EPA/600/8-85/011F
August 1985
Summary Overview of Health Effects
Associated with Chloroprene:
Health Issue Assessment
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
RESEARCH TRIANGLE PARK, NC 27711
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DISCLAIMER
This document has been reviewed in accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for presentation and publication.
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CONTENTS
Page
List of Tables iv
I. Introduction 1
II. Air Quality 2
III. Health Effects 4
1. Systemic Toxicity in Humans 4
2. Systemic Toxicity in Animals 5
3. Carcinogenicity in Animals and Man 6
4. Mutagenicity and Cell Transformation 9
IV. Summary and Conclusions 11
V. References 13
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LIST OF TABLES
Page
1. Chloroprene Producers and Captive Users 3
2. Effects on Rats from Subchronic Inhalation Exposure to
Chloroprene 7
3. Studies of Mutagenic Potential of Chloroprene 10
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I. INTRODUCTION
The purpose of this paper is to summarize available information concerning
possible health effects associated with exposure to chloroprene. Emphasis has
been placed on reviewing the available information useful for determining
whether or not chloroprene affects human health at air concentrations which
might be encountered by the general public under ambient conditions. This
summary addresses the acute and chronic toxicity, reproductive effects,
mutagenicity, and carcinogenicity of chloroprene. Also discussed is back-
ground information on air quality aspects of chloroprene, including sources,
distribution, and fate.
Chloroprene, a monomer used in the manufacture of synthetic rubber, is a
volatile and highly reactive chemical, with an estimated residence time in the
atmosphere of 4.8 hours. Chloroprene affects the liver and the hematopoietic,
circulatory, immune, and nervous systems at high levels of acute exposure.
Limited epidemiological studies of rubber workers in the Soviet Union have
indicated a possible association between exposure to chloroprene and cancer
of skin and lung. However, limited epidemiological studies of U.S. workers have
not confirmed this association. There are needs for research in epidemiology,
chronic toxicity, and pharmacokinetics of chloroprene as well as for measure-
ment of chloroprene concentrations in the atmosphere.
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II. AIR QUALITY
Chloroprene (2-chloro-1,3-butadiene) is a flammable, volatile liquid with an
ether-like odor. It is soluble in alcohol, and from an industrial perspective
appears to be slightly soluble in water. Chloroprene is a highly reactive
electrophile and will autocatalytically combine with oxygen, polymerize
spontaneously at room temperature, and react with a wide variety of organic
and inorganic chemicals.
Chloroprene is currently produced in the United States by gas-phase
chlorination of butadiene to dichlorobutene, followed by distillation and
dehydrohalogenation with aqueous sodium hydroxide to Chloroprene. Facilities
for the commercial production of Chloroprene are located in the United States,
the Federal Republic of Germany, Northern Ireland, France, Japan, and the
U.S.S.R. No estimates are available of the number of persons exposed to
Chloroprene during its manufacture and use, however, 4.7 million people live
within 50 kilometers of Chloroprene facilities (Cote, 1985). In 1976, U.S.
production was reported to be 164 million kg (361 million Ib); in 1977, world
production was estimated to have been 300 million kg (660 million Ib)
(International Agency for Research on Cancer, 1979). A more recent report
(49FR 46938, November 29, 1984) places the annual world production of
Chloroprene at approximately 1.2 x 105 megagram (254 million Ib).
Table 1 lists the sites where Chloroprene is produced. DuPont also uses
Chloroprene transported from La Place, LA at a facility in Louisville, KY which
would be a source of air emissions.
Chloroprene's only known use is in the manufacture of polychloroprene
elastomers. Solid elastomer, also known as neoprene synthetic rubber, is used
in the automotive industry for tubing, belts, and gaskets, in the construction
industry, in the manufacture of wire and cable jackets, and consumer goods.
Liquid or latex elastomers are used in adhesives and as fabric coatings.
Chloroprene is manufactured by a continuous process in a closed system;
however, because such a system includes valves, piping, and reactor vessels,
the possibility for fugitive emissions exists. Also, venting of Chloroprene vapors
to the atmosphere may occur during cleaning and maintenance of the system.
Releases may occur during loading and unloading when Chloroprene is
transported to other sites for elastomer production, during transfer from
storage tanks by pipeline, or in the process of manufacturing neoprene.
