Styrene and Human Health

SIRC’s 30-year mission has been to sponsor research to answer 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 that the final reports will be published in appropriate peer-reviewed journals.

While much of SIRC’s work has focused on addressing styrene’s carcinogenic potential, researchers also have investigated styrene’s potential neurotoxicity, reproductive and developmental toxicity, mutagenicity, and genotoxicity, as well as its environmental fate, which describes the processes by which chemicals move and are transformed in the environment. The following sections review the scientific data on styrene for a variety of potential health endpoints, scientific topics, and environmental impacts. Because these sections merely summarize the scientific research, footnotes to specific studies or publications are limited. Additional citations are available upon request.

 


Central Nervous System

Styrene 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.

Ototoxicity

Studies have been conducted in workers and in laboratory animals to investigate the potential for styrene exposure to have an adverse effect on hearing. In studies conducted before 2009, limited evidence was found for styrene-induced hearing loss in workers due to co-exposure to noise and other solvents. In Triebig et al. (2009), [1] no hearing deficits were found in workers exposed to styrene for 10 years to 12.5 ppm and 50 ppm. However, there was an indication for styrene-induced hearing losses in workers exposed to styrene concentration of 25-33 ppm from 15 to 26 years. Higher exposures of 80-100 ppm, which existed for over 10 years before this study was initiated, may have contributed to the noted hearing loss.

Color Vision

A 1997 literature review investigated reports of color vision deficiencies associated with occupational exposure to styrene (Sheedy, The SIRC Review, 1997). [2] The author noted that although some of the studies were inconclusive, evidence of slight decreases in color perception was noted. However, in all studies where slight changes were detected, the effects were reversible, and the individuals concerned were not aware of any deficit, nor was there an indication that performance was affected in jobs requiring good color discrimination. The effect was associated with higher styrene concentrations, and styrene-induced color vision deficiencies improved when exposure was decreased. Similar differences in color perception are normally found in the general population in individuals between the ages of 35 and 65. These results were confirmed by Seeber et al. (2009), [3] who did not find color deficiencies at exposures up to 50-100 ppm.

There is no conclusive evidence indicating that styrene is a human carcinogen.

Human Epidemiology Studies

“There were no increases in cancer deaths based on the most common exposure metrics—cumulative exposure or duration of exposure.” — Kogevinas et al.Collectively, the human epidemiology studies show that styrene exposure does not cause an increase in deaths due to cancer or any other disease. These studies, considered together, involved a number of employee groups (“cohorts”) totaling more than 55,000 workers in styrene-related industries in the United States and Europe, with exposures beginning at least 60 years ago in some of these workers. Also, many of the workers included in these studies worked in the industry when exposure levels were much higher than they are in today’s workplaces. Since workplace exposures to styrene are as much as 1,000 fold higher than environmental levels, a lack of effects in workers is an indicator that exposure of the general public to current environmental levels of styrene would not be expected to cause adverse health effects.

Occupational exposures to styrene are greatest in the reinforced plastics and composites (RPC) industry. Another industry in which styrene exposure occurs is the styrene-butadiene rubber (SBR) industry.

Previous epidemiology reviews of exposure to styrene and the risk of cancer considered studies published through November 13, 2013. Since then, additional relevant research has been published. No review has included meta-analyses. The current systematic review considered research published through June 2017 included meta-analyses of the relationship between any exposure to styrene and cancers identified previously as being of concern, including non-Hodgkin lymphoma (NHL), leukemia and cancers of the esophagus, pancreas, lung, and kidney, and it also evaluated several other forms of cancer. Meta-relative risks for all studies were 1.14 (95% confidence interval (CI), 0.91-1.43) for NHL, 1.00 (95% CI, 0.80-1.26) for multiple myeloma, 0.98 (95% CI, 0.87-1.09) for all leukemia, 1.03 (95% CI, 0.92-1.15) for esophageal cancer, 1.02 (95% CI, 0.93-1.12) for pancreatic cancer, 1.09 (95% CI, 0.95-1.24) for lung cancer, and 1.10 (95% CI, 0.99-1.22) for kidney cancer. Individual studies provided little evidence of exposure-response or induction time trends. Limitations of the available research and of the meta-analyses included reliance in most studies on mortality data rather than on incidence data, lack of quantitative estimates of styrene exposure for individual subjects, and lack of information of lifestyle factors. This review found no strong and consistent indication of a causal association between styrene and cancer of any type. Consideration of all pertinent data, including substantial recent research, indicates that the epidemiologic evidence on the potential carcinogenicity of styrene is inconclusive and does not establish that styrene causes any form of cancer in humans.

