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

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Summary As part of the 2012 Consolidated Appropriations Act (112th Congress, 1st Session; Public Law 112-74), Congress directed the Department of Health and Human Services to arrange for the National Academy of Sciences to carry out an independent review of the formaldehyde assessment in the National Toxicol- ogy Program (NTP) 12th Report on Carcinogens (RoC).1 In response, the Acad- emy’s National Research Council (NRC) 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. It considered literature published by June 10, 2011 (reflecting the date of publication of the 12th RoC), and it organized its review on the basis of the headings and subhead- ings of the substance profile. The committee then conducted its own independ- ent assessment of the formaldehyde literature, extending its review to include literature through November 8, 2013, and concluding with its own listing rec- ommendation for formaldehyde. The committee noted that the assessment of chemicals for the purposes of listing in the RoC constitutes a hazard assessment, not a risk assessment. A haz- ard assessment focuses on the identification of substances that may pose a haz- ard to human health, and it “makes a classification regarding toxicity, for exam- ple, whether a chemical is ‘carcinogenic to humans’ or ‘likely to be’.”2 A risk assessment focuses on the likely degree of damage and requires much more in- formation, including completion of a hazard identification, dose–response analy- 1 NTP (National Toxicology Program). 2011. Formaldehyde. Pp. 195-205 in Report on Carcinogens, 12th Ed. 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/profiles/formaldehyde.pdf. 2 NRC (National Research Council). 2009. Science and Decision: Advancing Risk As- sessment. Washington, DC: National Academies Press. 3 

4 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens sis, exposure quantification, and characterization of risk. The committee thus approached its assessment of formaldehyde as an evaluation of hazard, not risk. It evaluated measures of association in a population (such as risk ratios, odds ratios, and incidence ratios) from epidemiology studies to inform its assessment of formaldehyde, but it did not identify exposure scenarios that could pose can- cer risk as part of a full risk assessment. The committee examined the 2011 NRC report, Review of the Environ- mental Protection Agency (EPA) Draft IRIS (Integrated Risk Information Sys- tem) Assessment of Formaldehyde.3 Although the present report and the 2011 report both focused on formaldehyde, the two committees had different state- ments of task. The Committee to Review EPA’s Draft IRIS Assessment of For- maldehyde was asked to “conduct an independent scientific review of [EPA’s] draft human health assessment of formaldehyde for [IRIS].” It was also asked to address specific questions related to EPA’s inhalation reference concentration (RfC) for noncancer health effects and its risk estimate for carcinogenicity. That committee assessed how well the narrative presented in the draft IRIS assess- ment supported the IRIS assessment’s conclusions regarding health effects. That committee did not conduct its own literature search, review all relevant evi- dence, systematically formulate its own conclusions regarding causality, or rec- ommend values for the RfC and unit risk. In contrast, the committee that wrote the present report was asked to identify relevant peer-reviewed literature, docu- ment its decisions regarding inclusion or exclusion of the literature, apply NTP’s RoC listing criteria, and make an independent listing recommendation for for- maldehyde. The two projects were also different because of inherent differences be- tween EPA’s IRIS assessments and NTP’s RoC. IRIS assessments are compre- hensive human health assessments that evaluate cancer and noncancer end points and include hazard and dose-response assessments that are used to derive toxicity values (that is, reference values and unit risk values), whereas NTP qualitatively weighs evidence of carcinogenicity and compiles lists of substanc- es that it classifies as known human carcinogens or reasonably anticipated hu- man carcinogens to produce the biennial RoC. Because of those differences, the committee cautions readers against making direct comparisons between the two reports. THE NATIONAL TOXICOLOGY PROGRAM AND FORMALDEHYDE NTP is an interagency program involving the National Institutes of Health’s National Institute of Environmental Health Sciences (the administrative lead), the Centers for Disease Control and Prevention’s National Institute for 3 NRC (National Research Council). 2011. Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde. Washington, DC: National Acade- mies Press. 

Summary 5 Occupational Safety and Health, and the Food and Drug Administration’s Na- tional Center for Toxicological Research. Since 1980, NTP has published the RoC, which is a cumulative summary of substances that have been nominated for review and judged to meet two conditions. The first condition is that a signif- icant number of people living in the United States are exposed to the substance of interest. The second condition is that there is judged to be evidence that the substance of interest is either known to be a human carcinogen or reasonably anticipated to be a human carcinogen on the basis of NTP’s established listing criteria. In the late 1970s and early 1980s, NTP assessed the potential carcinogen- icity of formaldehyde, and the substance was listed as “reasonably anticipated to be a human carcinogen” in the 2nd RoC (1981). Three decades later, NTP reas- sessed formaldehyde and upgraded its listing to “known to be a human carcino- gen” in the 12th RoC (2011). Formaldehyde is a substance of interest because many people in the United States are exposed. Exposure can occur from envi- ronmental 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 in humans intracellularly as a component of the one- carbon pool intermediary metabolism pathway. Scientists have studied formal- dehyde for decades to determine whether exogenous formaldehyde exposure may be associated with cancer in humans. Much of the focus has been on can- cers of the upper respiratory tract because those tissues were thought to be the most biologically plausible targets. However, there is increasing interest in a potential relationship between formaldehyde exposure and some lymphohema- topoietic cancers (for example, leukemia). The Report on Carcinogens Listing Criteria The committee’s assessment of formaldehyde was guided by the RoC list- ing 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 expla- nations, such as chance, bias, or confounding factors, could not adequately be excluded.” 4 NTP (National Toxicology Program). 2010. Report on Carcinogens Background Document for Formaldehyde, January 22, 2010. 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/2009/November/Formal dehyde_BD_Final.pdf. 

