Styrene and Human Health

SIRC’s approach 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 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. There are three groups of RPC workers which have been investigated (“epidemiology” studies) for styrene-related causes of death.

• Kogevinas et al. (1994) [4] studied about 40,000 RPC workers in six European countries, with an average follow-up period of about 13 years. There were no increases in cancer deaths based on the most common exposure metrics—cumulative exposure or duration of exposure. There was a trend for increasing death from total lymphomas based on average exposure.

• Ruder et al. (2004) [5] studied a cohort of about 5,200 RPC workers in the state of Washington with a follow-up period of about 30 years. While the study is based on a relatively small group of workers, it has a long follow-up period. The authors reported no styrene-related increased cancer deaths.

• The most recent report comes from Collins et al. (2013) [6], who studied about 16,000 RPC workers from 30 U.S. companies, with a follow-up of more than 30 years. The researchers reported no increase in styrene-related deaths for any cause of death in this cohort, including total lymphomas or Non-Hodgkin lymphoma based on cumulative or average exposure, or duration of exposure. This finding addresses the result related to average exposure reported in Kogevinas et al. (1994).

Another industry in which styrene exposure occurs is the styrene-butadiene rubber (SBR) industry. Delzell et al. (2006) [7] studied causes of death in a cohort of about 15,000 SBR workers, who had styrene exposures one-tenth to one-hundredth the levels of the RPC workers. There was a suggestion of increased deaths from non-Hodgkin lymphoma (NHL) possibly related to styrene. The authors of the study did not attribute this increase to styrene because increased NHL was not seen in more highly exposed RPC workers.

Animal Studies

By the early 1990s, 12 long-term studies had been conducted in which laboratory animals were exposed to styrene or a styrene ß-nitrostyrene mixture. These studies were reviewed in a report by McConnell and Swenberg (1993) [8] published by the International Agency for Research on Cancer (IARC). Each published study was reviewed and evaluated for adequacy of design and reported data, appropriateness of interpretation, and whether it had been peer-reviewed. The purpose of the review was to determine the weight of evidence for carcinogenic activity in animals, and to judge whether the data were adequate for drawing conclusions about carcinogenic activity. Based on the available data, the authors concluded:

• There was no convincing evidence for carcinogenic action of styrene in animals, even though it has been studied in several species and by several routes of exposure (inhalation, gavage, in drinking water, and by intraperitoneal and subcutaneous injection).

• None of the studies reviewed was well suited for extrapolating potential carcinogenic activity in humans; all had deficiencies in design, conduct, or interpretation.

• An up-to-date chronic inhalation study was therefore needed in order to evaluate this gap in the research data.

To address this need, SIRC, the U.S. EPA’s Office of Research and Development (ORD), and the U.S. National Toxicology Program (NTP) discussed and agreed upon the need to clarify the toxicology data on styrene through state-of-the-art chronic animal bioassays. Working in consultation with ORD and NTP on study protocols, SIRC sponsored 24-month inhalation studies in both the rat and mouse. Both studies were conducted according to internationally recognized Good Laboratory Practice (GLP) standards.

A final report on the rat study was released in 1996 and published in 1998 (Cruzan et al., 1998) [9]. The animals had been exposed to styrene at levels of 50, 200, 500, and 1,000 parts per million (ppm). The results showed that styrene is not carcinogenic in rats.

A final report on a two-year mouse study was issued in mid-1998 and published in 2001 (Cruzan et al., 2001) [10]. The mice were exposed at levels of 20, 40, 80, and 160 ppm. As can be anticipated due to the sensitivity of this species, increased lung tumors were found at the end of the two-year study period and did not affect survival. Malignancy occurred only in the high-dose females, and tumors were not noted during interim sacrifices at 12 and 18 months.

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 mechanism 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) [11] 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), but no studies found any tumors 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 relevant for human risk assessment. This view is similar to the conclusion reached by the European Union and several other regulatory agencies.

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) [12] 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) [13].

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. Furthermore, 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. 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.

SIRC has provided mode of action and other relevant scientific data developed since SIRC’s inception to a number of federal and state agencies / review bodies, including U.S. EPA, the U.S. National Toxicology Program, and the National Academy of Sciences to help inform their styrene reviews.

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.

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. Recent studies using genetically modified mice demonstrate that styrene does not cause increased cell replication (Cruzan et al., 2012) or excessive cells or tumors (Cruzan et al., 2017) if a specific enzyme (CYP2F2) is removed from the mice.

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.” [14]

In 2006, the U.S. National Toxicology Program (NTP), in a comprehensive review [15] 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 [16] 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 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.[17] 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) [18] 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 [19] 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 [20] of styrene. Regarding endocrine disruption, the risk assessment report states, “Overall, there is no evidence that styrene possesses significant endocrine disruption activity.”

However, EPA also 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). [21]

The U.S. EPA is currently implementing an endocrine disruptor screening and testing program, and has recently 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. [22]  

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.

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 [23]NS
Genotoxicity studies of SO [24]S+/-+/-No data
No CA in lungs of mice exposed to styrene [25]NS
No lung tumor initiation in Strain A mice [26]NSNo dataNo data
No increased lung tumors from SO [27]NSNSNo data
Lung toxicity from SO [28]SNSNo data
No decreased lung toxicity when SO decreased (2E1-KO mice) [29]NSNo data
Blood SO rats > mice [30]NSNS
Lung SO ex vivo rats> mice [31]NSNS
Urinary SO-derived metabolites rats > mice [32]NSNS
Lack of SO lung toxicity in 2F2-KO mice [33]NS
DNA adducts in rats > mice [34]NSNS
Forestomach tumor incidence in rats [35]NS

 

Genotoxicity studies suggest that styrene is not mutagenic (causing DNA mutations), or only very weakly so.

