Summary

As part of the 2012 Consolidated Appropriations Act (112th Congress, 1st Session; Public Law 112-74), Congress directed the Department of Health and Human Services to arrange for the National Academy of Sciences to carry out an independent review of the styrene assessment in the National Toxicology Program’s (NTP) 12th Report on Carcinogens (RoC).1 In response, the Academy’s National Research Council convened an expert committee that has prepared this report.

The committee approached its statement of task by first conducting a review of the substance profile for styrene as presented in the NTP 12th RoC. It considered literature published by June 10, 2011 (the date of publication of the 12th RoC), and it organized its review on the basis of the headings and subheadings of the substance profile. The committee then conducted its own independent assessment of the styrene literature, extending its review to include literature through November 13, 2013, and concluding with its own listing recommendation for styrene.

THE NATIONAL TOXICOLOGY PROGRAM AND STYRENE

NTP is an interagency program supported and managed by the National Institutes of Health’s National Institute of Environmental Health Sciences (the administrative lead), the Centers for Disease Control and Prevention’s National Institute for Occupational Safety and Health, and the Food and Drug Administration’s National Center for Toxicological Research. Since 1980, NTP has published the RoC, which is a cumulative summary of substances that have been nominated for review and judged to meet two conditions. The first condition is that a significant number of people living in the United States are exposed to the substance of interest. The second condition is that there is evidence that the sub-

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1NTP (National Toxicology Program). 2011a. Styrene. Pp. 383-392 in Report on Carcinogens, 12th Ed. U.S. Department of Health and Human Services, National Toxicology Program, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Styrene.pdf.



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Summary As part of the 2012 Consolidated Appropriations Act (112th Congress, 1st Session; Public Law 112-74), Congress directed the Department of Health and Human Services to arrange for the National Academy of Sciences to carry out an independent review of the styrene assessment in the National Toxicology Program’s (NTP) 12th Report on Carcinogens (RoC).1 In response, the Acade- my’s National Research Council convened an expert committee that has pre- pared this report. The committee approached its statement of task by first conducting a re- view of the substance profile for styrene as presented in the NTP 12th RoC. It considered literature published by June 10, 2011 (the date of publication of the 12th RoC), and it organized its review on the basis of the headings and subhead- ings of the substance profile. The committee then conducted its own independ- ent assessment of the styrene literature, extending its review to include literature through November 13, 2013, and concluding with its own listing recommenda- tion for styrene. THE NATIONAL TOXICOLOGY PROGRAM AND STYRENE NTP is an interagency program supported and managed by the National Institutes of Health’s National Institute of Environmental Health Sciences (the administrative lead), the Centers for Disease Control and Prevention’s National Institute for Occupational Safety and Health, and the Food and Drug Admin- istration’s National Center for Toxicological Research. Since 1980, NTP has published the RoC, which is a cumulative summary of substances that have been nominated for review and judged to meet two conditions. The first condition is that a significant number of people living in the United States are exposed to the substance of interest. The second condition is that there is evidence that the sub- 1 NTP (National Toxicology Program). 2011a. Styrene. Pp. 383-392 in Report on Car- cinogens, 12th Ed. U.S. Department of Health and Human Services, National Toxicology Program, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/roc /twelfth/profiles/Styrene.pdf. 3

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4 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens stance of interest is either known to be a human carcinogen or reasonably antici- pated to be a human carcinogen on the basis of NTP’s established listing criteria. The committee noted that the assessment of chemicals for the purpose of listing in the RoC constitutes a hazard assessment, not a risk assessment. Styrene was first listed in the 12th Report on Carcinogens (RoC) as rea- sonably anticipated to be a human carcinogen, although a major metabolite of styrene, styrene-7,8-oxide, was first listed in the NTP 10th RoC as reasonably anticipated to be a human carcinogen in 2002. Styrene is a substance of interest because many people in the United States are exposed. Sources of environmen- tal exposures include food (from migration of styrene from polymer packaging materials), cigarette smoke, vehicle exhaust, and other forms of combustion and incineration of styrene polymers. Occupational exposure to humans can occur during the industrial processing of styrene. It is used to create a broad spectrum of products, including latex paints and coatings; synthetic rubbers; construction materials, such as pipes, fittings, and lighting fixtures; packaging; household goods, such as synthetic marble, flooring, and molded furnishings; and automo- tive parts. REVIEW OF THE STYRENE PROFILE IN THE NATIONAL TOXICOLOGY PROGRAM 12TH REPORT ON CARCINOGENS To address the first part of its statement of task, this committee reviewed the styrene substance profile in the NTP’s 12th RoC. The committee examined the primary literature cited in the background document for styrene2 and other literature published by June 10, 2011 (the date when the 12th RoC was re- leased). The headings and structure of the committee’s review parallel the major headings that NTP used in the substance profile for styrene. As part of its re- view, the committee determined whether NTP had described and conducted its literature search appropriately, whether the relevant literature identified during the literature search was cited and sufficiently described in the background doc- ument, whether NTP had selected the most informative studies in making its listing determination, and whether NTP’s arguments supported its conclusion that styrene is reasonably anticipated to be a human carcinogen. Cancer Studies in Humans The “Cancer Studies in Humans” section of the NTP substance profile for styrene considers whether the epidemiologic literature published by June 10, 2 NTP (National Toxicology Program). 2008. Report on Carcinogens Background Doc- ument for Styrene, September 29, 2008. U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/NTP/roc/twelfth/2010/FinalBDs/Styrene_Final_508.pdf.

