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

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1 Introduction Many people in the United States are exposed to formaldehyde 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) (NTP 2011a; IARC 2012). Scientists have studied formal- dehyde for decades to determine whether exogenous formaldehyde exposure might be associated with cancer in humans. Much of the focus has been on cancers of the upper respiratory tract because they were thought to be the most biologically plausible (Collins and Lineker 2004). However, there is increasing interest in a potential relationship between formaldehyde exposure and some lymphohemato- poietic cancers (for example, leukemia) (NTP 2010a; IARC 2012). The National Toxicology Program (NTP) first assessed the potential car- cinogenicity of formaldehyde in the late 1970s and early 1980s, and the substance was listed as “reasonably anticipated to be a human carcinogen” in the 2nd Report on Carcinogens (RoC) (NTP 1981). Three decades later, NTP reassessed formal- dehyde and upgraded its listing to “known to be a human carcinogen” in the 12th RoC (NTP 2011a). In 2012, Congress directed the Department of Health and Hu- man Services (DHHS) to contract with the National Academy of Sciences to carry out an independent review of the formaldehyde substance profile in the 12th RoC (112th Congress, 1st Session; Public Law 112-74). This report presents findings and conclusions in response to the congressional request. THE REPORT ON CARCINOGENS NTP is an interagency program involving the National Institutes of Health’s National Institute of Environmental Health Sciences (NIEHS, the administrative lead), the Centers for Disease Control and Prevention’s National Institute for Oc- cupational Safety and Health, and the Food and Drug Administration’s National Center for Toxicological Research. It currently publishes the RoC, which was congressionally mandated in 1978 as part of the Public Health Service Act (Sec- tion 262, Public Law 95-622, Part E). The act directed DHHS to publish an annual report that includes a list of all substances that meet two conditions: a significant number of people living in the United States are exposed and the substance is ei- ther known to be a carcinogen or may reasonably be anticipated to be a carcino- 20 

Introduction 21 gen. The report was also required to include supporting information, such as the nature of exposure and an estimated number of persons exposed. The full congres- sional mandate is in Box 1-1. In 1993, an amendment moved the RoC from an annual to a biennial report (42 US Code 241). Nominations for substances to be added, reclassified, or removed from the RoC can come from anyone, but the submitter must include a rationale and, if possible, background information to support the addition, reclassification, or removal (NTP 2011b). Staff of the Office of the Report on Carcinogens review each submission and decide whether a substance should move forward for fur- ther evaluation. From that point, staff of the office invite partnering agencies to review the substance, solicit public comments through the Federal Register, and develop a brief draft concept document with information on the substance, expo- sure, major relevant issues, and an approach to the cancer-evaluation component of an ROC. After consideration of comments from NTP’s Board of Scientific Counselors and public comments, the NTP director makes the final decision as to whether the substance will be evaluated in an RoC. Each RoC is cumulative and includes substances listed as “known to be a human carcinogen” or “reasonably anticipated to be a human carcinogen” since the 1st RoC in 1980. The 12th RoC contains 240 listings; 54 substances are listed as known human carcinogens and 186 as reasonably anticipated to be human car- cinogens. The criteria that are currently used to guide the establishment of a listing as either known or reasonably anticipated to be a human carcinogen have been in use since the 8th RoC, published in 1998. Box 1-2 provides the specific listing criteria. In preparation for a new RoC, the Office of the Report on Carcinogens creates a background document for each substance, which describes in detail properties, production and use, human exposure, toxicokinetics, cancer studies in humans and animals, and mechanisms of action of cancer induction. The pur- pose of the background document is to describe the strengths, limitations, and overall quality of studies that make up the scientific body of evidence for or against carcinogenicity. For the 12th RoC, background documents for reclassi- fied or newly listed substances were reviewed by an expert panel, and the panel was asked to recommend a listing status for each substance in accordance with the RoC listing criteria (see Figure 1-1 for a depiction of the 12th RoC process). An Interagency Scientific Review Group and an NIEHS–NTP Scientific Review Group were also asked to review each background document and to recommend a listing status. A corresponding draft substance profile was then prepared by NTP on the basis of the background document, the aforementioned reviews, and the listing recommendations, and the draft profile was reviewed by the NTP Board of Scientific Counselors. Public comments were solicited at multiple stages in the process. At the end of the process, the profiles of all 240 substances were compiled into a draft RoC that was submitted to the NTP director for re- 