Animal Studies

There are eight chronic studies of styrene in rats (reviewed in Cruzan et al., 1998). One study, in which styrene was administered via intraperitoneal (ip) at 50 mg/rat 4 times at 2 month intervals, and another, in which styrene was administered once at 50 mg/rat by subcutaneous injection (Conti et al., 1988), were not included because of the low dose and abnormal study design. There are no consistent increases in tumors. Mammary fibroadenomas in rodents are benign, do not advance to malignant tumors, and have no human correlate; therefore, they are not considered relevant for human risk assessment. Malignant mammary tumors (adenocarcinomas) are considered relevant for human risk assessment. Malignant mammary tumors were increased in one inhalation study (Conti et al., 1988), but not in a gavage study conducted at similar doses at the same laboratory at the same time. Malignant mammary tumors were found at 600 ppm styrene by inhalation, but not at 1000 ppm; the incidence at 600 ppm was within the historical control range for the laboratory (Jersey et al., 1978). No increase in mammary tumors occurred from exposure to 50 or 200 ppm styrene by inhalation (Cruzan et al., 1998), and a dose-related decrease in malignant mammary tumors was found at 500 and 1000 ppm. When analyzed by cumulative dose, there is no consistent increase in malignant mammary tumors across studies (Cruzan et al., 1998). Based on a weight of evidence evaluation of 8 chronic rat studies using oral gavage, drinking water, or inhalation and a 350-fold cumulative lifetime dose range, styrene does not increase tumors in rats.

There have been long-term 4 gavage studies of styrene in mice and 1 by inhalation. In the inhalation study, there were increase lung tumors in CD-1 mice at 40, 80, and 160 ppm. These were mostly benign and the increase was not seen until after 18 months of exposure. In a gavage study, increased lung tumors were found only in males at the high dose (300 mg/kg/day for 78 weeks, observed additional 13 weeks) (NCI, 1979a). Tumors in both studies were found in the periphery of the lung which encompasses areas of terminal bronchioles and aveoli. Because the origin of the tumors cannot be determined by cellular anatomy or location, they are referred to as bronchoalveolar adenomas or adenocarcinomas. Based on 5 chronic mouse studies using oral gavage and inhalation exposure, styrene caused increased lung tumors.

Given an absence of carcinogenic effect in both human epidemiology and rat chronic study data, SIRC has conducted additional research to better define the nature of the mouse lung effects. Results of this work to date suggest that the effects seen in mice are unique to the mouse, and are not relevant for extrapolation to potential human effects. Additional information can be found under “Styrene Metabolism & Mode of Action” section below.

“Mode of action” refers to the way in which a substance acts biologically within and upon an organism. Susceptibility to a chemical’s toxic effects in different species is determined by the interaction of differences in genetic makeup, which can lead to structural, metabolic, and other differences.

Understanding the underlying mechanisms by which exposure to a chemical may, or may not, result in a response that produces a tumor is gaining increased importance for carcinogen risk assessment. Indeed, the U.S. Environmental Protection Agency’s (EPA’s) Guidelines for Carcinogen Risk Assessment (2005) [4] place much greater weight on the evaluation of mechanistic action as an interpretive tool.

Concerning styrene, one state-of-the-art “lifetime” inhalation study in mice found an increase in late-developing lung tumors only at the end of the two-year study period (the tumors did not affect survival); two of four studies in which styrene was administered to mice by gavage (oral intubation) also suggested increases in lung tumors. No other tumor sites were increased in mice and no tumor sites were increased in rats, even though the rats were exposed to much higher levels of styrene. Extensive data on workers do not indicate any increase in cancer (lung or otherwise) from styrene exposure.

These findings led SIRC to ask, “Why do mice develop lung tumors following styrene exposure while rats and humans do not appear to develop similar tumors?”

Once the study in which increased mouse lung tumors were observed was completed, SIRC and its European counterpart, the Styrenics Steering Committee of Cefic, embarked on a significant research program to better define the tumorigenic process (mode of action) of styrene in the mouse and examine why styrene does not produce the same response in rats and humans.

