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Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens (2014)

Chapter: Appendix D: Literature-Search Strategies Completed in Support of the Committee's Independent Assessment of Formaldehyde

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Suggested Citation:"Appendix D: Literature-Search Strategies Completed in Support of the Committee's Independent Assessment of Formaldehyde." National Research Council. 2014. Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens. Washington, DC: The National Academies Press. doi: 10.17226/18948.
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Suggested Citation:"Appendix D: Literature-Search Strategies Completed in Support of the Committee's Independent Assessment of Formaldehyde." National Research Council. 2014. Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens. Washington, DC: The National Academies Press. doi: 10.17226/18948.
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Page 200
Suggested Citation:"Appendix D: Literature-Search Strategies Completed in Support of the Committee's Independent Assessment of Formaldehyde." National Research Council. 2014. Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens. Washington, DC: The National Academies Press. doi: 10.17226/18948.
×
Page 201
Suggested Citation:"Appendix D: Literature-Search Strategies Completed in Support of the Committee's Independent Assessment of Formaldehyde." National Research Council. 2014. Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens. Washington, DC: The National Academies Press. doi: 10.17226/18948.
×
Page 202
Suggested Citation:"Appendix D: Literature-Search Strategies Completed in Support of the Committee's Independent Assessment of Formaldehyde." National Research Council. 2014. Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens. Washington, DC: The National Academies Press. doi: 10.17226/18948.
×
Page 203
Suggested Citation:"Appendix D: Literature-Search Strategies Completed in Support of the Committee's Independent Assessment of Formaldehyde." National Research Council. 2014. Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens. Washington, DC: The National Academies Press. doi: 10.17226/18948.
×
Page 204
Suggested Citation:"Appendix D: Literature-Search Strategies Completed in Support of the Committee's Independent Assessment of Formaldehyde." National Research Council. 2014. Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens. Washington, DC: The National Academies Press. doi: 10.17226/18948.
×
Page 205
Suggested Citation:"Appendix D: Literature-Search Strategies Completed in Support of the Committee's Independent Assessment of Formaldehyde." National Research Council. 2014. Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens. Washington, DC: The National Academies Press. doi: 10.17226/18948.
×
Page 206

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Appendix D Literature-Search Strategies Completed in Support of the Committee’s Independent Assessment of Formaldehyde The committee used the background document for formaldehyde as a starting point for its independent assessment of formaldehyde. In addition, it undertook several literature searches to identify any relevant literature that was published after the release of the 12th RoC. Each search covered the period from January 1, 2009 (the year in which the background document for formaldehyde was published; Bucher 2013), to November 8, 2013. Databases searched were PubMed, MEDLINE (Ovid), Embase (Ovid), Scopus, and Web of Science. The general topics of the searches include epidemiology, experimental-animal studies, and mechanisms of carcinogenicity (specifically, genotoxicity, mutagen- icity, and hematologic effects). Each search was originally run on May 10, 2013, and updated on November 8, 2013. The search strategies, exclusion strategies, and number of resulting studies are described below. CANCER STUDIES IN HUMANS The committee established exclusion criteria and a literature-search strategy to identify studies in humans (Box D-1). The search resulted in 245 articles, as depicted in Figure D-1. National Research Council staff reviewed the titles and abstracts and excluded 221 as not relevant on the basis of the exclusion criteria. That left 24 articles that were identified as probably or possibly relevant. Two committee members reviewed the titles and abstracts and found 20 more that could be excluded. That left four articles that were considered as part of the committee’s independent assessment. EXPERIMENTAL-ANIMAL STUDIES The literature search for publications of animal carcinogenicity bioassays yielded 280 results. The search terms are described in Box D-2, and a search tree 199

