Appendix D

Literature Search Strategies Used in Support of the Committee’s Independent Assessment of Styrene

The committee undertook several literature searches to inform its independent assessment of styrene. The general topics of the searches included metabolism, human epidemiology, experimental-animal studies, and mechanisms of carcinogenicity (specifically, genotoxicity, mutagenicity, immunosuppression, and cytotoxicity). Each search was originally run on May 28, 2013, and updated on November 13, 2013.1 The search strategies, exclusion criteria, and number of resulting studies are described below. The committee completed the searches with guidance from NRC (2011), and its work was informed by a recently published case study of applying the principles of systematic review to identify and present mechanistic evidence in human health assessments (Kushman et al. 2013).

METABOLISM

The search strategy used for studies relevant to the metabolism of styrene is presented in Box D-1. The search resulted in 229 papers. National Research Council staff reviewed the titles and abstracts of all 229 results and excluded 184 as not relevant (see Figure D-1). Studies were excluded on the basis of the criteria described in Box D-1. The 45 remaining studies were identified as likely to be relevant or possibly relevant. A committee member reviewed the titles and abstracts and found 27 that could be excluded because they were not focused on styrene; they were focused on urinary biomarkers or on reversible physiologic effects; or they were more pertinent to the consideration of cytotoxicity than of metabolism of styrene. The remaining 18 studies were examined in detail to determine whether they contained information or analysis that should be included as part of the committee’s independent assessment.

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1The cutoff date for the literature search was chosen to allow the committee time to review the literature within the time constraints of the project schedule.



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Appendix D Literature Search Strategies Used in Support of the Committee’s Independent Assessment of Styrene The committee undertook several literature searches to inform its inde- pendent assessment of styrene. The general topics of the searches included me- tabolism, human epidemiology, experimental-animal studies, and mechanisms of carcinogenicity (specifically, genotoxicity, mutagenicity, immunosuppres- sion, and cytotoxicity). Each search was originally run on May 28, 2013, and updated on November 13, 2013.1 The search strategies, exclusion criteria, and number of resulting studies are described below. The committee completed the searches with guidance from NRC (2011), and its work was informed by a re- cently published case study of applying the principles of systematic review to identify and present mechanistic evidence in human health assessments (Kush- man et al. 2013). METABOLISM The search strategy used for studies relevant to the metabolism of styrene is presented in Box D-1. The search resulted in 229 papers. National Research Council staff reviewed the titles and abstracts of all 229 results and excluded 184 as not relevant (see Figure D-1). Studies were excluded on the basis of the criteria described in Box D-1. The 45 remaining studies were identified as likely to be relevant or possibly relevant. A committee member reviewed the titles and abstracts and found 27 that could be excluded because they were not focused on styrene; they were focused on urinary biomarkers or on reversible physiologic effects; or they were more pertinent to the consideration of cytotoxicity than of metabolism of styrene. The remaining 18 studies were examined in detail to determine whether they contained information or analysis that should be includ- ed as part of the committee’s independent assessment. 1 The cutoff date for the literature search was chosen to allow the committee time to review the literature within the time constraints of the project schedule. 168

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Appendix D 169 BOX D-1 Exclusion Criteria and Search Strategy for Studies of the Metabolism of Styrene Exclusion Criteria:  The study was not focused on styrene metabolism or was focused on biomarkers.  The publication was already cited in the substance profile of styrene in the NTP 12th RoC.  The publication did not contain primary data.  The publication did not include information sufficient to determine what experimental methods were used. Search Strategy: PubMed: [(“Styrene”[Title/Abstract]) AND (“Cytochrome P-450 Enzyme Sys- tem”[Mesh] OR “Cytochrome P-450 Enzyme System” OR “Biotransfor- mation”[Mesh] OR “Biotransformation “ OR “Metabolism”[Mesh] OR “Metabo- lism “ OR “Pharmacokinetics”[Mesh] OR “Pharmacokinetics”) AND (activation OR bioactivation OR clearance OR detoxif* OR distribution OR excretion OR kinetics OR mechanism OR metabolite)]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13-2013. Medline and Embase: [(styrene.ab. or styrene.ti.) and (Cytochrome P-450 En- zyme System/ or Cytochrome P-450 Enzyme System.mp. or Biotransformation/ or Biotransformation .mp. or Metabolism/ or Metabolism.mp. or Pharmacokinet- ics or Pharmacokinetics.mp.) AND (activation.mp. OR bioactivation.mp. OR clearance.mp. OR detoxif*.mp. OR distribution.mp. OR excretion.mp. OR kinet- ics.mp. OR mechanism.mp. OR metabolite.mp.)]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13-2013. Scopus: [(“styrene”) AND (“Cytochrome P-450 Enzyme System” OR “Bio- transformation” OR “Metabolism” OR “Pharmacokinetics”) AND (“activation” OR “bioactivation” OR “clearance” OR “detoxif*” OR “distribution” OR “excre- tion” OR “kinetics” OR “mechanism” OR “metabolite”)]. Search run on 05-28- 2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13-2013. Web of Science: [(“styrene”) AND (“Cytochrome P-450 Enzyme System” OR “Biotransformation” OR “Metabolism” OR “Pharmacokinetics”) AND (“activa- tion” OR “bioactivation” OR “clearance” OR “detoxif*” OR “distribution” OR “excretion” OR “kinetics” OR “mechanism” OR “metabolite”)]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13- 2013.