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Summary 5 2011, provides evidence of human carcinogenicity or whether that evidence reaches the level of being limited or sufficient for such a listing. Overall, NTP’s background document and substance profile for styrene include appropriate lit- erature reviews and identify the most informative studies. The text and tables in the background document clearly describe and critique the major strengths and limitations of the key epidemiologic studies, and the background document itself presents accurate data summaries. On the basis of the studies available to NTP by June 10, 2011, the commit- tee agrees with NTP’s conclusion that there is limited but credible evidence that exposure to styrene in some occupational settings is associated with an increase in the frequency of lymphohematopoietic cancers. The evidence comes primari- ly from two occupational-cohort studies of reinforced-plastics workers in Eu- rope.3 The committee also agreed with NTP’s conclusion that there is limited but credible evidence for esophageal and pancreatic cancers. The most informa- tive studies were four cohort studies of the reinforced-plastics industry that cov- ered subjects and controls in Washington state, the United States, Denmark, and combined European nations.4 The strengths of those studies and the associations observed are credible because the studies were of high quality, of varied design (mortality and incidence), and consistent in their findings of associations of sty- rene with these cancers, especially when internal comparisons—many with an apparent exposure–response relationship—were presented. Examples of internal comparisons are incidence rate ratios and mortality rate ratios that compare workers with different levels of exposure in the same plant or industry. Kidney cancer should also have been mentioned in the styrene substance profile as hav- ing some evidence of styrene carcinogenicity on the basis of data published be- tween 2008 and June 10, 2011. A case–control study of renal-cell cancer and 3 Kogevinas, M., G. Ferro, A. Andersen, T. Bellander, M. Biocca, O. Coggon, V. Gennaro, S. Hutchings, H. Kolstad, I. Lundberg, E. Lynge, T. Partanen, and R. Saracci. 1994. Cancer mortality in a historical cohort study of workers exposed to styrene. Scand. J. Work Environ. Health 20(4):251-261; Kolstad, H.A., E. Lynge, J. Olsen, and N. Breum. 1994. Incidence of lymphohematopoietic malignancies among styrene-exposed workers of the reinforced plastics industry. Scand. J. Work Environ. Health 20(4):272- 278. 4 Kogevinas, M., G. Ferro, A. Andersen, T. Bellander, M. Biocca, O. Coggon, V. Gennaro, S. Hutchings, H. Kolstad, I. Lundberg, E. Lynge, T. Partanen, and R. Saracci. 1994. Cancer mortality in a historical cohort study of workers exposed to styrene. Scand. J. Work Environ. Health 20(4):251-261; Kolstad, H.A., E. Lynge, J. Olsen, and N. Breum. 1994. Incidence of lymphohematopoietic malignancies among styrene-exposed workers of the reinforced plastics industry. Scand. J. Work Environ. Health 20(4):272- 278;Wong, O., L.S. Trent, and M.D. Whorton. 1994. An updated cohort mortality study of workers exposed to styrene in the reinforced plastics and composites industry. Occup. Environ. Med. 51(6):386-396; Ruder, A.M., E.M. Ward, M. Dong, A.H. Okun, K. Davis- King. 2004. Mortality patterns among workers exposed to styrene in the reinforced plastic boatbuilding industry: An update. Am. J. Ind. Med. 45(2):165-176.

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6 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens occupational exposures, including exposure to styrene, was published in Febru- ary 20115 after the background document was issued but before the publication of the substance profile. That study should have been included in the NTP eval- uation for styrene. The committee concludes that the description and analysis of literature presented in the background document and the substance profile support NTP’s classification of styrene in the 12th RoC as “reasonably anticipated to be a hu- man carcinogen”. The committee’s assessment is based on the following listing criterion: “there is limited evidence of carcinogenicity from studies in humans which indicates that causal interpretation is credible but that alternative explana- tions, such as chance, bias, or confounding factors, could not adequately be ex- cluded”.6 Neither the background document nor the substance profile was ex- plicit about how NTP defined the term limited in the context of the epidemiology evidence. So, the committee used its professional judgment (de- scribed in its independent assessment in Chapter 3) to develop and apply a set of factors that it used to evaluate the credibility of evidence on human carcinogen- icity of styrene. Cancer Studies in Experimental Animals The section “Cancer Studies in Experimental Animals” in the NTP sub- stance profile and supporting information in the background document summa- rized findings from several studies in which a carcinogenic response was evalu- ated in mice or rats after administration of styrene by various routes (inhalation, ingestion via gavage or drinking water, and injection). The committee is not aware of any informative studies of styrene carcinogenicity in animals that were available before June 10, 2011, and were not included in the NTP evaluation. In the substance profile, NTP correctly focused on the key animal studies that provide evidence for and against styrene carcinogenicity. The substance profile states that lung tumors were not observed in styrene-treated rats and briefly summarized equivocal findings regarding mammary gland tumors. Find- ings of lung tumors in CD-1 mice after inhalation exposure7 and supporting data 5 Karami, S., P. Boffetta, P. Brennan, P.A. Stewart, D. Zaridze, V. Matveev, V. Janout, H. Kollarova, V. Bencko, M. Navratilova, N. Szeszenia-Dabrowska, D. Mates, J.P. Gromiec, R. Sobotka, W.H. Chow, N. Rothman, and L.E. Moore. 2011. Renal cancer risk and occupational exposure to polycyclic aromatic hydrocarbons and plastics. J. Occup. Environ. Med. 53(2):218-223. 6 NTP (National Toxicology Program). 2011b. Listing Criteria [online]. Available: http://ntp.niehs.nih.gov/?objectid=47B37760-F1F6-975E-7C15022B9C93B5A6. 7 Cruzan, G., J.R. Cushman, L.S. Andrews, G.C. Granville, K.A. Johnson, C. Bevan, C.J. Hardy, D.W. Coombs, P.A. Mullins, and W.R. Brown. 2001. Chronic toxici- ty/oncogenicity study of styrene in CD-1 mice by inhalation exposure for 104 weeks. J. Appl. Toxicol. 21(3):185-198.