6 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens  “There is sufficient evidence of carcinogenicity from studies in experi- mental animals, which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors (1) in multiple species or at multiple tissue sites, or (2) by multiple routes of exposure, or (3) to an unusu- al degree with regard to incidence, site, or type of tumor, or age at onset.”  “There is less than sufficient evidence of carcinogenicity in humans or laboratory animals; however, the agent, substance, or mixture belongs to a well- defined, structurally related class of substances whose members are listed in a previous Report on Carcinogens as either known to be a human carcinogen or reasonably anticipated to be a human carcinogen, or there is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans.” A substance can be listed in the RoC as “known to be a human carcino- gen” if “there is sufficient evidence of carcinogenicity from studies in humans, which indicates a causal relationship between exposure to the agent, substance, or mixture, and human cancer.” Sufficient evidence in humans from only one type of cancer is adequate for a substance to be listed in the RoC as “known to be a human carcinogen”. Evidence in experimental animals and a known mech- anism 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 infor- mation needed to fulfill the criteria of sufficient evidence in experimental ani- mals; however, the type of information needed to meet the RoC listing criteria for limited or sufficient evidence in humans required more interpretation. There- fore, consistent with the RoC listing criteria, the committee used its expert scien- tific judgment to interpret and apply the listing criteria to the evidence evaluated in Chapters 2 and 3. It established its own set of evaluation attributes and made judgments on the strength of each of the epidemiology studies it reviewed (stud- ies were judged to be strong, moderately strong, or weak). Limited evidence was defined by the committee as evidence from two or more strong or moderately strong studies with varied study designs and populations that suggested an asso- ciation between exposure to formaldehyde and a specific cancer type, but alter- native explanations, such as chance, bias, or confounding factors, could not be adequately ruled out because of limitations in the studies, and so a causal inter- pretation could not be accepted with confidence. Sufficient evidence was defined by the committee as consistent evidence from two or more strong or moderately strong studies with varied study designs and populations that found an associa- tion between exposure to formaldehyde and a specific cancer type and for which chance, bias, and confounding factors could be ruled out with reasonable confi- dence because of the study methodologies and the strength of the findings. 

Summary 7 REVIEW OF THE FORMALDEHYDE PROFILE IN THE NATIONAL TOXICOLOGY PROGRAM 12TH REPORT ON CARCINOGENS To address the first part of its statement of task, this committee reviewed the formaldehyde substance profile in the NTP’s 12th RoC. The committee ex- amined the primary literature cited in NTP’s background document for formal- dehyde and other literature published by June 10, 2011 (the date when the 12th RoC was released). The headings and structure of the committee’s review paral- lel the major headings that NTP used in the substance profile for formaldehyde. As part of its review, the committee determined whether NTP had described and conducted its literature search appropriately, whether the relevant literature iden- tified during the literature search was cited and sufficiently described in the background document, whether NTP had selected the most informative studies in making its listing determination, and whether NTP’s arguments supported its conclusion that formaldehyde is known to be a human carcinogen. Cancer Studies in Humans The committee reviewed the “Cancer Studies in Humans” section in the NTP substance profile and the corresponding sections in the background docu- ment for formaldehyde. The committee concluded that NTP did a thorough job of describing the epidemiology literature in the background document and syn- thesizing information about key studies in the substance profile. The committee agrees with NTP’s focus on three principal types of cohort and case–control studies in humans: studies of industrial workers, studies of professional groups that have high exposure (embalmers), and studies of general-population cohorts and case–control studies. On the basis of the committee’s definition of limited and sufficient evi- dence discussed above and its peer review of the substance profile for formalde- hyde, it concurs with NTP that there is sufficient evidence in studies that had adequate characterization of relevant exposure metrics to enable a conclusion about human cancer after exposure to formaldehyde. 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 formal- dehyde exposure and cancers of the nasopharyngeal region and sinonasal cavi- ties and myeloid leukemia. NTP considered the most informative study for eval- uating nasopharyngeal cancer to be a case-control study5 that drew incident 5 Vaughan, T.L., P.A. Stewart, K. Teschke, C.F. Lynch, G.M. Swanson, J.L. Lyon, and M. Berwick. 2000. Occupational exposure to formaldehyde and wood dust and nasopha- ryngeal carcinoma. Occup. Environ. Med. 57(6):376-384. 

