested for
significance). Eight of these malignancies were in workers with 15
or more years of exposure.
Monson, et al. (1974) conducted a proportional mortality study
of vinyl chloride workers (two plants) who died from 1947 to 1973.
Death certificates were obtained for 142 out of 161 workers who
died within this time period. Deaths attributable to cancer were
50 percent higher than expected (a statistically significant dif-
C-41
-------
ference). A 900 percent increase in cancers of the liver and bili-
ary tract was noted (five angiosarcomas). Excluding angiosarcoma,
a 275 percent excess was observed in the remaining forms of cancer.
Two brain tumors (320 percent excess) and 13 lung cancers (60 per-
cent excess) were observed. In addition the cancer death rate
increased during the period.
Nicholson, et al. (1975) studied a group of 257 workers (of
whom 255 were traced) exposed to vinyl chloride for at least five
years prior to 1946. Their mortality status was evaluated begin-
ning 10 years after start of employment until 1974. Exposures were
estimated to often exceed 10,000 ppm. Among the 24 deaths were
three cases of angiosarcoma of the liver. Preliminary findings
indicated a 25 percent increase over expected in all deaths and a
131 percent increase in all cancer deaths although neither of these
increases was statistically significant.
The National Institute for Occupational Safety and Health
(NIOSH) conducted a study which involved 950 individuals who were
exposed for at least five years and for whom at least 10 years had
elapsed since initial employment. Of these individuals, 285 were
located. A total of 109 deaths was reported versus 105 expected
(not a significant difference). A 57 percent increase over the
expected for cancer deaths was noted - statistically significant.
Cancerous lesions were noted in the respiratory system, blood form-
ing tissues, brain, and central nervous system. Liver cancer
deaths were 12-fold greater than expected and brain cancer deaths
were 5-fold higher (both statistically significant differences)
(Wagoner, 1974).
C-42
-------
Chiazze, et al. (1977) have reported a cross-sectional mortal-
ity study of 4,341 employees from 17 PVC plants who died between
1964 and 1973. No angiosarcoma deaths were identified. Total can-
cer deaths increased in white employees (especially due to cancer
of the digestive system). In white women employees deaths from
cancer of the breast and urinary organs were greater than expected.
On the other hand, in a mortality study of 7,000 British work-
ers exposed to vinyl chloride between 1940 and 1974, the authors
found no evidence of increased cancer mortality other than from
liver cancer. In this study, four cases of malignant liver tumor
were diagnosed and two of these were confirmed to be angiosarcoma.
Both cases were in men exposed to high levels of vinyl chloride
(Pox and Collier, 1977).
In addition, Byren, et al. (1976) studied 771 Swedish vinyl
chloride plant workers, of which only 21 could not be traced. A
four-to fivefold increase over expected in pancreas and liver
tumors was found and two cases were diagnosed as angiosarcoma.
Numbers of other tumors did not deviate significantly from ex-
pected.
Ten cases of hepatic angiosarcoma have been found among the
relatively small work force employed at a vinyl chloride polymeri-
zation plant in Quebec, this being the largest number of cases to
be diagnosed in a single plant (Makk, et al. 1976). As a result of
this unusually large number of occurrences, Delorme and Theriault
(1978) have retrieved more detailed information on these employees.
The authors suggest that the cases-'of hepatic angiosarcoma appear
to be associated with high vinyl chloride exposure levels and over-
C-43
-------
time work hours. No correlation was found between occurrence of
this tumor and alcohol or cigarette use.