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170 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens 229 Publications identified in the literature search for metabolism studies 184 Publications excluded according to exclusion criteria 45 Publications were further evaluated using full text 27 Publications excluded as not relevant according to exclusion criteria 18 Publications identified as relevant and evaluated in Chapter 3 FIGURE D-1 Literature tree for search of studies relevant to styrene metabolism. CANCER STUDIES IN HUMANS The search algorithms and exclusion criteria used to identify human epi- demiology studies are in Box D-2. The initial search yielded 46 articles (see Figure D-2). National Research Council staff reviewed the titles and abstracts of all 46 and excluded 29 as not relevant. The 17 remaining studies were identified as likely to be relevant or possibly relevant. Two committee members reviewed the titles and abstracts and found 13 that could be excluded. The remaining four studies were examined in detail to determine whether they contained infor- mation or analysis that should be included as part of the committee’s independ- ent assessment. EXPERIMENTAL ANIMAL STUDIES The literature search for publications of animal carcinogenicity bioassays published from January 2008 to November 13, 2013, yielded 118 results. The search terms are described in Box D-3 and a search tree representing the results is depicted in Figure D-3. National Research Council staff reviewed the titles and abstracts of the remaining 118 results and excluded 115 as not relevant. A committee member reviewed the titles and abstracts and found that all three could be excluded. No studies that exposed experimental animals to styrene and evaluated them for the presence of tumors were identified. Thus, the commit- tee’s independent evaluation of the evidence of styrene carcinogenicity in exper- imental animals relies on studies available to NTP when it conducted its review in 2011.

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Appendix D 171 BOX D-2 Exclusion Criteria and Search Strategy for Human Studies Exclusion Criteria:  The publication did not evaluate ambient or occupational exposures of humans to styrene.  The publication did not evaluate health effects related to carcinogenesis or genetic damage.  The publication was already cited in the substance profile of styrene in the NTP 12th RoC.  The publication did not include primary data. Search Strategy: PubMed: [(“Styrene”[Title/Abstract]) AND (“Neoplasms”[Mesh] OR neoplasms OR cancer OR carcinogenic or tumor) AND (“Epidemiology”[Mesh] OR “Epi- demiologic Studies”[Mesh] OR epidemiolog* OR case-referent OR “Occupa- tional Exposure”[Mesh] OR workers OR cohort)]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13-2013. Medline and Embase:[ (styrene.ab. or styrene.ti.) and (Neoplasms/ or neo- plasms.mp. or cancer.mp. or carcinogenic.mp. or tumor.mp.) and (Epidemiol- ogy/ or Epidemiologic Studies/ or epidemiolog*.mp. or case-referent.mp. or Occupational Studies/ or coworkers.mp. or cohort.mp.)]. Search run on 05-28- 2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13-2013. Scopus: [(“styrene”) AND (“neoplasms” OR “cancer” OR “carcinogenic” OR “tumor”) AND (“epidemiology” “epidemiologic studies” OR “epidemiolog*” OR “case-referent” OR “occupational exposure” OR “workers” OR “cohort”)]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13-2013. Web of Science: [(“styrene”) AND (“neoplasms” OR “cancer” OR “carcinogen- ic” OR “tumor”) AND (“epidemiology” OR “epidemiologic studies” OR “epide- miolog*” OR “case-referent” OR “occupational exposure” OR “worker” OR “co- hort”)]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01- 01-2008 to 11-13-2013. STUDIES OF MECHANISMS OF CARCINOGENESIS Genotoxicity and Mutagenicity The committee identified and evaluated relevant, publicly available, peer- reviewed literature on the genotoxicity and associated mechanistic events that have been associated with exposure to styrene or styrene-7,8-oxide. Exclusion criteria for study relevance were defined and applied to the retrieved literature by reviewing the abstracts of the retrieved publications and then reviewing full

