Since 1987, SIRC has developed and undertaken a comprehensive research program to enhance understanding of styrene’s potential to affect human health.
SIRC’s 36-year mission has been to sponsor research focused on answering questions about the potential health effects of exposure to styrene. SIRC also commissions independent reviews of the health effects studies on styrene where data already exist. Research studies and literature reviews are sponsored with the intention of making regulators and the public aware of this information via publication in peer-reviewed journals.
While much of SIRC’s work has focused on addressing styrene’s carcinogenic potential, researchers also have investigated styrene’s potential effects on non-cancer health effects, including: neurotoxicity, reproductive and developmental toxicity, and genotoxicity.
The following sections review the scientific data on styrene for a variety of potential health endpoints. These effects are of possible concern at higher exposures that may be experienced in the workplace, but not for the low exposures associated with consumer uses or the environment. Because these sections merely summarize the scientific information, specific references are not provided but are available upon request.
The nervous system is the most sensitive target of long-term styrene exposure. Neurological impacts reported include neurobehavioral and neurosensory effects (impaired olfaction, audition, and color discrimination). The styrene concentrations that cause these effects are more than 1,000 times higher than the levels usually found in the environment.
Styrene, like many volatile hydrocarbon chemicals, can cause mild and reversible nervous system effects if workplace exposures are not controlled.
At exposures in excess of 50 ppm (8-hour time-weighted average), styrene may cause temporary nervous system effects such as drowsiness and delayed reaction time.
The styrene concentrations that cause neurobehavioral and neurosensory effects are more than 1,000 times higher than the levels usually found in the environment.
Hearing Deficits (Ototoxicity)
Researchers have conducted studies in workers and in laboratory animals to investigate the potential effects styrene exposure may have on hearing. Studies in animals have shown that oral and inhalation exposures (concentrations > 200 – 500 ppm) to styrene can cause hearing loss due to irreversible damage within the cochlea of the ear. Occupational studies indicate styrene is ototoxic in humans, as exhibited by increases in hearing thresholds at high sound frequencies, although there are uncertainties regarding the dose-response (threshold) relationship and the impact of co-exposure to noise. The best information currently available on the threshold for hearing deficits in humans comes from a study of German boat-building workers that found no hearing loss for current exposures of 7.6–15.2 ppm and six years of exposure to 39-49 ppm, whereas workers that had work exposures of about 30-50 ppm for approximately 15 years and experienced approximately five years of median TWA styrene exposure of 80 ppm had evidence of hearing loss.
Color Vision Impairment (Dyschromatopia)
Visual function deficits are reported in rats and monkeys exposed to styrene, although color vision impairment has not been specifically examined. In humans, styrene has been reported to affect color vision (usually of the tritan type affecting blue-yellow color discrimination), although, as with ototoxicity, interpreting the dose-response (threshold) concentrations is difficult due to past higher exposures that may have impacted color vision. A number of older studies linked small losses in color discrimination with workplace air concentrations of greater or equal to 18.5 ppm. Similar differences in color perception are normally found in the general public in individuals between the ages of 35 and 65 and these small changes have uncertain impact, if any, on quality of daily living. A 2009 study of German boat-building workers found no significant associations between color vision and styrene exposures up to 50-100 ppm.
In rats and mice, styrene exposures can produce toxicity to the olfactory epithelium of the nasal cavity. Mice are more susceptible than rats to styrene-induced nasal toxicity (20 ppm produced nasal toxicity in mice, whereas no nasal toxicity was observed at 200 ppm in rats) and humans are expected to be considerably less sensitive than rodents due to significant anatomical and metabolic differences. An investigation of the effect of chronic occupational exposure to styrene in workers on olfactory function found no effects on smell with mean styrene exposures of 26 ppm (range 10-60 ppm).
There are no strong or consistent indications that styrene causes any form of cancer in humans. Although some studies suggest that styrene-exposed workers may be at increased cancer risk, the human evidence for styrene carcinogenicity is inconclusive. Studies of general population environmental and consumer styrene exposure and cancer are less informative than the worker studies, but the available evidence does not suggest these low exposures are a concern. Extensive studies on mouse lung tumors show these are of low relevance to human cancer risk.
