People in the United States are exposed to styrene from environmental sources and in occupational settings. Sources of environmental 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” (IARC 2002, p. 456). Occupational exposure to humans can occur during industrial processes that use styrene (ACGIH 2001; IARC 2002). To improve understanding of those exposures and potential adverse health outcomes, including cancer, scientists have studied styrene in vitro and in humans and animals for many years (IARC 2002; NTP 2011a).
The National Toxicology Program (NTP) assessed the potential carcinogenicity of styrene over the past decade and styrene was first listed in the 12th Report on Carcinogens (RoC) as reasonably anticipated to be a human carcinogen (NTP 2011a). Given some of the scientific controversies surrounding the assessment of styrene (Hegstad 2011, 2012), Congress directed the Department of Health and Human Services (DHHS) to arrange for the National Academy of Sciences to carry out an independent review of the styrene substance profile in the 12th RoC (112th Congress, 1st Session; Public Law 112-74). This report presents findings and conclusions in response to the congressional request.
NTP is an interagency program of the National Institute of Environmental Health Sciences (NIEHS), the administrative lead and a part of the National Institutes of Health; the National Institute for Occupational Safety and Health, a part of the Centers for Disease Control and Prevention; and the National Center for Toxicological Research, a part of the Food and Drug Administration. NTP publishes the RoC, which was congressionally mandated in 1978 as part of the Public Health Service Act (Section 262, Public Law 95-622, Part E). The act directed DHHS to publish an annual report that includes a list of all substances that meet two conditions: a significant number of people living in the United States are exposed and the substance is either known to be a human carcinogen or reasonably anticipated to be a human carcinogen. The RoC was required to include supporting information, such as the nature of exposure and an estimated number of persons exposed. The full congressional mandate is in Box 1-1. A
1993 amendment changed the RoC from an annual to a biennial report (42 US Code 241).
Nominations for substances to be added to, reclassified in, or removed from the RoC can come from anyone, but the submitter must include a rationale and, if possible, include background information to support the proposed change (NTP 2011a). Staff of the Office of the Report on Carcinogens review each submission and decide whether there is enough supporting evidence to move a substance forward for further evaluation. If so, the staff invite partnering agencies to review the substance, solicit public comments through the Federal Register, and develop a brief draft concept document with information on the substance, including exposure, major relevant issues, and approach to the cancer-evaluation component of the draft RoC. After consideration of comments from NTP’s Board of Scientific Counselors and the public, the NTP director makes the final decision of whether the substance will be evaluated in a later RoC volume.
A. a list of all substances
i. which either are known to be carcinogens or may reasonably be anticipated to be carcinogens and
ii. to which a significant number of persons residing in the United States are exposed;
B. information concerning the nature of such exposure and the estimated number of persons exposed to such substances;
C. a statement identifying
i. each substance contained in the list under subparagraph (A) for which no effluent, ambient, or exposure standard has been established by a Federal agency, and
ii. for each effluent, ambient, or exposure standard established by a Federal agency with respect to a substance contained in the list under subparagraph (A), the extent to which, on the basis of available medical, scientific, or other data, such standard, and the implementation of such standard by the agency, decreases the risk to public health from exposure to the substance; and
D. a description of
i. each request received during the year involved
I. from a Federal agency outside the Department of Health, Education, and Welfare for the Secretary, or
II. from an entity within the Department of Health, Education, and Welfare to any other entity within the Department, to conduct research into, or testing for, the carcinogenicity of substances or to provide information described in clause (ii) of subparagraph (C), and
ii. how the Secretary and each such other entity, respectively, have responded to each such request.
Source: Section 262, Public Law 95-622, Part E (pp. 3435-3436).
The RoC is cumulative and includes all substances known or reasonably anticipated to be human carcinogens that have been listed since the first RoC in 1980. The 12th RoC has 240 listings: 54 substances known to be human carcinogens and 186 substances reasonably anticipated to be human carcinogens. The criteria that are currently used to establish a listing as either known or reasonably anticipated to be a human carcinogen have been in use since the eighth RoC, which was published in 1998. Box 1-2 provides the specific listing criteria.