8 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens cases from five US cancer registries that participated in the Surveillance Epide- miology and End Results program of the National Cancer Institute (NCI). Im- portant corroborating evidence for an association was provided by an NCI in- dustrial worker cohort6 and several case-control studies.7 NTP considered the most informative study for evaluating sinonasal cancer to be a pooled analysis8 of several high-quality case–control studies that shared the same method of ex- posure assessment. Earlier case–control studies9 combined as a group provided consistent supporting evidence of an association. The potential confounding of the formaldehyde–sinonasal-cancer association by wood-dust exposure was ad- equately considered by NTP. 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. Stewart, R.B. Hayes, and A. Blair. 2004. Mortality from solid cancers among workers in formaldehyde industries. Am. J. Epidemiol. 159(12):1117-1130. 7 Roush, G.C., J. Walrath, L.T. Stayner, S.A. Kaplan, J.T. Flannery, and A. Blair. 1987. Nasopharyngeal cancer, sinonasal cancer, and occupations related to formaldehyde: A case-control study. J. Natl. Cancer Inst. 79(6):1221-1224; West, S., A. Hildesheim, and M. Dosemerci. 1993. Non-viral risk factors for nasopharyngeal carcinoma in the Philip- pines: Results from a case-control study. Int. J. Cancer 55(5):722-727; Hildesheim, A., M. Dosemeci, C.C. Chan, C.J. Chen, Y.J. Cheng, M.M. Hsu, I.H. Chen, B.F. Mittl, B. Sun, P.H. Levine, J.Y. Chen, L.A. Brinton, and C.S. Yang. 2001. Occupational exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal carcinoma. Cancer Epi- demiol. Biomarkers Prev. 10(11):1145-1153. 8 Luce, D., A. Leclerc, D. Begin, P.A. Demers, M. Gerin, E. Orlowski, M. Kogevinas, S. Belli, I. Bugel, U. Bolm-Audorff, L.A., Brinton, P. Comba, L. Hardell, R.B. Hayes, C. Magnani, E. Merler, S. Preston-Martin, T.L. Vaughan, W. Zheng, and P. Boffetta. 2002. Sinonasal cancer and occupational exposures: A pooled analysis of 12 case-control stud- ies. Cancer Causes Control 13(2):147-157. 9 Olsen, J.H., S.P. Jensen, M. Hink, K. Faurbo, N.O. Breum, and O.M. Jensen. 1984. Occupational formaldehyde exposure and increased nasal cancer risk in man. Int. J. Can- cer 34(5):639-644; Hayes, R.B., J.W. Raatgever, A. de Bruyn, and M. Gerin. 1986. Can- cer of the nasal cavity and paranasal sinuses, and formaldehyde exposure. Int. J. Cancer 37(4):487-492; Olsen, J.H., and S. Asnaes. 1986. Formaldehyde and the risk of squamous cell carcinoma of the sinonasal cavities. Br. J. Ind. Med. 43(11):769-774; Roush, G.C., J. Walrath, L.T. Stayner, S.A. Kaplan, J.T. Flannery, and A. Blair. 1987. Nasopharyngeal cancer, sinonasal cancer, and occupations related to formaldehyde: A case-control study. J. Natl. Cancer Inst. 79(6):1221-1224; Luce, D., M. Gerin, A. Leclerc, J.F. Morcet, J. Brugere, and M. Goldberg. 1993. Sinonasal cancer and occupational exposure to formal- dehyde and other substances. Int. J. Cancer. 53(2):224-231. 10 Beane Freeman, L.E., A. Blair, J.H. Lubin, P.A. Stewart, R.B. Hayes, R.N. Hoover, and M. Hauptmann. 2009. Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries: The National Cancer Institute Cohort. J. Natl. Can- cer Inst. 101(10):751-761. 