Human Epidemiology Studies
The human carcinogenic potential of styrene has been evaluated in a number of epidemiology studies of workers employed in three industrial settings: the fiber-reinforced polymer composites (FRP) industry, manufacture of styrene monomer and polystyrene, and production of synthetic rubber (styrene-butadiene rubber, SBR). These workplace studies have found limited evidence of an association between occupational exposure to styrene and human cancer. There are reports of human cancers in workplaces that have styrene exposures, but the observations are not consistent across studies and exposure–response relationships are lacking. Chance findings and confounders cannot be ruled out in these cancers. The human cancer evidence for styrene and workplace exposure is inconclusive and not supported by animal toxicity and mechanistic information but, as such, remains a concern. Studies of general population environmental and consumer exposure and cancer are less informative than the occupational cohort studies given generally lower number of subjects and imprecise exposure information.
The human cancer evidence for styrene and workplace exposure is inconclusive and not supported by animal toxicity and mechanistic information.
Styrene has been tested in 20 laboratory animal (10 rat, 10 mouse) cancer bioassays. The studies in rats found no consistent increase in tumors, although mammary tumors were increased in two inhalation studies. Increases in malignant mammary tumors were found in all styrene exposure groups in one study and in a second study at 600 ppm styrene but not at 1000 ppm, but a third study found a dose-related decrease in malignant mammary tumors at all styrene concentrations (50-1000) ppm styrene. Five of the mouse studies found increases in lung tumors identified as bronchoalveolar adenomas or adenocarcinomas. The most recently performed inhalation study was a cancer mechanistic study that examined the role of a mouse metabolism enzyme, Cytochrome P450 2F2 (CYP2F2) and a human metabolism enzyme, CYP2F1, on lung toxicity and tumorigenicity. This study found lung toxicity in mice that retained the lung enzyme, whereas mice with this enzyme absent or with the human enzyme present exhibited no lung toxicity. Gene expression was also studied during the course of the 104 weeks of exposure finding significant differences over time and between mice with and without the mouse lung enzyme or with the human lung enzyme. This study and many preceding mechanistic studies establish the following mode of action (MOA) for lung tumor development in mice that indicates these tumors are a low cancer concern for humans. Mouse lung tumors result from mouse-specific metabolism of styrene by CYP2F2. Styrene is metabolized in mice to ring-oxidized metabolites that, when produced in sufficient amounts, result in gene expression changes in mouse lung tissue. The gene expression changes signify a non-genotoxic, rodent- and rodent strain-specific MOA-related to activation of nuclear receptor signaling with attendant cell proliferation (primarily mitogenesis), changes in cellular metabolism, and activation of immune response pathways, and, later, alteration in circadian clock genes associated with control of cancer. The CYP2F2 metabolism has been shown to be a key event (gateway) to styrene mouse lung toxicity as evidenced by both short- and long-term studies in mice where the CYP2F2 enzyme is absent have completely attenuated lung toxicity. This species-specific MOA is further supported by findings in rats. Rats have less of a comparable lung enzyme, CYP2F4, than mice, produce less ring-oxidized metabolites, and are demonstrated to have no cytotoxic, proliferative, or tumorigenic lung changes at high exposures (up to 1000 ppm) for two years. Overall, this MOA demonstrates that styrene-induced mouse lung tumors are likely qualitatively, or possibly quantitatively, not relevant to humans.
Styrene-induced mouse lung tumors are likely not relevant to humans.
Styrene is of low concern for potential genotoxic effects.
Since the late 1970s, researchers have investigated the genotoxicity of styrene and its primary metabolite, styrene oxide (SO).