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Summary 7 from a study of perinatal styrene exposure in mice8 are appropriately described, as are the negative findings. The background document and substance profile also described a National Cancer Institute oral (gavage) study,9 which found that alveolar and bronchiolar adenomas and carcinomas combined were increased significantly in male B6C3F1 mice compared with concurrent study controls. The issue of controls is not discussed in the substance profile and appears only in the background docu- ment. It is easy for studies conducted in different laboratories, even under the same experimental protocol, to vary in subtle but important respects and conse- quently to yield different tumor incidences. Therefore, drawing historical con- trols from other laboratories is seldom justified. The committee considers the comparison of concurrent controls in the NCI styrene oral bioassay with histori- cal vehicle control data from other laboratories to be of little value. The same concern applies to comparison with historical untreated controls in the NCI bio- assay. Therefore, in the case of the NCI styrene bioassay, the interpretive value of comparison with historical untreated controls is also of limited value. Alt- hough limited in number, the historical vehicle controls from the same laborato- ry at about the same time are most relevant and are consistent with the concur- rent controls. The committee finds that the use of concurrent controls reported by the National Cancer Institute is appropriate. Studies on Mechanisms of Carcinogenesis The section “Studies on Mechanisms of Carcinogenesis” in the NTP sub- stance profile for styrene and supporting information in the background docu- ment summarize the mechanistic events that might link styrene exposure to can- cer in experimental animals and humans. The mechanistic evidence on styrene and its major metabolites that was available to NTP is extensive and comes from a variety of studies in diverse model systems and from exposed humans. Alt- hough neither the substance profile nor the background document provides the exact search strategy that was used in collecting the evidence on the mechanisms of carcinogenesis, these documents present a balanced, comprehensive, and thorough review of the literature on the subject. Evidence tables and narrative descriptions of each study were used in the background document to present mechanistic evidence from primary studies and meta-analyses, and the commit- tee finds the presentation of information to be inclusive and balanced. 8 Ponomarkov, V., and L. Tomatis. 1978. Effects of long-term oral administration of styrene to mice and rats. Scand. J. Work Environ. Health 4(suppl. 2):127-135. 9 NCI (National Cancer Institute). 1979a. Bioassay of Styrene for Possible Carcino- genicity. Technical Report No. 185. NIH 79-1741. National Cancer Institute, National Institute of Health, Bethesda, MD [online]. Available: http://ntp.niehs.nih.gov/ntp/htdocs/ LT_rpts/tr185.pdf.

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8 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens The committee agrees with the conclusions presented in the background document and the substance profile that the mechanisms of styrene carcinogen- icity are not fully understood. Overall, the background document and substance profile clearly stated that the carcinogenicity of styrene depends on its metabo- lism to styrene-7,8-oxide and other reactive intermediates and that such metabo- lism occurs in both rodents and humans. Even though species, tissue, and indi- vidual differences in metabolic capacity or in enzymes involved in styrene metabolism have been reported, strong evidence presented in the substance pro- file and the background document for styrene suggests that mechanistic events that may lead to carcinogenesis (such as genotoxicity) occur in both exposed rodents and humans. Furthermore, the listing correctly states that multiple mechanistic events may occur and that they are not necessarily mutually exclu- sive. Summary and Conclusions for the Committee’s Review of the Styrene Profile in the National Toxicology Program 12th Report on Carcinogens The committee concludes that NTP correctly determined that styrene should be considered for listing in the RoC. There is sufficient evidence of ex- posure to a significant number of persons residing in the United States to war- rant such consideration. NTP adequately documented that exposure to styrene occurs in occupational settings and in the general public regardless of smoking status. After conducting a scientific review of the styrene assessment presented in the NTP 12th RoC, the committee finds that the overall conclusion reached by NTP in 2011, that styrene is “reasonably anticipated to be a human carcinogen”, was appropriate. The following points of the listing criteria10 support NTP’s conclusion:  “There is limited evidence of carcinogenicity from studies in humans”. Publications available to NTP as of June 10, 2011, provided limited but credible evidence that exposure to styrene is associated with lympho- hematopoietic, pancreatic, and esophageal cancers. The most informative human epidemiologic studies that support that conclusion are those by Ruder et al. (2004), Wong et al. (1994), Kolstad et al. (1994), and Kogevinas et al. (1994). The evidence is limited in that chance, bias, or confounding factors could not be adequately excluded. 10 NTP (National Toxicology Program). 2008a. Report on Carcinogens Background Document for Styrene, September 29, 2008. U.S. Department of Health and Human Ser- vices, Public Health Service, National Toxicology Program, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/NTP/roc/twelfth/2010/FinalBDs/Styrene_Fin al_508.pdf.