In preparation for a new RoC volume, the Office of the Report on Carcinogens creates a background document for each substance that is being considered for inclusion in the next ROC. Each background document includes an evaluation of the substance’s properties, production, and use; human exposure to the substance; the substance’s toxicokinetics; cancer studies of the substance in humans and animals; and possible mechanisms of cancer induction by the substance. The goal of the evaluation is to describe the strengths, limitations, and overall quality of the evidence. For the most recent RoC, the 12th, each background document that was created underwent review by an expert panel, and that panel was asked to recommend a listing status for the substance under review (see Figure 1-1). NTP also asked an Interagency Scientific Review Group and an NIEHS/NTP Scientific Review Group to recommend a listing status for the substances under review. The draft substance profile was then prepared and peer-reviewed by the NTP Board of Scientific Counselors. Public comments were solicited at multiple stages in the process. The draft was submitted to the NTP director for review and to the NTP Executive Committee1 for consultation, review, and comment. It then went to the NTP director for final approval and finally to the secretary of health and human services for review, approval, and transmittal to Congress. The 12th RoC was released in 2011.
One substance profile in the 12th RoC that has drawn science, policy, and mass-media attention is that of styrene. Styrene is an oily or viscous, colorless to yellowish liquid (IARC 2002; O’Neil et al. 2006). It has a pungent odor that has been described as sweet or floral (IARC 2002; NTP 2008a). In 2000, 10.79 billion pounds of styrene were produced in the United States (HSDB 2005) and by
1The NTP Executive Committee is made up of the heads of the Consumer Product Safety Commission, the Department of Defense, the Environmental Protection Agency, the Food and Drug Administration, the National Cancer Institute, the National Center for Environmental Health, the Agency for Toxic Substances and Disease Registry, the National Institute of Environmental Health Sciences, the National Institute for Occupational Safety and Health, and the Occupational Safety and Health Administration. The committee gives programmatic and policy advice to the NTP director.
Known To Be Human Carcinogen:
There is sufficient evidence of carcinogenicity from studies in humans,* which indicates a causal relationship between exposure to the agent, substance, or mixture and human cancer.
Reasonably Anticipated To Be Human Carcinogen:
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,
there is sufficient evidence of carcinogenicity from studies in experimental animals, which indicates there is an increased incidence of malignant 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 members are listed in a previous Report on Carcinogens as either known to be a human carcinogen or reasonably anticipated to be a human carcinogen, or there is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans.
Conclusions regarding carcinogenicity in humans or experimental animals are based on scientific judgment, with consideration given to all relevant information. Relevant information includes, but is not limited to, dose response, route of exposure, chemical structure, metabolism, pharmacokinetics, sensitive subpopulations, genetic effects, or other data relating to mechanism of action or factors that may be unique to a given substance. For example, there may be substances for which there is evidence of carcinogenicity in laboratory animals, but there are compelling data indicating that the agent acts through mechanisms which do not operate in humans and would therefore not reasonably be anticipated to cause cancer in humans.
*This evidence can include traditional cancer epidemiology studies, data from clinical studies, and/or data derived from the study of tissues or cells from humans exposed to the substance in question, which can be useful for evaluating whether a relevant cancer mechanism is operating in humans.
Source: NTP 2008a, p.v.
2006, the production capacity was more than 13 billion pounds (ATSDR 2010). Over half the styrene that is produced in the United States is used for the manufacture of polystyrene, which is a component of such products as plastic packaging, building and refrigeration-equipment insulation, and disposable plates and cups (NTP 2008a). A smaller quantity is used as an intermediate in synthesizing styrene polymers and copolymers, such as styrene–acrylonitrile, acrylonitrile–butadiene–styrene, and styrene–butadiene rubber (ATSDR 2010). Styrene and styrene polymers and copolymers are used in the manufacture of a wide array of products, including food containers, toys, electric devices, automobile parts, construction items, waxes and polishes, adhesives, and personal-care products (WHO 2000; NTP 2008a). It is also used in polyester resins for fiber-reinforced plastics, such as boats, bathtubs, and tanks (NTP 2008a). In 2006, the US consumption of styrene was 9.6 billion pounds (Berthiaume and Ring 2006).
