To address the first part of its statement of task, this committee reviewed the formaldehyde substance profile in the National Toxicology Program (NTP)’s 12th Report on Carcinogens (RoC) (NTP 2011). The committee’s review was informed by many documents, including those in Table 1-1. The committee also examined the primary literature cited in the background document for formaldehyde and other literature published by June 10, 2011 (the date when the 12th RoC was released). The headings and structure of the present chapter parallel the major headings that NTP used in the substance profile for formaldehyde—that is, cancer studies in humans, cancer studies in experimental animals, other relevant data, and studies of mechanisms of carcinogenesis. The committee also reviewed the following sections in the substance profile: properties, use, production, exposure, regulations, and guidelines.
As part of its review, the committee determined whether NTP had described and conducted its literature search appropriately, whether the relevant literature identified 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. Instead of discussing the strengths and weaknesses of each study in detail as part of this chapter, the committee chose to discuss such detail as part of its independent analysis in Chapter 3. Detailed data from individual studies can be found in Chapter 3 and in the background document for formaldehyde (NTP 2010). On the basis of its review and analysis of the substance profile, the committee ends this chapter with a review of NTP’s literature-search methods, suggestions of clarifications that NTP could make to improve future iterations of the background document or substance profile for formaldehyde, and an assessment of whether the evidence presented by NTP in the background document and the substance profile support the listing of formaldehyde as a known human carcinogen in the 12th RoC.
NTP began the substance profile with a clear statement of its conclusions—that is, formaldehyde is known to be a human carcinogen. That conclusion was based on evidence from studies in humans and supporting mechanistic data. The introductory paragraph also informs the reader that formaldehyde was first listed in the 2nd RoC as reasonably anticipated to be a human carcinogen, and that the substance was upgraded to its current listing status of known to be a human carcinogen in the 12th RoC. The committee finds this paragraph to be informative.
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 document. NTP described the search strategy used to identify relevant epidemiologic studies, and the committee judged the choice of substance-specific and topic-specific terms to be reasonable. The committee did not identify any informative epidemiologic studies that were omitted from the background document. The committee judged that the most informative studies were cited by NTP and were appropriately summarized in the substance profile.
The distinctions among subtypes of nasopharyngeal and sinonasal cancers were adequately discussed in the background document and in the substance profile. The relevance of the subtypes for the determination of carcinogenicity is appropriately discussed. The evidence in the available literature on which subtypes of nasopharyngeal and sinonasal cancers are increased in incidence by exposure to formaldehyde is modest and not definitive. An increase in incidence that is modest and not definitive is not surprising given the rarity of these tumors and the difficulty of having sufficient statistical power to distinguish patterns of association by subtype of cancer (NTP 2010). The limitation in the literature related to cancer subtypes is appropriately discussed in the substance profile and does not materially limit the validity of the carcinogenicity determination.
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. The first two of those provided the most informative evidence because of greater opportunities for exposure of workers and because of higher-quality exposure assessment as a component of the study method. The committee agrees with NTP’s judgment that the two most informative occupational studies for evaluating human cancer hazard posed by formaldehyde are the National Cancer Institute (NCI) study of a cohort of more than 25,000 workers in industries that use formaldehyde (Beane Freeman et al. 2009) and the NCI nested case–control study of cancer in embalmers (Hauptmann et al. 2009). That judgment was based on the strengths of the studies—
they are large, high-quality studies that used well-documented methods and high-discrimination exposure assessments. The committee judged the exposure assessments to be of good quality because they included detailed evaluations of the sources and variations in exposure and used appropriate statistical modeling to estimate unmeasured historical exposures (see Appendix C for more discussion). Additional strengths of the NCI embalmer study are the likelihood of high exposures for long periods, a well-conducted exposure reconstruction, and a careful analysis of alternative measures of quantitative exposure (Hauptmann et al. 2009).
The National Institute for Occupational Safety and Health has produced a mortality study of a cohort of garment workers (Pinkerton et al. 2004). The cohort was relatively small (2,206 total deaths observed over more than 40 years), and the exposure assessment was less detailed, but the likelihood of substantial exposure before 1970 was clearly documented (Elliot et al. 1987), and the study methods and conduct were rigorous. The study was not informative on the question of an association between formaldehyde and nasopharyngeal or sinonasal cancers because of low statistical power. If the cohort had experienced the mortality rates of the general population in the United States, not even one nasopharyngeal cancer death would have been expected in a population of this size. And, consistent with this expectation, no nasopharyngeal cancer deaths were observed. The same is true in this study for sinonasal cancer—less than one death was expected and zero were observed. A British chemical-worker study conducted by Coggon et al. (2003) had a semi-quantitative exposure assessment and was probably also insufficiently powered to determine whether nasopharyngeal carcinoma or sinonasal carcinoma is associated with formaldehyde exposure.
NTP considered several population-based case–control studies to be particularly valuable in the assessment of carcinogenicity. The assessment of formaldehyde exposure and nasopharyngeal cancer was informed by a population–based case–control study by Vaughan et al. (2000) and three smaller case–control studies of nasopharyngeal cancer by Roush et al. (1987), West et al. (1993), and Hildesheim et al. (2001).The assessment of formaldehyde exposure and sinonasal cancer was informed by the pooled case–control studies of sinonasal cancer reported by Luce et al. (2002) and several smaller case–control studies of sinonasal cancer by Olsen et al. (1984), Hayes et al. (1986), Olsen and Asnaes (1986), Roush et al. (1987), and Luce et al. (1993). Because sinonasal cancers are rare (NTP 2010), it was appropriate for NTP to give substantial weight to the findings from the pooled analysis by Luce et al. (2002) of 12 case–control studies, each of which individually lacked sufficient statistical power to detect an effect. The data from those studies could be combined (pooled) because of common methods of data collection and because a detailed exposure reconstruction was conducted specifically for the pooled analysis.
NTP drew on the findings of a meta-analysis by Zhang et al. (2009) and cited meta-analyses by Bachand et al. (2010) and Bosetti et al. (2008). Meta-analyses can be useful in summarizing results of multiple studies, but after re-
viewing the published meta-analyses on formaldehyde and evaluating their methodologic differences, the committee decided not to use the published meta-analyses or to conduct its own meta-analysis for its independent assessment of formaldehyde in Chapter 3. Because of the considerable heterogeneity in design, particularly among the exposure assessments, the results of a meta-analysis of the full range of observational studies published on formaldehyde exposure and cancer would be highly sensitive to inclusion and exclusion criteria and to other methodologic decisions (Checkoway et al. 2004).
The substance profile described only briefly why Zhang et al. (2009) was given some weight in the assessment of carcinogenicity but Bachand et al. (2010) and Bosetti et al. (2008) were not. Zhang et al. (2009) hypothesized that acute myeloid leukemia (AML) was associated with formaldehyde exposure. The study was unusual in that, unlike some meta-analyses, it had a careful exposure rationale for its approach. The authors decided to focus their analyses by using only the highest exposure categories to obtain the strongest test for a relationship between exposure and disease frequency. They assumed that if an increased frequency of AML was observed, it would most likely be found by analyzing the contrast between the most highly exposed subjects and the unexposed subjects. They argued that higher relative risks were less susceptible to type 2 errors, higher-exposure categories would be less affected by risk dilution by subjects who had low exposures, and high relative risks were less likely to be a result of confounding factors. They also focused on myeloid leukemia instead of all leukemias because they had hypothesized that AML was causally linked to formaldehyde exposure. In the committee’s own assessment (described in Chapter 3), no meta-analyses were considered, because they were not deemed necessary in reaching a strong conclusion and because of the difficulties in evaluating conflicting results from different meta-analyses.