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Summary 9  “There is sufficient evidence of carcinogenicity from studies in experi- mental animals”. Literature published by June 10, 2011, provided suffi- cient evidence that “there is an increased incidence of . . . a combination of malignant and benign tumors” in experimental animals induced by sty- rene administered by multiple routes of exposure (inhalation and oral ga- vage). The most informative experimental animal studies that support that conclusion are studies in mice (NCI 1979; Cruzan et al. 2001).  “There is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans”. Litera- ture published by June 10, 2011, provided convincing evidence that gen- otoxicity is observed in cells from humans who were exposed to styrene. That evidence is derived from a large body of publications. In addition, styrene-7,8-oxide “was listed in a previous Report on Carcinogens as . . . reasonably anticipated as a human carcinogen”. Styrene-7,8-oxide, a compound that is structurally related to styrene, is a major metabolite of styrene in both experimental animals and humans; it was first listed in the 10th RoC as reasonably anticipated to be a human carcinogen. INDEPENDENT ASSESSMENT OF STYRENE The second part of the committee’s task was to conduct an independent assessment of styrene carcinogenicity. The committee started with the review it undertook in the first part of its task and the background document that supports the styrene profile in the 12th RoC. It searched for additional peer-reviewed literature published by November 13, 2013. Relevant human, experimental ani- mal, and mechanistic studies were incorporated into this independent assess- ment. The cut-off date for the literature search was chosen to allow the commit- tee time to review the literature within the time constraints of the project schedule. Details of the search strategy, exclusion criteria, and corresponding literature trees are provided in Appendix D of this report. Although the commit- tee focused its attention on literature that contained primary data, it did examine review articles published in peer-review journals and reviews by other authorita- tive bodies to ensure that relevant literature was not missed and to ensure that all plausible interpretations of primary data were considered. In accordance with the listing criteria, expert judgment was used to inter- pret and apply the RoC listing criteria to evidence in human and animal studies and to make an independent listing recommendation for styrene. A substance can be classified in the RoC as “reasonably anticipated to be a human carcino- gen” if at least one of the following three criteria are fulfilled:  “There is limited evidence of carcinogenicity from studies in humans, which indicates that causal interpretation is credible, but that alternative explanations, such as chance, bias, or confounding factors, could not adequately be excluded.”

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10 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens  “There is sufficient evidence of carcinogenicity from studies in experi- mental animals, which indicates there is an increased incidence of ma- lignant and/or a combination of malignant and benign tumors (1) in multiple species or at multiple tissue sites, or (2) by multiple routes of exposure, or (3) to an unusual degree with regard to incidence, site, or type of tumor, or age at onset.”  “There is less than sufficient evidence of carcinogenicity in humans or laboratory animals; however, the agent, substance, or mixture belongs to a well-defined, structurally related class of substances whose mem- bers are listed in a previous Report on Carcinogens as either known to be a human carcinogen or reasonably anticipated to be a human carcin- ogen, or there is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in hu- mans.” In the committee’s peer review of the substance profile for styrene (Chapter 2), it discussed the information that was needed to meet the criterion for sufficient evidence in experimental animals. The type of information needed to meet the criterion for limited or sufficient evidence in humans required more interpreta- tion and expert judgment on behalf of the committee. In its evaluation of the epidemiology literature, the committee described the information it used to iden- tify informative studies and to evaluate those studies. Metabolism and Toxicokinetics The metabolism of styrene is key to its toxic and carcinogenic effects. Or- gan-specific tumorigenic responses to styrene will depend, in large part, on the balance between the rate of activation and the rate of detoxification in each or- gan. Thorough information on styrene activation and detoxification rates specif- ic to target sites, particularly in the human, is not available. Given the wide array of CYP450 isozymes that can oxidize styrene, including forms that are known to be expressed in extrahepatic tissues (for example, CYP2E1 and CYP2A13), it is not possible to exclude the possibility that styrene bioactivation can occur in multiple target tissues. The presence of styrene-7,8-oxide in blood indicates that there is widespread tissue exposure to this genotoxic metabolite even in tissues that have low capacity for styrene activation. That highlights the importance of cellular detoxification capacities relative to organ-specific effects of styrene. In tissues that have low activity of epoxide hydrolase or glutathione-S-transferase, it might take only low levels of oxidation of styrene to produce cellular effects. The absence of marked toxicity in organs other than the liver or lung of mice suggests detoxification capacities in that species are sufficient to prevent overt toxicity, except in the liver and lung. However, specific information on capaci- ties for detoxification of styrene metabolites (such as epoxide hydrolase and glutathione-S-transferase) in critical target tissues in humans is not available.

