VOL.: 82 (2002) (p. 437)
5. Summary of Data Reported and Evaluation
5.1 Exposure dataStyrene is a commercially important monomer which is used extensively in the manufacture of polystyrene resins (plastic packaging, disposable cups and containers, insulation) and in copolymers with acrylonitrile and/or 1,3-butadiene (synthetic rubber and latex, reinforced plastics). Human exposure occurs at levels of milligrams per day during its production and industrial use and at much higher levels in the glass fibre-reinforced plastics industry. Exposure to the general population occurs at levels of micrograms per day due mainly to inhalation of ambient air and cigarette smoke and intake of food that has been in contact with styrene-containing polymers.
5.2 Human carcinogenicity data
Retrospective cohort studies of styrene have been conducted in three types of industry: production of styrene monomer and styrene polymers, production of glass fibre-reinforced plastic products, and production of styrene–butadiene rubber.In a European multinational cohort study of workers in the glass fibre-reinforced plastics industry (the largest component of which was Danish), there was no excess mortality from lymphatic and haematopoietic neoplasms in the entire cohort in comparison with the general population, but the results may have been biased by problems with mortality ascertainment in some of the sub-cohorts. In internal analyses, using unexposed cohort members as the comparison group, the risk of lymphatic and haematopoietic neoplasms was significantly increased among exposed workers after more than 20 years since their first exposure to styrene, and increased with increasing intensity of exposure but not with increasing cumulative exposure to styrene. Another study of cancer incidence in the reinforced-plastics industry conducted in Denmark involved many workers who had been included in the European study. Overall, a small and non-significant excess of leukaemia was observed. A significant excess of leukaemia was observed among workers employed before 1971 (the period with the highest styrene exposures). There was also a significant increase in the incidence of leukaemia when attention was restricted to the follow-up period after 10 years since first exposure to styrene, but only among workers with very short employment (less than 1 year). There was evidence that the available data on duration underestimated the true duration of exposure for many of the workers. (This also applies to the European cohort since the Danish cohort constituted a large fraction of this cohort).
A large study of workers exposed to styrene in the reinforced-plastics industry in the USA found no overall excess of lymphatic and haematopoietic neoplasms.
Two studies of chemical workers in the USA and the United Kingdom involved in the production of styrene and styrene derivatives found a weak association between exposure to styrene and lymphatic and haematopoietic cancers. Styrene exposures were poorly documented in these studies, and exposures to several other chemicals may have occurred.
A follow-up study of cancer incidence in Finnish workers biologically monitored for occupational exposures to styrene during the 1970s and early 1980s did not show any increase in risk for lymphatic and haematopoietic neoplasms. The relatively small size of this study and the low exposures of workers detracted from its power to detect an effect of the magnitude found in some of the other studies.
A small excess of leukaemia mortality has been reported in studies of styrene–butadiene workers in the USA. This excess increased with cumulative exposure to styrene in analyses that only considered this exposure; however, in analyses that included 1,3-butadiene, the exposure–response relationship became non-monotonic. Interpretation of the findings from this study is hampered by the high correlation between styrene and 1,3-butadiene exposures, which makes it difficult to disentangle the effects of these two exposures.
There have also been reports of increased risks of rectal, pancreatic and nervous system cancers in some of the cohort and case–control studies. The numbers of cases were quite small in these studies, and most of the larger cohort studies have not yielded similar findings. Many of the cohort studies did not examine these sites in detail.
The studies of glass fibre-reinforced plastics workers are the most informative with regard to the hypothesis that styrene exposure is associated with an increased risk of cancer in humans. This is because these workers had higher styrene exposures and less potential for exposure to other substances than the other cohorts studied. On the other hand, they are hampered by the high mobility of this workforce. In the overlapping European and Danish studies, a small excess of lymphatic and haematopoietic neoplasms was found, particularly in subgroup analyses of workers with relatively high exposures and a sufficiently long time (e.g., > 10 years) since first exposure. There was no relationship between lymphatic and haematopoietic neoplasms and cumulative styrene exposure, but these studies had problems in accurately estimating duration of employment and hence cumulative exposures.
The increased risks for lymphatic and haematopoietic neoplasms observed in some of the studies are generally small, statistically unstable and often based on subgroup analyses. These findings are not very robust and the possibility that the observations are the results of chance, bias or confounding by other occupational exposures cannot be ruled out.
5.3 Animal carcinogenicity dataStyrene was tested for carcinogenicity in mice in one inhalation study and four oral gavage studies. In the inhalation study, in male mice there was an increase in the incidence of pulmonary adenomas and in female mice, there was an increase in the incidence of pulmonary adenomas, and only an increase in that of carcinomas in the high-dose group. Two of the gavage studies were negative. The other two were considered inadequate for an evaluation of the carcinogenicity of styrene. A screening study by intraperitoneal administration also did not find an increase in tumour incidence or multiplicity in mice. Styrene was tested for carcinogenicity in rats in four gavage studies, one drinking-water study and two inhalation studies. Overall, there was no reliable evidence for an increase in tumour incidence in rats. Styrene 7,8-oxide is a major metabolite of styrene and has been evaluated previously (IARC, 1994b). The evaluation at that time was that there was sufficient evidence in experimental animals for the carcinogenicity of styrene 7,8-oxide.