The committee concluded that NTP did a thorough job of describing the epidemiology literature in the background document and synthesizing information about key studies in the substance profile. However, the substance profile was not transparent about how the epidemiology evidence met the RoC listing criteria. The listing criteria indicate that formaldehyde should be categorized as reasonably anticipated to be a human carcinogen if “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 be adequately excluded” (NTP 2010, p. iv). Formaldehyde should be categorized as known to be a human carcinogen if “there is sufficient evidence of carcinogenicity from studies in humans, which indicates a causal relationship between exposure to [formaldehyde]…and human cancer” (NTP 2010, p. iv). There was no discussion in the “Cancer Studies in Humans” section of the background document or substance profile about how NTP defined the terms limited evidence and sufficient evidence. Therefore, consistent with the RoC listing criteria, the committee used its expert scientific judgment to interpret and apply the listing criteria to the evidence evaluated in Chapters 2 and 3. 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 association between exposure to formaldehyde and a specific cancer type, but alternative explanations, such as chance, bias, or confounding factors, could not be adequately ruled out because of limitations in the studies, and so a causal interpretation 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 association between exposure to formaldehyde and a specific cancer type and for which chance, bias, and confounding factors could be ruled out with reasonable confidence because of the study methodologies and the strength of the findings. The way in which the committee categorized studies as strong, moderately strong, or weak is described in more detail in Chapter 3.
As was accurately summarized in the substance profile, nasopharyngeal cancers are a group of uncommon tumors with several histologic types, including differentiated keratinizing squamous-cell carcinoma, differentiated nonkeratinizing carcinoma, and undifferentiated nonkeratinizing carcinoma. NTP based its evaluation of epidemiologic evidence of nasopharyngeal cancer on several lines of evidence. The committee reviewed the background document and the findings of a previous expert panel (McMartin et al. 2009) and concurs with the choice of the key studies presented in the substance profile.
NTP found several case–control studies to be highly informative, notably a case–control study by Vaughan et al. (2000) that drew incident cases from five US cancer registries that participated in the Surveillance Epidemiology and End Results program of NCI (Vaughan et al. 2000). The committee noted two important contributions of the Vaughan et al. (2000) multicenter case–control study: it was able to evaluate risks separately for the three principal types of nasopharyngeal tumors described above, and the exposure assessment was sufficiently detailed to provide evidence of a strong dose–response relationship. Corroborating evidence was provided by additional case–control studies by Roush et al. (1987), West et al. (1993), and Hildesheim et al. (2001).
The NCI industrial worker cohort also provided important corroborating evidence of an association between formaldehyde exposure and nasopharyngeal-cancer mortality, although the rarity of the tumors limited the statistical power of the study (Hauptmann et al. 2004). The authors observed a pattern of increased mortality among categories of exposure defined by duration of exposure, average intensity cumulative exposure, and peak exposure. Although the number of cases was not as large, the study was strengthened by its high-quality exposure assessment. The design of the NCI industrial worker cohort consisted of employees in 10 plants. The objective was to obtain a sufficiently large study group to determine causes of increased mortality for common cancers. However, only a small number of nasopharyngeal-cancer deaths occurred. Of the nine
deaths, five occurred in workers in a single plant, which was the second largest plant in the study (Hauptmann et al. 2004). As noted by Hauptmann et al. (2005), it is not unusual to see large variation in small numbers of rare cancers across small plants. Two possible explanations for the heterogeneity in outcomes by plant is the heterogeneity in exposures across the plants and the possibility of confounding by other carcinogenic exposures in the plant that had the most cases. To evaluate that possibility, the investigators conducted analyses that adjusted for the plant. The results of the adjusted analyses were substantially similar to the unadjusted findings, although limited by the small numbers of cases.
The committee agreed with NTP’s assessment that the Luce et al. (2002) study of sinonasal cancer was particularly useful. As noted, it was a pooled analysis of several high-quality case–control studies that shared the same exposure assessment, and the resulting statistical power was critical for the study’s findings. The study found a substantial increase in the frequency of one type of sinonasal cancer—adenocarcinoma—after high cumulative exposure to formaldehyde in both men and women. NTP determined that earlier case–control studies by Olsen et al. (1984), Hayes et al. (1986), Olsen and Asnaes (1986), Roush et al. (1987), and Luce et al. (1993) taken as a group provided consistent supporting evidence of an association.
The committee found that the issue of potential confounding of the formaldehyde–sinonasal-cancer association by wood dust was adequately considered by NTP. The substance profile noted that Hansen and Olsen (1995, 1996) were conducted in occupational cohorts in which wood-dust exposure was very unlikely. In addition, several studies either stratified by likely wood-dust exposure (Olsen et al. 1984; Hayes et al. 1986; Olsen and Asneas 1986) or fitted models to control for confounding by wood dust statistically (Luce et al. 2002). Although each of the studies taken alone had some limitations because of small numbers of cases, on balance the evidence supports NTP’s conclusion that the observed association between formaldehyde and sinonasal cancer is unlikely to be due to confounding by wood-dust exposure. No other important confounders were identified in the available studies.
The committee reviewed the background document (NTP 2010) and the findings of the previous expert panel (McMartin et al. 2009) and concurs with the choice of key studies presented under the heading “Lymphohematopoietic Cancer” in the substance profile (NTP 2011). The committee agrees with NTP that the most informative primary studies for evaluating formaldehyde exposures and lymphohematopoietic cancers were the NCI study of the cohort of industrial workers
exposed to formaldehyde (Beane Freeman et al. 2009) and the NCI nested case–control study of embalmers (Hauptmann et al. 2009). As previously mentioned, those studies are informative because of their size and the quality of their design and conduct, particularly because the quality of the extensive exposure assessments permitted quantitative evaluations with a variety of plausible exposure metrics. NTP determined that the most informative studies for evaluating formaldehyde exposure and myeloid leukemia specifically were the British cohort of industrial workers (Coggon et al. 2003), the NIOSH cohort of garment workers (Pinkerton et al. 2004), the NCI cohort of industrial workers (Beane Freeman et al. 2009), and the NCI nested case–control study of embalmers (Hauptmann et al. 2009). The epidemiology literature is discussed in more detail in Chapter 3.
The committee found that the assessment of lymphohematopoietic cancers presented in the substance profile supports NTP’s conclusion that the most strongly supported association is that between myeloid leukemia and formaldehyde. Broader diagnostic categories (all leukemias and all lymphohematopoietic cancers) also show evidence of an association with formaldehyde exposure in some studies, but a likely explanation for those increases is the inclusion of myeloid leukemia in the broader groupings that include it. The committee agrees with NTP that the evidence demonstrates an association between exposure to high concentrations of formaldehyde (by several different metrics) and some lymphohematopoietic cancers, specifically myeloid leukemia. That association cannot be explained by chance, bias, or confounding factors (NTP 2011).