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Summary 11 Therefore, the available information on styrene metabolism is insufficient to exclude any tissue from being a plausible target for styrene-induced cytotoxici- ty, which could contribute to carcinogenesis. Epidemiologic Studies As was mentioned in the committee’s peer review of the substance profile, it used its professional judgment to develop and apply a set of factors to evaluate the credibility of evidence on the human carcinogenicity of styrene. Those fac- tors were high estimates of relative risks or its surrogates; exposure–response relationships for any reliably established exposure metric; consistency of obser- vations among independent cohort studies of the reinforced-plastics industry or between cohort and case–control studies; and at least two informative studies in independent populations or with varied study designs. The committee judged the evidence to be limited if the epidemiology evidence was credible but chance, bias, and confounding could not be adequately excluded. The evidence was judged to be sufficient if the epidemiology evidence was credible and chance, bias, and confounding could be excluded as an alternative explanation for the observed association. The committee identified what it judged to be the eleven most informative epidemiologic publications: six studies that used four cohorts in the reinforced- plastics industry that were conducted in Europe11 and the United States12 and five case–control studies conducted in Europe13 and Canada.14 The results of 11 Kogevinas, M., G. Ferro, A. Andersen, T. Bellander, M. Biocca, O. Coggon, V. Gennaro, S. Hutchings, H. Kolstad, I. Lundberg, E. Lynge, T. Partanen, and R. Saracci. 1994. Cancer mortality in a historical cohort study of workers exposed to styrene. Scand. J. Work Environ. Health 20(4):251-261; Kolstad, H.A., E. Lynge, J. Olsen, and N. Breum. 1994. Incidence of lymphohematopoietic malignancies among styrene-exposed workers of the reinforced plastics industry. Scand. J. Work Environ. Health. 20(4):272- 278; Kolstad, H.A., K. Juel, J. Olsen, and E. Lynge. 1995. Exposure to styrene and chron- ic health effects: Mortality and incidence of solid cancers in the Danish reinforced plas- tics industry. Occup Environ Med. 52(5):320-327. 12 Wong, O., L.S. Trent, and M.D. Whorton. 1994.An updated cohort mortality study of workers exposed to styrene in the reinforced plastics and composites industry. Occup. Environ. Med. 51(6):386-396; Ruder, A.M., E.M. Ward, M. Dong, A.H. Okun, and K. Davis-King. 2004. Mortality patterns among workers exposed to styrene in the reinforced plastic boatbuilding industry: An update. Am. J. Ind. Med. 45(2):165-176; Collins, J.J., K.M. Bodner, and J.S. Bus. 2013. Cancer mortality of workers exposed to styrene in the U.S. Reinforced plastics and composite industry. Epidemiology 24(2):195-203. 13 Scélo, G., V. Constantinescu, I. Csiki, D. Zaridze, N. Szeszenia-Dabrowska, P. Rudnai, J. Lissowska, E. Fabiánová, A. Cassidy, A. Slamova, L. Foretova, V. Janout, J. Fevotte, T. Fletcher, A. Mannetje, P. Brennan, and P. Boffetta. 2004. Occupational expo- sure to vinyl chloride, acrylonitrile and styrene and lung cancer risk (Europe). Cancer Causes Control 15(5):445-452; Seidler, A., M. Mohner, J. Berger, B. Mester, E. Deeg, G.

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12 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens those studies were evaluated to inform a judgment of whether the evidence of carcinogenesis in humans after exposure to styrene is sufficient, limited, or in- conclusive. The following end points were evaluated:  Lymphohematopoietic Cancers. The epidemiologic data provide credible but limited evidence that styrene is a risk factor for lympho- hematopoietic cancers on the basis of two European cohort studies.15 Studies of specific types of lymphohematopoietic cancer generate standardized mortality ratios, standardized incidence ratios, and relative risks with wider confidence intervals because of the smaller number of observed events (cancer incidence or deaths). Specifically, the epide- miologic data provide credible but limited evidence that styrene expo- sure is a risk factor for leukemia on the basis of the same two European cohort studies. The epidemiologic data provide credible but limited ev- idence that styrene exposure is a risk factor for non-Hodgkin lympho- ma on the basis of a cohort study16 and two case–control studies.17 Be- Elsner, A. Nieters, and N. Becker. 2007. Solvent exposure and malignant lymphoma: A population-based case-control study in Germany. J. Occup. Med. Toxicol. 2:2; Cocco, P., A. t'Mannetje, D. Fadda, M. Melis, N. Becker, N., S. de Sanjose, L. Foretova, J. Mareckova, A. Staines, S. Kleefeld, M. Maynadie, A. Nieters, P. Brennan, and P. Boffet- ta. 2010. Occupational exposure to solvents and risk of lymphoma subtypes: Results from the Epilymph case-control study. Occup. Environ. Med. 67(5):341-347; Karami, S., P. Boffetta, P. Brennan, P.A. Stewart, D. Zaridze, V. Matveev, V. Janout, H. Kollarova, V. Bencko, M. Navratilova, N. Szeszenia-Dabrowska, D. Mates, J.P. Gromiec, R. Sobotka, W.H. Chow, N. Rothman, and L.E. Moore. 2011. Renal cancer risk and occupational exposure to polycyclic aromatic hydrocarbons and plastics. J. Occup. Environ. Med. 53(2):218-223. 14 Gerin, M., J. Siemiatychi, M. Desy, and D. Krewski. 1998. Associations between several sites of cancer and occupational exposure to benzene, toluene, xylene, and sty- rene: Results of a case-control study in Montreal. Am. J. Ind. Med. 34:144-156. 15 Kogevinas, M., G. Ferro, A. Andersen, T. Bellander, M. Biocca, O. Coggon, V. Gennaro, S. Hutchings, H. Kolstad, I. Lundberg, E. Lynge, T. Partanen, and R. Saracci. 1994. Cancer mortality in a historical cohort study of workers exposed to styrene. Scand. J. Work Environ. Health 20(4):251-261; Kolstad, H.A., E. Lynge, J. Olsen, and N. Breum. 1994. Incidence of lymphohematopoietic malignancies among styrene-exposed workers of the reinforced plastics industry. Scand. J. Work Environ. Health 20(4):272- 278. 16 Kogevinas, M., G. Ferro, A. Andersen, T. Bellander, M. Biocca, O. Coggon, V. Gennaro, S. Hutchings, H. Kolstad, I. Lundberg, E. Lynge, T. Partanen, and R. Saracci. 1994. Cancer mortality in a historical cohort study of workers exposed to styrene. Scand. J. Work Environ. Health 20(4):251-261. 17 Gerin, M., J. Siemiatychi, M. Desy, and D. Krewski. 1998. Associations between several sites of cancer and occupational exposure to benzene, toluene, xylene, and sty- rene: Results of a case-control study in Montreal. Am. J. Ind. Med. 34:144-156; Cocco, P., A. t’Mannetje, D. Fadda, M. Melis, N. Becker, N., S. de Sanjose, L. Foretova, J. Mareckova, A. Staines, S. Kleefeld, M. Maynadie, A. Nieters, P. Brennan, and P. Boffet-

