Policy Watch
Carcinogenicity of 1,3-butadiene, ethylene oxide, vinyl
chloride, vinyl fluoride, and vinyl bromide
Yann Grosse, Robert Baan, Kurt Straif, Béatrice Secretan, Fatiha El Ghissassi, Véronique Bouvard, Andrea Altieri, Vincent
Cogliano, on behalf of the WHO International Agency for Research on Cancer Monograph Working Group
In June, 2007, 25 scientists from eight
countries met at the International
Agency for Research on Cancer
(IARC) in Lyon, France, to reassess
the carcinogenicity of 1,3-butadiene,
ethylene oxide, vinyl chloride, vinyl
fluoride, and vinyl bromide. These
industrial gases or their epoxide meta-
bolites are direct-acting mutagens that
induce malignant tumours at many
sites in rodents. These assessments will
be published as volume 97 of the IARC
Monographs.1 Details can also be found
at http://monographs.iarc.fr/.
1,3-butadiene is used mainly in the
production of synthetic rubbers and
polymers. Workplace concentrations
in Canada, the USA, and western
Europe, are generally below 2 mg/m3,
but can be higher in countries that use
older technologies. Some workplace
tasks are still characterised by short-
term high exposures (~200 mg/m3).
Butadiene is also a by-product of
combustion and is ubiquitous in the
environment at lower concentrations.
Inhalation studies in mice have
shown increased incidences of lymph-
oma, and neoplasms of the lung, liver,
kidney, heart, fore-stomach, Harderian
gland, preputial gland, ovary, and
mammary gland.2,3 A similar study in
rats showed an increased incidence
of tumours in the pancreas, thyroid,
Zymbal gland, testis, uterus, and
mammary gland.4
An epidemiological study in the
styrene–butadiene rubber industry5
examined the mortality of around
17 000 workers from eight facilities
in the USA and Canada. An increased
risk of mortality from chronic lymph-
ocytic and myelogenous leukaemia
was seen in the most highly exposed
workers, especially those hired before
and during the 1950s or those
http://oncology.thelancet.com Vol 8 August 2007
employed for long periods of time
(≥10 years). Furthermore, in a study
of workers involved in butadiene-
monomer production,6 an association
with non-Hodgkin lymphoma was
seen. Mechanistic data support these
findings: butadiene is metabolised
to epoxides, which form DNA
adducts in humans and rodents
and induce micronuclei in mice
and micronuclei and chromosomal
aberrations in human lymphocytes in
vitro.7 The Working Group classified
1,3-butadiene as “carcinogenic to
humans” (Group 1),8 on the basis of
“sufficient evidence” in humans of an
increased risk for leukaemias.
Ethylene oxide is used for the
production of chemicals, although
most human exposure occurs from its
use in sterilisation medical equipment.
Average concentrations in hospitals
and production facilities have decreas-
ed substantially in western Europe
and North America and are now
<2 mg/m3.
An inhalation study in mice showed
an increased incidence of alveolar and
bronchiolar lung tumours, tumours
of the Harderian gland, malignant
lymphomas, uterine adenocarcinomas,
and mammary carcinomas.9 Inhalation
experiments in male and female rats
showed an increased incidence of
mononuclear-cell leukaemia, brain tum-
ours, peritoneal mesotheliomas of the
testis, and subcutaneous fibromas.10
A key epidemiological study11 invol-
ved 18 000 employees at 14 industrial
facilities in the USA where ethylene
oxide was used as a sterilant. This
study benefited from a low potential
for confounding by concomitant expo-
sure to other chemicals. Although
there was no overall increase in the
risk of mortality from non-Hodgkin
lymphoma or multiple myeloma,
internal analyses showed associations
between cumulative exposure and
mortality from lymphoid tumours (ie,
non-Hodgkin lymphoma, multiple
myeloma, and chronic lymphocytic
leukaemia) in men. However, results
from other cohort studies of ethylene- Upcoming meetings
oxide exposure did not point clearly October 2–9, 2007
or consistently to an increased risk Fire-fighting, painting, and
shift-work
for these cancers, although moderate
February 5–12, 2008
increases in risk were sometimes report- Some industrial and cosmetic
ed. An increase in breast cancer has not dyes, and related exposures
been consistently reported in other http://monographs.iarc.fr/
studies; however, an internal analysis
in a study of 7500 women12 showed
a significant exposure–response rel-
ationship between ethylene-oxide
exposure and breast-cancer incidence,
with the risk doubled among women
with higher cumulative exposures.