22 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens view; to the NTP Executive Committee1 for consultation, review, and comment; to the NTP director again for final approval; and finally to the secretary of health and human services for review, approval, and transmittal to Congress. The 12th RoC was published on June 10, 2011. BOX 1-1 Congressional Language Mandating the Report on Carcinogens A. a list of all substances i. which either are known to be carcinogens or may reasonably be antici- pated to be carcinogens and ii. to which a significant number of persons residing in the United States are exposed; B. information concerning the nature of such exposure and the estimated number of persons exposed to such substances; C. a statement identifying i. each substance contained in the list under subparagraph (A) for which no effluent, ambient, or exposure standard has been established by a Federal agency, and ii. for each effluent, ambient, or exposure standard established by a Fed- eral agency with respect to a substance contained in the list under sub- paragraph (A), the extent to which, on the basis of available medical, scientific, or other data, such standard, and the implementation of such standard by the agency, decreases the risk to public health from expo- sure to the substance; and D. a description of i. each request received during the year involved I. from a Federal agency outside the Department of Health, Education, and Welfare for the Secretary, or II. from an entity within the Department of Health, Education, and Welfare to any other entity within the Department, to conduct research into, or testing for, the carcinogenicity of substances or to provide information described in clause (ii) of subparagraph (C), and ii. how the Secretary and each such other entity, respectively, have re- sponded to each such request. Source: Section 262, Public Law 95-622, Part E (pp. 3435-3436). 1 The NTP Executive Committee is made up of the heads of the Consumer Product Safety Commission, the Department of Defense, the Environmental Protection Agency, the Food and Drug Administration, the National Cancer Institute, the National Center for Environmental Health, the Agency for Toxic Substances and Disease Registry, the Na- tional Institute of Environmental Health Sciences, the National Institute for Occupational Safety and Health, and the Occupational Safety and Health Administration. The commit- tee gives programmatic and policy advice to the NTP director. 

Introduction 23 BOX 1-2 Listing Criteria for the Report on Carcinogens Known To Be Human Carcinogen: 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. Reasonably Anticipated To Be Human Carcinogen: There is limited evidence of carcinogenicity from studies in humans,* which indi- cates that causal interpretation is credible, but that alternative explanations, such as chance, bias, or confounding factors, could not adequately be excluded, or there is sufficient evidence of carcinogenicity from studies in experimental an- imals, which indicates there is an increased incidence of malignant and/or a combination of malignant and benign tumors (1) in multiple species or at multi- ple tissue sites, or (2) by multiple routes of exposure, or (3) to an unusual de- gree with regard to incidence, site, or type of tumor, or age at onset, or 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 previ- ous Report on Carcinogens as either known to be a human carcinogen or rea- sonably 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. Conclusions regarding carcinogenicity in humans or experimental animals are based on scientific judgment, with consideration given to all relevant infor- mation. Relevant information includes, but is not limited to, dose response, route of exposure, chemical structure, metabolism, pharmacokinetics, sensi- tive sub-populations, genetic effects, or other data relating to mechanism of action or factors that may be unique to a given substance. For example, there may be substances for which there is evidence of carcinogenicity in laboratory animals, but there are compelling data indicating that the agent acts through mechanisms which do not operate in humans and would therefore not reason- ably be anticipated to cause cancer in humans. *This evidence can include traditional cancer epidemiology studies, data from clinical studies, and/or data derived from the study of tissues or cells from hu- mans exposed to the substance in question, which can be useful for evaluating whether a relevant cancer mechanism is operating in humans. Source: NTP 2010a, p. iv. 