Summary 9 NIOSH garment workers cohort,11 the cohort of chemical workers in six British factories,12 and the NCI nested case–control study of embalmers.13 The commit- tee agrees with NTP’s assessment that the evidence for cancer at other sites is insufficient at this time and does not rise to the level of limited evidence of a carcinogenic effect in humans. Cancer in Experimental Animals The section “Cancer Studies in Experimental Animals” in NTP’s sub- stance profile for formaldehyde discusses the degree of certainty of the carcino- genicity of formaldehyde on the basis of evidence from experimental animal studies. 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. One component was met because there is evidence in animals of increased incidence of malignant tumors or of a combination of malignant and benign tumors in multiple species (several studies in rats and mice) and multiple tissue types (malignancies of the nasal epithelium and gastrointestinal tract). A second component was met because there is evidence in animals of increased incidence of malignant tumors or of a combination of malignant and benign tumors after exposure by multiple routes (inhalation and oral routes). The committee agrees with NTP’s overall conclusions. Studies on Mechanisms of Carcinogenesis The section “Studies on Mechanisms of Carcinogenesis” in the substance profile for formaldehyde and the associated sections in the background docu- ment describe the scientific evidence and mechanistic knowledge available con- cerning the carcinogenicity of formaldehyde. NTP focused on the mechanisms related to specific clinical sites of cancers, specifically, nasopharyngeal, sinona- sal, and lymphohematopoietic cancers. The committee finds that delineation of 11 Pinkerton, L.E., M.J. Hein, and L.T. Stayner. 2004. Mortality among a cohort of gar- ment workers exposed to formaldehyde: An update. Occup. Environ. Med. 61(3):193-200. 12 Coggon, D., E.C. Harris, J. Poole, and K.T. Palmer. 2003. Extended follow-up of a cohort of British chemical workers exposed to formaldehyde. J. Natl. Cancer Inst. 95(21):1608-1615. 13 Hauptmann, M., P.A. Stewart, J.H. Lubin, L.E. Beane Freeman, R.W. Hornung, R.F. Herrick, R.N Hoover, J.F. Fraumeni Jr., A. Blair, and R.B. Hayes. 2009. Mortality from lymphohematopoietic malignancies and brain cancer among embalmers exposed to for- maldehyde. J. Natl. Cancer Inst. 101(24):1696-1708. 

10 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens the available mechanistic evidence into portal-of-entry or systemic effects14 would have made the background document and the substance profile stronger because the mechanisms of carcinogenicity of highly reactive chemicals, includ- ing formaldehyde, can differ between portal-of-entry sites and distal sites that their native forms or metabolites might not readily reach. However, the commit- tee found that such changes of presentation would not affect NTP’s overall con- clusions in the substance profile for formaldehyde. The committee concludes that NTP correctly stated in the substance pro- file that “the mechanisms by which formaldehyde causes cancer are not com- pletely understood.” There may be several mechanisms of action involved, and the mechanisms proposed by NTP are not mutually exclusive and might be re- lated. Cytotoxicity-induced cellular-proliferation and genotoxicity are two mechanisms that are supported by available evidence in sinonasal and nasopha- ryngeal regions where inhaled formaldehyde first comes into contact with the mucous layer of the respiratory tract in mammals. Mechanistic evidence of car- cinogenicity at distal sites is more uncertain. The substance profile for formal- dehyde acknowledges that there is little evidence that formaldehyde or its me- tabolites would reach systemic circulation or tissues other than those in direct contact with the agent. Given the uncertainties in the scientific understanding of the potential mechanisms of the systemic effects of formaldehyde, the commit- tee 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 leu- kemia.”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 con- sistent and balanced. The substance profile appropriately cites studies showing positive associations that support the listing. However, the substance profile 14 Portal-of-entry effects are effects that arise from direct interaction of inhaled or in- gested formaldehyde with the affected cells or tissues. Systemic effects are effects that occur beyond tissues or cells at the portal of entry. 15 McMartin, K.E., F. Akbar-Khanzadeh, G.A. Boorman, A. DeRoos, P. Demers, L. Peterson, S.M. Rappaport, D.B. Richardson, W.T. Sanderson, and M.S. Sandy. 2009. Part B – Recommendation for Listing Status for Formaldehyde and Scientific Justification for the Recommendation. Formaldehyde Expert Panel Report [online]. Available: http://ntp. niehs.nih.gov/ntp/roc/twelfth/2009/November/FA_PartB.pdf. 

Summary 11 would be more complete if it included more discussion on why weaker, unin- formative, inconsistent, or conflicting evidence did not alter NTP’s conclusions. Although the committee identified that as a limitation in the substance profile, it would not likely alter NTP’s final conclusions as presented in the substance pro- file for formaldehyde. 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 sup- porting 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. INDEPENDENT ASSESSMENT OF FORMALDEHYDE The second part of the committee’s task was to conduct an independent assessment of formaldehyde. The committee started with the review it undertook in the first part of its task and the background document that supports the for- maldehyde profile in the 12th RoC. It searched for additional peer-reviewed literature that has been published by November 8, 2013, and incorporated rele- vant human, experimental animal, and mechanistic studies into the independent assessment. The cut-off date for the literature search was chosen to allow the committee time to review the literature within the time constraints of the project schedule. Details of the committee’s search strategy, exclusion criteria, and cor- responding literature trees are provided in Appendix D of this report. The com- mittee focused its attention on literature that contained primary data, but it also examined published review articles and reviews by other authoritative bodies to ensure that all plausible interpretations of primary data were considered. The committee considered comments presented to it during its first meeting, com- ments and documents received from other sources during the study process, and independent literature searches carried out by National Research Council staff. The RoC listing criteria places an emphasis on evidence of carcinogenicity in animals or humans for a listing of “reasonably anticipated to be a human car- cinogen”, and it places an emphasis specifically on evidence in human studies for a listing of “known to be a human carcinogen”. For that reason, the commit- tee’s independent assessment includes a detailed discussion of its approach for evaluating the epidemiology literature. The committee’s judgment about the strength of a study depended on both the epidemiologic design elements and the exposure assessment dimensions. Particular attention was paid to the choice of summary measures of exposure. Ideally, an epidemiologist chooses the appropriate measure to summarize expo- sure data on the basis of an understanding or hypothesis about the pharmacoki- netics and pharmacodynamics of the exposure-to-dose and dose-to-response processes. The investigators studying the association between formaldehyde and 