Lymphohematopoietic cancers make up a diverse group that are often analyzed together in epidemiologic studies because of the rarity of the individual types. Concerns have been raised about the usefulness of such a broad category of tumors when evidence of carcinogenicity is being evaluated because the different cancers of the hematopoietic system are understood to arise from different cells and so might have different etiologic mechanisms (NRC 2011). There is a common assumption in epidemiology, dating back at least to Bradford Hill (Hill 1965), that specific hazardous exposures, such as exposures to chemicals, tend to cause diseases by a small number of specific pathways (or modes of action), so there is an expectation of observing stronger associations between exposures and narrowly defined disease entities than between exposures and broad categories. Nevertheless, it is common practice in epidemiology to begin an evaluation of exposure–disease associations by looking for signals of an association in broad and heterogeneous groups of diseases (including, for example, the very broad category of all cancers combined or all lung diseases combined). If evidence of an association is found in a broad disease category in an exposed population, the next step is to look into more narrowly defined disease subgroups, such as different types of leukemias. Sometimes, the result is that an association is observed only in the broad group and not in any of the constituent disease subgroups. In such cases, the result is spurious and could possibly be explained by bias in study design or data collection. The more likely explanation, though, is that the association observed in the broad disease category might be accounted for by an increase in the association of one or a small number of specific disease
entities when the rest of the broad group shows no increase in the association. The latter pattern is interpreted by the study authors as evidence of an association between the exposure and the specific subgroup or subgroups of the disease.
Cancer at Other Tissue Sites
The substance profile discusses cancer at other sites only briefly, so the committee’s assessment of this section is based on the review in the background document (which is also brief but more informative) and a review of some of the primary literature. The committee concurred with NTP’s assessment that the literature published by June 10, 2011, does not meet the requirement of limited evidence of a carcinogenic effect at any additional sites. As stated in the background document, “in general, the reported estimates were null [relative risk = 1.0] or slightly elevated but statistically nonsignificant, and studies have not consistently reported an elevated risk in cancer associated with formaldehyde exposure at any of these sites” (NTP 2010, p. 232).
Conclusions Regarding Epidemiologic Evidence
The committee 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. The strongest studies are ones that had high-quality exposure assessments and ones that presented alternative exposure metrics. As noted above, there are several such studies. NTP’s discussions of chance, bias, confounding factors, and other limitations of the most informative studies in the substance profile are clear and thorough. The committee agrees with NTP’s determination that the human evidence published by June 10, 2011, on the association of exposure to formaldehyde with cancer of the nasopharyngeal region and sinonasal cavities and of myeloid leukemia was sufficient to support a listing as known to be a human carcinogen.
Cancer Studies in Experimental Animals
The section “Cancer Studies in Experimental Animals” in the substance profile discusses the degree of certainty of the carcinogenicity of formaldehyde on the basis of evidence from experimental animal studies. According to the NTP listing criteria (Box 1-2), evidence from animal studies is to be judged sufficient to categorize a chemical as reasonably anticipated to be a human carcinogen if “there is increased incidence of malignant and/or a combination of malignant and benign tumors in multiple species or multiple tissue sites; by multiple routes of exposure; or to an unusual degree with regard to incidence, site, or type of tumor, or age at onset” (NTP 2010, p. iv). The committee reviewed the substance profile in the context of those criteria.
Neither the formaldehyde substance profile (NTP 2011) nor the background document (NTP 2010) present details of the approach taken to search the literature for animal carcinogenicity studies although a good description of the literature-search strategy was provided by NTP in response to committee inquiry (Bucher 2013; see Table 2-1). The committee reviewed the comprehensive compilation of animal bioassays in the US Public Health Service 149 series Survey of Compounds Which Have Been Tested for Carcinogenicity and evaluations by the International Agency for Research on Cancer (IARC 1982, 1995, 2006), but it did not find other important or informative animal carcinogenesis studies that were missed by NTP and should have been included in the background document or in the substance profile. It found a few early studies of low power (small numbers of animals were used), of poor quality, or of short duration that were not described in the background document. Examples include a 6-month lung exposure study in rabbits that found atypical proliferation (Garschin and Schabad 1936), a study with no controls that administered formaldehyde to 10 rats via subcutaneous injection and found injection-site sarcomas in four (Watanabe et al. 1954), and a 10-month oral experiment in six rabbits that found intraepithelial carcinoma in the exposed mucosa in two (Muller et al. 1978). Those studies contribute little evidence on formaldehyde carcinogenicity, and the RoC and background document are not remiss or deficient for not evaluating them.
In the “Inhalation” section of the formaldehyde background document, studies are grouped by species. Two studies discussed in the background document used mice. The study by Horton et al. (1963) focused on the lung and did not examine the nasal epithelium. C3H mice were exposed to formaldehyde at 0.05 mg/L (50 mg/m3) for 35 weeks and then for 29 weeks of repeated formaldehyde exposure to 0.15 mg/L (150 mg/m3), for a total of 64 weeks, and then all mice were sacrificed. None of the mice were found to develop pulmonary neoplasms. The committee judged that this omission from the background document was appropriate given the severe limitations of the study. Furthermore, the study was not noted in the animal-evidence section of the substance profile and, given the limitations of the study, NTP was reasonable to exclude it from further consideration.
Kerns et al. (1983a) conducted a 2-year study of male and female B6C3F1 mice with relatively large dose groups, interim sacrifices (at 6, 12, 18, and 24 months), adequate statistical evaluation, and thorough histopathologic examination of the nasal turbinates and other components of the respiratory tract. Nasal lesions of increasing severity with increasing dose were reported, and two of 17 surviving males in the highest-dose group had squamous-cell carcinoma (Kerns et al. 1983b). The two squamous-cell carcinomas were attributed to formaldehyde given the rareness of the tumors (the background document reported no
tumors of this type in 2,800 historical control animals from NTP studies) and the similarity of the lesions observed in rats by the same authors. The substance profile cited that as evidence of carcinogenicity in male mice, and the committee finds this reasonable.
The discussion of the studies in rats in the background document groups the studies as “subchronic” and “chronic”. The subchronic-exposure studies (Rusch et al. 1983; Woutersen et al. 1987; Wilmer et al. 1989) might have been more appropriately placed in a section on “other relevant data” that discussed proliferative lesions. The proliferative lesions observed in the short-term studies (for example, squamous-cell metaplasia and hyperplasia of the nasal epithelium) were observed to precede squamous-cell carcinoma in the chronic studies. However, the short-term studies were of insufficient duration to produce tumors and are not themselves carcinogenesis studies. Their exclusion from the substance profile discussion of animal carcinogenesis is appropriate.
The subchronic study by Feron et al. (1988) exposed male Wistar rats to formaldehyde for 13 weeks and then sacrificed the animals after an additional 118 weeks. The 118-week followup period allowed sufficient time for the effects of the 13-week exposure to be manifested. The background document noted the variety of nonneoplastic changes in the olfactory epithelium in addition to the nasal tumors observed (polypoid adenoma, squamous-cell carcinoma, and carcinoma in situ). The fact that tumors developed after short-term exposure was appropriately noted in the substance profile.
The discussion of the chronic rat studies in the background document begins with the large multidose studies in male and female Fischer 344 (F344) rats sponsored by the Chemical Industry Institute of Toxicology (Swenberg et al. 1980a,b; Kerns et al. 1983a). The studies were considered to be state-of-the-art for the time; the methods included a large group, multiple interim sacrifice times, and full histopathologic evaluation of nasal tissue for characterization of neoplastic and nonneoplastic lesions. The studies were well described in the background document. The finding of a high incidence of rare nasal tumors in male and female rats provides a logical and definitive basis for NTP’s conclusion on formaldehyde-induced nasal carcinogenesis.