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Summary 13 cause Hodgkin’s lymphoma and multiple myeloma are rarer and there is a paucity of data from existing studies, the committee concludes that there are insufficient data to assess whether exposure to styrene is asso- ciated with an increase in the frequency of these two malignancies.  Kidney Cancer: The epidemiologic data provide credible but limited evidence that styrene is a carcinogen for the kidney on the basis of the US cohort studies18 and a European case–control study.19  Pancreatic Cancer: The epidemiologic data on pancreatic cancer con- stitute credible but limited evidence that styrene exposure is associated with pancreatic cancer on the basis of four cohort studies.20  Esophageal Cancer: The epidemiologic data on esophageal cancer constitute credible but limited evidence that styrene exposure is associ- ated with esophageal cancer on the basis of observations from three co- hort studies.21 ta. 2010. Occupational exposure to solvents and risk of lymphoma subtypes: Results from the Epilymph case-control study. Occup. Environ. Med. 67(5):341-347. 18 Wong O., Trent L.S., Whorton MD. 1994. An updated cohort mortality study of workers exposed to styrene in the reinforced plastics and composites industry. Occup Environ Med. 51(6):386-396; Ruder AM, Ward EM, Dong M, Okun AH, Davis-King K. 2004. Mortality patterns among workers exposed to styrene in the reinforced plastic boatbuilding industry: an update. Am J Ind Med. 45(2):165-176; Collins, J.J., K.M. Bod- ner, and J.S. Bus. 2013. Cancer mortality of workers exposed to styrene in the U.S. Rein- forced plastics and composite industry. Epidemiology 24(2):195-203. 19 Karami, S., P. Boffetta, P. Brennan, P.A. Stewart, D. Zaridze, V. Matveev, V. Janout, H. Kollarova, V. Bencko, M. Navratilova, N. Szeszenia-Dabrowska, D. Mates, J.P. Gromiec, R. Sobotka, W.H. Chow, N. Rothman, and L.E. Moore. 2011. Renal cancer risk and occupational exposure to polycyclic aromatic hydrocarbons and plastics. J. Occup. Environ. Med. 53(2):218-223. 20 Ruder, A.M., E.M. Ward, M. Dong, A.H. Okun, K. Davis-King. 2004. Mortality patterns among workers exposed to styrene in the reinforced plastic boatbuilding industry: An update. Am. J. Ind. Med. 45(2):165-176; Kogevinas, M., G. Ferro, A. Andersen, T. Bellander, M. Biocca, O. Coggon, V. Gennaro, S. Hutchings, H. Kolstad, I. Lundberg, E. Lynge, T. Partanen, and R. Saracci. 1994. Cancer mortality in a historical cohort study of workers exposed to styrene. Scand. J. Work Environ. Health 20(4):251- 261; Kolstad, H.A., K. Juel, J. Olsen, and E. Lynge. 1995. Exposure to styrene and chron- ic health effects: Mortality and incidence of solid cancers in the Danish reinforced plas- tics industry. Occup. Environ. Med. 52(5):320-327; Collins, J.J., K.M. Bodner, and J.S. Bus. 2013. Cancer mortality of workers exposed to styrene in the U.S. Reinforced plas- tics and composite industry. Epidemiology 24(2):195-203. 21 Kogevinas, M., G. Ferro, A. Andersen, T. Bellander, M. Biocca, O. Coggon, V. Gennaro, S. Hutchings, H. Kolstad, I. Lundberg, E. Lynge, T. Partanen, and R. Saracci. 1994. Cancer mortality in a historical cohort study of workers exposed to styrene. Scand. J. Work Environ. Health 20(4):251-261; Wong, O., L.S. Trent, and M.D. Whorton. 1994. An updated cohort mortality study of workers exposed to styrene in the reinforced plastics and composites industry. Occup. Environ. Med. 51(6):386-396; Ruder, A.M., E.M. Ward, M. Dong, A.H. Okun, and K. Davis-King. 2004. Mortality patterns among