In the workers engaged in the polymerization of vinyl chloride
who were studied (Popper and Thomas, 1975) , a characteristic hepat-
ic fibrosis was present in all cases of angiosarcoma. Although the
relation of fibrotic lesions to the development of angiosarcomas
requires further study, a transition from the fibrotic stage to
angiosarcoma is suggested by the focal proliferation of the sinus-
oidal lining cells and of the hepatocytes that are seen in the
fibrotic stage but become even more pronounced in the initial
stages of angiosarcoma development. These findings suggest that
the fibrotic lesions without angiosarcomas, frequently described in
the workers exposed to vinyl chloride (Lilis, et al. 1975), might
be only the pre-stage of developing neoplastic lesions. The diag-
nosis of the fibrotic lesions in these workers may imply a longer
latency period for tumor appearance based on a possibly lower expo-
sure level. The series of changes observed in the liver appear to
represent a multicentric development of angiosarcoma and are simi-
lar to the changes induced by thorotrast and inorganic arsenicals
(Berk, 1976).
In the most recent update of the NIOSH register (Spritas and
Kaminski, 1978) a total of 64 cases of hepatic angiosarcoma has
been identified worldwide among vinyl chloride-exposed industrial
workers (Figure 1). A listing of all documented cases by country
is presented in Table 15.
Of the 64 cases, 23 have been reported in the U.S., represent-
ing more than one third of all diagnosed cases. Six of these cases
have been documented since 1975.
C-44
-------
l'60 |'6S
YEAR OF DIAGNOSIS
FIGURE 1
Number of cases of vinyl chloride/PVC related angiosarcomas
reported to NIOSH by year of diagnosis (representing only 63 of the
64 cases known to NIOSH since information on diagnosis is missinq
for one case).
Source: Spirtas and Kaminski, 1978
C-45
-------
TABLE 15
Angiosarcoma of the Liver in Vinyl Chloride/PVC Workers
O
I
*>
CTi
Country
Belgium
Canada
Canada
Canada
Canada
Canada
Canada
Canada
Canada
Canada
Canada
Czechoslovakia
Czechoslovakia
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
Fed Rep Germany
France
France
France
France
France
France
France
France
Great. Rr itain
Great Britain
Case
No.
01
01*
02*
03*
04*
05*
06*
07*
08
09
10
01*
02*
01*
02*
04
05*
07*
08*
09*
10*
11*
01*
02
03*
04*
05*
06*
07
08*
01*
03
Birth
Date
00-00-00
12-15-13
03-06-14
08-26-19
04-05-19
05-07-11
12-15-19
11-09-19
05-13-20
07-19-21
05-16-15
00-00-28
00-00-26
06-04-30
07-26-31
09-04-30
01-01-32
09-29-26
10-19-17
12-13-34
07-25-29
32-29-36
04-15-24
06-03-11
00-00-19
01-27-27
01-29-3R
04-14-34
00-00-27
04-01-34
04-20-01
06-02-37
1st VC
of PVC
Exposure
00-00-00
00-00-44
00-00-43
00-00-41
00-00-45
00-00-44
00-00-47
00-00-46
00-00-61
00-00-46
00-00-53
00-00-57
00-00-51
10-01-56
10-14-57
04-16-57
12-16-62
04-15-54
04-19-54
12-02-59
10-10-55
01-02-61
01-00-46
07-06-59
00-00-46
10-19-49
00-00-65
00-00-58
07-01-50
05-23-57
00-00-44
02-00-66
Diagnosis of
Angiosarcoma
00-00-00
00-00-55
00-00-57
00-00-62
00-00-67
00-00-68
00-00-71
00-00-72
00-00-73
00-00-74
00-00-76
00-00-73
00-00-66
09-19-68
09-25-70
00-00-74
00-00-75
00-00-75
00-00-75
06-16-76
06-28-77
00-00-77
02-18-67
01-08-75
01-00-75
01-04-76
04-00-76
09-00-76
07-00-76
12-03-76
12-00-72
12-00-74
Age
at
Diagnosis
00
41
43
42
48
57
51
53
53
53
61
46
40
38
39
44
43
49
58
42
47
41
43
63
55
49
38
42
49
42
71
37
Years from
1st Exposure
to Diagnosis
00
11
14
21
22
24
24
26
12
28
23
16
15
12
13
17
13
21
22
17
22
16
21
15
29
26
11
18
26
19
28
09
Total
Years of
Exposure
00
11
14
20
22
05
23
25
05
26
14
16
15
12
12
17
12
12
21
15
22
10
19
12
29
26
10
17
23
19
22
04
Date
of
Death
06-29-76
09-02-55
12-21-57
03-22-62
01-21-68
07-05-68
04-10-71
12-24-72
06-12-73
09-04-74
04-00-77
00-00-74
00-00-66
01-25-69
12-14-71
11-25-74
01-09-75
11-13-75
12-25-75
Alive
06-28-77
03-07-77
02-19-67
01-24-75
06-29-75
01-04-76
05-13-76
09-12-76
07-02-76
01-30-77
12-00-72
12-24-74
-------
TABLE 15 (Continued)
O
I
*»•
-J
Country
Italy
Italy
Japan
Norway
Sweden
Sweden
Sweden
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
U.S.A.
