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2 Review of the Styrene Profile in the National Toxicology Program 12th Report on Carcinogens
Pages 32-56

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From page 32...
... . To guide its review, the committee considered whether NTP described and conducted the literature search appropriately, whether all the relevant literature identified during the literature search was cited and sufficiently described in the background document, whether NTP had selected the most informative studies to support the listing determination, and whether NTP's arguments supported its conclusions.
From page 33...
... Cancer Studies in Humans The "Cancer Studies in Humans" section of the substance profile for styrene considers whether the epidemiologic literature published by June 10, 2011, provides limited evidence of human carcinogenicity or whether that evidence reaches the level of being sufficient for such a listing. Overall, the background document and the substance profile include appropriate literature reviews and identify the most informative studies (NTP 2008, 2011a)
From page 34...
... However, the committee is limited by the methods used in the existing studies and is unable to separate lymphohematopoietic cancers into finer categories if the investigators of the studies did not separate them. That has been a challenge for many types of exposures in the epidemiologic literature and is not specific to studies of styrene exposure.
From page 35...
... The substance profile for styrene reported credible evidence of a cause–effect relationship between styrene exposure and cancers of the esophagus and pancreas (NTP 2011a)
From page 36...
... , and the cumulative positive exposure trend had a p value of 0.068. Kidney There were multiple reports of associations of kidney cancers with styrene exposure in the reinforced-plastics industry, and some exhibit exposure– response relationships.
From page 37...
... For this reason, NTP could consider describing the evidence of genetic damage in the section "Studies of Mechanisms of Carcinogenesis" rather than the section "Cancer Studies in Humans" if the background document and the substance profile for styrene are updated for a future edition of the RoC. Cancer Studies in Experimental Animals In the background document for styrene, NTP summarized findings from several studies in which a carcinogenic response was evaluated in mice or rats after administration of styrene by various routes (inhalation, ingestion via gavage or drinking water, and injection)
From page 38...
... , under the same protocol, and with animals from the same source. NTP reported in the background document that the incidence of combined lung tumors in those historical vehicle controls was 4% (11/273)
From page 39...
... NTP has been criticized for using historical vehicle control data from other laboratories to determine that the lung tumor incidences in the NCI styrene bioassay were not unusually low (Rhomberg et al.
From page 40...
... The references provided are appropriately interpreted and described in the background document for styrene. However, the substance profile does not provide complete citations for the information that is presented; for example, the substance profile states without citation that over 90% of styrene is metabolized to styrene-7,8-oxide.
From page 41...
... and supporting information in the background document (NTP 2008) summarize the mechanistic events that might link styrene exposure to cancer in experimental animals and humans.
From page 42...
... . Even though species, tissue, and individual differences in metabolic capacity or in enzymes involved in styrene metabolism have been reported, strong evidence presented in the substance profile and the background document for styrene suggests that mechanistic events that may lead to carcinogenesis (such as genotoxicity)
From page 43...
... In the background document, over 20% of the entire document is dedicated to the presentation and critical evaluation of the data pertinent to this mechanism. The substance profile concludes correctly that styrene-associated "genotoxicity [is]
From page 44...
... With respect to the cytotoxicity of different styrene metabolites, the most detailed, rigorous, and informative studies cited in the background document are discussed in the substance profile. However, in an independent literature search the committee identified six additional studies that could have added strength to the discussion of the mechanisms by which styrene produces cytotoxicity in the lungs (Harvilchuck and Carlson 2009; Harvilchuck et al.
From page 45...
... The committee found that NTP provided inadequate evidence and few citations to support the argument that exposure to styrene may cause immunosuppression. Basic but critical data pertaining to immunity -- such as the number of lymphocytes, the weight of lymphoid organs, the function of systemic and localized lymphoid organs, and effects on innate vs specific immunity after styrene exposure in experimental animals or humans -- were not fully reviewed in the background document or the substance profile for styrene.
From page 46...
... Such information provides critical context for the hazard classification of any chemical, including styrene. The background document for styrene contains relevant information and is comprehensive and well organized.
From page 47...
... , and exposures from other sources. NTP could also consider including information on whether there is a relationship between pack-years of smoking and styrene exposure and on the magnitudes of styrene exposure from tobacco-smoking vs exposure in various occupations.
From page 48...
... In spite of that deficiency, the essential literature appears to be cited and discussed appropriately in the substance profile and the background document. The second area of improvement identified by the committee pertains to the way in which NTP used the listing criteria to reach the determination that styrene is "reasonable anticipated to be a human carcinogen".
From page 49...
... The introductory section of the 12th RoC describes the multiple layers of expert judgment involved in the RoC process, but neither the background document nor the substance profile for styrene transparently describe the way in which the different studies and the attributes of those studies were integrated to support a conclusion of limited evidence. The background document would be more transparent if it stated the considerations that were used to evaluate evidence from studies in humans (such as study population characteristics, approach used for exposure assessment, potential for bias and confounding, and precision of estimate of effect)
From page 50...
... Metabolism  Include a more complete presentation of information on styrene metabolism in the substance profile, particularly with respect to detoxification pathways. Studies on Mechanisms of Carcinogenesis  Provide greater concordance among the headings of the executive summary of the background document, the body of the background document, and the substance profile.
From page 51...
... o the effect of modulation of bioactivation and detoxification pathways and antioxidant pools on the cytotoxic response in whole animals or specific organs. Provide a more complete review of data pertaining to immunity, such as the number of lymphocytes, the weight of lymphoid organs, the function of systemic and localized lymphoid organs, and effects on innate vs specific immunity after styrene exposure in experimental animals or humans.
From page 52...
... 52 TABLE 2-1 Continued Sections in the Substance Profile for Styrene Suggested Revisions  Make a point at the beginning of the subsection "General population" that nearly all members of the general population, not only those exposed in a workplace or through smoking, have detectable styrene in their biologic fluids (for example, blood and breast milk)
From page 53...
... . Literature published by June 10, 2011, provided sufficient evidence that "there is an increased incidence of .
From page 54...
... 2009. 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.
From page 55...
... U.S. Department of Health and Human Services, Public Health Service, National Toxicology Program, Research Triangle Park, NC [online]
From page 56...
... Styrene Expert Panel Report [online]


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