Mono97 8

VINYL CHLORIDE
This substance was considered by previous IARC Working Groups in June 1974
(IARC, 1974), February 1978 (IARC, 1979) and March 1987 (IARC, 1987). Since that
time new data have become available, and these have been incorporated into the
monograph and taken into account in the present evaluation.
1. Exposure Data
1.1 Chemical and physical data

From IARC (1999), WHO (1999), IPCS-CEC (2000), Lide (2005), ATSDR (2006),
Cowfer and Gorensek (2006) and O’Neil (2006), unless otherwise specified
1.1.1 Nomenclature
Chem. Abstr. Services Reg. No.: 75-01-4
Chem. Abstr. Name: Chloroethene; chloroethylene; monochloroethylene; VC; VCM;
vinyl C monomer
RTECS No.: KU9625000
UN TDG No.: 1086 (stabilized)
EC Index No.: 602-023-00-7
EINECS No.: 200-831-0
1.1.2 Structural and molecular formulae and relative molecular mass
H Cl
C C
H H
C2H3C1 Relative molecular mass: 62.5
–311–
312 IARC MONOGRAPHS VOLUME 97
1.1.3 Chemical and physical properties of the pure substance

(a) Description: Colourless gas
(b) Boiling-point: –13 °C
(c) Melting-point: –154 °C
(d) Relative density: d240 0.9106 (as liquid)
(e) Relative vapour density: 2.2 (air = 1)
(f) Refractive index: nD20 1.3700
(g) Spectroscopy data: Infrared, nuclear magnetic resonance and mass spectral data
have been tabulated (Grasselli & Ritchey, 1975).
(h) Solubility: Slightly soluble in water (1.1 g/L at 25 °C); soluble in ethanol; very
soluble in ether, carbon tetrachloride and benzene
(i) Volatility: Vapour pressure, 2530 mm Hg at 20 °C
(j) Flash-point: –78 °C (closed cup)
(k) Stability: The substance can, under specific circumstances, form peroxides and
initiate explosive polymerization. The substance decomposes on burning to
produce toxic and corrosive fumes (hydrogen chloride, phosgene).
(l) Octanol/water partition coefficient: log Pow, 0.6
(m) Auto ignition temperature: 472 °C
(n) Explosion limit in air: 3.6–33%
(o) Henry’s law constant: 18.8 at 20 °C
(p) Conversion factor: mg/m3 = 2.6 × ppm1
1.1.4 Technical products and impurities

Vinyl chloride is generally supplied as a compressed liquefied gas.
1.1.5 Analysis
Several reviews of methods of sampling and analysis of vinyl chloride in the work-
place atmosphere, ambient air, water, water piping, food and cigarette smoke, and of
polyvinyl chloride (PVC) are available (Environmental Protection Agency, 1975;
Laramy, 1977; Egan et al., 1978).
Several methods for the analysis of vinyl chloride in ambient air have been devel-
oped. The Environmental Protection Agency method TO-1 analyses volatile organic com-
pounds in ambient air using Tenax® and detection by gas chromatography (GS)–mass
spectrometry (MS); method TO-14 analyses volatile organic compounds in ambient air
using canister sampling followed by high-resolution GC (Environmental Protection
Agency, 1999).
1
Calculated from: mg/m3 = (relative molecular mass/24.45) × ppm, assuming normal temperature (25 °C) and
pressure (101.3 kPa)
VINYL CHLORIDE 313
A GC analytical method has been used since 1978 to determine vinyl chloride con-
centrations in foodstuffs and in vinyl chloride polymers and copolymers that are intended
to come into contact with food (Directive 78-142-EEC; European Commission, 1978).
The Department of Labor (1989) of the USA published the Occupational Safety and
Health Administration method 75 that detects vinyl chloride in air with a reliable quan-
titation limit of 0.020 ppm [0.051 mg/m3]. More recently, Charvet et al. (2000) proposed
the use of a solid-phase microextraction/GS/MS to analyse vinyl chloride in materials and
aqueous samples.
1.2 Production and use

1.2.1 Production
The most common method for the production of vinyl chloride monomer (VCM) is
by thermal cracking of ethylene dichloride (1,2-dichloroethane). Over 95% of the VCM
produced worldwide in 2006 was made by this method. A less common method is by
hydrochlorination of acetylene (WHO, 1999; Cowfer & Gorensek, 2006).
In the ethylene-based process, ethylene dichloride is synthesized by the reaction of
elemental chlorine with ethylene over a catalyst. The crude ethylene dichloride is washed,
dried and purified. Pure, dry ethylene dichloride is thermally cracked to produce VCM
and hydrogen chloride. Hydrogen chloride recovered from the cracking of ethylene di-
chloride is recycled in the process via reaction with oxygen and ethylene over a copper
catalyst to make more ethylene dichloride. This process is known as oxychlorination.
VCM is purified by distillation, and side-products can be recovered for the manufacture
of chlorinated solvents, or combusted or catalytically oxidized usually with recovery of
hydrogen chloride (WHO, 1999; Cowfer & Gorensek, 2006).
VCM was initially produced commercially by the acetylene-based process, in which
acetylene (usually produced by the reaction of water with calcium carbide) is reacted with
hydrogen chloride over a mercury-based catalyst. VCM is again purified by distillation
(WHO, 1999; Cowfer & Gorensek, 2006). Acetylene-based plants continue to operate
solely in China. In 2001, the chemical corporation Borden stopped production at its
acetylene plant in Louisiana, USA (Borruso, 2006).
The ethylene dichloride/VCM/PVC production chain represents the largest single
consumer of chlorine (European Commission, 2003).
Vinyl chloride has been produced commercially in the USA for over 70 years (Tariff
Commission, 1928). In 1988, the production of vinyl chloride in the USA was 9.1 billion
pounds [4.1 million tonnes] and increased to around 13.75 billion pounds [6.2 million
tonnes] in 1993 (ACGIH Worldwide, 2005). In Taiwan, China, production has increased
from 12 000 tonnes in 1971 (Luo et al., 1999) to 1.7 million tonnes in 2005 (Borruso,
2006).
In 1999, worldwide production capacity was around 30 million tonnes (SIDS, 2001).
Worldwide production capacity of VCM in 2005 was 35 million tonnes (Dow Chemical
Company, 2007). Table 1 gives production levels in various countries and regions
(Borruso, 2006).
Table 1. World production capacity for vinyl chloride monomer in 2005
Region/country Capacity (thousands of tonnes)
North America
USA/Canada 8 934
Mexico 270
South America
Brazil 635
Other 410
Western Europe 6 650
Central and eastern Europe 2 195
Africa and the Middle East 1 557
Asia
Japan 3 050
China 3 443
China, Province of Taiwan 1 710
Korea, Republic of 1 466
Other Asiaa 2 304
Oceania 0
Total 32 624
From Borruso (2006)

a
Includes India, Indonesia, Korea (People’s Democratic Republic of), Malaysia and Thailand
1.2.2 Use
Vinyl chloride is used primarily (> 95%) in the manufacture of PVCs, which
comprise about 12% of plastic usage (WHO, 1999). The largest use of PVC resins is in
the production of plastic piping. Other important uses are in floor coverings, consumer
goods, electrical applications and transport applications. About 1% of PVC capacity is
used to produce vinyl chloride/vinyl acetate copolymer. Other minor uses of VCM
include the manufacture of chlorinated solvents (primarily 10 000 tonnes per year of
1,1,1-trichloroethane) and ethylene diamine production for the manufacture of resins
(WHO, 1999; European Commission, 2003).
Vinyl chloride has been used in the past as a refrigerant, as an extraction solvent for
heat-sensitive materials, in the production of chloroacetaldehyde, as an aerosol propellant
and in drug and cosmetic products; these uses were banned in the USA by the Environ-
mental Protection Agency in 1974 (ATSDR, 2006).
VINYL CHLORIDE 315
1.3 Occurrence
1.3.1 Natural occurrence

Vinyl chloride is not known to occur naturally.
1.3.2 Occupational exposure

According to the 1990–93 CAREX database for 15 countries of the European Union
(Kauppinen et al., 2000) and the 1981–83 National Occupational Exposure Survey in the
USA (NOES, 1997), approximately 40 000 workers in Europe and 80 000 workers in the
USA were potentially exposed to vinyl chloride (see General Remarks).
The major categories of industries that entail exposure to VCM in Europe comprise
the manufacture of industrial chemicals (10 400 persons), plastic products (9100 persons)
and other chemical products (7600) (Kauppinen et al., 2000). In the USA, the major cate-
gories of industries were the production of chemicals and allied products (15 400),
business services (10 000) and the production of rubber and miscellaneous plastic
products (9600) (NOES, 1997).
The Finnish Register of occupational exposure to carcinogens reported that 90
workers were notified as being exposed to vinyl chloride in 2004. This is below 0.01% of
the 2.4 million people employed in Finland. Most of the exposed were employed in the
chemical industry. The register is based on annual notifications of employers and its
completeness is unknown (Saalo et al., 2006).
In Taiwan, China, where production has increased dramatically in recent decades,
thousands of workers could be exposed to VCM (Luo et al., 1999).
The main route of occupational exposure is by inhalation, which occurs primarily in
vinyl chloride/PVC plants and in PVC processing plants. Few measured exposure data
have been reported but estimates from the chemical industry indicate that exposure to
VCM amounted to several thousands of milligrams per cubic metre in the 1940s and
1950s, and were several hundreds of milligrams per cubic metre in the 1960s and early
1970s. After its recognition as a carcinogen, occupational exposure standards were set at
approximately 13–26 mg/m3 [5–10 ppm] in most countries in the 1970s (Fleig & Thiess,
1974; WHO, 1999).
A report from the Centers for Disease Control and Prevention (CDC) in the USA
concluded that the development and acceptance by the PVC industry of a closed-loop
polymerization process in the late 1970s “almost completely eliminated worker expo-
sures” and that “new cases of hepatic angiosarcoma in vinyl chloride polymerization
workers have been virtually eliminated” (CDC, 1997; see also Section 1.4). Even after the
late 1970s, however, high concentrations were reported and may still be encountered in
some countries (see Table 2).
316
Table 2. Levels of vinyl chloride reported in workplace air samples in vinyl chloride/polyvinyl chloride (PVC)
production plants
Reference Year of study Country Workplace Concentration (mg/m3)
Filatova & Gronsberg (1957) NR Former USSR PVC producing plant 50–800 (occasionally 87 300)
Anghelescu et al. (1969) 1965–67 Romania PVC production plant 112–554
Baretta et al. (1969) NR USA PVC plant ≤ 650 (weekly TWA)
IARC MONOGRAPHS VOLUME 97

Fleig & Theiss (1974) 1974 Germany PVC production department < 65–81
Ott et al. (1975) 1950–59 USA PVC plant ≤ 10 400; 13–2140 (8-h TWA)
1960–63 ≤ 1300; 13–620 (8-h TWA)
Rowe (1975) 1973 USA Vinyl chloride/PVC plants ≤ 390 (TWA); peaks 2600–10 400
Barnes (1976) ‘Early days’ United Kingdom PVC production plant (full- 7800
time autoclave cleaner)
Orusev et al. (1976) 1974 Former Yugoslavia PVC production plant > 195
German Environmental 1977 Germany PVC production plant 1.3–91
Office (1978)
Hansteen et al. (1978) 1974 Norway PVC plant 65
Haguenoer et al. (1979) 1977–78 France PVC production plant 2.3–7.3 (range of monthly means)
Heger et al. (1981) 1979 Germany PVC production plant 12 (12-h TWA, stationary);
15.5 (12-h TWA, personal)
Bao et al. (1988) 1981 China PVC production plant 9.9–229
Holm et al. (1982) 1974–81 Sweden PVC production plant 0.26–114 (8-h TWA)
1974–80 0.26–5.7 (6-h TWA)
Coenen (1986); BIA (1996) 1981–84 Germany 24 plants 3% of 33 samples > 5 (90th
percentile, < 1) (shift means)
1989–1992 46 plants All of 117 samples < 5 (90th
percentile < 0.1) (shift means)
Table 2 (contd)
De Jong et al. (1988) 1976–77 The Netherlands PVC plant 2.6–26 (8-h TWA)
Smulevich et al. (1988) Early 1950s Former USSR Vinyl chloride/PVC plants 100–800
Studniarek et al. (1989) 1974 Poland Vinyl chloride/PVC plant (30–600)a
1975 (several departments) (30–270)a
1976 (15–60)a
1977 (6–150)a
1978 (1–30)a
1979 (1–15)a
VINYL CHLORIDE
1981 (0.1–36)a
1982 (0.1–12)a
1974 (autoclave cleaners) (990)a
1982 (9–180)a
Fucic et al. (1990) NR Croatia Plastics industry Mean, 13; 5200 (occasional peak)
Hrivnak et al. (1990) NR Former NR 2–41
Czechoslovakia
Ho et al. (1991) 1976 Singapore PVC production plant 2.6–54 (15.3)a
After 1983 ≤ 26 (short-term) (3.9)a
Pirastu et al. (1991) 1950–85 Italy Vinyl chloride/PVC plants < 13– ≥ 1300
Dobecki & Romaniwicz 1986 Poland Vinyl chloride synthesis 21.3
(1993) 1987 mechanic, breathing zone 66.9
1988 43.7
1989 0.7
1990 0.2
Viinanen (1993) 1981-85 Finland PVC production plant, 1.6 (8-h TWA); range, < 0.3–57
1986–89 breathing zone 1.6 (8-h TWA); range, < 0.3–46
1993 0.3 (8-h TWA); range, < 0.3–26
317
318
Table 2 (contd)
Gáliková et al. (1994) 1990–93 Russian Federation Vinyl chloride/PVC plant

Whole plant (16 probes) 1–9 (range of annual means)
Under the reactor ≤ 200 (range of annual means)
In compressor room ≤ 400 (range of annual means)
Rashad et al. (1994) NR Egypt Vinyl chloride/PVC plant 0.05–18 (8-h TWA)
Du et al. (1996) NR Taiwan, China 5 PVC plants
15 different operation units Range (114 samples), ND (0.13)–
1009
Outside reaction tankb Range (4 samples), 6–1009
(mean, 296; median, 86)
15 different job titles Range of TWA (85 samples), ND–
3680
Tank supplierb Range (9 samples), 5.7–3680
(mean, 660; median, 23.7)
Hozo et al. (1996, 1997) 1949–87 Croatia Vinyl chloride/PVC plant Mean, 543; up to 1300 (peak)
Zhu et al. (2005a) NR China PVC plant Geometric mean, 7.1; range, 0.8–48.4
Updated from WHO (1999)

ND, not detected; NR, not reported; TWA, time-weighted average
a
Geometric means
b
Highest mean concentrations of vinyl chloride
VINYL CHLORIDE 319
(a) Production of vinyl chloride and its derivatives

Measured levels of VCM concentrations in vinyl chloride/PVC production are sum-
marized in Table 2 (WHO, 1999). Only one recent study was found in which levels of
exposure to vinyl chloride were reported (Zhu et al., 2005a).
Zhu et al. (2005a) reported the exposure to VCM of workers in a plant in China.
Ambient air levels of VCM at different worksites in the plant ranged from 0.3 to
17.8 ppm [0.8–48.4 mg/m3]; the geometric average concentration was 2.6 ppm
[7.1 mg/m3]. In another study in Taiwan, China (Du et al., 1996), the highest median
concentration was reported for short-term exposure (15–40 min) of a tank cleaner was
70 mg/m3 [27 ppm].
In former socialist countries in eastern Europe, the stringent regulations for PVC
production that were introduced in western Europe and the USA in the 1970s could not be
met for socioeconomic reasons, and large plants with old-fashioned technologies con-
tinued to function with concentrations of VCM that remained at levels of former
standards (Hozo et al., 1996).
In vinyl chloride production, workers may be exposed to ethylene dichloride and to
catalysts such as iron(III) chloride. In PVC production, concurrent exposure to PVC dust
may occur (Casula et al., 1977). The polymerization inhibitor bisphenol-A has been
reported to leach from polycarbonate flasks during autoclaving (Krishnan et al., 1993).
(b) PVC processing

Measured levels of VCM in plants where PVC was being processed are considerably
lower than those in vinyl chloride and PVC producing plants (Table 3; WHO, 1999).
Improvements in PVC production in the 1970s resulted in a much lower content of
residual VCM in PVC resin. The lower monomer content led automatically to concen-
trations in the ambient air of PVC processing factories < 0.1 ppm [0.26 mg/m3] (Holm et
al., 1982).
In PVC processing, the polymer may be mixed with antixodants (such as
p-nonylphenol), stabilizers (such as organic tin compounds), plasticizers (phthalates) and
colouring agents (pigments) (reviewed in Summers, 2006) and occupational exposure to
these compounds, as well as to PVC dust, may occur (Boraiko & Batt, 2005).
1.3.3 Environmental occurrence

(a) Ambient air
Vinyl chloride has been reported in landfill gas and groundwater as a degradation
product of chlorinated solvents that were deposited in landfills (WHO, 1999).
In recent years, the industrial release of vinyl chloride into the air in the USA slowly
decreased from 734 259 pounds [333 tonnes] in 2001 to 670 992 pounds [305 tonnes] in
2002, 645 804 pounds [293 tonnes] in 2003, 653 837 pounds [297 tonnes] in 2004 and
545 252 pounds [248 tonnes] in 2005 (National Library of Medicine, 2007).
320
Table 3. Levels of vinyl chloride reported for workplace air samples in polyvinyl chloride (PVC) processing plants
Reference Country Workplace Year Concentration (mg/m3)
Bol’shakov (1969) Russia PVC processing plant (synthetic Before 1966 < 114
leather plant)

Fleig & Thiess (1974) Germany PVC processing department 1974 < 2.6–68
Murdoch & Hammond (1977) United Kingdom PVC processing plants (cable NR 0.4–0.9
factories)
Holm et al. (1982) Sweden PVC processing plant 1974 < 0.26–0.8
Bao et al. (1988) China PVC processing plant 1981–85 ≤ 30
Solionova et al. (1992) Russia PVC processing plant (rubber Before 1990 0.007–1.26
footwear plant)
Lundberg et al. (1993) Sweden PVC processing plant
Mixing Before 1975 < 26
After 1975 <<< 26
Others Before 1975 < 13
After 1975 < 2.6
Nelson et al. (1993) USA Automotive assembly plant(s) 1970s 0.13–7.8 (2 personal samples)
BIA (1996) Germany Polymer extrusion (17 plants) 1989–92 All of 33 samples < 8 (90 percentile,
< 0.15) (shift means)
From WHO (1999)

NR, not reported; TWA, time-weighted average
VINYL CHLORIDE 321
Atmospheric concentrations of VCM in ambient air are low (usually < 3 µg/m3). A
monitoring programme in the 1970s that measured VCM in the air around vinyl chloride
and PVC production plants found some relatively high concentrations of vinyl chloride in
ambient air. Maximum 24-h average concentrations ranged from 0.32 to 10.6 ppm [0.8–
28 mg/m3]. Levels of VCM were much lower in the vicinity of PVC product manu-
facturing plants than near vinyl chloride and PVC production plants (Dimmick, 1981).
(b) Accidental releases

In June 1996, 10 of 18 tank wagons filled with vinyl chloride were derailed on the
Magdeburg–Halle railway line just outside the Schönebeck station in Germany. One
wagon exploded and four others ignited; 28 people received in-patient treatment in a
nearby hospital and 268 others were treated as outpatients. Vinyl chloride concentrations
of 0.06–8 ppm [0.16–20.8 mg/m3] were measured in residential areas. Almost 300 urine
samples that were taken from rescue workers, residents and a control group were analysed
for the vinyl chloride metabolite thiodiacetic acid. The measured values appeared to be in
the range of those of unexposed people (Thriene et al., 2000).
(c) Residues in PVC resin and products

PVC products contain VCM as a residue from production (WHO, 1999). In a survey
from 1976 to 1977, the following articles contained VCM at levels > 0.05 ppm
[0.13 mg/m3]: bathroom tiles, piping, plastic bottles for table oil and kitchen wrapping
film. The highest concentrations were found in vinyl music records. The VCM content of
toys, kitchen utensils, food wrappings, wallpaper and car interiors was < 0.05 ppm
(German Environmental Office, 1978). The introduction of improved manufacturing
practices has considerably reduced the residual content of VCM in PVC products (WHO,
1999).
(d) Other occurrences

VCM was identified in mainstream smoke of cigarettes (1.3–16 ng/cigarette) and
cigars (14–27 ng/cigar). The measured levels correlated with chloride content of the
tobacco (Hoffmann et al., 1976; IARC, 2004).
There has been no report of vinyl chloride levels found in food, pharmaceutical or
cosmetic products in recent years (WHO, 1999).
1.4 Regulations and guidelines

Historically, the American Conference of Government Industrial Hygienists threshold
limit values (ACGIH TLV) were lowered from a maximum allowed concentration–
time-weighted average (MAC–TWA) of 500 ppm in 1946–47 to a TLV–TWA of 200
ppm in 1972. In 1978–79, the carcinogenic classification A1c was added. In 1980, a
TLV–TWA value of 5 ppm was recommended together with the carcinogen classification
of A1c, which changed to A1a and then to A1 in 1987. In 1999, a TLV–TWA value of 1
ppm was accepted with the A1 carcinogen classification (ACGIH, 2001).
Many countries, regions or organizations have established exposure guidelines for
vinyl chloride in the workplace (Table 4).
The international, national and state regulations and guidelines regarding vinyl
chloride in air, water and other media have been summarized by ATSDR (2006).
Since 1978, the European Union has controlled the presence of vinyl chloride in
polymers and copolymers that are intended to come into contact with food (78/142/EEC;
European Commission, 1978).
Table 4. Exposure guidelines for vinyl chloride in the workplace
Country/region or TWA STEL (ppm)a Carcinogenicityb Notes

organization (ppm)a
Australia 5 1
Belgium 3 Ca
Brazil 156 (ceiling)
Canada
Alberta 1
British Columbia 1 1 ALARA
Ontario 1
Quebec 1 5 A1 Recirculation prohibited
China 10 mg/m3 25 mg/m3 STEL based on ultra
limit coefficient
China, Hong Kong SAR 5 A1
Czech Republic 7.5 mg/m3 15 mg/m3
Finland 3 MAC
Germany-MAK 1
Ireland 3 Ca1
Japan-JSOH 2.5 (ceiling) 1
Malaysia 1 Medical surveillance is
appropriate
Mexico 5 A1
Netherlands 7.77 mg/m3 Ca
New Zealand 5 A1
Norway 1 Caa
Poland 5 mg/m3 30 mg/m3 Ca
South Africa-DOL-RL 7
Spain 3 Ca1
Sweden 1 5 Ca Skin
VINYL CHLORIDE 323
Table 4 (contd)
Country/region or TWA STEL (ppm)a Carcinogenicityb Notes

organization (ppm)a
United Kingdom 3 R45

USA
ACGIH 1 A1
NIOSH REL Ca
OSHA PEL 1 5 STEL is an average not
to exceed 15 minutes
From ACGIH Worldwide (2005)

ACGIH, American Conference of Governmental Industrial Hygienists; ALARA, as low as reasonably
achievable; DOL-RL, Department of Labour-recommended limit; JSOH, Japanese Society of
Occupational Health; MAC, maximum acceptable concentration; MAK, maximum allowed
concentration; NIOSH, National Institute of Occupational Safety and Health; OSHA, Occupational
Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit;
STEL, short-term exposure limit; TWA, time-weighted average
a
Unless otherwise specified
b
1, established human carcinogen/substance which causes cancer in humans/carcinogenic to humans;
Ca, Carcinogen/substance is carcinogenic; Caa, potential cancer-causing agent; A1, confirmed human
carcinogen; Ca1, substance known to be carcinogenic to humans; R45, may cause cancer
2. Studies of Cancer in Humans
2.1 Case reports

A case report of three cases of angiosarcoma of the liver in men who had been
employed in the manufacture of PVC resins provided the first evidence of an association
between vinyl chloride and cancer in humans (Creech & Johnson, 1974). The case report
was particularly informative because of the rarity of the tumour. Case reports of hepato-
cellular carcinoma in workers exposed to vinyl chloride have been published since the
mid-1970s in France (Saurin et al., 1997), Germany (Gokel et al., 1976; Koischwitz et al.,
1981; Dietz et al., 1985; Lelbach, 1996; Weihrauch et al., 2000), China (Hong Kong
SAR) (Evans et al., 1983), Italy (Pirastu et al., 1990), Japan (Makita et al., 1997) and the
USA (Bond et al., 1990).
2.2 Methods and main results of epidemiological cohort studies of workers

exposed to vinyl chloride
Two epidemiological multicentric investigations of workers who were employed in
the vinyl chloride industry have been carried out: one in North America and one in
Europe. In addition to reports that related to these cohorts in their entirety, a number of
studies reported findings from individual subcohorts. In this section, results for subcohorts
are described only when they provide important information that is not available in
analyses of the full cohorts. Six cohort studies have also been reported in addition to and
separately from the two multicentric investigations.
2.2.1 North American multicentric study

The North American multicentric cohort was originally assembled under the sponsor-
ship of the Chemical Manufacturers’ Association (now known as the American Chemis-
try Council). The first published report of this study (Cooper, 1981) included 10 173
workers from 37 plants, whose vital status was updated through to 31 December 1972.
Among the 37 plants included in the study, 11 plants with 1214 workers produced only
VCM, 18 plants with 6848 workers produced only PVC, three plants with 935 workers
produced both VCM and PVC and five plants with 1176 workers produced homo-
polymers and copolymers. To be eligible for inclusion into the cohort, male employees at
the 37 participating plants were required to have been exposed to VCM for at least 1 year
before 31 December 1972 and to have been employed in or after 1942. The time at which
the employees were included in the study depended on the date at which the plant where
they worked began making or using VCM and the earliest date at which personnel
records were complete for all employees, whichever was later. A second major follow-up
of this cohort was published by Wong et al. (1991), at which time vital status had been
updated through to 31 December 1989; this update included 10 173 individuals who satis-
fied the original entry criteria for this study. A third major update included the same
eligibility criteria; after minor corrections to study records, 10 109 subjects were included
in the analysis and vital status was updated through to 31 December 1995 (Mundt et al.,
2000). On the basis of state reference rates, the standardized mortality ratio (SMR) was
0.83 (95% confidence interval [CI], 0.80–0.86) for all causes, 0.96 (95% CI, 0.90–1.03)
for all malignant neoplasms and 3.59 (80 deaths; 95% CI, 2.84–4.46) for cancer of the
liver and biliary tract. Results for cancer at other sites were given for brain and central
nervous system (36 deaths; SMR, 1.42; 95% CI, 1.00–1.97), lung (303 deaths; SMR,
0.82; 95% CI, 0.73–0.92), lymphatic and haematopoeitic tissue (71 observed; SMR, 0.86;
95% CI, 0.67–1.08), lymphosarcoma and reticulosarcoma (International Classification of
Diseases (ICD)-9 code 200; 12 deaths; SMR, 1.20; 95% CI, 0.62–2.09) and skin (ICD-9
code 172–173; 12 deaths; SMR, 0.64; 95% CI, 0.33–1.12).
A separate analysis for a plant located in Louisville, KY (USA), that was included in
the multicentric cohort was published by Lewis et al. (2003). The plant was the site at
VINYL CHLORIDE 325
which an excess of deaths from angiosarcoma had first been detected in workers exposed
to vinyl chloride; it had opened in 1942 and has produced VCM, PVC resin and nitrile
rubber copolymers. Among 2200 workers who had been employed for at least 1 year in
jobs that entailed exposure to VCM in 1942–72 and who were followed-up during 1942–
95, mortality from all causes was below that expected (903 deaths versus 1008.8 ex-
pected; SMR, 0.88), while that for all cancers combined was above expectation (264
deaths versus 248.2 expected; SMR, 1.06); mortality from cancer of the liver and biliary
tract was also greater than that expected (24 deaths versus six expected; SMR, 4.00).
A subsequent study at this plant compared the exposure histories of cases of liver
angiosarcoma and brain cancer with those of 1817 workers who had been exposed for at
least 1 year and had been hired before 1967 (Lewis & Rempala, 2003). Exposure
variables included history of employment in various PVC and nitrile rubber production
buildings, ranked peak exposure to VCM and estimated cumulative exposure to VCM,
acrylonitrile (IARC, 1999), 1,3-butadiene (see this volume) and styrene (IARC, 2002). In
a nested case–control study, each case was individually matched to controls by year of
birth, year of hire and duration of employment. The matched case–control analysis con-
sidered ranked exposure to VCM, vinylidene chloride (IARC, 1999), vinyl acetate
(IARC, 1995), PVC, acrylonitrile (IARC, 1999), 1,3-butadiene (see this volume) and
styrene (IARC, 2002). The occurrence of angiosarcoma was strongly associated with
exposure to vinyl chloride but not with exposure to the other chemicals; the risk for brain
cancer was highest among workers who had been hired before 1950 but was not
associated with exposure to vinyl chloride.
2.2.2 European multicentric study