24 FIGURE 1-1 Schematic of the review process for the 12th Report on Carcinogens. Source: NTP 2011b. 

Introduction 25 FORMALDEHYDE AND THE REPORT ON CARCINOGENS One substance profile in the 12th RoC that has drawn science, policy, and news-media attention is that of formaldehyde (Risk Policy Report 2011a,b; Kris- tof 2012). Formaldehyde is a colorless gas at room temperature with a pungent smell, has a simple chemical structure, and is one of the most reactive aldehydes (NTP 2010a). It is an economically important chemical in the United States— ranking 25th in overall chemical production—and products that contain formal- dehyde account for more than 5% of the annual US gross domestic product (Zhang et al. 2009). The most common use of formaldehyde is in the production of synthetic resins, such as urea– and phenol–formaldehyde resins, that are used as adhesives in particleboard, fiberboard, and plywood. Formaldehyde is also used in textiles to make materials creaseproof, crushproof, flame-resistant, and shrinkproof; to mold plastic parts for automobiles, home appliances, hardware, garden equipment, and sporting equipment; to preserve dried food, fish, oils, and fats; to disinfect containers in the food industry; and, in agriculture, as a pre- servative, fumigant, germicide, fungicide, and insecticide. In a smaller market, formaldehyde is used in medicines to modify and reduce the toxicity of viruses, venoms, and irritating pollens (ATSDR 1999; NTP 2010a). Characterizing exposure to formaldehyde and linking exposure to disease are complicated by the many possible sources of exposure, both environmental and occupational. Epidemiologic studies undertaken to understand the potential linkage are sometimes confounded by exposures to other agents known to cause disease, such as cigarette smoke or wood-dust particles. An additional complexi- ty is the fact that formaldehyde is produced naturally in humans and other ani- mals (IARC 2006; NTP 2010a). The chemical “is an essential metabolic inter- mediate in all cells and is produced endogenously from serine, glycine, ethionine, and choline, and from the demethylation of N-, O-, S-, methyl com- pounds” (NTP 2010a, p.14). Formaldehyde was first listed in the 2nd RoC (1981) as reasonably antici- pated to be a human carcinogen. However, it was nominated for possible reclas- sification by NIEHS on the basis of the International Agency for Research on Cancer (IARC) review of the substance in 2004 (NTP 2007). IARC has re- viewed formaldehyde several times, concluding with increasing certainty that formaldehyde causes cancer in humans. In 1982, it was classified as “possibly carcinogenic to humans” (IARC 1982); in 1987 and 1995, it was classified as “probably carcinogenic to humans” (IARC 1987, 1995); and in 2006, IARC “concluded that there was sufficient evidence for the carcinogenicity of formal- dehyde in humans” (IARC 2006). IARC again listed formaldehyde as carcino- genic to humans in another recent review (IARC 2012). Formaldehyde was accepted by NTP for review and possible reclassifica- tion, and it was reviewed according to established NTP policies and procedures. NTP released a final background document for the assessment of formaldehyde in January 2010, and the substance profile for formaldehyde was published in June 2011 as part of the 12th RoC. In the 12th RoC, formaldehyde was listed as 

26 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens known to be a human carcinogen on the basis of the listing criteria described in Box 1-2 and the supporting information provided in the background document (NTP 2010a, 2011a). THE COMMITTEE’S TASK Congress directed DHHS to arrange for the National Academy of Sciences to conduct an independent scientific peer review of the 12th Report on Carcino- gens determinations related to formaldehyde and styrene. The request was made in 2012 as part of the Consolidated Appropriations Act (112th Congress, 1st Session; Public Law 112-74). In response, the National Research Council con- vened the Committee to Review the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens, which wrote the present re- port. The committee included experts in epidemiology, exposure assessment, toxicology, toxicokinetic modeling, and mechanisms of carcinogenesis (see Ap- pendix A for biographic information on the committee). The committee’s Statement of Task is presented in Appendix B. The com- mittee was asked to conduct a peer review of the formaldehyde assessment in the 12th RoC. As part of that review, it was asked to identify and evaluate relevant peer-reviewed scientific literature, with emphasis on literature that had been pub- lished by June 10, 2011, the release date of the 12th RoC. The committee was also asked to undertake an independent assessment of formaldehyde, which was to include documentation of its decisions related to inclusion or exclusion of litera- ture, identification of critical studies and information, application of the RoC list- ing criteria to the scientific evidence, and making independent level-of-evidence determinations with respect to the human and animal studies. Considering all rele- vant information in accordance with the RoC listing criteria, the committee was asked to make an independent listing recommendation for formaldehyde and pro- vide scientific justification for the recommendation. The committee’s listing rec- ommendation is based on “scientific judgment, with consideration given to all relevant information”, as instructed in the RoC listing criteria. THE COMMITTEE’S APPROACH In writing its report, the committee reviewed documents pertaining to formaldehyde that were written for or by NTP in preparation for the 12th RoC (see Table 1-1). It considered presentations heard during its open-session meet- ing, comments submitted from the general public,2 and abstracts presented dur- ing recent conferences. It reviewed reports published by other authoritative bod- ies, and it examined primary literature, reviews, and meta-analyses that were 2 A list and copies of materials submitted from the general public can be obtained by contacting the National Academies Public Access Records Office. 