The general public is mainly exposed to styrene in indoor environments. Sampling indicates the median concentration of styrene in indoor air ranges from 0.07 to 11.5 parts per billion (ppb) (ATSDR 2010). Sources of emissions include off-gassing of building materials, skin contact with consumer products that contain styrene, and tobacco smoke (NTP 2008a; ATSDR 2010). People can also be exposed outdoors from combustion sources, such as automobiles, waste incinerators, wood stoves, and industrial facilities. Median styrene concentrations in urban air samples range from 0.07 to 4.6 ppb and rural and suburban samples range from 0.06 to 0.1 ppb (ATSDR 2010). In the general population, the average daily exposure to styrene in air is estimated to be 18 to 54 µg/person/day and the average daily exposure to styrene in food is estimated to be 0.2 to 1.2 µg/person/day (ATSDR 2010).
The largest occupational exposures are in the reinforced-plastics, styrene–butadiene, and styrene monomer and polymer industries (IARC 2002; NTP 2008a). Surveys conducted in 1962 and 1976 of US plants that manufactured styrene-based products indicated that the average exposure of employees to styrene was below 10 ppm (43 mg/m3) (Ott et al. 1980). Another study indicated average occupational exposures to styrene rarely exceed 20 ppm (85 mg/m3), but instances where such exposures do occur are usually the result of occasional bursts and leakages of reactors, tubing, and other equipment (Tossavainen 1978; IARC 2002).
A major metabolite of styrene is styrene-7,8-oxide, and there is evidence that this metabolite has genotoxic and mutagenic properties. Styrene-7,8-oxide was listed by the International Agency for Research on Cancer (IARC) as probably carcinogenic in humans (IARC 1994) and first listed in 2002 in the NTP RoC as reasonably anticipated to be a human carcinogen (NTP 2002). Because of the genotoxic properties of a major metabolite of styrene (styrene-7,8-oxide) and because the general population is exposed to styrene through several different routes, styrene is of concern to many scientific bodies, including NTP. NTP’s Web site states that the chemical was nominated for inclusion by a private individual on the basis of the IARC finding that there is some evidence in humans and experimental animals of the carcinogenicity of styrene (NTP 2007).
After the multistep review process described above, styrene was listed as “reasonably anticipated to be a human carcinogen” (NTP 2011a, p. 383) in the 12th RoC.
Several IARC working groups have reviewed the potential carcinogenicity of styrene and the most recent review was published in 2002 (IARC 1979, 1987, 1994, 2002). In 1979, IARC determined that styrene was mutagenic, and it supported the need for additional epidemiologic research. In an update of IARC monograph volumes 1–42 in 1987, IARC listed styrene in group 2B (possibly carcinogenic in humans) on the basis of inadequate human data, limited evidence in animals, and supporting genotoxic data that showed its mutagenic potential. Although new information was incorporated into an IARC monograph in 1994, the listing of styrene continued to cite human data as inadequate and animal data as limited, and the listing of the substance remained categorized in group 2B. In the most recent IARC review of styrene (IARC 2002), the human, animal, and mechanistic evidence was updated, and the working group again came to the conclusion that styrene was possibly carcinogenic in humans (group 2B); however, IARC’s categorization of styrene in this category is now based on limited evidence in humans and limited evidence in animals.