The European multicentric cohort was conducted in four countries (Italy, Norway,
Sweden and the United Kingdom). The first report of the study results (Simonato et al.,
1991) included follow-up of vital status through to 31 December 1986; an update of the
study (Ward et al., 2001) analysed incidence and mortality through to the latest year for
which data were available in each country, which ranged between 1993 and 1997. The
study included a total of 19 factories; 11 of these produced VCM/PVC, two produced
VCM only, five produced PVC only and one was a PVC processing plant. Male workers
who had been employed for at least 1 year in 1942–72 in jobs that entailed exposure to
VCM were included. The observation period for the cohort began in 1955, the year for
which reference rates were first available. The most recent report provided updated
information on vital status for 17 of the 19 factories and on cancer incidence for 13
factories in three countries. In addition, results for most of the national cohorts were
published separately (Byren et al., 1976; Fox & Collier, 1977; Molina et al., 1981;
Heldaas et al., 1984, 1987; Jones et al., 1988; Hagmar et al., 1990; Pirastu et al., 1990,
1998; Langărd et al., 2000).
Of the 12 700 men included in the updated analysis of the full cohort (Ward et al.,
2001), 9688 (76.3%) were alive (range by country, 66–89%), 2665 (21.0%; range by
country, 10–33%) had died, 63 (0.5%) were lost to follow-up and 284 (2.2%) had
emigrated. Overall, the follow-up was 97.3% complete.
Age- and calendar period-specific (men only) national mortality rates were used as
the reference for the SMR analysis. These were computed using the WHO mortality
database, in which only three-digit ICD codes have been stored consistently since 1955. A
search for the best available data for a diagnosis of liver cancer was conducted by
reviewing all available documentation. For Sweden and Norway, this included histology
on the death certificate, if noted, and morphology coded by the cancer registry. For Italy,
where cancer registry data were not available, information was obtained from the death
certificate or from medical records. In the United Kingdom, sources of histological diag-
nosis included the death certificate, cancer registry, medical records and a registry of
angiosarcomas developed by the Health and Safety Executive (Baxter, 1981). Records of
cases of liver cancer from all of the countries were also matched by indirect identifiers to
records of an angiosarcoma registry maintained by the Association of European Plastics
Manufacturers (Forman et al., 1985).
Analysis by production process was based on the type of plant. The majority of
workers (8032) were employed in mixed VCM/PVC production facilities, followed by
PVC production (3047), PVC processing (1353) and VCM production (206). Calendar
period-specific job–exposure matrices were provided by industrial hygienists for 13 of the
19 factories, and matrices that provided job- and calendar time-specific estimates of
exposure to vinyl chloride in parts per million were created. Each job–exposure matrix
was checked and validated as being generally accurate by two other industrial hygienists,
one from Sweden and one from the United Kingdom, both of whom had had several
years of experience in the vinyl chloride industry.
In general, exposure estimates for the study plants were highest in the earliest years of
operation. For example, estimates of exposure to VCM in the highest exposure categories,
including reactor operators, were as high as > 500 ppm [> 1300 mg/m3] in 1950–65 in
several of the Italian plants, 2000 ppm [5200 mg/m3] in 1950–54 in a Norwegian plant,
approximately 3000 ppm [7800 mg/m3] in 1940–44 in one of the Swedish plants and
770 ppm [2000 mg/m3] in 1944–50 in one of the British plants. Exposure estimates for
high-exposure jobs in the 1960s were substantially lower in most plants, and the majority
were below 200 ppm [520 mg/m3]. By the mid-1970s, very few plants had estimated ex-
posures > 5 ppm [> 13 mg/m3]. Exposure variables in the analysis were autoclave worker
(ever/never), duration of employment, and ranked level of exposure and cumulative ex-
posure to VCM in air in ppm–years. Exposures to vinyl chloride in the study plants were
estimated to be < 1 ppm [< 2.6 mg/m3] for all jobs between 1976 and 1988. Most factories
had a specific job category for autoclave workers, and the classification of individuals as
‘ever autoclave worker’ was based on ever having held a job in this category. For these
workers, three categories were created: 1, known to have been an autoclave worker; 2, not
known to have been an autoclave worker, and from a factory with a specific job code for
autoclave worker; and 3, from a factory in which work as an autoclave worker could not
be determined.
VINYL CHLORIDE 327
In addition to the job–exposure matrix with job- and calendar time-specific estimated
exposures to vinyl chloride in parts per million, an index of ranked level of exposure was
developed. Classification of subjects in this index was based on the maximum exposure
level for any job held by an individual, based on the job- and the calendar time-specific
exposure estimates given for that job in the job–exposure matrix. In order to examine the
potential association of exposure to PVC dust with lung cancer and non-malignant respi-
ratory disease, stratified analyses were conducted for those workers who had only, ever or
never been employed in curing, filtering and packing jobs.
Using national mortality and incidence rates as the reference, mortality from all
causes (SMR, 0.85; 95% CI, 0.82–0.88) and from all cancers (SMR, 0.99; 95% CI, 0.93–
1.06) was below the reference, as was total cancer incidence (standardized incidence ratio
[SIR], 0.85; 95% CI, 0.79–0.91). An increase in the occurrence of primary liver cancer
was observed (53 deaths and 29 incident cases; SMR, 2.40; 95% CI, 1.80–3.14; SIR,
3.98; 95% CI, 2.67–5.72). From the best available data on diagnosis, 71 cases of liver
cancer were identified and used in the internal analysis for latency, duration of employ-
ment, cumulative exposure and employment as autoclave cleaner. On the same basis, 37
cases of angiosarcoma and 10 cases of hepatocellular carcinoma were ascertained for
which detailed analyses of latency, duration of exposure, cumulative exposure and ever
versus never having worked as an autoclave cleaner were conducted. The results of these
internal analyses are presented in Section 2.3. Results for other cancer sites (Ward et al.,
2001) were: brain cancer — SMR, 0.93 (24 deaths; 95% CI, 0.60–1.39) and SIR, 0.91 (19
cases; 95% CI, 0.55–1.42); lung cancer — SMR, 0.95 (272 deaths; 95% CI, 0.84–1.07)
and SIR, 0.80 (154 cases; 95% CI, 0.68–0.94); and lymphatic and haematopoeitic cancer
— SMR, 0.94 (62 deaths; 95% CI, 0.72–1.21) [SIR not reported]; no significant excess
was reported in any category of leukaemia or lymphoma. A non-significantly elevated
SMR was found for malignant melanoma (15 deaths; SMR, 1.60; 95% CI, 0.90–2.65) but
the analysis of incidence did not show an excess (18 observed cases; SIR, 1.06; 95% CI,
0.63–1.68) (Ward et al., 2001). Results of internal analyses for selected sites are presented
in Sections 2.3–2.9.
The European study found evidence of a significant association between exposure to
VCM and mortality from liver cirrhosis. The relative risks for cumulative exposures of
< 524 (reference), 524–998, 999–3429, 3430–5148 and ≥ 5149 ppm–years were 1.00,
9.38 (eight cases; 95% CI, 3.52–25.0), 4.01 (nine cases; 95% CI, 1.55–10.4), 9.77 (eight
cases; 95% CI, 3.66–26.1) and 8.28 (nine cases; 95% CI, 3.15–21.8), respectively.
In a Swedish study of 2031 workers employed for ≥ 3 months in a PVC processing
plant during 1961–80 (Hagmar et al., 1990), mortality and cancer incidence in 1961–85
were studied; vital status was established for 95.5% of cohort members. Work activities
were classified for estimated exposure to VCM as none, low, moderate or high. The
cohort was later included in the European multicentric study. The incidence of all cancers
was higher than expected (SIR, 1.16; 95% CI, 0.99–1.36). Two incident cases of cancer
of the liver and biliary tract were observed among workers with 10 or more years latency,
an incidence that was higher than expected (SIR, 2.44; 95% CI, 0.30–8.80).
A Swedish cohort of 717 workers who had been employed for ≥ 3 months in three
PVC processing plants in 1964–74 was followed up for mortality in 1964–86 and for
incidence of disease in 1964–84; work activities were classified as having high, inter-
mediate or low potential exposure to VCM and national reference rates were used for
comparison. Mortality from all causes was as expected (SMR, 1.0; 95% CI, 0.8–1.2), and
no cases of liver cancer were observed (Lundberg et al., 1993).
A prospective follow-up study of French VCM workers was initiated in 1980
(Laplanche et al., 1992). The study population included exposed and unexposed workers
from 12 plants; 1096 employees, aged 44–55 years, had been exposed to VCM in 1980–
81 or earlier and were free of disease at the time of enrolment; the unexposed group
included 1093 employees who were individually matched to the exposed group by age,
plant and plant physician. Interviews and data collection were conducted by plant physi-
cians. Occupational and medical histories, parental history of cancer, employment status,
nationality, tobacco smoking status and alcoholic beverage consumption were recorded.
The follow-up period ended in December 1988. During the study period, 20 deaths from
cancer were observed among the exposed and 22 among the unexposed. Cancer mor-
bidity was higher among the exposed (38 cases observed) than the unexposed (32 cases
observed; relative risk, 1.3; 95% CI, 0.8–2.1).
In an Italian plant in Porto Marghera that was included in the European multicentric
study, an internal analysis was completed with mortality follow-up for 1972–95 and
employment histories for 1972–85 (Gennaro et al., 2003). The relative risks for mortality
from all causes and all cancers for autoclave workers versus all other workers were 1.32
(11 deaths; 95% CI, 0.55–3.15) and 1.09 (six deaths; 95% CI, 0.36–3.31), respectively; an
increase was also observed for mortality from liver cancer (four deaths; relative risk, 9.57;
95% CI, 1.69–54.1).
In the same plant, mortality and occupational history were updated until 1999 (Pirastu
et al., 2003). On the basis of job- and time-specific exposure estimates, cumulative
exposure was calculated and classified into six exposure categories (0–735, 735–2379,
2379–5188, 5188–7531 and 7531–9400 ppm–years); employment as an autoclave worker
(ever/never) was also considered in the analyses. Data (clinical and pathological) that
gave the best diagnosis were used to identify cases of liver angiosarcoma and hepato-
cellular carcinoma. Regional rates were used as a reference, mortality from primary liver
cancer was determined and internal analyses for duration, latency and exposure were
completed. A comparison of mortality in the cohort with local reference rates was made
for all causes (SMR, 0.75; 90% CI, 0.68–0.83) and all cancers (SMR, 0.94; 90% CI,
0.81–1.09), both of which were lower than expected. For all causes, the analysis by time
since leaving employment and adjusted for latency showed that the SMR in the first year
after leaving employment was 2.76 (90% CI, 1.94–3.91). Mortality rates for liver angio-
sarcoma (six cases) increased with latency and cumulative exposure; no cases were asso-
ciated with duration of employment of < 12 years, latency of < 10 years or cumulative
exposure of < 2379 ppm–years. Mortality rates for hepatocellular carcinoma (12 cases)
and liver cirrhosis (20 cases) showed a similar pattern.
VINYL CHLORIDE 329
A cross-sectional study in the same plant examined occupational and non-occupa-

tional risk factors for cirrhosis of the liver and hepatocellular carcinoma among 13 indi-
viduals who had liver cancer (eight confirmed histologically), 40 individuals who had
liver cirrhosis (24 confirmed histologically) and 139 referents who had been examined in
a medical surveillance programme in 1999–2002 and were found not to have had any
evidence of liver disease or cancer at any site (Mastrangelo et al., 2004). Among the 13
cases of hepatocellular carcinoma, 11 also had liver cirrhosis and were included in both
groups. [The Working Group noted that it was not clear how the 139 referent subjects
with no evidence of liver disease were selected from among the 643 persons examined in
the medical surveillance programme.] Exposure to VCM was evaluated using a job–
exposure matrix developed by Pirastu et al. (1990); history of alcoholic beverage con-
sumption was ascertained from clinical or health surveillance records and chronic infec-
tion with hepatitis B (HBV) or hepatitis C virus was examined by serological markers. An
association between exposure to VCM and both liver cirrhosis and hepatocellular carci-
noma was found with much higher odds ratios among those exposed to multiple risk
factors.
2.2.3 Other studies

A proportionate mortality study of workers employed in 1964–73 at 55 PVC pro-
cessing plants in the USA used national mortality rates for comparison; six deaths from
primary liver cancer were observed versus an expected 4.19 (Chiazze & Ference, 1981).
Thériault and Allard (1981) compared the mortality of a small cohort of 451 male
workers who had been employed for 5 or more years in 1948–72 in a Canadian VCM
production and polymerization plant with that of a group of 870 workers who had been
employed for ≥ 5 months at a nearby industrial complex that was not involved in the
production of VCM or PVC and who were considered to be unexposed, and also with the
mortality of the Québec general population in 1971. Occupational histories were obtained
by interview either at home or at work with the worker himself or his next of kin. Vital
status was ascertained as at the end of 1977. The relative risk for exposed versus un-
exposed workers for mortality from all causes was 1.48 (95% CI, 0.84–2.61). Eight cases
of liver cancer were observed with only 0.14 expected in comparison with the general
population; all of these were angiosarcomas. Two deaths from cancer of the ‘bone, skin,
connective tissue’ (ICD codes 170–173) were observed compared with 0.38 expected.
Weber et al. (1981) reported findings in a historical cohort of 7021 VCM/PVC
production workers in Germany. The cohort included German and Austrian men who had
been employed from the beginning of VCM/PVC production in all German plants [no
details given] to the end of 1974. Vital status and follow-up for cause of death [methods
not described] were 93.2% and 92.7% complete, respectively. Mortality rates of the West
German male population were used as the reference. To calculate expected numbers for
person–years of observation before 1968, rates from 1968 were used. A method described
by Tabershaw and Gaffey (1974) was used to take into account unknown causes of
deaths. No information on exposure levels was available. The SMRs for mortality from
all causes, all cancers and liver cancer (ICD-8 155) were 0.95 (414 deaths), 1.12 (94
deaths) and 15.23 (12 deaths), respectively. [The Working Group noted that an earlier
cohort studied by Frentzel-Beyme et al. (1978) appeared to be included in this cohort.]
Smulevich et al. (1988) conducted a cohort study at the oldest PVC plants in the
former Soviet Union. Overall, 3232 workers (2195 men) were identified as having held
jobs that entailed exposure to VCM. Exposure levels were greater than 300 mg/m3
[115 ppm] for part of the cohort [number unspecified]. Expected deaths were computed in
strata of age (15–74 years) from death rates in the same city, based on follow-up for the
years 1939–77. The total number of deaths was not in excess in the cohort. The SMR for
all cancer was 1.07 (63 deaths). No cases of liver cancer were observed. The proportion of
the cohort that was ever exposed to the highest estimated levels of VCM was not
reported; however, 40 of 63 cancer deaths occurred in the high-exposure category. A
statistically significant excess (p < 0.05) was detected for leukaemias and lymphomas
(five deaths; SMR, 4.17), while excess mortality from for pancreatic cancer in both sexes
(SMR, 1.43) and skin cancer (both melanoma and non-melanoma) in men (SMR, 1.67)
were not statistically significant. Histological confirmation of causes of death was avail-
able for 60% of the cancer cases. A significant increase in the occurrence of lymphomas
and leukaemias (seven deaths; SMR, 6.36) was noted at the highest level of exposure
(p < 0.05). Although the number of cohort members per exposure level was not reported,
28 cancer deaths occurred in the highest-exposure group, 15 in the intermediate (30–
300 mg/m3 [11.5–115 ppm])-exposure group and one in the lowest (< 30 mg/m3
[11.5 ppm])-exposure group. [The Working Group noted that few details were provided
on the methods used for the computation of expected numbers of deaths.]
Du and Wang (1998) conducted a proportionate morbidity study in Taiwan, China, at
five PVC plants that were operational in 1989–95. The 2224 workers who had been
exposed to VCM (97% of the total) and who were traced were compared with two other
cohorts who were unexposed to VCM—one of optical workers and one of motorcycle
manufacturers (work histories were ascertained from records of the Labour Insurance
Bureau). Hospital admissions for cancer at several sites were compared with admissions
for cardiovascular and cerebrovascular disease as reference conditions and morbidity odds
ratios were calculated. An excess of primary liver cancer was noted (morbidity odds ratio,
4.5; 95% CI, 1.5–13.3; or 6.5; 95% CI, 2.3–18.4, depending on the comparison cohort).
An excess of deaths from haematopoietic cancer (morbidity odds ratio, 3.4; 95% CI, 1.0–
11.8) was seen. Overall, 12 cases of primary liver cancer were observed in the PVC
workers, including six hepatocellular carcinomas and six with unknown histology. [The
Working Group noted that in a morbidity study, as in a proportionate mortality study, risk
estimates may be influenced by differences in the occurrence of the reference diseases as
well as those of the disease of interest.]
Wong, O. et al. (2002) conducted a retrospective mortality study of a cohort of
workers from six vinyl chloride polymerization factories in Taiwan, China. A total of
3293 male workers met the eligibility criteria for the study: they must have been em-
VINYL CHLORIDE 331
ployed for at least 1 year between 1 January 1950 and 31 December 1992 and have been
alive on 1 January 1985. The workers were followed for ascertainment of vital status from
1 January 1985 to 31 December 1997 through a national mortality registry. More than
99% of the study subjects was successfully traced using this method, and the remaining
1% was excluded from the analysis. SMRs were estimated using national rates for men as
the reference. Exposure to VCM was estimated to be about 500 ppm [1300 mg/m3] in the
1960s based on a previous report (Du et al., 2001). The SMR for all causes was 0.78
(95% CI, 0.65–0.91) and the number of deaths from for all cancers combined was greater
than that expected (SMR, 1.30; 95% CI, 0.99–1.69). A significant excess of mortality
from liver cancer was observed in this study (25 cases; SMR, 1.78; 95% CI, 1.15–2.62).
None of the deaths from liver cancer appeared to be due to angiosarcoma, although
diagnosis of primary liver cancer was only histologically confirmed for five cases.
A study on risk factors for hepatocellular carcinoma was conducted at six PVC
polymerization plants in Taiwan, China, an area that has a high prevalence of chronic
HBV and hepatitis C virus infection and an associated high incidence of hepatocellular
carcinoma (Wong et al., 2003a). Among a cohort of 4096 workers, 25 cases of liver
cancer were diagnosed in 1985–97. Of the 18 cases of liver cancer for whom medical
records were available, all were considered to be hepatocellular carcinomas, although
only five were confirmed histopathologically. Four control subjects were selected from
among a pool of eligible workers who had known HBV status, no evidence of liver
disease and provided information on questionnaires. Indices of exposure to VCM were
developed based on job titles. HBV surface antigen (HBsAg)-negative subjects with
history of tank cleaning had a 4.0-fold greater risk for liver cancer (95% CI, 0.2–69.1).
HBsAg carriers with no history of tank cleaning had a 25.7-fold (95% CI, 2.9–229.4)
increased risk, whereas the HBsAg carriers with a history of tank cleaning had the
greatest risk (odds ratio, 396.0; 95% CI, 22.6–∞), which suggested an interaction between
occupational exposure to VCM and HBV infections for the development of liver cancer.
A meta-analysis of cohort studies of vinyl choride-exposed workers that had been
published up to 2002 was conducted (Boffetta et al., 2003). The meta-analysis was based
on eight independent studies, two multicentric investigations (Mundt et al., 2000; Ward et
al., 2001) and six smaller additional studies (Thériault & Allard, 1981; Weber et al.,
1981; Smulevich et al., 1988; Laplanche et al., 1992; Huang, 1996; Wong, O. et al.,
2002). For a selection of cancer sites, a meta-SMR and 95% CIs were calculated using a
random-effects model when the p-value for the test for heterogeneity was ≥ 0.01. Six of
eight studies reported results for liver cancer, but these were considered to be too hetero-
geneous to be included in a meta-analysis because, for both liver cancer overall and for
liver cancer other than angiosarcoma, the p value for heterogeneity was < 0.001. For the
two multicentric studies (Mundt et al., 2000; Ward et al., 2001), the lack of heterogeneity
allowed the calculation of meta-SMRs of 2.96 (95% CI, 2.00–4.39) for liver cancer
overall (p value for heterogeneity = 0.03) and 1.35 (95% CI, 1.04–4.39) for liver cancer
other than angiosarcoma (p value for heterogeneity = 0.7). [The Working Group noted
that the meta-analysis did not evaluate the quality of the studies and that some
heterogeneity between studies may have resulted from variable data quality. Excluding
one study in China, other studies reported SMRs that ranged from 1.78 (95% CI, 1.15–
2.62) to 57.1 (95% CI, 24.6–113) for liver cancer overall and from 1.27 (95% CI, 0.84–
1.83) to 10.1 (95% CI, 4.37–20.0) for liver cancer other than angiosarcoma.]
2.3 Cancer of the liver

2.3.1 Cohort studies (Table 5)
(a) North American multicentric study
The most recent update of the multicentric cohort study of men in the North Amer-
ican vinyl chloride industry (Mundt et al., 2000) and reports relative to previous follow-
up periods for the same cohort (Tabershaw & Gaffey, 1974; Cooper, 1981; Wong et al.,
1991) found, on the basis of state reference rates, an SMR for cancer of the liver and
biliary tract of 3.59 (80 deaths; 95% CI, 2.84–4.46). SMRs increased with increasing
duration of exposure: 0.83 (95% CI, 0.33–1.71), 2.15 (95% CI, 1.03–3.96), 6.79 (95% CI,
4.83–9.29) and 6.88 (95% CI, 4.40–10.23) for 1–4, 5–9, 10–19 and ≥ 20 years, respec-
tively; and latency: 2.87 (95% CI, 1.31–5.44), 3.23 (95% CI, 2.00–4.93) and 4.34 (95%
CI, 3.22–5.72) for 10–19, 20–29 and ≥ 30 years, respectively. In the Cox’s proportional
hazard model, duration of exposure had the strongest independent and significant effect in
comparison with age and year of first exposure; adjusting for age and year of first ex-
posure, and using 1–4 years as the reference, the relative risk values for 5–9, 10–19 and
≥ 20 years of duration were 2.8 (95% CI, 1.0–7.3), 9.0 (95% CI, 4.0–20.7) and 6.0 (95%
CI, 2.5–14.4), respectively. For a total of 48 cases of angiosarcoma identified from both
death certificates and the World Angiosarcoma Registry, Cox’s proportional hazard anal-
ysis, adjusting for age and year of first exposure, showed an increase in risk for increasing
duration of exposure: using 1–4 years duration as the reference, the relative risks for 5–9,
10–19 and ≥ 20 years of duration were 3.7 (95% CI, 0.9–14.7), 15.9 (95% CI, 4.6–54.8)
and 9.7 (95% CI, 2.6–36.4), respectively. [It is not known whether the 32 deaths from
liver cancer that were not identified as angiosarcoma were angiosarcoma or hepatocellular
carcinoma; however, the number of expected deaths from liver and biliary tract cancer
was 22.30.]
In a separate analysis of one plant located in Louisville, KY (USA), that was included
in the multicentric cohort (Lewis et al., 2003), mortality from cancer of the liver and
biliary tract was higher than that expected on the basis of local rates (24 observed deaths
versus six expected; SMR, 4.00). The analysis showed that SMRs for cancer of the liver
and biliary tract increased with increasing duration of exposure (durations of 10–19 and
≥ 20 years had SMRs of 10.85 and 3.64, respectively; p < 0.05 for both categories) and
latency (latencies of 10–19, 20–29 and ≥ 30 years had SMRs of 6.49, 6.94 and 2.55,
respectively; p < 0.05 for all three categories). In this plant, a total of 28 liver angio-
sarcomas, 18 from deaths from liver cancer and 10 from other causes of death, were
identified.
Table 5. Cohort studies of liver cancer in vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) production workers
Name of study Cohort Exposure Type of cancer Exposure categories No. of Relative risk (95% CI) Adjustment Comments
Reference, description assessment (ICD code) cases/ for potential
location deaths confounders
North American multicentric study

Mundt et al. 10 109 white JEM Liver and SMR (state rates) Reference
(2000), USA male workers biliary tract Job exposed to VCM 80 3.59 (2.84–4.46) rates: state and
(race unknown, (ICD-9 155– Duration of exposure (state rates) USA
6%) employed 156) (years) population; in
VINYL CHLORIDE
≥ 1 year in jobs 1–4 7 0.83 (0.33–1.71) Cox model,
that entailed 5–9 10 2.15 (1.03–3.96) duration of
exposure to VCM 10–19 39 6.79 (4.83–9.29) exposure
in 1942–72; ≥ 20 24 6.88 (4.40–10.23) strongest and
mortality follow- Latency (years) significant
up, 1942–95; vital 10–19 9 2.87 (1.31–5.44) versus age at
status, 96.8%; 20–29 21 3.23 (2.00–4.93) and year of
cause of death, ≥ 30 50 4.34 (3.22–5.72) first exposure
99%; 37 plants First exposure (year)
≤ 1950 48 4.99 (3.68–6.62)
1950–59 32 3.11 (1.97–4.67)
48 ASL (33 Duration of exposure Hazard ratio Age at first
death (years) exposure,
certificate, 15 1–4 3 Reference duration of
World 5–9 6 3.7 (0.9–14.7) exposure
Angiosar- 10–19 26 15.9 (4.6–54.8) and year of
coma ≥ 20 13 9.7 (2.6–36.4) first
Registry) exposure
333
334
Table 5 (contd)
SMR
Lewis et al. 2200 male JEM Liver and Job exposed to VCM 24 4.00 (p < 0.05; 6 exp.) Reference
(2003), Lousville, workers biliary tract Duration of exposure rates: state of
KY, USA employed (ICD-9 155– (years) Kentucky

≥ 1 year in jobs 156) 1–4 2 0.91 (2.19 exp.)
that entailed 5–9 2 2.20 (0.91 exp.)
exposure to VCM 10–19 14 10.85 (p < 0.05; 1.29
in 1942–72; exp.)
mortality follow- ≥ 20 6 3.64 (p < 0.05; 1.65
up, 1942–95; vital exp.)
status, 98.5% Latency (years)
1–9 0 0 (0.27 exp.)
10–19 5 6.49 (p < 0.05; 0.77
exp.)
20–29 10 6.94 (p < 0.05; 1.44
exp.)
≥ 30 9 2.55 (p < 0.05; 3.53
exp.)
First exposure (year)
< 1950 12 3.57 (p < 0.05; 3.36
exp.)
1950–59 10 4.76 (p < 0.05; 2.10
exp.)
1960–72 2 3.51 (0.57 exp.)
Table 5 (contd)
European multicentric study

Ward et al. 12 700 male Calendar period Liver cancer SMR Reference
(2001), Italy, workers JEM for 13/19 (ICD-9 155) 53 2.40 (1.80–3.14) rates: national
Norway, Sweden, employed in 19 factories grouped SIR Reference
United Kingdom VCM/PVC plants in 22 broad 29 3.98 (2.67–5.72) rates: national
for ≥ 1 year in categories; SMR
VINYL CHLORIDE
1950–85; factory-specific PVC production 10 2.28 (1.09–4.18)
mortality follow- JEM with VCM and PVC 41 2.85 (2.05–3.87)
up, 1955–97; validated exposure production
incidence follow- estimates (ppm) Duration (years)
up, 1955–96 1–9 15 1.00
10–16 17 2.58 (1.28–5.24)
17–20 9 3.48 (1.49–8.15)
21–25 18 8.21 (3.98–16.9)
≥ 26 12 9.39 (4.17–21.1)
Test for linear trend,
p < 0.001
Latency (years ) Age, Poisson
0–20 17 1.00 calendar regression
21–25 12 2.44 (1.09–5.45) period analysis
26–30 12 2.99 (1.26–7.09)
31–36 17 5.58 (2.34–13.3)
≥ 37 12 6.20 (2.30–16.7)
p < 0.001
335
336
Table 5 (contd)
Ward et al. Cumulative exposure

(2001) (contd) (ppm–years)
0–734 13 1.00
735–2379 12 3.97 (1.81–8.71)

2380–5188 15 7.55 (3.57–15.9)
5189–7531 13 14.0 (6.43–30.7)
≥ 7532 15 28.27 (12.84–62.25)
p < 0.001
Autoclave workers
Never 22 1.00
Ever 38 6.61 (3.90–11.2)
Unknown 11 5.43 (2.63–11.2)
ASL Duration (years)

1–9 7 1.00
10–16 8 3.01 (1.06–8.54)
17–20 2 2.04 (0.41–10.3)
21–25 12 15.7 (5.60–44.0)
≥ 26 8 19.67 (6.28–61.59)
Trend test, p < 0.001
Latency (years) Age, Poisson
0–20 10 1.00 calendar regression
21–25 6 2.77 (0.89–8.69) period analysis
26–30 7 4.80 (1.47–15.7)
31–36 10 10.38 (3.09–34.9)
≥ 37 4 7.99 (1.71–37.3)
Table 5 (contd)

0–734 4 1.00
735–2379 6 6.56 (1.85–23.3)
2380–5188 8 13.6 (4.05–45.5)
VINYL CHLORIDE
5189–7531 7 28.0 (8.00–98.2)
≥ 7532 12 88.2 (26.4–295)
Autoclave workers
Never 4 1.0
Ever 26 25.5 (8.86–73.2)
Unknown 7 19.3 (5.66–66.2)
HCC Duration (years)

1–9 1 1.0
10–16 3 6.94 (0.71–67.5)
17–20 2 12.6 (1.11–143)
21–25 1 7.34 (0.44–122)
≥ 26 3 35.5 (3.34–377)
Trend test, p = 0.002
Latency (years) Age, Poisson
< 26 2 1.00 calendar regression
26–30 1 3.72 (0.29–48.3) period analysis
31–36 3 15.9 (1.86–135)
≥ 37 4 35.7 (3.56–359)
337
338
Table 5 (contd)

0–734 3 1.0

735–2379 2 3.02 (0.50–18.1)
2380–5188 1 2.47 (0.26–23.9)
5189–7531 1 5.33 (0.54–52.5)
≥ 7532 2 20.27 (2.98–138)
Autoclave worker
Never 5 1.0
Ever 4 2.97 (0.80–11.1)
Unknown 1 2.04 (0.24–17.4)
Gennaro et al.. 1658 male JEM Liver cancer Autoclave workers 4 9.57 (1.69–54.1) Age, Internal
(2003), Porto workers (ICD-9 155) PVC baggers 4 3.44 (0.62–18.97) calendar comparison ;
Marghera, Italy employed in Autoclave + PVC 9 4.08 (0.85–19.57) time, ‘job title
1956–85; baggers + compound duration, groups’ versus
mortality follow- latency other workers
up, 1973–95
Pirastu et al. 1658 male JEMs: job- and Primary liver SMR Reference
(2003), Porto workers time-specific cancer (ICD-9 17 2.78 (1.86–4.14)a rates: regional
Marghera, Italy employed in VCM estimates 155.0)
1956–99; (ppm); ever/never Relative risk Age, Internal
mortality follow- autoclave worker Autoclave worker: 4.4 (1.9–10.0)a calendar comparison of
up, 1973–99; vital ever/never time, rates
status, 100%; latency
cause of death,
99%
Table 5 (contd)
Pirastu et al. ASL Autoclave worker: 6 21.1 (3.5–128.7)a Age, Best available
(2003) (contd) ever/never calendar clinical and
HCC Autoclave worker: 12 3.5 (1.4–9.2)a time, pathological
ever/never latency data; internal
HCC and ASL Cumulative exposure × 100 000)
Rate (× comparison of
(ppm–years) rates
VINYL CHLORIDE
0–735 3 10.0
735–2379 1 18.6
2379–5188 7 191.7
5188–7531 1 62.8
7531–9400 0 χ2 14.52
Other studies
Thériault & 451 male workers JEM Digestive tract 14 (6 6.25 (2.69–14.52) Reference
Allard (1981), exposed to VCM cancer (ICD-7 deaths rates:
Québec, Canada for ≥ 5 years in a 150–159) from Canadian
polymerization liver population in
plant, employed cancer) 1971;
in 1948–72; comparison
mortality follow- population:
up, 1948–77 870 workers
not exposed to
VCM for
≥ 5 months
339
340
Table 5 (contd)
Weber et al. 7021 male JEM Malignant SMR Reference

(1981), Germany VCM/PVC tumour of the 12 15.23 rates: national
production liver (ICD-8 Duration of exposure

workers from 155) (months)
beginning of < 12 0 –
operation to 13–60 2 8.74
1974; mortality 61–120 3 15.25
follow-up, from ≥ 121 7 25.28
beginning of
operation to
1974; vital status,
> 90%; cause of
death, 7–13%
Smulevich et al. 3232 (2195 men, Exposure data in Malignant Estimated area 0 City (Gorki)
(1988), former 1037 women) 1953–66 from liver neoplasm exposure: low, mean death
Soviet Union VCM/PVC JEM (ICD-8 155) medium and high rates in 1959,
production 1969 and 1975
workers
employed for
≥ 1 month in
VCM-exposed
jobs; mortality
follow-up, 1939–
77
Table 5 (contd)
Laplanche et al. 1100 VCM- JEM Liver cancer 3 ex- NR Prospective

(1992), France exposed and 1100 (ICD-9 155) posed study
unexposed 0 unex-
subjects; matched posed
on age, plant,
VINYL CHLORIDE
physician, aged
40–55 years,
identified in
1980; mortality
and morbidity
follow-up, 1980–
88
Du & Wang 2224 workers Liver cancer VCM versus optical 4.5 (1.5–13.3)
(1998), Taiwan, with occupational (ICD-9 155) workers
China exposure to VCM versus motor 6.5 (2.3–18.4)
VCM; controls cycle workers
were optical or
motor cycle
equipment
workers.
341
342
Table 5 (contd)
Wong, O. et al. 3293 male Malignant SMR Reference

(2002); Wong et workers in 6 PVC neoplasm of 25 1.78 (1.15–2.62) rates, national;
al. (2003a), polymerization the liver (ICD- Duration of exposure cohort
Taiwan, China plants exposed to 9 155) (years) assembled
VCM ≥ 1 year in < 10 13 2.45 (1.30–4.19) from records
1950–92; 10–19 10 1.76 (0.84–3.24) of Labour
mortality follow- ≥ 20 2 – (3.2 exp.) Insurance
up, 1985–97; vital Latency (years ) Bureau
status, 99% < 15 8 1.29 (0.56–2.54)
15–24 7 1.46 (0.58–3.61)
≥ 25 10 3.13 (1.50–5.75)
First exposure (year)
≤ 1970 11 4.82 (2.41–8.63)
1970–79 8 1.92 (0.83–3.79)
After 1980 6 0.78 (0.28–1.69)
Age at first exposure
(years)
< 30 10 2.24 (1.07–4.12)
30–39 6 1.78 (0.65–3.88)
≥ 40 9 1.43 (0.65–2.71)
Odds ratio
HCC Tank cleaners 2.9 (1.1–7.3)
ASL, angiosarcoma of the liver; CI, confidence interval; exp., expected; HCC, hepatocellular carcinoma; ICD, International Classification of Diseases; JEM, job–exposure
matrix; SIR, standardized incidence ratio; SMR, standardized mortality ratio
a
90% confidence interval
VINYL CHLORIDE 343
(b) European studies