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172 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens 46 Publications identified in the literature search for human studies 29 Publications excluded according to exclusion criteria 17 Publications were further evaluated using full text 13 Publications excluded as not relevant according to exclusion criteria 4 Publications identified as relevant and evaluated in Chapter 3 FIGURE D-2 Literature tree for search of studies relevant to humans. text of selected papers. The committee’s exclusion criteria and detailed search terms for studies related to genotoxicity and mutagenicity are presented in Box D-4. Literature trees were used to document identification and selection of the literature evidence (Figure D-4). The selected studies were summarized in evi- dence tables (see Tables 3-12 to 3-16). Immunosuppression The committee undertook a literature search to identify relevant publica- tions on styrene exposure and immunosuppression. Because there was not a spe- cific section in the background document for styrene (NTP 2008) that discussed immunosuppression in detail, the committee undertook a broad search without any date limits (see Box D-5 and Figure D-5). It considered studies relevant if they reported data on changes in basic hematologic measures, such as white blood cell (WBC) count and WBC differential count. The committee included studies that reported such measures as weight of lymphoid organs and expres- sion of functional markers. Efforts were made to identify and include studies that reported effects on local, systemic, innate, and specific immunity in exposed animals or humans. Studies that reported genotoxic measures were excluded from discussion in this section because they are discussed in more detail in the genotoxicity sections of Chapters 2 and 3. The literature search yielded 233 re- sults, 19 of which were relevant articles that were not already cited in the back- ground document for styrene.

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Appendix D 173 BOX D-3 Exclusion Criteria and Search Strategy for Experimental Animal Studies Exclusion Criteria:  The publication did not evaluate styrene exposures in animal models.  The publication did not evaluate the incidence of tumors.  The publication was already cited in the substance profile of styrene in the NTP 12th RoC.  The publication did not include primary data. Search Strategy: Pubmed: [(“Styrene”[Title/Abstract]) AND (“Neoplasms”[Mesh] OR “Carcino- gen”[Mesh] OR cancer OR Foci OR Malignant* OR Oncogenic* OR Tumor OR Tumorigenic*) AND (“Animals”[Mesh] OR mice OR rats)]. Search run on 05-28- 2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13-2013. Medline and Embase: [(styrene.ab. or styrene.ti.) AND (neoplasms/ or carcino- gens/ or cancer.mp. or foci.mp. or malignan*.mp. or oncongenic.mp. or tu- mor.mp. or tumorgenic*.mp.) AND (animals/ or mice.mp. or rats.mp.)]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01-01-2008 to 11- 13-2013. Scopus: [(“Styrene”) AND (“neoplasms” OR “carcinogens” OR “cancer” OR “fo- ci” OR “malignan*” OR “oncogenic*” OR “tumor” OR “tumorigenic*”) AND (“an- imals” OR “mice” OR “rats”)]. Search run on 05-28-2013; updated on 11-13- 2013; and limited to 01-01-2008 to 11-13-2013. Web of Science: [(“Styrene”) AND (“neoplasms” OR “carcinogens” OR “cancer” OR “foci” OR “malignan*” OR “oncogenic*” OR “tumor” OR “tumorigenic*”) AND (“animals” OR “mice” OR “rats”)]. Search run on 05-28-2013; updated on 11-13- 2013; and limited to 01-01-2008 to 11-13-2013. Cytotoxicity The committee and National Research Council staff developed a search algorithm to identify relevant cytotoxicity studies that were published in Pub- Med (see Box D-6 and Figure D-6). The first literature search was run by using selected metabolites as keywords, and a total of 259 references were identified, 12 of which were animal toxicity studies. A second search was undertaken by using styrene in the title or abstract in combination with keywords related to lung toxicity. This search identified 37 references, 14 of which dealt with origi- nal research on animal toxicity studies and two of which were reviews. Of the 14, 12 were duplicates of the previous search. On August 8, 2013, a third search was performed by refining the terms used in the first search. In this third search, each metabolite was searched in combination with keywords related to lung tox- icity. A total of 12 references were identified, all of which had been identified in

