For definition of Groups, see Preamble Evaluation.
VOL.: 60 (1994) (p. 233)
Chem. Abstr. Name: Ethenylbenzene
Styrene has been produced since the 1920s by catalytic dehydrogenation of ethylbenzene. It is one of the most important monomers, worldwide, and finds major use in the production of polystyrene, acrylonitrile-butadiene-styrene resins, styrene-butadiene rubbers and latexes, and unsaturated polystyrene resins. Occupational exposure levels, measured both by air measurements and biological monitoring, have been highest in the manufacture of fibre glass-reinforced polyester products and lower in the production of styrene, polystyrene and styrene-based plastics and rubbers.
Epidemiological studies of styrene have been done in three types of industry: production of glass-reinforced plastic products, production of styrene monomer and styrene polymerization and production of styrene-butadiene rubber. The malignancies observed in excess most frequently are of the lymphatic and haematopoietic system.
In a European multinational study of over 40 000 workers in the glass-reinforced plastics industry, no overall excess of deaths from lymphatic and haematopoietic cancers was observed in comparison with national controls. Within the cohort, the risks for these cancers were significantly related to average intensity of exposure and to years since first exposure but were not related to cumulative exposure.
A study of cancer incidence in the reinforced plastics industry in Denmark involved 12 800 male workers who had been included within the European multinational mortality study and a further 24 000 workers with lower probability of exposure to styrene. A nonsignificant overall increase in risk was seen for lymphatic and haematopoietic cancer. The increase was concentrated mainly in those workers not previously included in the international cohort, in short-term workers with at least 10 years since first employment and in those employed before 1970.
In a large study of the reinforced plastics industry in the USA, no overall increase in risk for lymphatic and haematopoietic cancer was seen, although a nonsignificant increase was found among workers with the highest exposure.
A study of chemical workers in the production of styrene and styrene derivatives in the USA found a nonsignificant association between exposure to styrene and lymphatic and haematopoietic cancers. A smaller study from the United Kingdom also found a nonsignificant association with cancers at this site but lacked detailed information on exposure.
A large cohort study of the styrene-butadiene rubber industry showed increased risks for lymphatic and haematopoietic malignancies, but a nested case-control analysis that evaluated exposure to both styrene and butadiene found no relationship with exposure to styrene. Two additional studies showed increased risks for lymphatic and haematopoietic cancers but provided little information on exposure to styrene.
Exposures to styrene are highest in the reinforced plastics industry, where less opportunity for confounding occurs than in the other industries studied. The two largest, most informative, but partly overlapping, studies of reinforced plastics manufacturers have certain features that are suggestive of a cancer hazard insofar as, in one, risk increased with average intensity of exposure and time since first exposure, and in the other risk was greatest in men employed at times when the highest exposures occurred. More importantly, however, they do not indicate an increase in risk with increasing cumulative exposure to styrene (as the excesses occurred mainly in short-term employees), and there is no overall increase in risk for lymphatic and haematopoietic cancer in studies of the reinforced plastics industry.
Styrene was tested for carcinogenicity in mice and rats by oral administration and in rats by inhalation exposure. Administration of styrene by gastric intubation resulted in a small increase in the incidence of pulmonary tumours in male mice and of hepatocellular adenomas in females and no increase in tumour incidence in rats. Prenatal exposure followed by postnatal gastric intubation of styrene resulted in a significant increase in the occurrence of pulmonary tumours in male and female mice of one strain and no increase in tumour incidence in rats. Exposure of rats to styrene by inhalation in one study was associated with an increase in the incidence of mammary tumours in females; however, because of limitations in the reporting of the data, the results of the study were considered to be inconclusive. Two studies by gastric intubation of a styrene/b-nitrostyrene mixture in mice and rats were of limited value for the evaluation.