Yugoslavia
Yugoslavia
Total Reported Cases
Case
No.
02*
03*
01
01*
01*
03*
04*
01*
02*
03*
04*
05*
06*
07*
08*
09*
10*
11*
12*
13*
16*
17*
Ifl*
19*
20*
21*
22*
23*
24*
25*
01*
02*
64
Birth
Date
11-13-29
03-14-20
08-01-22
12-23-15
06-23-27
06-10-10
11-16-14
10-17-23
08-19-33
05-25-15
01-15-24
01-25-12
11-23-28
05-03-22
05-06-20
11-08-31
08-16-13
05-27-09
11-17-18
12-01-21
11-04-27
05-06-31
04-22-28
00-00-15
08-31-17
09-02-09
10-02-23
00-00-23
05-07-17
08-07-10
04-05-14
11-15-31
1st VC
of PVC
Exposure
00-00-57
00-00-53
04-00-53
03-00-50
08-14-51
05-00-47
00-00-46
12-09-48
11-15-55
11-28-45
07-06-52
06-19-44
01-17-62
08-27-44
10-07-46
05-28-45
06-12-51
10-14-46
09-13-49
12-11-42
05-08-50
06-23-55
09-15-54
00-00-43
00-00-55
12-00-46
07-11-47
09-00-58
00-00-30
02-00-47
00-00-53
00-00-50
Diagnosis of
Angiosarcoma
12-13-72
07-10-75
08-21-74
12-20-71
08-00-74
03-19-76
05-12-77
03-03-73
05-00-70
12-19-73
08-19-67
04-09-64
02-00-74
00-00-68
08-00-61
03-01-74
05-00-68
03-00-70
05-02-69
05-00-74
00-00-69
10-11-74
00-00-75
06-19-75
01-30-76
00-00-77
01-00-76
04-06-73
05-27-77
03-10-77
04-08-73
07-12-73
Age
at
Diagnosis
43
55
52
56
43
65
62
49
37
58
43
52
46
45
41
43
55
61
50
52
41
43
46
60
58
67
52
50
60
67
59
42
Years from
1st Exposure
to Diagnosis
15
22
22
22
19
29
31
24
14
28
15
20
12
24
15
29
17
23
20
32
19
19
21
32
21
30
29
15
38
30
20
23
Total
Years of
Exposure
06
21
22
21
18
21
31
21
13
28
15
20
12
17
15
24
17
23
19
26
04
19
11
22
18
21
28
14
26
20
20
18
Date
of
Death
12-00-72
07-10-75
10-24-75
01-04-72
10-20-70
03-19-76
05-12-77
03-03-73
09-28-71
12-19-73
01-07-68
04-09-64
07-24-75
03-23-68
08-29-61
03-00-75
05-10-68
03-16-70
05-02-69
07-04-74
03-27-69
Alive
11-02-75
04-06-76
01-30-77
01-02-77
12-04-76
04-06-73
05-27-77
03-10-77
04-08-73
07-12-73
Spirtas and Kaminski, 1978
*Diagnosis was microscopically confirmed
00 indicates unknown data
-------
It is apparent from Table 15 that both the age at diagnosis
and the latency period for cancer induction appear to be increas-
ing. The authors suggest three explanations for this phenomena:
(1) early cases may have had heavier exposure; (2) the initial
cases were more biologically susceptible; (3) random fluctuation.