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174 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens the previous search. An additional PubMed search was performed on November 22, 2013. This search identified a total of 217 references, 16 of which addressed animal studies of toxicity of styrene or its metabolites, including two reviews, and all of which had been identified in the previous searches. 118 Publications identified in the literature search for experimental animal studies 115 Publications excluded according to exclusion criteria 3 Publications were further evaluated using full text 3 Publications excluded as not relevant according to exclusion criteria 0 Publications identified as relevant and evaluated in Chapter 3 FIGURE D-3 Literature tree for search of studies relevant to experimental animals. BOX D-4 Exclusion Criteria and Search Strategy for Studies of Genotoxicity and Related Mechanisms of Styrene Exclusion Criteria  The publication did not evaluate health effects of styrene or its metabo- lites known to be formed in humans.  The study evaluated cellular, biochemical, or molecular effects not relevant to the carcinogenesis or the mechanistic event under consideration.  The publication did not contain primary data.  The publication did not include information sufficient to determine what species were studied or what experimental methods were used. Search Strategy PubMed: [(“Styrene”[Title/Abstract]) AND (“Mutation”[Mesh] OR “Cell Transfor- mation, Neoplastic”[Mesh] OR “Cytogenetic Analysis”[Mesh] OR “Muta- gens”[Mesh] OR “Oncogenes”[Mesh] OR “Genetic Processes”[Mesh] OR chro- mosom* OR clastogen* OR “genetic toxicology” OR “strand break” OR “unscheduled DNA synthesis” OR “DNA damage” OR “DNA adducts”)]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13- 2013. (Continued)

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Appendix D 175 BOX D-4 Continued Medline and Embase: [(styrene.ab. or styrene.ti.) and (1 or 2 or 3 or 4 or 5 or 6 or chromosom*.mp. or clastogen*.mp. or genetic toxicology.mp. or strand break.mp. or unscheduled DNA synthesis.mp. or DNA damage.mp. or DNA adducts.mp.), where the following keywords are: 1) Mutation, 2) Cell Trans- formation, Neoplastic, 3) Cytogenetic Analysis, 4) Mutagens, 5) Oncogenes, 6) Genetic Processes]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13-2013. Scopus: [((“Styrene”) AND (“mutation” OR “cell transformation, neoplastic” OR “cytogenetic analysis” OR “mutagens” OR “oncogenes” OR “genetic pro- cesses” OR “chromosom*” OR “clastogen* OR “genetic toxicology” OR “strand break” OR “unscheduled DNA synthesis” OR “DNA damage” OR “DNA adducts”)]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13-2013. Web of Science: [((“Styrene”) AND (“mutation” OR “cell transformation, neo- plastic” OR “cytogenetic analysis” OR “mutagens” OR “oncogenes” OR “ge- netic processes” OR “chromosom*” OR “clastogen*” OR “genetic toxicology” OR “strand break” OR “unscheduled DNA synthesis” OR “DNA damage” OR “DNA adducts”)]. Search run on 05-28-2013; updated on 11-13-2013; and limited to 01-01-2008 to 11-13-2013. 144 Publications identified in the literature search for genotoxicity and mutagenicity studies 114 Publications removed according to exclusion criteria 30 Publications were further evaluated using full text 16 Publications removed as not relevant according to exclusion criteria +4 Publications +20 Publications 14 added from IARC added from Scott (1994a,b; 2002) and Preston (1994) 38 Publications identified as relevant and evaluated in Chapter 3 FIGURE D-4 Literature tree for search of studies relevant to genotoxicity and mutagen- icity.

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176 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens BOX D-5 Exclusion Criteria and Search Strategy for Immunosuppression Studies Exclusion Criteria:  The publication did not report data on changes in basic hematologic measures after exposure to styrene.  The publication did not report measures of lymphoid organs.  The publication did not contain primary data.  The publication was already cited in the substance profile for styrene in the NTP 12th RoC.  The publication did not include information sufficient to determine what species were studied or what experimental methods were used. Search Strategy: PubMed: (“styrene”[Title/Abstract]) AND (“lymph node” OR leukopenia OR lymphocyt* OR immunotoxicity OR immunosuppression OR hematologic OR hematopoietic). Search run on 05-28-2013 and updated on 11-26-2013. 233 Publications identified in the literature search for immunosuppression studies 214 Publications removed according to exclusion criteria 19 Publications were further evaluated using full text 0 Publications removed as not relevant according to exclusion criteria 19 Publications identified as relevant and evaluated in Chapter 3 FIGURE D-5 Literature tree for search of studies relevant to styrene immunosuppres- sion.