In bacteria and yeast cells, styrene generally produced negative genotoxic results, although some studies gave positive findings using exogenous metabolic activation systems, suggesting that styrene can become metabolically activated (presumably to SO) in vitro. Mixed results are reported for styrene in cultured mammalian cells. Styrene produced both negative and positive mutations in Chinese hamster V79 cells and chromosomal aberrations in Chinese hamster lung cells and human lymphocytes. Indicator tests detecting sister chromatid (SCE), DNA strand breaks, DNA methylation, and DNA adducts have also produced variable results for styrene. Styrene has been tested for potential to induce genetic damage in several animal species (mouse, rat, Chinese hamster) using different genetic endpoints and exposure routes. These studies indicate styrene does not cause genetic damage at high concentrations that produce systemic toxicity. Confirmation for lack of genotoxic effects is provided by recently completed studies in rats and mice that were negative for increases in mutagenesis (Pig-a mutations in standard strain rats and mice and mutations at the cII gene locus in transgenic mice), clastogenesis/aneugenesis (micronucleus frequencies) and DNA damage (comet assay) following high oral doses.
There is no convincing evidence that styrene has shown genotoxic activity in humans.
There are many studies that have examined the genotoxic potential of styrene in styrene exposed workers. Much of this information, however, cannot be meaningfully interpreted given limitations in study design, population heterogeneity, potential co-exposures to other genotoxic substances, and in the styrene exposure information. Overall, the human genotoxicity information shows a lack of evidence of consistent relationships between exposure levels and study outcome and a lack of any consistent profile of endpoints. Therefore, there is no convincing evidence that styrene has shown genotoxic activity in humans.
Developmental, Reproductive, and Endocrine Toxicity
There are no indications that occupational or environmental exposures to styrene produces adverse effects on fertility or development including potential endocrine disruptor effects.
Styrene has been thoroughly evaluated for reproductive and developmental effects in animal studies. A reproductive toxicity study conducted over two generations in rats found no effects on fertility or reproductive performance at exposures up to 500 ppm, a concentration that caused toxicity in the parental animals. Animal studies that assessed developmental effects show styrene does not cause malformations or developmental structural changes at inhalation exposures of up to 600 ppm and oral exposures of up to 250 mg/kg/day. However, reduced pup growth and pup developmental delays were seen postnatally in rats at exposure levels (300-500 ppm) causing, in some cases, maternal toxicity. With the exception of a small reduction (up to 10%) in pup body weight, no developmental effects were observed at 150 ppm in the rat 2-generation reproductive/ developmental neurotoxicity study.
Human studies have primarily examined female fertility whereas fewer studies examined male fertility, congenital malformations, and spontaneous abortions. Overall, these fertility studies did not find a consistent pattern of adverse effects and reports on malformations/abortions are limited by small number of subjects, imprecise exposure information for styrene, and potential exposure to other substances.
Authorities in the United States and the United Kingdom have found styrene to be a low concern for reproductive and developmental toxicity at environmental and occupational exposures.
The potential for styrene to produce effects on the endocrine system, specifically on (anti)estrogenic, (anti)androgenic, thyroid, and prolactin activities has been the subject of a number of studies. Most of the information is from cell systems and animal studies, whereas only limited information is reported in humans. There is one report of styrene exposed workers that suggested an interaction of styrene with the thyroid, but this study has important limitations and this finding is not supported by a large number of repeated-dose and multigeneration guideline animal studies showing no effects on thyroid histopathology or organ weight. Overall, the available information indicates that styrene does not interfere with the estrogen-androgen-thyroid systems. Styrene’s potential to affect prolactin is less clear. Several studies have reported elevated serum prolactin concentrations in FRP workers associated with high styrene exposures, however, the prolactin levels reported were within normal ranges and adverse effects associated with these findings have not been identified. Considering the nature of the workplace exposures and the physiology of prolactin, work-place stress has been identified as a plausible explanation for the observed prolactin elevations.
Authorities in the United States and the United Kingdom have assessed styrene’s potential for reproductive and developmental toxicity and found styrene to be a low concern for reproductive and developmental toxicity at environmental and occupational exposures. Both assessments, however, did identify elevated prolactin levels in exposed workers as a finding noting that the interpretation of the clinical relevance is uncertain.