Other agencies and organizations have also reviewed the potential carcinogenicity of styrene. The Agency for Toxic Substances and Disease Registry undertook a review of styrene and determined that styrene may be a weak human carcinogen on the basis of studies in humans and animals (ATSDR 2010). In contrast, the American Conference of Governmental Industrial Hygienists (ACGIH) reviewed the epidemiologic evidence and animal bioassay data on styrene and determined that styrene exposure does not result in an excess risk of cancer. On the basis of the available data, ACGIH has listed styrene in category A4 (not classifiable as a human carcinogen). The European Union undertook a risk assessment of styrene and concluded that, “based on human studies, there is no clear and consistent evidence for a causal link between specific cancer mortality and exposure to styrene” (EU 2008, p. 271). The reason for different classifications from different organizations is partly a reflection of the criteria used and the process by which each organization integrates information to reach a conclusion on carcinogenicity, but it is also a reflection of the amount of evidence on styrene carcinogenicity in the scientific literature and some of the uncertainties surrounding that literature at the time of the assessment.
In 2012, as part of the Consolidated Appropriations Act (112th Congress, 1st Session; Public Law 112-74), Congress directed the assistant secretary for health in the Department of Health and Human Services to contract with the National Research Council “to conduct a scientific peer review of the 12th Report on Carcinogens determinations related to formaldehyde and styrene. Included in the review should be all relevant, peer-reviewed research related to
formaldehyde and styrene.” In response, the National Research Council convened the Committee to Review the Styrene Assessment in the National Toxicology Program 12th Report on Carcinogens, which wrote the present report. The committee included experts in epidemiology, exposure assessment, toxicology, toxicokinetic modeling, and mechanisms of carcinogenesis (see Appendix A for biographic information on the committee).
The committee’s Statement of Task is presented in Appendix B. The committee was asked to conduct a peer review of the styrene assessment in the 12th RoC. As part of that review, it was asked to identify and evaluate relevant peer-reviewed literature, with particular emphasis on literature that had been published as of June 10, 2011, the release date of the 12th RoC. The committee was also asked to undertake an independent assessment of styrene, which was to include documentation of its decisions for inclusion or exclusion of literature, identification of the most critical studies and information, application of the RoC listing criteria to the scientific evidence, and independent level-of-evidence determinations with respect to the human and animal studies. Considering all relevant information in accordance with the RoC listing criteria, the committee was asked to make an independent listing recommendation for styrene and provided scientific justification of its recommendation.
In writing its report, the committee reviewed documents pertaining to styrene that were written for or by NTP in preparation for the 12th RoC (see Table 1-1). It considered presentations heard during its open-session meeting, comments submitted by the general public,2 and abstracts presented during recent conferences. It reviewed reports published by other authoritative bodies, and it examined primary literature, reviews, and meta-analyses publicly available in the peer-reviewed literature. The committee relied on its own expert judgment to assess the body of evidence related to the potential carcinogenicity of styrene. It was guided by the language and terminology of the RoC listing criteria (see Box 1-2), although some of the language in the criteria, such as sufficient and limited, required informed interpretation. The committee worked toward the goal of clearly describing its methods in writing this report, how it used the language of the listing criteria, and its analysis of the body of evidence related to styrene.
2A list and copies of presentations heard during the open-session meeting and comments submitted by the general public can be obtained by contacting the National Academies Public Access Records Office.