The background document cited additional long-term inhalation-carcinogenesis studies in rats. Woutersen et al. (1989) evaluated the effects of damage to the nasal epithelium in male Wistar rats. During the first week of the study, the nasal mucosa of some rats was severely damaged by electrocoagulation. A higher nasal-tumor incidence was observed in exposed rats that had damaged nasal epithelium than in rats that had undamaged nasal epithelium, although the study of rats with undamaged epithelium had smaller groups (this was not noted in the background document). Monticello et al. (1996) reported on the relationship between indexes of cell proliferation and induction of nasal tumors in relatively large groups (90–147) of male F344 rats that were exposed to a range of concentrations (0.7–15 ppm for 6 hours/day, 5 days/week) for up to 2 years. Squamous-cell carcinoma and polypoid adenoma of the nasal cavity were again found. Kamata et al. (1997) exposed smaller groups of male F344 rats (32
per group), performed histopathologic evaluations of respiratory tract and non–respiratory tract tissue, and similarly found squamous-cell carcinoma of the nasal cavity but no cancers at other sites. Sellakumar et al. (1985) studied the effects of formaldehyde in male Sprague Dawley rats and performed a histopathologic evaluation of other major tissues; the study did not appear to include bone marrow. Nasal squamous-cell carcinoma was found at a relatively high incidence (38% in the group dosed with formaldehyde at approximately 15 ppm). The studies were each adequately described in the background document and reported in the substance profile as providing evidence of formaldehyde-induced carcinogenicity in the nasal epithelium. The committee agrees with the inclusion of the studies because they support the overall sufficiency of evidence of carcinogenicity in animals exposed to formaldehyde.
One chronic study in female Sprague Dawley rats was not cited in the substance profile and was discounted in the background document because of small groups (Holmström et al. 1989). Squamous-cell metaplasia was observed, but only one animal developed nasal squamous-cell carcinoma. The study authors concluded that the finding in the one animal was related to formaldehyde exposure, but NTP did not include that as supportive in the substance profile—a reasonable decision given the observation of a single tumor.
Two monkey studies presented in the background document’s table of nasal-tumor results were too short to be reported with other carcinogenesis studies, especially in such long-lived animals. One study was in cynomolgus monkeys and was 26 weeks long (Rusch et al. 1983), and the other study was in rhesus monkeys and was only 6 weeks long (Monticello et al. 1989). The limitation regarding study length was not noted in the study description in the background document but was noted in the summary table of carcinogenicity results. It would have been more appropriate not to include those studies in the section on cancer-bioassay data. They were not mentioned in the substance profile, and that is appropriate.
Two inhalation studies in Syrian golden hamsters are discussed in the background document. One was only 26 weeks in duration, included a small group size (10 male and 10 female), and resulted in no significant findings (Rusch et al. 1983). The background document reported that the study was of short exposure duration and used a small number of animals. The study was not noted in the substance profile and, because it was not a carcinogenesis study, that is appropriate. The study was insufficient as a carcinogenesis study, and NTP would not have been faulted if it had left it out of the background document. The second inhalation study exposed two groups of Syrian golden hamsters over a lifetime (Dalbey 1982). One group (n=88) was exposed 5 hours/day, 5 days/week at 10 ppm, and the second group (n=50) was exposed 5 hours/day, 1 day/week at 30 ppm. Higher incidences of nasal metaplasia and hyperplasia were observed in the 10-ppm group than in the 132 control animals, but no nasal tumors were present. The substance profile did not include the study as a basis of its finding of sufficient evidence for carcinogenesis, and that is appropriate.
The background document describes studies in which relatively high concentrations of formaldehyde were administered to rats in drinking water. In the first study described, eight of 10 Wistar rats that received 5,000 ppm of formalin in drinking water developed squamous-cell papilloma of the forestomach compared to none of 10 control animals (Takahashi et al. 1986). The finding is noted in the substance profile, and the committee finds that appropriate. Two other drinking-water studies in Wistar rats (Til et al. 1989; Tobe et al. 1989) found epithelial hyperplasia and hyper keratosis of the forestomach and hyperplasia of the glandular stomach, but no statistically significant differences in tumors between the treated and control animals. One of the studies (Til et al. 1989), which had a reasonable size (70 animals/group), exposed male and female rats for up to 2 years to average concentrations of 20, 260, and 1,900 ppm in drinking water. Tobe et al. (1989) designed a 2-year study with concentrations of formaldehyde in drinking water at 0, 200, 1,000, and 5,000 ppm and group sizes of 20 animals of each sex. None of the high-dose animals survived to the end of the study.
The background document describes well the series of drinking-water experiments conducted by Soffritti et al. (1989, 2002) in male and female Sprague Dawley rats. Soffritti et al. (1989) exposed animals in utero (dams exposed via drinking water) and postnatally for 2 years. Breeders were exposed for a lifetime. In the female offspring, the incidence of malignant intestinal tumors was significantly increased. In a statistical analysis of the study, IARC (2006) found that the incidence of intestinal leiomyosarcoma was significantly increased in female offspring and in male and female offspring combined. The substance profile noted that benign and malignant gastrointestinal tumors were reported, including rare intestinal leiomyosarcomas in females. Because leiomyosarcoma is rare, even with the low incidence NTP deemed the finding significant; this is similar to the IARC (2006) conclusion. The substance profile includes the finding and, although the finding is not robust, it is not unreasonable for NTP to include it. In the second series of studies by Soffritti et al. (2002), rats were exposed as adults, and males in the high-dose group were observed to have gastrointestinal leiomyosarcomas, and females in the high-dose group were observed to have leiomyomas. This second finding of gastrointestinal leiomyosarcoma was again given weight because of the rarity of the tumor. In those studies, an increased incidence of hemolymphoreticular tumors was observed, but the finding was not given much weight, because of large discrepancies between the initial incidence reported in a preliminary report and the final published incidence, because of pooling of lymphomas and leukemias, and because limited information was given on the tumor incidence in historical controls. Soffritti et al. (2002) also reported significant increases in tumors of the mammary gland, but the significance did not persist when liposarcomas were removed from the group. The committee agrees with not giving weight to the hemolymphoreticular and mammary tumors in the substance profile and with attaching some weight to the leiomyosarcomas.
Coexposure with Other Substances
The substance profile notes that formaldehyde promotes tumors of the stomach and lung in rats and cites the background document as a reference. There were nine coexposure carcinogenicity studies of varied study design. The results of some studies were null. NTP did not include any of the studies in its findings on the sufficiency of the evidence in animals. That scientific judgment is consistent with the NTP criteria.
Conclusion Regarding Animal Evidence
NTP concluded that the experimental evidence was sufficient to find that formaldehyde is an animal carcinogen. With regard to NTP’s application of its criteria, it noted that formaldehyde caused “tumors in two rodent species, at several different tissue sites, and by two different routes of exposure” (NTP 2011, p. 197). A positive finding on any one of the three conditions listed below in which malignant or combined malignant and benign tumors occur would fulfill the criteria for sufficiency in animals. NTP found that two were met.
1. In multiple species or multiple tissue types:
- Multiple species: NTP cites studies that showed increases in malignant tumors in rats (Feron et al. 1988; Kerns et al. 1983a; Sellakumar et al. 1985; Soffritti et al. 1989; Woutersen et al. 1989; Monticello et al. 1996; Kamata et al. 1997) and in mice (Kerns et al. 1983a).
