Review of the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens (2014) / Chapter Skim
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convened an expert committee that has prepared this report. THE COMMITTEE'S APPROACH The NRC Committee to Review the Formaldehyde Assessment in the NTP 12th RoC approached its statement of task by first conducting a review of the substance profile for formaldehyde as presented in the 12th RoC.
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That committee did not conduct its own literature search, review all relevant evidence, systematically formulate its own conclusions regarding causality, or recommend values for the RfC and unit risk. In contrast, the committee that wrote the present report was asked to identify relevant peer-reviewed literature, document its decisions regarding inclusion or exclusion of the literature, apply NTP's RoC listing criteria, and make an independent listing recommendation for formaldehyde.
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. The Report on Carcinogens Listing Criteria The committee's assessment of formaldehyde was guided by the RoC listing criteria.4 A substance can be classified in the RoC as "reasonably anticipated to be a human carcinogen" if at least one of the following criteria is fulfilled: "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." 4 NTP (National Toxicology Program)
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Evidence in experimental animals and a known mechanism of action can provide supporting evidence, but that information is not required by the RoC listing criteria in making a listing recommendation that a substance is known to be a human carcinogen. The committee found the RoC listing criteria to be clear about the information needed to fulfill the criteria of sufficient evidence in experimental animals; however, the type of information needed to meet the RoC listing criteria for limited or sufficient evidence in humans required more interpretation.
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Discussions of chance, bias, confounding factors, and other limitations of the most informative studies in the substance profile are clear and thorough. Epidemiologic evidence was strongest for an association between formaldehyde exposure and cancers of the nasopharyngeal region and sinonasal cavities and myeloid leukemia.
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NTP considered the most informative studies for evaluating lymphohematopoietic cancers, specifically myeloid leukemia, to be the NCI cohort study of industrial workers exposed to formaldehyde,10 the 6 Hauptmann, M., J.H. Lubin, P.A.
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NTP concluded that there is sufficient evidence of carcinogenicity of formaldehyde from experimental animal studies. In NTP's discussion of the specific animal findings, it demonstrated that two components of the RoC listing criteria were met.
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Given the uncertainties in the scientific understanding of the potential mechanisms of the systemic effects of formaldehyde, the committee finds that NTP could have explicitly acknowledged, as stated in a previous expert panel's report, that "while it would be desirable to have an accepted mechanism that fully explains the association between formaldehyde exposure and distal cancers, the lack of such mechanism should not detract from the strength of the epidemiological evidence that formaldehyde causes myeloid leukemia."15 Summary and Conclusions for the Committee's Review of the Formaldehyde Profile in the National Toxicology Program 12th Report on Carcinogens The committee found that NTP's background document for formaldehyde describes the strengths and weaknesses of relevant studies in a way that is consistent and balanced. The substance profile appropriately cites studies showing positive associations that support the listing.
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The committee concludes that NTP comprehensively considered available evidence and applied the listing criteria appropriately in reaching its conclusion. The 12th RoC states that "formaldehyde is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans and supporting data on mechanisms of carcinogenesis." The committee agrees with NTP's conclusion, which is based on evidence published by June 10, 2011, that formaldehyde is a known human carcinogen.
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But in the few cases in which data are adequate to examine the relative performance of different exposure metrics, it has been found that cumulative exposure is generally not proportional to cancer risk and should not necessarily be assumed to be the correct summary measure of exposure for cancer risk. Evidence of this finding first came from studies of smoking and lung cancer,16 asbestos exposure and risk of mesothelioma,17 both asbestos and silica and risk of lung cancer,18 and leukemia risk and benzene exposure.19 16 Doll, R
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Summaries were not presented for other kinds of cancer because of a lack of strong evidence that formaldehyde exposure causes other types of cancer in humans. Nasopharyngeal and Sinonasal Cancers The committee found clear and convincing epidemiologic evidence of an association between formaldehyde exposure and nasopharyngeal cancer and sinonasal cancer in humans.
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2002. Sinonasal cancer and occupational exposures: A pooled analysis of 12 case-control studies.
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Two of the studies used F344 rats,26 and one used Sprague Dawley rats.27 The evidence is corroborated by other rat studies28 and by a study in mice.29 Although there are limitations in extrapolating findings on nasal tumors in rodents to nasopharyngeal and sinonasal cancers in humans, the experimentalanimal evidence indicates that exposure to inhaled formaldehyde is associated with carcinogenic effects on tissues at the portal of entry. Inhalation of formaldehyde at sufficient concentrations substantially increases formaldehyde to above the total endogenous concentration in tissues at the portal of entry in both animal and human studies.
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On the basis of three strong studies with widely different coexposures (NCI formaldehyde industry cohort,30 NIOSH garment workers cohort,31 NCI funeral industry cohort32) and several moderately strong studies,33 the committee concludes that there is a causal association between formaldehyde exposure and myeloid leukemia.
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The committee concludes that these findings provide plausible mechanistic pathways supporting a relationship between formaldehyde exposure and cancer, even though the potential mechanisms of how formaldehyde may cause such systemic effects are not fully understood. It would be desirable to have a more complete understanding about how formaldehyde exposure may cause systemic effects, but the lack of known mechanisms should not detract from the findings of an association between formaldehyde exposure and myeloid leukemia in epidemiology studies.
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On the basis of the information summarized directly above for nasopharyngeal and sinonasal cancers and for myeloid leukemia, the committee makes its independent determinations as follows: There is sufficient evidence of carcinogenicity from studies of humans based on consistent epidemiologic findings on nasopharyngeal cancer, sinonasal cancer, and myeloid leukemia for which chance, bias, and confounding factors can be ruled out with reasonable confidence. There is sufficient evidence of carcinogenicity in animals based on malignant and benign tumors in multiple species, at multiple sites, by multiple routes of exposure, and to an unusual degree with regard to type of tumor.
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Summary 19 Because there is sufficient evidence of carcinogenicity from studies in humans that indicates a causal relationship between exposure to formaldehyde and at least one type of human cancer, the committee concludes that formaldehyde should be listed in the RoC as "known to be a human carcinogen".
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