Executive Summary: Introduction: Formaldehyde is a high-production-volume chemical with a wide array of uses. The predominant use of formaldehyde in the United States is in the production of industrial resins (mainly urea-formaldehyde, phenol-formaldehyde, polyacetal, and melamine-formaldehyde resins) that are used to manufacture products such as adhesives and binders for wood products, pulp and paper products, plastics, and synthetic fibers, and in textile finishing. Formaldehyde is also used as a chemical intermediate. Resin production and use as a chemical intermediate together account for over 80% of its use. Other, smaller uses of formaldehyde that may be important for potential human exposure include use in agriculture, medical use as a disinfectant and preservative (for pathology, histology, and embalming), and use in numerous consumer products as a biocide and preservative. Formaldehyde (gas) is listed in the Eleventh Report on Carcinogens (RoC) as reasonably anticipated to be a human carcinogen based on limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in laboratory animals (NTP 2005a); it was first listed in the 2nd RoC (NTP 1981). Formaldehyde (all physical forms) was nominated by NIEHS for possible reclassification in the 12th RoC based on the 2004 review by the International Agency for Research on Cancer (IARC 2006), which concluded that there was sufficient evidence for the carcinogenicity of formaldehyde in humans. Human Exposure: Formaldehyde has numerous industrial and commercial uses and is produced in very large amounts (billions of pounds per year in the United States) by catalytic oxidation of methanol. Its predominant use, accounting for roughly 55% of consumption, is in the production of industrial resins, which are used in the production of numerous commercial products. Formaldehyde is used in industrial processes primarily as a solution (formalin) or solid (paraformaldehyde or trioxane), but exposure is frequently to formaldehyde gas, which is released during many of the processes. Formaldehyde gas is also created from the combustion of organic material and can be produced secondarily in air from photochemical reactions involving virtually all classes of hydrocarbon pollutants. In some instances, secondary production may exceed direct air emissions. Formaldehyde is also produced endogenously in humans and animals. Formaldehyde is a simple, one-carbon molecule that is rapidly metabolized, is endogenously produced, and is also formed through the metabolism of many xenobiotic agents. Because of these issues, typical biological indices of exposure, such as levels of formaldehyde or its metabolites in blood or urine, have proven to be ineffective measures of exposure. Formaldehyde can bind covalently to single-stranded DNA and protein to form crosslinks, or with human serum albumin or the N-terminal valine of hemoglobin to form molecular adducts, and these reaction products of formaldehyde might serve as biomarkers for exposure to formaldehyde. Occupational exposure to formaldehyde is highly variable and can occur in numerous industries, including the manufacture of formaldehyde and formaldehyde-based resins, wood-composite and furniture production, plastics production, histology and pathology, embalming and biology laboratories, foundries, fiberglass production, construction, agriculture, and firefighting, among others. In fact, because formaldehyde is ubiquitous, it has been suggested that occupational exposure to formaldehyde occurs in all work places. Formaldehyde is also ubiquitous in the environment and has been detected in indoor and outdoor air; in treated drinking water, bottled drinking water, surface water, and groundwater; on land and in the soil; and in numerous types of food. The primary source of exposure is from inhalation of formaldehyde gas in indoor settings (both residential and occupational); however, formaldehyde also may adsorb to respirable particles, providing a source of additional exposure. Major sources of formaldehyde exposure for the general public have included combustion sources (both indoor and outdoor sources including industrial and automobile emissions, home cooking and heating, and cigarette smoke), off-gassing from numerous construction and home furnishing products, and off-gassing from numerous consumer goods. Ingestion of food and water can also be a significant source of exposure to formaldehyde. Numerous agencies, including the Department of Homeland Security, CPSC, DOT, EPA, FDA, HUD, the Mine Safety and Health Administration, OSHA, ACGIH, and NIOSH, have developed regulations and guidelines to reduce exposure to