12 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens cancer have little information on which to base that choice. In practice, there- fore, it is common and appropriate to test the associations by using several dif- ferent summary measures, including cumulative exposure, average exposure, duration of exposure, and peak exposure. It is expected that, on average, choos- ing the wrong metric will result in an underestimation of an association if one exists—that is, it is not expected that choosing the wrong summary measure of exposure will falsely create evidence of an association where one does not exist except by chance. Another factor that complicates the assessment of risks by alternative met- rics is the imprecision and other limitations of the exposure-intensity data on which the summary measures are based. Those data are often only approxima- tions and are likely to have substantial uncertainty. That makes it even more difficult to assert with confidence that one summary measure is more likely than another to be “correct”. For those reasons, the committee looked at the measures of association between cancer risk and all the available summary measures pre- sented in each study rather than choosing or preferring one a priori. Further- more, patterns in disease associations and associated confidence intervals from smaller studies that did not reach traditional significance (that is, a p value less than 0.05 and the exclusion of 1.0 from the 95% CI) were not discarded in the committee’s evaluation of the literature; they were weighed as weaker but still relevant evidence of consistency in the results. The committee reviewed the available literature on the topic of which ex- posure metrics are more appropriate for environmental and occupational cancer studies. There is a long history of using cumulative exposure (the product of average intensity and exposure duration) as the summary measure of exposure. Cumulative exposure tends to be proportional to disease risk and loss of function for nonmalignant respiratory diseases caused by dusts, such as coal dust, silica, and asbestos. Possibly because of that consistency, cumulative exposure has often been used as the summary measure of exposure for other exposures and other diseases, including cancer. 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 expo- sure 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. and R. Peto. 1978. Cigarette smoking and brochial carcinoma: dose and time relationships among regular smokes and lifelong non-smokers. J. Epideol. Community Health. 32(4):303-313. 17 Peto, J., H. Seidman, I.J. Selikoff. 1982. Mesothelioma mortality in asbestos workers: implications for models of carcinogenesis and risk assessment. Br. J. Cancer 45(1):124-135. 18 Zeka, A. 2011. The two-stage clonal expansion model in occupational cancer epi- demiology: results from three cohort studies. Occ. Env. Med. 68:618-624. 

Summary 13 Although it is unclear whether those examples apply to formaldehyde or wheth- er formaldehyde’s carcinogenic effects on nasal or bone marrow cells would be expected to show similar exposure–response dynamics, the committee conclud- ed that there was no compelling reason to prefer findings for one of the standard exposure metrics mentioned above over another. Summary of Evidence for the Committee’s Independent Assessment The statement of task specifically asked the committee to “integrate the level-of-evidence conclusions, and considering all relevant information in ac- cordance with the RoC listing criteria, make an independent listing recommen- dation for formaldehyde and provide scientific justification for its recommenda- tion” (Appendix B). The committee notes that the term integrate does not have a standard definition in the context of hazard assessment. The committee under- stood the term in its conventional sense of bringing together parts into a whole. To be listed as “reasonably anticipated as a human carcinogen” or “known to be a human carcinogen”, the RoC listing criteria only requires information to be integrated across human studies or across animal studies, and supporting infor- mation can be derived from mechanistic studies. Mechanistic information “can be useful for evaluating whether a relevant cancer mechanism is operating in people”,20 but a known mechanism is not required for a substance to be listed in the RoC. In the subsections below, the committee summarizes human, experi- mental-animal, and mechanistic information on nasopharyngeal and sinonasal cancer and myeloid leukemia. 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. On the basis of evidence of an association between nasopharyngeal cancer and exposure to formaldehyde in two strong studies—a 19 Richardson, D.B., C. Terschuren, and W. Hoffmann. 2008. Occupational risk factors for non-Hodgkin's lymphoma: A population-based case-control study in Northern Ger- many. Am. J. Ind. Med. 51(4):258-268. 20 NTP (National Toxicology Program). 2010. Report on Carcinogens Background Document for Formaldehyde, January 22, 2010. 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/2009/November/Formal dehyde_BD_Final.pdf. 