Should the first of these hypotheses prove to be correct, it would
have a profound impact upon risk assessment related to low level
exposures of vinyl chloride in the next 10 to 20 years.
In addition to the large numbers of workers occupationally
exposed to vinyl chloride, individuals residing near PVC processing
plants may also be at risk (Baxter, et al. 1977). It has been esti-
mated that 4.6 million people live within five miles of PVC or
vinyl chloride production plants in the United States. Prior to
restriction of plant emissions the average exposure level for this
population has been estimated to be 17 ppm (Kuzmak and McGaughy,
1975).
Brady, et al. (1977) have examined annual rates of hepatic
angiosarcoma from 1970 through 1975 in residents of the State of
New York (excluding New York City). Direct exposures to arsenic,
vinyl chloride, or thorium dioxide were suggested to be significant
factors in the etiology of these tumors. Direct exposures to these
agents could not be demonstrated for 19 of the 26 study cases. Five
of the 19 patients lived closer to vinyl chloride plants than did
their matched controls. This may lend some support to the idea
that "indirect modes of exposure, not specifically related to occu-
pation might be important in the etiology of this disorder" (Brady,
et al. 1977).
C-48
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It should be noted that a relatively short time period elapsed
since the large scale development of the vinyl chloride-PVC indus-
tries. If the trend of increased age at diagnosis and the longer
latent period for hepatic angiosarcoma induction are indeed related
to lower levels of occupational exposure, then the latent period
for cancer induction as a result of these very low levels of envi-
ronmental exposure may be much longer than previously anticipated,
i.e., it would be many years before the ultimate outcome of these
exposures will be known.
C-49
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CRITERION FORMULATION
Existing Guidelines and Standards
In the 1950's an upper limit of 500 ppm of VC at the work place
was recommended in the United States; for comparison, in the USSR,
the upper limit was set at 400 ppm. Exposures in the USA were most-
ly below the time-weighted average (TWA) of 500 ppm; however, peak
exposures as high as 4,000 ppm were recorded in some work areas
(Ott, et al. 1975). About 1960, Dow Chemical Company established a
company standard for a limit of 50 ppm (TWA). They were successful
in reducing exposures to workers to about 25 ppm vinyl chloride,
however, excursions up to 500 ppm did occur. Dow Chemical also
initiated continuous sampling and analysis using a multi-point
remote sampler and gas chromatography.
In 1962, a Threshold Limit Value (TLV) of 500 ppm was set by
the American Conference of Government Industrial Hygienists which
was later adopted after its establishment by the Occupational Safe-
ty and Health Administration (Table 16).
Inhalation exposures dropped drastically after the carcino-
genicity of vinyl chloride was reported (Viola, et al. 1971; Mal-
toni and Lefemine, 1974a; and Creech and Johnson, 1974). The Occu-
pational Safety and Health Administration set an emergency tempo-
rary standard of 50 ppm (TWA) on April 5, 1974. A flurry of epide-
miological studies was performed. Based on all of the information
available at the time, a permanent standard of 1 ppm (TWA) with a
maximum excursion of 5 ppm for a period of no longer than 15 minutes
in one day was promulgated for the workplace (39 PR 35890) . The
U.S. EPA and other government agencies [Food and Drug Administra-
C-50
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TABLE 16
Regulations Concerning Vinyl Chloride (Compiled by J.F. Stara)
Year
1962
1971
1974 (4/5)
1974
1974
O 1974
£ 1974 (10/4)
1974
1975
1976
Agency or Organization Air Standard (ppm)
ACGIH 500 (TLV)
OSHA 500 (TLV)
OSHA 50 (Max. TLV)
EPA***
FDA*
CPSC**
OSHA 1 (8 hr TWA)
U.S. Coast Guard
EPA
EPA
Other Action
Emergency temp, standard
Banned as propellant in pesticide aerosols
Banned as propellant in cosmetics and drug aerosols
Banned as propellent in all aerosols for household use
5 ppm max. for 15 min.