formaldehyde. Human Cancer Studies: A large number of epidemiological studies have evaluated the relationship between formaldehyde exposure and carcinogenicity in humans. The studies fall into the following main groups: (1) historical cohort studies and nested case-control studies of workers in a variety of industries that manufacture or use formaldehyde, including the chemical, plastics, fiberglass, resins, and woodworking industries, as well as construction, garment, iron foundry, and tannery workers; (2) historical cohort studies and nested case-control studies of health professionals, including physicians, pathologists, anatomists, embalmers, and funeral directors; (3) population-based cohort or cancer registry studies; and (4) population-based or occupationally based case-control incidence or mortality studies of specific cancer endpoints. In addition, several studies have re-analyzed data from specific cohort or case-control studies or have conducted pooled analyses or meta-analyses for specific cancer endpoints. The largest study available to date is the cohort mortality study of combined mixed industries conducted by the National Cancer Institute (NCI). This cohort includes 25,691 male and female workers, enrolled from 10 different formaldehyde-producing or -using plants, employed before 1966 and followed most recently to 1994 and 2004, most of whom were exposed to formaldehyde (Hauptmann et al. 2003, 2004 and Beane Freeman et al. 2009). Quantitative exposure data were used to construct job-exposure matrices for individual workers, some of whom experienced peak exposures to formaldehyde >/= 4 ppm. This cohort is the only study in which exposure-response relationships between peak, average, cumulative, and duration of exposure and mortality for multiple cancer sites were investigated. Two other large cohort studies are available: (1) a large multi-plant cohort study (N = 14,014) of workers in six chemical manufacturing plants in the United Kingdom (Coggon et al. 2003), which calculated SMRs among ever-exposed and highly exposed workers for formaldehyde, and (2) a NIOSH cohort of garment workers (N = 11,039) (Pinkerton et al. 2004) which evaluated mortality for duration of exposure, time since first exposure, and year of first exposure to formaldehyde for selected cancer sites. The other cohort studies (for both industrial and health professional workers) were smaller, and in general only reported mortality or incidence for ever-exposed workers in external (SMR or PMR) analyses, although some of the studies of health professional workers attempted indirect measures of exposure (such as length in a professional membership) as a proxy for exposure duration. Several of the nested case-control studies attempted to evaluate exposure-response relationships, but were limited by small numbers of exposed cases, and many of the population-based case-control studies lacked quantitative data or sufficient numbers of cases to evaluate exposure-response relationships. However, the nested case-control study of lymphohematopoietic, nasopharyngeal, and brain cancers among U.S. embalmers and funeral directors by Hauptmann et al. (2009) had large numbers of exposed cases of lymphohematopoietic cancer and used both questionnaire- and experimental model-based exposure metrics of exposure, including average, cumulative, peak, and duration of exposure, and number of embalmings. [Since most of the cohorts have relatively low statistical power to evaluate rare cancers such as sinonasal and nasopharyngeal cancers, case-control studies are generally more informative for these outcomes.] Findings across studies for cancer sites that have been the principal focus of investigation are summarized below. Sinonasal cancers: In cohort studies, increased risks of sinonasal cancers were observed among male (SPIR = 2.3, 95% CI = 1.3 to 4.0, 13 exposed cases) and female (SPIR = 2.4, 95% CI = 0.6 to 6.0, 4 exposed cases) Danish workers exposed to formaldehyde (Hansen and Olsen 1995, 1996) and among formaldehyde-exposed workers in the NCI cohort (SMR = 1.19, 95% CI = 0.38 to 3.68, 3 deaths) (Hauptmann et al. 2004). One death from squamous-cell sinonasal cancer was reported in the study of tannery workers among formaldehyde-exposed workers by Stern et al. (1987). No increase in risk was found among formaldehyde-exposed workers in the other large cohort studies (Coggon et al. 2003, Pinkerton et al. 2004). The smaller cohort studies did not report findings or did not observe any deaths for this specific endpoint. [Sinonasal cancers are rare, and even the larger cohort studies have insufficient numbers of exposed workers and expected