In the European multicentric cohort study of workers in the vinyl chloride industry, an
increase in the incidence of primary liver cancer was observed (53 deaths and 29 incident
cases; SMR, 2.40; 95% CI, 1.80–3.14; SIR, 3.98; 95% CI, 2.67–5.72) using national
mortality and incidence rates as the reference. On the basis of the best available data for
diagnosis, 71 cases of liver cancer were identified and used in the internal analysis for
latency, duration of employment, cumulative exposure and employment as an autoclave
cleaner. The risk increased with increasing duration and latency of employment with a
significant trend (for both latency and duration, p < 0.001). For durations of exposure of
10–16, 17–20, 21–25 and ≥ 26 years (1–9 years as the reference), the relative risks for
liver cancer were 2.58 (95% CI, 1.28–5.24), 3.48 (95% CI, 1.49–8.15), 8.21 (95% CI,
3.98–16.9) and 9.39 (95% CI, 4.17–21.1), respectively. For latencies of 21–25, 26–30,
31–36 and ≥ 37 years (0–20 years as reference), the relative risks were 2.44 (95% CI,
1.09–5.45), 2.99 (95% CI, 1.26–7.09), 5.58 (95% CI, 2.34–13.3) and 6.20 (95% CI, 2.30–
16.7), respectively. The trend was also significant for cumulative exposure (p < 0.001);
the risk was almost four times that for the reference category (0–734 ppm–years) starting
with cumulative exposures of 735–1379 ppm–years (relative risk, 3.97; 95% CI, 1.81–
8.71); for 2380–5188, 5189–7531 and ≥ 7532 ppm–years, the relative risks were 7.55
(95% CI, 3.57–15.9), 14.0 (95% CI, 6.43–30.7) and 28.27 (95% CI, 12.84–62.25), respec-
tively. Analysis of the exposure–response trends at low doses (defined as < 1500 ppm–
years and thus including 20 cases of liver cancer) yielded a relative risk of 2.0 (95% CI,
1.3–3.0) for one logarithmic unit of cumulative dose. From the best available data for
diagnosis, 37 cases of angiosarcoma were ascertained for which a significant increasing
trend (p < 0.001) was observed for latency, duration of exposure and cumulative expo-
sure; for ever versus never autoclave cleaners, the relative risk was 25.5 (95% CI, 8.86–
73.2). Ten cases of hepatocellular carcinoma were also used in the internal analysis. For
latency and duration of exposure, the trend in risk was significant (p = 0.001 and
p = 0.002, respectively); the risk was also significant for 7532 ppm–years of cumulative
exposure (relative risk, 20.27; 95% CI, 2.98–137.71; p = 0.004); for ever versus never
having been an autoclave cleaner, the relative risk was 2.97 (95% CI, 0.80–11.1).
In the study of the Porto Marghera plant in Italy (Pirastu et al., 2003), mortality from
primary liver cancer was higher than that expected from regional rates (SMR, 2.78; 90%
CI, 1.86–4.14). In an internal comparison, death rates for primary liver cancer with laten-
cies of 10–30 years (26.1/100 000) and ≥ 30 years (160.7/100 000) were higher than those
for the reference (latency ≤ 10 years). In the internal analysis for employment as an auto-
clave worker (ever/never), the relative risk was 4.4 (90% CI, 1.9–10.0); a significant increasing
trend was seen for increasing cumulative estimated exposure (p <0.001). The analyses of rates
for both liver angiosarcoma (six cases) and hepatocellular carcinoma (12 cases) showed that
longer latency implied higher rates; employment as an autoclave worker (ever/never) was
associated with an increased risk for both angiosarcoma (relative risk, 21.1; 90% CI, 3.5–
128.7) and hepatocellular carcinoma (relative risk, 3.5; 90% CI, 1.4–9.2); for both histo-
types, there was a significant increasing trend with increasing estimated exposure (p < 0.001).
In the same plant (Porto Marghera), an analysis that used internal reference groups
(Gennaro et al., 2003) showed that the relative risk for mortality from liver cancer of
autoclave workers versus all other workers was 9.57 (four deaths; 95% CI, 1.69–54.1); for
two job title groups, ‘compound workers’ and ‘compound + autoclave + PVC bagger
workers’, the relative risks were 3.44 (four deaths; 95% CI, 0.62–18.97) and 4.08 (nine
deaths; 95% CI, 0.85–19.57), respectively.
(c) Other studies

In the Canadian cohort study (Thériault & Allard, 1981), histopathological confir-
mation was available from medical files at the hospitals for 19 of 20 causes of death from
cancer: eight were angiosarcomas of the liver. Two more angiosarcomas of the liver were
notified as cirrhosis on the death certificate and were considered as such throughout this
study. In comparison with an unexposed cohort, the relative risk for digestive cancers
(ICD codes 150–159) was 6.25 (14 observed deaths; 95% CI, 2.69–14.52). [No relative
risks for more specific cancer sites were given.]
In the study by Weber et al. (1981), the SMRs for liver cancer by duration of expo-
sure for < 12 months, 13–60 months, 61–120 months and > 121 months were 0, 8.74 (two
deaths), 15.25 (three deaths) and 25.28 (seven deaths), respectively. [The Working Group
noted that an increased mortality from liver cancer was briefly described in a cohort of
PVC processing workers. This cohort probably included the data of Frentzel-Beyme et al.
(1978).]
No deaths from liver cancer were reported in PVC plants in the former Soviet Union
(Smulevich et al., 1988).
In the French study (Laplanche et al., 1992), three angiosarcomas of the liver and
three liver cancers were observed among the exposed workers compared with none in the
unexposed [no relative risk estimates given].
In a proportionate morbidity study in Taiwan, China (Du & Wang, 1998), an excess
of primary liver cancer was noted (morbidity odds ratio, 4.5 or 6.5, depending on the
comparison group).
In a retrospective cohort study of mortality in Taiwan, China (Wong, O. et al., 2002),
the risk for liver cancer decreased with duration of exposure; the authors suggested that
this might be attributable to a higher turnover of workers in jobs that entailed high
exposures or because workers with illnesses retired early. The excess mortality from liver
cancer was most pronounced among workers who began employment before 1970 (SMR,
4.82; 95% CI, 2.41–8.63), when, according to the authors, exposures to VCM were
higher, because permissible exposure limits for VCM were not established in Taiwan
until 1981. The excess mortality from liver cancer was found to increase with time since
first exposure and to reach a peak after more than 25 years (SMR, 3.13; 95% CI, 1.50–
5.75). It was also found to be inversely related to age at first exposure; workers who were
VINYL CHLORIDE 345
under 30 years of age at first exposure demonstrated the highest risk (SMR, 2.24; 95% CI,
1.07–4.12).
A study of risk factors for hepatocellular carcinoma that was conducted in Taiwan,
China (Wong et al., 2003a), reported an odds ratio of 15.7 (95% CI, 3.6–68.4) for HBsAg
status. An odds ratio of 3.6 (95% CI, 1.4–9.2) was estimated for jobs that entailed high
exposure to VCM; for tank cleaners specifically, the odds ratio was 2.9 (95% CI, 1.1–
7.3). [The Working Group noted that, due to problems in the methodology of this study,
the results were not considered to be useful for the evaluation of the potential relationship
between exposure to vinyl chloride and hepatocellular carcinoma. These methodological
problems included lack of histological confirmation for the majority of cases of hepato-
cellular carcinoma, the resulting potential that some of the cases were truly angio-
sarcomas, lack of detail in the methodology for selection of controls and exclusion of
individuals with evidence of liver disease from the control group.]
[The Working Group considered that the evidence that exposure to VCM is asso-
ciated with cirrhosis of the liver supports the likelihood that exposure to vinyl chloride
increases the risk for hepatocellular carcinoma, although relative risks for hepatocellular
carcinoma are smaller than those associated with angiosarcoma of the liver. Inflammatory
and regenerative processes associated with HBV and hepatitis C viral infection and
chronic alcoholism are considered to be an important pathway through which the risk for
hepatocellular carcinoma is increased by these exposures in the general population.]
(d) Meta-analysis
In meta-analysis of cohort studies of vinyl chloride (Boffetta et al., 2003), duration of
employment was available in three studies (Weber et al., 1981; Mundt et al., 2000; Ward
et al., 2001): in the two multicentric investigations (Mundt et al., 2000; Ward et al.,
2001), an increase in mortality from liver cancer was evident beginning at durations of
≥ 7 years and up to 25 years whereas, in the German study (Weber et al., 1981), a sharp
increase was found starting from 13–16 years of duration of exposure. Mortality from
liver cancer by year of first employment was increased in the two multicentric studies
(Mundt et al., 2000; Ward et al., 2001). [Adjustment for time since first employment
would be advisable; the lack of adjustment could be misleading, as a very strong decrease
in risk over calendar time was shown, while more recently exposed workers had not
completed the latency time necessary for liver cancer to be expressed.]
2.3.2 Case–control studies (Table 6)

A case–control analysis of 23 liver angiosarcomas was conducted at the plant in
Louisville, KY (USA), and confirmed a strong and significant association with exposure to
vinyl chloride and PVC (exposure to vinyl chloride, p < 0.001; exposure to PVC, p = 0.003);
in a case–cohort analysis that used exposure estimated on the basis of a six-point ranking
scale of chemicals present in the plant, cases of angiosarcoma had significantly greater
exposure to vinyl chloride than the reference cohort (Lewis & Rempala, 2003).
346
Table 6. Case–control studies of liver cancer in vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) production
workers
Reference, Organ site Characteristics of Characteristics of Exposure Exposure categories Relative risk Adjustment Comments
location (ICD code) cases controls assessment (95% CI) for potential
confounders
Lewis & ASL 23 men; Matched by year CERM Logistic In Lewis et al.
Rempala histologically of birth and regression (2003), 28

(2003), confirmed duration of analysis showed ASL reported
Louisville, employment strong, highly
KY, USA significant
association with
exposure to VC
(p < 0.001)
and PVC
(p = 0.003)
1817 white men CERM ASL cases had
hired before 1967 significantly
who had worked greater exposure
at least 1 year to VC (69.9%
> 1000 VC–
CERM)
Wong et al. Liver 18 men; 5 histolo- 68 randomly Job titles; high History of high- 2.9 (1.1–7.3) Nested case–
(2003a), cancer; gically confirmed; selected from a VCM-exposure exposure job control; for
Taiwan, HCC 5 AFP > 1000 µg/L pool of eligible jobs: tank cleaning, HBsAg-positive versus 15.7 (3.6–68.4) deceased
China + at least one workers; matched unloading PVC, HBsAg-negative status individuals,
positive image on age and adding catalyst; History of tank cleaning 3.6 (1.4–9.2) validation of
from angiography, specific plant HBsAg status from versus no history exposure by
sonography, liver employment medical next of kin
scan and/or CT; surveillance versus co-
8 from clinical records workers and
manifestation and industrial
imaging studies hygienist
Table 6 (contd)
confounders
Wong et al. HBsAg-positive status 4.0 (0.2–69.1) Family Reference:

(2003a) and history of tank history of HBsAg-
(contd) cleaning chronic liver negative
HBsAg-negative status 396 (22.6–∞) disease status and no
and history of tank history of
cleaning tank cleaning
VINYL CHLORIDE
HBsAg-positive status 25.7 (2.9–229.4)
and no history of tank
cleaning
HBsAg-negative status 2.9 (0.2–50.0)
and history of high
exposure job
HBsAg-positive status 184.5 (15.0–∞)
and history of high
exposure job
HBsAg–positive status 26.1 (2.9–235.1)
and no history of high
exposure job
347
348
Table 6 (contd)
confounders
Mastrangelo HCC 13 men; 8 139 workers with JEMs, job- and Cumulative VCM Nested case–
et al. (2004), histologically no clinical or time-specific VCM exposure (ppm–years) control

Porto confirmed; 5 focal biochemical estimates (ppm); < 500 Reference
Marghera, hepatic lesions at evidence of information for 500–2500 6.32 (0.48–336)
Italy sonography + AFP chronic liver cases from > 2500 29.3 (3.61–1298)
> 400 µg/L disease or cancer company files, < 2500/alcohol < 60 Reference Adjusted for Odds ratio in
at any site from from medical g/day age, univariate
medical surveillance data > 2500/alcohol < 60 18.8 (1.62–218.0) hepatitis analysis
surveillance in for controls; g/day infection
1999–2002 alcoholic beverage < 2500/alcohol > 60 42.9 (3.41–540.0)
consumption from g/day
hospital/clinical > 2500/alcohol > 60 409 (19.6–8553.0)
records and g/day
surveillance data;
serological markers < 2500/HBsAg/HCV- Reference Age,
for HBsAg and negative alcoholic
anti-HCV > 2500/HBsAg/HCV- 25.0 (2.77–226.0) beverage
antibodies negative consumption
< 2500/HBsAg/HCV- 106.9 (4.43–
positive 2578.0)
> 2500/HBsAg/HCV- 210.3 (7.13–
positive 6203.0)
AFP, α-fetoprotein; ASL, angiosarcoma of the liver; CERM, cumulative exposure rank months; CI, confidence interval; CT, computed tomography; HBsAg, hepatitis B
virus surface antigen; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICD, International Classification of Diseases; JEM, job–exposure matrix; VC, vinyl
chloride
VINYL CHLORIDE 349
In the case–control study of cases of liver cancer nested in the cohort in Taiwan, China
(Wong et al., 2003a), tobacco smoking, alcoholic beverage consumption and familial
history of chronic liver disease were not found to be associated with liver cancer, which
may be attributed to the low prevalence of these risk factors in the study population.
A history of employment in a high-exposure job was associated with an increased risk
of 2.9 (95% CI, 1.1–7.3). A strong association was observed with HBsAg (odds ratio,
15.7; 95% CI, 3.6–68.4) or a history of tank cleaning (odds ratio, 3.6; 95% CI, 1.4–9.2).
Models were also fitted that included both HBsAg and a history of tank cleaning, and a
parameter for the potential interaction between the two. Strong evidence for an interaction
between HBsAg and a history of tank cleaning was observed in this model; a history of
tank cleaning and HBsAg negativity had an odds ratio of 4.0 (95% CI, 0.2–69.1), HBsAg
positivity and no history of tank cleaning had an odds ratio of 25.7 (95% CI, 2.9–229.4)
and combined HBsAg positivity and a history of tank cleaning had an odds ratio of 396
(95 % CI, 22.6–∞). Similar results were observed when the analysis was based on a
history of high exposure to VCM rather than a history of tank cleaning. [The Working
Group was concerned that the method used to select controls may have biased the study.
The age at which controls were matched to cases was not clear. Of greater concern is that
the controls were restricted to individuals who had no history of chronic liver disease.
This may have biased the study towards the null since this restriction was not applied to
the cases.]
A cross-sectional study of hepatocellular carcinoma in the Porto Marghera (Italy)
cohort (Mastrangelo et al., 2004) found an association between exposure to VCM and
both liver cirrhosis and hepatocellular carcinoma. The odds ratio for cumulative exposure
to VCM of > 2500 ppm × year was 29.3 (95% CI, 3.61–1298). Odds ratios tended to be
higher for those subjects who were exposed to multiple risk factors. For example, the
odds ratio for exposure to > 2500 ppm × year and consumption of > 60 g per day of
alcohol was 409 (95% CI, 19.6–8553). These analyses controlled for age and hepatitis
viral infection. Similar patterns were seen in analyses of the relationship between expo-
sure to VCM and HBV/hepatitis C viral infection that controlled for alcoholic beverage
consumption. [The Working Group noted that the methodology used to select controls for
this analysis, which excluded individuals who had liver cirrhosis, may have resulted in a
positive bias in the relative risk estimates.]
2.4 Cancer of the brain and central nervous system

2.4.1 Cohort studies (Table 7)
(a) North American multicentric study
An update of the North American multicentric study found an overall SMR for cancer
of the brain and central nervous system of 1.42 (36 exposed deaths; 95% CI, 1.00–1.97)
(Mundt et al., 2000). There was no apparent trend with increasing duration of expo-
sure (9 observed deaths; hazard ratio, 1.9; 95% CI, 0.8–5.0). The risk for brain cancer was
350
Table 7. Cohort studies of brain cancer in vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) production workers
Name of study Cohort description Exposure Type of Exposure categories No. of Relative risk (95% Adjustment Comments
Reference, assessment cancer cases/ CI) for potential

location (ICD deaths confounders
code)

Mundt et al. 10 109 white male JEM Brain and SMR Reference rates:
(2000), USA workers employed CNS Job exposed to VC 36 1.4 (1.0–2.0) state rates and
in 37 plants ≥ 1 year (ICD-9 Age at first exposure (years) Hazard ratio Age at first USA population
in jobs that entailed 191–192) < 25 11 1.0 exposure, p value for
exposure to VCM in 25–34 12 0.9 (0.4–2.0) duration of likelihood ratio
1942–72; mortality ≥ 35 13 2.6 (1.2–5.9) exposure, test for equality
follow–up, 1942– p = 0.02 year of first of survivor
95; vital status, Duration of exposure (years) exposure functions,
96.8%; cause of <5 11 1.0 controlling for
death, 99% 5–9 11 2.0 (0.9–4.7) time at risk
10–19 5 0.7 (0.2–2.0)
≥ 20 9 1.9 (0.8–5.0)
p = 0.09
Table 7 (contd)
code)

Ward et al. 12 700 male Calendar period Brain and SMR Reference rates:
(2000, 2001), workers employed JEM for 13/19 CNS Employed in VC industry 24 0.93 (0.60–1.39) national
Italy, Norway, in 19 VCM/PVC factories grouped (ICD-9 (full cohort) SIR Reference
Sweden, United plants ≥ 1 year in in 22 broad 191–192) 19 0.91 (0.55–1.42) incidence rates:
Kingdom 1950–85; mortality categories; SMR Age, national
VINYL CHLORIDE
follow-up, 1955–97; factory-specific VCM production only 0 0.00 (0.00–5.64) calendar
incidence follow-up, JEM with PVC production only 5 0.96 (0.31–2.25) period
1955–96 validated VCM and PVC production 16 0.93 (0.53–1.51)
exposure PVC processing 18 1.10 (0.23–3.22)
estimates (ppm) Latency (years) Relative risk Age, Poisson
< 16 9 1.00 calendar regression
16–21 4 0.71 (0.19–2.68) period analysis
22–26 3 0.71 (0.16–3.29)
27–34 6 1.37 (0.33–5.63)
≥ 35 2 0.77 (0.11–5.47)
p= 0.82
Duration (years)
1–2 5 1.00
3–6 6 1.34 (0.41–4.40)
7–11 4 0.95 (0.25–3.57)
12–18 4 0.96 (0.25–3.69)
≥ 19 years 5 1.59 (0.43–5.91)
p = 0.72
351
352
Table 7 (contd)
code)
Ward et al. Cumulative exposure (ppm–

(2000, 2001) years)
(contd) 0–34 3 1.00
35–99 3 1.37 (0.28–6.82)
100–535 10 3.45 (0.94–12.6)
536–2811 2 0.75 (0.12–4.50)
≥ 2812 3 1.58 (0.31–8.04)
p = 0.778
Autoclave worker
Never 17 1.00
Ever 5 1.08 (0.40–2.92)
Unknown 2 1.27 (0.29–5.49)
Other studies
Weber et al. 7021 male JEM Brain and SMR Reference rates:
(1981), VCM/PVC CNS VCM/PVC production and 2 1.62 (NR) national
Germany production workers (ICD-8 processing
from beginning of 191)
operation to 1974;
mortality follow-up,
from beginning of
operation to 1974;
vital status, > 90%;
cause of death, 7–
13%
Table 7 (contd)
code)
Smulevich et 3232 VCM/PVC Exposure data in Brain and SMR City (Gorki)
al. (1988), production workers 1953–66 from CNS Estimated area exposure: 4 1.54 (0.41–3.94) mean death
former Soviet (2195 men, 1037 JEM (ICD-9 low, medium and high rates in 1959,
Union women) employed 191–192) 1969 and 1975
for ≥ 1 month in
VINYL CHLORIDE
VCM-exposed jobs;
mortality follow-up,
1939–77
Wong, O. et al. 3293 male workers JEM Brain and SMR Reference rates,
(2002), in 6 PVC CNS 2 [2.86 (0.57–9.16)] national; cohort
Taiwan, China polymerization (ICD-9 assembled from
plants exposed to 191–192) records of the
VCM ≥ 1 year in Labour
1950–92; mortality Insurance
follow-up, 1985–97; Bureau
vital status 99%
CI, confidence interval; CNS, central nervous system; ICD, International Classification of Diseases; JEM, job–exposure matrix; NR, not reported; SIR, standardized
incidence ratio; SMR, standardized mortality ratio; VC, vinyl chloride
353
significantly increased with time since first exposure of ≥ 35 years (hazard ratio, 2.6;
95% CI, 1.2–5.9). The highest SMR was found for those first exposed before 1950
(SMR, 1.74; 95% CI, 0.97–2.88). Mortality from brain cancer was also in excess
among subjects who had worked in plants that began production before 1946 (22
deaths; SMR, 1.77; 95% CI, 1.11–2.68).
(b) European multicentric study

An update of the European multicentric study found an overall SMR for brain cancer
of 0.93 (24 observed deaths; 95% CI, 0.60–1.39); the SIR was 0.91 based on 19 cases
(Ward et al., 2000, 2001). No trends in the SMRs were observed with respect to time
since first employment, duration of employment, cumulative exposure or calendar period
of hire. The risk for brain cancer among those who had ever been autoclave workers was
similar to that of those who had never been autoclave workers. Poisson regression
analyses of deaths from brain cancer found no significant trends with latency, duration of
employment or cumulative exposure to vinyl chloride, although the rate ratio was ele-
vated in the middle-dose category of cumulative dose (relative risk, 3.45; 95% CI, 0.94–
12.6).
In the incidence analyses, significant excesses were found for the category of 27–35
years since first employment (eight observed deaths; SMR, 2.67; 95% CI, 1.15–5.27) and
in the highest category of duration of employment (six observed deaths; SMR, 2.15; 95%
CI, 0.79–4.68), but no apparent trend with cumulative exposure was observed (data not
shown).
(c) Other studies

An SMR of 1.62 (based on two deaths) was reported in the historical cohort study of
VCM/PVC production workers in Germany (Weber et al., 1981). The SMRs by duration
of exposure of < 12 months, 13–16 months, 61–120 months and > 121 months were 0, 0,
3.50 (one death) and 2.78 (one death), respectively.
An SMR of 1.54 (four observed deaths) was reported in a Russian cohort of more
than 3200 VCM/PVC production workers (Smulevich et al., 1988). The SMR was 0.9 for
men and 5 for women.
An SMR of 2.86 for brain cancer (based on two deaths) was reported in a cohort in
Taiwan, China (Wong, O. et al., 2002).
(d) Meta-analysis
In the meta-analysis by Boffetta et al. (2003), the meta-SMR for brain cancer
calculated from five studies was 1.26 (95% CI, 0.98–1.62). The authors noted that the
increase in the meta-SMR was mainly due to the North American multicentric study
(Mundt et al., 2000) and that no trend with duration of exposure was found in either of the
two large studies (Mundt et al., 2000; Ward et al., 2000).
VINYL CHLORIDE 355
2.4.2 Case–control and case–cohort studies

A case–cohort and matched case–control analysis of brain cancer was conducted at a
polymer production plant included in the North American multicentric cohort (Lewis &
Rempala, 2003) in which 15 of 36 deaths from brain cancer were identified. The SMR for
brain cancer was 2.29 (95% CI, 1.29–3.81) at this facility and 1.12 (95% CI, 0.69–1.71) at
all other plants combined (Lewis et al., 2003). Sixteen deaths from brain cancer from
1963 to 2000 were included in the case–cohort and case–control studies. The cases of
brain cancer were slightly less likely than other cohort members to have worked in any
PVC building (18.8% versus 26.5%, respectively), and slightly more likely to have
worked in the building that manufactured nitrile rubber copolymers (31.3% versus 25.9%,
respectively). In general, estimates of cumulative exposure to materials used in PVC pro-
duction among cases of brain cancer were lower than those for other cohort members,
while exposures to chemicals used in nitrile rubber production were similar. In the
matched case–control analysis, no significant associations were observed between status
of brain cancer case and any of the materials used in either PVC or nitrile rubber co-
polymer production.
2.5 Cancer of the lung and respiratory tract

2.5.1 Lung cancer
(a) Cohort studies (Table 8)
(i) North American multicentric study
In an update of the North American multicentric study (Mundt et al., 2000), there was
no evidence of any association between employment with exposure to vinyl chloride and
mortality from lung cancer overall (303 deaths; SMR, 0.82; 95% CI, 0.73–0.92), nor was
there any pattern of association by year of first exposure or year at which production of
vinyl chloride began. The authors noted that regional mortality rates for lung cancer, used
as the primary referent rates in the analysis, were higher than those in the USA as a
whole. The SMR for lung cancer based on national referent rates was 0.96 (95% CI,
0.86–2.07).
(ii) European multicentric study
An update of the European multicentric study found an overall SMR for lung cancer
of 0.95 (272 cases; 95% CI, 0.84–1.07) and an SIR of 0.80 (154 deaths; 95% CI, 0.68–
0.94). No association was observed between mortality from lung cancer and exposure to
vinyl chloride, as estimated by ranked level of exposure, latency, duration of employment,
cumulative exposure to vinyl chloride and ever/never employment as an autoclave worker
(Ward et al., 2000, 2001). Non-significant associations were found for time since first
employment, production or processing and duration of employment. In Poisson regression
356
Table 8. Cohort studies of lung cancer in vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) production workers
location (ICD code) deaths confounders

Mundt et al. 10 109 white male JEM Trachea, SMR (state rates) Reference rates:
(2000), USA workers employed bronchus Job exposed to VC 303 0.82 (0.73–0.92) state rates and
at least ≥ 1 year in and lung SMR (national USA population
jobs that entailed (ICD-9 rates)
exposure to VCM 162) 0.96 (0.86–2.07)
in 1942–72;
mortality follow-
up, 1942–95; vital
status, 96.8%;
cause of death,
99%

Ward et al. 12 700 male Calendar period Trachea, SMR Reference rates:
(2000, 2001), workers employed JEM for 13/19 bronchus Employed in VC industry 272 0.95 (0.84–1.07) national;
Italy, Norway, in 19 VCM/PVC factories and lung (full cohort) SIR incidence rates:
Sweden, United plants ≥ 1 year in grouped in 22 (ICD-9 154 0.80 (0.68–0.94) national
Kingdom 1950–85; mortality broad 162) SMR Age,
follow-up, 1955– categories; VCM production 14 1.47 (0.80–2.47) calendar
97; incidence factory-specific PVC production 56 0.88 (0.67–1.15) period
follow-up, 1955– JEM with VCM and PVC production 184 0.91 (0.79–1.05)
96 validated PVC processing 18 1.43 (0.85–2.26)
exposure
estimates (ppm)
Table 8 (contd)
Ward et al. Latency (years) Relative risk Age, Poisson

(2000, 2001) < 16 57 1.00 calendar regression
(contd) 16–21 55 0.96 (0.65–1.41) period analysis
22–26 66 1.21 (0.82–1.78)
VINYL CHLORIDE
27–34 54 0.73 (0.48–1.11)
≥ 35 40 0.76 (0.47–1.25)
p = 0.119
Duration (years)
1–2 57 1.00
3–6 55 1.12 (0.76–1.64)
7–11 66 1.31 (0.91–1.88)
12–18 54 0.89 (0.60–1.30)
≥ 19 years 40 0.77 (0.52–1.15)
p = 0.094
Cumulative exposure
(ppm–years)
0–34 52 1.00
35–99 52 1.11 (0.75–1.62)
100–535 55 0.90 (0.62–1.32)
536–2811 46 0.85 (0.57–1.27)
≥ 2812 43 0.84 (0.56–1.26)
p = 0.190
357
358
Table 8 (contd)
Ward et al. Autoclave worker

(2000, 2001) Never 220 1.00

(contd) Ever 44 0.84 (0.61–1.16)
Unknown 8 0.38 (0.19–0.77)
Cumulative exposure
(ppm–years)
Ever employed as packers
and baggers
0–34 9 1.12 (0.51–2.13)
35–99 9 0.99 (0.45–1.88)
100–535 14 1.08 (0.59–1.82)
536–2811 9 0.85 (0.39–1.60)
≥ 2812 10 1.02 (0.49–1.88)
Never employed as packers
and baggers
0–34 43 0.98 (0.71–1.33)
35–99 43 1.09 (0.79–1.46)
100–535 41 0.83 (0.60–1.13)
536–2811 37 0.86 (0.60–1.18)
≥ 2812 33 0.87 (0.60–1.23)
Only employed as packers
and baggers
0–34 5 0.88 (0.28–2.04)
35–99 6 1.28 (0.47–2.78)
100–535 11 1.63 (0.81–2.92)
536–2811 4 1.37 (0.37–3.52)
≥ 2812 4 3.12 (0.85–8.00)
Test for trend χ2,
p = 0.009
Table 8 (contd)
Pirastu et al. 1658 male workers JEMs, job- and Lung SMR Reference rates:
(2003), Porto employed in 1956– time-specific cancer Full cohort 40 0.83 (0.64–1.07)a regional
Marghera, Italy 99; mortality VCM estimates (ICD-9 Only versus never baggers 7 1.73 (0.93–3.21) Not Internal
follow–up, 1973– (ppm); 162.1– SMR adjusted comparison
99; vital status, ever/never 162.9) 7 2.31 (1.15–4.61)a Latency versus never
100%; cause of autoclave baggers
death, 99% worker
VINYL CHLORIDE
Other studies
Thériault & 451 male workers Questionnaire Trachea, SMR Reference rates:
Allard (1981), exposed to VCM to the worker or bronchus Exposed to VCM 2 0.34 (0.04–1.25) Canadian
Québec, Canada for ≥ 5 years in a next of kin on and lung population in
polymerization detailed (ICD-9 1971;
plant, employed in occupational 162) comparison
1948–72; mortality history population: 870
follow-up, 1948– workers not
77 exposed to
VCM for ≥ 5
months
Smulevich et al. 3232 VCM/PVC Exposure data Trachea, SMR City (Gorki)
(1988), former production workers in 1953–66 bronchus Estimated area exposure: 17 1.39 (0.81–2.23) mean death
Soviet Union (2195 men, 1037 from JEM and lung low, medium and high rates in 1959,
women) employed (ICD-9 1969 and 1975
for ≥ 1 month in 162)
VCM-exposed
jobs; mortality
follow-up, 1939–
77
359
360
Table 8 (contd)
Laplanche et al. 1100 VCM– JEM Trachea, 6 among NR Prospective

(1992), France exposed and 1100 bronchus exposed; study
unexposed and lung 2 among
subjects; matched (ICD-9 un-
on age, plant, 162) exposed
physician, aged
40–55 years,
identified in 1980;
mortality and
morbidity follow-
up, 1980–88
Wong, O. et al. 3293 male workers JEM Trachea, SMR Reference rates:
(2002), Taiwan, in 6 PVC bronchus 4 0.59 (0.16-1.52) national; cohort
China polymerization and lung enumerated
plants exposed to (ICD-9 from records of
VCM ≥ 1 year in 162) the Labour
1950–92; mortality Insurance
follow–up, 1985– Bureau
97; vital status 99%
CI, confidence interval; ICD, International Classification of Diseases; JEM, job–exposure matrix; NR, not reported; SIR, standardized incidence ratio; SMR,
standardized mortality ratio; VC, vinyl chloride
a
90% confidence interval
VINYL CHLORIDE 361
analyses, non-significant negative trends were observed with increasing cumulative

exposure.
A possible association between exposure to PVC dust and lung cancer was suggested
by several early studies as well as recent investigations of PVC baggers in a VCM/PVC
manufacturing plant in Italy (Pirastu et al., 1998; Mastrangelo et al., 2003). Therefore,
packers and baggers were examined separately in the European multicentric cohort study.
No trend in risk was observed with increasing cumulative exposure for those who had
ever been employed as packers and baggers, among whom 53 deaths from lung cancer
occurred (Ward et al., 2000). However, among individuals who only worked as packers
and baggers, 30 deaths from lung cancer occurred, and the trend with increasing cumu-
lative exposure was statistically significant.
In the cohort of 1658 vinyl chloride workers in Porto Marghera (Pirastu et al., 2003),
an SMR for lung cancer of 1.73 (seven deaths; 90% CI, 0.93–3.21) was observed among
‘only baggers’; the SMR for ‘only baggers’ versus ‘never baggers’ adjusted for latency
was 2.31 (90% CI, 1.15–4.61; p = 0.047).
(iii) Other studies
In a Canadian cohort, an SMR of 0.34 (95% CI, 0.04–1.25) was reported for cancer of
the lung, trachea or bronchus (Thériault & Allard, 1981).
A study in the former Soviet Union (Smulevich et al., 1988) showed an SMR of 1.39
(17 observed deaths; 95% CI, 0.81–2.23) for lung cancer and a cohort study in France
(LaPlanche et al., 1992) reported eight observed deaths from lung cancer but did not
include risk estimates.
A study in Taiwan, China, reported an SMR of 0.59 (four observed deaths) for lung
cancer (Wong, O. et al., 2002).
(iv) Meta-analysis
The meta-analysis by Boffetta et al. (2003) showed a meta-SMR for lung cancer of
0.90 (95% CI, 0.77–1.06) based on five studies.
(b) Case–control studies (Table 9)