It is SIRC’s position that, based on this extensive 15-year long research effort to examine styrene’s mode of action in mice versus rats versus humans, that the finding of lung tumors in mice exposed to styrene is not likely to represent a human risk. This view is similar to the conclusion reached by the European Union and several other regulatory agencies. (Note, however, the U.S. National Toxicology Program and California’s OEHHA regard styrene as a carcinogen.)

A report published in the peer-reviewed Journal of Regulatory Toxicology and Pharmacology summarized and interpreted the initial results of the SIRC / Cefic-sponsored research program. Cruzan et al. (2002) [5] proposed that the mouse lung tumors were the result of metabolism of styrene by an enzyme (CYP2F) in mouse lung that is different from enzymes found in other organs in mice or in rats or humans.

Subsequent research has demonstrated that styrene and similar chemicals have a common mode of action requiring metabolism in mouse lung by this same enzyme to produce tumors. A compilation of this research is found in “Mouse specific lung tumors from CYP2F2-mediated cytotoxic metabolism: An endpoint / toxic response where data from multiple chemicals converge to support a mode of action,” (Cruzan et al. 2009). [6]

In short term studies in several strains of mice, styrene causes death of certain cell types and increased production of new cells; longer term exposures lead to excessive cells and eventually tumors. Further evidence of the mode of action has been obtained using mice which have been genetically engineered to eliminate production of the CYP2F2 enzyme. Neither styrene nor styrene oxide produce toxicity in the absence of CYP2F2 metabolism (Cruzan et al., 2012); furthermore, mice without CYP2F2 enzyme do not develop preneoplastic or neoplastic alterations during lifetime exposure to styrene (Cruzan et l., 2017). Additionally, when using mice with the human CYP2F1 enzyme instead of the mouse CYP2F2 enzyme, neither styrene nor styrene oxide produce toxicity from metabolism by the human enzyme (Cruzan et al., 2013). These data indicate that extensive metabolism by CYP2F in the lung is required to trigger the tumorigenic response from styrene, and this does not occur to a biologically meaningful extent in rats or humans.

In September 2013, SIRC organized a workshop on the mode of action of three specific chemicals – ethylbenzene, naphthalene, and styrene. The workshop highlighted recent research in order to provide a better understanding of the mode of action of mouse-lung tumors and the relevance for human hazard assessment. Learn more and review/download a report from the workshop.

Mouse Lung Mode of Action Infographic (PDF – 224 KB)

The developmental and reproductive data indicate that styrene does not cause birth defects, and provides little support for the idea that styrene exposure could lead to developmental or reproductive toxicity, including potential endocrine disruptor effects.

In 1995, SIRC sponsored Dr. Nigel Brown of the University of London, U.K. to conduct an update of a previously-published review of the published studies related to styrene’s potential, if any, for reproductive and developmental effects. Dr. Brown’s paper concluded “the potential developmental toxicity of styrene has been tested in several mammalian experimental species, but only one study is of good quality. Throughout all studies, there is no evidence for teratogenicity [birth defects]. There are reports of increases in embryonic, fetal, and neonatal death … but these effects are restricted to exposures that are maternally toxic. There is a lack of well-replicated studies, but the bulk of information suggests that styrene does not exert any specific developmental toxicities.” [7]

In 2006, the U.S. National Toxicology Program (NTP), in a comprehensive review [8] of the science related to developmental and reproductive effects, determined that there is “negligible concern” for adverse developmental and reproductive effects resulting from styrene exposures in humans.

Despite these findings, styrene has been recommended for classification as a Category 2 reproductive toxicant under ANNEX XV of the European Classification and Labelling (CLP) Directive and as a Category 3 reproductive toxicant under the European Dangerous Substances Directive (DSD).

In late 2012, the Risk Assessment Committee (RAC) of the European Chemicals Agency adopted an opinion [9] in which the RAC recommended that styrene’s classification should be changed to include a “Category 2” designation for reproductive toxicity (“suspected of damaging the unborn child”), hazard code H361d, under the CLP Directive and a “Category 3” designation (“toxic to reproduction”), hazard code R63 (development), under the DSD regulation.

These actions are expected to be published by the European Commission in early 2014 and then come into effect eighteen months thereafter.

In SIRC’s view, the developmental and reproductive data indicate that styrene does not cause birth defects (is not teratogenic), and, consistent with NTP’s conlusion, provides little support for the idea that styrene exposure could lead to developmental or reproductive toxicity, including potential endocrine disruptor effects (see “Endocrine Disruption” section below).

Styrene has not been shown to be an endocrine disruptor.