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Appendix D 177 BOX D-6 Exclusion Criteria and Search Strategy for Cytotoxicity Studies Exclusion Criteria:  The publication did not contain information on lung cytotoxicity or dam- age to the lung, liver, or kidney in relation to exposure to styrene or to a metabolite of styrene.  The publication did not contain primary data.  The publication was already cited in the substance profile for styrene in the NTP 12th RoC.  The publication did not include information sufficient to determine what species were studied or what experimental methods were used. Search Strategies: PubMed: [(styrene oxide OR vinylphenol OR 4-vinylphenol OR styrene-3,4- epoxide OR styrene-7,8-oxide OR epoxyethylbenzene OR mandelic acid OR hydroxymandelic acid OR poly(2-hydroxyethylmethacrylate)]. Search run on 05-09-2013 and limited from 01-01-2010 to 05-09-2013. PubMed: [(“Styrene”[Title/Abstract]) AND (lung OR pulmonary OR bronchiole OR bronchiolar OR “Clara cell” OR “alveolar type 2 cell”)]. Search run on 05- 28-2013 and limited from 01-01-2008 to 05-28-2013. PubMed: [(lung OR pulmonary OR bronchiole OR bronchiolar OR “Clara cell” OR “alveolar type 2 cell”) AND (styrene oxide OR vinylphenol OR 4-vinylphenol OR styrene-3,4-epoxide OR styrene-7,8-oxide OR epoxyethylbenzene OR man- delic acid OR hydroxymandelic acid OR poly(2-hydroxyethylmethacrylate)]. Search run on 08-08-2013 and limited from 01-01-2010 to 08-08-2013. Pubmed: [(styrene) AND (lung OR liver OR kidney)]. Search run on 11-22-2013 and limited from 01-01-2008 to 11-22-2013. 261 Publications identified in the literature search for cytotoxicity studies 247 Publications removed according to exclusion criteria 14 Publications were further evaluated using full text 0 Publications removed as not relevant according to exclusion criteria 14 Publications identified as relevant and evaluated in Chapter 3 FIGURE D-6 Literature tree for search of studies relevant to styrene cytotoxicity.

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178 Review of the Styrene Assessment in the NTP 12th Report on Carcinogens REFERENCES IARC (International Agency for Research on Cancer). 1994a. Styrene. Pp. 233-320 in Some Industrial Chemicals. IARC Monographs on the Evaluation of the Carcino- genic Risk to Humans, Vol. 60. Lyon, France: IARC Press [online]. Available: http://monographs.iarc.fr/ENG/Monographs/vol60/mono60.pdf [accessed Feb. 12, 2014]. IARC (International Agency for Research on Cancer). 1994b. Styrene-7,8-oxide. Pp. 321- 346 in Some Industrial Chemicals. IARC Monographs on the Evaluation of the Car- cinogenic Risk to Humans, Vol. 60. Lyon, France: IARC Press [online]. Available: http://monographs.iarc.fr/ENG/Monographs/vol60/mono60.pdf [accessed Feb. 12, 2014]. IARC (International Agency for Research on Cancer). 2002. Styrene. Pp. 437-550 in Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene. IARC Monographs on the Evaluation of the Carcinogenic Risk to Humans Vol. 82. Lyon, France: IARC Press [online]. Available: http://monographs.iarc.fr/ENG/Mo nographs/vol82/mono82.pdf [accessed Feb. 12, 2014]. Kushman, M.E., A.D. Kraft, K.Z. Guyton, W.A. Chiu, S.L. Makris, and I. Rusyn. 2013. A systematic approach for identifying and presenting mechanistic evidence in hu- man health assessments. Regul. Toxicol. Pharmacol. 67(2):266-277. NRC (National Research Council). 2011. Review of the Environmental Protection Agen- cy’s Draft IRIS Assessment of Formaldehyde. Washington, DC: The National Academies Press. NTP (National Toxicology Program). 2008. Report on Carcinogens Background Docu- ment 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/Final BDs/Styrene_Final_508.pdf [accessed Aug. 14, 2013]. Scott, D., and R.J. Preston. 1994. A re-evaluation of the cytogenetic effects of styrene. Mutat. Res. 318(3):175-203.