In a nested case–control study in Porto Marghera, Italy, risk factors for lung cancer
were examined among 38 subjects who had lung cancer and 224 subjects with no history
of cancer (Mastrangelo et al., 2003). Although no association was observed between
estimated cumulative exposure to VCM and lung cancer, the odds ratio for exposure to
PVC dust among baggers with known length of exposure was 5.60 (95% CI, 2.03–16.3).
When stratified by duration of work as a bagger, the odds ratio was 2.87 (95% CI, 0.84–
8.56) among those who were employed for < 3.6 years and 7.15 (95% CI, 2.55–19.3)
among those employed for > 3.6 years. Although the quantity of cigarettes smoked per
day was associated with lung cancer, this did not appear to confound the association
between lung cancer and work as a bagger.
362
Table 9. Case–control studies of lung cancer in vinyl chloride monomer (VCM) and polyvinyl chloride (PVC) production
workers
Reference, Organ site Characteristics Characteristics Exposure Exposure category No. of Odds ratio Adjustment for Comments
location (ICD code) of cases of controls assessment cases/controls (95% CI) potential
confounders

Mastrangelo et Trachea, 38 228 with no Facility- Cumulative Smoking habits Italian
al. (2003), Italy bronchus histologically history of specific JEM exposure to VCM in relation to cohort of
and lung confirmed cancer (ppm–years) years of work 1658 vinyl
(ICD-9 162) lung cancers ≤ 392 16/71 1.00 as a bagger chloride
393–1650 13/74 0.78 (0.32–1.87) workers;
≥ 1651 9/79 0.51 (0.18–1.31) nested
χ2 trend p > 0.01 case–
Circumstances of control
exposure to PVC
dust
None 8/87 1.00
PVC 8/49 1.78 (0.54–5.78)
compounding
Baggers 5/55 0.99 (0.24–3.63)
(unknown length)
Baggers (known 17/33 5.60 (2.03–16.3)
length)
PVC compounding
None 30/175 1.00
≤ 8.0 years 4/23 1.10 (0.24–3.28)
> 8.0 years 4/26 0.90 (0.21–2.86)
Table 9 (contd)
Reference, Organ site Characteristics Characteristics Exposure Exposure No. of Odds ratio Adjustment for Comments
location (ICD code) of cases of controls assessment category cases/controls (95% CI) potential
confounders
Mastrangelo et Baggers Nested

al. (2003) Duration of job case–
(contd) None 21/191 1.00 control
VINYL CHLORIDE
< 3.6 years 6/19 2.87 (0.84–8.56)
≥ 3.6 years 11/14 7.51 (2.55–19.3)
Calendar year of
onset
None 21/191 1.00
Before 1967 10/19 4.79 (1.73–12.5)
Since 1967 7/14 4.55 (1.38–13.6)
onwards
Age at onset
No 21/191 1.00
≤ 33 years 6/20 2.73 (0.80–8.07)
> 33 years 11/13 7.70 (2.72–21.1)
Length of time
elapsed from
onset of job to end
of follow-up or
death
None 21/191 1.00
20 years 12/29 3.76 (1.51–8.99)
≤ 20 years 5/4 11.4 (2.21–60.7)
363
364
Table 9 (contd)
Reference, Organ site Characteristics Characteristics Exposure Exposure No. of Odds ratio Adjustment for Comments
location (ICD code) of cases of controls assessment category cases/controls (95% CI) potential
confounders
Scélo et al. Trachea, 2861 lung 3118 (excluded For each job Never 2822/3098 1.00 Gender, age, Population-

(2004), seven bronchus cancers in hospital held, local Ever 1.05 (0.68–1.62) tobacco, based
European and lung 1998–2002 patients experts Duration (years) acrylonitrile,
countries (ICD-9 162) admitted for assessed None 2794/3062 1.0 styrene, plastics
tobacco-related intensity and 1–6 18/17 0.74 (0.35–1.56) pyrolysis
diseases) frequency of 7–14 15/18 0.86 (0.39–1.90) products,
exposure to > 14 34/21 1.56 (0.81–3.03) chromium dust
vinyl Test for linear
chloride, trend, p= 0.119
acrylonitrile Cumulative
and styrene exposure (ppm–
years)
None 2794/3062 1.00
0.01–1.75 25/23 0.90 (0.46–1.75)
1.76–12.50 24/16 0.96 (0.47–1.98)
> 12.50 18/17 1.51 (0.65–3.47)
CI, confidence interval; ICD, International Classification of Diseases; JEM, job–exposure matrix
VINYL CHLORIDE 365
In a case–control study from seven European countries (Scélo et al., 2004) that included
2861 cases of lung cancer and 3118 hospital controls, the odds ratio for ever exposure to
vinyl chloride was 1.05 (95% CI, 0.68–1.62). A modest non-significant increase in the
risk for lung cancer was found in the highest-exposed subgroup.
2.5.2 Other cancers of the respiratory tract

With respect to other cancers of the respiratory tract, neither the European nor the
North American multicentric cohort studies found any evidence of an excess incidence of
or mortality from laryngeal cancer. Mortality from cancer of the pleura was moderately
elevated in the update of the European multicentric cohort (nine deaths; SMR, 1.89; 95%
CI, 0.86–3.59) (Ward et al., 2000, 2001). In an update of the North American multicentric
study (Mundt et al., 2000), an elevated SMR was found for cancer of other parts of the
respiratory tract (six deaths; SMR, 1.80; 95% CI, 0.66–3.92).
2.6 Cancer of the lymphatic and haematopoeitic tissues (Table 10)

2.6.1 North American multicentric study
In the update of the North American multicentric study, the SMR for cancer of the
lymphatic and haematopoeitic tissues was 0.86 (71 observed deaths; 95% CI, 0.67–1.08).
The SMR for lymphosarcoma and reticulosarcoma (defined as ICD-9 code 200) was 1.20
(12 deaths; 95% CI, 0.62–2.09). No excesses were reported for other leukaemias or
Hodgkin lymphoma (Mundt et al., 2000).
2.6.2 European multicentric study

In an update of the European multicentric cohort study, an SMR of 0.94 (62 deaths;
95% CI, 0.72–1.21) was observed for cancers of lymphatic and haematopoeitic tissue; no
significant excess was reported in any category of leukaemia or lymphoma. The overall
SMR of 1.19 (26 deaths; 95% CI, 0.78–1.75) for non-Hodgkin lymphoma (Ward et al.,
2000, 2001) was much lower than that observed in the original study (seven deaths; SMR,
1.70; 95% CI, 0.69–3.71) (Simonato et al., 1991). The SIR for non-Hodgkin lymphoma
(ICD-9 code 200 and 202) in the updated study was 0.78 (20 deaths; 95% CI, 0.48–1.21);
SIRs reported for other leukaemias and lymphomas were all below 1.00. Among the four
countries, Italy had the highest SMR of 1.86 (95% CI, 0.84–3.54) and much of the excess
was in the mixed production plants (SMR, 1.52; 95% CI, 0.96–2.27). No significant
trends were observed with time since first employment, duration of employment, cumu-
lative exposure or calendar period of hire. In the Poisson regression analyses, there ap-
peared to be some elevation in rate ratios above the baseline category of cumulative dose,
but the trend was not statistically significant (data not shown).
366
Table 10. Cohort studies of lymphohaematopoietic neoplasms in vinyl chloride monomer (VCM) and polyvinyl chloride (PVC)
production workers
Name of study Cohort description Exposure Type of cancer Exposure categories No. of Relative risk (95% Adjustment Comments
Reference, assessment (ICD code) cases/ CI) for potential

Mundt et al. 10 109 white male JEM Job exposed to VC SMR Reference rates:

(2000), USA workers from 37 Lymphohaemato- 71 0.86 (0.67–1.08) state rates
plants (race poeitic (ICD-9
unknown, 6%) 200–208)
employed at least Lymphosarcoma or 12 1.20 (0.62–2.09)
≥ 1 year in jobs reticulosarcoma
that entailed (ICD-9 200)
exposure to VCM Hodgkin lymphoma 3 0.44 (0.09–1.29)
in 1942–72; (ICD-9 201)
mortality follow- Leukaemia/ 31 0.94 (0.64–1.34)
up, 1942–95; vital aleukaemia (204–
status, 96.8%; 208)
cause of death,
99%

Ward et al. 12 700 male Calendar period Employed in VC SMR Reference rates
(2000, 2001), workers employed JEM for 13/19 Lymphohaemato- industry (full 62 0.94 (0.72–1.21) Age, and incidence
Italy, Norway, at 19 VCM/PVC factories poeitic (ICD-9 cohort) calendar rates: national
Sweden, United plants ≥ 1 year in grouped in 22 200–208) period Poisson regression
Kingdom 1950–85; mortality broad Non-Hodgkin 26 1.19 (0.78–1.75) analysis
follow-up, 1955– categories; lymphoma
97; incidence factory-specific (ICD-9 200, 202)
follow-up, 1955–96 JEM with Hodgkin lymphoma 7 1.03 (0.41–2.12)
validated (ICD-9 201)
exposure Leukaemia 22 0.87 (0.54–1.31)
estimates (ppm) (ICD-9 204–208)
Table 10 (contd)
Other studies
Thériault & 451 male workers Questionnaire Leukaemia (ICD-9 Exposed versus SMR Reference rates:
Allard (1981), exposed to VCM to the worker or 200–209) unexposed 1 0.60 (NR) Canadian
Québec, Canada for ≥ 5 years in a next of kin on population in
polymerization detailed 1971; comparison
VINYL CHLORIDE
plant, employed in occupational population: 870
1948–72; mortality history workers not
follow-up, 1948–77 exposed to VCM
for ≥ 5 months
Weber et al. 7021 male JEM Lymphatic and Exposed versus 15 2.14 (1.12–3.53) Reference rates:
(1981), VCM/PVC haematopoietic unexposed national
Germany production workers (ICD-8 200–209)
from beginning of
operation to 1974;
mortality follow-
up, from beginning
of operation to
1974; vital status,
> 90%; cause of
death, 7–13%
367
368
Table 10 (contd)
Smulevich et al. 3232 VCM/PVC Exposure data Estimated area SMR City (Gorki) mean

(1988), former production workers in 1953–66 Non-Hodgkin exposure: low, 5 4.17 (p < 0.05) death rates in
Soviet Union (2195 men, 1037 from JEM lymphoma and medium and high 1959, 1969 and
women) employed multiple myeloma 1975
for ≥ 1 month in (ICD-9 200, 202,
VCM-exposed 203)
jobs; mortality Leukaemia (ICD-9 5 5.00 (p < 0.05)
follow-up, 1939–77 204–207)
Wong, O. et al. 3293 male workers JEM SMR Reference rates:
(2002), Taiwan, in 6 PVC Lymphatic and 7 2.71 (1.09–5.60) national; cohort
China polymerization haematopoietic assembled from
plants exposed to (ICD-9 200–208) Bureau of Labour
VCM ≥ 1 year in Insurance
1950–92; mortality
follow-up, 1985–
97; vital status,
99%
CI, confidence interval; ICD, International Classification of Diseases; JEM, job–exposure matrix; NR, not reported; SMR, standardized mortality ratio; VC, vinyl chloride
VINYL CHLORIDE 369
2.6.3 Other studies

Only one death from leukaemia (1.67 expected; SMR, 0.60) was reported in the
Canadian study (Thériault & Allard, 1981).
Two independent European studies in Germany (Weber et al., 1981) and the former
Soviet Union (Smulevich et al., 1988) have reported significantly increased mortality
from neoplasms of the lymphatic and haematopoeitic system (Germany: SMR, 2.14; 95%
CI, 1.12–3.53; former Soviet Union: SMR, 4; p < 0.05.
A study in Taiwan, China, reported a significant SMR for neoplasms of the lymphatic
and haematopoeitic system (seven deaths; SMR, 2.71; 95% CI, 1.09–5.60) (Wong, O. et
al., 2002).
2.6.4 Meta-analysis
The meta-analysis by Boffetta et al. (2003) showed a meta-SMR for neoplasms of the
lymphatic and haematopoeitic system of 0.90 (95% CI, 0.75–1.07) based on the two
multicentric cohorts. A meta-SMR for all studies was not calculated due to the high
degree of heterogeneity between studies.
Non-Hodgkin lymphoma and multiple myeloma (ICD-9 200, 202, 203) were
combined in the meta-analysis (Boffetta et al., 2003). SMRs for both the European and
North American multicentric cohorts were below 1.00. However, an independent study
from the former Soviet Union reported a significantly elevated SMR of 4.17 (p < 0.05) for
this category of neoplasms (Smulevich et al., 1988). Due to borderline results for tests of
heterogeneity, the multicentric cohorts and three independent studies were combined in
the meta-analysis to yield a meta-SMR of 1.23 (95% CI, 0.70–2.19).
2.7 Malignant melanoma and cancer of the skin (Table 11)

2.7.1 North American multicentric cohort study
In the update of the North American cohort (Mundt et al., 2000), no elevation in mortality
from skin cancer was observed (12 observed deaths; SMR, 0.64; 95% CI, 0.33–1.12).
2.7.2 European multicentric cohort study

An update of the European multicentric study found a non-significantly elevated
SMR for malignant melanoma (15 deaths; SMR, 1.60; 95% CI, 0.90–2.65) (Ward et al.,
2000, 2001). The analysis of incidence did not show an excess of melanoma (18 observed
cases; SIR, 1.06; 95% CI, 0.63–1.68). An excess of mortality from melanoma had been
previously noted for the Norwegian cohort and was found to be dose-related (Heldaas et
al., 1984, 1987; Langărd et al., 2000). In the update of the European multicentric study,
the excess in Norway was statistically significant (five deaths; SMR, 6.27; 95% CI, 2.04–
14.6) (Ward et al., 2001). An excess of mortality from melanoma was also observed in
370
Table 11. Cohort studies of malignant melanoma or skin cancer in vinyl chloride monomer (VCM) and polyvinyl chloride
(PVC) production workers
Name of Cohort description Exposure Type of Exposure categories No. of Relative risk (95% Adjustment Comments
study assessment cancer cases/ CI) for potential
Reference, (ICD deaths confounders
location code)

Mundt et al. 10 109 white male workers JEM Skin Job exposed to VC SMR Reference rates:

(2000), USA in 37 plants (race (ICD-9 12 0.64 (0.33–1.12) state and USA
unknown, 6%) employed 172–173) population
at least ≥ 1 year in jobs
that entailed exposure to
VCM in 1942–72;
mortality follow-up, 1942–
95; vital status, 96.8%;
cause of death, 99%
Ward et al. 12 700 male workers Calendar Melanoma Employed in VC industry SMR Reference rates
(2000, 2001), employed in 19 period JEM (ICD-9 (full cohort) 15 1.60 (0.90–2.65) and incidence
Italy, VCM/PVC plants ≥ 1 year for 13/19 172) SIR rates: national
Norway, in 1950–85; mortality factories 18 1.06 (0.63–1.68)
Sweden, follow-up, 1955–97; grouped in 22 SMR Age, calendar
United incidence follow-up, broad VCM production 1 5.13 (0.13–28.6) period
Kingdom 1955–96 categories; PVC production 0 (0.00–2.45)
factory- VCM and PVC production 13 2.12 (1.13–3.62)
specific JEM PVC processing 1 0.66 (0.02–3.68)
with validated Latency (years) Relative risk Age, calendar Poisson
exposure < 16 4 1.00 period regression
estimates 16–21 3 1.06 (0.20–5.61) analysis
(ppm) 22–26 1 0.49 (0.04–5.43)
27–34 3 1.78 (0.25–12.8)
≥ 35 4 4.41 (0.51–38.4)
p= 0.193
Table 11 (contd)
Name of Cohort description Exposure Type of Exposure categories No. of Relative risk (95% Adjustment Comments
study assessment cancer cases/ CI) for potential
Reference, (ICD deaths confounders
location code)
Ward et al. Duration (years)

(2000, 2001) 1–2 5 1.00
(contd) 3–6 1 0.22 (0.03–1.85)
7–11 1 0.22 (0.03–1.89)
12–18 4 0.83 (0.22–3.16)
≥ 19 4 1.10 (0.27–4.44)
VINYL CHLORIDE
p = 0.665
Cumulative exposure
(ppm–years)
35–99 3 1.00
100–535 4 2.31 (0.51–10.3)
536–2811 4 2.57 (0.57–11.5)
≥ 2812 3 2.68 (0.53–13.7)
p = 0.193
Other studies
Smulevich et 3232 VCM/PVC Exposure data Estimated area exposure: SMR City (Gorki)
al. (1988), production workers (2195 in 1953–66 low, medium and high 1 2.00 (p > 0.05) mean death
former men, 1037 women) from JEM rates in 1959,
Soviet Union employed for ≥ 1 month in 1969 and 1975
VCM-exposed jobs;
mortality follow-up, 1939–
77
CI, confidence interval; ICD, International Classification of Diseases; JEM, job–exposure matrix; SIR, standardized incidence ratio; SMR, standardized mortality ratio;
VC, vinyl chloride
371
the Italian cohort (four deaths; SMR, 1.96; 95% CI, 0.53–5.01). No association was
observed with previous employment as an autoclave cleaner.
2.7.3 Other cohort studies

In a study in the former Soviet Union (Smulevich et al., 1988), one case of melanoma
skin cancer was reported (SMR, 2.00; p > 0.05).
No cases were reported from the other independent studies (Thériault & Allard, 1981;
Weber et al., 1981; Laplanche et al., 1992; Wong, O. et al., 2002).
2.7.4 Meta-analysis
In the meta-analysis, results for mortality from skin cancer were heterogeneous,
with no overall indication of an increased risk (meta-SMR, 1.11; 95% CI, 0.49–2.54)
(Boffetta et al., 2003).
2.8 Cancer of the breast

Although concern has been raised about a potential association between exposure
to vinyl chloride and the risk for breast cancer, human studies to date are not informative
on this issue because of the very small numbers of women included. The analyses of both
the European and North American cohorts included only men because of the extremely
small number of women available for analysis (59 in the European multicentric cohort
and 11 in the North American cohort) (Mundt et al., 2000; Ward et al., 2000, 2001). No
deaths from breast cancer were observed in the European multicentric cohort (Ward et al.,
2000), with only 0.53 expected, and two deaths were observed in the North American
cohort, with 1.05 expected (SMR, 1.90; 95% CI, 0.23–6.87) (Mundt et al., 2000).
2.9 Soft-tissue sarcoma

2.9.1 North American multicentric cohort study
In the update of the North American multicentric study (Mundt et al., 2000), the SMR
for cancer of connective and soft tissue was 2.70 (12 deaths; 95% CI, 1.39–4.72);
significant excesses were observed for those employed for 10–19 years (SMR, 4.77; 95%
CI, 1.55–11.1) and for those employed for 20 years or more (SMR, 7.25; 95% CI, 1.97–
18.6). SMRs were also significantly increased for first exposure before 1950 (SMR, 3.33;
CI, 1.08–7.77) and between 1950 and 1959 (SMR, 4.68; 95% CI, 1.88–9.64). Seven of
the 12 cancers were specific soft tissue other than angiosarcomas, and four were angio-
sarcomas with site not specified.
VINYL CHLORIDE 373
2.9.2 European multicentric cohort study

A total of six soft-tissue sarcomas were observed in the European multicentric study
(SMR, 1.89; 95% CI, 0.69–4.11) (Ward et al., 2000, 2001), all of which occurred in the
United Kingdom. Three additional soft-tissue sarcomas were identified from the inci-
dence data (one in the United Kingdom and two in Sweden). However, during the review
of the best available data for diagnosis to ascertain cases of liver cancer, it became appar-
ent that three of the six deaths coded as tumours of the connective tissue were actually
angiosarcomas of the liver, the primary site of which had been miscoded. A Poisson re-
gression analysis was not conducted for the remaining soft-tissue sarcomas due to the
small number of cases involved.
2.9.3 Other cohort studies

Two deaths from soft-tissue sarcoma were observed in the Canadian cohort (SMR,
5.26) (Thériault & Allard, 1981).
One case of soft-tissue sarcoma was observed in the cohort from the former Soviet
Union (SMR, 1.43; p > 0.05) (Smulevich et al., 1988)
3. Studies of Cancer in Experimental Animals
Studies of the carcinogenicity of vinyl chloride following oral, inhalation and/or intra-
tracheal administration, subcutaneous and/or intramuscular administration, intraperitoneal
administration and perinatal exposure have been reviewed previously (IARC, 1979,
1987). Those that were found to be adequate and/or reported more fully in later publi-
cations are included in this section.
The carcinogenicity of vinyl chloride has been studied intensively and repeatedly by
inhalation exposure of experimental animals at a range of concentrations that spanned
decimal orders of magnitude. The numerous studies were generally mutually reinforced
and consistently yielded hepatic and extrahepatic angiosarcomas in mice, rats and ham-
sters. Various other malignant neoplasms also occurred at several anatomical sites.
However, the reporting of this multitude of data has often been incomplete, and the
outcomes of many studies are available only from summary tables in the published
literature, in which technical details are given only as footnotes.
3.1 Inhalation exposure

3.1.1 Mouse
Groups of 12 male and 12 female NMRI mice, 12 weeks of age, were exposed by
inhalation to 50 or 500 ppm [130 or 1300 mg/m3] vinyl chloride [purity unspecified] on
6 h per day for 5 days per week for either 26 (500 ppm) or 52 (50 ppm) weeks. Two
groups of 12 male and 12 female control mice were untreated and were observed for
either 26 or 52 weeks. The treatment with 500 ppm vinyl chloride was terminated at week
26 because of poor survival. The incidence of treatment-related tumours in males of the
two control groups combined, and low- and high-dose groups, respectively, was: extra-
hepatic angiosarcomas, 0/24, 6/12 and 3/12; and lung tumours, 0/24, 9/12 and 12/12. That
in females was: extrahepatic angiosarcomas, 0/24, 8/12 and 5/12; and lung tumours, 0/24,
4/12 and 12/12. Mammary carcinomas were observed in 1/24, 1/12 and 4/12 control, low-
dose and high-dose females, respectively [no statistical analysis reported] (Holmberg
et al., 1976).
Groups of 36 male and 36 female CD-1 mice, 2 months of age, were exposed by
inhalation to 0, 50, 250 or 1000 ppm [0, 130, 650 or 2600 mg/m3] vinyl chloride (99.8%
pure) in air for 6 h per day on 5 days per week for 52 weeks. Four animals per group were
terminated at 1, 2, 3, 6 or 9 months for laboratory tests and gross and histological exam-
ination. The incidence of liver angiosarcomas in control, 50-, 250- and 1000-ppm vinyl
chloride-treated mice, respectively, was 0/26, 3/29, 7/29 (p < 0.05, Fisher’s exact test) and
13/33 (p < 0.05) males and 0/36, 0/34, 16/34 (p < 0.05) and 18/36 [p < 0.05] females; that
of extrahepatic angiosarcomas was 0/26, 5/29 (p < 0.05), 2/29 and 0/33 males and 0/36,
1/34, 3/34 and 9/36 (p < 0.05) females, respectively; and that of lung tumours (adenomas)
was 1/26, 8/29, 10/29 and 22/33 males and 0/36, 4/34, 12/34 and 26/36 females, respec-
tively. The incidence of mammary tumours (adenocarcinomas and carcinomas) in female
mice was 0/36, 9/34, 3/34 and 13/36, respectively [no statistical analysis reported for lung
and mammary tumours] (Lee et al., 1978).
Groups of 8–28 male and 8–28 female CD1 mice, 2 months of age, were exposed by
whole-body inhalation to 0, 130, 650 or 2600 mg/m3 [0, 340, 1690 or 6760 ppm] vinyl
chloride (99.8% pure) for 6 h per day on 5 days per week for 1, 3 or 6 months and were
then removed from exposure chambers and observed for an additional 12 months. The
incidence of haemangiosarcoma and lung and mammary gland tumours is presented in
Table 12. An increased cumulative incidence of haemangiosarcomas and bronchiolo-
alveolar lung tumours was seen in male and female mice and an increase in the cumu-
lative incidence of mammary gland adenocarcinomas/carcinomas in females (Hong et al.,
1981).
Groups of 30 male and 30 female Swiss mice [data reported for both sexes
combined], 11 weeks of age, were exposed by inhalation to 50, 250, 500, 2500, 6000 or
10 000 ppm [130, 650, 1300, 6500, 15 600 or 26 000 mg/m3] vinyl chloride (99.97%
pure) on 4 h per day on 5 days per week for 30 weeks. Control animals comprised 150
untreated mice [sex distribution not specified; data reported for both sexes combined].
Animals were observed until 81 weeks, when the experiment (experiment BT4) was
terminated. Survival rates of the groups were not reported. The incidence of treatment-
related tumours in control and 50-, 250-, 500-, 2500-, 6000- and 10 000-ppm vinyl
chloride-treated mice, respectively, was: liver angiosarcomas, 0/150, 1/60, 18/60, 14/60,
16/59, 13/60 and 10/56; extrahepatic angiosarcomas, 1/150, 1/60, 3/60, 7/60, 8/59, 1/60
VINYL CHLORIDE 375
Table 12. Tumour incidence in CD1 mice exposed by inhalation to vinyl

chloride for 1–6 months and observed for an additional 12 months
Tumour type Tumour incidence/no. examined
Concentration (ppm) [mg/m3]

0 50 [130] 250 [650] 1000 [2600]
Males
1 month
Liver
Haemangiosarcoma 0/16 1/16 0/16 0/16
Lung
Bronchioloalveolar tumour 2/16 3/16 10/16 11/16
3 months
Liver
Lung
6 months
Liver
Lung
Cumulative incidence
Liver
Haemangiosarcomaa 0/60 1/40 8/44c 6/38c
Lung
Bronchioloalveolar tumourb 8/60 12/40 29/44c 27/38c
Females
1 month
Liver
Lung
Mammary gland
Adenocarcinoma/carcinoma 1/16 4/16 2/16 0/16
3 months
Liver
Lung
Mammary gland
Table 12 (contd)
Tumour type Tumour incidence/no. examined
Concentration (ppm) [mg/m3]

0 50 [130] 250 [650] 1000 [2600]
6 months
Liver
Lung
Mammary gland
Cumulative incidence
Liver
Haemangiosarcomaa 1/60 1/40 5/40c 12/38c
Lung
Bronchioloalveolar tumourb 8/60 6/40 23/40c 23/38c
Mammary gland
Adenocarcinoma/carcinoma 4/60 10/40d 13/40d 6/38d
From Hong et al. (1981)

a
Significant dose-related incidence (males and females combined); Cochran-Armitage trend test
b
Significant non-linearity in dose–incidence curve (males and females combined); Cochran-Armitage
trend test
c
Combined incidence in males and females significantly different from controls (p < 0.05, Fisher’s exact
test)
d
Incidence in females significantly different from controls (p < 0.05, Fisher’s exact test)
and 1/56; lung tumours, 15/150, 6/60, 41/60, 50/60, 40/59, 47/60 and 46/56; and
mammary carcinomas, 1/150, 12/60, 12/60, 8/60, 8/59, 8/60 and 13/56. A low incidence
of skin tumours was also reported [no statistical analysis provided] (Maltoni et al., 1981).
Groups of female Swiss CD-1 mice [initial numbers not specified], 8–9 weeks of age,
were exposed by whole-body inhalation to 0 (control) or 130 mg/m3 [0 or 50 ppm] vinyl
chloride (commercial grade) [purity unspecified] for 6 h per day on 5 days per week for 6,
12 or 18 months. Animals were allowed to complete their lifespan and were necropsied
when moribund or dead. There was a significant decrease (p < 0.01) in survival of the
animals treated for 6, 12 and 18 months compared with controls. Statistically significant
increases (p < 0.01, life-table analysis) in the incidence of haemangiosarcomas (all sites,
mainly peritoneal and skin), mammary gland carcinomas and lung carcinomas were
observed in all exposure groups. The incidence of haemangiosarcomas (all sites) was:
control, 1/71; exposed for 6 months, 29/67; 12 months, 30/47; and 18 months, 20/45. The
incidence of mammary gland carcinomas was 2/71, 33/67, 22/47 and 22/45, respectively;
and that of lung carcinomas was 9/71, 18/65, 15/47 and 11/45, respectively. In the same
VINYL CHLORIDE 377
study, groups of female Swiss CD-1 mice [initial numbers not specified], 8 or 14 months
of age, were exposed by whole-body inhalation to 0 (control) or 130 mg/m3 [0 or 50 ppm]
vinyl chloride for 6 h per day on 5 days per week for 6 or 12 months. Animals were
allowed to complete their lifespan and were necropsied when found moribund or dead.
Among animals exposed for 6 months beginning at 8 and 14 months of age, statistically
significant increases (life-table analysis) in the incidence of haemangiosarcomas (all sites)
(control, 1/71; 8 months of age, 11/49, p < 0.01; and 14 months of age, 5/53), mammary
gland carcinomas (control, 2/71; 8 months of age, 13/49, p < 0.01; and 14 months of age,
2/53) and lung carcinomas (control, 9/71; 8 months of age, 13/49, p < 0.05; and 14
months of age, 7/53) were observed in the animals exposed beginning at 8 months of age
only. Among those exposed for 12 months, statistically significant increases in the
incidence of haemangiosarcomas (all sites) (control, 1/71; 8 months of age, 17/46,
p < 0.01; and 14 months of age, 3/50), mammary gland carcinomas (control, 2/71;
8 months of age, 8/45, p < 0.01; and 14 months of age, 0/50) and lung carcinomas
(control, 9/71; 8 months of age, 9/46, p < 0.05; and 14 months of age, 3/50) were
observed in the animals exposed beginning at 8 months of age only (Drew et al., 1983).
Groups of female B6C3F1 mice [initial number not specified], 8–9 weeks of age,
were exposed by whole-body inhalation to 0 (control) or 130 mg/m3 [0 or 5.0 ppm] vinyl
chloride (commercial grade) [purity unspecified] for 6 h per day on 5 days per week for 6
or 12 months. Animals were allowed to complete their lifespan and were necropsied
when found moribund or dead. There was a significant decrease (p < 0.01) in survival of
the animals treated for 6 or 12 months compared with controls. Statistically significant
increases (p < 0.01, life-table analysis) in the incidence of haemangiosarcomas (all sites)
and mammary gland tumours were observed in all exposure groups. The incidence of
haemangiosarcomas (all sites, mainly peritoneal and subcutis) was: control, 4/69; exposed
for 6 months, 46/67; and 12 months, 69/90; that of mammary gland carcinomas was 3/69
(control), 29/67 and 37/90, respectively. In the same study, groups of female B6C3F1
mice [initial number not specified], 8 or 14 months of age, were exposed by whole-body
inhalation to 0 (control) or 130 mg/m3 [0 or 50 ppm] vinyl chloride for 6 h per day on 5
days per week for 6 or 12 months. Animals were allowed complete their lifespan and
were necropsied when found moribund or dead. There was a significant decrease
(p < 0.01) in survival of the treated animals compared with controls. Among the animals
exposed for 6 and 12 months, statistically significant increases (p < 0.01 except p < 0.05
where indicated, life-table analysis) were observed in the incidence of haemangio-
sarcomas (all sites) (control, 4/69; 6-month exposures: 8 months of age, 27/42; and 14
months of age, 30/51; 12-month exposures: 8 months of age, 30/48; and 14 months of
age, 29/48) and mammary gland carcinomas (control, 3/69; 6-month exposures: 8 months
of age, 13/42; and 14 months of age, 4/51, p < 0.05; 12-month exposures: 8 months of
age, 9/48; and 14 months of age, 4/48) (Drew et al., 1983).
[The Working Group noted that lung tumours were not observed in B6C3F1 mice
exposed to vinyl chloride in the studies of Drew et al. (1983), whereas Swiss CD-1 mice,
a strain that is more susceptible to the induction of lung tumours, did develop such
tumours in these and other studies.]
Groups of 30, 40 or 60 male CD1 mice, 5–6 weeks of age, were exposed by whole-
body inhalation to 0, 2.6, 26, 260, 780 or 1560 mg/m3 [0, 1, 10, 100, 300 or 600 ppm]
vinyl chloride [purity unspecified] for 6 h per day on 5 days per week for 4 weeks and
were then observed for an additional 0, 12 or 40–41 weeks. Surviving animals were killed
after each observation period. The study focused on lung tumours. After 12 weeks of
exposure, the incidence of pulmonary tumours was 0/18, 0/10, 0/9, 0/6, 6/9 and 8/9 for
mice treated with 0 (control), 2.6, 26, 260, 780 and 1560 mg/m3, respectively; after 40–41
weeks of exposure, the incidence was 0/17, 1/9, 3/9, 6/9, 5/7 and 6/7, respectively [no
statistical analysis provided] (Suzuki, 1983).
3.1.2 Rat
Groups of 36 male and 36 female CD rats, 2 months of age, were exposed by
inhalation to 0, 50, 250 or 1000 ppm [0, 130, 650 or 2600 mg/m3] vinyl chloride (99.8%
pure) in air for 6 h per day on 5 days per week for 52 weeks. Four animals per group were
terminated at 1, 2, 3, 6 or 9 months for laboratory tests and gross and histological exam-
ination. The combined incidence of liver angiosarcomas by increasing level of exposure
was 0/35 (control), 0/36, 2/36 and 6/34 in males and 0/35 (control), 0/36, 10/34 (p < 0.05,
Fisher’s exact test) and 15/36 (p < 0.05) in females, respectively. Similarly, the incidence
of extrahepatic angiosarcomas was 0/35 (control), 1/36, 2/36 and 4/34 in males and 0/35
(control), 1/36, 3/34 and 10/36 (p < 0.05) in females, respectively (Lee et al., 1978).
Groups of 62 newly weaned male and female Wistar rats were exposed by whole-
body inhalation to 0 or 13 000 mg/m3 [0 or 5000 ppm] vinyl chloride (≥ 99.97% pure) for
7 h per day on 5 days per week for 52 weeks. Ten animals per dose per sex were killed at
4, 13, 26 and 52 weeks. No information on survival was provided. At 52 weeks, an in-
crease in the incidence of angiosarcomas of the liver (males, 3/9; females, 6/10), Zymbal
gland squamous-cell carcinomas (males, 3/9; females, 2/10) and carcinomas of the nasal
cavity (males, 2/9; females, 5/10) compared with controls (no tumours) was observed [no
statistical evaluation provided] (Feron & Kroes, 1979; Feron et al., 1979).
Groups of 110–128 male and 110–128 female Sprague-Dawley rats, 6, 18, 32 or 52
weeks of age, were exposed in chambers by whole-body inhalation to 0 (controls) or
2465 mg/m3 [0 or 940 ppm] vinyl chloride [purity unspecified] for 7 h per day on 5 days
per week for 24.5 weeks. An epidemic of pneumonia in exposed rats during the 28th week
forced premature conclusion of the study and all surviving rats were killed 43 weeks after
the beginning of exposure. Rats killed at 3, 6 or 9 months (interim sacrifice group) were
evaluated separately from rats that either died, were killed in poor condition or were killed
at the conclusion of the study (non-scheduled sacrifice group). Angiosarcomas, mostly
primary tumours in the liver, were highly anaplastic and frequently metastasized to the
lung. The incidence of angiosarcomas in vinyl chloride-exposed male rats in the non-
scheduled sacrifice group was 0/37, 0/44, 3/45 and 13/55 in rats that were exposed
VINYL CHLORIDE 379
beginning at 6, 18, 32 or 52 weeks of age, respectively. The corresponding incidence of