In recent years, significant attention has focused on chemicals that may act as potential endocrine disruptors (also referred to as endocrine modulators or estrogen mimics). The inclusion of the term “styrenes” in early lists of chemicals identified as potential endocrine disruptors led to the appearance of styrene monomer on other lists, such as the “priority list of substances for further evaluation of their role in endocrine disruption” prepared by the European Commission in 2000.

The documentation for the European listing also cited a limited number of studies that suggested an effect on pituitary gland secretion of prolactin (“hyperprolactinemia”). Prolactin is a peptide hormone which can be associated with menstrual dysfunction. However, other studies have found no effect on prolactin. Dr. Nigel Brown (see “Styrene Metabolism and Mode of Action” in the section above)  also reviewed these studies and noted that the studies reporting a possible effect on prolactin were few in number, had serious limitations, and had not been replicated. [10] Dr. Brown also concluded that, at the time of his review, the available data on styrene did not support a conclusion that styrene acts as an endocrine disruptor.

A study by Nishihara et al. (2000) [11] found that styrene monomer was non-estrogenic when tested against a yeast two-hybrid assay.

In 2005, the U.S. National Toxicology Program, which is part of the U.S. Department of Health and Human Services, reviewed all the relevant data and determined [12] that styrene was of “negligible concern” for effects on human development and reproduction (includes endocrine effects).

In 2008, the European Union drafted a risk assessment [13] of styrene. Regarding endocrine disruption, the risk assessment report states, “Overall, there is no evidence that styrene possesses significant endocrine disruption activity.”

The U.S. EPA is currently implementing an endocrine disruptor screening and testing program, and has included styrene among a list of many other substances for which EPA plans to issue “test orders” which will require industry to conduct “Tier 1 screening” in order to investigate potential endocrine disruption effects. [14]  

However, EPA specifically noted that inclusion of a chemical on its screening list should not be considered an indication that the chemical is an endocrine disruptor, stating “… [this list] should not be construed as a list of known or likely endocrine disruptors. Nothing in the approach for generating the second list provides a basis to infer that by simply being on this list these chemicals are suspected to interfere with the endocrine systems of humans or other species, and it would be inappropriate to do so.” Following this Tier 1 testing, EPA has said that substances that “… are found to have the potential to interact with the estrogen, androgen, or thyroid hormone systems will proceed to the next stage” of EPA’s testing program (U.S. EPA Tier 1, 2013). [15]

Based on the currently available information, styrene would not be expected to proceed to further testing beyond Tier 1 under EPA’s program.

Styrene is of low concern for potential genotoxic effects.

Starting in the late 1970s, researchers have investigated the genotoxicity of styrene and its primary metabolite, styrene oxide (SO). The most recent critical reviews of the extensive styrene/SO genotoxicity literature were published more than 10 years ago. The Organization for Economic Cooperation and Development (OECD) recently updated the genotoxicity test guidelines, making substantial new recommendations. Thus, a critical review of the in vitro, in vivo, and occupational human studies for styrene and SO is timely. Based on current recommendations, relevant publications were critically reviewed and the following conclusions drawn. Styrene itself is not genotoxic. However, when metabolized to SO (and SO is not further metabolized to nongenotoxicants), positive results can be obtained. SO is clearly mutagenic in the Ames Test.

While technical deficiencies made the majority of in vitro mammalian gene mutation studies uninterpretable, a mouse lymphoma gene mutation study, using SO, was evaluated as positive. SO is clastogenic and causes DNA strand breaks in cultured mammalian cells. No in vivo mutation studies were identified. There is no evidence that styrene is clastogenic in rodents. Chemical-specific and non-specific DNA and protein adducts can be formed in vitro and in rodents. A number of deficiencies were identified in the human studies (small numbers of subjects, poorly matched workers and controls, insufficient exposure assessment, temporal problems with exposure assessment and sample evaluation, and confounding exposures). Styrene-specific DNA and protein adducts can be produced in humans, but it is not clear whether this primary DNA damage can result in mutation.

Thus, despite the large amount of available literature, it is not possible to determine whether styrene does or does not induce mutations in somatic cells of exposed humans.