Chloroprene is a highly volatile liquid (vapor pressure 181 mm Hg @ 20°C)
and therefore can be expected to volatilize quickly under normal environmental
conditions. Estimated values of the evaporative half-life of Chloroprene in
water under experimental conditions based on the method of Dilling (1977)
indicated a rapid evaporation of Chloroprene from water under natural
conditions.
Chloroprene's fate in the environment depends on chemical, degradative
processes as well as degradation or accumulation in biological systems. Cupitt
(1980) describes two chemical removal processes in air that affect organic
compounds, such as Chloroprene, that contain double bonds. The first is
reaction with ambient hydroxyl radicals which add across the double bonds of
Chloroprene to form compounds such as aldehydes, ketones, and dicarbpnyls.
Halogenated organics such as Chloroprene tend to lose halogen atoms in the
form of halo-oxy radicals.
The second chemical removal process is reaction with ozone (ozonolysis),
which results in the formation of a carbonyl (aldehyde or ketone) and a
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Table 1. Chloroprene Producers and Captive Users
Company
DuPont
DuPont
Denka
Conoco
Location
La Place. LA
Louisville, KY
Houston, TX
Houston, TX
1984
Capacity
(M Ib)
275
__
60
--
1984
Production
(M Ib)
240
48
1.7a
Total
335
289.7
Source: Serenbetz. 1985; Henkson, 1985
^Chloroprene produced as by-product.
percarbonyl biradical that may undergo further rearrangement to form, for
example, organic acids and carbon dioxide. Although the rate of the ozone
reaction is much lower than that of the hydroxyl reaction, the former may have
an equal influence on atmospheric levels because the levels of ozone are much
greater than that of the hydroxyl radical. According to Cupitt (1980) the
calculated atmospheric residence time for chloroprene, defined as the time
required for the concentration to be reduced to 1 /e (approximately 37%) of its
initial value, is O.2 days (4.8 hrs). Physical processes are unlikely to have
significant roles in the removal of chloroprene from the atmosphere.
No published reports were found in which levels of chloroprene in the
environment were determined. There are limited data from industrial hygiene
monitoring of the workplace, indicating that the occurrence of chloroprene in
the atmosphere near manufacturing and processing facilities is a possibility,
but quantification of these atmospheric emissions is lacking. Detectable
chloroprene concentrations are only likely in the ambient air in proximity to
emission sources involved in high volume production or use of the chemical.
Measurements made in Deer Park, TX by Pellizzari et al. (1979) ranged from
266-4000 ng/m3.
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III. HEALTH EFFECTS
No studies were found on the absorption or distribution of chloroprene
following inhalation, oral, or dermal exposure. From the observation of toxic
effects in humans and animals after acute exposure via these routes, it can be
inferred that absorption can occur from the lungs, gastrointestinal tract, and
skin. An approximation of chloroprene's systemic distribution can be made by
considering the organs showing injury after acute or subchronic exposure.
Organs affected include the liver, lungs, spleen, central nervous system,
kidneys, epicardium, testes, and bone marrow. Based on several in vivo and in
vitro studies and its structural similarity to vinyl chloride, the metabolism of
chloroprene is likely to involve the hepatic mixed-function oxidase system and
the production of epoxide intermediates (Agadzhanov et al., 1973; Shukuryan,
1967; Bartsch, 1977; Bartsch et al., 1979). Detoxification involves glutathione
and results in the excretion of conjugates in the urine (Summer and Greim,
1980).
1. Systemic Toxicity In Humans
Reported symptoms due to acute human exposure to high concentrations of
chloroprene include headache, irritability, dizziness, insomnia, fatigue,
respiratory irritation, cardiac palpitations, chest pains, gastrointestinal dis-
orders, dermatitis, temporary hair loss, conjunctivitis, and corneal necrosis
(International Agency for Research on Cancer, 1979). Toxic effects in humans
from acute high-level chloroprene exposures have been reported for the liver,
circulatory system, hematopoeitic, central and peripheral nervous systems,
immune system, reproductive system, and the periodontium. Chloroprene has
also been reported to cause chromosomal aberrations in humans, and
exposure of workers has been linked in some studies to an increased incidence
of skin and lung cancer. Levels of exposure causing symptoms and clinical
signs have not generally been well defined, and there are conflicting reports
concerning many of the clinical and epidemiological findings (International
Agency for Research on Cancer, 1979).