angiosarcomas in exposed females was 2/38, 7/47, 23/49 and 11/54. Only one angio-
sarcoma occurred in subcutaneous tissues in a control male placed on study at 32 weeks
of age (incidence for this control group, 1/86; incidence for all control males, 1/357). The
incidence of angiosarcomas in control females was 0/382. Pituitary tumours and mam-
mary tumours occurred in both control and exposed rats at comparable rates. A few rats in
the control and exposed groups had Zymbal gland or brain tumours (Groth et al., 1981).
Five groups of 51–93 male random-bred white rats, weighing 160–180 g at the
beginning of the experiment, were exposed by whole-body inhalation to 0 (control), 14,
25, 266 or 3690 mg/m3 [0, 5.4, 9.6, 102 or 1420 ppm] vinyl chloride [purity unspecified]
for 4.5 h per day on 5 days per week for 52 weeks and observed until their death, but no
longer than 126 weeks. The authors reported the development of angiosarcomas of liver
or other sites in rats of the three highest-dose groups (9.3–15.7%). No such tumours were
observed in control animals (Kurlyandski et al., 1981).
Groups of 30 male and 30 female Sprague-Dawley rats [data reported for both sexes
combined], 12 weeks of age, were exposed by inhalation to 50, 250, 500, 2500, 6000 or
10 000 ppm [130, 650, 1300, 6500, 15 600 or 26 000 mg/m3] vinyl chloride (99.97%
pure) for 4 h per day on 5 days per week for 17 weeks. Control animals comprised 190
untreated rats [data reported for both sexes combined]. Animals were observed until 156
weeks, when the experiment (experiment BT3) was terminated. Survival rates of the
groups were not reported. The incidence of tumours was: liver angiosarcomas, 0/190,
0/58, 0/59, 1/60, 1/60, 1/60 and 0/58 in control, 50-, 250-, 500-, 2500-, 6000- and 10 000-
ppm vinyl chloride-treated rats, respectively; ‘hepatomas’, 0/190 (control), 0/58, 0/59,
0/60, 2/60, 1/60 and 1/58, respectively; Zymbal gland carcinomas, 2/190 (control), 0/58,
1/59, 1/60, 7/60, 9/60 and 9/58, respectively; and ‘skin epitheliomas’, 1/190 (control),
1/58, 0/59, 0/60, 2/60, 5/60 and 5/58, respectively [no statistical analysis reported]
(Maltoni et al., 1981).
combined], 13 weeks of age, were exposed by inhalation to 6000 or 10 000 ppm [15 600
or 26 000 mg/m3] vinyl chloride (99.97% pure) for 4 h per day on 5 days per week for
5 weeks (groups I and II), for 1 h per day on 4 days per week for 25 weeks (groups III and
IV) or for 4 h per day once a week for 25 weeks (groups V and VI). Control animals
comprised two groups of 120 untreated rats [data reported for both sexes combined].
Animals were observed until 154 weeks, when the experiment (experiment BT10) was
terminated. Survival rates of the groups were not reported. The incidence of tumours was:
liver angiosarcomas, 0/227, 1/118, 0/120, 1/119, 3/118, 1/119 and 1/120 in controls and
groups I, II, III, IV, V and VI, respectively; extrahepatic angiosarcomas, 0/227 (control),
0/118, 0/120, 0/119, 2/118, 0/119 and 1/120, respectively; Zymbal gland carcinomas,
0/227 (control), 9/118, 9/120, 9/119, 5/118, 8/119 and 9/120, respectively; and mammary
tumours, 17/227 (control), 13/118, 13/120, 16/119, 11/118, 20/119 and 12/120,
respectively. The predominant carcinogenic effect was in the Zymbal gland [no statistical
analysis reported] (Maltoni et al., 1981).
Five experiments (BT1, BT2, BT6, BT9, BT15) performed by Maltoni et al. (1981)
were combined to construct a dose–response table. Groups of 60–300 male and female
Sprague-Dawley rats [data reported for both sexes combined], 13–17 weeks of age, were
exposed by inhalation to 1, 5, 10, 25, 50, 100, 150, 200, 250, 500, 2500, 6000, 10 000 or
30 000 ppm [2.6, 13, 26, 65, 130, 260, 390, 520, 650, 1300, 6500, 15 600, 26 000 or
78 000 mg/m3] vinyl chloride (99.97% pure) for 4 h per day on 5 days per week for 52
weeks. Controls comprised 461 untreated rats from four experiments [data reported for
both sexes combined]. Animals were observed until 68 (BT6) or 135–147 (BT1, BT2,
BT9, BT15) weeks, when the experiments were terminated. Survival rates of the groups
were not reported. Selected tumour incidences are presented in Table 13 [no statistical
analysis reported] (Maltoni et al., 1981). [The Working Group noted that the clearest
dose–response was observed for hepatic angiosarcomas and Zymbal gland carcinomas.]
Groups of 30–40 male (BT7) or 120–130 male [exact numbers not specified] (BT17)
Wistar rats, 11–13 weeks of age, were exposed by inhalation to 1, 50, 250, 500, 2500,
6000 or 10 000 ppm [2.6, 130, 650, 1300, 6500, 15 600 or 26 000 mg/m3] vinyl chloride
(99.97% pure) for 4 h per day on 5 days per week for 52 weeks. Control animals
comprised 40 (BT7) or 120–130 [exact number not specified] (BT17) untreated rats.
Animals were observed until 134 (BT17) or 165 (BT7) weeks, when the experiment was
terminated. Survival rates of the groups were not reported. The incidence of selected
tumours in order of increasing doses was: liver angiosarcomas, 0/132 (control), 0/99,
0/28, 1/27, 3/28, 3/25, 3/26 and 8/27, respectively; extrahepatic angiosarcomas, 1/132
(control), 3/99, 0/28, 1/27, 0/28, 1/25, 1/26 and 0/27, respectively; ‘hepatomas’, 0/132
(control), 1/99, 0/28, 0/27, 0/28, 1/25, 2/26 and 0/27, respectively; and Zymbal gland
carcinomas, 3/132 (control), 2/99, 0/28, 0/27, 0/28, 0/25, 2/26 and 2/27, respectively [no
statistical analysis provided] (Maltoni et al., 1981). [The Working Group noted the lack of
a dose–response for extrahepatic angiosarcomas, Zymbal gland carcinomas and
hepatomas.]
Groups of 55–112 female Fischer 344 rats, 8–9 weeks of age, were exposed by
whole-body inhalation to 0 (control) or 260 mg/m3 [0 or 100 ppm] vinyl chloride
(commercial grade) [purity unspecified] for 6 h per day on 5 days per week for 6, 12, 18
or 24 months. Animals were allowed to complete their lifespan and were necropsied
animals exposed for 1 year or more compared with controls. Statistically significant
increases (p < 0.01, life-table analysis) were observed in the incidence of liver haeman-
giosarcomas, haemangiosarcomas (all sites), mammary gland fibroadenomas and liver
neoplastic nodules [hepatocellular adenomas] in all exposure groups and of mammary
gland adenocarcinomas and hepatocellular carcinomas in the groups exposed for 12, 18
and 24 months. Tumour incidence after 24 months of exposure was: haemangiosarcoma
of the liver, 1/112 control versus 19/55 exposed; haemangiosarcoma (all sites), 2/112
control versus 24/55 exposed; fibroadenoma of the mammary gland, 24/112 control
versus 26/55 exposed; adenocarcinoma of mammary gland, 5/112 control versus 5/55
exposed; liver neoplastic nodules [hepatocellular adenomas], 4/112 control versus 6/55
Table 13. Tumour incidence in a dose–response study of vinyl chloride administered by inhalation to Sprague-
Dawley rats for 52 weeks
Exposure (ppm) Experiment Liver Extrahepatic Hepatomas Zymbal gland Mammary Nephroblastomasa Neuroblastomasb
[mg/m3] angiosarcomas angiosarcomas carcinomas tumours
0 BT1, BT2, 0/461 2/461 0/461 4/461 19/461 0/461 0/461

BT9, BT15
1 [2.6] BT15 0/118 0/118 0/118 1/118 15/118 0/118 0/118
5 [13] BT15 0/119 0/119 0/119 1/119 22/119 0/119 0/119
VINYL CHLORIDE
10 [26] BT15 1/119 2/119 0/119 2/119 21/119 0/119 0/119
25 [65] BT15 5/120 0/120 0/120 4/120 17/120 1/120 0/120
50 [130] BT1 1/60 1/60 0/60 0/60 2/60 1/60 0/60
50 [130] BT9 14/294 9/294 0/294 9/294 62/294 1/294 0/294
100 [260] BT2 1/120 0/120 0/120 1/120 4/120 10/120 0/120
150 [390] BT2 6/119 0/119 0/119 4/119 6/119 11/119 0/119
200 [520] BT2 12/120 1/120 3/120 4/120 6/120 7/120 0/120
250 [650] BT1 3/59 2/59 1/59 0/59 2/59 5/59 0/59
500 [1300] BT1 6/60 1/60 5/60 4/60 1/60 6/60 0/60
2500 [6500] BT1 13/60 3/60 2/60 2/60 2/60 6/60 4/60
6000 [15 600] BT1 13/59 3/59 1/59 7/59 0/59 5/59 3/59
10 000 [26 000] BT1 7/60 3/60 1/60 16/60 3/60 5/60 7/60
30 000 [78 000] BT6 18/60 1/60 1/60 35/60 2/60 0/60 1/60
From Maltoni et al. (1981)

a
Primary renal tumours were not necessarily embryonal in morphology.
b
See Working Group comment on this diagnosis in the text that describes the Maltoni and Cotti (1988) study.
381
exposed; and hepatocellular carcinoma, 1/112 control versus 9/55 exposed. In the same
study, groups of 51–112 female Fischer 344 rats, aged 2, 8, 14 or 20 months, were
exposed by whole-body inhalation to 0 (control) or 260 mg/m3 [100 ppm] vinyl chloride
for 6 h per day on 5 days per week for 6 or 12 months. Exposures were initiated when the
animals were 2, 8, 14 or 20 months of age for the 6-month exposures and 2, 8 or 14 months
of age for the 12-month exposures. Animals were allowed to complete their lifespan and
were necropsied when found moribund or dead. The incidence of haemangiosarcomas,
and mammary gland and liver tumours is presented in Table 14. For the 6-month
exposures, increases were observed in the incidence of liver haemangiosarcomas in one
exposure group, of mammary gland fibroadenomas and neoplastic liver nodules
[hepatocellular adenomas] in the 2- and 8-month-old groups, respectively, and of hepato-
cellular carcinomas in the 8-month-old group. After the 12-month exposures, increases
were observed in the incidence of liver haemangiosarcomas, haemangiosarcomas (all
sites) and mammary gland fibroadenomas in the 2- and 8-month-old groups and of
mammary gland adenocarcinomas, neoplastic liver nodules [hepatocellular adenomas]
and hepatocellular carcinomas in the 2-month-old group (Drew et al., 1983).
Table 14. Incidence of tumours in female Fischer 344 rats exposed to 260 mg/m3
[100 ppm] vinyl chloride by inhalation
Exposure Age Haemangiosarcoma Mammary gland Liver neoplastic Hepato-

period at start nodules [hepatocellular
(months) (months) Liver All sites Fibro- Adeno- cellular adenoma] carcinoma
adenoma carcinoma
0 (control) – 1/112 2/112 24/112 5/112 4/112 1/112

6 2 4/76a 4/76 28/76a 6/76 15/75a 3/75
6 8 2/52 2/53 23/53b 2/53 10/52a 6/52a
6 14 0/51 0/53 17/53 3/53 2/51 0/51
6 20 0/53 0/53 20/53b 2/53 4/53 1/53
12 2 11/55a 12/56a 28/56a 11/56a 20/56a 4/56a
12 8 5/54a 5/55a 16/55a 4/55 4/54 1/54
12 14 2/49 2/50 15/50 0/50 4/49 0/49
Adapted from Drew et al. (1983)

a
Difference from controls, p < 0.01 (life-table analysis)
b
3.1.3 Hamster
Groups of 30 male Golden hamsters, 11 weeks of age, were exposed by inhalation to
50, 250, 500, 2500, 6000 or 10 000 ppm [30, 650, 1300, 6500, 15 600 or 26 000 mg/m3]
vinyl chloride (99.97% pure) for 4 h per day on 5 days per week for 30 weeks. Control
animals comprised 60 untreated male hamsters. Animals were observed until 109 weeks,
when the experiment (experiment BT8) was terminated. Survival rates of the groups were
VINYL CHLORIDE 383
not reported. The incidence of treatment-related tumours by increasing dose of exposure

was: liver angiosarcomas, 0/60 (control), 0/30, 0/30, 2/30, 0/30, 1/30 and 0/30, respec-
tively; skin epitheliomas, 3/60 (control), 9/30, 3/30, 7/30, 3/30, 1/30 and 7/30, respec-
tively; and forestomach papillomas and acanthomas, 3/60 (control), 3/30, 4/30, 9/30,
17/30, 10/30 and 10/30, respectively. Leukaemia was observed at a similar incidence in
control and treated groups (8/60 (control), 6/30, 6/30, 5/30, 9/30, 6/30 and 5/30, respec-
tively), but the authors reported a decrease in the latency period [no statistical analysis
provided] (Maltoni et al., 1981).
Groups of female Syrian golden hamsters [initial numbers not specified], 8–9 weeks
of age, were exposed by whole-body inhalation to 0 or 520 mg/m3 [0 or 200 ppm] vinyl
chloride (commercial grade) [purity unspecified] or 6 h per day on 5 days per week for 6,
12 or 18 months. Animals were allowed to complete their lifespan and were necropsied
all exposed animals compared with controls. Statistically significant increases (see Table
15) were observed in the incidence of mammary gland carcinomas and stomach ade-
nomas in all exposure groups and of haemangiosarcomas (all sites) in the groups exposed
for 6 and 12 months. A significant increase in the incidence of skin carcinomas was also
seen in the 12-month exposure group. In the same study, groups of female Syrian golden
hamsters, 2, 8, 14 or 20 months of age (Groups I, II, III and IV, respectively) [initial
numbers not specified], were exposed by whole-body inhalation to 0 or 520 mg/m3 [0 or
Table 15. Incidence of tumours in female Syrian golden hamsters exposed to

520 mg/m3 [200 ppm] vinyl chloride by inhalation
Exposure period Age at first Haemangiosarcoma Mammary gland Stomach Skin carcinoma
(months) exposure (all sites)a carcinoma adenoma
0 (control) – 0/143 0/143 5/138 0/133
6 8 weeks 13/88b 28/87 b 23/88b 2/80
12 8 weeks 4/52 b 31/52 b 3/50c 9/48b
18 8 weeks 2/103 47/102b 20/101b 3/90
6 8 months 3/53 c 2/52c 15/53b 0/49
6 14 months 0/50 0/50 6/49c 0/46
6 20 months 0/52 1/52 0/52 0/50
12 2 months 4/52 b 31/52b 3/50c 2/80
12 8 months 1/44 6/44 b 10/44b 0/38
12 14 months 0/43 0/42 3/41 0/30
Modified from Drew et al. (1983)

a
These tumours occurred primarily in the skin, spleen and liver.
b
c
200 ppm] vinyl chloride for 6 h per day on 5 days per week for 6 or 12 months. Exposures
were initiated when the animals were 2, 8, 14 or 20 months of age for the 6-month
exposures and 2, 8 or 14 months of age for the 12-month exposures. Animals were
allowed to complete their lifespan and were necropsied when found moribund or dead.
There was a significant decrease (p < 0.01) in the survival of animals that were exposed
early in life for 12 months compared with controls. In some of the 6-month and 12-month
exposure groups (see Table 15), statistically significant increases were observed in the
incidence of stomach adenomas, haemangiosarcomas (all sites) and mammary gland
carcinomas (Drew et al., 1983).
[The Working Group noted the successful induction of hepatic angiosarcomas in
three species (rats, mice and hamsters) exposed to vinyl chloride by inhalation.]
3.2 Oral administration

Rat
Groups of 40 male and 40 female Sprague-Dawley rats [data reported only for both
sexes combined], 13 weeks of age, were administered 3.3, 17 or 50 mg/kg bw vinyl
chloride (99.97% pure) in olive oil by gastric intubation four or five times a week for 52
weeks. Control rats comprised 40 males and 40 females [data reported for both sexes
combined] that were treated with olive oil alone. Animals were observed until 136 weeks,
when the experiment (experiment BT11) was terminated. Survival rates of the groups
were not reported. The incidence of treatment-related tumours in control and 3.3-, 17- and
50-mg/kg bw vinyl chloride-treated rats, respectively, was: liver angiosarcomas, 0/80,
0/80, 10/80 and 17/80; extrahepatic angiosarcomas, 0/80, 2/80, 0/80 and 2/80; and
primary renal tumours (‘nephroblastomas’), 0/80, 0/80, 3/80 and 2/80 [no statistical
analysis reported] (Maltoni et al., 1981).
Groups of 75 male and 75 female Sprague-Dawley rats [data reported only for both
sexes combined], 10 weeks of age, were administered 0.03, 0.3 or 1 mg/kg bw vinyl
chloride (99.97% pure) in olive oil by gastric intubation four or five times a week for 52–
59 weeks. Controls comprised 75 males and 75 females [data reported for both sexes
combined] that were treated with olive oil alone. Animals were observed until 136 weeks,
when the experiment (experiment BT27) was terminated. Survival rates of the groups
were not reported. The incidence of several tumours was increased in the treated groups.
The incidence in control and 0.03-, 0.3- and 1-mg/kg bw vinyl chloride-treated rats,
respectively, was: hepatic angiosarcomas, 0/150, 0/150, 1/148 and 3/149; extrahepatic
angiosarcomas, 0/150, 0/150, 0/148 and 1/149; hepatomas [not otherwise specified],
0/150, 0/150, 1/148 and 1/149; Zymbal gland carcinomas, 1/50, 0/150, 0/148, 5/149; and
mammary tumours, 7/150, 14/150, 4/148 and 12/149 [no statistical analysis reported]
(Maltoni et al., 1981).
Groups of 60–80 male and 60–80 female Wistar rats, 5 weeks of age, were fed diets
that contained 0, 1, 3 or 10% of 4000 ppm vinyl chloride (≥ 99.97% pure) in a PVC
VINYL CHLORIDE 385
powder (vehicle) (which resulted in calculated daily doses of 0, 1.7, 5.0 or 14 mg/kg bw
vinyl chloride, respectively) during a 4-h feeding period each day on 7 days per week.
Animals were treated for a total of 135 (males) or 144 (females) weeks, after which the
experiment was terminated. Survival of males at the end of the study was 14/60 control,
20/60 low-dose, 0/60 intermediate-dose and 0/60 high-dose animals; for females, survival
was 19/60 control, 5/60 low-dose, 0/60 intermediate-dose and 0/60 high-dose animals.
Neoplastic responses included a significantly increased incidence (p < 0.05, χ2 test) of
liver haemangiosarcomas and lung angiosarcomas in high- and mid-dose males and high-
dose females, of hepatocellular carcinomas in high-dose males and high- and mid-dose
females and of neoplastic liver nodules (hepatocellular adenomas) in high- and mid-dose
males and females. The incidence of hepatocellular carcinomas was 0/55 control, 1/58
low-dose, 2/56 mid-dose and 8/59 high-dose males and 0/57 control, 4/58 low-dose,
19/59 mid-dose and 29/57 high-dose females; that of liver haemangiosarcomas was 0/55
control, 0/58 low-dose, 6/56 mid-dose and 27/59 high-dose males and 0/57 control, 0/58
low-dose, 2/59 mid-dose and 9/57 high-dose females; and that of neoplastic nodules
(hepatocellular adenomas) was 0/55 control, 1/58 low-dose, 7/56 mid-dose and 23/59
high-dose males and 2/57 control, 26/58 low-dose, 39/54 mid-dose and 44/57 high-dose
females (Feron et al., 1981).
As in the previous experiment, groups of 50–100 male and 50–100 female Wistar rats
[age unspecified] were fed diets similar to those described in Feron et al. (1981) that
resulted in calculated daily doses of 0, 0.014, 0.13 and 1.3 mg/kg bw vinyl chloride
(≥ 99.97% pure), respectively, during a daily 4–6-h feeding period on 7 days per week.
Animals were treated for a total of 149 (males) or 150 (females) weeks, after which the
experiment was terminated. Survival of males at the end of the study was 20/100 control,
20/100 low-dose, 18/100 intermediate-dose and 8/50 high-dose animals; for females,
survival was 24/100 control, 23/100 low-dose, 26/100 intermediate-dose and 5/50
(p < 0.05) high-dose animals. Neoplastic responses included a significantly increased
incidence of hepatocellular carcinomas in high-dose males and of liver neoplastic nodules
(hepatocellular adenomas) in high-dose females (p < 0.05). The incidence of hepato-
cellular carcinoma was 0/99 control, 0/99 low-dose, 0/99 mid-dose and 3/49 high-dose
males and 1/98 control, 0/100 low-dose, 1/96 mid-dose and 3/49 high-dose females; that
of neoplastic nodules (hepatocellular adenomas) was 0/99 control, 0/99 low-dose, 0/99
mid-dose and 1/49 high-dose males and 0/98 control, 1/100 low-dose, 1/96 mid-dose and
9/49 high-dose females; and that of liver haemangiosarcomas was 0/99 control, 0/99 low-
dose, 0/99 mid-dose and 1/49 high-dose males and 0/98 control, 0/100 low-dose, 0/96
mid-dose and 2/49 high-dose females (Til et al., 1991).
3.3 Subcutaneous injection

Rat
Groups of 35 male and 40 female Sprague-Dawley rats, 21 weeks of age, were
administered a single subcutaneous injection of 4.25 mg vinyl chloride (99.97% pure) in
1 mL olive oil. Control animals comprised 35 male and 40 female rats that were treated
with olive oil alone (1 mL). Animals were followed until 145 weeks, when the experi-
ment [BT13] was terminated. Survival rates of the groups were not reported. No hepatic
or extrahepatic angiosarcomas were observed. Tumour incidence was reported for both
sexes combined. Mammary tumours were observed in 1/75 vinyl chloride-treated rats and
3/75 controls. Nephroblastomas were observed in 1/75 treated rats and 0/75 controls. No
other tumour types were reported in vinyl chloride-treated animals (Maltoni et al., 1981).
3.4 Intraperitoneal injection

Rat
combined], 17 weeks of age, were administered 4.25 mg vinyl chloride (99.97% pure) in
1 mL olive oil by intraperitoneal injection once, twice, three times or four times at
2-month intervals. Control animals comprised 60 rats that were treated with olive oil
alone (1 mL) [number of treatments not reported; data reported for both sexes combined].
Animals were followed until 144 weeks, when the experiment (BT12) was terminated.
Survival rates of the groups were not reported. No liver angiosarcomas were observed.
Extrahepatic angiosarcomas were observed in 0/55 controls, and 0/55, 1/56, 1/53 and
0/56 rats treated with vinyl chloride once, twice, three times or four times, respectively;
mammary tumours were observed in 0/55 controls, and 2/55, 3/56, 1/53, and 1/56 rats
treated with vinyl chloride once, twice, three times or four times, respectively [no statis-
tical analysis reported] (Maltoni et al., 1981).
3.5 Transplacental administration

Rat
Groups of 30–54 pregnant female Sprague-Dawley rats, 19 weeks of age, were
exposed by inhalation to 6000 or 10 000 ppm [15 600 or 26 000 mg/m3] vinyl chloride
(99.97% pure) for 4 h per day for 7 days, from days 12 to 18 of pregnancy (experiment
BT5). Both dams and offspring were observed until the experiment was terminated at 143
weeks, without further exposure to vinyl chloride [the Working Group noted the lack of
control groups]. Survival rates of the various groups were not reported. No hepatic or
extrahepatic angiosarcomas or hepatomas were observed in either dams or offspring.
Tumours appeared at several sites in offspring, including extrahepatic angioma (1/32 low-
dose, 0/51 high-dose), kidney tumours (0/32 low-dose, 3/51 high-dose), Zymbal gland
VINYL CHLORIDE 387
carcinomas (3/32 low-dose, 5/51 high-dose), skin epitheliomas (1/32 low-dose, 0/51 high-
dose), forestomach papillomas and achanthomas (1/32 low-dose, 1/51 high-dose) and
mammary gland tumours (2/32 low-dose, 1/51 high-dose). No tumours occurred at these
sites in low-dose dams. One Zymbal gland carcinoma was seen in a high-dose dam (1/30)
(Maltoni et al., 1981). [The Working Group considered that, despite the lack of controls,
this study provides some evidence of the transplacental carcinogenicity of vinyl chloride.]
3.6 Perinatal exposure

Rat
Male and female Sprague-Dawley rats (breeders), 21 weeks of age, were exposed by
inhalation together with their newborn offspring to 6000 or 10 000 ppm [15 600 or
26 000 mg/m3] vinyl chloride (99.97% pure) on 4 h per day on 5 days per week for
5 weeks. Offspring [data reported for both sexes combined] included 44 rats in the high-
dose and 42 in the low-dose group. All vinyl chloride-treated rats were followed until 124
weeks, when the experiment (experiment BT14) was terminated [the Working Group
noted the lack of controls]. Survival rates of the groups were not reported. In rats treated
perinatally, the incidence of hepatic angiosarcomas was 17/42 and 15/44 in 6000- and
10 000-ppm vinyl chloride-treated animals, respectively. Other tumours that occurred in
low-dose and high-dose groups, respectively, were liver angiomas (1/42, 0/44), extra-
hepatic angiosarcomas (1/42, 0/44), extrahepatic angiomas (1/42, 3/44), ‘hepatomas’
(20/42, 20/44), Zymbal gland carcinomas (2/42, 1/44), skin epitheliomas (2/42, 1/44) and
mammary tumours (1/42, 0/44). No tumours were reported in breeders at the sites where
tumours occurred in offspring (Maltoni et al., 1981).
Male and female Sprague-Dawley rats (breeders), 13 weeks of age, were exposed by
inhalation to 0 (controls) or 2500 ppm [6500 mg/m3] vinyl chloride (99.97% pure) for 4 h
per day on 5 days per week for an initial 7-week period during which 54 exposed females
and 60 control females became pregnant and delivered young. Exposed dams then con-
tinued to receive vinyl chloride by inhalation for 7 h per day on 5 days per week for an
additional 69 weeks. Offspring [details of delivery and perinatal husbandry not given]
were exposed with their dams pre- and postnatally during the initial 7-week exposure
period, and were then either exposed similarly to their dams for 7 h per day on 5 days per
week for a further 69 weeks (63 males, 64 females; Group I) or for a shorter 8-week
period (60 males, 60 females; Group II). Control offspring were 158 males and 149
females. Hepatocarcinomas occurred in 5/54 exposed female breeders and 0/60 control
breeders, in 27/64 male and 38/63 female Group I offspring, in 42/60 male and 43/60
female Group II offspring and in 1/158 control male and 0/149 control female offspring.
Angiosarcomas [origin not specified; presumably hepatic] occurred in 27/54 exposed
female breeders, in 36/64 male and 46/63 female Group I offspring and 24/60 male and
28/60 female Group II offspring. No angiosarcomas were seen in 60 control breeders or in
158 male and 149 female control offspring. Latencies for both hepatocellular carcinomas
and angiosarcomas averaged approximately 52 weeks in Group I offspring and approx-

imately 80 weeks in Group II offspring. Tumours in the brain described as ‘neuro-
blastomas’ were seen in vinyl chloride-exposed rats only: 32/54 female breeders, 31/64
male and 27/63 female Group I offspring and 7/60 male and 11/60 female Group II
offspring (Maltoni & Cotti, 1988). [The Working Group noted that these latter neoplasms
occurred at a high frequency in vinyl chloride-exposed adult rats which is unprecedented
for primary brain tumours in bioassays; that this diagnosis has not been established in
other bioassays of vinyl chloride or other chemicals; and that the photomicrographs and
the preferential location of the tumours in the anterior frontal lobes support the alternative
diagnosis of an origin in the metabolically active olfactory neuroepithelium of the pos-
terior nasal cavity (aesthesioneuroepithelioma).]
3.7 Carcinogenicity of metabolites