- Multiple tissue types: NTP cites studies that showed malignancies of the nasal epithelium (mostly squamous-cell carcinomas) (Kerns et al. 1983a; Sellakumar et al. 1985; Feron et al. 1988; Woutersen et al. 1989; Monticello et al. 1996; Kamata et al. 1997) and gastrointestinal tract (leiomyosarcoma) (Soffritti et al. 1989 [offspring]; Soffritti et al. 2002 [adults]). The substance profile also noted that benign testicular adenoma was seen in the Soffritti et al. (2002) study.
2. After exposure by multiple routes: NTP cites exposure by inhalation (Kerns et al. 1983a; Sellakumar et al. 1985; Woutersen et al. 1987; Feron et al. 1988; Monticello et al. 1996; Kamata et al. 1997) and oral routes (Soffritti et al. 1989 [offspring]; Soffritti et al. 2002).
3. To an unusual degree with respect to incidence, site, type of tumor, or age at onset: NTP did not state that this criterion was met; however, nasal tumors are rarely increased in animal studies, and these tumors were observed at relatively high incidences in the formaldehyde animal studies (Kerns et al. 1983a; Monticello et al. 1996).
The committee agrees with NTP’s conclusion that there is sufficient evidence of carcinogenicity in animals to support a listing in the 12th RoC.
Other Relevant Data
The section “Other Relevant Data” of the substance profile presents a selection of studies that deal with formaldehyde and the following topics: chemical reactivity, toxicity (in vivo and in vitro), systemic and organ-specific effects, genomic effects (mutagenic), covalent adducts (protein and DNA), carcinogenicity of formaldehyde metabolites and related compounds, and absorption, distribution, metabolism, and kinetics. Many of the studies are referred to in detail in other sections of the substance profile. The text in this section succinctly and appropriately describes the current understanding of the regional respiratory-tract absorption of formaldehyde and provides appropriate literature citations. The text also accurately describes the reactivity of formaldehyde with water and biologic molecules and accurately indicates the short plasma half-life of formaldehyde. Biomarkers of formaldehyde’s interaction with macromolecules (blood proteins and DNA adducts) are well documented. The current understanding of the cytotoxicity of formaldehyde is adequately covered.
Studies on Mechanisms of Carcinogenesis
The section “Studies on Mechanisms of Carcinogenesis” in the substance profile and the associated sections in the background document describe the scientific evidence and mechanistic knowledge available on the carcinogenicity of formaldehyde. The committee finds that the extent, quality, and interpretation of the mechanistic evidence described in these documents are comprehensive and that the importance of this information for the decision to list formaldehyde as a known human carcinogen is clearly explained.
Neither the background document nor the substance profile explicitly describes the literature-search strategy; however, as previously stated, the collection of search terms and other information were available on request from NTP (Bucher 2013). On the basis of this information and the content of the background document and the substance profile, the committee concludes that NTP performed a thorough search and appropriately evaluated studies on mechanisms of carcinogenesis that were published in peer-reviewed sources. The committee concludes that the information presented in the background document and the substance profile is comprehensive, balanced, and inclusive and is accompanied by informative evidence tables and short narratives of individual studies. Summaries were written in a clear manner, and the limitations of the individual studies, where appropriate, are acknowledged and taken into consideration. The mechanistic information provided critical evidence that demonstrates the plausibility of formaldehyde-induced carcinogenesis in both experimental animals and humans. Although there was no clear cutoff date for inclusion of the additional mechanistic studies in the peer-reviewed literature between the time of completion of the background document (November 2009) and the final release of the 12th RoC, the committee concludes that NTP did not miss any publications that
had strong mechanistic evidence that would have caused NTP to change the listing of formaldehyde as a known human carcinogen. (See Chapter 3 and Appendix D for more information on the committee’s literature search beginning in 2009.)
The substance profile focuses on the mechanisms related to specific clinical sites of cancers, specifically, nasopharyngeal, sinonasal, and lymphohematopoietic cancers. The committee finds that delineation of the available mechanistic evidence into portal-of-entry or systemic effects as defined by NRC (2011) would have made the background document and the substance profile stronger. The mechanisms of carcinogenicity of highly reactive chemicals, including formaldehyde, can differ between portal-of-entry sites and distal sites that their native forms or metabolites might not readily reach. Although there are shortcomings of the evidence described in the section “Cancer at Other Tissue Sites” as acknowledged by NTP, the mechanistic evidence pertaining to the systemic effects of formaldehyde would probably be applicable to any distal tissues.
The committee concludes that NTP correctly states that “the mechanisms by which formaldehyde causes cancer are not completely understood” (NTP 2011, p. 198). There may be several mechanisms of action involved and the mechanisms proposed by NTP are not mutually exclusive and might be related. Although it is clear that the overall strength of evidence differs between the portal-of-entry and systemic health effects, most of the evidence presented in the introductory paragraph in this section focuses on a genotoxic mode of action (NTP 2011). An expert panel that reviewed a draft version of the background document stated that two mechanisms are supported by available evidence in sinonasal–pharyngeal regions where inhaled formaldehyde first comes into contact with the mucous layer of the respiratory tract in mammals (McMartin et al. 2009): a cytotoxicity-induced cellular-proliferation mechanism and a genotoxic mechanism. The information presented in this section appropriately details studies in model organisms and cell-culture systems that provide general evidence applicable to a wide array of human tissues.
Most of the upper aerodigestive tract1 is directly exposed to formaldehyde when it is inhaled. Various anatomic structures in this region have been identified as potential sites of formaldehyde-associated carcinogenesis in both experimental animals and humans (NTP 2010). This section in the substance profile and the corresponding parts of the background document are comprehensive and
1The aerodigestive tract is “the combined organs and tissues of the respiratory tract and the upper part of the digestive tracts (including the lips, mouth, tongue, nose, throat, vocal cords, and part of the esophagus and windpipe)” (NCI 2014).
balanced. The committee finds that the information presented in the substance profile agrees with that presented in the background document. Nomenclature of the exact anatomic structures affected by exposure to formaldehyde is important and the section would be clearer if the title reflected the two distinct anatomic sites that have been identified as potential portal-of-entry target sites of formaldehyde carcinogenesis in humans: the nasopharyngeal and sinonasal regions.
Although the emphasis on the various forms of genetic damage observed in the nasal tissue is warranted and the description is comprehensive, the substance profile could have provided a stronger summary of the genotoxic mode of action of formaldehyde in the anatomic sites that come into direct contact with formaldehyde. For example, the nasal passages and surrounding anatomic sites in the upper respiratory tract are affected in rodents (which are obligatory nose-breathers) and humans. However, the oral cavity (for example, the buccal epithelium in exposed humans, who might breathe primarily through the mouth because of irritating effects of formaldehyde on the nasal epithelium) and upper digestive tract (in rodent gavage studies) are also target tissues that come into direct contact with formaldehyde. There is mechanistic evidence of adverse health effects of formaldehyde in those anatomic regions (NTP 2010).
The substance profile identifies several types of genetic damage that have been observed in exposed humans and animal models. They include DNA–protein cross-links, DNA cross-links, nucleotide base adducts and mutations, and micronuclei. Although the description of genetic damage in the substance profile mentioned key findings and cited appropriate references, the topic would benefit from a clear structure and a clear presentation of the evidence similar to the structure and presentation of evidence in the background document. That could be achieved with a tiered presentation of the information, from damage at the level of a nucleotide (for example, adducts and mutations) to that at the level of the DNA structure (for example, cross-links) or chromatin (for example, micronuclei). By focusing on the types of damage and pointing to whether evidence supporting or refuting each type is available from in vitro or ex vivo, animal, or human studies, the substance profile could provide an even more concise and structured description of the plausibility of this mechanism.