|Substance profile for styrene||The substance profile as presented in the 12th RoC.||NTP 2011a|
|Background document for styrene||Background information that was prepared by staff in the Office of the Report on Carcinogens to assist in the review of styrene for the 12th RoC.||NTP 2008a|
|Primary literature||Primary literature cited in the background document or obtained from other sources.||—|
|Expert panel reports||An expert panel was charged with doing a peer review of the draft background document on styrene and making a recommendation for the listing of styrene in the 12th RoC.||Phillips et al. 2008a,b|
|NTP Executive Committee Interagency Scientific Review Group (ISRG) report||The interagency scientific review group reviewed the body of literature on styrene and made a recommendation for the listing of styrene in the 12th RoC.||NTP 2008b|
|National Institute of Environmental Health Sciences (NIEHS)/NTP Scientific Review Group report||The NIEHS NTP scientific review group reviewed the body of literature on styrene and made a recommendation for the listing of styrene in the 12th RoC.||NIEHS/NTP 2008|
|Minutes from a Board of Scientific Counselors (BSC) meeting||The BSC assessed whether the scientific information in the draft substance profile was technically correct, was clearly stated, and supported NTP’s preliminary listing of styrene in the 12th RoC.||NTP 2009|
|NTP’s response to the expert panel reports and to the BSC||NTP’s review and response to expert panel reports.||NTP 2011b, 2011c|
|Public comments||Comments from the public in response to Federal Register notices on May 19, 2004 (Vol. 69, No. 97), May 20, 2008 (Vol. 73, No. 98), September 8, 2008 (Vol. 73, No. 174), and December 22, 2008 (Vol. 73, No. 246), and additional public comments that were not associated with any Federal Register notices.||see http://ntp.niehs.nih.gov/go/9920|
|NTP’s response to public comments||NTP’s responses to public comments related to specific issues from the expert panel report that were applicable to the substance profile; comments on the final background document, the review process, or nontechnical or nonscientific issues were excluded by NTP.||NTP 2011d|
The assessment of chemicals for the purposes of listing in the RoC constitutes a hazard assessment, not a risk assessment. A hazard assessment focuses on the identification of substances that may pose a hazard to human health and “makes a classification regarding toxicity, for example, whether a chemical is ‘carcinogenic to humans’ or ‘likely to be’” (NRC 2009). A risk assessment3 focuses on the likely degree of damage and requires much more information, including completion of a hazard identification, dose–response analysis, exposure quantification, and quantitative characterization of risk (NRC 1983). The committee approached its statement of task as an evaluation of hazard, not of risk. It evaluated measures of an association in a population (such as risk ratios, odds ratios, and incidence ratios) from epidemiology studies to inform its assessment of styrene, but it did not identify exposure scenarios that could pose cancer risk as part of a full risk assessment.
The committee worked in parallel with the Committee to Review the Formaldehyde Assessment in the NTP 12th RoC, which was also convened in response to the 2012 Consolidated Appropriations Act. Three persons served on both committees. The committees had identical statements of task except for the specific substance profile being reviewed, and the two committees met jointly for their first meeting. During the open session of that joint meeting, the committees heard presentations from and had an open discussion with representatives of DHHS and NTP. The committees also heard from several stakeholders who participated in the public session. During the meeting’s closed session, members discussed the open-session presentations by the sponsor and the public and the committees’ approach to the statements of task. The committees did not have another joint meeting. To accomplish its task, the present committee held four additional meetings, during which it discussed literature and other materials relevant to understanding styrene carcinogenicity and developed this report.
The committee approached its statement of task by first doing a review, reported in Chapter 2, of the substance profile for styrene as presented in the
3“Risk assessment is the use of the factual base to define the health effects of exposure of individuals or populations to hazardous materials and situations…. Risk assessments contain some or all of the following four steps: Hazard identification: the determination of whether a particular chemical is or is not causally linked to particular health effects. Dose–response assessment: the determination of the relation between the magnitude of exposure and the probability of occurrence of the health effects in question. Exposure assessment: the determination of the extent of human exposure before or after application of regulatory controls. Risk characterization: the description of the nature and often the magnitude of human risk, including attendant uncertainty” (NRC 1983, p. 3).
12th RoC. It considered only literature that had been published as of June 10, 2011 (the release date of the 12th RoC). The background document did not include a description of NTP’s literature search, so that information was obtained directly from NTP and presented in Appendix C. Chapter 2 is organized according to the headings and subheadings of the substance profile and concludes with findings on the appropriateness of NTP’s listing for styrene on the basis of the RoC listing criteria.
Chapter 3 is the committee’s independent assessment of the styrene literature, including literature pertaining to styrene carcinogenicity up to November 13, 2013. The assessment was accomplished by using the 12th RoC and the background document for styrene as supplemented by a search of the literature from 2008 on. The goal of the literature search was to capture literature published since the release of the background document for styrene (NTP 2008a). Details of the search are described in Appendix D. The committee did not do a systematic review of all literature published on styrene, because it determined in Chapter 2 that NTP cited and thoroughly described in the background document the relevant styrene literature that was published before 2008.
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