Some research in animals and humans has measured DNA adducts following exposure to styrene. DNA adducts are covalently-bonded chemical structures which result from a reaction between an exogenous substance and DNA. DNA adducts are used primarily as biomarkers of exposure rather than as indicators of an adverse impact, because adducts can be repaired and have no permanent effect unless they cause mutations.

Other studies in animals and humans have focused on chromosomal changes. One published literature review concluded that increases in cytogenetic (cell) effects reported in some studies involving styrene workers were probably attributable to the presence of other chromosome-damaging agents in the workplace, and/or to inadequate investigations (Scott, 1993; Scott and Preston, 1994) [36][37].

Animal Studies

Low levels of DNA adducts are found after styrene exposure in rats or mice. The level of adducts is not greater in mice than in rats, nor is it greater in lungs than in liver. Thus, DNA adducts do not represent a key event in the formation of mouse lung tumors. A series of studies in rats and mice have consistently demonstrated a lack of mutations, based on micronucleus tests, and chromosomal aberrations from high doses of styrene. A weak response in sister chromatid exchange assays has been reported consistently; this may result from repair of DNA adducts during cell replication.

Human Studies

Styrene-exposed workers have been studied extensively over three decades for induction of various types of genotoxic effects. A number of different assay types have been used to detect possible DNA damage, and low levels of styrene. DNA adducts have been found in reinforced plastics workers. DNA adducts are used primarily as biomarkers of exposure rather than as indicators of an adverse impact, because adducts can be repaired and have no permanent effect unless they cause mutations. There is no evidence of DNA mutations in workers exposed to styrene.

Studies of the effects of styrene on chromosomes have provided conflicting results. Increased frequencies of chromosomal aberrations in the human body were reported in about half of the studies, but do not appear to be related to the styrene exposure level. Since styrene does not cause chromosomal aberrations in rodent studies, even at styrene concentrations of up to 20 times higher than workplace exposure levels, it is unlikely the results seen in some worker studies are the result of exposure to styrene.

Some studies of workers report a weak induction of sister chromatid exchange but both Scott and Preston (1994) [38] and Bonassi et al. (1996) [39] agreed there was no dose-response increase in sister chromatid exchanges in human studies.

Overall, the genotoxicity studies of styrene in workers demonstrate low levels of DNA adducts, but show no mutagenicity and questionable effects on chromosomes.

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 public health concern.

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). [40] 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. Kogevinas, M. et al., “Cancer mortality in a historical cohort study of workers exposed to styrene,” Scandinavian Journal of Work, Environment & Health, v. 20, issue 4, pp. 251-261, Aug. 1994, doi:10.5271/sjweh.1400; http://www.sjweh.fi/show_abstract.php?abstract_id=1400
  5. Ruder, A.M. et al., “Mortality patterns among workers exposed to styrene in the reinforced plastics boatbuilding industry: an update,” American Journal of Industrial Medicine, v. 45, issue 2, pp. 165-176, Feb. 2004, doi:10.1002/ajim.10349; http://onlinelibrary.wiley.com/doi/10.1002/ajim.10349/abstract.
  6. Collins, J.J. et al., “Cancer Mortality of Workers Exposed to Styrene in the US Reinforced Plastics and Composite Industry,” Epidemiology, v. 24, issue 2, pp. 195-203, Mar. 2013, doi:10.1097/EDE.0b013e318281a30f; http://journals.lww.com/epidem/Abstract/2013/03000/Cancer_Mortality_of_Workers_Exposed_to_Styrene_in.5.aspx.
  7. Delzell, E. et al., “An Updated Study of Mortality Among North American Synthetic Rubber Industry Workers,” Health Effects Institute Research Report Number 132, Aug. 2006, 84 pp.; https://www.ncbi.nlm.nih.gov/pubmed/17326338
  8. McConnell, E.E. and Swenberg, J.A., “Styrene and styrene oxide: results of studies on carcinogenicity in experimental animals,” in Butadiene and Styrene: Assessment of Health Hazards, IARC Scientific Publications No. 127. Sorsa, M., Peltonen, K., Vainio, H., Hemminki, K., editors, Lyon, France: International Agency for Research on Cancer. pp. 323-333, 1993.
  9. Cruzan, G. et al., “Chronic Toxicity/Oncogenicity Study of Styrene in CD Rats by Inhalation Exposure for 104 Weeks,” Toxicological Sciences, v. 46, issue 2, pp. 266-281, 1998, doi:10.1093/toxsci/46.2.266; http://toxsci.oxfordjournals.org/content/46/2/266.full.pdf.
  10. Cruzan, G. et al., “Chronic toxicity/oncogenicity study of styrene in cd-1 mice by inhalation exposure for 104 weeks,” Journal of Applied Toxicology, v. 21, issue 3, pp. 185–198, May/June 2001, doi:10.1002/jat.737; http://onlinelibrary.wiley.com/doi/10.1002/jat.737/abstract.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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
  19. 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
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
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