Mouse
Local tumours (mainly fibrosarcomas) were observed in 15/28 male, 12/24 female
and 0/30 control male XVIInc/Z mice, 8–10 weeks of age, following 32 subcutaneous
injections of 0 (controls) or 0.1 mg chloroethylene oxide [purity unspecified] over 42
weeks (the experiment was terminated 36.5 weeks post-exposure). Chloroethylene oxide
increased the incidence of skin papillomas and carcinomas in male XVIInc/Z mice in a
classical initiation–promotion experiment (chloroethylene oxide was used as an initiator
and 12-O-tetradecanoylphorbol-13-acetate [TPA] as a promoter) (skin papilloma, 18/28
versus 4/28 TPA controls; skin carcinoma, 5/28 versus 0/28 TPA controls), whereas
chloroacetaldehyde [purity unspecified]did not produce such tumours under comparable
conditions (Zajdela et al., 1980).
Chloroacetaldehyde (≥ 95% pure with no identifiable impurities) slightly increased
the incidence of hepatocellular tumours (10/26 versus 3/20 controls [not significant]) in
male B6C3F1 mice when administered orally in the drinking-water at a mean daily
ingested dose of 17 mg/kg bw per day for 104 weeks (Daniel et al., 1992).
3.8 Co-exposure with modifying agents

Rat
Groups of 80 male Sprague-Dawley rats [age not specified] were used in a 2 × 2
factorial design and were exposed by whole-body inhalation to 1500 mg/m3 [577 ppm]
vinyl chloride (99.9% pure) for 4 h per day on 5 days per week for 12 months and were
then held for an additional 18 months. Animals were kept until spontaneous death or were
killed at the end of the 18-month post-exposure observation period. Additional groups
were exposed to vinyl chloride and ingested 5% ethanol in water (v/v), were exposed to
filtered air and ethanol or were exposed to filtered air alone. Ingestion of 5% ethanol was
begun 4 weeks before inhalation of vinyl chloride and continued for life or until ter-
VINYL CHLORIDE 389
mination of the study 30 months after the first vinyl chloride exposure. No information on
survival was provided. The incidence of hepatocellular carcinomas was: 1/80 control,
8/80 ethanol-treated, 35/80 vinyl chloride-treated and 48/80 vinyl chloride plus ethanol-
treated rats; that of liver angiosarcomas was: 0/80 control, 0/80 ethanol-treated, 18/80
vinyl chloride-treated and 40/80 vinyl chloride plus ethanol-treated rats; that of pituitary
tumours was: 8/80 control, 26/80 ethanol-treated, 19/80 vinyl chloride-treated and 12/80
vinyl chloride plus ethanol-treated; and that of lymphosarcomas was 2/80 control, 4/80
ethanol-treated, 6/80 vinyl chloride-treated and 11/80 vinyl chloride plus ethanol-treated
rats. The authors stated that these results indicate that ethanol potentiates the carcino-
genicity of vinyl chloride (Radike et al., 1981). [The Working Group noted that isocaloric
and isonutrient intakes were not controlled in either the treated or control groups.]
4. Mechanistic and Other Relevant Data
4.1 Absorption, distribution, metabolism and excretion

4.1.1 Humans
No data on absorption, distribution, metabolism or elimination of vinyl chloride in
humans were presented in the previous review (IARC, 1979). Since that time, a number
of studies have contributed to the understanding of the inhalation pharmacokinetics of
vinyl chloride in humans.
Pulmonary absorption of vinyl chloride in humans appeared to be rapid and the
percentage absorbed was independent of the concentration inhaled. Krajewski et al.
(1980; cited in ATSDR, 2006) reported that adult male volunteers exposed for 6 h to 2.9,
5.8, 11.6 or 23.1 ppm [7.5, 15, 30 or 60 mg/m3] by gas mask retained on average
approximately 42% of inhaled vinyl chloride. Pulmonary uptake is determined in part by
the blood:air partition coefficient, which is 1.16 for vinyl chloride (Gargas et al., 1989).
No data were available on human tissue:blood partition coefficients or tissue
concentrations of vinyl chloride in exposed humans. However, calculations based on the
assumption of an identical solubility of vinyl chloride in rodent and human tissues
indicate that the tissue:blood partition coefficients of vinyl chloride would be twofold
greater in humans (Clewell et al., 2001), as a consequence of the twofold lower blood:air
partition coefficient of vinyl chloride in humans compared with rats and mice.
Vinyl chloride is primarily and rapidly metabolized in the liver, and this metabolism
is saturable (Bolt, 2005). The proposed metabolic pathways for vinyl chloride are
presented in Figure 1. The first step in the metabolism of vinyl chloride is oxidation,
which is predominantly mediated by human cytochrome P450 (CYP) 2E1, to form the
highly reactive chloroethylene oxide, which can spontaneously rearrange to chloro-
acetaldehyde (Barbin et al., 1975). Both metabolites can bind with proteins, DNA and
RNA and form etheno-adducts; chloroethylene oxide is the most reactive with nucleotides
Figure 1. Proposed metabolic pathways for vinyl chloride
ClHC CH2
Vinyl chloride
CYP2E1
mixed-function oxidase
DNA adducts
Protein O
adducts
H2C CH
O Cl H2O HCl O
Re-arrangement
ClH2C C 2-Chloroethylene oxide HO CH2 C
Epoxide hydrolase Glycolaldehyde
H Glutathione Glutathione H
2-Chloroacetaldehyde
Aldehyde O
dehydrogenase G S CH2 C
O
S-Formylmethyl glutathione H
ClH2C C
OH
2-Chloroacetic acid (u)
O
Glutathione cys-S CH2 C
H
S-Formylmethyl cysteine (u)
G S CH2 COOH
S-Carboxymethyl glutathione
cys-S CH2 CH2OH

cys-S CH2 COOH S-(2-Hydroxyethyl)cysteine
S-Carboxymethyl cysteine (u)
NH3
(Transamination) N-Ac-cys- S CH2 CH2OH

N-Acetyl-S-(2-Hydroxyethyl)cysteine (u)
CO2
(Oxidative decarboxylation)
Major pathway
Minor pathway
HOOC CH2 S CH2 COOH

Thiodiglycolic acid (thiodiacetic acid) (u)
From Barbin et al. (1975); Plugge & Safe (1977); Green & Hathway (1977); Guengerich & Watanabe
(1979); Guengerich et al. (1979); Bolt et al. (1980); adapted from ATSDR (2006)
CYP, cytochrome P450; (u), excreted in urine
VINYL CHLORIDE 391
(Guengerich et al., 1979). Conjugation of chloroethylene oxide and chloroacetaldehyde

with glutathione (GSH) eventually leads to the major urinary metabolites N-acetyl-S-(2-
hydroxyethyl)cysteine and thiodiglycolic acid. Chloroethylene oxide and chloro-
acetaldehyde can also be detoxified to glycolaldehyde by microsomal epoxide hydrolase
(mEH) and to the urinary metabolite chloroacetic acid by aldehyde dehydrogenase
2 (ALDH2), respectively (Guengerich & Watanabe, 1979; ASTDR, 2006).
A number of in-vitro studies that used purified human CYP2E1 and liver
microsomes confirmed that vinyl chloride is activated mainly by CYP2E1 (reviewed
in WHO, 1999). In hepatic postmitochondrial fractions, Sabadie et al. (1980) found
significant interindividual variability in the metabolism of vinyl chloride, although the
average activity in human samples was comparable with that in rat samples.
The main routes of elimination of vinyl chloride and its metabolites are exhalation
and urinary excretion, respectively. Accordingly, thiodiglycolic acid has been reported to
be the major metabolite of vinyl chloride detected in the urine of exposed workers (Cheng
et al., 2001). Urinary levels of thiodiglycolic acid were correlated with levels of vinyl
chloride in the air at concentrations of > 5 ppm (ATSDR, 2006). In contrast, exhalation of
unmetabolized vinyl chloride has been reported to occur in humans at low levels (Müller
et al., 1978; Krajewski et al., 1980; Pleil & Lindstrom, 1997). For example, the mean
concentration in expired air of humans exposed for 6 h to air that contained 6.8–23.1 ppm
[15–60 mg/m3] vinyl chloride ranged from 0.21 to 1.11 ppm [0.54–2.84 mg/m3], which
represented 3.6 and 4.73% of the inhaled amounts, respectively (Krajewski et al,. 1980).
4.1.2 Experimental systems

The absorption, distribution, metabolism and elimination of vinyl chloride in rats and
mice have been reviewed (IARC, 1979; WHO, 1999; ATSDR, 2006). The following
section summarizes the salient features of the studies reviewed in IARC (1979) as well as
significant new information on the metabolism and pharmacokinetics of vinyl chloride in
animals.
Animal data have demonstrated that pulmonary and gastrointestinal absorption of
vinyl chloride occurs readily and rapidly. On the contrary, dermal absorption of airborne
vinyl chloride is probably not significant. In monkeys, Hefner et al. (1975a) reported that
only 0.023–0.031% of the total available vinyl chloride was absorbed by the dermal route,
whereas absorption in rats was virtually complete following single oral doses (44–
92 mg/kg bw) of vinyl chloride in aqueous solution (Withey, 1976). When rats were
exposed to initial concentrations of < 260 mg/m3 [100 ppm], about 40% of inhaled
[14C]vinyl chloride was absorbed by the lung (Bolt et al., 1976).
The tissue:blood partition coefficients (which determine the volume of distribution) of
vinyl chloride range from 0.4 (muscle) to 10 (fat) in male rats (Barton et al., 1995). The
fat:air partition coefficient for vinyl chloride, reported by several authors, tended to be
higher in female than in male rats (WHO, 1999). Bolt et al. (1976) reported that,
following inhalation exposure to [14C]vinyl chloride, several tissues (brain, liver, spleen,
kidney, adipose tissue and muscle) contained radioactivity, and that the highest levels
were found in liver and kidney. Ungvary et al. (1978) reported that vinyl chloride was
present in fetal blood and amniotic fluid following exposure of pregnant rats on gestation
day 18 to ~2000–13 000 ppm [5500–33 000 mg/m3] (2.5-h exposures), which indicates
that vinyl chloride crossed the placental barrier.
Osterman-Golkar et al. (1977) reported the alkylation of cysteine and histidine of
haemoglobin and small amounts of alkylated histidine in proteins from the testis mice
exposed to [14C]vinyl chloride.
The metabolism of vinyl chloride to chloroethylene oxide, the probable carcinogenic
metabolite, appears to be a saturable, dose-dependent process that occurs in the liver
predominantly through the CYP system (Reynolds et al., 1975; Ivanetich et al., 1977;
Barbin & Bartsch, 1989; Lilly et al., 1998; Bolt, 2005). CYP2E1 appears to account for
all metabolic activity in rat liver microsomes, with a maximum velocity (Vmax) of
4674 pmol/mg protein/min and a Michaelis-Menten constant (Km) of 7.42 µmol/L (El
Ghissassi et al., 1998). Since CYP2E1 has been demonstrated to be present in several
other tissues at low levels (compared with the liver), it is reasonable to anticipate that
extrahepatic metabolism of systemically available vinyl chloride occurs
Inhibitors of CYP, such as 3-bromophenyl-4(5)-imidazole or 6-nitro-1,2,3-
benzothiadiazole, reduced the metabolism of vinyl chloride in vivo (Bolt et al., 1976).
Chloroethylene oxide, which has a half-life of 1.6 min in aqueous solution at neutral pH
(Barbin et al., 1975), rearranges to chloroacetaldehyde (Bonse et al., 1975), conjugates
with GSH and can be hydrolysed by EH to glycolaldehyde (WHO, 1999). Chloro-
acetaldehyde combines directly or enzymatically via glutathione-S-transferase (GST) with
GSH to form S-formylmethyl glutathione, which is excreted as N-acety1-S-(2-hydroxy-
ethyl)cysteine (Green & Hathway, 1977) (Figure 1). Chloroacetaldehyde can be oxidized
to chloroacetic acid, which is either excreted as such or bound to GSH to form S-carboxy-
methyl glutathione, which, upon further enzymic degradation, is excreted as thiodi-
glycolic acid (thiodiacetic acid) (Plugge & Safe, 1977).
Chloroacetic acid was metabolized in rats to two major urinary metabolites,
S-carboxymethyl cysteine and thiodiacetic acid (Yllner, 1971). N-Acetyl-S-(2-hydroxy-
ethyl)cysteine (a major metabolite) (Watanabe et al., 1976a,b; Green & Hathway, 1977),
S-(carboxymethyl)cysteine and N-acetyl-S-vinyl cysteine have been shown to be metab-
olites of vinyl chloride in rats after oral administration (Green & Hathway, 1977) and
N-acetyl-S-(2-hydroxyethyl)cysteine after inhalation (Watanabe et al., 1976b);
S-(2-chloroethyl)cysteine was also identified after oral administration of vinyl chloride to
rats (Green & Hathway, 1975). As thiodiglycolic acid was obtained as a common metab-
olite in rats dosed separately with chloroacetaldehyde, chloroacetic acid or S-(carboxy-
methyl)cysteine, the identification of the same S-containing metabolite from vinyl
chloride-treated animals gives further support to the hypothesis that chloroethylene oxide
or chloroacetaldehyde are formed and react with GSH (Green & Hathway, 1977).
VINYL CHLORIDE 393
Following oral administration of [14C]vinyl chloride, [14C]carbon dioxide (Green &

Hathway, 1975; Watanabe et al., 1976a), 14C-labelled urea and glutamic acid were iden-
tified as minor metabolites (Green & Hathway, 1975).
Saturation of the metabolism of vinyl chloride (Gehring et al., 1978; Filser & Bolt,
1979) appears to occur at an inhalation concentration of above 200 ppm [518.6 mg/m3] in
rhesus monkeys (Buchter et al., 1980) and 250 ppm [648 mg/m3] in rats (Bolt et al., 1977;
Filser & Bolt, 1979). The plateau of incidence of hepatic angiosarcoma in rat
carcinogenicity bioassays is also observed at above 250 ppm (reviewed in Bolt, 2005).
ATSDR (2006) summarized the kinetic constants obtained in vivo in male Sprague-
Dawley rats (Vmax, 58 µmol/h/kg; Km, 1 µM) and rhesus monkeys (Vmax, 50 µmol/h/kg)
(based on Buchter et al., 1980; Barton et al., 1995). The Vmax of 50 µmol/h/kg in rhesus
monkeys was suggested to be a closer approximation of metabolism in humans than the
value of 110 µmol/h/kg estimated for rats by Filser and Bolt (1979) (ATSDR, 2006).
Although vinyl chloride has not been associated with the induction of CYP, several
authors reported the destruction of CYP protein following exposures to vinyl chloride
(WHO, 1999). However, Watanabe et al. (1978a) reported that the rate of elimination of
vinyl chloride was not altered during repeated exposures (5 days per week for 7 weeks)
compared with single inhalation exposure (~13 000 mg/m3 [5000 ppm]).
Urinary excretion of polar metabolites is the predominant process of elimination at
low concentrations of exposure, and very small amounts are expired in air as unchanged
vinyl chloride (Hefner et al., 1975b). Following exposure of male rats by inhalation to
26 mg/m3 [10 ppm] [14C]vinyl chloride for 6 h, urinary 14C activity and expired vinyl
chloride comprised 68 and 2%, respectively, of the recovered radioactivity; after exposure
to 2600 mg/m3 [1000 ppm] [14C]vinyl chloride, the proportion of radioactivity in the urine
was lower and that expired as vinyl chloride was higher, and represented 56 and 12%,
respectively (Watanabe et al., 1976b). Following a single oral administration of 0.05, 1 or
100 mg/kg bw [14C]vinyl chloride to male rats, excretion in the urine was 68, 59 and 11%,
respectively; [14C]carbon dioxide in expired air accounted for 9, 13 and 3%, respectively;
pulmonary elimination of unchanged vinyl chloride represented only 1–3% of the lower
dose and 67% of the higher dose (Watanabe et al., 1976a). These data are consistent with
the fact that, once metabolic saturation is attained, the elimination of vinyl chloride occurs
via other routes, mainly exhalation of the parent chemical. The route of elimination also
depends upon the route of administration; urinary excretion is favoured following oral or
intraperitoneal administration, which indicates a first-pass effect due to metabolism in the
liver (reviewed in Clewell et al., 2001).
Several investigators have observed the binding of non-volatile metabolites of
14
[ C]vinyl chloride to liver macromolecules, both in vitro and in rats exposed by inha-
lation (Kappus et al. 1976; Watanabe et al., 1978a,b; Guengerich & Watanabe, 1979;
Guengerich et al., 1979; Bolt et al., 1980; Guengerich et al., 1981; Barton et al., 1995).
Jedrychowski et al. (1984) reported a decrease in non-protein sulfhydryl concentration in
rats exposed to high concentrations of vinyl chloride, and Kappus et al. (1975) and Laib
and Bolt (1977) reported binding of vinyl chloride to RNA in vitro and in vivo. In single-
exposure experiments at various concentrations, the extent of macromolecular binding

increased proportionately to the amount of vinyl chloride metabolized and dispropor-
tionately to the exposure concentration (Watanabe et al., 1978b).
4.1.3 Toxicokinetic models

The data on absorption, distribution, metabolism and excretion of vinyl chloride have
been analysed with the use of empirical and physiologically based compartmental models
(Gehring et al., 1978; Chen & Blancato, 1989; Clewell et al., 1995; Reitz et al., 1996;
Clewell et al., 2001). These models indicate that vinyl chloride is rapidly absorbed by the
inhalation and oral routes and is distributed to all tissues; the adipose tissues show the
greatest affinity. The physiologically based pharmacokinetic models developed by Chen
and Blancato (1989), Clewell et al. (1995, 2001) and Reitz et al. (1996) permit the
prediction of the pharmacokinetics, GSH depletion and the amount of vinyl chloride
metabolized in animals and/or humans exposed to various concentrations by different
routes and schedules. However, these models do not currently permit the simulation of the
time course of the formation and persistence of DNA adducts in target tissues.
4.2 Genetic and related effects

Since the last review of vinyl chloride (IARC, 1979), a large amount of data on vinyl
chloride has been produced and reviewed (WHO, 1999). Only the more recent data that
are relevant to the comprehension of vinyl chloride-induced carcinogenicity are reported
in this section.
4.2.1 Humans
(a) DNA adducts
In vitro, both chloroethylene oxide, the biologically reactive intermediate of vinyl
chloride that is formed in the liver, and its rearrangement product, chloroacetaldehyde,
can form etheno adducts with nucleic acid bases. Chloroethylene oxide has, however,
greater reactivity and it was shown in vitro to be the main entity that gives rise to etheno
adducts (Guengerich, 1992). The reaction of 2-chloroethylene oxide with nucleic acid
bases yields the N-7-(2-oxoethyl)guanine adduct (7-OEG) and four etheno adducts—
1,N6-ethenoadenine (εA), 3,N4-ethenocytosine (εC), N2,3-ethenoguanine (N2,3-εG) and
1,N2-ethenoguanine (1,N2-εG) (Figure 2) (Ciroussel et al., 1990; Guengerich, 1992).
Another adduct, formed by chloroethylene oxide, 5,6,7,9-tetrahydro-7-hydroxy-9-
oxoimidazo[1,2-a]purine (HO-ethanoG), has also been identified in vitro (Müller et al.,
1996).
Data on the occurrence and persistence of DNA adducts in tissues of humans exposed
to vinyl chloride are lacking. Only one study that used immunoaffinity purification of the
etheno adducts and subsequent 32P-postlabelling reported levels of 14.1 εA and 8.1 εC per
VINYL CHLORIDE 395
109 parent bases in non-neoplastic liver tissue of a vinyl chloride-exposed patient with
hepatocellular carcinoma (Nair et al., 1995). These adducts can also result from lipid
peroxidation (El Ghissassi et al., 1995) and their level can be quite high (in the range of
≤ 0.5–40 εA and εC per 109 parent bases in liver DNA samples from patients with
unknown exposure) (Bartsch & Nair, 2000a,b).
Figure 2. Reactive metabolites and main nucleic acid adducts of vinyl chloride
identified in vitro and in vivo
Cl O
H Rearrangement
H C1 CYP2E1 C C ClCH2 C H
C C
H H H O H Chloroacetaldehyde
Vinyl chloride
Chloroethylene oxide
H
O C
CH2 N N O
O O
N N HN N N
HN N N N
H2N N N N N N N N N N N
O N
dR dR dR dR H dR
N-7-(2-Oxoethyl)guanine adduct 3,N4-Ethenocytosine adduct 1,N6-Ethenoadenine adduct N2,3-Ethenoguanine adduct 1,N2-Ethenoguanine adduct
(7-OEG) (εεC) (εεA) (N2,3-εεG) (1,N2-εεG)
Adapted from Ciroussel et al. (1990)

CYP, cytochrome P450
(b) Mutations and other related effects
(i) Mutated p21ras and p53 proteins in the blood of vinyl chloride-
exposed workers
Mutated p21ras and p53 proteins in the blood of vinyl chloride-exposed workers may
reflect the mutagenic effects of vinyl chloride. A G→A transition at the second base of
codon 13 of the Ki-ras gene was found in four liver angiosarcomas that were associated
with occupational exposure to vinyl chloride (Marion et al., 1991). The resulting
Asp13p21ras protein was also detected in the serum of these four patients by immuno-
histochemistry using a monoclonal antibody specific for the Asp13p21ras protein
(De Vivo et al., 1994). The presence of the mutant RAS protein in the blood correlates
with the mutated ras gene in the tumour (Table 16).
Several studies showed a high concentration of the Asp13p21ras mutant protein in the
sera of workers who had been heavily exposed to vinyl chloride whereas all unexposed
controls showed negative results. In addition, these studies found a significant dose–
Table 16. Ki-ras and p53 Gene analysis of vinyl chloride-related liver angio-
sarcoma (ASL) and detection of mutated p21ras and p53 proteins and anti-p53
antibodies in the serum from the same patients
Ki-ras 2 Gene p53 Gene

Tissue Serum Tissue Serum
ras ras
DNA Asp13p21 Asp13p21 DNA Mutant Anti-p53
GGC13→GAC13 p53 protein antibodies
ASL1 + + + ATC→TTC + –a
ASL2 + + + AGG→TGG + ++
ASL3 + + + – – –
ASL4 + + + – – –
ASL5b – – – CAT→CTT ± +
ASL6 – – – NR – ++
From Marion (1998)

NR, not reported; +, positive; –, negative; ±, equivocal; ++, strongly positive
a
Patient with abnormal immunological response
b
Fibroblastic cell line established from a liver angiosarcoma
response relationship between exposure to vinyl chloride and the detection of Asp13p21ras
mutant protein in the sera of exposed workers (Tables 17 and 18).
Mutated p53 proteins and/or anti-p53 antibodies were also found in the blood of vinyl
chloride-exposed patients. In a pilot study, Trivers et al. (1995) analysed 148 serum
samples from 92 vinyl chloride-exposed workers from factories in France and industrial
plants in Kentucky, USA. Serum anti-p53 antibodies were found in five of 15 workers
who had liver angiosarcoma (33%), two of whom had confirmed mutated p53 gene
(Hollstein et al., 1994), and in four (5%) of 77 workers with no clinical evidence of
cancer. Two of 26 workers who had clinical symptoms of vinyl chloride toxicity had
antibodies that were detectable by enzyme immunoassays. No antibodies were detected in
the two workers who had hepatocellular carcinoma or in seven of eight workers who had
liver angiomas. In two liver angiosarcoma patients, anti-p53 antibodies were detected
4 months and 11 years, respectively, before the diagnosis of cancer and one patient had
anti-p53 antibodies before and after surgery. Anti-p53 antibodies were thought to be the
result of earlier antigenic presentation to the immune system, through accumulation of the
mutated protein.
The main purpose of these studies was to determine whether the expression of serum
biomarkers was indeed related to exposure to vinyl chloride. The finding of a significant
dose–response relationship strongly supports this hypothesis and confirms that RAS gene
mutations are involved in the onset of liver angiosarcoma induced by vinyl chloride and
that mutant p21ras plays a key role in the development of vinyl chloride-induced liver
Table 17. Dose–response relationship between the detection of Asp13p21ras protein in blood and exposure to vinyl chloride (VC)
References Cohort description Exposure assessment Exposure categories No. of Odds ratio (95% Adjustment
Asp13p21- CI) (adjusted) for potential
positive confounders
De Vivo et 60 male workers heavily exposed to Estimates of VC based Years of total exposure None
al. (1994) VC (at least 1 year before 1974 or 5 on years worked with 0 (n = 28) 0 1.0
years of total exposure); average VC: total years worked < 10 (n = 10) 4 37
exposure, 19.5 years with an average and years worked 10–19 (n = 22) 11 56
of 12.2 years before 1974; 5 ASL, before 1974 20–29 (n = 20) 13 104
1 HCC, 9 liver angiomas, 45 subjects ≥ 30 (n = 8) 6 168
with no liver lesion χ2 for linear trend =
VINYL CHLORIDE
24.986; p < 10–5
Li et al. 225 men randomly selected among the VC exposure levels 0 (n = 111) 4 Age, smoking,
(1998a) job categories involving exposure to were attributed to each ≤ 500 ppm–years 13 10.18 (2.94–35.25) alcoholic
VC; average exposure level, subject on the basis of (n = 54) beverage
3735 ppm–years (range, 4– the job, using estimated 501–2500 ppm–years 19 13.61 (4.26–43.46) consumption
46 702 ppm–years); 42.2% with a values assigned to the (n = 62)
history of having smoked cigarettes, various jobsa 2501–5000 ppm–years 18 15.43 (4.83–49.28)
25.3% with regular daily alcoholic (n = 51)
beverage consumption > 5000 ppm–years (n = 58) 26 21.55 (6.99–66.44)
p < 0.0001
Luo et al. 117 randomly selected workers Estimated accumulated No exposure (n = 18) 0 1.0 Age, alcoholic
(1998) including 7 with liver tumours ppm–months > 1000 ppm–months (n = 69) 10 2.65 (0.42–16.8) beverage
(angiomas); average exposure, ≤ 1000 ppm–months (n = 48) 4 1.64 (0.17–15.8) consumption,
2734.9 ± 4299.9 ppm–months (range, χ2 for linear trend = smoking,
5.4–34 521 ppm–months) 3.92; p = 0.048 hepatitis C
and HBV
infection
ASL, liver angiosarcoma; CI, confidence interval; HBV, hepatitis B virus; HCC, hepatocellular carcinoma
a
Estimates of VC exposure in ppm–years were based on years of a given job category weighted by the presumed level of exposure as defined by the exposure matrix of
Heldaas et al. (1984)
397
Table 18. Prevalence of Asp13p21ras mutant protein in blood samples of vinyl

chloride-exposed workers
Reference Mean exposure to vinyl chloride No. of subjects tested Asp13p21-positive (%)
De Vivo et 19.5 years, 12.2 years before 60, including 5 ASL 56.6 (0 in controls)
al. (1994) 1974 and 1 HCC
Li et al. 2735 ppm–years 225 33.8 (3.7 in controls)
(1998a) (range, 4–46 702 ppm–years)
Luo et al. 2734.9 ppm–months 117 12 (0 in controls)
(1998) (range, 5.4–34 521 ppm–months)
ASL, liver angiosarcoma; HCC, hepatocellular carcinoma
angiosarcoma (Table 17). A similar relationship was found between the presence of
mutated p53 in blood and exposure to vinyl chloride (Tables 19 and 20).
Anti-p53 antibodies have also been tested as a possible biomarker of exposure to
vinyl chloride. The occurrence of anti-p53 antibodies in the blood of vinyl chloride-
exposed workers seems to be related to the level of exposure with a threshold
[~1000 ppm–years]. Below this threshold, this effect is not detected (Table 21).
When two markers, Asp13p21ras and mutated p53, were tested against exposure to
vinyl chloride, each biomarker alone demonstrated a highly statistically significant trend
with exposure (p < 0.0001). Similarly, a highly statistically significant increase was
observed in the serum concentration of one or both of the biomarkers with increasing
exposure (Table 22).
(ii) Cytogenetic studies of vinyl chloride-exposed workers
Studies on the genotoxicity of vinyl chloride, including studies of chromosomal
aberrations, micronucleus formation and sister chromatid exchange, have recently been
reviewed (WHO, 1999). There was a clear relationship between the incidence of chromo-
somal aberrations and exposure concentration, although exposure concentration and
duration of exposure were only estimated. Lesser or no effects were seen when the expo-
sure was reduced to levels < 5 ppm [< 13 mg/m3].
The frequency of sister chromatid exchange increased with the level of exposure to
vinyl chloride, and sister chromatid exchange was generally not detected in the blood of
workers exposed to levels < 5 ppm [< 13 mg/m3]. A recent study conducted to investigate
the genotoxicity of vinyl chloride at low levels confirmed the absence of sister chromatid
exchange in the blood of workers exposed to vinyl chloride levels of approximately
1 ppm [2.59 mg/m3] (Cheng et al., 2000).
DNA single-strand breaks measured in the alkaline comet assay were thought to
occur by transformation of apurinic sites that resulted from repair of vinyl chloride–etheno
Table 19. Dose–response relationship between detection of mutant p53 protein in blood and occupational exposure to vinyl
chloride (VC)
Reference, Cohort description Exposure assessment Exposure categories No of Odds ratio (95% CI) Adjustment
location mutant (adjusted) for potential
p53- confounders
positive
Smith et al. 225 men randomly selected VC exposure levels were 0 (n = 111) 9 1 Age, smoking
(1998), among job categories that attributed to each subject on ≤ 500 ppm–years (n = 54) 16 4.16 (1.63–10.64) status,
VINYL CHLORIDE
France involved exposure to VC; the basis of the job, using 501–2500 ppm–years (n = 62) 21 5.76 (2.39–13.85) alcoholic
average VC exposure level, estimated values assigned 2501–5000 ppm–years (n = 51) 24 10.24 (4.20–24.95) beverage
3735 ppm–years (range, 4– to the various jobsa > 5000 ppm–years (n = 58) 30 13.26 (5.52–31.88) consumption
46 702 ppm–years) p < 0.0001
CI, confidence interval

a
399
Table 20. Prevalence of mutant p53 and anti-p53 antibody-positive blood

samples in vinyl chloride-exposed workers
Reference Mean cumulative exposure to No of Mutant p53- Anti-p53 antibody-

vinyl chloride subjects positive (%) positive (%)
tested
Smith et al. 3735 ppm–years 225 40.4 (8 in controls) –

(1998) (range, 4–46 702 ppm–years)
Luo et al. 1341 ± 3148 ppm–months 251 11 (2.8 in controls) 3.6 (2.3 in controls)
(1999) (range, 0–34 521 ppm–months)
Mocci & 484 ppm–years 151 2 (0 in controls) 3.3 (0 in controls)
Nettuno (2006) (range, 4–2823 ppm–years)
adducts through base-excision repair by glycosylase. The level of DNA single-strand

breaks was found to be significantly higher in workers exposed to levels of vinyl chloride
> 5 ppm [13 mg/m3] than in workers exposed to levels < 5 ppm (Lei et al., 2004).
(iii) Mutations at the hypoxanthine guanine phosphoribosyl
transferase (HPRT) locus
With the HPRT lymphocyte clonal assay, it is possible to determine the mutation
frequency of the HPRT gene and to characterize its mutant spectra. Mutagenesis induced
in the lymphocytes of PVC production workers was measured by selecting resistant
mutant T cells in a medium that contained 6-thioguanine. Exposed workers and controls
had similar mutation frequencies. However, great differences occurred in the spectrum of
mutants. In particular, the percentage of large deletions in the exposed group was much
higher (21%) than in unexposed controls (11%) (Hüttner & Holzapfel, 1996). The mutant
frequency of HPRT in T lymphocytes of 29 individuals accidentally exposed to levels of
vinyl chloride between 1 and 8 ppm [2.6–20.7 mg/m3] was measured after the accident
and in a follow-up study 2 years later. A statistically significantly higher cloning
efficiency was observed in the exposed population after the accident (68.1 versus 50.7%
in the controls; p = 0.007, Mann-Whitney test). However, no significant difference in the
mutant frequency could be found between the exposed population and controls
(3.28 ± 1.84 × 10–6 versus 3.01 ± 2.38 × 10–6) (Becker et al., 2001).
4.2.2 Experimental systems

(a) DNA adducts
Studies on the formation of DNA adducts in animals have recently been reviewed
(WHO, 1999). New data are summarized in Table 23.
Table 21. Dose–response relationship between detection of mutant p53 protein and anti-p53 antibody in blood and occupational
exposure to vinyl chloride (VC)
Reference, Cohort Exposure Exposure categories No of Odds ratio No. of Odds ratio Adjustment Comments
location description assessment mutant (95% CI) total p53 (95% CI) for potential
p53- (adjusted) responses (adjusted) confounders
positive (mutant or
antibody)
Luo et al. 251 workers Estimated 0 (n = 36) 1 1 2 1 Age, Significant dose–