200 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens BOX D-1 Exclusion Criteria and Search Strategy for Human Studies Exclusion Criteria  The study did not evaluate ambient or occupational exposures of humans to formaldehyde.  The study did not evaluate health effects related to carcinogenesis or ge- netic damage.  The publication was already cited in the substance profile for formalde- hyde in the National Toxicology Program 12th Report on Carcinogens.  The publication did not include primary data. Search Strategy PubMed: [("Formaldehyde"[Title/Abstract]) AND ("Neoplasms"[MeSH] OR neoplasms OR cancer OR carcinogenic or tumor) AND ("Epidemiolo- gy"[MeSH] OR "Epidemiologic Studies"[MeSH] OR epidemiolog* OR case- referent OR "Occupational Exposure"[MeSH] OR workers OR cohort)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009–2013. Medline and Embase:[(formaldehyde.ab. or formaldehyde.ti.) and (neo- plasms/ or neoplasms.mp. or cancer.mp. or carcinogenic.mp. or tumor.mp.) and (epidemiology/ or epidemiologic studies/ or epidemiolog*.mp. or case- referent.mp. or occupational exposure or coworkers.mp. or cohort.mp.)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009–2013. Scopus: [("Formaldehyde") AND ("neoplasms" OR "cancer" OR "carcinogen- ic" OR "tumor”) AND (“epidemiology” "epidemiologic studies" OR "epidemi- olog*" OR "case-referent" OR “occupational exposure” OR “workers” OR “co- hort”)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009–2013. Web of Science:[("Formaldehyde") AND ("neoplasms" OR "cancer" OR "car- cinogenic" OR "tumor") AND ("epidemiology" OR "epidemiologic studies" OR "epidemiolog*" OR “case-referent” OR “occupational exposure” OR “worker” OR “cohort”)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009–2013. representing the results is depicted in Figure D-2. A committee member and National Research Council staff independently screened the titles for potential papers reporting on animal cancer bioassays. No studies that exposed experimental animals to formaldehyde and evaluated them for the presence of tumors were identified. Thus, the committee’s independent evaluation of the evidence of formaldehyde carcinogenicity in experimental animals relies on studies that were available to the National Toxicology Program when it conducted its review in 2011.

Append dix D 2201 STUDIES S OF MECHA ANISM OF CA ARCINOGEN NESIS Genotoxicity and Mutaggenicity Itt is generally accepted a that fo ormaldehyde, bbecause of its hhigh reactivity,, is genotox xic and may cause mutatio ons and otherr cytogenetic effects that aare collectiively recognizeed as a mutageenic mode of aaction. Multiplle types of DN NA damagee and later herritable changess in the cellulaar genome have been identifiied as possible consequeences of expo osure of DNA A, cells, or tisssues in vivo to formald dehyde. Thus, the literature-ssearch terms ppertinent to this mode of actiion were defined broadly y to represent a variety of endd points (Box DD-3). The searrch was infformed by a recently publish hed case studyy of applying the principles of the sysstematic review w to identify anda present m mechanistic eviidence in hum man health assessments a (K Kushman et al. 2013). T literature search for th The his topic resullted in 554 ppublications. T The literatu ure tree in Figu ure D-3 shows how the initiaal search resultts were narrow wed down to t 83 publicatiions by Nation nal Research CCouncil staff uusing publicatiion titles and a abstracts.. The remain ning publicatioons were evaaluated by tw wo committee members using the titlles, abstracts, and full text.. In the end, 54 studies were considerred relevant to the committeee’s independentt assessment. FIGUR RE D-1 Literaturre tree for human n studies searchh. See Box D-1 ffor a descriptionn of the excllusion criteria an nd search strategy.

202 Review R of the Fo ormaldehyde Asssessment in the N NTP 12th Repoort on Carcinogeens BOX D-2 D Exclusion Criteria C and Sea arch Strategy ffor Experimental-Animal Stuudies Exclus sion Criteria  The study did not evaluate fo ormaldehyde exxposures in animal models.  The study did not evaluate th he incidence off tumors.  The publication was already cited in the s ubstance profiile for formalde e- hyd de in the Nation nal Toxicology Program 12th Report on Carrcinogens.  The publicationn did not includ de primary dataa. Searc ch Strategy Pubmmed: [("Formaldehyde"[Title/A Abstract]) AN D ("Neoplasm ms"[MeSH] OR "Carcinogen"[MeSH] OR cancer OR O Foci OR M Malignant* OR O Oncogenic* OR Tumoor OR Tumorige enic*) AND ("A Animals"[MeSHH] OR mice OR R rats)]. Searcch run on n 05-10-2013 and a updated on n 11-08-2013; l imited to 2009– –2013. Medlinne and Emba ase: [(formalde ehyde.ab. or formaldehyde..ti.) AND (neo o- plasmms/ or carcinoge ens/ or cancerr.mp. or foci.mpp. or malignan*.mp. or onconn- genic..mp. or tumor.mp. or tumorrgenic*.mp.) AN ND (animals/ or mice.mp. o or rats.m mp.)]. Search ru un on 05-10-2013 and upda ated on 11-08-22013; limited tto 2009––2013. Scopuus: [("Formalde ehyde") AND (""neoplasms" O OR "carcinogen ns" OR "cancer" OR "ffoci" OR “maliignan*” OR “ooncogenic*” OR R “tumor” OR “tumorigenic*”) AND ("animals" ( OR "mice" OR "ratts")]. Search ru un on 05-10-20 013 and update ed on 11-08-2013; limite ed to 2009–2013. Web ofo Science: [("Formaldehyde") AND ("neop plasms" OR "ca arcinogens" OR "canceer" OR “foci” OR O “malignan**” OR “oncoge enic*” OR “tummor” OR “tumor- igenic c*”) AND ("animmals" OR "mic ce" OR "rats"))]. Search run on 05-10-2013 and updated on 11-0 08-2013; limited to 2009–201 3. FIGUR RE D-2 Literaturre tree for experrimental-animal studies search. See Box D-2 foor a d search strategy . descripttion of the exclusion criteria and