Exposure of human subjects to chloroprene vapors at— 3500 mg/m causes
giddiness and nausea in less than 15 minutes (Nystrom, 1948). The odor
threshold is ~ 500 mg/m3.
Symptoms of chronic exposure (to 200 to 1230 mg/m3) in rubber workers
were fatigue, pressure and pain in the chest, giddiness, and irritability.
Dermatitis and hair loss were observed in some cases. Symptoms usually
appeared about one month after initial exposure to these high levels of
chloroprene and were less severe after a weekend without exposure. EKGs
showed no abnormalities (Nystrom, 1948).
A biochemical and hematological evaluation of workers exposed to
chloroprene (Gooch and Hawn, 1981) showed no significant statistical
differences in any of the parameters measured, compared with controls.
However, Ward et al. (1981) suggested that exposure to chloroprene vapor
associated with neoprene production may contribute to liver function
abnormalities.
Soviet scientists (Sanotskii, 1980; Volkova et al., 1976) reported adverse
effects on reproduction (functional disturbances in spermatogenesis and
increased spontaneous abortions in wives of exposed workers) in workers
exposed to chloroprene. However, insufficient details are available in the
reports to adequately evaluate the results.
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The Sanotskii (1 980) study presents interpretational difficulties concerning
the level of participation of the exposed workers and their wives, the
quantitative interpretation of the reported sperm abnormalities, and the
appropriate matching of exposed and control populations. As embryos with
chromosome abnormalities are spontaneously aborted very early in pregnancy,
the chances that a retrospective questionnaire such as that used in this study
would have discovered a real increase in the rate of spontaneous abortion are
remote. In addition to the problem of recall bias, nearly three-quarters of these
chromosomally abnormal embryos are expelled at the time of the normally
expected menses. This minimizes any woman's ability to document embryonic
loss. It has been reported that only 15-20% of the abortions that occur during
pregnancy can be documented by recall under the best of circumstances. Also.
it is strongly suggested that most abortions occur (in excess of 60%) at the time
of first-expected menses. Reporting bias during this early gestational period is
especially damaging to any meaningful interpretation of this report. Thus it is
not reasonable to draw conclusions on the possible effect of chloroprene on
early fetal losses from the use of the method in this report. Also, the very low
rate of reported miscarriages for both exposed individuals (9.3%) and controls
(5.4%) suggests that marked underreporting took place.
In addition, in view of the large number of males available for sperm analysis.
the 9.5% participation (15/143) indicates that a considerable degree of
selection bias may have been present. Males with reproductive problems may
have self-selected themselves to the detriment of meaningful interpretation.
Had a representative or larger sample been enlisted, a different picture might
have emerged. For the above reasons, it is not possible to interpret this study
with any degree of reliability.
2. Systemic Toxicity In Animals
Since chloroprene exposure occurs primarily via inhalation, most of the
reported animal studies on chloroprene have used this route of exposure. Few
such studies have been reported from the U.S.; most have been performed in
the USSR, and several have been performed in the Scandinavian countries.
The Soviet animal toxicology studies explored male and female reproductive
impacts of chloroprene in the ppm or mg/m3 range (1ppm = 3.6 mg/m3 at
25@C and 760 mm Hg). The Soviet literature on studies of chronic chloroprene
exposure in male rats reports a decreased number of spermatogonia and a
decline in sperm motility, as well as an increased number of dead sperm, at
exposure levels as low as 0.15 mg/m3 (0.04 ppm). Female rats exposed via
inhalation to chloroprene were reported to have increased embryonal mortality,
with decreased birth weights of pups at levels of exposure of approximately 3
mg/m (approximately 1 ppm). Continuous exposures throughout gestation at
levels as low as 0.13 mg/m3 (~ 0.04 ppm) also were reported to show a
significant elevation in embryonal mortality, with a "no observed effect level"
(NOEL) of 0.056 mg/m3 (0.015 ppm). Except for male reproductive effects at
approximately 0.01 ppm, the Soviet literature emphasizes a NOEL of slightly
belowO.1 ppm (0.6 ppm is the 1977 USSR recommendation forthreshold limit
value).
In contrast to the USSR studies, a U.S. study (Culik et al., 1978), where
careful attention has been paid to the purity of the chloroprene, maternal
toxicity and fetotoxicity have been reported only at levels of 25 ppm or above.
