Review of the Styrene Assessment in the National Toxicology Program 12th Report on Carcinogens (2014) / Chapter Skim
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Pages 3-17
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From page 3... ...
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.
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From page 4... ...
As part of its review, 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 document, 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)
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From page 5... ...
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 committee 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.
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From page 6... ...
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 human 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 explanations, such as chance, bias, or confounding factors, could not adequately be excluded".6 Neither the background document nor the substance profile was explicit about how NTP defined the term limited in the context of the epidemiology evidence.
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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 substance profile for styrene and supporting information in the background document summarize the mechanistic events that might link styrene exposure to cancer in experimental animals and humans.
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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".
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From page 9... ...
In accordance with the listing criteria, expert judgment was used to interpret 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 carcinogen" 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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From page 10... ...
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)
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Those factors were high estimates of relative risks or its surrogates; exposure–response relationships for any reliably established exposure metric; consistency of observations 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.
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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)
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From page 13... ...
1994. An updated cohort mortality study of workers exposed to styrene in the reinforced plastics and composites industry.
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Cancer in Experimental Animals The committee did not identify any experimental animal studies using styrene or styrene-7,8-oxide that were not already cited in the background document. 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 methods.
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From page 15... ...
Furthermore, the evidence reviewed by the committee indicates that styrene-7,8-oxide, a major reactive metabolite of styrene that is produced in exposed humans, reacts with DNA to form covalent adducts and other premutagenic forms of DNA damage, which result in genotoxic effects. The committee recognizes that styrene-7,8-oxide may not be the only genotoxic metabolite of styrene.
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From page 16... ...
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 recommendation for styrene and provide scientific justification for its recommendation." As discussed throughout this report, a substance can be categorized as reasonably anticipated to be a human carcinogen on the basis of sufficient evidence in animals or limited evidence in humans and a substance can be categorized as known to be a human carcinogen on the basis of sufficient evidence in humans.
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From page 17... ...
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".
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