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Appendix D Literature-Search Strategies Completed in Support of the Committeeâs 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 committeeâs 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 ï· The study did not evaluate ambient or occupational exposures of humans to formaldehyde. ï· The study did not evaluate health effects related to carcinogenesis or ge- netic damage. ï· The publication was already cited in the substance profile for formalde- hyde in the National Toxicology Program 12th Report on Carcinogens. ï· 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 2009â2013. 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 2009â2013. Scopus: [("Formaldehyde") AND ("neoplasms" OR "cancer" OR "carcinogen- ic" OR "tumorâ) AND (âepidemiologyâ "epidemiologic studies" OR "epidemi- olog*" OR "case-referent" OR âoccupational exposureâ OR âworkersâ OR âco- hortâ)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009â2013. Web of Science:[("Formaldehyde") AND ("neoplasms" OR "cancer" OR "car- cinogenic" OR "tumor") AND ("epidemiology" OR "epidemiologic studies" OR "epidemiolog*" OR âcase-referentâ OR âoccupational exposureâ OR âworkerâ OR âcohortâ)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009â2013. 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 committeeâs 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 committeeeâs 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 ï· The study did not evaluate fo ormaldehyde exxposures in animal models. ï· The study did not evaluate th he incidence off tumors. ï· 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. ï· 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 2009â â2013. 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 2009ââ2013. Scopuus: [("Formalde ehyde") AND (""neoplasms" O OR "carcinogen ns" OR "cancer" OR "ffoci" OR âmaliignan*â OR âooncogenic*â OR R âtumorâ OR âtumorigenic*â) AND ("animals" ( OR "mice" OR "ratts")]. Search ru un on 05-10-20 013 and update ed on 11-08-2013; limite ed to 2009â2013. Web ofo Science: [("Formaldehyde") AND ("neop plasms" OR "ca arcinogens" OR "canceer" OR âfociâ OR O âmalignan**â OR âoncoge enic*â OR âtummorâ OR âtumor- igenic c*â) AND ("animmals" OR "mic ce" OR "rats"))]. Search run on 05-10-2013 and updated on 11-0 08-2013; limited to 2009â201 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 ï· The study did not evaluate health effects of formaldehyde or its metabo- lites known to be formed in humans. ï· The study evaluated cellular, biochemical, or molecular effects not rele- vant to the carcinogenesis or the mechanistic event under consideration. ï· The publication did not contain primary data. ï· 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 âDNA damageâ OR âDNA adductsâ)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009â2013. 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 2009â2013. Scopus: [("Formaldehyde") AND ("mutation" OR "cell transformation, neo- plastic" OR "cytogenetic analysis" OR "mutagens" OR "oncogenesâ OR âge- netic processesâ OR âchromosom*â OR âclastogen*â OR âgenetic toxicologyâ OR âstrand breakâ OR âunscheduled DNA synthesisâ OR âDNA damageâ OR âDNA adductsâ)]. Search run on 05-10-2013 and updated on 11-08-2013; lim- ited to 2009â2013. Web of Science: [("Formaldehyde") AND ("mutation" OR "cell transformation, neoplastic" OR "cytogenetic analysis" OR âmutagensâ OR âoncogenesâ OR âgenetic processesâ OR âchromosom*â OR âclastogen*â OR âgenetic toxicolo- gyâ OR âstrand breakâ OR âunscheduled DNA synthesisâ OR âDNA damageâ OR âDNA adductsâ)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009â2013. 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 ï· The study did not evaluate health effects of formaldehyde or its metabo- lites known to be formed in humans. ï· The study evaluated immune effects not relevant to carcinogenesis. ï· The publication did not contain primary data. First Search Strategy PubMed: [(âFormaldehyde"[Title/Abstract]) AND (âimmun*â OR âbone marrowâ OR âbone marrowâ[MeSH] OR âlymphocytesâ OR âlymphocytesâ[MeSH] OR âhematopoieticâ OR âallergyâ OR âsensitizationâ OR âlymph nodeâ OR leuko- penia OR lymphocytopenia OR immunotoxicity)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009â2013. 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 2009â2013. Scopus: [(âFormaldehydeâ) AND (âimmun*â OR âbone marrowâ OR âlympho- cytesâ OR âhematopoiticâ OR âallergyâ OR âsensitizationâ OR âlymph nodeâOR âleucopeniaâ OR âlymphocytopeniaâ OR âimmunotoxicityâ)]. Search run on 05- 10-2013 and updated on 11-08-2013; limited to 2009â2013. Web of Science: [(âformaldehydeâ) AND (âimmun*â OR âbone marrowâ OR lym- phocytesâ OR âhematopoieticâ OR âallergyâ OR âsensitizationâ OR âlymph nodeâOR âleucopeniaâ OR âlymphocytopeniaâ OR âimmunotoxicityâ)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009â2013. Second Search Strategy PubMed: [(âFormaldehyde"[Title])]. Search run on 11-06-2013; limited to 2009â 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 âHematologic Effectsâ section of Chapter 3. To identify studies that may have been missed, a second search was performed with the search term âFormaldehyde[Title]â 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