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14 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens After identifying the most informative epidemiologic studies and evaluat- ing their results, the committee found that there is limited evidence on the car- cinogenicity of styrene on the basis of epidemiologic studies. A causal interpre- tation is credible, but alternative explanations—such as chance, bias, and confounding factors—cannot adequately be excluded. Cancer in Experimental Animals The committee did not identify any experimental animal studies using sty- rene or styrene-7,8-oxide that were not already cited in the background docu- ment. In general, the committee considered studies to be more informative when they included more than one dose, well-matched controls, chronic exposure, treatment groups of adequate size, the use of well-characterized test material of high purity, thorough necropsy and pathologic evaluation of tissues according to established criteria, and statistical evaluation of tumor data with accepted meth- ods. The quality of the studies varied considerably; the value of some of them is limited by the numbers of animals treated, exposure duration, observation peri- od, dose selection, or incomplete reporting of methods or results. Studies were considered less informative if any of those attributes were missing or could not be verified from the study description. Positive findings of lung tumors in mice have been observed after both in- halation and oral administration of styrene in well-conducted chronic bioas- says.22 Results of another study that is more limited in value for assessing car- cinogenicity23 are also reasonably consistent with the production of lung tumors in mice after styrene exposure. Studies of rats exposed to styrene by both oral and inhalation routes have been consistently negative;24 the tumorigenic re- sponse appears to be species-specific. workers exposed to styrene in the reinforced plastic boatbuilding industry: An update. Am. J. Ind. Med. 45(2):165-176. 22 NCI (National Cancer Institute). 1979. Bioassay of Styrene for Possible Carcinogenic- ity. Technical Report No. 185. NIH 79-1741. National Cancer Institute, National Institute of Health, Bethesda, MD [online]. Available: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr1 85.pdf.; Cruzan, G., J.R. Cushman, L.S. Andrews, G.C. Granville, K.A. Johnson, C. Bevan, C.J. hardy, D.W. Coombs, P.A. Mullins, and W.R. Brown. 2001. Chronic toxici- ty/oncogenicity study of styrene in CD-1 mice by inhalation exposure for 104 weeks. J. Appl. Toxicol. 21(3):185-198. 23 Ponomarkov, V., and L. Tomatis. 1978. Effects of long-term oral administration of styrene to mice and rats. Scand. J. Work Environ. Health 4(suppl. 2):127-135. 24 Jersey, G.C., M.F. Balmer, J.F. Quast, C.N. Park, D.J. Schuetz, J.E. Beyer, K.J. Ol- son, S.B. McCollister, and L.W. Rampy. 1978. Two-Year Chronic Inhalation Toxicity and Carcinogenicity Study on Monomeric Styrene in Rats. Final Report. The Dow Chem- ical Company, Midland, MI.; NCI (National Cancer Institute). 1979. Bioassay of Styrene for Possible Carcinogenicity. Technical Report No. 185. NIH 79-1741. National Cancer Institute, National Institute of Health, Bethesda, MD [online]. Available: http://ntp.niehs.

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Summary 15 A carcinogenic effect of exposure by more than one route in animals, even if in only one species, satisfies the criteria for “reasonably anticipated to be a human carcinogen”. Thus, styrene-increased incidences of lung tumors in male mice after both inhalation and oral exposure constitute adequate evidence for listing under this classification. Mechanistic and Other Relevant Data The committee reviewed the evidence for styrene carcinogenicity via three modes of action: genotoxicity, immunosuppression, and cytotoxicity. The geno- toxicity of styrene has been thoroughly and comprehensively investigated. Ob- servations in various studies performed over the last 3 decades have been con- sistent. Temporal and exposure–response relationships have been established. Not only is the experimental evidence extensive, it is likely to be relevant to all target tissues that have been associated with cancer after exposure to styrene. A causal interpretation is strengthened by the large amount of evidence obtained from studies of exposed humans. Furthermore, the evidence reviewed by the committee indicates that styrene-7,8-oxide, a major reactive metabolite of sty- rene that is produced in exposed humans, reacts with DNA to form covalent adducts and other premutagenic forms of DNA damage, which result in geno- toxic effects. The committee recognizes that styrene-7,8-oxide may not be the only genotoxic metabolite of styrene. For example, styrene-3,4-oxide may also be mutagenic.25 However, to the committee’s knowledge, the potential contribu- tion of styrene-3,4-oxide to the carcinogenic response to styrene and the poten- tial contribution of other aromatic-ring metabolites of styrene in addition to sty- rene-7,8-oxide have not been investigated. Information pertaining to styrene exposure and immunosuppression is var- iable and inconsistent. In animals, the committee observed both inhibitory ef- fects (such as decreases in lymphocyte counts, suppressed monocyte and macro- phage activity, and suppressed natural killer cell activity) and stimulatory effects nih.gov/ntp/htdocs/LT_rpts/tr185.pdf; Beliles, R.P., J.H. Butala, C.R. Stack, and S. Ma- kris. 1985. Chronic toxicity and three-generation reproduction study of styrene monomer in the drinking water of rats. Fundam. Appl. Toxicol. 5(5):855-868; Conti, B., P. Maltoni, G. Perino, and A. Ciliberti. 1988. Long-term carcinogenicity bioassays on styrene admin- istered by inhalation, ingestion and injection and styrene oxide administered by ingestion in Sprague-Dawley rats, and para-methylstyrene administered by ingestion in Sprague- Dawley rats and Swiss mice. Ann. NY Acad. Sci. 534:203-234; Cruzan, G., J.R. Cush- man, L.S. Andrews, G.C. Granville, K.A. Johnson, C.J. Hardy, D.W. Coombs, P.A. Mul- lins, and W.R. Brown. 1998. Chronic toxicity/oncogenicity study of styrene in CD rats by inhalation exposure for 104 weeks. Toxicol. Sci. 46(2):266-281. 25 Watabe, T., N. Ozawa, and K.Yoshikawa. 1982. Studies on metabolism and toxicity of styrene. V. The metabolism of styrene, racemic, (R)-(+)-, and (S)-(–)-phenyloxiranes in the rat. J. Pharmacobiodyn. 5(2):129–133.