Amended carriage on tank vessels
Declared a hazardous pollutant (under Sec. 112, Clean
Air Act), and proposed fugitive emission standard
at the outlet not to exceed 10 ppm (ace. to BAT)
Clarified proposed emission standard for various indus-
trial processes including discharges in waste water.
* American Conference of Governmental Industrial Hygienists
** Occupational Safety and Health Administration
*** U.S. Environmental Protection Agency
Food and Drug Administration
Consumer Product Safety Commission
-------
tion (FDA), Consum. Prod. Safety Comm.] have begun to investigate
vinyl chloride inhalation exposures of humans in the general envi-
ronment. Because of reports that 41 pesticide spray products con-
tained vinyl chloride as a propellant, there was published (39 FR
14753) a notice of intent to cancel registrations of all such prod-
ucts. Other aerosol products such as hair spray, also found to
utilize vinyl chloride as a propellant, were banned from the market
in the U.S. and some other countries shortly thereafter (IARC,
1974). In 1975, the U.S. EPA declared vinyl chloride to be a haz-
ardous substance under Sec. 112 of the Clean Air Act. Further, it
promulgated in 1975 and 1976 emission standards of total emissions
with a limit of 10 ppm at the stack. Other government agencies have
published new control measures during this time, or have new stan-
dards under consideration, e.g., FDA concerning packaging of food
substances containing oil in PVC containers. Since 1975, when EPA
published its intent to issue new standards for total emissions at
the stack, the proposal has been litigated in court action initiat-
ed by the Environmental Defense Fund and questioned by industry.
In support of the proposed regulations, the U.S. EPA evaluated
the risk to populations living in the vicinity of vinyl chloride
and PVC plants in a document entitled "Quantitative Risk Assessment
for Community Exposure to Vinyl Chloride" by Kuzmack and McGaughy
in 1975. A number of factors influenced the estimate of risk to
this population, i.e., the number of persons living at distances up
to five miles from vinyl chloride and PVC plants (Table 17).
The total number of persons at risk was estimated at 4.6 mil-
lion. Using standard diffusion models, the annual average ambient
C-52
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TABLE 17
Estimate of Exposed Population in the Vicinity
of Vinyl Chloride and PVC Plants*
Distance (mi) Population
47,000
203,000
1,491,000
2,838,000
4,579,000
*Source: American Public Health
Association, 1975
C-53
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concentrations of vinyl chloride were calculated for distances 0-
0.5; 0.5-1.0; 1.0-3.0; and 3.0-5.0 miles from the plants (Table
18). The average exposure of a person chosen at random living in
the 5-mile radius was calculated to be 17 ppb.
Data published by Maltoni and Lefemine in 1975 which reported
liver hemangiosarcoma induction in rats due to vinyl chloride inha-
lation, were used for calculation of the probability of angiosarco-
ma cases in highly-exposed populations of workers. This prediction
was tested using epidemiological studies of workers and projecting
the results to ambient air concentrations of vinyl chloride in the
vicinity of the plants. Incidence rates of hemangiosarcoma in rats
were compared to incidence rates in exposed workers with the as-
sumption that a long-term exposure of rats would produce the same
incidence of effects as a long-term exposure of humans. In this
instance, the incidence rate following 1-year exposure of rats
would compare to the incidence rate of 30 years of human exposure.