5.4 Other relevant dataStyrene is absorbed following exposure via inhalation, dermal contact and orally in humans and laboratory animals. In humans, approximately 70% of the inhaled dose is absorbed. Styrene is distributed throughout the body, with the highest concentration generally found in adipose tissue. There are both quantitative and qualitative interspecies differences in styrene metabolism. In humans, styrene is metabolized primarily via the styrene 7,8-oxide pathway to be excreted in the urine as mandelic and phenylglyoxylic acids. In rodents, but not in humans, glutathione conjugation of styrene 7,8-oxide to form mercapturic acids is an important metabolic pathway. Metabolism of styrene to 1- and 2-phenylethanol and then to phenylacetaldehyde and finally to phenylacetic, phenylaceturic and hippuric acids is more important in animals than in humans.
CYP2E1 and CYP2F are the most important cytochrome P450 enzymes in rodents and humans responsible for the metabolism of styrene to styrene 7,8-oxide. In addition, CYP2B6 may be important in humans. In vitro, the rates of metabolism of styrene to styrene 7,8-oxide are much higher in mouse lung than in rat or human lung.
Occupational styrene exposure causes central and peripheral nervous system effects in humans. It causes a reversible decrease in colour discrimination and in some studies effects on hearing have been reported. Studies of effects of styrene on the haematopoietic and immune systems, liver and kidney in exposed workers did not reveal consistent changes.
Central nervous system effects of styrene were reported in rats, guinea-pigs and rabbits. Styrene exposure causes liver and lung toxicity in mice and nasal toxicity in rats and mice.
In humans, there is no evidence for an association between workplace exposure to styrene and spontaneous abortions, malformations or decreased male fecundity.
In rats, there is some evidence for reduced sperm count and peripubertal animals may be more sensitive than adult animals. Styrene crosses the placenta in rats and mice. It increases prenatal death at dose levels causing decreased maternal weight gain. Decreased pup weight, postnatal developmental delays as well as neurobehavioural and neurochemical abnormalities have been reported in rats exposed to styrene during pre- or postnatal development. In-vitro studies indicate that the potential for developmental toxicity is much higher for styrene 7,8-oxide than for styrene.
Occupational exposure to styrene leads to formation of O6-deoxyguanosine (O6-(2-hydroxy-1-phenylethyl)-2˘-deoxyguanosine-3˘-monophosphate) and N7-deoxyguanosine adducts in DNA. Low levels of these two adducts were also detected in liver of mice and rats exposed to styrene.
Inconsistent results have been reported for chromosomal aberrations, micronuclei and sister chromatid exchange in approximately 30 studies of workers exposed to styrene in various industries. These studies were predominantly from the reinforced-plastics industry where styrene exposure is high, but there was no indication of a dose–response relationship in any of the studies reporting positive results. Induction of chromosomal aberrations was reported in 12 of 25 studies, sister chromatid exchange in six of 16 studies and micronuclei in three of 14 studies.
Sister chromatid exchange and to a lesser degree chromosomal aberrations were induced in rodents in vivo and consistently in human lymphocytes in vitro.
Styrene was predominantly inactive in assays for gene mutations in bacteria, although some studies reported mutations in the presence of a metabolic activation system.
Data from both laboratory (in vitro and in vivo) and human studies indicate that styrene exposure can result in low levels of DNA adducts and DNA damage in individuals who possess the capacity to activate styrene metabolically to styrene 7,8-oxide. However, as noted above, mice, but not rats, develop lung tumours following styrene exposure, even though both species form DNA adducts. DNA adducts are also found in organs other than the lung. Circulating styrene 7,8-oxide may also play a role. However, the concentration in rat blood is two orders of magnitude higher than in the mouse.
The lung tumours in mice probably develop as a result of in-situ formation of styrene 7,8-oxide which causes cytotoxicity and increased cell proliferation, but the roles of circulating styrene 7,8-oxide and of DNA adducts cannot be discounted. Based on metabolic considerations, it is likely that the proposed mechanism involving metabolism of styrene to styrene 7,8-oxide in mouse Clara cells is not operative in human lungs to a biologically significant extent. However, based on the observations in human workers regarding blood styrene 7,8-oxide, DNA adducts and chromosomal damage, it cannot be excluded that this and other mechanisms are important for other organs.
There is limited evidence in humans for the carcinogenicity of styrene.
There is limited evidence in experimental animals for the carcinogenicity of styrene.
Styrene is possibly carcinogenic to humans (Group 2B).For definition of the italicized terms, see Preamble Evaluation.
[N.B. - Two Working Group members, Dr Carlson and Dr Cruzan, recused themselves from the final discussion and the evaluation of styrene.]
Previous evaluation: Vol. 60 (1994)
See Also: Toxicological Abbreviations Styrene (EHC 26, 1983) Styrene (ICSC) Styrene (WHO Food Additives Series 19) STYRENE (JECFA Evaluation) Styrene (PIM 509) Styrene (IARC Summary & Evaluation, Volume 60, 1994)