Evaluation of hypothesis that styrene induces mouse lung tumors via a genotoxic MoA through SO
[NS: Not Supporting ; S: Supporting]
Key FindingsIn vitroMouseRatHuman
Styrene negative in Ames assays [16]NS
Genotoxicity studies of SO [17]S+/-+/-No data
No CA in lungs of mice exposed to styrene [18]NS
No lung tumor initiation in Strain A mice [19]NSNo dataNo data
No increased lung tumors from SO [20]NSNSNo data
Lung toxicity from SO [21]SNSNo data
No decreased lung toxicity when SO decreased (2E1-KO mice) [22]NSNo data
Blood SO rats > mice [23]NSNS
Lung SO ex vivo rats> mice [24]NSNS
Urinary SO-derived metabolites rats > mice [25]NSNS
Lack of SO lung toxicity in 2F2-KO mice [26]NS
DNA adducts in rats > mice [27]NSNS
Forestomach tumor incidence in rats [28]NS

SIRC commissioned Sciences International (SI) of Alexandria, Virginia, to perform a screening-level risk assessment to determine the potential health impact of children’s indoor exposure associated with styrene. This unpublished report addressed exposure associated with styrenic-based toys, other styrenic-based materials found indoors, in food, and in indoor air. SI reviewed available literature on styrene monomer migration from plastic materials, children’s mouthing behavior, styrene naturally occurring in food, and styrene measurements in indoor air. They considered the following exposure pathways: (a) ingestion of styrene from mouthing of toys, (b) ingestion of styrene from mouthing of other styrenic-based objects, (c) ingestion of styrene in food due to migration from food-contact articles, (d) ingestion of naturally occurring styrene in food, and (e) inhalation of styrene in indoor air. Additionally, SI conducted an aggregate assessment combining all of these pathways to consider the total styrene ingestion exposure. The conclusion of this conservative, screening-level risk assessment was that styrene monomer exposures to children are very low and are well below levels of regulatory limits for ambient air or oral exposures.

For more information about the unpublished SI report discussed here, please contact SIRC.

Styrene is detectable in many foods in their natural state.

SIRC sponsored a study to determine amounts of styrene found in common foods obtained directly from the farm, or site of import (i.e., with no potential for exposure to processing, packaging, or preparation materials). The study showed that concentrations of styrene were present in eight of twelve selected food types, including cinnamon, beef, coffee beans, peanuts, wheat, oats, strawberries, and peaches (Steele et al. 1994). [29] The results indicate styrene may be a component of many foods at their source, and that the occurrence of styrene in processed foods cannot be assumed to be related to the use of styrene-based packaging, storage containers, or preparation materials.

Footnotes    (↵ returns to text)