Maltoni's rat liver angiosarcoma data (Rat Experiment BT-1)
were analyzed using a linear-dose response model to calculate the
probability of incidence of liver angiosarcoma in high level ex-
posed workers during each year of continuous exposure to vinyl
chloride. Such treatment of the data resulted in an estimate of 71
cases per year of uninterrupted exposure to 1 ppm of vinyl chloride
per million persons exposed. Using the same technique, the prob-
ability of cancer in all body organs was approximately doubled,
i.e., 150 cases per year of continuous exposure to 1 ppm of vinyl
chloride per million persons (Kuzmack and McGaughy, 1978).
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TABLE 18
Annual Average Concentrations (ppb) of Vinyl Chloride in
the Vicinity of a Vinyl Chloride and PVC Plant*
Vinyl Chloride Concentration (ppb)
Distance (mi) ~ ~~~ —
_' PVC Plant VC Plant
0-% 323 113
%-l 57 20
1-3 15 5.2
3-5 5.7 2.0
*Source: Kuzmack and McGaughy, 1975
C-55
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Four epidemiological studies in workers (Ott, et al. 1975;
Tabershaw and Gaffey, 1974; Nicholson, et al. 1975; Heath and Falk,
1975) were used to estimate the hemangiosarcoma incidence rate
based on human experience, and to compare the results with the
incidence rates derived from animal data. From the epidemiological
data the probability that a vinyl chloride worker would suffer from
angiosarcoma of the liver at some point in his life was calculated
to be 0.0031 per year of exposure. If the animal derived-data are
converted to a standard work exposure time (7 hrs, 5 days/wk, an
exposure to 350 ppm of vinyl chloride), the probability was calcu-
lated to be 0.0052. Since such estimates contain a number of
inherent errors, the authors concluded that "the slope of the
linear animal dose-response relationship for angiosarcomas is con-
sistent with human data."
The results of this analysis were used in estimating the risk
to the 4.6 million persons living in the vicinity of the vinyl
chloride and PVC plants employing the animal dose-response esti-
mates, which were applied to the 17 ppb of vinyl chloride (the
average estimated concentration in the 5-mile radius of the
plants). Both mathematical probability models were used. The
results are tabulated in Table 19.
Based on the linear model it was estimated that an incidence
of 5.5 cases of liver angiosarcoma per year can be expected in the
exposed population living in the vicinity of vinyl chloride and PVC
plants. The calculation using the log-probit model predicted an
incidence rate which is 10 to 100 times lower. The estimates for
all cancers were about twice as great in both cases. The uncer-
C-56
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TABLE 19
Estimated Incidence of Cancer in Populations Living
in the Vicinity of Vinyl Chloride-PVC Plants*
Cases per Year of Exposure
Type of Effect ModeT Log-Probit Model
All Cancer 11 0.1-1.0
Liver Angiosarcoma 5.5 0.05-0.5
*Source: Kuzmack and McGaughy, 1975
C-57
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tainties in extrapolation process to low doses are reflected in
this wide range of estimated effects.
The vinyl chloride-related cancer incidence probability cal-
culations by Kuzmack and McGaughy (1975) provide the best available
quantitative estimate of the risk resulting from vinyl chloride
inhalation exposure of a large segment of U.S. human population
living in the vicinity of vinyl chloride-polymerization and fabri-
cation plants. Recently published epidemiological studies indi-
rectly support their conclusions. Brady, et al. (1977) investigat-
ed the annual incidence rate for angiosarcoma of the liver among
residents of New York State (excluding New York City). The study
lends support to the hypothesis that direct exposure to vinyl chlo-
ride, arsenic, and thorium dioxide was a significant factor in the
etiology of this type of cancer (P = <0.02); and that it resulted
in its increased incidence by a factor of 2 over the expected annu-
al incidence for the U.S. (0.25 per million for New York State vs.
0.14 per million for the U.S.). The important finding in this
study was the diagnosis of five new cases of angiosarcoma of the
liver in persons living in the vicinity of vinyl chloride polymeri-
zation and fabrication plants for 8 to 62 years prior to diagnosis
of the disease.