Styrene is absorbed by inhalation and dermal transfer in both man and rat. In man, 60-70% of inhaled styrene is absorbed. It is rapidly distributed throughout the body in treated rats. A large percentage of absorbed styrene is excreted as urinary mandelic and phenylglyoxylic acids, glutathione conjugates forming a minor fraction of the metabolites. Saturation of metabolic activation of styrene becomes apparent at concentrations above 200-300 ppm (850-1280 mg/m3) in rats and mice, and above 100-200 ppm (430-850 mg/m3) in humans. The dominant first metabolite is styrene-7,8-oxide, the formation of which appears to be catalysed in man principally by the cytochrome P450 isoenzyme CYP2B6 but also by CYP2E1 and CYP1A2. Isolated erythrocytes are also capable of nonenzymatic conversion of styrene to styrene-7,8-oxide. The amounts of styrene-7,8-oxide present in the blood of rats and mice exposed to styrene at concentrations below 100 ppm (430 mg/m3) were about 5-20 fold greater than those in similarly exposed humans.
Exposure to styrene leads to the formation of both protein and DNA adducts in man, rat and mouse. The levels of the N-terminal valine adduct of haemoglobin, N-(1-hydroxy-2-phenylethyl)valine, have been found to be four times higher in styrene-exposed workers than in controls, and the levels of the DNA adduct, O6-(2-hydroxy-1-phenylethyl)-2'-deoxy-guanosine-3'-monophosphate, have been found to be about five times higher than in controls.
Central and peripheral neurotoxicity have been described in workers, rats and rabbits exposed to styrene, but the mechanism has not been established.
No clear association was seen in a number of studies between occupational exposure of either mothers or fathers to styrene and the frequency of spontaneous abortions or congenital malformations. In rats and rabbits exposed to styrene at doses up to those that induce maternal toxicity, no adverse reproductive effect has been observed. Damage to seminiferous tubules and decreased sperm counts have been observed in male rats.
Some 25 studies on chromosomal aberrations, micronuclei and sister chromatid exchange have been performed in workers exposed to styrene in various countries and different industries. These have provided variable results with regard to the association between exposure to styrene and chromosomal damage. While clear dose-response relationships were not observed, those studies that showed effects were conducted in the reinforced plastics industry, where exposure to styrene is high; only one study was available on the styrene monomer and polystyrene manufacturing industries. Chromosomal aberrations were observed in 9 of 22, sister chromatid exchange in 3 of 12 and micronuclei in 3 of 11 studies.
The frequency of single-strand DNA breakage/alkali-labile sites was increased in workers exposed to styrene at less than 20 ppm (85 mg/m3).
Chromosomal aberrations have not been seen in most studies in rodents, while several studies indicate weak induction of sister chromatid exchange in various tissues of rats and mice. Contradictory results have been obtained with regard to the induction of micronuclei in mice.
Significant increases have been observed consistently in the frequency of sister chromatid exchange and chromosomal aberrations in human lymphocytes in vitro. Most studies did not show mutation in bacteria, although mutation was seen in some studies in the presence of an exogenous metabolic activation system.
There is inadequate evidence in humans for the carcinogenicity of styrene.
There is limited evidence in experimental animals for the carcinogenicity of styrene.
In making the overall evaluation, the Working Group took into consideration the following supporting evidence: Styrene is metabolized to styrene-7,8-oxide, which binds covalently to DNA and shows activity in various in-vitro and in-vivo assays for genetic effects. The genetic and related effects of styrene are therefore associated with its oxidation, which also occurs, e.g. in human whole blood cultures, where styrene induces dose-related responses of chromosomal damage at low concentrations. Styrene-7,8-oxide is detected in blood of workers exposed to styrene. Adducts in haemoglobin and DNA, DNA single-strand breaks/alkali-labile sites, as well as significant increases in the frequency of chromosomal damage have been found in workers exposed to styrene in the reinforced plastics industry. Positive results are associated with higher overall styrene levels and negative results with decreasing exposures to styrene. Although in human studies the role of other contaminants cannot be excluded, their occurrence is variable and their concentrations are very low in comparison with that of styrene.
Styrene is possibly carcinogenic to humans (Group 2B).
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluation: Suppl. 7 (1987) (p. 345)
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 82, 2002)