(1999), including 7 with accumulated Low exposure 14 1.6 19 1.49 smoking, response relationship
Taiwan, liver tumours ppm–months ≤ 480 ppm–months (0.21–12.54) (0.24–9.2) alcoholic between plasma total
China (assumed to be (n = 156) χ2 for linear χ2 for linear beverage p53 protein
angiomas); trend = 1.37; trend = 0.95; consumption overexpression and
VINYL CHLORIDE
average cumu- p = 0.24 p = 0.33 cumulative VC
lative exposure, High exposure 11 3.5 14 2.5 exposure
1341 ± 3148 > 480 ppm-months (0.54–22.5) (0.5–12.14) concentration
ppm–months (n = 95)
(range, 0–34 521
ppm–months)
Mocci & 151 male VC exposure 0 (n = 136) 0 0 Age, Trend for increasing
Nettuno workers; mean levels before 1–100 ppm–years 0 0 smoking, serum positivity for
(2006), Italy cumulative 1983 were (n = 86) alcoholic p53 antibodies with
exposure, 484 ± attributed to 101–1000 ppm– 0 1 1 beverage increasing level of VC
725 ppm–years each subject on years (n = 35) consumption exposure; logistic
(range, 4–2823 the basis of the 1001–2000 ppm– 1 1 2 regression using
ppm–years) job, using years (n = 18) mutant p53 antigen or
estimated > 2000 ppm–years 2 3 11.33 p53 antibodies
values assigned (n = 12) χ2 for linear adjusted for smoking,
to the various trend = 5.6; alcoholic beverage
jobs p = 0.02 consumption and age
shows cumulative VC
exposure as only
significant predictor
(p = 0.03 and 0.005)
401
402
Table 22. Dose–response relationship between detection of Asp13p21ras protein and/or mutated p53 protein in blood of vinyl
chloride (VC)-exposed workers
Reference, Cohort description Exposure Exposure categories One Both Odds ratio (95% Adjustment Comments
location assessment marker markers CI) (adjusted) for potential
positive positive confounders

Li et al. 172 exposed men VC exposure 0 (n = 43) 5 0 1 Age, Each biomarker alone
(1998b), randomly selected levels were ≤ 500 ppm–years 21 1 11.1 (3.3–37.5) smoking, demonstrated a highly
France among job categories attributed to (n = 42) alcoholic statistically significant
that involved VC each subject on 501–2500 ppm–years 21 4 12.8 (4.1–40.2) beverage trend with exposure
exposure employed the basis of the (n = 45) consumption (p < 0.0001).
since 1950; average job, using 2501–5000 ppm–years 19 6 29.9 (9.0–99.1) Similarly, highly
VC exposure level, estimated values (n = 31) statistically significant
4107 ppm–years assigned to the > 5000 ppm–years 22 17 31.2 (10.4–94.2) increasing likelihood
(range, 4–46 702 various jobsa (n = 54) p < 0.0001 of seropositivity for
ppm–years) one or both of the
biomarkers with
increasing exposure
Luo et al. 251 workers (7 with Estimated 0 (n = 44) 2 0 1 Significant linear trend
(2003), liver tumours accumulated 0–10 ppm–years 12 1 2.18 (0.09–54.8) between exposure
Taiwan, assumed to be ppm–months (n = 71) concentration and one
China angiomas); average 10–40 ppm-years 13 1 2.01 (0.08–50.5) oncoprotein over-
cumulative exposure, (n = 77) expression
112 ± 262 ppm–years > 40 ppm–years 29 0 –
(range, 0–2877 ppm– (n = 95)
years)

a
Table 23. Formation of DNA adducts in rats exposed to vinyl chloride (VC)
Strain, sex, age Treatment Organs Alkylated bases/108 unmodified bases in DNA Comments Reference
investigated
Background levels After vinyl chloride exposure
Sprague- 1300 mg/m3 Liver, lung, εA: mean value from εA: 4.1 ± 1.5 in liver, lung, Levels of VC-induced and Barbin
Dawley, male, [500 ppm], 4 h/d, kidney, 0.043 in the liver to 35 lymphocytes and testis; no endogenous adducts were not (1999)
6 weeks 5 d/wk for 8 wks circulating in brain increase in kidney and spleen higher in the liver, the major
lymphocytes, εC: mean value from εC: 7.8 ± 1.2 in liver, kidney, target organ of VC, than in
brain, spleen 0.062 in the liver to 20.4 lymphocytes and spleen other tissues
testis in brain No significant increase in
brain for either etheno adduct
VINYL CHLORIDE
Sprague- 600 ppm Liver NR εA: (immunohistochemical After VC exposure, staining Yang et
Dawley, [139 mg/m3], 4 h/d, levels) 1.5 times higher in for εA was higher in both al. (2000)
female, 10 days 5d VC-exposed rats than in parenchymal cells and non-
controls parenchymal cells.
Significantly elevated adduct
levels persisted in the liver of
VC-exposed rats 14 days
after cessation of exposure
Fischer 344 0, 10, 100, 1100 ppm Liver N2,3-εεG: 9 ± 0.4 N2,3-εεG: After 10 ppm VC exposure, Swenberg
[0, 26, 259, 2858 10 ppm VC, 5 d: 20 ± 5.0 respectively 2.2- and 5.9-fold et al.
mg/m3], 6 h/d, 10 ppm VC, 20 d: 53 ± 1.1 increase in N2,3-εG (2000)
5 d/wk, 1 or 4 wks 100 ppm VC, 5 d: 68 ± 9 compared with the amount of
100 ppm VC, 20 d: 228 ± 18 endogenous N2,3-εG
Sprague- 0 and 1100 ppm Liver NR N2,3-εεG: 20 d, 80.6 ± 2.58 Morinello
Dawley, male, [2858 mg/m3], 6 h/d, 1,N2-εεG: below the detection et al.
11 weeks 5 d/wk, 1 or 4 wks limit of 15 fmol (2001)
403
404
Table 23 (contd)
Strain, sex, age Treatment Organs Alkylated bases/108 unmodified bases in DNA Comments Reference
investigated
Background levels After vinyl chloride exposure
Adult study Whole-body Liver, brain Adult study Adult study Adult study Morinello
Sprague- inhalation: N2,3-εεG: ~ 5 in liver and N2,3-εεG: 110 ± 20 in liver No increase after 5 d et al.
Dawley, male, 0 and 1100 ppm brain after 20 d exposure exposure in liver; no increase (2002a)

11 weeks [2852 mg/m3], 6 h/d, observed in brain
Weanling study 5 d/wk, 1 or 4 wks Weanling study Weanling study Weanling study
40 pups weaned N2,3-εεG: ~ 1.5 in liver N2,3-εεG: 97 ± 5.0 in liver after Levels of N2,3-εG in
at day 25 and brain 5 d exposure; 4.4 ± 1.1 in wealings after 5 d exposure
brain after 5 d exposure similar to those in adults
exposed for 4 wks; small but
statistically significant
increase of N2,3-εG in brain
Adult study Whole-body Liver, Adult study Adult study Morinello
Sprague- inhalation: 0, 10, hepatocytes N2,3-εεG: ~ 5 in HEP; ~ 9 N2,3-εεG: ~35 in HEP and Linear increase from 0 to et al.
Dawley, male, 100, 1100 ppm [0, (HEP) and in NPC NPC after 5 d exposure to 100 ppm and plateau (2002b)
11 weeks 26, 259, 2852 non- 100 ppm; 110 ± 1 and 71 ± 1.1 between 100 and 1100 ppm
mg/m3], 6 h/d, 5 parenchymal in HEP and NPC,
d/wk, 1 or 4 wks cells (NPC) respectively, after 20 d
exposure to 100 ppm
Weanling study Weanling study Weanling study In contrast to adults,
40 pups weaned N2,3-εεG: ~1.6 in HEP; N2,3-εεG: 90 ± 0.7 and 43 ± 0.5 difference in adducts
at day 25 ~ 4.9 in NPC in HEP and NPC, concentration detected
respectively, after 5 d between the HEP and NPC
exposure to 100 ppm populations from the
weanlings
d, day; εA: 1,N6-ethenoadenine; εC: 3,N4-ethenocytosine; N2,3-εεG: N2,3-ethenoguanine; 1,N2-εεG: 1,N2-ethenoguanine; NR, not reported; wk, week
VINYL CHLORIDE 405
The DNA adducts εA and εC have been found in various organs in rats after inhalation
exposure to vinyl chloride. 7-OEG was shown to be the major DNA adduct formed in
vivo and was found in greater amounts in young animals (Swenberg et al., 2000).
However, 7-OEG has a short half-life of about 62 h while etheno adducts were more
persistent. For example, N2,3-εG has a half-life of about 30 days (Fedtke et al., 1990). Of
the etheno adducts, N2,3-εG was present in greatest amounts in tissues of exposed animals
(10–100-fold greater than other etheno adducts).
After exposure of rats to 500 ppm [1300 mg/m3] vinyl chloride for 8 weeks, the level
of εA was increased significantly above background in the liver, lung, lymphocytes and
testis. The level of εC was also increased significantly in the liver, kidney, lymphocytes
and spleen. No significant increase was found in brain for either ethano adducts (Guichard
et al., 1996; Barbin, 1999). When adult rats were exposed to 1100 ppm [2858 mg/m3]
vinyl chloride for 1 or 4 weeks, there was a significant increase in the level of N2,3-εG in
hepatocytes, but not in the brain. In contrast to adults, there was a small, statistically
significant increase in N2,3-εG in the brain of weanling animals exposed for 5 days. In
addition, in weanlings, the concentration of N2,3-εG in hepatocytes was significantly
greater than that measured in non-parenchymal cells after exposures to 10 and 100 ppm
[26 and 259 mg/m3 ] vinyl chloride (Morinello et al., 2002a). These differential responses
between weanlings and adults may contribute to the particular susceptibility of young rats
to vinyl chloride-induced neuroblastomas and hepatocarcinomas (Maltoni & Cotti, 1988).
In adult rats, N2,3-εG was clearly induced in both hepatocytes and non-parenchymal
cells after exposure to vinyl chloride for 1 or 4 weeks, with a linear increase at exposure
concentrations from 0 to 100 ppm [259 mg/m3] and a plateau at levels of 100–1100 ppm
[259–2852 mg/m3]. There was no significant difference in N2,3-εG adduct levels, nor in
the rate of repair between hepatocytes and non-parenchymal cells (Morinello et al.,
2002b), which confirms the earlier observation of Yang et al. (2000) (see also Table 23).
(b) Mutations and other related effects (see Table 24)

Genotoxicity studies on vinyl chloride in vitro and in vivo have recently been
reviewed (WHO, 1999). The genotoxicity of vinyl chloride has been clearly demonstrated
in several in-vitro systems. Vinyl chloride vapour induced reverse mutation in various
strains of Salmonella typhymurium. In aqueous or alcoholic solutions, vinyl chloride in-
duced mutations in Escherichia coli, Saccharomyces cerevisiae and Schizosaccharomyces
pombe. It was also mutagenic in the recessive lethal test in Drosophila melanogaster, but
not in the dominant lethal test in mice. It induced DNA strand breaks, sister chromatid
exchange, micronucleus formation and chromosomal aberrations in rodents. In vitro, a
higher mutagenic response was obtained in the presence of an exogenous metabolic
activation system from rat liver.
406
Table 24. Genetic and related effects of vinyl chloride
Test system Resulta Doseb Reference

(LED or HID)
Without With
exogenous exogenous
metabolic metabolic
system system
Salmonella typhimurium TA100, TA1535, reverse mutation + + 200 000 ppm/48 h McCann et al. (1975)

Salmonella typhimurium TA100, TA1535, reverse mutation + + 1000 ppm Shimada et al. (1985)
Salmonella typhimurium TA1530, TA1535, G-46, reverse mutation + + 2000 ppm/48 h Bartsch et al. (1975)
Salmonella typhimurium TA1530, reverse mutation + + 2---20% in air de Meester et al. (1980)
Salmonella typhimurium TA1535, reverse mutation + + 110 000 ppm Rannug et al. (1974)
Salmonella typhimurium TA1536, TA1537, TA1538, reverse mutation --- --- 200 000 ppm Rannug et al. (1974)
Salmonella typhimurium TA1538, G-46, reverse mutation (+) (+) 200 000 ppm Bartsch et al. (1975)
Salmonella typhimurium TA1537, TA1538, TA98, reverse mutation --- --- 100 000 ppm Shimada et al. (1985)
Escherichia coli K12, gene mutation + 10.6 mM (medium) Greim et al. (1975)
Schizosaccharomyces pombe P1, SP.198, gene mutation + + 16---48 mM (medium) Loprieno et al. (1976)
+
Drosophila melanogaster male Berlin K, sex-linked recessive lethal 850 ppm/2 d or Verburgt & Vogel (1977)
mutation 30 ppm/17 d
+
Drosophila melanogaster male Karnäs, sex-linked recessive lethal mutation 10 000 ppm/3 h Magnusson & Ramel (1978)
Drosophila melanogaster male Berlin K, dominant lethal test --- 30 000 ppm/2 d Verburgt & Vogel (1977)
Drosophila melanogaster male Berlin K, aneuploidy (sex chromosome loss) --- 30 000 ppm/2 d Verburgt & Vogel (1977)
Drosophila melanogaster male Berlin K, aneuploidy (sex chromosome loss) + 48 500 ppm Ballering et al. (1996)
Host-mediated assay, forward mutation, Schizosaccharomyces pombe + 74 mg/kg bw po Loprieno et al. (1976)
SP.198 in Swiss mice
Host-mediated assay, gene conversion, Saccharomyces cerevisiae in male + 10 000 ppm/24 h Eckardt et al. (1981)
Wistar rats
DNA single-strand breaks, female NMR mice in vivo + 500 ppm, 6 h/d × 5 Walles & Holmberg (1984)
Mouse spot test, pregnant female C57BL mice --- 4600 ppm/5 h Peter & Ungvá ry (1980)
Sister chromatid exchange, male and female Chinese hamsters in vivo + 12 500 ppm/6 h Basler & Röhrborn (1980)
Micronucleus formation, male CBA mice in vivo + 50 000 ppm/4 h Jenssen & Ramel (1980)
Micronucleus formation, male and female C57BL/6J mouse bone-marrow + 50 000 ppm/6 h Richardson et al. (1983)
cells in vivo
Table 24 (contd)
Test system Resulta Doseb Reference

(LED or HID)
Without With
exogenous exogenous
metabolic metabolic
system system
Chromosomal aberrations, male and female Chinese hamster bone-marrow + 25 000 ppm/24 h Basler & Röhrborn (1980)
cells in vivo
Chromosomal aberrations, male Wistar rat bone-marrow cells in vivo + 1500 ppm, 6 h/d × 5 Anderson & Richardson
VINYL CHLORIDE
(1981)
Dominant lethal test, male CD-1 mice in vivo --- 30 000 ppm, 6 h/d × 5 Anderson et al. (1976, 1977)
Dominant lethal test, male CD-1 mice in vivo --- 10 000 ppm, 4 h/d × 5 Himeno et al. (1983)
Dominant lethal test, male CD-1 mice in vivo --- 5000 ppm, 4 h/d, Himeno et al. (1983)
5 d/wk × 10
Dominant lethal test, male CD rats in vivo --- 1000 ppm, 6 h/d × 5 Short et al. (1977)
a
+, positive; (+), weak positive; ---, negative
b
LED, lowest effective dose; HID, highest ineffective dose; d, day; po, orally; wk, week
407
4.2.3 Mutagenic or promutagenic properties of DNA adducts formed by vinyl

chloride metabolites
The major DNA adduct 7-OEG lacks miscoding properties (Barbin et al., 1985). In
contrast, promutagenic properties have been shown for the etheno and related exocyclic
DNA adducts, εΑ, εC, N2,3-εG, and HO-ethanoG that involve mainly base-pair sub-
stitution mutations (WHO, 1999; see Table 25)
Various assays have been designed to explore the mutagenic properties of DNA
adducts, which have been incorporated into oligonucleotides or into site-specific vectors
and used in experiments of misincorporation. Vector plasmids have also been treated with
2-chloroethyleneoxide or 2-chloroacetaldehyde and propagated in E. coli or mammalian
cells. The more significant and recent studies are listed in Table 25. The mechanism by
which adducts cause mutations still remains unclear. At least two vinyl chloride-induced
DNA adducts, HO-ethanoG and 1, N2-εG have been shown to block replication with
many different polymerases, thereby causing base misincorporation (Langouët et al.,
1997, 1998; Guengerich et al., 1999). The misincorporation events appear to be clearly
dependent on the individual mechanisms of DNA polymerases (Choi et al., 2006).
Mutation frequencies induced by etheno adducts may also depend on the system used
since εA was shown to be highly miscoding in COS7 simian kidney cells, in contrast to
the findings in E. coli (Pandaya & Moriya, 1996). [Clearly, the patterns of base
substitution vary among the different systems used and cannot be extrapolated easily to
predict mutations in human tumour tissue.]
4.2.4 Alterations in oncogenes and suppressor-genes in tumours

(a) RAS genes
Carcinogens are believed to alter genes that are involved in cell proliferation and
differentiation. The RAS genes, Ha-ras, Ki-ras and N-ras, are members of a family of
genes that code for closely homologous proteins that are termed p21ras and function as
signal-switch molecules in the cell. RAS genes activated by point mutations are found in a
wide variety of human cancers. In a study of mutations of RAS oncogenes at codons 12,
13 and 61 in angiosarcomas of the liver of vinyl chloride-exposed workers, five of six
tumours were found to contain a G→A transition at the second base of codon 13
(GGC→GAC) of the Ki-ras-2 gene (Marion et al., 1991). This mutation leads to
substitution of glycine by aspartic acid at amino acid residue 13 in the encoded p21ras
protein. In another series, eight of 15 tumours contained a mutated Ki-ras gene, either at
codon 12 or at codon 13. In five cases, the mutation led to substitution of glycine by
aspartic acid. Two mutations were also found in non-neoplastic tissue (Weihrauch et al.,
2002a).
In studies of hepatocellular carcinomas of vinyl chloride-exposed workers, three
tumours were found to contain mutations at codon 12 in the first exon of the Ki-ras-2
gene due to a G→A transition in two tumours (GGT→GAT) and to a G→T transversion
Table 25. Miscoding specificities of etheno bases
Method Etheno base Incorporation Mutation Comments Reference

tested opposite the lesion
Incorporation of etheno bases into εC A, T CGTA εC facilitates translesional Zhang et al. (1995)
oligodeoxynucleotides and used as CGAT synthesis
templates with the Klenow fragment of
Escherichia coli DNA polymerase I
Incorporation of etheno bases into 1,N2-εG A, G GCAT (2%) Both adducts strongly Langouët et al. (1997,
oligodeoxynucleotides and used as GCTA (0.74%) blocked replication with all 1998)
templates with various polymerases HO-ethanoG A, G GCAT (0.71%) polymerases tested.
GCTA (0.71%)
Incorporation of 1,N2-εG into 1,N2-εG G Incorporation events are Choi et al. (2006)
VINYL CHLORIDE
oligodeoxynucleotides and used as determined by the individual
templates with translesion human DNA mechanisms of DNA
polymerases polymerases.
Incorporation of 1,N2-εG at a single 1,N2-εG G Various mutations Akasaka & Guengerich
site in a pCNheIA vector integrated in mainly GCAT (1999)
the chromosomes, CHO cells
Incorporation of HO-ethanoG in the HO-ethanoG GCTA (11 mutations) Fernandes et al. (2005)
single-stranded vector pMS2, COS7 GCCG (2 mutations)
simian kidney cell line GCAT (1 mutation)
Single-stranded vector pMS2 εA G>T>C ATGC (63%) εA highly miscoding in COS Pandya & Moriya
containing a single εA residue; ATTA (6%) cells (frequency of mutations (1996)
propagated in 5 strains of E. coli and in ATCG (1%) 70%) in contrast to results
COS7 simian kidney cell line for E. coli
supF Gene in vector plasmid pMY189 εC and GCAT (53.8%) 71% of mutations were Matsuda et al. (1995)
treated with CAA, human fibroblast N2,3-εG as GCTA (29.5%) single base mutations
W138-VA13 cells possible GCCG (6.4%)
adducts
εA, 1,N6-ethenoadenine; εC, 3,N4-ethenocytosine; N2,3-εG, N2,3-ethenoguanine; 1,N2-εG, 1,N2-ethenoguanine; CAA, chloroacetaldehyde; CHO, Chinese hamster ovary;
HO-ethanoG, 5,6,7,9,-tetrahydro-7-hydroxy-9-oxoimidazo[1,2-a]purine
409
in one tumour (GGT→TGT). In addition, one tumour contained a mutation due to a

G→T transversion at the second base of codon 12 (GGT→GTT) in neoplastic tissue and
a G→A transition at the second base of codon 12 in non-neoplastic tissue (GGT→GAT).
One tumour contained a mutation at the first base of codon 13 (G→T transversion,
GGC→TGC) in neoplastic tissue and a G→A transition at the second base of codon 13 in
non-neoplastic tissue (GGC→GAC). In one case, the wild-type Ki-ras-2 gene was detec-
ted in neoplastic tissue while a codon 13 mutation was found in non-neoplastic cirrhotic
tissue (GGC→CAT) (Weinrauch et al., 2001a). In the same study, 20 hepatocellular
carcinomas from a control group and associated with hepatitis B or C virus infection or
alcoholic beverage consumption were also analysed. Ki-ras-2 mutations were found in
three cases, two of which were attributed to HBV infection (GGT→GTT and GGC→GAC)
and one to hepatitis C virus infection (GGT→TGT) (Weihrauch et al., 2001a,b).
No mutations were found in the Ki-ras gene in vinyl chloride-induced liver angio-
sarcoma or hepatocellular carcinoma in rats. One mutation was found at codon 13 of
N-ras in a liver angiosarcoma (G→A, GGC→GAC). However, mutations that involved
the second base of codon 61 of the Ha-ras gene and were due to A→T transversions
(CAA→CTA) were found in five of eight hepatocellular carcinomas (Froment et al.,
1994; Boivin-Angèle et al., 2000a) (Table 26).
(b) p53
The p53 gene is a tumour-suppressor gene at the crossroads of many cellular
pathways that involve cell cycle control, DNA repair, DNA replication, apoptosis and
senescence. The majority of cancer-related mutations in p53 cluster in several regions of
the gene that determine the protein structure and that have been highly conserved through
evolution. These regions occur in the sequence-specific DNA-binding core domain of the
protein between amino acid residues 102 and 292. The mutations found in malignancies
could result in substitution of amino acid residues in these regions that are critical for p53
function (Cho et al., 1994; Brandt-Rauf et al., 1996).
A comparison of the mutation spectra in the p53 gene in vinyl chloride-associated
liver tumours in humans and rats is detailed in Table 27.
Five liver tumours (four liver angiosarcomas and one hepatocellular carcinoma) from
workers who were heavily exposed to vinyl chloride were investigated for mutations in
the p53 gene in exons 5 to 8. Two A→T missense mutations were found in a highly
conserved domain: one at codon 249 (AGG→TGG, Arg to Trp) and one at codon 255
(ATC→TTC, Ile to Phe) each in the tumour but not in the normal cells of two of the liver
angiosarcoma patients, of whom both were smokers (Hollstein et al., 1994). A third
mutation, also due to an A→T transversion, was found at codon 179 (CAT→CTT, His to
Leu) in a fibroblastic cell line established from a liver angiosarcoma from a vinyl
chloride-exposed patient (Boivin-Angèle et al., 2000b). Such mutations are uncommon in
human cancers (2.7% of a total of 5085 cancers; Hollstein et al., 1996). Futhermore, p53 gene
mutations are uncommon in sporadic (non-vinyl chloride-induced) liver angiosarcomas
Table 26. Comparison of the mutation spectra in ras proto-oncogenes in vinyl chloride-associated liver tumours
in humans and rats
Tumour origin Gene involved Codon No. of No. of base-pair changes/codon change Reference
mutations/
no. of tumours
Human ASL Ki-ras-2 13 5/6 5 G→A/GGC→GAC Marion et al. (1991)

Human ASL Ki-ras-2 12 5/8 3/5 G→A/GGT→GAT Weihrauch et al.
2/5 G→T/GGT→GTT, GGT→TGT (2002a)
13 3/8 2/3 G→A/GGC→GAC, GGC→CAT
VINYL CHLORIDE
1/3 G→T/GGC→TGC
12 1/2 G→T/GGT→TGT (non-neoplastic tissue)
1/2 G→A/GGT→GAT (non-neoplastic tissue)
Human HCC Ki-ras-2 12 4/12 2 G→A/GGT→GAT Weihrauch et al.
G→T/GGT→TGT (2001a)
G→T/GGT→GTT (with GGT→GAT in the non-
neoplastic tissue)
13 1/12 G→T/GGC→TGC (with GGC→GAC in the non-
neoplastic tissue)
G→A/GGC→CAT non-neoplastic tissue
Rat ASL Ki-ras-2 12, 13, 0/11 None Froment et al. (1994);
N-ras A and 61 Boivin-Angèle et al.
13 2/11 G→A/GGC→GAC (2000a)
36 A→T/ATA→CTA
Rat HCC Ha-ras 61 5/8 5 A→T/CAA→CTA Froment et al. (1994);
Boivin-Angèle et al.
(2000a)
411
Table 27. Comparison of the mutation spectra in the p53 gene in vinyl chloride-
associated liver tumours in humans and rats
Tumour origin No. of Codon (exon) No. of base-pair changes/ References

mutations/no. of codon change
tumours
Human ASL 2/4 2 A→T/ Hollstein et al.

249 (7) AGG→TGG (1994)
255 (7) ATC→TTC
Human ASL 6/17 131 (5) 1 A→T/AAC→ATC Weihrauch et al.
248 (7) 1 G→A/CGG→CAG (2002b)
282 (8) 1 C→T/CGG→TGG
342 (10) 1 C→T/CGA→TGA
200 (6) del-2
216 (6) del-3
Human 1/1 179 (5) 1 A→T/CAT→CTT Boivin-Angèle et al.
fibroblastic cell (2000b)
line from an
ASL
Human HCC 11/18 130 (5) 1 T→G/CTC→CGC Weihrauch et al.
175 (5) 1 C→A/CAC→AAC (2000)
282 (8) 1 C→T/CGG→TGG
179 (5) 1 A→T/CAT→CTT
193 (6) 1 A→C/CAT→CCT
246 (7) 1 A→G/ATG→GTG
3 G→A/
245 (7) GGC→GAC
248 (7) CGG→CAG
273 (8) CGT→CAT
226 (6) 1 G→C/GGC→GCC
236 (7) del(-3)
Rat ASL 11/25 4 A→T/ Barbin et al. (1997)
160 (5) ATC→TTC
235 (7) ATG→TTG
253 (7) ATC→TTC
253 (7) ATC→TTC
235 (7) 1 A→C/ATG→CTG
2 A→G/
203 (6) TAT→TGT
203 (6) TAT→TGT
2 G→A/
152 (5) GGT→AGT
246 (7) CGC→CAC
147 (5) 1 C→T/TCC→TCT
235 (7) 1 T→G/ATG→AGG
177–181 (5) del(-12)
Rat HCC 1/8 283 (8) 1 A→T/GAG→GTG Barbin et al. (1997)

VINYL CHLORIDE 413
(2/21 cases, 9%; Soini et al., 1995), which supports the evidence that links exposure to
vinyl chloride with liver angiosarcoma that contains p53 mutations due to A→T
transversions.
In another series, six mutations were found in 17 vinyl chloride-induced liver
angiosarcomas (four point mutations and two deletions); only one mutation was due to an
A→T transversion (codon 131, AAC→ATC) (Weihrauch et al., 2002b).
Eighteen hepatocellular carcinomas from vinyl chloride-exposed workers were
analysed for mutations in the p53 gene in exons 5–9. In this series, 11 of 18 hepatocellular
carcinomas exhibited a p53 gene mutation, with five transversions and five transitions.
Five of the 11 mutations (codons 175, 245, 248, 273 and 282) affected CpG dinu-
cleotides, three of which (codons 175, 248, 273) were also found in hepatocellular
carcinomas induced by alcoholic beverage consumption and viral or autoimmune cir-
rhosis, which led the authors to conclude that the p53 mutations in their series might be
due to spontaneous processes such as deamination of 5-methylcytosine (Weihrauch et al.,
2000). In studies of both liver angiosarcoma and hepatocellular carcinoma, no p53
mutations were found in the surrounding non-neoplastic tissue.
Mutations in the p53 gene were also found in 11 of 25 (44%) liver angiosarcomas
induced by vinyl chloride in Sprague-Dawley rats and in one of eight hepatocellular
carcinomas (Barbin et al., 1997). Five mutations involved an A→T transversion as seen
in human vinyl chloride-induced liver angiosarcoma. The A→T transversion in the first
base of codon 253 in two rat liver angiosarcomas was equivalent to the transversion
observed in codon 255 in one human liver angiosarcoma associated with exposure to
vinyl chloride (Hollstein et al., 1994) (Table 27).
4.3 Mechanisms of carcinogenesis