The most recent report on this subject is a worldwide review
of all cases of liver angiosarcoma in workers published by Spirtas
and Kaminski in June, 1978. The conclusions concerning the work-
ers' age at diagnosis of the disease and the latency period, both
of which appear to be increasing in recent years, are most impor-
tant. Lloyd reported in 1975 that the median age at diagnosis was
C-58
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44 years and the latency period from first exposure to diagnosis
averaged 17 years. Spirtas and Kaminski (1978) reported 49 as the
median age at diagnosis and a latency period of 21 years. It is
probable that the initial cases may have had higher exposures of
vinyl chloride and that the recent cases are due to more moderate
exposures. It is also possible some variation is caused by statis-
tical uncertainty in the age and latency parameter.
Insufficient information is available on the exposure levels
and associated risk to man from vinyl chloride-contaminated water
supplies. Toxicologic or epidemiologic data are not available in
the current literature. However, from the available data, it is
thought that the hazard is small in comparison to the inhalation
route of exposure.
There are some published hard data available on the vinyl
chloride exposure levels of persons living in the vicinity of vinyl
chloride/PVC fabricating plants and on the amount of the vinyl
chloride monomer released in time from various plastic products.
In addition there are some initial data on vinyl chloride concen-
tration in food packaged in PVC containers. The food oils require
a special attention; toxicologic data support this evidence.
Recent epidemiologic reports indicate that the median latency
period for hemangiosarcoma occurrence in vinyl chloride-exposed
workers is shifting to the right; and suggest that the recently
diagnosed cases may have been due to lower exposures than the ini-
tial cases. This is an observation which, if confirmed, may have
important consequences regarding the estimation of future risk for
the population living in the vicinity of vinyl chloride/PVC plants,
in addition to the workers.
C-59
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Special Groups at Risk
Other than those that work in or live near vinyl chloride
plants, special risk groups have not been identified.
Basis and Derivation of Criterion
Vinyl chloride is a well-known human and animal carcinogen.
Several occupational epidemiology studies in highly exposed workers
have reported excess rates of liver angiosarcoma and tumors at
other organ sites. Animal experiments using both inhalation and
oral routes of exposure have shown induced liver angiosarcoma.
The recommended water quality criterion is calculated using
the tumor incidence data from chronic rat inhalation studies. The
validity of these incidence rates for humans was established by
evaluating the cancer incidence in workers after accounting for
their exposure.
Under the Consent Decree in NRDC v. Train, criteria are to
state "recommended maximum permissible concentrations (including
where appropriate, zero) consistent with the protection of aquatic
organisms, human health, and recreational activities." Vinyl chlo-
ride is suspected of being a human carcinogen. Because there is no
recognized safe concentration for a human carcinogen, the recom-
mended concentration of vinyl chloride in water for maximum protec-
tion of human health is zero.
Because attaining a zero concentration level may be infeasible
in some cases and in order to assist the Agency and states in the
possible future development of water quality regulations, the con-
centrations of vinyl chloride corresponding to several incremental
lifetime cancer risk levels have been estimated. A cancer risk
C-60
-------
level provides an estimate of the additional incidence of cancer
that may be expected in an exposed population. A risk of 10~5 for
example, indicates a probability of one additional case of cancer
for every 100,000 people exposed, a risk of 10~6 indicates one
additional case of cancer for every million people exposed, and so
forth.
In the Federal Register notice of availability of draft ambi-
ent water quality criteria, EPA stated that it is considering set-
ting criteria at an interim target risk level of 10~5, 10~6, or
10~ as shown in the following table.
Exposure Assumptions Risk Levels and Corresponding Criteria (1)
(per day)
10 ' 10"6 1Q"5
2 liters of drinking
water and consumption - ,, ,. _ n
of 6.5 g fish and °'2 ^/l 2.0 yg/1 20 ug/1
shellfish (2)
Consumption of fish __ ,. „
and shellfish only. 52'5 W/1 525 *g/l 5,246 ug/1
(1) Calculated by applying a linearized multistage model as dis-
cussed in the Human Health Methodology Appendices to the Octo-
ber 1980 Federal Register notice which announced the avail-
ability of this document to the animal bioassay data summa-
rized in the Appendix. Since the extrapolation model is
linear at low doses, the additional lifetime risk is directly
proportional to the water concentration. Therefore, water
concentrations corresponding to other risk levels can be
derived by multiplying or dividing one of the risk levels and
corresponding water concentrations shown in the table by fac-
tors such as 10, 100, 1,000, and so forth.