The Soviet literature has only limited descriptions of the procedures used to
produce and characterize the chloroprene exposure atmospheres, but repro-
ductive effects were consistently reported in the range of 1 -10 ppm. However,
the problem of contaminant by-product effects needs to be evaluated. The
complex effects of chloroprene and its by-products on reproduction are
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important, and, depending upon synthetic and exposure conditions, may vary.
Thus, the actual exposure atmosphere used in the studies becomes critical in
any evaluation of the USSR studies.
Animal toxicity studies with chloroprene indicate that high-level exposures
by inhalation, gavage, or subcutaneous injection affect the liver, lungs,
kidneys, and central nervous system (CNS). The effects include vascular
congestion in most organs examined; hepatic centrilobular necrosis, degener-
ation, and repair; degeneration of the renal tubular epithelium; lung edema;
CNS depression; and ultimately death. Oxidized chloroprene was more toxic
than the unoxidized test material in several species (Nystrom, 1948), and
fasted rats were more sensitive to the toxic effect of chloroprene than were fed
rats (Aznauryan et al., 1981).
Table 2 summarizes the information on the effects caused by inhalation of
chloroprene vapor by rats and the doses at which they occurred. Two studies
showed toxic effects at low exposure concentrations (Salnikova and Fomenko,
1973; Davtyan, 1972). In the study by Aznauryan et al. (1981) a group of
animals given a high-protein diet plus amino acid supplementation did not
show the effects of chloroprene exposure as did those animals on a normal diet
and at the same exposure level.
Two studies (Fichidzhyan and Zil'fyan, 1 976; Agakhanyan, 1982) reported
that chloroprene exposure by subcutaneous injection was associated with
reduced antibody production and suppression of the transplantation rejection
reaction in rats; also, germinal centers of the spleen and lymph nodes showed
hypoplasia and atrophy.
Based on the available information, the liver appears to be the primary target
organ of chloroprene toxicity in animals, following high levels of exposure
regardless of the route of exposure. Glutathione conjugation appears to be a
major detoxification pathway (Clary et al., 1978). However, there is some
indication of a more subtle systemic toxicity in that both immunocompetence
and behavioral changes, such as extinction of conditioned reflexes, were
" affected by chloroprene exposure.
Liver regeneration and repair were reported during the longer term inhalation
studies (4 to 6 months) of chloroprene. Chronic (- - 2 yr) inhalation studies of
well characterized chloroprene atmospheres are needed to adequately address
the systemic toxicity of chloroprene.
3. Carcinogenicity In Animals and Man
The evaluation of carcinogenicity of chemicals such as chloroprene depends
heavily on animal bioassays and any available epidemiologic evidence.
However, other factors, including mutagenicity, metabolism (particularly in
relation to interaction with DNA), and pharmacokinetic behavior, have an
important bearing on both the qualitative and quantitative assessment of
carcinogenicity.
Zil'fyan and Fichidzhyan (1 972) studied the effect of chloroprene in 60 white
mixed-breed mice, each weighing about 18-20 g. Thirty mice were sub-
cutaneously injected with 0.1 mg peach oil per 1 g body weight, and the other
30 mice were injected with peach oil and a Crocker murine sarcoma tumor
suspension. Increased tumor growth (2 times in diameter and 4 to 5 times in
weight) was found after chloroprene administration into mice before and after
transplantation of the Crocker murine sarcoma. The report suggests that this
effect of chloroprene was related to an immunodepressant activity of the
chloroprene.
Three series of skin application studies were conducted by Zil'fyan et al.
(1977). In these studies, three groups of random-bred mice received dermal
application of 50% chloroprene in benzene twice weekly for 25 weeks, 0.1 %
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Table 2. Effects on Rats from Subchronic Inhalation Exposure to
Chloroprene
Exposure Level
Duration
Effect
171 mg/m3
100 mg/m3
44 mg/m3
30 mg/m3
30 mg/m3
11 mg/m3
3 mg/m3
<2 mg/m3
1 mg/m3
6 hr/day/5 days/wk
for 4 wks
4 hr/day for 5 mo
6 hr/day, 5 days/wk
for 4 wks
5 hr/day for 7 mo
5 hr/day, 6 days/wk
for 6 mo
6 hr/day, 5 days/wk
for 4 wks
Dams exposed during
gestation
4 hr/day for 5.5 mo
5 hr/day, 6 days/wk
for 6 mo
Increased mortality, changes
in relative weight of kidney,
liver, and lungs. (Clary
eta/., 1978).