Many key events in the pathway of vinyl chloride-induced hepatocarcinogenesis have
been established. These include (a) metabolic activation (to chloroethylene oxide),
(b) DNA binding of the reactive metabolites (characteristic exocyclic etheno-adducts,
(c) promutagenicity of these adducts that lead to G→A and A→T transitions and
(d) effects of such mutations on proto-oncogenes/tumour-suppressor genes at the gene
and gene product levels, with tumorigenesis as the final outcome (Bolt, 2005).
Vinyl chloride has been demonstrated to be a genotoxic carcinogen in animal and
human studies (Block, 1974; Creech & Johnson, 1974; Lee & Harry, 1974; Maltoni et al.,
1974, 1981). It is absorbed rapidly after inhalation and oral exposure (Bolt, 1978), and is
metabolized (activated) mainly by CYP2E1 to 2-chloroethylene oxide which spon-
taneously rearranges to 2-chloroacetaldehyde. 2-Chloroethylene oxide and 2-chloro-
acetaldehyde can be transported intercellularly from parenchymal cells to non-paren-
chymal cells in the liver (Kuchenmeister et al., 1996). The primary detoxification reaction
of the two reactive metabolites is conjugation with GSH catalysed by GST; the
conjugation products are then excreted in urine (reviewed in WHO, 1999).
Both 2-chloroethylene oxide and 2-chloroacetaldehyde can form DNA adducts. Five
DNA adducts are formed by 2-chloroethylene oxide or 2-chloroacetaldehyde (Cheng et
al., 1991; Basu et al., 1993). These include the major adduct, 7-OEG, and four cyclic
etheno adducts (1,N2-εG, εC, εA and N2,3-εG). These etheno adducts generate mainly
base-pair substitution mutations and specific mutations in cancer-related genes (i.e. RAS
oncogenes, p53 tumour-suppressor genes). The major reaction product of 2-chloro-
ethylene oxide is 7-OEG, but 2-chloroacetaldehyde does not form this adduct. 7-OEG
does not exhibit promutagenic properties whereas εA, εC, N2,3-εG and 1,N2-εG do. εA,
εC and N2,3-εG have demonstrated miscoding potential in vitro and in vivo (Singer et al.,
1987; Cheng et al., 1991; Mroczkowska & Kusmierek, 1991; Singer et al., 1991; Basu et
al., 1993) and others have shown that εA causes A→G transitions and A→T trans-
versions, εC causes C→A transversions and C→T transitions and εG causes G→A
transitions (reviewed in Bolt, 2005; see Table 25). These changes were consistent with the
mutations of p53 and RAS genes observed in tumours from vinyl chloride-exposed
humans and rats (Tables 26 and 27).
Etheno adducts appear to have long persistence and are repaired by glycolases (Gros
et al., 2004). In addition to the DNA adducts produced by vinyl chloride, a physiological
background of endogenously produced etheno adducts is possibly the product of oxi-
dative stress and lipid peroxidation (Bartsch & Nair, 2000a,b; De Bont & van Larebeke,
2004; Bolt, 2005).
The induction of extrahepatic tumours by vinyl chloride has been established experi-
mentally, but the mechanism for this extrahepatic tumour formation, e.g. in the brain or
lung, is not well elucidated (Bolt, 2005).
While the data overall suggest that etheno adducts are probably involved in the
initiation of hepatocarcinogenesis by vinyl chloride, some factors have yet to be
explained. These include observed tissue and cell specificity and variability in various
biomarkers such as mutant p53 protein and anti-p53 antibodies in vinyl chloride-exposed
workers with tumours (Trivers et al., 1995; Brand-Rauf et al., 1996). One source for this
variability might be explained by differences in genetic polymorphisms of genes that
encode for enzymes involved in vinyl chloride metabolism and for proteins involved in
DNA repair (Li et al., 2003a).
4.4 Susceptibility
4.4.1 Genetic polymorphisms and enzyme induction
The enzymes that are involved in vinyl chloride activation and detoxification,
i.e. CYP2E1, ALDH2, GST and mEH (Figure 1), are known to have polymorphic
variants with altered activity. Polymorphisms of each of these enzymes may modulate the
metabolism of vinyl chloride, the levels of 2-chloroethylene oxide and 2-chloro-
acetaldehyde and hence the frequency and nature of vinyl chloride-induced mutations.
VINYL CHLORIDE 415
For example, individuals who have high-activity variants of CYP2E1 and/or low-
activity variants of ALDH2 or GST enzymes may have elevated levels of chloroethylene
oxide and chloroacetaldehyde and increased DNA damage.
Among the many CYP2E1 polymorphisms described, c1 and c2 alleles have been
identified in the 5-regulatory region of the gene. According to in-vitro studies that inves-
tigated gene transcription and enzyme activity, workers who have at least one c2 allele
may have higher CYP2E1 activity than the homozygous c1c1, although this was not
clearly confirmed in vivo. The frequency of the rare c2 allele is 24–30% for Asian pop-
ulations, 2–3% for Caucasians, 0.3–7% for African-Americans, 15% for Mexican
Americans and 18% for Chinese (Province of Taiwan) (Danko & Chaschin, 2005). The
levels of CYP2E1 vary in human populations and have been shown in addition to be
induced by repetitive alcoholic beverage consumption and exposure to other agents
(Lieber & DeCarli, 1970; Roberts et al., 1995; Mastrangelo et al., 2004).
GSTs are encoded by a supergene family that is divided, on the basis of the chromo-
somal location and sequence homology, into four classes; Alpha, Mu, Pi and Theta (Lo &
Li-Osman, 2007). Approximately half of the Caucasian population has no GSTM1-1
enzyme because of a homozygous deletion of the GSTM1 gene. The other half is either
heterozygous or homozygously normal. The frequency of the GSTM1 null-null genotype
is similar in Asians but lower in African-Americans (~ 27%) (Parl, 2005).
Genotypic differences are also frequent for the GSTT1 gene. The GSTT1–/– genotype
is more common in Asians, at frequencies that range from 47 to 64%, whereas this homo-
zygous null genotype is found only in 20% of Caucasians (Parl, 2005).
There is a structural polymorphism at amino acid position 487 of the ALDH2 gene. A
substitution of lysine for glutamic acid results from a transition of G (allele 1) to A (allele
2). The ALDH2 alleles that encode the active and inactive subunits are termed ALDH2*1
and ALDH2*2, respectively (Farres et al., 1994). The dominant-negative mutant allele,
ALDH2*2, is extremely rare in Caucasians, but is widely present in Mongoloids (28–
45%; Goedde et al., 1992).
Polymorphisms in genes that encode for the proteins that are involved in DNA-repair
processes, such as XRCC1 (X-ray cross-complementing group 1) and XPD (xeroderma
pigmentosum group D), may also modulate the occurrence of vinyl chloride-induced
mutations. The XRCC1 protein is responsible for the repair of DNA lesions that are
caused by alkylating agents. Etheno adducts produced by vinyl chloride are normally
removed by the base-excision repair pathway which contains several proteins that are
coordinated by XRCC1. Three polymorphisms have been identified at codon 194 (Arg to
Trp), 280 (Arg to His) and 399 at codon 10 (Arg to Gln, termed Gln phenotype) for
XRCC1 (Lindahl & Wood, 1999; Goode et al., 2002).
The XPD protein is an adenosine triphosphate-dependent 5’-3’ helicase involved in
nucleotide excision repair. Several polymorphisms have also been described for the XPD
gene (Lindahl & Wood, 1999; Goode et al., 2002).
Few studies have investigated vinyl chloride-induced alterations at the chromosome
level (sister chromatid exchange) and at the gene level (RAS and p53 point mutations) in
vinyl chloride-exposed workers with various polymorphisms. In a study from Taiwan,

China, CYP2E1c1c2/c2c2, ALDH2 1-2/2-2 and XRCC1 Gln-Gln polymorphisms
appeared to be weak susceptibility factors for the frequency of sister chromatid exchange
in relation to exposure to vinyl chloride, but not GSTT1 or GSTM1 genes (Table 28).
CYP2E1 c2c2 was also associated with a higher risk for p53 protein overexpression in the
plasma of vinyl chloride-exposed workers (adjusted odds ratio, 9.8; 95% CI, 1.2–81.6),
and this increased risk was also associated with GSTT1 non-null (odds ratio, 2.4; 95% CI,
0.8–7.6) or ALDH2 1-2/2-2 (odds ratio, 1.6; 95% CI, 0.5–4.6), particularly in the low-
exposure group (≤ 40 ppm–years) (Wong, R.H. et al., 2002). These authors suggested that
frequency of sister chromatid exchange reflects recent exposure to vinyl chloride, while
p53 gene mutations reflect cumulative exposure to vinyl chloride. However, CYP2E1
c1/c2 genotype compared with the wild-type c1/c1 genotype appeared to contribute only
slightly to the occurrence of mutant p21ras or p53 proteins in French vinyl chloride-
exposed workers (Li et al., 2003b).
In contrast, a joint effect of the XRCC1 codon 399 polymorphism and cumulative
exposure to vinyl chloride on the occurrence of the p53 biomarker was observed (Li et al.,
2003a). While GSTM1, GSTT1 and GSTP1 polymorphisms were not found to be asso-
ciated with an increased occurrence of mutant p53, a significant trend for the prevalence
of p53 biomarkers was observed when the combined effects of GSTM1, GSTT1 and
XRCC1 were analysed. The GSTM1 and GSTT1 null genotypes appeared to modify the
effect of XRCC1 codon 399 genotype on p53 biomarker status, possibly in a synergistic
fashion (Table 29) (Li et al., 2005a). All XRCC1 codon 194, 280 and 399 polymorphisms
also had an effect on the occurrence of the p53 biomarker (Table 30), but not on that of
the p21ras biomarker in the blood of vinyl chloride-exposed workers (Li et al., 2006). In
contrast, the mEH genotype has no effect on p21ras or p53 biomarkers of vinyl chloride-
induced mutagenic damage and may not be involved as a major detoxification enzyme in
the metabolism of vinyl chloride in humans (Li et al., 2005b). A follow-up of these
studies has recently reported the analysis of a cohort of 597 French vinyl chloride-
exposed workers. The presence of biomarkers for mutant p21ras and mutant p53 was
found to be highly significantly associated with cumulative exposure to vinyl chloride
(p for trend < 0.0001). The CYP2E1 variant c2 allele was significantly associated with the
presence of either or both mutant biomarkers even after controlling for potential con-
founders including cumulative exposure to vinyl chloride (odds ratio, 2.3; 95% CI, 1.2–
4.1), and the effects of the c2 allele and vinyl chloride exposure were approximately
additive. GSTT1 null status was found to have an increased but not significant association
with the presence of either or both biomarkers after controlling for confounders (odds
ratio, 1.3; 95% CI, 0.8–2.0) (Schindler et al., 2007).
The effects of polymorphisms of the DNA repair gene XPD on DNA damage in
lymphocytes were studied in vinyl chloride-exposed workers in China using the comet
assay. The study compared workers with ≥ 5 damaged cells per 100 cells studied with
workers with no DNA damage who were matched for age, gender, cumulative exposure
to VCM and worksite. Three XPD polymorphisms were investigated: Ile199Met, Asp312Asn
Table 28. Association between frequency of sister chromatid exchange and different polymorphisms (multiple regression
model for frequencies of sister chromatid exchange per cell)
Reference Cohort description Exposure assessment Exposure categories One marker positive Regression p value
coefficient/SE
Wong et al. 44 men with 4–36 years’ A TWA exposure to High VC exposure Smoking status, yes versus no 0.85/0.31 < 0.01
(1998) exposure to VC, from VC assigned to each group > 1 ppm VC exposure, high versus low 0.64/0.34 0.06
3 PVC plants; study based category of job based (n = 28) CYP2E1 c1c2/c2c2 versus c1c1 0.50/0.33 0.14
on predetermined VC on monitored air Low VC exposure ALDH2 1-2/2-2 versus 1-1 0.63/0.31 0.05
exposure levels and levels of VC < 1 ppm (n = 16) GSTM1 non-null versus null –0.41/0.31 0.19
VINYL CHLORIDE
smoking status; mean age, GSTT1 non-null versus null 0.27/0.30 0.38
45.1 ± 1.4 years; current
smokers, 55.6%
Wong et al. 61 men, 29 controls A TWA exposure to Controls (n = 29) Smoking status, yes versus no 0.56/0.26 0.03
(2003b) VC assigned to each High VC exposure > Alcohol drinking, yes versus no –0.21/0.33 0.52
category of job based 1 ppm (n = 32) High VC exposure versus controls 1.00/0.46 0.03
on monitored air Low VC exposure < 1 Low VC exposure versus controls 0.60/0.42 0.16
levels of VC ppm (n = 29) XRCC1 exon 10: Gln-Gln versus 1.09/0.49 0.03
Arg-Arg/Arg-Gln
CYP2E1 c2c2 versus c1c1/c1c2 1.54/0.72 0.04
ALDH2 1-2/2-2 versus 1-1 0.44/0.25 0.08
GSTT1 null versus non null 0.12/0.25 0.63
ALDH2, aldehyde dehydrogenase 2; CYP, cytochrome P450; GST, glutathione-S-transferase; PVC, polyvinyl chloride; SE, standard error; TWA, time-weighted
average ; VC, vinyl chloride; XRCC1, X-ray cross-complementing group 1
417
418
Table 29. Association between XRCC1/GSTM1/GSTT1 polymorphisms and mutant p53 in vinyl chloride (VC) workers
Reference Cohort description Exposure assessment XRCC1 codon 399/GSTM1 or Exposure categories No. positive Adjusted odds ratio
GSTT1 genotypes (in ppm–years) mutant p53 (95% CI)a
biomarker (%)
Li et al. 211 VC-exposed workers; Average cumulative Arg-Arg ≤ 1000 (n = 24) 6 (25) 1.00
(2003a) average age, 56 years exposure, 5871 ppm– 1001–4000 (n = 31) 12 (39) 2.19 (0.65–7.40)
(range, 35–74 years); years (range, 6– > 4000 (n = 31) 11 (35) 1.96 (0.56–6.80)

current smokers, 39%; 46 702 ppm–years);
current drinkers, 20% VC exposure levels Arg-Gln ≤ 1000 (n = 26) 10 (38) 1.90 (0.55–6.52)
were attributed to each 1001–4000 (n = 25) 9 (36) 1.89 (0.53–6.69)
subject on the basis of > 4000 (n = 39) 23 (59) 5.43 (1.57–18.83)
the job, using
estimated values Gln-Gln ≤ 1000 (n = 11) 5 (45) 2.50 (0.54–11.51)
assigned to the various 1001–4000 (n = 14) 10 (71) 8.84 (1.87–41.70)
jobsb > 4000 (n = 10) 8 (80) 12.17 (1.88–78.67)
p for trend = 0.0004
Li et al. Same cohort as Li et al. Same as Li et al. Arg-Arg/both wild types (n = 31) NR 8 (26) 1
(2005a) (2003a) (2003a) Arg-Arg/either null (n = 47) 18 (38) 1.8 (0.7–5.0)
Arg-Arg/ both null (n = 8) 3 (38) 1.8 (0.3–9.3)
Arg-Gln+Gln-Gln/both wild 25 (50) 2.9 (1.1–7.8)
types (n = 50)
Arg-Gln+Gln-Gln/either null 35 (51) 3.2 (1.2–8.3)
(n = 68)
Arg-Gln+Gln-Gln/both null 5 (71) 8.4 (1.3–54.0)
(n = 7)
p for trend = 0.00037
CI, confidence interval; GST, glutathione-S-transferase; NR, not reported; XRCC1, X-ray cross-complementing group 1
a
Adjusted for age, smoking, alcoholic beverage consumption and cumulative VC exposure
b
Estimates of VC exposure in ppm–years based on years of a given job category weighted by the presumed ppm level of exposure as defined by the exposure matrix of
Table 30. Association between XRCC1 codons 194, 280 and 399 polymorphisms and mutant p53 in vinyl chloride (VC)
workers
Reference Cohort description Exposure assessment XRCC1 codons 194, 280 Mutant p53 biomarker Adjusted odds ratio
and 399 (95% CI)a
+ –
Li et al. (2006) 211 VC-exposed workers; Average cumulative exposure, All wild type 21 (34%) 41 (66%) 1
average age, 56 years 5871 ppm–years (range, 6– One variant allele 41 (43%) 55 (57%) 1.5 (0.8–3.0)
(range, 35–74 years); 46 702 ppm–years); VC exposure Two variant alleles 32 (60%) 21 (40%) 3.1 (1.4–6.7)
current smokers, 39%; levels were attributed to each p for trend = 0.005
VINYL CHLORIDE
current drinkers, 20% subject on the basis of the job,
using estimated values assigned
to the various jobsb
CI, confidence interval; XRCC1, X-ray cross-complementing group 1

a
Adjusted for age, smoking, alcoholic beverage consumption and cumulative exposure to VC
b
Estimates of VC exposure in ppm–years based on years of a given job category weighted by the presumed ppm level of exposure as defined by the exposure matrix of
419
and Lys751Gln. Using univariate analysis, it was shown that only the XPD751 Lys/Gln
and Gln/Gln genotypes were significantly associated with DNA damage (odds ratio, 2.21;
95% CI, 1.01–5.13; p < 0.05). After adjusting for the effects of smoking, alcoholic
beverage consumption, liver damage and polymophisms of the DNA repair gene, and
using the group with low exposure to vinyl chloride and the XPD312 Asp/Asp genotype
as a reference, it was found that workers with high exposure and the XPD312 Asp/Asn
and Asn/Asn genotypes had a significantly reduced risk for DNA damage (odds ratio,
0.33; 95% CI, 0.11–0.95) (Zhu et al., 2005b).
These results suggest possible interactions between polymorphisms in the metabolic
pathway of vinyl chloride and/or in the DNA repair processes and exposure to vinyl
chloride that could contribute to the variable susceptibility to the mutagenic effects of
vinyl chloride in exposed populations and might shed some light on the mechanism of
tumour formation in humans.
4.4.2 Age
After results were published to indicate that hepatocytes of young, postnatal rats are
much more susceptible than those of adult rats to the carcinogenic effect of vinyl chloride
(Maltoni et al., 1981; see Section 3), several investigations began to characterize the
potentially susceptible period and the underlying mechanisms.
Laib et al. (1985a) investigated the age-dependence of the induction of preneoplastic
enzyme-altered hepatic foci. Male and female Wistar rats were exposed to 2000 ppm
[5186 mg/m3] vinyl chloride either transplacentally or immediately (1 day) after birth for
a period of 5, 11, 17, 47 or 83 days, or from age 7 days or 21 days until death. Adenosine
triphosphatase-deficient foci were increased compared with control rats after newborn
exposures of 11 days or more, although foci area did not further increase after 17 days.
Transplacental exposure and exposures before day 5 did not increase adenosine triphos-
phatase-deficient foci.
In accompanying studies, Laib et al. (1985b) also investigated the effects of a range
of lower concentrations administered early in life. Wistar rats were exposed to 10, 40, 70,
150, 500 or 2000 ppm [26, 104, 182, 389, 1300 or 5186 mg/m3] vinyl chloride for
10 weeks beginning at 1 day of age, and Wistar and Sprague–Dawley rats were exposed
to 2.5, 5, 10, 20, 40 or 80 ppm [6.5, 13, 26, 52, 104 or 208 mg/m3] vinyl chloride for
3 weeks beginning at 3 days of age. In each case, a linear relationship was observed
between the concentration of vinyl chloride and the percentage of foci area induced, with
no obvious threshold for the induction of preneoplastic foci.
Ciroussel et al. (1990) measured the levels of εA and εC adducts in DNA from
several target organs. Rats were exposed to 500 ppm [1300 mg/m3] vinyl chloride for
2 weeks beginning at 7 days or 13 weeks of age. Both εA and εC adducts were detected in
the liver, lungs and brain (but not kidneys) of rats that were 7 days old when first exposed.
In rats that were 13 weeks old when first exposed, only liver DNA was analysed and
levels of each adduct were one-sixth of those observed in the younger rats.
VINYL CHLORIDE 421
Fedtke et al. (1990) investigated the formation and persistence of the DNA adducts
7-OEG and N2,3-εG. Lactating Sprague–Dawley rats and their 10-day-old offspring were
exposed to 600 ppm [1560 mg/m3] vinyl chloride for 4 h per day for 5 days. In the neo-
natal rats, concentrations of both DNA adducts were highest in the liver, followed by
kidney and lung. No adducts were found in the brain or spleen. DNA adducts were detec-
ted only in the liver and lung of the dams. Concentrations of DNA adducts in the liver and
lung were fourfold higher in the neonatal rats than in the dams.
Morinello et al. (2002a) studied the exposure–response relationship of N2,3-εG
adducts over a range of dose levels. Adult Sprague-Dawley rats were exposed to 0, 10,
100 or 1100 ppm [0, 26, 260 or 2852 mg/m3] vinyl chloride for 1 or 4 weeks, and
weanlings were similarly exposed for 5 days. The exposure–response relationship was
linear from 0 to 100 ppm, then did not increase further. Compared with adult rats, two- to
threefold higher concentrations of N2,3-εG adduct were measured in hepatocytes in the
weanlings.
5. Summary of Data Reported
5.1 Exposure data

Vinyl chloride is a gas that is produced predominantly by breaking down ethylene
dichloride into smaller molecules. Production of vinyl chloride by the initial acetylene-
based process is still carried out in China. More than 95% of vinyl chloride is used for the
production of polyvinyl chloride resin, which in turn is mainly used to produce plastic
piping and other plastic items. Vinyl chloride is also used in the manufacture of chlori-
nated solvents. Production of vinyl chloride monomer is increasing. In 2005, production
in Asia had outgrown that in both western Europe and North America. An increasing
number of workers worldwide are exposed to vinyl chloride monomer during either its
production, the manufacture of polyvinyl chloride or polyvinyl chloride processing. Since
the late 1970s when the closed-loop polymerization process was introduced, the concen-
trations to which workers are exposed have decreased substantially in North America and
western Europe. Levels before that time had been higher than 100 mg/m3. In low- and
medium-resource countries, older technologies have continued to be used and therefore
high exposures probably occur. Exposures in polyvinyl chloride processing plants are
usually considerably lower than those in vinyl chloride monomer/polyvinyl chloride
production; in western Europe and North America, current exposure levels are generally
below 1 mg/m3. Concentrations of vinyl chloride monomer in ambient air are normally
below 0.01 mg/m3, but higher concentrations have been measured in the vicinity of vinyl
chloride/polyvinyl chloride production plants.
5.2 Cancer in humans

Epidemiological evidence for the carcinogenicity of vinyl chloride in humans derives
principally from two large, multicentric cohort studies, one of which was carried out in
the USA and the other in Europe. These investigations focused on plants that manu-
factured vinyl chloride monomer, polyvinyl chloride or polyvinyl chloride products.
Additional information is provided by several smaller cohort studies.
Both of the multicentric cohort studies found a substantial increase in the relative risk
for angiosarcoma of the liver, a tumour that is extremely rare in the general population, in
exposed workers. In both studies, the risk for liver angiosarcoma increased strongly with
duration of exposure to vinyl chloride. In the European study, there was also a clear trend
of higher risk with increasing cumulative exposure. Multiple cases of liver angiosarcoma
were also reported in two smaller cohort studies. Overall, these findings constitute com-
pelling evidence that vinyl chloride causes angiosarcoma of the liver.
Assessment of whether vinyl chloride also causes hepatocellular carcinoma is
complicated because many studies do not have histological or other definitive clinical
information to discriminate hepatocellular carcinoma from angiosarcoma of the liver
and/or secondary neoplasms. However, in an internal analysis of the European multi-
centric cohort, the risk for hepatocellular carcinoma increased significantly and
substantially with cumulative exposure to vinyl chloride, based on nine confirmed cases.
Another analysis of a single Italian plant with extended follow-up that was included in the
European multicentric study included 12 confirmed hepatocellular carcinomas. The
maximal overlap between these two analyses was four cases, since only four hepato-
cellular carcinomas from Italy were included in the multicentric cohort. In this subcohort,
the incidence of hepatocellular carcinoma again increased significantly with cumulative
exposure to vinyl chloride. Together with the observation that vinyl chloride increases the
risk for liver cirrhosis, which is a known risk factor for hepatocellular carcinoma, these
findings provide convincing evidence that vinyl chloride causes hepatocellular carcinoma
as well as angiosarcoma of the liver.
There was suggestive evidence that the risk for hepatocellular carcinoma from vinyl
chloride is substantially higher among workers who are infected with hepatitis virus or
report high levels of alcoholic beverage consumption.
Among vinyl chloride workers overall, there was no evidence of an increased risk for
lung cancer. However, in polyvinyl chloride packers and baggers, the risk for lung cancer
increased significantly with cumulative exposure to vinyl chloride. These workers are
known to have had concomitant exposure to polyvinyl chloride dust, and the study did not
allow attribution of the association to a specific agent or combination of agents.
Among the other cancer sites, suggestive evidence was found for malignant neo-
plasms of connective and soft tissue. This derived from the multicentric study in North
America, in which a nearly threefold statistically significant overall increase in incidence
was observed that persisted after the exclusion of four angiosarcomas for which the site
was unknown. The risk was higher for workers with longer duration of employment
VINYL CHLORIDE 423
(i.e. 10–19 and ≥ 20 years). These findings were not supported by the European multi-
centric study, in which too few cases of connective tissue neoplasms were observed for an
evaluation of exposure–response.
The Working Group did not find strong epidemiological evidence for associations of
exposure to vinyl chloride with cancers of the brain or lymphatic and haematopoeitic
tissue or melanoma. Although the associations found for these cancers in specific studies
may reflect true increases in risk, the findings were inconsistent between studies, no clear
exposure–response relationships were found in the European multicentric study and, for
several of the sites, the numbers of observed and expected cases were small. No conclu-
sion could be reached for breast cancer since the studies included too few women.
5.3 Cancer in experimental animals

The carcinogenicity of vinyl chloride has been studied intensively and repeatedly in
experimental animals. The numerous studies are generally mutually reinforced. This
wealth of data has generally been incompletely reported, however, and the outcomes of
many experiments in the published studies are available only from summary tables, in
which technical details are given only as footnotes.
Vinyl chloride was tested by inhalation exposure in seven studies in mice, in nine
studies in rats and in two studies in hamsters. Male and female animals were treated in all
three species, although some experiments were carried out only in one sex. Vinyl chloride
induced hepatic angiosarcomas in three studies in mice and in eight studies in rats; a
positive dose–response was observed for hepatic angiosarcomas in mice and rats over a
wide range of exposures. It induced angiosarcomas (all sites) in four studies in mice, in
three studies in rats and in one study in hamsters. Extrahepatic angiosarcomas related to
treatment with vinyl chloride were observed in three studies in mice and two studies in
rats. Vinyl chloride increased the incidence of mammary tumours in six studies in mice,
in three studies in rats and in one study in hamsters. Exposure to vinyl chloride increased
the incidence of skin tumours in one study in rats and in two studies in hamsters, and
increased the incidence of Zymbal gland carcinomas in four studies in rats, with a dose–
response pattern in one experiment. Vinyl chloride increased the incidence of lung
tumours in six studies in mice, induced renal tumours and tumours of the nasal cavity in
one study in rats, increased the incidence of hepatocellular carcinomas in two studies in
rats and increased the incidence of glandular stomach tumours in one study in hamsters.
In one study in rats, combined oral administration of ethanol and inhalation exposure
to vinyl chloride caused more liver tumours (including angiosarcomas and hepatocellular
carcinomas) than exposure to vinyl chloride alone.
Vinyl chloride was tested by oral administration in four studies in male and female
rats. It induced hepatic angiosarcomas in all studies, extrahepatic angiosarcomas in one
study and hepatocellular carcinomas in two studies. When vinyl chloride was tested by
subcutaneous injection and by intraperitoneal injection in single studies in rats, no hepatic
angiosarcomas were induced.
The transplacental carcinogenicity of vinyl chloride was evaluated in one study in the
offspring of rats exposed by inhalation during pregnancy. A low but significant incidence
of tumours was observed in exposed offspring at sites that included the kidney, Zymbal
gland and several others. However, no angiosarcomas or liver-cell tumours developed in
the offspring.
Vinyl chloride was tested by perinatal inhalation exposure in two studies in rats. In
one study, rats were exposed transplacentally, neonatally and during adulthood. Treat-
ment with vinyl chloride induced hepatic angiosarcomas and hepatocellular carcinomas.
Rats also demonstrated high incidences of tumours that were probably of olfactory neuro-
epithelial origin, but which were formerly reported as cerebral neuroblastomas in some
studies. In a second study, rats were exposed to vinyl chloride for 5 weeks only beginning
at birth. Hepatic angiosarcomas and ‘hepatomas’ occurred at a high incidence in the off-
spring, but not in the dams that were co-exposed with the offspring.
Chloroethylene oxide, a chemically reactive metabolite of vinyl chloride, was tested
for carcinogenicity in a single study in mice by subcutaneous injection and in an initiation–
promotion protocol on the skin. It caused fibrosarcomas at the site of subcutaneous injec-
tion and increased the incidence of squamous-cell papillomas and carcinomas of the skin
at the site of application.
5.4 Mechanistic and other relevant data

Pulmonary absorption of vinyl chloride in humans appears to be rapid, and the
percentage that is absorbed (about 40%) is independent of the concentration inhaled.
Vinyl chloride is oxidized to highly reactive chloroethylene oxide, which rearranges to
chloroacetaldehyde. The initial oxidation is predominantly mediated by cytochrome P450
2E1, an enzyme that is induced by ethanol among other agents. In rats, the metabolism of
vinyl chloride is saturable at an inhalation concentration of 250 ppm [∼650 mg/m3], at
which the incidence of hepatic angiosarcoma in these animals has been reported to
plateau. The rate of vinyl chloride metabolism in humans is approximately 50 µmol/h/kg.
The rate of elimination of vinyl chloride does not appear to be altered during repeated
compared with single inhalation exposures.
Following metabolic activation of vinyl chloride in rats, the two metabolites, chloro-
ethylene oxide and chloroacetaldehyde, react with nucleic acid bases to form adducts.
These include the major adduct N7-(2-oxoethyl)guanine, four etheno adducts and
5,6,7,9-tetrahydro-7-hydroxy-9-oxoimidazol[1,2-a]purine, as identified in vitro and in rats
in vivo. In rats exposed to vinyl chloride, increased levels of etheno adducts have been
found in different organs, such as the liver, lung and kidney, and in lymphocytes but not
in the brain. Young animals are particularly prone to the formation and persistence of
vinyl chloride-induced adducts. In rats, adducts have been found equally in non-paren-
chymal liver cells and in hepatocytes. In humans, etheno adducts are formed by lipid per-
oxidation; there is, however, a paucity of data on the occurrence of such adducts in vinyl
VINYL CHLORIDE 425
chloride-exposed humans. The mechanism that leads to base misincorporation following

adduct formation is still unclear.
Vinyl chloride is mutagenic, usually in the presence of metabolic activation, in
various assays with bacteria, yeast or mammalian cells and is clastogenic in in-vivo and
in-vitro systems. It induces unscheduled DNA synthesis and increases the frequency of
sister chromatid exchange in rat and human cells. Exposure to vinyl chloride has been
associated with an increase in the frequency of chromosomal aberrations, micronucleus
formation and sister chromatid exchange in humans.
Ki-ras gene mutations are associated with vinyl chloride-induced angiosarcoma in
humans but not in rats. In half of the cases, Ki-ras mutations lead to the incorporation of
aspartate instead of glycine. Ki-ras mutations were also found to a lesser extend in vinyl-
chloride induced hepatocellular carcinomas. A specific Ha-ras gene mutation (CAA61CTA)
was found vinyl chloride-induced hepatocarcinomas in rats. A mutated p53 gene was
found in approximately half of the angiosarcomas in humans and rats that resulted from
exposure to vinyl chloride. The p53 mutations in both species are often due to A→T
transversions.
The presence of mutated p21ras and p53 proteins in the blood of a high proportion of
workers exposed to vinyl chloride and the positive correlation between the occurrence of
the mutated proteins and cumulative exposure to vinyl chloride suggest that the mutation
is an early event.
In humans, genetic polymorphisms in genes that encode the enzymes involved in the
metabolism of vinyl chloride (CYP2E1, GSTT1, GSTM1, ALDH2) and in DNA repair
(XRCC1) modulate the DNA damage induced by vinyl chloride.
6. Evaluation and Rationale
6.1 Carcinogenicity in humans

There is sufficient evidence in humans for the carcinogenicity of vinyl chloride. Vinyl
chloride causes angiosarcomas of the liver and hepatocellular carcinomas.
6.2 Carcinogenicity in experimental animals

There is sufficient evidence in experimental animals for the carcinogenicity of vinyl
chloride.
There is sufficient evidence in experimental animals for the carcinogenicity of
chloroethylene oxide.
6.3 Overall evaluation
Vinyl chloride is carcinogenic to humans (Group 1).
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VINYL CHLORIDE

1.1 Chemical and physical data

1.1.2 Structural and molecular formulae and relative molecular mass

1.1.3 Chemical and physical properties of the pure substance

1.1.4 Technical products and impurities

1.2 Production and use

Table 1. World production capacity for vinyl chloride monomer in 2005

Region/country Capacity (thousands of tonnes)

From Borruso (2006)

1.3.1 Natural occurrence

1.3.2 Occupational exposure

Reference Year of study Country Workplace Concentration (mg/m3)

IARC MONOGRAPHS VOLUME 97

Reference Year of study Country Workplace Concentration (mg/m3)

Reference Year of study Country Workplace Concentration (mg/m3)

Gáliková et al. (1994) 1990–93 Russian Federation Vinyl chloride/PVC plant

IARC MONOGRAPHS VOLUME 97

Updated from WHO (1999)

(a) Production of vinyl chloride and its derivatives

(b) PVC processing

1.3.3 Environmental occurrence

Reference Country Workplace Year Concentration (mg/m3)

IARC MONOGRAPHS VOLUME 97

From WHO (1999)

(b) Accidental releases

(c) Residues in PVC resin and products

(d) Other occurrences

1.4 Regulations and guidelines

Table 4. Exposure guidelines for vinyl chloride in the workplace

Country/region or TWA STEL (ppm)a Carcinogenicityb Notes

Country/region or TWA STEL (ppm)a Carcinogenicityb Notes

United Kingdom 3 R45

From ACGIH Worldwide (2005)

2. Studies of Cancer in Humans

2.1 Case reports

2.2 Methods and main results of epidemiological cohort studies of workers

2.2.1 North American multicentric study

2.2.2 European multicentric study

A cross-sectional study in the same plant examined occupational and non-occupa-

2.2.3 Other studies

2.3 Cancer of the liver

North American multicentric study

IARC MONOGRAPHS VOLUME 97

European multicentric study

Ward et al. Cumulative exposure

IARC MONOGRAPHS VOLUME 97

ASL Duration (years)

Ward et al. Cumulative exposure

HCC Duration (years)

Ward et al. Cumulative exposure

IARC MONOGRAPHS VOLUME 97

Weber et al. 7021 male JEM Malignant SMR Reference

IARC MONOGRAPHS VOLUME 97

Laplanche et al. 1100 VCM- JEM Liver cancer 3 ex- NR Prospective

Wong, O. et al. 3293 male Malignant SMR Reference

IARC MONOGRAPHS VOLUME 97

(b) European studies

(c) Other studies

2.3.2 Case–control studies (Table 6)