deaths (e.g., approximately three in the NCI cohort) to be very informative.] Of the six case-control studies reviewed, four (Olsen et al. 1984 and Olsen and Asnaes 1986; Hayes et al. 1986; Roush et al. 1987; and Luce et al. 1993) reported an association between sinonasal cancers and formaldehyde exposure; statistically significant risks were found in three studies among individuals ever exposed to formaldehyde or with higher probabilities or levels of exposure (Olsen et al. 1994 and Olsen and Asnaes 1986; Hayes et al. 1986; and Luce et al. 1993). All of these studies found elevated risks among individuals with low or no exposure to wood dust or after adjusting for exposure to wood dust. Stronger associations were found for adenocarcinoma, with higher risks for this endpoint observed among individuals with higher average and cumulative exposure, duration of exposure, and earlier dates of first exposure (Luce et al. 1993). A pooled analysis of 12 case-control studies of sinonasal cancer from seven countries (Luce et al. 2002) found statistically significant increases in adenocarcinoma among subjects in the highest exposure groups (OR = 3.0, 95% CI = 1.5 to 5.7, 91 exposed cases for men, adjusted for wood dust exposure; and OR = 6.2, 95% CI = 2.0 to 19.7, 5 exposed cases for women, unadjusted for wood dust exposure). For squamous-cell carcinoma, the corresponding ORs were 1.2 (95% CI = 0.8 to 1.8, 30 exposed cases) for men and 1.5 (95% CI = 0.6 to 3.8, 6 exposed cases) for women; neither OR was adjusted for wood dust exposure. A statistically significant increase in risk for sinonasal cancers (mRR = 1.8, 95% CI = 1.4 to 2.3, 933 deaths) was found in a meta-analysis of 11 case-control studies by Collins et al. (1997); however, no increase in risks was found in meta-analyses of three cohort studies by Collins et al. (1987) or in eight industrial cohort studies by Bosetti et al. (2008). Nasopharyngeal cancers: Similar to sinonasal cancers, nasopharyngeal cancers are rare [and most of the risk estimates reported in the cohort studies are based on small numbers of expected cases or deaths]. Among cohort studies, a statistically significant increase in mortality from nasopharyngeal cancer was observed in the large NCI cohort (SMR = 2.10, 95% CI = 1.05 to 4.21, 8 deaths) (Hauptmann et al. 2004), and statistically nonsignificant elevated risks were observed among white embalmers from the United States (PMR = 1.89, 95% CI = 0.39 to 5.48, 3 deaths) (Hayes et al. 1990) and among male Danish workers exposed to formaldehyde (SPIR = 1.3, 95% CI = 0.3 to 3.2, 4 cases) (Hansen and Olsen 1995, 1996). One incident case of nasopharyngeal cancer was reported among Swedish workers in the abrasive materials industry (expected deaths not reported, but only 506 workers were potentially exposed) (Edling et al. 1987b). No associations between formaldehyde exposure and nasopharyngeal cancer were found in the other two large cohorts: one death was observed (vs. 2 expected) in the British chemical workers cohort (Coggon et al. 2003) and no deaths were observed (vs. 0.96 expected) in the NIOSH cohort (Pinkerton et al. 2004). The other, smaller, cohort studies did not report findings or did not observe any deaths for nasopharyngeal cancer. Exposure-response relationships between formaldehyde exposure and nasopharyngeal cancer were evaluated in the large NCI cohort study. Among seven exposed and two unexposed deaths, relative risks of nasopharyngeal cancers increased with cumulative exposure (Ptrend = 0.025 among exposed groups) and with peak and average exposure (Ptrend = 0.044 and 0.126, respectively, across exposed and unexposed groups, using unexposed as the referent as no deaths were observed in the lowest exposed group). Adjustment for duration of exposure to a number of potentially confounding substances and plant type did not substantively alter the findings. Most of the deaths occurred at one factory (Plant 1), which appears to have had the largest numbers of highly exposed workers. In a nested case-control analysis of nasopharyngeal deaths in this plant, Marsh et al. (2007b) reported that several of the nasopharyngeal cancers occurred among workers with previous employment in metal-working occupations. Six of the nine available case-control studies reported increases in nasopharyngeal cancers in association with probable exposure to formaldehyde or at higher levels or duration of estimated exposure (Olsen et al. 1984 [women only], Vaughan et al. 1986a, Roush et al. 1987, West et al. 1993, Vaughan et al. 2000, and Hildesheim et al. 2001). Risks of nasopharyngeal cancers increased with exposure duration and