Although the epidemiological evi-
dence was “limited”, the Working
Group classified ethylene oxide as
“carcinogenic to humans” (Group 1)8
taking into consideration that: ethylene
oxide is an alkylating agent that
directly reacts with DNA; it induces a
dose-related increase in the amount
of haemoglobin adducts in humans
and rodents; it induces DNA adducts
in rodents13,14; it consistently acts
as a mutagen and clastogen at all
phylogenetic levels15; it induces heritable
translocations in the germ cells of
rodents15; and it induces a dose-related
increase in the frequency of sister
chromatid exchange, chromosomal
aberrations, and micronucleus form-
ation in lymphocytes of exposed
workers16. The two latter effects have
been shown to be associated with an
increased risk for human cancer.17
Exposure of workers to vinyl chloride
has decreased in North America and
western Europe (to <1 mg/m3), as
679
 Policy Watch
Monograph Working Group
Members
L Stayner—Chair (USA); M Baril,
K Krishnan (Canada);
T Kauppinen, K Peltonen
(Finland); MJ Marion (France);
F Oesch (Germany); PA Bertazzi,
R Pirastu (Italy); H Kromhout
(Netherlands); D Coggon,
P Vineis (UK); JA Bond (not
present for evaluations),
D Eastmond, A Elfarra,
R Henderson, CW Jameson,
R Melnick, JM Rice, PA Schulte
(unable to attend), V Walker,
EM Ward (USA)
Conflicts of interest
PAB chairs a department that has
a research contract with Plastics
Europe. RP has been an expert
government advisor in a court
case involving vinyl chloride. JMR
helped organise, and received
industry travel funds to attend,
an open scientific meeting on
chloroprene and butadiene
health risks. All other members
of the Working Group declared
no conflicts of interest.
Invited Specialists
TA Dragani (Italy); E Delzell,
MJ Teta (USA)
Conflicts of interest
TAD served as a consultant to
Enichem (Syndial) in Italy for a
court case on vinyl chloride.
ED provides consultation on
scientific matters to several
companies with an interest in
vinyl chloride, including Modine
and Cooper Industries. MJT is a
consultant for the American
Chemistry Council (ACC) Olefins
Panel and the Ethylene Oxide/
Ethylene Glycols Panel. Her
research on butadiene and
ethylene oxide is funded by ACC
and Union Carbide and she also
owns shares in Dow Chemical.
Representative
J Jinot (US Environmental
Protection Agency)
Observers
JC Besson, M Boeckx (European
Council of Vinyl Manufacturers);
RJ Lewis (International Institute
of Synthetic Rubber Producers)
680
a result of regulations adopted and
enforced after the identification of vinyl
chloride as a human carcinogen in the
1970s. However, an increasing number
of workers worldwide are exposed to
vinyl chloride, many of whom live in
countries where exposure is less strictly
regulated.
When inhaled, vinyl chloride induces
angiosarcomas (at many sites) and
mammary tumours in mice, rats, and
hamsters, lung tumours in mice, and
hepatocellular carcinomas in rats.18,19
After oral administration to rats, liver
angiosarcomas and hepatocellular carci-
nomas have also been seen.20 Evidence
from animal studies suggests a higher
susceptibility early in life. Perinatal
exposure in rats led to high incidences
of angiosarcomas and hepatocellular
carcinomas in offspring, but not
in breeders exposed for the same
duration.18,21 Animals less than 4 weeks
of age are especially susceptible to the
formation and persistence of vinyl-
chloride-induced DNA adducts.22
Two large multicentre cohort
studies in facilities that manufactured
vinyl chloride, polyvinyl chloride, or
polyvinyl chloride products showed
a substantial increase in the relative
risk for liver angiosarcoma in exposed
workers; this risk increased strongly
with duration of exposure23,24 or
cumulative exposure.24 An internal
analysis,24 based on patients with
histologically confirmed hepatocellular
carcinoma, showed that the risk for
this cancer increased substantially
with cumulative exposure, which was
supported by another cohort study.25
Together with the finding that vinyl
chloride increases the risk for liver
cirrhosis,26 a risk factor for hepatocellular
carcinoma, these results provide “suffi-
cient evidence” in humans that vinyl
chloride causes angiosarcoma of the
liver and hepatocellular carcinoma,
leading to the overall classification
of vinyl chloride as “carcinogenic to
humans” (Group 1).8 Some evidence
exists of an increased risk for lung
cancer and malignant neoplasms of
connective and soft tissue.
Vinyl fluoride and vinyl bromide
are gases used predominantly for
the manufacture of their respective
polymers. The Working Group took
into consideration that all available
studies showed a consistently parallel
response between these chemicals
and vinyl chloride, and classified vinyl
fluoride and vinyl bromide separately
as “probably carcinogenic to humans”
(Group 2A).8 They stressed that for
practical purposes, these chemicals
should be considered to act similarly
to the human carcinogen, vinyl
chloride.
The IARC authors declared no conflicts of interest.
1 IARC. IARC Monographs on the evaluation of
carcinogenic risks to humans. Volume 97.
1,3-Butadiene, ethylene oxide, and vinyl
halides (vinyl fluoride, vinyl chloride and vinyl
bromide). Lyon: International Agency for
Research on Cancer (in press).
2 National Toxicology Propram. NTP toxicology
and carcinogenesis studies of 1,3-butadiene
(CAS No. 106–99-0) in B6C3F1 mice
(inhalation studies). Natl Toxicol Program Tech
Rep Ser 1984; 288: 1–111.
3 National Toxicology Program. NTP toxicology
and carcinogenesis studies of 1,3-butadiene
(CAS No. 106–99-0) in B6C3F1 mice
(inhalation studies). Natl Toxicol Program Tech
Rep Ser 1993; 434: 1–389
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Inhalation toxicity studies with 1,3-
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5 Graff JJ, Sathiakumar N, Macaluso M,
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