14 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens large case-control study21 and a large cohort study22—and other supporting stud- ies that were judged to be moderately strong,23 the committee concludes that the relationship is causal and chance, bias, and confounding factors can be ruled out with reasonable confidence. For sinonasal cancer, there is evidence of an associ- ation based on a strong, well-conducted pooled case–control study (which used pooled data from 12 separate case–control studies)24 and other, corroborating studies that were judged to be moderately strong.25 The committee concludes that the relationship between formaldehyde and sinonasal cancer is causal and 21 Vaughan, T.L., P.A. Stewart, K. Teschke, C.F. Lynch, G.M. Swanson, J.L. Lyon, and M. Berwick. 2000. Occupational exposure to formaldehyde and wood dust and naso- pharyngeal carcinoma. Occup. Environ. Med. 57(6):376-384. 22 Beane Freeman, L.E., A. Blair, J.H. Lubin, P.A. Stewart, R.B. Hayes, R.N. Hoover, and M. Hauptmann. 2013. Mortality from solid tumors among workers in formaldehyde industries: An update of the NCI cohort. Am. J. Ind. Med. 56(9):1015-1026. 23 Vaughan, T.L., C. Strader, S. Davis, and J.R. Daling. 1986a. Formaldehyde and can- cers of the pharynx, sinus and nasal cavity: I. Occupational exposures. Int. J. Cancer 38(5):677-683; Vaughan, T.L., C. Strader, S. Davis, and J.R. Daling. 1986b. Formalde- hyde and cancers of the pharynx, sinus and nasal cavity: II. Residential exposures. Int. J. Cancer 38(5):685-688; West, S., A. Hildesheim, and M. Dosemerci. 1993. Non-viral risk factors for nasopharyngeal carcinoma in the Philippines: Results from a case-control study. Int. J. Cancer 55(5):722-727; Hildesheim, A., M. Dosemeci, C.C. Chan, C.J. Chen, Y.J. Cheng, M.M. Hsu, I.H. Chen, B.F. Mittl, B. Sun, P.H. Levine, J.Y. Chen, L.A. Brin- ton, and C.S. Yang. 2001. Occupational exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal carcinoma. Cancer Epidemiol. Biomarkers Prev. 10(11):1145- 1153; Siew, S.S., T. Kauppinen, P. Kyyronen, P. Heikkila, and E. Pukkala. 2012. Occu- pational exposure to wood dust and formaldehyde and risk of nasal, nasopharyngeal, and lung cancer among Finnish men. Cancer. Manag. Res. 4:223-232. 24 Luce, D., A. Leclerc, D. Begin, P.A. Demers, M. Gerin, E. Orlowski, M. Kogevinas, S. Belli, I. Bugel, U. Bolm-Audorff, L.A., Brinton, P. Comba, L. Hardell, R.B. Hayes, C. Magnani, E. Merler, S. Preston-Martin, T.L. Vaughan, W. Zheng, and P. Boffetta. 2002. Sinonasal cancer and occupational exposures: A pooled analysis of 12 case-control stud- ies. Cancer Causes Control 13(2):147-157. 25 Hayes, R.B., J.W. Raatgever, A. de Bruyn, and M. Gerin. 1986. Cancer of the nasal cavity and paranasal sinuses, and formaldehyde exposure. Int. J. Cancer 37(4):487-492; Olsen, J.H., and S. Asnaes. 1986. Formaldehyde and the risk of squamous cell carcinoma of the sinonasal cavities. Br. J. Ind. Med. 43(11):769-774; Vaughan, T.L., C. Strader, S. Davis, and J.R. Daling. 1986a. Formaldehyde and cancers of the pharynx, sinus and nasal cavity: I. Occupational exposures. Int. J. Cancer 38(5):677-683; Vaughan, T.L., C. Strad- er, S. Davis, and J.R. Daling. 1986b. Formaldehyde and cancers of the pharynx, sinus and nasal cavity: II. Residential exposures. Int. J. Cancer 38(5):685-688; Luce, D., M. Gerin, A. Leclerc, J.F. Morcet, J. Brugere, and M. Goldberg. 1993. Sinonasal cancer and occu- pational exposure to formaldehyde and other substances. Int. J. Cancer. 53(2):224-231; Siew, S.S., T. Kauppinen, P. Kyyronen, P. Heikkila, and E. Pukkala. 2012. Occupational exposure to wood dust and formaldehyde and risk of nasal, nasopharyngeal, and lung cancer among Finnish men. Cancer. Manag. Res. 4:223-232. 