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16 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens (such as increases in type IV hypersensitivity and increased cytokine produc- tion). In humans exposed to styrene, effects were more varied and both suppres- sive and stimulatory effects were observed. Additional research is needed to understand the effects of styrene on the immune system and to understand whether immunosuppression is a possible mechanism for styrene-induced car- cinogenesis. The evidence pertaining to cytotoxicity indicates that this mode of action and later proliferation at injured sites depends on the cellular, metabolic, and chemical processes involved in different organs and how their interactions mod- ulate the toxic response. When the response in the liver was compared with that in the lung, it became clear that at least two organs are targets for styrene and its circulating metabolites. Studies of workers in the styrene industry found styrene or its metabolites in both blood and urine and identified additional target organs in at least three other systems—the lymphohematopoietic system (bone marrow, lymph nodes, and spleen), gastrointestinal system (esophagus and pancreas), and urinary system (kidney and bladder). The toxic responses of multiple organs may play a role in modulating the circulating concentrations of styrene, its me- tabolites, and other key compounds, such as glutathione, and in affecting the toxic response of other organs in the same individual. Summary of Evidence and Conclusions The statement of task (Appendix B) directed the committee to “integrate the level-of-evidence conclusions, and considering all relevant information in accordance with the RoC listing criteria, make an independent listing recom- mendation for styrene and provide scientific justification for its recommenda- tion.” As discussed throughout this report, a substance can be categorized as reasonably anticipated to be a human carcinogen on the basis of sufficient evi- dence in animals or limited evidence in humans and a substance can be catego- rized as known to be a human carcinogen on the basis of sufficient evidence in humans. Guided by the RoC listing criteria, the committee integrated data from individual studies to determine whether the evidence in experimental animals reached the level of limited or sufficient and to determine whether the evidence in humans reached the level of limited or sufficient. Supporting information was provided from mechanistic studies. The RoC listing criteria do not provide guid- ance on the integration of information across data streams (that is, across human, experimental animal, and mechanistic information) or the reconciliation of cross-data inconsistencies, so the committee only integrated information within data streams to derive a listing recommendation. The committee identified evidence that styrene exposure could potentially lead to carcinogenicity through genotoxic and mutagenic mechanisms, and that evidence is considered strong, inasmuch as it has been found in vivo and in vitro in both humans and rodents. The genotoxic mechanism is probably relevant for all target tissues associated with cancer after exposure to styrene. Identification

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Summary 17 of styrene metabolites, such as styrene-7,8-oxide, strongly supports the produc- tion of reactive intermediates in a variety of tissues in both humans and animals. The reactive metabolites, which may be produced in one organ and transported to produce toxicity in other sites, have been identified in the blood of humans exposed to styrene. Animal toxicology and carcinogenesis studies clearly sup- port the possibility that multiple organs can be affected regardless of their capac- ity for metabolic activation. In humans, evidence of carcinogenicity in multiple organs is credible but limited. Those findings were based on large occupational cohort studies in the reinforced-plastics industry and on case–control studies. In sum, the committee finds that compelling evidence exists to support a listing of styrene as, at a minimum, reasonably anticipated to be a human carcinogen. That conclusion is based on credible but limited evidence of carcinogenicity in traditional epidemiologic studies, on sufficient evidence of carcinogenicity in animals, and on convincing evidence that styrene is genotoxic in exposed humans. The listing criteria state that a substance should be classified as known to be a human carcinogen if “there is sufficient evidence of carcinogenicity from studies in humans”. The footnote associated with that sentence states that “this evidence can include data derived from the study of tissues or cells from humans exposed to [styrene] that can be useful for evaluating whether a relevant cancer mechanism is operating in people”. The evidence of styrene genotoxicity in ex- posed humans is convincing, so a strong argument could be made to support the listing of styrene as a known human carcinogen if data derived from the study of tissues or cells from humans in and of themselves are considered sufficient for making such a determination. The committee notes that there is ambiguity with respect to weighing the mechanistic evidence in applying the listing criteria. The types of evidence that are available to determine the listing and classi- fication of substances in the RoC continue to evolve. In the future, there will probably be more powerful mechanistic evidence in exposed humans to use for cancer hazard evaluation. Similarly, improvements in exposure-assessment methods may be developed to improve the identification and characterization of exposed persons. This is true not only for styrene and styrene-7,8-oxide, but for all substances in the RoC. Thus, the committee finds that further clarification and expanded guidance by NTP regarding the types and strength of mechanistic evidence and the use of that evidence in the context of the RoC listing criteria are warranted.