Fatty degeneration of liver,
effects on renal tubules and
glomeruli, and on myocardium
(Aznauryan et a/., 1981).
Eye irritation, restlessness,
nasal discharge, hair loss.
Increased mortality, growth
retardation, and liver damage.
Lung hemorrhages and edema
in animals that died. (Clary et
a/., 1978).
Extinction of conditioned re-
flexes (Airapetyan and Mate-
vosyan, 1973).
Irreversible changes in
histopathology of adrenal
gland and anterior pituitary
(Markaryan and Shakhlamov,
1975a, 1975b).
Skin and eye irritation and
weight loss in rats and ham-
sters. (Clary et a/., 1978).
Decrease in spontaneous
motor activity in 2-mo.-old
progeny (Salnikova and
Fomenko, 1973).
CNS depression, decrease in
Oz demand and liver function
(male rats) (Davtyan, 1972).
Reversible changes in adrenal
cortex (Markaryan and
Shakhlamov, 1975
9,10-dimethyl-1,2-benzanthracene (DMBA) in benzene twice weekly for 25
weeks, or 50% chloroprene solution in benzene twice weekly for 25 weeks
followed by five skin treatments with 0.01% DMBA in benzene. Of 100 mice
treated with 50% chloroprene, 58 survived 6 months, and 37 survivors were
killed at 18 months. In the eighty mice'that were painted with 0.1% DMBA
alone, skin carcinomas appeared in 55 of 60 animals alive. Times to tumor
formation were not reported. Forty-two of 80 mice treated with chloroprene
and 0.01% DMBA survived for 6 months. No skin or other tumors were
reported. Because of a lack of experimental detail in this study, a conclusive
evaluation of the results is not possible.
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In a study by Zil'fyan et al. (1975), 100 random-bred albino rats were dosed by
gavage twice weekly with chloroprene at 200 mg/kg in sunflower oil for 25
weeks. Forty rats survived for 2 years. No tumors were observed. However,
chloroprene was reported to be carcinogenic when administered intratracheal-
ly-at 200 mg/kg to 100 random-bred albino rats at 20-day intervals until the
animals had received five treatments, with an observation period of 14 months.
It is difficult to draw definite conclusions from this study because the
experiment was of insufficient duration and was not reported in adequate
detail {International Agency for Research on Cancer, 1979).
At the end of 2 years, no local sarcomas were observed in 100 random-bred
albino rats given 10 subcutaneous injections of 400 mg chloroprene/kg and in
100 rats given 50 subcutaneous injections of 200 mg/kg of chloroprene in
sunflower oil (Zil'fyan et al., 1977). Eighty-eight rats survived in the former
group and 46 in the latter group for 6 months or more. Among 60 rats injected
with single doses of DMBA at 0.5 mg/animal, 50 survived to the appearance of
first tumor (3.5 months), and 32 (64%) of these 50 animals developed local
sarcomas. Sixty rats received single injections of 0.5 mg DMBA into the left
flank and 50 subcutaneous injections of chloroprene at 200 mg/kg into the
right flank. Local sarcomas (site not specified) were observed in 24 of these
rats.
Ponomarkov and Tomatis (1980) studied the carcinogenicity of chloroprene.
In this experiment, chloroprene (100 mg/kg body weight) dissolved in olive oil
was administered in single oral doses to female DBIV rats on the 17th day of
pregnancy, and their progeny (89 males and 90 females) received weekly doses
of 50 mg/kg 0.3 mL olive oil. Fourteen control female DBIV rats received 0.3 ml
olive oil on the 17th day of pregnancy, and their progeny (53 males and 53
females) were given 0.3 mL olive oil weekly for life, beginning at weaning. All
survivors were killed at 120 weeks or when moribund. All animals were
autopsied and internal organs were examined histologically. In chloroprene-
treated male rats, several tumor types were observed that were not seen in
controls. Although subcutaneous fibromas were more numerous in chloro-
prene-treated males than in controls, the total incidence of tumors was similar
in chloroprene-treated and control rats. The authors concluded that the use of
other species and, possibly, administration by inhalation, would be necessary
before the carcinogenicity of chloroprene could be fully assessed.
