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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.
×

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, mutagenicity, 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

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.
×

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 genetic damage
  • The publication was already cited in the substance profile for formaldehyde 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 (“Epidemiology”[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 (neoplasms/ 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 “carcinogenic” OR ̶tumor”) AND (“epidemiology” “epidemiologic studies” OR “epidemiolog*” OR “case-referent” OR “occupational exposure” OR “workers” OR “cohort”)]. 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 “carcinogenic” 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.

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.
×

STUDIES OF MECHANISM OF CARCINOGENESIS

Genotoxicity and Mutagenicity

It is generally accepted that formaldehyde, because of its high reactivity, is genotoxic and may cause mutations and other cytogenetic effects that are collectively recognized as a mutagenic mode of action. Multiple types of DNA damage and later heritable changes in the cellular genome have been identified as possible consequences of exposure of DNA, cells, or tissues in vivo to formaldehyde. Thus, the literature-search terms pertinent to this mode of action were defined broadly to represent a variety of end points (Box D-3). The search was informed by a recently published case study of applying the principles of the systematic review to identify and present mechanistic evidence in human health assessments (Kushman et al. 2013).

The literature search for this topic resulted in 554 publications. The literature tree in Figure D-3 shows how the initial search results were narrowed down to 83 publications by National Research Council staff using publication titles and abstracts. The remaining publications were evaluated by two committee members using the titles, abstracts, and full text. In the end, 54 studies were considered relevant to the committee’s independent assessment.

images

FIGURE D-1 Literature tree for human studies search. See Box D-1 for a description of the exclusion criteria and search strategy.

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.
×

BOX D-2 Exclusion Criteria and Search Strategy for Experimental-Animal Studies

Exclusion Criteria

• The study did not evaluate formaldehyde exposures in animal models.

• The study did not evaluate the incidence of tumors.

• The publication was already cited in the substance profile for formaldehyde 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 “Carcinogen”[MeSH] OR cancer OR Foci OR Malignant* OR Oncogenic* OR Tumor OR Tumorigenic*) AND ("Animals"[MeSH] OR mice OR rats)]. 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 (neoplasms/ or carcinogens/or cancer.mp. or foci.mp. or malignan*.mp. or oncon-genic.mp. or tumor.mp. or tumorgenic*.mp.) AND (animals/ or mice.mp. or rats.mp.)]. Search run on 05-10-2013 and updated on 11-08-2013; limited to 2009–2013.

Scopus: [(“Formaldehyde”) 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 05-10-2013 and updated on 11-08-2013; limited to 2009–2013.

Web of Science: [(“Formaldehyde”) 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 05-10-2013 and updated on 11-08-2013; limited to 2009–2013.

images

FIGURE D-2 Literature tree for experimental-animal studies search. See Box D-2 for a description of the exclusion criteria and search strategy.

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.
×

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 metabolites 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 study did not include information sufficient to determine what species 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 toxicology.mp. or strand break.mp. or unscheduled DNA synthesis.mp. or DNA damage.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, neoplastic” OR “cytogenetic analysis” OR “mutagens” OR "oncogenes” OR “genetic 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; limited 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 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.

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

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.
×

images

FIGURE D-3 Literature tree for genotoxicity search. See Box D-3 for a description of the exclusion criteria and search strategy.

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.
×

BOX D-4 Exclusion Criteria and Search Strategy for Immune Effects

Exclusion Criteria

• The study did not evaluate health effects of formaldehyde or its metabolites 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 leukopenia 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 (immune*.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 immunotoxicity.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 “lymphocytes” 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 lymphocytes” 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

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.
×

considered and, when appropriate, abstracts and full text were reviewed. The search resulted in identification of four additional studies. In its reading of the literature, the committee also identified three studies that were relevant to this section that were not cited in the background document or substance profile for formaldehyde. Those results are depicted in Figure D-4.

images

FIGURE D-4 Literature tree for immune-effects search. See Box D-4 for a description of the exclusion criteria and search strategy.

REFERENCES

Bucher, J.R. 2013. Follow-up Questions. Material submitted by the NAS Committee on Review of the Formaldehyde Assessment in the NTP 12th RoC and the NAS Committee on Review of the Styrene Assessment in the NTP 12th RoC, April 2, 2013.

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 human health assessments. Regul. Toxicol. Pharmacol. 67(2):266-277

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.
×
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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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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