cumulative exposure in two population-based case-control studies (Vaughan et al. 2000, Hildesheim et al. 2001). In some studies, higher risks were found among individuals in the high-exposure groups (Vaughan et al. 1986a, Roush et al 1987), or with more years since first exposure (West et al. 1993), and some studies reported that risks were still elevated after taking into account smoking (Vaughan et al. 2000, Vaughan et al. 1986a, West et al. 1993) or exposure to wood dust (Hildesheim et al. 2001, Vaughan et al. 2000, West et al. 1993). No associations between nasopharyngeal cancer and formaldehyde exposure were found in population-based case-control studies in Denmark (Olsen et al. 1984 [men only]), and Malaysia (Armstrong et al. 2000), a case-cohort study among Chinese textile workers (Li et al. 2006), or in a nested case-control study among embalmers (Hauptmann et al. 2009). Several meta-analyses were available. A statistically significant increase in risk (mRR = 1.3, 95% CI = 1.2 to 1.5, 455 deaths) was reported in a large meta-analysis of 12 case-control and cohort studies (Collins et al. 1997), and a nonsignificant increase in risk in a small meta-analysis of three other cohort mortality studies (SMR = 1.33, 95% CI = 0.69 to 2.56, 9 deaths) (Bosetti et al. 2008). Bachand et al. (2010) reported a borderline statistically significant risk in a meta-analysis of seven case-control studies (mRR = 1.22, 95% CI = 1.00 to 1.50) but did not find an increase in risk (mRR = 0.72, 95% CI = 0.4 to 1.29) in an analysis of data from six cohort studies, which excluded Plant 1 of the NCI cohort and used the re-analysis data from Marsh et al. (2005) for the other plants. [The Bachand meta-analysis used data for all pharyngeal cancer or buccal cavity cancer from some cohort studies and one case-control study, however.] Other head and neck cancers, and respiratory cancer Most of the cohort studies reported risk estimates for cancers of the buccal cavity, pharynx, larynx, and lung, or combinations of these cancers. Most of these studies, including two of the large cohorts (Pinkerton et al. 2004 and Coggon et al. 2003), three of the professional health worker studies (Hayes et al. 1990, Walrath and Fraumeni 1983 and 1984), and two of the smaller industrial cohorts (Andjelkovich et al. 1995 and Hansen and Olsen 1995, 1996) found elevated (between approximately 10% and 30%) but statistically nonsignificant risks for cancers of the buccal cavity or buccal cavity and pharynx combined; risk estimates were usually based on small numbers of deaths or cases. In the NCI cohort, increased risks for all upper respiratory cancers or buccal cavity cancer combined were generally found among workers in the highest categories of exposure (compared with the lowest category), but trends were not statistically significant (Hauptmann et al. 2004). Most of the population-based or nested case-control studies that reported on head and neck cancers found small increases (usually statistically nonsignificant) in risks for formaldehyde exposure and cancers of the buccal cavity and pharynx (or parts of the pharynx) (Vaughan et al. 1986a, Merletti et al. 1991, Gustavsson et al. 1998, Laforest et al. 2000, Marsh et al. 2002, Wilson et al. 2004, Berrino et al. 2003) or of the upper respiratory tract (Partanen et al. 1990). Exposure-response relationships were not clear in most of the available studies; however, positive exposure-response relationships between probability and duration of exposure and cancers of the hypopharynx and larynx combined were reported by Laforest et al. (2000) and between combined probability and intensity of exposure and salivary cancer by Wilson et al. (2004). No associations between formaldehyde exposure and pharyngeal cancers (subtypes or combinations) were observed in case-control studies by Shangina et al. (2006) and Tarvainen et al. (2008). Most of the cohort studies and two of the four available case-control studies found no association between formaldehyde exposure and laryngeal cancer. Two case-control studies (Wortley et al. 1992, Shangina et al. 2006) reported increased risk among subjects with the highest exposure to formaldehyde. Small excesses of mortality or incidence of cancers of the lung or respiratory system among formaldehyde-exposed workers were observed in four cohort studies (Andjelkovich et al. 1995, Dell and Teta 1995, Hansen and Olsen 1996 [women only], and Coggon et al. 2003). A statistically significant increase in risk of lung cancer was observed in the large study of British chemical workers (SMR = 1.22, 95% CI = 1.12 to 1.32, 594 deaths, among all workers) (Coggon et al. 2003). In