Menezes et al. (1979) used an established cell line (ICP) derived from the
hamster lung for the purpose of detecting the possible transforming capability
of chloroprene in vitro. After 17 generations in culture, the cells were treated
with chloroprene (purity 99%, contained 0.8% of chloro-1 -butadiene) at
concentrations of 1,10, and 100 mg/ml for 42 days. The treated and untreated
cells were transplanted subcutaneously into newly born hamsters or, using the
intraocular tract, into adult hamsters. The cells not treated with chloroprene
did not produce any tumors after transplantation. Those treated with 1 mg/mL
of chloroprene produced tumors at 14 weeks after transplantation. Treatment
with higher concentrations (10 and 100 mg/mL) did not accelerate the
transformation process. Untreated cells did not produce any tumors even with
transplantation of 1 x 106 cells. The cells treated with chloroprene (1 to 100
mg/mL) produced tu mors with transplantation of as low as 1 x 10" cells. These
tumors were fibrosarcomas, and some of them showed a very high degree of
malignancy. The cells treated with the lowest concentration (1 mg/mL) had the
strongest transformation characteristics. The author concluded that as
chloroprene is mutagenic, the results obtained in these in vitro transformation
studies were not surprising.
Only limited epidemiological studies from chloroprene-exposed workers are
available. Five reports of epidemiologic studies have been reported, but these
are based on data obtained from only three populations. In one population
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(Yerevan, USSR), cancer morbidity was studied (Khachatryan, 1972a, 1972b).
In the other two populations (both Du Pont plants in the United States), only
mortality data were collected (Pell, 1978, 1980; Leet and Selevan, 1982).
Analyses of lung cancer and skin cancer occurrence in an industrial region of
the USSR (Yerevan) suggest an increased risk of each of these cancers among
persons working with chloroprene or its derivatives (Khachatryan, 1972a,
1972b). However, the lack of information on potentially important confounding
variables, as well as the brevity and lack of clarity in the description of the study
design, make the evaluation of the results very difficult and subject to error.
More rigorous epidemiologic exploration of this large data set might prove
highly productive and should be encouraged.
Analyses of two cohorts of DuPont workers exposed to chloroprene at the
Chambers and Louisville Works (Pell, 1978, 1980; Leet and Selevan, 1982)
also provided suggestive evidence of a slightly increased risk of lung cancer
death. While this finding is consistent with that of Khachatryan, drawbacks in
both study designs preclude definitive conclusions. As recommended by the
NIOSH report on chloroprene (Leet and Selevan, 1982), the Louisville Works
data set should be expanded to include men who terminated before the present
study's enrollment date of 1957. This action would not only increase the
sample size but would also remove a potentially major bias in the death rates.
That bias may be obscuring a greater excess of lung cancer deaths among
workers exposed to chloroprene than is currently evident in the reports that
have been prepared to date.
In summary, the evidence for human carcinogenicity of chloroprene must be
classified as either very limited or inadequate at the present time.
4. Mutagenicity and Cell Transformation
The mutagenic potential of chloroprene was assessed from an evaluation of
10 studies (Table 3): one host-mediated, two in vitro, four whole animal, and
three human cytogenetic (workplace exposure). The majority of these studies
yielded positive results in the presence of metabolic activation, indicating that
chloroprene is a promutagen—i.e., chloroprene requires metabolic activation
to exhibit a positive mutagenic response. The low level of mutagenicity
observed in the Salmonella histidine reversion assay in the absence of an
exogenous S9 activation system may have been due to bacterial metabolism of
chloroprene. The potentially mutagenic metabolites are probably generated by
epoxidation of a double bond. (Bartsch et al., 1979).
Chloroprene was determined to be mutagenic in the sex-linked recessive
lethal test in Drosophila (Vogel, 1976, 1979). Thus chloroprene caused
heritable effects in the fruit fly. Additional information, particularly from well-
designed studies in mammals, is necessary before any conclusions can be
made regarding the potential of chloroprene to cause heritable effects in man.
Chloroprene has also been found to cause chromosomal aberrations in
cultured lymphocytes of humans exposed in the workplace (Katosova, 1972).
Suggestive evidence for chromosomal effects was also found in bone marrow
cells of mice exposed in vivo (Sanotskii, 1976). In addition, chloroprene was
reported to be positive in the dominant lethal test in rats and mice (Sanotskii,
1976). These results suggest that chloroprene is a clastogen.