Cytotoxicity-induced cellular proliferation is identified as a second plausible mechanism of carcinogenicity of formaldehyde at the portal-of-entry sites. The substance profile presented evidence from studies in rodents that histopathologic lesions in the upper respiratory tract lead to cell proliferation. The committee finds the description and analysis of those studies to be robust and well presented. The substance profile also appropriately points out that several concentration–response studies identified strong concordance between cytotoxicity and proliferation (in subchronic studies) and nasal-tumor incidence (in chronic studies) in rodents.
The substance profile acknowledges that cytotoxicity-induced cellular proliferation has been observed “at anatomical sites that are not thought to be the origin of squamous cell carcinoma” (NTP 2011, p. 199). Although it is not entirely clear what anatomic sites are being referred to here, this subsection cor-
rectly points out that this mechanism is not exclusively responsible for formaldehyde’s carcinogenicity in the upper respiratory tract, inasmuch as a variety of compounds that alone might induce cell proliferation are known not to pose a cancer hazard in the upper respiratory tract. Those compounds include glutaraldehyde, chlorine, and ethylacrylate (Miller et al. 1985; Wolf et al. 1995; NTP 1999).
The mechanistic studies of the genotoxicity and cytotoxicity of formaldehyde and the later studies of compensatory cell proliferation and apoptosis in the upper aerodigestive tract in rodents have reported effects at concentrations that are within an order of magnitude of human exposures reported in several occupational studies. Whereas few studies involving human subjects have examined cytotoxicity-induced cellular proliferation after exposure to formaldehyde, studies performed with rodent models provide strong mechanistic support for the listing of formaldehyde as a known human carcinogen.
The section “Leukemia” in the substance profile focuses on the systemic effects of formaldehyde at distal sites and specifically on myeloid leukemia. The committee points out that the issue of nomenclature of the anatomic structures affected by exposure to formaldehyde is important, and the section would be clearer if the title was revised to make it clear that the information in it pertains to systemic effects of formaldehyde.
Overall, the substance profile and background document provide a comprehensive and balanced presentation of the evidence pertinent to the effects of formaldehyde at distal sites. It also properly acknowledges the limitations in the current scientific understanding of the mechanisms associated with the plausibility that formaldehyde causes malignancies of the hematopoietic system. The committee finds that the information presented in the substance profile is in agreement with that presented in the background document.
The section “Leukemia” of the substance profile addresses three main issues: the cellular origin of myeloid leukemia, the lack of evidence of systemic distribution of formaldehyde or its metabolites, and a general description of several plausible mechanisms. A brief discussion of the cellular origins of myeloid leukemia frames the challenge that formaldehyde does not seem to reach the bone marrow, where most known leukemogens have been shown to affect hematopoietic progenitor cells. However, there might be indirect mechanisms by which formaldehyde affects bone marrow and circulating cells (see Chapter 3). The committee finds this logic to be reasonable. The substance profile acknowledges that there is little evidence that formaldehyde or its metabolites would reach systemic circulation or tissues other than those in direct contact with the agent. Several key studies have evaluated blood concentrations of formaldehyde after exposure of humans and laboratory animals but found no measurable increases (Heck et al. 1985; Casanova et al. 1988; Heck and Casanova 2004). And
a study in rats that used 13C-labeled formaldehyde and evaluated DNA-adduct formation in the nasal epithelium and distal anatomical sites, including the bone marrow, was also acknowledged in the substance profile (but not in the background document) to support the assertion that there is an apparent lack of systemic distribution of inhaled formaldehyde (Lu et al. 2010). One additional study (Moeller et al. 2011) that examined the presence of formaldehyde-associated endogenous and exogenous N2-hydroxymethyl-dG adducts in nasal mucosa and bone marrow DNA of cynomolgus macaques exposed to 13C-labeled formaldehyde was published within months of the release of the 12th RoC and was not referred to in the substance profile. The committee finds that the information presented in the study was consistent with the evidence presented by Lu et al. (2010) and the arguments that were already laid out in the substance profile; inclusion of the new publication in the 12th RoC would not have changed the overall conclusions.
Given the uncertainties in the scientific understanding of the potential mechanisms of the systemic effects of formaldehyde, the committee finds that NTP could have explicitly acknowledged, as stated in a previous expert panel’s report (McMartin et al. 2009), that “while it would be desirable to have an accepted mechanism that fully explains the association between formaldehyde exposure and distal cancers, the lack of such mechanism should not detract from the strength of the epidemiological evidence that formaldehyde causes myeloid leukemia” (p. 28).
Systemic Effects Observed after Inhalation or Oral Exposure
The section “Systemic Effects Observed after Inhalation or Oral Exposure” in the substance profile describes several additional lines of evidence that support the notion that formaldehyde has systemic adverse health effects. Such evidence includes data demonstrating toxicity, genotoxicity, and increased incidence of malignancies at distal sites (NTP 2011) following inhalation of formaldehyde. This section in the substance profile and the corresponding parts of the background document are comprehensive and balanced. The committee finds that the information presented in the substance profile agrees with that presented in the background document. Studies presented in this section are highly informative and argue that although it is yet to be established how formaldehyde can exert adverse effects systemically, the strongest evidence of a systemic effect of formaldehyde is evidence of genotoxicity in blood cells that circulate beyond the portal of entry.
The committee concludes that the study by Lu et al. (2010) and other supporting studies strongly argue for the lack of systemic distribution of inhaled formaldehyde. However, it also concludes that the relevance of formaldehyde-induced DNA adducts to formaldehyde-induced carcinogenesis is uncertain given that the background concentrations of these adducts formed by endogenous exposure to formaldehyde are greater than those induced by exogenous formal-
dehyde at carcinogenic doses, and that tissue concentrations of the adducts vary within and among species tested. In that regard, the committee highlights a point from a previous expert panel’s report that chromosome aberrations are an important biomarker of human cancer (McMartin et al. 2009). The chromosomal aberrations observed in lymphocytes of exposed human subjects constitute strong evidence of potentially genotoxic effects of formaldehyde in circulating blood cells. As acknowledged in the substance profile, evidence of genotoxicity of formaldehyde is extensive. Studies that successfully detected DNA–protein cross-links, strand breaks, micronuclei, and chromosomal aberrations in the circulating blood cells of exposed human subjects are convincing and reproducible. No one study performed with human subjects can establish that formaldehyde is the sole genotoxic agent that caused the observed effects, but the diversity of studies, populations, and exposure scenarios gives strong credence to the overall conclusion. Studies of such effects in experimental animals are less consistent, and the substance profile rightly states that “most [experimental animal] studies found no cytogenetic effects” (NTP 2011, p. 199).
The background document and substance profile also note that toxicity of formaldehyde has been reported to occur in the liver, testes, central nervous system, and other organs that would suggest a systemic effect. The publications that were evaluated by NTP include case reports of humans who ingested formaldehyde, reports of epidemiologic studies of occupational cohorts, and reports of in vivo exposures of experimental animals (rats and mice) of varied duration and dosage. Although the evidence presented in those studies is diverse and credible, NTP correctly states that “the mechanisms for systemic toxicity…are not known” (NTP 2011, p. 199).