this study, risks increased with increasing exposure level (Ptrend /= 4 ppm) vs. the lowest exposed category for all lymphohematopoietic cancers (RR = 1.37, 95% CI = 1.03 to 1.81, 108 deaths, Ptrend = 0.02), and statistically nonsignificant increases for all leukemias combined and peak exposure >/= 4 ppm (RR = 1.42, 95% CI = 0.92 to 2.18, 48 deaths, Ptrend = 0.12) and for myeloid leukemia and peak exposure >/= 4 ppm (RR = 1.78, 95% CI = 0.87 to 3.64, 19 deaths, Ptrend = 0.13; trends among exposed person-years). No associations were found with cumulative or average exposure. An excess of leukemia, especially myeloid leukemia, was also found among garment workers in the large NIOSH cohort (Pinkerton et al. 2004), but not in the British chemical workers cohort (Coggon et al. 2003). In the NIOSH cohort, risks for leukemia, myeloid leukemia, and acute myeloid leukemia were higher among workers with longer duration of exposure (10+ yrs), longer time since first exposure (20+ years), and among those exposed prior to 1963 (when formaldehyde exposure was thought to be higher) (Pinkerton et al. 2004). In the smaller industrial cohort studies, some studies reported excesses for all lymphohematopoietic cancers combined among formaldehyde-exposed workers (Bertazzi et al. 1989, Stellman et al. 1998) or leukemia (Hansen and Olsen 1995, 1996), but others observed no association for all lymphohematopoietic cancers combined (Andjelkovich et al. 1995, Stern 2003, Pinkerton et al. 2004) or leukemia (Andjelkovich et al. 1995, Stellman et al. 1998, Stern 2003). Each of the six cohort studies of health professionals, and the nested case-control study of embalmers from three of these studies, found elevated mortality for lymphohematopoietic cancers. Hall et al. (1991), Hayes et al. (1990), Stroup et al. (1986), Levine et al. (1984) and Walrath and Fraumeni (1983, 1984) reported increases in risk for all lymphohematopoietic cancers combined and for leukemia. Most estimates were statistically nonsignificant with the exception of the studies of Hayes et al. (1990) and Stroup et al. (1986), where statistically significant excess mortality was found for all leukemia combined or for myeloid leukemia in association with formaldehyde exposure. In the nested case-control study by Hauptmann et al. (2009), sufficient numbers of cases of lymphohematopoietic cancer deaths among embalmers and funeral directors were identified to enable evaluation of exposure-response relationships, using models of potential formaldehyde exposure. A significant increase in nonlymphoid lymphohematopoietic cancers was observed among ever-embalmers (OR = 3.0, 95% CI = 1.0 to 9.5, 44 exposed cases), and significant increases in risk were observed at the highest levels of cumulative, average, and peak exposure. Most of the increase was attributable to myeloid leukemia, which was significantly elevated among ever-embalmers (OR = 11.2, 95% CI = 1.3 to 95.6, 33 exposed cases) and showed significant trends with duration of exposure and peak exposure, and a more attenuated trend with 8-hour time-weighted average intensity of exposure. In further analyses of non-lymphoid lymphohematopoietic cancers using workers with /= 4 ppm was associated with a statistically significant increase in risk in the NCI cohort (RR = 2.04, 95% CI = 1.01 to 4.12, 21 deaths, Ptrend = 0.08 among the exposed group) (Beane Freeman et al. 2009), although an increase in risk was also seen among unexposed workers for this endpoint. Increased risks also were seen among British chemical workers (Coggon et al. 2003), abrasive materials workers (Edling et al. 1987b), and U.S. embalmers (Hayes et al. 1990). Other cohort studies did not find associations, based on small numbers of observed deaths or cases, or did not report findings. Among case-control studies, statistically nonsignificant increases in risks were observed by Boffetta et al. (1989), Pottern et al. (1992) (women only), and Hauptmann et al. (2009), but not by Heineman et al. (1992) (men only). Several meta-analyses were available. (Hauptmann et al. [2009] was not available for any of the analyses.) Statistically significant risks were reported for all lymphohematopoietic cancers and leukemia among cohort studies of health professionals by Bosetti et al. (2008) (RR = 1.31, 95% CI = 1.16 to 1.47, 263 deaths for all lymphohematopoietic cancers; and RR = 1.39, 95% CI = 1.15 to 1.68, 106 deaths for leukemia) and among studies of occupations with known high formaldehyde exposure by Zhang et al. (2009a), (mRR = 1.25, 95% CI = 1.09 to 1.43, 19 studies for all lymphohematopoietic cancers combined; mRR = 1.54, 95% CI = 1.18 to 2.00, P