Many people in the United States are exposed to formaldehyde from environmental 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 formaldehyde 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 lymphohematopoietic cancers (for example, leukemia) (NTP 2010a; IARC 2012).
The National Toxicology Program (NTP) first assessed the potential carcinogenicity 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 formaldehyde 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 Human 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.
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 Occupational 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 (Section 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 either known to be a carcinogen or may reasonably be anticipated to be a carcino-
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 congressional 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 further 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, exposure, 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 carcinogens. 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 purpose 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 reclassified 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-
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.
A. a list of all substances
i. which either are known to be carcinogens or may reasonably be anticipated 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;
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 Federal agency with respect to a substance contained in the list under subparagraph (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 exposure to the substance; and
C. a statement identifying
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 responded to each such request.
Source: Section 262, Public Law 95-622, Part E (pp. 3435-3436).
1The 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 National Institute of Environmental Health Sciences, the National Institute for Occupational Safety and Health, and the Occupational Safety and Health Administration. The committee gives programmatic and policy advice to the NTP director.
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 indicates that causal interpretation is credible, but that alternative explanations, such as chance, bias, or confounding factors, could not adequately be excluded,
there is sufficient evidence of carcinogenicity from studies in experimental 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 unusual 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.
Conclusions regarding carcinogenicity in humans or experimental animals are based on scientific judgment, with consideration given to all relevant information. Relevant information includes, but is not limited to, dose response, route of exposure, chemical structure, metabolism, pharmacokinetics, sensitive 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 reasonably 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 humans 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.
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; Kristof 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 formaldehyde 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 preservative, 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 complexity is the fact that formaldehyde is produced naturally in humans and other animals (IARC 2006; NTP 2010a). The chemical “is an essential metabolic intermediate in all cells and is produced endogenously from serine, glycine, ethionine, and choline, and from the demethylation of N-, O-, S-, methyl compounds” (NTP 2010a, p.14).
Formaldehyde was first listed in the 2nd RoC (1981) as reasonably anticipated to be a human carcinogen. However, it was nominated for possible reclassification by NIEHS on the basis of the International Agency for Research on Cancer (IARC) review of the substance in 2004 (NTP 2007). IARC has reviewed 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 formaldehyde in humans” (IARC 2006). IARC again listed formaldehyde as carcinogenic to humans in another recent review (IARC 2012).
Formaldehyde was accepted by NTP for review and possible reclassification, 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
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).
Congress directed DHHS to arrange for the National Academy of Sciences to conduct an independent scientific peer review of the 12th Report on Carcinogens 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 convened the Committee to Review the Formaldehyde Assessment in the National Toxicology Program 12th Report on Carcinogens, which wrote the present report. The committee included experts in epidemiology, exposure assessment, toxicology, toxicokinetic modeling, and mechanisms of carcinogenesis (see Appendix A for biographic information on the committee).
The committee’s Statement of Task is presented in Appendix B. The committee 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 published 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 literature, identification of critical studies and information, application of the RoC listing criteria to the scientific evidence, and making independent level-of-evidence determinations with respect to the human and animal studies. Considering all relevant information in accordance with the RoC listing criteria, the committee was asked to make an independent listing recommendation for formaldehyde and provide scientific justification for the recommendation. The committee’s listing recommendation is based on “scientific judgment, with consideration given to all relevant information”, as instructed in the RoC listing criteria.
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 meeting, comments submitted from the general public,2 and abstracts presented during recent conferences. It reviewed reports published by other authoritative bodies, and it examined primary literature, reviews, and meta-analyses that were
2A list and copies of materials submitted from the general public can be obtained by contacting the National Academies Public Access Records Office.
|Substance profile for formaldehyde||The substance profile as presented in the 12th RoC||NTP 2011a|
|Background document for formaldehyde||Background information that was prepared by staff in the Office of the RoC to support NTP’s assessment of formaldehyde||NTP 2010a|
|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 formaldehyde and making a recommendation for listing status in the 12th RoC||McMartin et al. 2009, 2010|
|NTP Executive Committee Interagency Scientific Review Group (ISRG) Report||The interagency scientific review group that reviewed the body of literature on formaldehyde and made a recommendation for the listing of formaldehyde in the 12th RoC||NTP 2010b|
|National Institute of Environmental Health Sciences (NIEHS)–NTP Scientific Review Group Report||The NIEHS–NTP scientific review group that reviewed the body of literature on formaldehyde and made a recommendation for the listing of formaldehyde in the 12th RoC||NTP 2010c|
|Minutes from the Board of Scientific Counselors (BSC) Meeting||Report of BSC’s assessment of whether the scientific information in the draft substance profile is technically correct, is clearly stated, and supports NTP’s preliminary listing of formaldehyde in the 12th RoC||NTP 2010d|
|NTP’s response to the expert panel reports and to BSC||NTP’s review of and response to expert panel reports||NTP 2011c, 2011d|
|Public comments||Comments from the public in response to Federal Register notices on October 18, 2005 (Vol. 70, 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 2011e|
|NTP’s response to public comments||NTP’s responses to public comments related to specific issues in the expert panel reports that were applicable to the substance profile (comments on the final background document, the review process, or nontechnical or nonscientific issues were excluded by NTP)||NTP 2011f|
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 sufficient 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 identification, dose–response analysis, exposure quantification, and characterization of risk (NRC 1983). 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 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 different statements of task. The Committee to Review EPA’s Draft IRIS Assessment 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 carcinogenicity. 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).
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 (see Appendix B).
The two projects were also different because of inherent differences between EPA’s IRIS assessments and NTP’s RoC. IRIS assessments are comprehensive 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 substances that it classifies as known human carcinogens or reasonably anticipated human 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 Committee to Review the Styrene Assessment in the National Toxicology Program 12th Report on Carcinogens, which was also convened in response to the 2012 Consolidated 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 committees heard presentations from and had an open discussion with representatives 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’ approach to their statements of task. The two committees also discussed general approaches to the domains of evidence to be examined (specifically, epidemiology, 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 committees after that first joint meeting. The membership of the two committees included 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 approaches for weighing scientific evidence for chemical hazard and dose–response assessments” (NRC 2014). Because the Committee to Review EPA’s
IRIS Process and the present committee wrote their reports concurrently, the methods of the present report could not be informed by the conclusions and recommendations 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.
The committee approached its statement of task by first conducting a review 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 document and substance profile for formaldehyde. The committee then conducted its own independent assessment of the formaldehyde literature (Chapter 3), extending its review to include literature through November 8, 2013, and concluding 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 Appendix E contains summary tables to supplement the genotoxicity and mutagenicity section of Chapter 3.
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