C-61
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(2) Zero point four percent of the vinyl chloride exposure results
from the consumption of aquatic organisms which exhibit an
average bioconcentration factor of 1.17-fold. The remaining
99.6 percent of vinyl chloride exposure results from drinking
water.
Concentration levels were derived assuming a lifetime exposure
to various amounts of vinyl chloride, (1) occurring from the con-
sumption of both drinking water and aquatic life grown in waters
containing the corresponding vinyl chloride concentrations and,
(2) occurring solely from consumption of aquatic life grown in the
waters containing the corresponding vinyl chloride concentrations.
Although total exposure information for vinyl chloride is dis-
cussed and an estimate of the contributions from other sources of
exposure can be made, this data will not be factored into ambient
water quality cirteria formulation until additional analysis can be
made. The criteria presented, therefore, assume an incremental
risk from ambient water exposure only.
C-62
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APPENDIX
Summary of Pertinent Data for Vinyl Chloride
The rat inhalation experiments of Maltoni and Lefemine (1975)
with vinyl chloride resulted in an incidence of total tumors as
given in the following table.
Vinyl Chloride
Concentration (ppm) Tumor Incidence
0 6/58
50 10/59
250 16/59
500 22/59
2,500 32/59
6,000 31/60
10,000 38/61
The slope parameter corresponding to this data is 4.05 x 10~4
(ppm) . All the other polynominal coefficients are zero. In the
process of fitting this data to the linearized multistage model the
highest two doses were not used.
Since the animals were exposed for four hours per day, five
days per week for 52 weeks and then held to two years for observa-
tion, the lifetime average concentration was 4/24 x 5/7 x 52/104 =
0.060 times the concentration administered. Therefore, based on
the animal slope parameter from inhalation, q^d), is:
q^I) = 4.05 x 10~4/0.06 = 6.80 x 10~3 (ppm)'1.
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The vinyl chloride uptake study by Withey and Collins (1976)
stated that for 200 gm rats the same blood concentration of vinyl
chloride is produced by either breathing 1.97 ppm or by ingesting
4.5 mg/kg/day by gavage. This relationship was true over a range
of gavage doses from 2 to 25 mg/kg. Although the linear relation-
ship between administered dose and the blood concentration did not
hold true for the 400 gm rats, the above data do at least give a
rough estimate of the relation between inhalation and ingestion.
Assuming this equivalence to be true, then 1 ppm inhaled
equals 2.28 mg/kg/day (i.e., 4.5/1.97). Therefore, the slope of
the dose-response curve for rats after oral gavage, q1(0), is esti-
mated by:
qi(0) = q1(I)/2.28,
= 6.8 x 10~3/2.28,
= 3.0 x 10~3 (mg/kg/day)'1.
The equivalent slope for humans after oral ingestion,, q1*^ is
estimated by:
70
0.350 '
= 1.74 x 10~2 (mg/kg/day)"1.
The water quality criterion for vinyl chloride is now a
straightforward calculation:
_ 70 x 10"5
""——
x (2 + 0.0065 x BCF)
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where 70 x 10" is the human cancer lifetime risk of interest, 2 and
0.0065 represent the daily water (in liters) and fish (in kg) con-
sumption, respectively, and BCF is the bioconcentration factor for
vinyl chloride. Therefore,
70 x 10'5
1.74 x 10~2 x (2 + 0.0065 x 1.17)
- 20 mg/1.
* U S GOVERNMENT PRINTING OFFICE 1980 720-016/5963
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