Appendix D 203 BOX D-3 Exclusion Criteria and Search Strategy for Genotoxicity and Mutagenicity Mechanisms of Carcinogenesis Exclusion Criteria  The study did not evaluate health effects of formaldehyde or its metabo- lites known to be formed in humans.  The study evaluated cellular, biochemical, or molecular effects not rele- vant to the carcinogenesis or the mechanistic event under consideration.  The publication did not contain primary data.  The study did not include information sufficient to determine what spe- cies were studied or what experimental methods were used. Search Strategy PubMed: [("Formaldehyde"[Title/Abstract]) AND ("Mutation"[MeSH] OR "Cell Transformation, Neoplastic"[MeSH] OR "Cytogenetic Analysis"[MeSH] OR "Mutagens"[MeSH] OR "Oncogenes"[MeSH] OR "Genetic Processes"[MeSH] OR chromosom* OR clastogen* OR "genetic toxicology" OR "strand break" OR "unscheduled DNA synthesis" OR “DNA damage” OR “DNA adducts”)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009–2013. Medline and Embase: [(formaldehyde.ab. or formaldehyde.ti.) and (mutation/ or cell transformation/ or cytogenetic analysis/ or mutagens/ or oncogenes/ or genetic processes or chromosom*.mp. or clastogen*.mp. or genetic toxicolo- gy.mp. or strand break.mp. or unscheduled DNA synthesis.mp. or DNA dam- age.mp. or DNA adducts.mp.)]. Search run on 05-10-2013 and updated on 11- 08-2013; limited to 2009–2013. Scopus: [("Formaldehyde") 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 05-10-2013 and updated on 11-08-2013; lim- ited to 2009–2013. Web of Science: [("Formaldehyde") AND ("mutation" OR "cell transformation, neoplastic" OR "cytogenetic analysis" OR “mutagens” OR “oncogenes” OR “genetic processes” OR “chromosom*” OR “clastogen*” OR “genetic toxicolo- gy” OR “strand break” OR “unscheduled DNA synthesis” OR “DNA damage” OR “DNA adducts”)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009–2013. Immune Effects The committee conducted two literature searches to identify recent studies pertaining to immune effects after exposure to formaldehyde (see Box D-4). The first search resulted in 2,405 publications. Through this approach, National

204 FIGURE D-3 Literature tree for genotoxicity searcch. See Box D-3 for a description of the ex xclusion criteria and search strategy.