TABLE 1-1 Documents Pertaining to Formaldehyde That Were Available to or Written by NTP Document Brief Description Reference Substance profile for formaldehyde The substance profile as presented in the 12th RoC NTP 2011a Background document for Background information that was prepared by staff in the Office of the RoC to support NTP’s NTP 2010a formaldehyde assessment of formaldehyde Primary literature Primary literature cited in the background document or obtained from other sources — Expert panel reports Reports of an expert panel charged with doing a peer review of the draft background document on McMartin et al. formaldehyde and making a recommendation for listing status in the 12th RoC 2009, 2010 NTP Executive Committee The interagency scientific review group that reviewed the body of literature on formaldehyde and NTP 2010b Interagency Scientific Review made a recommendation for the listing of formaldehyde in the 12th RoC Group (ISRG) Report National Institute of Environmental The NIEHS–NTP scientific review group that reviewed the body of literature on formaldehyde and NTP 2010c Health Sciences (NIEHS)–NTP made a recommendation for the listing of formaldehyde in the 12th RoC Scientific Review Group Report Minutes from the Board of Report of BSC’s assessment of whether the scientific information in the draft substance profile is NTP 2010d Scientific Counselors (BSC) technically correct, is clearly stated, and supports NTP’s preliminary listing of formaldehyde in the Meeting 12th RoC NTP’s response to the expert panel NTP’s review of and response to expert panel reports NTP 2011c, 2011d reports and to BSC Public comments Comments from the public in response to Federal Register notices on October 18, 2005 (Vol. 70, NTP 2011e No. 200), August 31, 2009 (Vol. 74, No. 167), December 21, 2009 (Vol. 74, No. 243), and April 22, 2010 (Vol. 75, No. 77) and additional public comments that were not associated with any Federal Register notices NTP’s response to public comments NTP’s responses to public comments related to specific issues in the expert panel reports that were NTP 2011f applicable to the substance profile (comments on the final background document, the review process, or nontechnical or nonscientific issues were excluded by NTP) 27 

28 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens publicly available in the peer-reviewed literature. The committee was guided by the language and terminology of the RoC listing criteria (see Box 1-2), and it used its own professional judgment for the interpretation of such terms as suffi- cient and limited. The committee worked toward the goal of clearly describing its own methods in writing this report, how it used the language of the listing criteria, and its analysis of the body of evidence related to 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 hazard assessment focuses on the identification of substances that may pose a hazard to human health, and it “makes a classification regarding toxicity, for example, whether a chemical is ‘carcinogenic to humans’ or ‘likely to be’ (EPA 2005)” (NRC 2009, p. 113). A risk assessment3 focuses on the likely degree of damage and requires much more information, including completion of a hazard identifi- cation, dose–response analysis, exposure quantification, and characterization of risk (NRC 1983). The committee thus approached its assessment of formalde- hyde 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 epide- miology studies to inform its assessment of formaldehyde, but it did not identify exposure scenarios that could pose cancer risk as part of a full risk assessment. This Review and the 2011 Draft IRIS Assessment of Formaldehyde The committee examined the National Research Council report, Review of the Environmental Protection Agency’s Draft IRIS [Integrated Risk Information System] Assessment of Formaldehyde (NRC 2011). Although the present report and the 2011 report both focused on formaldehyde, the two committees had dif- ferent statements of task. The Committee to Review EPA’s Draft IRIS Assess- ment of Formaldehyde 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 car- cinogenicity. That committee assessed how well the narrative presented in the draft IRIS assessment supported the IRIS assessment’s conclusions regarding health effects. That committee did not conduct its own literature search, review 3 “Risk assessment is the use of the factual base to define the health effects of exposure of individuals or populations to hazardous materials and situations. . . . Risk assessments contain some or all of the following four steps: Hazard identification: The determination of whether a particular chemical is or is not causally linked to particular health effects. Dose– response assessment: The determination of the relation between the magnitude of exposure and the probability of occurrence of the health effects in question. Exposure assessment: The determination of the extent of human exposure before or after application of regulatory controls. Risk characterization: The description of the nature and often the magnitude of human risk, including attendant uncertainty” (NRC 1983, p. 3). 