  1. Triebig, G. et al., “Occupational styrene exposure and hearing loss: a cohort study with repeated measurements,” International Archives of Occupational and Environmental Health, v. 82, issue 4, pp. 463-80, Mar. 2009, doi:10.1007/s00420-008-0355-8; http://link.springer.com/article/10.1007/s00420-008-0355-8.
  2. Sheedy, J.E., “Styrene Exposure and Color Vision,” The SIRC Review, v. 5, no. 1, Aug. 1997.
  3. Seeber, A. et al., “Occupational styrene exposure, colour vision and contrast sensitivity: a cohort study with repeated measurements.” International Archives of Occupational and Environmental Health, v. 82, issue 6, pp. 757-770, doi:10.1007/s00420-009-0416-7.
  4. U.S. EPA, 2005. Guidelines for carcinogen risk assessment, U.S. Environmental Protection Agency, Risk Assessment Forum, Washington, DC., 166 p., March 2005; http://www.epa.gov/ttnatw01/cancer_guidelines_final_3-25-05.pdf.
  5. Cruzan, G. et al., “Styrene Respiratory Tract Toxicity and Mouse Lung Tumors Are Mediated by CYP2F-Generated Metabolites,” Regulatory Toxicology and Pharmacology, v. 35, issue 3, pp. 308–319, June 2002, doi:10.1006/rtph.2002.1545; http://www.sciencedirect.com/science/article/pii/S027323000291545X.
  6. Cruzan, G. et al., “Mouse specific lung tumors from CYP2F2-mediated cytotoxic metabolism: An endpoint/toxic response where data from multiple chemicals converge to support a mode of action,” Regulatory Toxicology and Pharmacology, v. 55, issue 2, pp. 205–218, Nov. 2009, doi:10.1016/j.yrtph.2009.07.002; http://www.sciencedirect.com/science/article/pii/S0273230009001421.
  7. Brown, N. et al., “A Review of the Developmental and Reproductive Toxicity of Styrene,” Regulatory Toxicology and Pharmacology, v. 32, issue 3, pp. 228-247, Dec. 2000, doi:10.1016/rtph.2000.1406; http://www.sciencedirect.com/science/article/pii/S0273230000914065.
  8. U.S. NTP, “NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Styrene,” NIH Publication No. 06-4475, Center For The Evaluation Of Risks To Human Reproduction, U.S. National Toxicology Program, U.S. Department of Health and Human Services, 190 p., Feb. 2006; http://ntp.niehs.nih.gov/ntp/ohat/styrene/Styrene_Monograph.pdf.
  9. ECHA 2012, “Opinion proposing harmonised classification and labelling at EU level of Styrene, EC number: 202-851-5, CAS number: 100-42-5,” Committee for Risk Assessment (RAC), European Chemicals Agency, 14 p., adopted 28 Nov 2012; http://echa.europa.eu/documents/10162/d96caf76-f7fe-40cb-acd1-7859a4d3071d.
  10. Brown, N. et al., “A Review of the Developmental and Reproductive Toxicity of Styrene,” Regulatory Toxicology and Pharmacology, v. 32, issue 3, pp. 228-247, Dec. 2000, doi:10.1016/rtph.2000.1406; http://www.sciencedirect.com/science/article/pii/S0273230000914065.
  11. Nishihara, T. et al., “Estrogenic Activities of 517 Chemicals by Yeast Two-Hybrid Assay,” Journal of Health Science, v. 46, issue 4, pp. 292-298, 2000; http://jhs.pharm.or.jp/data/46(4)/46(4)p282.pdf
  12. U.S. NTP, “NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Styrene,” NIH Publication No. 06-4475, Center For The Evaluation Of Risks To Human Reproduction, U.S. National Toxicology Program, U.S. Department of Health and Human Services, 190 p., Feb. 2006; http://ntp.niehs.nih.gov/ntp/ohat/styrene/Styrene_Monograph.pdf
  13. EU Styrene RAR 2008, European Union Risk Assessment Report, Styrene, CAS No. 100-42-5, EINECS No. 202-851-5, Draft for Publication, prepared by the UK rapporteur on behalf of the European Union, June 2008, 448 p.; http://echa.europa.eu/documents/10162/13630/trd_rar_uk_styrene_en.pdf.
  14. U.S. EPA Tier 1, “Endocrine Disruptor Screening Program; Final Second List of Chemicals and Substances for Tier 1 Screening,” Federal Register, v. 78, no. 115, pp. 35922-35928, 14 Jun 2013; http://www.gpo.gov/fdsys/pkg/FR-2013-06-14/pdf/2013-14232.pdf.
  15. U.S. EPA Tier 1, “Endocrine Disruptor Screening Program; Final Second List of Chemicals and Substances for Tier 1 Screening,” Federal Register, v. 78, no. 115, pp. 35922-35928, 14 Jun 2013; http://www.gpo.gov/fdsys/pkg/FR-2013-06-14/pdf/2013-14232.pdf.
  16. International Agency for Research on Cancer (IARC), “Some Industrial Chemicals, Styrene,” IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, v. 60, pp. 287-290, 1994; http://monographs.iarc.fr/ENG/Monographs/vol60/mono60-11.pdf.
  17. International Agency for Research on Cancer (IARC), “Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene,” IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, v. 82, Table 12, pp. 507-510, 2002; http://monographs.iarc.fr/ENG/Monographs/vol82/mono82-9.pdf.