Appendix D 205 BOX D-4 Exclusion Criteria and Search Strategy for Immune Effects Exclusion Criteria  The study did not evaluate health effects of formaldehyde or its metabo- lites known to be formed in humans.  The study evaluated immune effects not relevant to carcinogenesis.  The publication did not contain primary data. First Search Strategy PubMed: [(“Formaldehyde"[Title/Abstract]) AND (“immun*” OR “bone marrow” OR “bone marrow”[MeSH] OR “lymphocytes” OR “lymphocytes”[MeSH] OR “hematopoietic” OR “allergy” OR “sensitization” OR “lymph node” OR leuko- penia OR lymphocytopenia OR immunotoxicity)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009–2013. Medline and Embase: [(Formaldehyde.ab OR formaldehyde.ti) AND (im- mune*.mp OR bone marrow.mp. OR bone marrow/ OR lymphocytes.mp. OR lymphocyte/ OR hematopoietic.mp. OR allergy.mp. OR sensitization.mp. OR lymph node.mp. OR leucopenia.mp. OR lymphocytopenia.mp. OR immuno- toxicity.mp.)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009–2013. Scopus: [(“Formaldehyde”) AND (“immun*” OR “bone marrow” OR “lympho- cytes” OR “hematopoitic” OR “allergy” OR “sensitization” OR “lymph node”OR “leucopenia” OR “lymphocytopenia” OR “immunotoxicity”)]. Search run on 05- 10-2013 and updated on 11-08-2013; limited to 2009–2013. Web of Science: [(“formaldehyde”) AND (“immun*” OR “bone marrow” OR lym- phocytes” OR “hematopoietic” OR “allergy” OR “sensitization” OR “lymph node”OR “leucopenia” OR “lymphocytopenia” OR “immunotoxicity”)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009–2013. Second Search Strategy PubMed: [(“Formaldehyde"[Title])]. Search run on 11-06-2013; limited to 2009– 2013. Research Council staff identified 46 studies that contributed an understanding of hematologic effects related to formaldehyde exposure of humans, animals, and isolated hematologic cell types (see Table 3-18). A committee member reviewed the abstracts in greater detail and identified 18 that warranted inclusion in the “Hematologic Effects” section of Chapter 3. To identify studies that may have been missed, a second search was performed with the search term “Formaldehyde[Title]” in Pubmed. There were 730 studies returned from the second search. Titles were reviewed to identify new studies not previously

206 Review R of the Fo ormaldehyde Asssessment in the N NTP 12th Repoort on Carcinogeens consideered and, wheen appropriate, abstracts andd full text werre reviewed. T The search resulted in ideentification of four additionaal studies. In iits reading of tthe literatu ure, the commiittee also identtified three stuudies that weree relevant to thhis sectionn that were not cited in the baackground doccument or subsstance profile ffor formald dehyde. Those results are deppicted in Figurre D-4. FIGUR RE D-4 Literaturre tree for immun ne-effects searchh. See Box D-4 ffor a descriptionn of the excllusion criteria an nd search strategy. REFERENCES Bucher,, J.R. 2013. Folllow-up Question ns. Material subm mitted by the N NAS Committee on Review R of the Formaldehyde F Assessment A in tthe NTP 12th R RoC and the NA AS Committee C on Review R of the Sttyrene Assessmeent in the NTP 12th RoC, Aprill 2, 2013. 2 Kushmaan, M.E., A.D. Kraft, K K.Z. Guytton, W.A. Chiu,, S.L. Makris, annd I. Rusyn. 2013. A systematic app proach for identiifying and preseenting mechanisttic evidence in hhu- man m health assessments. Regul. Toxicol. T Pharmaacol. 67(2):266-2277

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Many people in the United States are exposed to formaldehyde. Exposure can occur from environmental sources (for example, combustion processes, building materials, and tobacco smoke) or in occupational settings (for example, the furniture, textile, and construction industries). Formaldehyde exposure also has endogenous sources—it is produced intracellularly as a component of the one carbon pool intermediary metabolism pathway. Scientists have studied formaldehyde for decades to determine whether exogenous formaldehyde exposure may be associated with cancer in humans. In 1981, The National Toxicology Program (NTP) first listed formaldehyde in the 2nd Report on Carcinogens as "reasonably anticipated to be a human carcinogen". In 2011, NTP upgraded the listing of formaldehyde to "known to be a human carcinogen". Following the new listing, Congress directed the Department of Health and Human Services to arrange for the National Academy of Sciences to independently review formaldehyde's substance profile and listing. This report presents the findings and conclusions of the committee formed in response to the congressional request.

Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens concurs with NTP that there is sufficient evidence in studies that had adequate characterization of relevant exposure metrics to enable a strong conclusion about the association between formaldehyde exposure and cancer in humans. Additionally, the authoring committee independently reviewed the scientific evidence from studies in humans, experimental animals, and other studies relevant to the mechanisms of carcinogenesis and made level-of-evidence conclusions. This report finds clear and convincing epidemiologic evidence of an association between formaldehyde exposure and nasopharyngeal and sinonasal cancers in humans.

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