Theoretical Mechanisms for the Distribution of Formaldehyde to Distal Sites
The substance profile accurately describes the theoretical possibility that formaldehyde might diffuse through nasal epithelia to the bloodstream and then throughout the body. The section also provides appropriate literature citations for the information that is presented. Clearly expressed is the salient issue that because of the reversible nature of formaldehyde’s reaction with water (which forms methanediol) or macromolecules, it is theoretically possible that a formaldehyde or methanediol molecule might move throughout the body. Moreover, as appropriately noted in the background document, mathematical simulation modeling efforts that incorporate formaldehyde–methanediol kinetics suggest that formaldehyde might penetrate to the bloodstream in the nose (Georgieva et al. 2003); this raises the possibility that inhaled formaldehyde might reach the systemic circulation.
The section “Theoretical Mechanisms for Distribution to Distal Sites” of the substance profile is narrowly focused. Although it is theoretically possible that formaldehyde might distribute away from the portal of entry to distant tissues, the evaluation in the substance profile would be more complete if the po-
tential for formaldehyde to move throughout the body were discussed in the context of the large amounts of endogenous formaldehyde that are present. Such an evaluation would broaden the discussion from one of the theoretical possibility of systemic distribution to a more precise evaluation of whether it is likely to occur to any important extent. Published data that were not cited in this section of the substance profile indicate that inhaled formaldehyde does not increase blood formaldehyde to concentrations that are substantially above endogenous concentrations (Heck et al. 1985; Casanova et al. 1988; Lu et al. 2010; Moeller et al. 2011). Moreover, large amounts of formaldehyde have not been shown to penetrate to tissues distant from the portal of entry. See the detailed toxicokinetics discussion in Chapter 3.
Other Potential Mechanisms of Formaldehyde-Induced Leukemia
The section “Other Potential Mechanisms of Formaldehyde-Induced Leukemia” in the substance profile offers two additional potential mechanisms to explain formaldehyde-induced leukemia. The first suggested mechanism is that “formaldehyde could damage stem cells circulating in the blood, which travel to the bone and become initiated leukemia cells,” and the second is that formaldehyde “could damage stem cells that reside in the nasal turbinates or olfactory mucosa” (NTP 2011, pp. 199-200). Both mechanisms are related to potential direct damage to hematopoietic stem cells in the nasal circulation or nasal mucosa. Literature was cited to support the implicit hypothesis that formaldehyde-induced damage occurs to hematopoietic stem cells at the portal of entry. However, this hypothesis has not been proved experimentally (reported data are related to formaldehyde-induced damage in lymphocytes, not stem cells, in circulation or in nasal mucosa). Thus, this section might appear to provide evidence to support the listing (even using the term support twice) although it simply suggests some feasibility of the mechanisms. In the absence of direct evidence, these potential mechanisms do not explain how formaldehyde causes leukemia.
Supporting and critical literature are mentioned appropriately in the background document and substance profile. Because this section does not bear on the listing of formaldehyde and because there is no direct evidence of the mechanisms, the review of the literature and the discussion are appropriately brief.
In the section “Hematotoxicity” of the substance profile, NTP reviews evidence of formaldehyde-induced hematologic effects (NTP 2011). The term hematotoxicity might imply a health effect that is not addressed in the studies cited in the substance profile. Indeed, the studies presented in the listing profile demonstrate changes in blood-cell number or function but do not address whether the changes have consequences for the health of the animal or human (for example, autoimmunity, infection, bleeding, or leukemia).
The substance profile cites two studies that support the hypothesis that formaldehyde induces hematologic effects. Substantial space is given to Zhang et al. (2010), who investigated occupational exposure to formaldehyde, hematotoxicity, and leukemia-specific chromosomal changes in cultured myeloid progenitor cells. However, several others studies cited in the background document could also contribute to this topic in the substance profile. For example, Ying et al. (1999) investigated lymphocyte subsets and sister-chromatid exchanges in students exposed to formaldehyde vapor. The authors established some specificity of the hematologic effects of formaldehyde, so citing their study in the substance profile would have strengthened the discussion in this section. Some balance is achieved in the first two sentences of the section in the substance profile although no clear synthesis of the evidence is presented. Because a number of studies provide direct and indirect evidence relevant to this topic, a balanced summary sentence on the overall weight of evidence would be helpful. It is important to note that observed changes in hematopoietic cell number or function do not directly support a mechanism of leukemogenesis but rather establish that formaldehyde has effects either directly or indirectly on hematopoietic cells in the circulation. For clarity, it should be stated how this section affects NTP’s listing of formaldehyde as a carcinogen.
The section “Properties” of the substance profile details major physicochemical characteristics of formaldehyde. Chemical stability, reactivity, and flammability characteristics are also provided. Overall, this brief section serves its purpose well and provides all necessary information on the chemical itself. The section also includes information on various alternative states of formaldehyde, including a monomeric hydrate methylene glycol (methanediol) form of formaldehyde in dilute aqueous solutions, a solid form (1,3,5-trioxane), and various polymers of eight to 100 formaldehyde units that form paraformaldehyde.
The section “Use” of the substance profile and related background document provide a comprehensive review of industrial uses of formaldehyde and paraformaldehyde. Formaldehyde is used primarily in the production of polymer products and resins, so humans might come into contact with formaldehyde through a variety of consumer products and manufacturing processes. Overall, this section supports well the reasoning for considering inclusion of formaldehyde in the RoC in that it is clear that “a significant number of persons residing in the United State are exposed” (NTP 2010, p. 3) to this chemical.
The section “Production” of the substance profile covers the chemical processes used to manufacture formaldehyde and provides quantitative estimates of domestic production and of import and export volumes. Formaldehyde is a high-volume production chemical, and manufacturing of this compound is increasing. This section and corresponding information from the background document supports a potential wide exposure to formaldehyde in the United States, inasmuch as about 30 lb of formaldehyde was produced per person in the United States in the middle 2000s. Much of that formaldehyde is used to manufacture a wide variety of products and it enters the market as a component of industrial resins, building materials, home and office furnishings, mortuary chemicals and preservatives, disinfectants in farming, and consumer products. Substantial quantities are also produced from natural sources and combustion sources. This section supports the inclusion of formaldehyde in the RoC.
The goal of the section “Exposure” in the substance profile is to show that there is widespread occupational and general population exposure. The section is divided into two subsections: environmental exposures and occupational exposures. The section on “Human Exposure” in the background document has a subsection on “Biological Indices of Exposure”. That subsection is brief and does not consider effects of endogenous formaldehyde formation, which will limit the utility of a biomarker because the variation in endogenous formaldehyde will obscure the small signal produced by exogenous exposure. However, it seems to show that some biomarkers distinguish between exposed and nonexposed workers when the exposure is high enough.
The committee observed that the purpose of the section “Exposure” in the background document was not to critically evaluate the industrial exposures that were present for epidemiologic studies evaluated in the section “Cancer Studies in Humans”. Instead, it catalogs the highly heterogeneous data gathered in studies of a wide array of environmental and occupational exposure settings and establishes that substantial occupational exposures and widespread exposures of the general population occur.
The “Regulations” and “Guidelines” sections of the substance profile provides a comprehensive list of various rules, regulations, and advisory notices that pertain to formaldehyde. It is clear that many government agencies in the United States have set quantitative limits of exposure in various scenarios and regulate production, use, distribution, and disposal of formaldehyde, but the
level of detail provided on these in the background document and substance profile varies widely, and it is not clear in many cases whether the appropriate source can be easily found. Many regulations are dated without links to the appropriate document sources.