  18. Kligerman, A.D. et al., “Cytogenetic studies of rodents exposed to styrene by inhalation,” in Butadiene and Styrene: Assessment of Health Hazards, IARC Scientific Publications No. 127, Sorsa, M. et al., eds., Lyon, France: International Agency for Research on Cancer, pp. 217-224, 1993.
  19. Brunnemann, K.D. et al., “A study of tobacco carcinogenesis XLVII. Bioassays of vinylpyridines for genotoxicity and for tumorogenicity in A/J mice,” Cancer Letters, v. 65, issue 2, pp. 107-113, 14 Aug 1992; doi:10.1016/0304-3835(92)90153-M; http://www.sciencedirect.com/science/article/pii/030438359290153M.
  20. Lijinsky, W., “Rat and Mouse Forestomach Tumors Induced by Chronic Oral Administration of Styrene Oxide,” Journal of the National Cancer Institute, v. 77, issue 2, pp. 471-476, 1986; doi:10.1093/jnci/77.2.471; http://jnci.oxfordjournals.org/content/77/2/471.abstract.
  21. Cruzan, G. et al., “Mouse specific lung tumors from CYP2F2-mediated cytotoxic metabolism: An endpoint/toxic response where data from multiple chemicals converge to support a mode of action,” Regulatory Toxicology and Pharmacology, v. 55, issue 2, pp. 205–218, Nov. 2009; doi:10.1016/j.yrtph.2009.07.002; http://www.sciencedirect.com/science/article/pii/S0273230009001421. Cruzan, G. et al., “Styrene Respiratory Tract Toxicity and Mouse Lung Tumors Are Mediated by CYP2F-Generated Metabolites,” Regulatory Toxicology and Pharmacology, v. 35, issue 3, pp. 308–319, June 2002; doi:10.1006/rtph.2002.1545; http://www.sciencedirect.com/science/article/pii/S027323000291545X.
  22. Cruzan, G. et al., “Mouse specific lung tumors from CYP2F2-mediated cytotoxic metabolism: An endpoint/toxic response where data from multiple chemicals converge to support a mode of action,” Regulatory Toxicology and Pharmacology, v. 55, issue 2, pp. 205–218, Nov. 2009; doi:10.1016/j.yrtph.2009.07.002; http://www.sciencedirect.com/science/article/pii/S0273230009001421.
  23. Hofmann, C. et al., “Styrene-7,8-Oxide Burden in Ventilated, Perfused Lungs of Mice and Rats Exposed to Vaporous Styrene,” Toxicological Sciences, v. 90, issue 1, pp. 39-48, Mar. 2006; doi:10.1093/toxsci/kfj056; http://toxsci.oxfordjournals.org/content/90/1/39.full.pdf.
  24. Cruzan, G. et al., “Mouse specific lung tumors from CYP2F2-mediated cytotoxic metabolism: An endpoint/toxic response where data from multiple chemicals converge to support a mode of action,” Regulatory Toxicology and Pharmacology, v. 55, issue 2, pp. 205–218, Nov. 2009; doi:10.1016/j.yrtph.2009.07.002; http://www.sciencedirect.com/science/article/pii/S0273230009001421.
  25. Cruzan, G. et al., “Styrene Respiratory Tract Toxicity and Mouse Lung Tumors Are Mediated by CYP2F-Generated Metabolites,” Regulatory Toxicology and Pharmacology, v. 35, issue 3, pp. 308–319, June 2002; doi:10.1006/rtph.2002.1545; http://www.sciencedirect.com/science/article/pii/S027323000291545X.
  26. Cruzan, G. et al., “CYP2F2-generated metabolites, not styrene oxide, are a key event mediating the mode of action of styrene-induced mouse lung tumors,” Regulatory Toxicology and Pharmacology, v. 62, issue 1, pp. 214–220, Feb. 2012; doi:10.1016/j.yrtph.2011.10.007; http://www.sciencedirect.com/science/article/pii/S0273230011002005. Carlson, G.P., “Modification of the metabolism and toxicity of styrene and styrene oxide in hepatic cytochrome P450 reductase deficient mice and CYP2F2 deficient mice,” Toxicology, v. 294, issues 2-3, pp. 104-108, 11 Apr 2012; doi:10.1016/j.tox.2012.02.006; http://www.sciencedirect.com/science/article/pii/S0300483X12000480.
  27. Cruzan, G. et al., “Styrene Respiratory Tract Toxicity and Mouse Lung Tumors Are Mediated by CYP2F-Generated Metabolites,” Regulatory Toxicology and Pharmacology, v. 35, issue 3, pp. 308–319, June 2002; doi:10.1006/rtph.2002.1545; http://www.sciencedirect.com/science/article/pii/S027323000291545X.
  28. Dalbey, W.E. et al., “Cell Proliferation in Rat Forestomach Following Oral Administration of Styrene Oxide,” Fundamental and Applied Toxicology, v. 30, issue 1, pp. 67-74, 1996; doi:10.1006/faat.1996.0044; http://toxsci.oxfordjournals.org/content/30/1/67.full.pdf.
  29. Steele, D.H. et al., “Determination of styrene in selected foods,” Journal of Agricultural and Food Chemistry, v 42, issue 8, pp. 1661-1665, Aug. 1994, doi:10.1021/jf00044a015; http://pubs.acs.org/doi/abs/10.1021/jf00044a015.