Summary 15 chance, bias, and confounding factors can be ruled out with reasonable confi- dence. Several well-conducted studies in experimental animal models demon- strate an increase in nasal squamous cell-carcinoma after inhalation exposure to formaldehyde. Two of the studies used F344 rats,26 and one used Sprague Daw- ley 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 experimental- animal 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 in- creases formaldehyde to above the total endogenous concentration in tissues at the portal of entry in both animal and human studies. There is experimental evi- dence that, due to its chemical reactivity, formaldehyde exerts genotoxic and mutagenic effects and cytotoxicity followed by compensatory cell proliferation at the portal of entry in animals and humans exposed to formaldehyde; this pro- vides biologic plausibility of a relationship between formaldehyde exposure and cancer. The evidence on formaldehyde-associated DNA adducts, DNA–protein cross-links, DNA strand breaks, mutations, micronuclei, and chromosomal aber- rations is consistent, strong, and specific. In addition, both temporal and expo- sure–response relationships have been established, most strongly in studies of rodents and nonhuman primates. 26 Kerns, W.D., K.L. Pavkov, D.J. Donofrio, E.J. Gralla, and J.A. Swenberg. 1983. Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res. 43(9):4382-4392; Monticello, T.M., J.A. Swenberg, E.A. Gross, J.R. Lein- inger, J.S. Kimbell, S. Seilkop, T.B. Starr, J.E. Gibson, and K.T. Morgan. 1996. Correla- tion of regional and nonlinear formaldehyde-induced nasal cancer with proliferating pop- ulations of cells. Cancer Res. 56(5):1012-1022. 27 Sellakumar, A.R., C.A. Snyder, J.J. Solomon, and R.E. Albert. 1985. Carcinogenici- ty of formaldehyde and hydrogen chloride in rats. Toxicol. Appl. Pharmacol. 81(3 Pt 1):401-406. 28 Feron, V.J., J.P. Bruyntjes, R.A. Woutersen, H.R. Immel, and L.M. Appelman. 1988. Nasal tymours in rats after short-term exposure to a cytotoxic concentration of formaldehyde. Cancer Lett. 39(1):101-111; Soffritti, M., C. Maltoni, F. Maffei, and R. Biagi. 1989. Formaldehyde: An experimental multipotential carcinogen. Toxicol. Ind. Health 5(5):699-730; Woutersen, R.A., A. van Garderen-Hoetmer, J.P. Bruijntjes, A. Zwart, and V.J. Feron. 1989. Nasal tumors in rats after severe injury to the nasal mucosa and prolonged exposure to 10ppm formaldehyde. J. Appl. Toxicol. 9(1):39-46; Kamata, E., M. Nakadate, O. Uchida, Y. Ogawa, S. Suzuki, T. Kaneko, M. Saito, and Y. Juroka- wa. 1997. Results of a 28-month chronic inhalation toxicity study of formaldehyde in male Fisher-344 rats. J. Toxicol. Sci. 22(3):239-254. 29 Kerns, W.D., K.L. Pavkov, D.J. Donofrio, E.J. Gralla, and J.A. Swenberg. 1983. Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res. 43(9):4382-4392. 

16 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens Myeloid Leukemia The committee found clear and convincing epidemiologic evidence of an association between formaldehyde exposure and myeloid leukemia. There may also be an increase of other lymphohematopoietic cancers, although the evi- dence is less robust. 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. Chance, bias, and confounding factors can be ruled out with reasonable confidence given the consistent pattern of association in the larger studies that had good exposure assessment. Although multiple lines of reasoning and experimental evidence indicate that it is unlikely that inhalation exposure to formaldehyde will increase formal- dehyde to substantially above endogenous concentrations in tissues distant from the site of entry, there is a robust database of experimental studies of systemic mechanistic events that have been observed after exposure to formaldehyde (as discussed in detail in the section “Mechanisms of Carcinogenesis” of Chapter 3). The committee notes that it is plausible that some of the systemic effects, nota- bly findings of genotoxicity and transcriptional changes in circulating blood cells, may have resulted from the exposure of the cells at the portal of entry (for example, lymphoid tissue in the nasal mucosa). The mechanistic events that were considered by the committee to be relevant to the plausibility of formalde- hyde-associated tumors beyond the portal of entry included genotoxicity and mutagenicity, hematologic effects, and effects on gene expression. Overall, in mechanistic studies of experimental animals and exposed humans, the evidence 30 Beane Freeman, L.E., A. Blair, J.H. Lubin, P.A. Stewart, R.B. Hayes, R.N. Hoover, and M. Hauptmann. 2009. Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries: The National Cancer Institute Cohort. J. Natl. Can- cer Inst. 101(10):751-761. 31 Meyers, A.R., L.E. Pinkerton, and M.J. Hein. 2013. Cohort mortality study of gar- ment industry workers exposed to formaldehyde: update and internal comparisons. A. J. Ind. Med. 56:1027-1039. 32 Hauptmann, M., P.A. Stewart, J.H. Lubin, L.E. Beane Freeman, R.W. Hornung, R.F. Herrick, R.N Hoover, J.F. Fraumeni Jr., A. Blair, and R.B. Hayes. 2009. Mortality from lymphohematopoietic malignancies and brain cancer among embalmers exposed to for- maldehyde. J. Natl. Cancer Inst. 101(24):1696-1708. 33 Walrath, J., and J.F. Fraumeni, Jr. 1983. Mortality patterns among embalmers. Int. J. Cancer 31(4):407-411; Walrath, J., and J.F. Fraumeni, Jr. 1984. Cancer and other causes of death among embalmers. Cancer Res. 44(10):4638-4641; Stroup, N.E., A. Blair, and G.E. Erikson. 1986. Brain cancer and other causes of death in anatomists. J. Natl. Cancer Inst. 77(6):1217-1224; Coggon, D., G. Ntani, E.C. Harris, and K.T. Palmer. 2014. Upper airway cancer, myeloid leukemia, and other cancers in a cohort of British chemical work- ers exposed to formaldehyde. Am. J. Epidemiol. 179(11):1301-1311. 