Introduction 29 all relevant evidence, systematically formulate its own conclusions regarding causality, or recommend values for the RfC and unit risk. In contrast, the com- mittee that wrote the present report was asked to identify relevant peer-reviewed literature, document its decisions regarding inclusion or exclusion of the litera- ture, apply NTP’s RoC listing criteria, and make an independent listing recom- mendation for formaldehyde (see Appendix B). 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. This Review and Other Ongoing Studies The committee that wrote this report worked in parallel with the Commit- tee to Review the Styrene Assessment in the National Toxicology Program 12th Report on Carcinogens, which was also convened in response to the 2012 Con- solidated Appropriations Act. The two committees’ statements of task were identical except for the specific substance profiles being reviewed, and they met jointly for their first meeting. During the open session of that meeting, the com- mittees heard presentations from and had an open discussion with representa- tives of DHHS and NTP. Several stakeholders also participated in the public session. During the meeting’s closed session, members discussed the open- session presentations by the sponsor and the public and the committees’ ap- proach to their statements of task. The two committees also discussed general approaches to the domains of evidence to be examined (specifically, epidemiol- ogy, experimental animal studies, and mechanistic information). In particular, the committees discussed an approach that considered principles of the Bradford Hill criteria with respect to causality and an approach to make judgments about individual studies and about the overall body of evidence pertaining to exposure to a substance and cancer. No discussions took place between the full commit- tees after that first joint meeting. The membership of the two committees in- cluded three overlapping members who ensured that the committees continued to have compatible approaches to their statements of task. The committee was also cognizant of the ongoing work of the Committee to Review EPA’s IRIS Process (NRC 2014). Part of that committee’s task was to “review current methods for evidence-based reviews and recommend ap- proaches for weighing scientific evidence for chemical hazard and dose– response assessments” (NRC 2014). Because the Committee to Review EPA’s 

30 Review of the Formaldehyde Assessment in the NTP 12th Report on Carcinogens IRIS Process and the present committee wrote their reports concurrently, the methods of the present report could not be informed by the conclusions and rec- ommendations of the other one. However, the final report of the Committee to Review the IRIS Process goes beyond recommendations that are only applicable to the IRIS process. It includes discussions on best practices for systematically weighing and integrating scientific evidence that could be used to inform listing determinations in future editions of the RoC. ORGANIZATION OF THE REPORT The committee approached its statement of task by first conducting a re- view of the substance profile for formaldehyde as presented in the 12th RoC (Chapter 2). It considered literature published by June 10, 2011. Chapter 2 is organized on the basis of the headings and subheadings of the substance profile and concludes with a listing recommendation for formaldehyde that is based on the application of the RoC listing criteria to the evidence in the background doc- ument and substance profile for formaldehyde. The committee then conducted its own independent assessment of the formaldehyde literature (Chapter 3), ex- tending its review to include literature through November 8, 2013, and conclud- ing with its own listing recommendation for formaldehyde. Appendix A presents the biographies of the committee members, and Appendix B reproduces the committee’s statement of task. Appendix C discusses exposure assessment for epidemiologic carcinogenicity studies, Appendix D describes the literature search strategies used to support the evidence presented in Chapter 3, and Ap- pendix E contains summary tables to supplement the genotoxicity and mutagen- icity section of Chapter 3. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 1999. Toxicological Pro- file for Formaldehyde. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp111.pdf [accessed Sept. 23, 2013]. Collins, J.J., and G.A. Lineker. 2004. A review and meta-analysis of formaldehyde expo- sure and leukemia. Regul. Toxicol. Pharmacol. 40(2):81-91. EPA (Environmental Protection Agency). 2005.Guidelines for Carcinogen Risk Assess- ment. EPA/630/P-03/001F. Risk Assessment Forum, U.S. Environmental Protec- tion Agency, Washington, DC. March 2005. IARC (International Agency for Research on Cancer). 1982. Chemicals, Industrial Pro- cesses and Industries Associated with Cancer in Humans: An Updating of IARC Monographs Volumes 1 to 29. IARC Monographs on the Evaluation of the Car- cinogenic Risks to Humans Supplement 4. Lyon, France: IARC [online]. Availa- ble: http://monographs.iarc.fr/ENG/Monographs/suppl4/Suppl4.pdf [accessed June 10, 2013]. 

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