In summary, the weight of the available evidence suggests that chloroprene
is a mutagen and a clastogen and transforms cells in vitro. Positive results were
obtained (see Table 3) in bacteria, Drosophila, mice, rats, and humans
(chromosome aberration studies). Negative results were reported for mam-
malian cells in culture, but chloroprene transformed hamster cells in vitro as
indicated by tumors following transplantation of the cells (Menezes et al.,
1979).
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IV. SUMMARY AND CONCLUSIONS
The potential for the release of chloroprene to the environment exists during
its manufacture, transport, and storage, and during the manufacture of
polychloroprene elastomers and polychloroprene-containing products. Little
information is currently available regarding levels of chloroprene in the
environment resulting from any of these processes.
The ultimate environmental fate of chloroprene depends on its release,
transport, and persistence. Chloroprene is not expected to persist in the
environment or bioaccumulate due to its high reactivity. If released into the
atmosphere, its estimated half-life is measured in hours. If released at the
soil/air or water/air interface, chloroprene's volatility indicates that it will
partition into the air. Due to its relatively low soil sorption and substantial water
solubility (from an environmental perspective), release of chloroprene at the
soil/water interface is likely to result in its partitioning into aqueous
compartments. Reactivity with soil constituents is another possibility.
In occupationally exposed workers, chloroprene has been reported to cause
respiratory, skin, and eye irritation, temporary hair loss, dizziness, insomnia,
headache, and fatigue. Clinical signs of toxicity have been reported for liver,
circulatory system, hematopoietic, central and peripheral nervous systems,
immune system, reproductive system, and periodontium. Studies in animals
have indicated that exposure to high levels of chloroprene by inhalation,
gavage, or subcutaneous injection adversely affects the liver, lungs, kidneys,
and central nervous system. The effects included vascular congestion, hepatic
centrilobular necrosis and degeneration of the renal tubular epithelium, edema
of the lungs, CNS depression, and mortality. The results of two studies have
indicated that chloroprene suppresses immune system function; another study
reported histopathologic effects in the adrenal gland and anterior pituitary after
6 months of inhalation exposure to chloroprene. Insufficient, data were
available to identify levels at which subchronic or chronic exposures would
produce no systemic toxicity. The data for subchronic exposures are limited.
Several cytogenetic studies of chromosomal aberrations in occupationally
exposed men and women in the U.S.S.R. have indicated that chloroprene may
be mutagenic. There is evidence from in vivo and in vitro tests that
chloroprene is mutagenic and clastogenic. Positive results have been found in
bacteria, Drosophila, mice, and rats. Chloroprene also showed malignant
transformation in vitro with an established normal hamster lung cell line.
An epidemiologic study conducted in the U.S.S.R. has provided evidence
suggesting that chloroprene is related to increased incidences of lung and skin
cancer. Results from more recent studies of U.S. chloroprene workers,
provided some evidence of a slightly increased lung cancer risk. While the
findings of the American studies are similar to the Soviet studies with regard to
lung cancer risk, serious limitations in all of the cancer epidemiologic studies
preclude any definite conclusions.
Tumorigenic effects of chloroprene have been studied in mice following skin
application and in rats by oral, subcutaneous, and intratracheal administration.
No (or inconclusive) tumorigenic effects were found. However, the compound
was reported to increase the rate of tumor growth of transplanted tumor cells
possibly due to immunosuppression. None of these studies is adequate for
evaluating the carcinogenicity of chloroprene in experimental animals, as they
lacked adequate durations of exposure; the experimental details reported were
not adequate. According to the criteria of the International Agency for
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Research on Cancer (IARC), the weight of both human and animal evidence for
the carcinogenicity of chloroprene should be categorized as very limited or
inadequate at the presenttime. The overall evaluation of chloroprene, based on
IARC criteria, places it in Group 3, meaning that the chemical cannot be
classified as to its carcinogenicity for humans.
However, it should be noted that 1,3-butadiene, a non-chlorinated analog of
chloroprene, has been shown to be carcinogenic in mice and rats. This
structure-activity relationship and the mutagenic and cell-transforming
capability of chloroprene suggests that chloroprene could be carcinogenic and
should, therefore, be tested further.
No data exist which can be used for the quantitative estimation of the
potential human health effects, including carcinogenicity, of chloroprene.
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