NTP conducted several literature searches to identify carcinogenicity studies that inform the assessment of formaldehyde in the NTP 12th RoC, and some of that information is presented in the section “Human Cancer Studies” of the background document (NTP 2010). For that specific section in the background document, NTP identified some of its search terms, the databases searched, and the inclusion and exclusion criteria that were used. Such details were not included in the background document for other topics, including studies in experimental animals and mechanistic data.
In response to a request from the committee, NTP provided additional information on its literature search methods (Bucher 2013). PubMed, Scopus, and Web of Science were searched by using substance-specific terms (that is, the substance name, major synonyms, and major metabolites) and topic-specific terms (see Table 2-1). The results underwent a first level of review, during which titles and abstracts were screened for relevance, followed by a second level of review in which the full text of references was reviewed for relevance and substance. In the second level of review, 1,170 references were considered. Some 38 additional references were recommended to NTP by an expert panel (McMartin et al. 2009, 2010). In total, 798 references were cited in the final background document. The date when the searches were run and the specific search strings used for each database were not provided to the committee. The committee found that including more detail on the search strategies and on the inclusion and exclusion criteria would have improved transparency of the methods that NTP used to identify and evaluate relevant scientific literature related to formaldehyde exposure and carcinogenicity. Other committees of the National Academies (IOM 2011; NRC 2011, 2014) have made related recommendations about clearly and concisely describing literature searches, and approaches that ensure greater transparency in literature searches and systematic reviews are being initiated by the US Environmental Protection Agency’s Integrated Risk Information System (EPA 2013) and NTP’s Office of Health Assessment and Translation (NTP 2013).
The final background document summarizes the literature up to the date of the peer review of the background document (November 2009), and the substance profile includes literature up to the date of the peer review by the NTP Board of Scientific Counselors (June 2010) (Bucher et al. 2013). (see Figure 1-1
|Human Cancer||Animal Tumors||Genotoxicity||ADME and Mechanisms|
|MeSH terms||MeSH terms||MeSH terms||MeSH terms|
|Case–control studies||Adenoma||Cell transformation,||Biotransformation|
|Epidemiologic studies||Neoplasms||Cytogenic analysis||Cytochrome P-450 enzyme system|
|Mortality||Precancerous condition||DNA adducts|
|Neoplasms||Sarcoma||DNA damage||Text words|
|Occupational exposure||Animals||DNA repair||Activation|
|Prospective studies||Germ-line mutation||Bioactivation|
|Retrospective studies||Text words||Micronuclei||Clearance|
|Carcinogenic||Rats||Sister chromatid exchange||Metabolite|
|Unscheduled DNA synthesis|
*The asterisk, sometimes referred to as a “wildcard”, represents a truncation and it is used to find all terms that begin with the given text string. Abbreviations: ADME, absorption, distribution, metabolism, and excretion; MeSH, medical subject headings. Source: Bucher 2013.
for a schematic of the 12th RoC process.) NTP periodically reviewed the scientific literature up to the release of the 12th RoC (June 2011) “for any new studies that would warrant a re-review of the NTP’s preliminary recommendations to the HHS Secretary for the listing status of formaldehyde” (Bucher 2013). Describing that process in greater detail in the background document, including specific dates, would have added transparency to the development of the background document and substance profile.
Through its review of the background document and substance profile for formaldehyde, the committee identified several revisions that could be made to improve the formaldehyde listing in future iterations of the RoC (see Table 2-2). Addressing the suggestions in Table 2-2 would add clarity and improve the presentation of information in NTP’s assessment of formaldehyde, but making the revisions would not change the overall conclusion of carcinogenicity presented in the substance profile.
In response to the statement of task, the committee examined the substance profile published by NTP as part of the 12th RoC. It also examined supporting documents, including those presented in Table 1-1, and relevant primary literature. The committee considered information presented in review articles, reviews completed by such scientific bodies as IARC, and materials submitted to it by the public.
The committee found that the background document describes the strengths and weaknesses of relevant studies in a way that is consistent and balanced. The substance profile appropriately cites studies showing positive associations that support the listing. However, the substance profile would be more complete if it included more discussion on why weaker, uninformative, 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 change NTP’s final conclusions as presented in the substance profile.
The committee concludes that NTP comprehensively considered available evidence and applied the listing criteria appropriately in reaching its conclusion. The 12th RoC states that “formaldehyde is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans and supporting data on mechanisms of carcinogenesis” (NTP 2011, p. 195). The committee agrees with NTP’s conclusion, which is based on evidence published by June 10, 2011, that formaldehyde is a known human carcinogen.
|Sections in the Substance Profile for Formaldehyde||Suggested Revisions|
|Study Identification||• Describe the process for identifying relevant literature (including databases searched, keywords used, and search dates).|
|Cancer Studies in Humans||• Explicitly define the way in which RoC listing criteria terms such as limited and sufficient were used in the evaluation of the human studies.
• Clarify how the quality and relevance of meta-analyses were evaluated and how and why meta-analyses were included in the assessment of the epidemiology evidence.
• Add a more detailed description of how exposure assessments were used to evaluate the evidence from individual epidemiology studies.
• Include an explanation of the logic used to decide which tumor groupings or end points to include in evaluating epidemiologic evidence.
|Cancer Studies in Experimental Animals||• Consider including a finding that formaldehyde induces tumors to an unusual degree (high incidences of rare squamous-cell tumors of the nasal epithelium).|
|Other Relevant Data||• Include a description of the portal-of-entry toxicity of formaldehyde.
• Add a discussion in the background document for formaldehyde of the extensive metabolism of formaldehyde at the portal of entry.
• Add a discussion of formaldehyde as a well-established irritant that has the potential to produce an allergic response.
|Studies on Mechanisms of Carcinogenesis||Nasal Cancer
• Change the title of the section on “Nasal Cancer” to reflect the two distinct potential portal-of-entry target sites.
• Strengthen the summary of the genotoxic mode of action discussion.
• Restructure the discussion in the substance profile to parallel the presentation of information in the background document.
• Change the title of the section on “Leukemia” to make it clear that the information pertains to potential systemic effects of formaldehyde.
• Explicitly acknowledge that “while it would be desirable to have an accepted mechanism that fully explains the association between formaldehyde exposure and distal cancers, the lack of such mechanism should not detract from the strength of the epidemiological evidence that formaldehyde causes myeloid leukemia” (McMartin et al. 2009).
• Discuss the potential for formaldehyde to move throughout the body in the context of the large amounts of endogenous formaldehyde that are present.
• Make it clear that the section on “Other Potential Mechanisms of Formaldehyde-induced Leukemia” is intended to show feasibility, not evidence of or support for the mechanisms.
• Change the title of the section “Hematotoxicity” to “Hematologic and Immunologic Effects” so that the substance profile is consistent with the background document. In addition, add a balanced summary sentence to that section on the overall strength of the evidence and state how that section affects NTP’s listing for formaldehyde as a carcinogen.
|Exposure||• Integrate information from the section “Exposure” about environmental and occupational settings into the assessment of the epidemiologic studies in the “Human Studies” section.
• Strengthen and focus the listing of heterogeneous data in the background document by removing any incomplete and limited data and by providing a more organized presentation of the information.
• Compare and contrast different types of industries in a quantitative manner. Situations that involve exposure to particulate materials that contain formaldehyde could be treated separately. Occupational and other activities that produce peak exposures could also be noted and measured. Time trends, if any, in exposure could be identified.
• Adopt a consistent unit of exposure for occupational and environmental exposures.
|Regulations and Guidelines||• Provide more information on regulations and include proper references to the sources.|
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