Summary 17 is largely consistent and strong. Both temporal and exposure–response relation- ships have been demonstrated in studies of humans and animals exposed to for- maldehyde. 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. The animal cancer bioassay literature provided some information relevant to myeloid leukemia. One drinking water study34 reported a significant increase in lymphohematopoietic cancers following long-term exposure to formaldehyde in drinking water, but there is uncertainty regarding the finding. Of the three inhalation studies that included histopathologic examinations of non–respiratory tract tissues, two did not report leukemia.35 The full laboratory report36 of a third study37 discussed findings of leukemia and lymphoma that were not found to be compound related; however, diffuse multifocal bone marrow hyperplasia was observed in some male and female rats. Although that finding was not a finding of malignancy, it does indicate that long-term inhaled formaldehyde may cause effects in bone marrow. Final Conclusions and Listing Recommendation The committee identified and evaluated relevant, publicly available, peer- reviewed literature on formaldehyde, including attention to literature published between June 10, 2011 (the release date of the substance profile for formalde- hyde in the 12th RoC), and November 8, 2013. The committee applied NTP’s established RoC listing criteria to the scientific evidence on formaldehyde from 34 Soffritti, M. F. Belpoggi, L. Lambertin, M. Lauriola, M. Padovani, and C. Maltoni. 2002. Results of long-term exposreimental studies on the carcinogeneicity of formalde- hyde and acetaldehyde in rats. Ann. N.Y. Acad. Sci. 982:87-105. 35 Sellakumar, A.R., C.A. Snyder, J.J. Solomon, and R.E. Albert. 1985. Carcinogenici- ty of formaldehyde and hydrogen chloride in rats. Toxicol. Appl. Pharmacol. 81(3 Pt 1):401-406; Kamata, E., M. Nakadate, O. Uchida, Y. Ogawa, S. Suzuki, T. Kaneko, M. Saito, and Y. Jurokawa. 1997. Results of a 28-month chronic inhalation toxicity study of formaldehyde in male Fisher-344 rats. J. Toxicol. Sci. 22(3):239-254. 36 Battelle. 1981. Final Report on a Chronic Inhalation Toxicology Study in Rats and Mice Exposed to Formaldehyde. Prepared by Battelle Columbus Laboratories, Columbus, OH, for the Chemical Industry Institute of Toxicology (CIIT), Research Triangle Park, NC. CIIT Docket No. 10922. 37 Kerns, W.D., K.L. Pavkov, D.J. Donofrio, E.J. Gralla, and J.A. Swenberg. 1983. Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res. 43(9):4382-4392. 

18 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens studies of humans, studies of experimental animals, and other studies relevant to mechanisms of carcinogenesis. The type of information needed to meet the criteria for sufficient evidence in experimental animals is clear and transparent, as discussed above. In contrast, the RoC listing criteria do not provide detailed guidance about how evidence should be assembled to meet the requirement of limited evidence or sufficient evidence of carcinogenicity from studies in humans, except to note that limited evidence cannot exclude alternative explanations, such as chance, bias, or con- founding factors, and to note that conclusions should be based on “scientific judgment, with consideration given to all relevant information”.38 To evaluate the epidemiology evidence, the committee used scientific judgment to develop an approach to assessing the epidemiology evidence. The approach included careful review of individual studies, selection of studies that were most informa- tive, and evaluation of informative studies on the basis of the strength, con- sistency, temporality, dose-response, and coherence of the evidence. The committee notes that evidence in experimental animals and a known mechanism of action is not required by the RoC listing criteria in making a list- ing recommendation that a substance is known to be a human carcinogen if the evidence from studies in humans is sufficient and indicates an association be- tween exposure and human cancer. Also, and importantly, the RoC listing crite- ria require an association in only one type of cancer to make the determination. On the basis of the information summarized directly above for nasopharyngeal and sinonasal cancers and for myeloid leukemia, the committee makes its inde- pendent 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 ma- lignant 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.  There is convincing relevant information that formaldehyde induces mechanistic events associated with the development of cancer in humans, spe- cifically genotoxicity and mutagenicity, hematologic effects, and effects on gene expression. 38 NTP (National Toxicology Program). 2010. Report on Carcinogens Background Document for Formaldehyde, January 22, 2010. 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/2009/November/ Formaldehyde_BD_Final.pdf. 

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”.