4
Noncancer Health Effects

EPA assessed multiple noncancer health effects associated with formaldehyde exposure. These effects can be characterized as either portal-of-entry or systemic effects: portal-of-entry effects are those that arise from direct interaction of inhaled or ingested formaldehyde with the affected cells or tissues, while systemic effects are those that occur beyond tissues or cells at the portal of entry.

This chapter addresses EPA’s assessment of the selected noncancer health effects of formaldehyde. In line with its overall charge, the committee focused its review on whether the 2022 Draft Assessment (EPA, 2022) adequately and transparently evaluates the available studies and data, and uses appropriate methods in reaching hazard identification conclusions and dose-response analyses that are supported by the scientific evidence. The committee focused on health outcomes that led to derivation of a candidate reference concentration (cRfC).

The sections that follow address the following outcomes: sensory irritation, pulmonary function, respiratory pathology, allergy and asthma, reproductive and developmental toxicity, and neurotoxicity. The committee’s review encompassed consideration of whether EPA identified the appropriate studies; whether, according to its state-of-practice methods, it conducted the hazard identification appropriately; and whether suitable studies were advanced for calculation of the cRfC for each outcome. Each section provides a brief introduction to the health effect, steps used by EPA to identify the relevant literature, outcome specific criteria used to evaluate studies, an overview of EPA’s synthesis and integration judgments, EPA’s overall conclusions, and whether EPA used appropriate dose-response evaluations to derive cRfCs. A brief overview of the methods used by EPA to identify points of departure (PODs) and cRfCs is also provided. To complete this task, the committee broadly reviewed relevant portions of the Main Assessment, associated Appendices, and the Assessment Overview. Table 4-1 documents the specific materials considered for each health outcome.

Tier 2 and 3 recommendations specific to each outcome are provided in the sections below. The committee’s discussion of cross-cutting issues related to the methods used by EPA for its assessment of these outcomes is presented in Chapter 2. Although the committee was not charged with providing a comprehensive list, Appendix E gives specific examples of these issues to illustrate the committee’s recommendation and to serve as a guide to EPA’s revision. Thus, in implementing the Tier 2 and 3 recommendations provided for each outcome, EPA should take account of the additional relevant findings, recommendations, and detailed issues included in Chapter 2 (for general methodological issues), in the section below on EPA’s approach to dose-response, and in Appendix E.

NONCANCER PORTAL-OF-ENTRY EFFECTS

Portal-of-entry effects occur following direct interaction of inhaled formaldehyde with the respiratory tract or other tissues. Noncancer portal-of-entry effects include sensory irritation, decreased pulmonary function, respiratory tract pathology, and allergies and asthma. Although it is a portal-of-entry effect, the committee’s discussion concerning asthma is included in the evaluation of systemic effects, reflecting the broader inflammatory consequences of asthma.

TABLE 4-1 Documents Reviewed by the Committee during Its Evaluation of the EPA’s Assessment of Noncancer Health Outcomes in the 2022 Draft Assessment (EPA, 2022)

SENSORY IRRITATION

Sensory effects of formaldehyde, which has a strong odor, have been studied for several decades, although only a handful of studies have been published more recently. Sensory irritation encompasses eye, nose, and throat symptoms, and evidence concerning this outcome is based on experimental and observational studies in humans. According to EPA, sensory irritation in animals following formaldehyde inhalation is well established. The primary mechanism involved in sensory irritation is stimulation of the branch of the trigeminal nerve present in the respiratory mucosa. Oxidative stress at low formaldehyde concentrations may also contribute to sensory irritation. Using a systematic approach to identify and evaluate relevant studies, EPA identified three studies for POD analysis to derive cRfCs, and chose one study, representing an organ- or system-specific cRfC, for consideration of the overall formaldehyde RfC.

Literature Identification

In the Main Assessment and Appendices, EPA documents the steps it followed to formulate a population, exposure, comparator, and outcome (PECO) statement; develop inclusion and exclusion criteria; and conduct its literature search. EPA updated its literature searches annually through September 2016, after which systematic evidence mapping was used to search studies through 2021. For its literature search, EPA used four databases, and curated reference lists in published reviews and other national or international health assessments of formaldehyde (see Appendix A, Section A-231), although the flow diagram shows that only two databases were used (Figures A-22 and A-263). Search terms included formaldehyde, paraformaldehyde, formalin, irritation, irritant, and irritants (Table A-31).

Excluding outdoor studies from the 2022 Draft Assessment may skew the evidence pool in the direction of higher exposure studies relative to the levels commonly experienced by the general population. The committee also found unconvincing EPA’s argument that studies with lower exposure levels may have a limited ability to detect associations between formaldehyde exposure and health effects.

The committee notes further that the assertion that outdoor levels of formaldehyde are universally below 0.005 mg/m³ may not correctly represent true population exposures for all geographies and time periods. For example, the Hanrahan et al. (1984) study, which is a pivotal sensory irritation study for this assessment, reported mean outdoor levels of 0.04 ppm (0.05 mg/m³) with high variation (standard deviation [SD] = 0.03 ppm). The committee noted that additional studies reported ambient levels at or above 0.005 mg/m³, as summarized in Table 4-2.

Study Evaluation

Outcome-specific criteria used to evaluate human studies of formaldehyde-induced sensory irritation included participant selection; information bias; potential for confounding; statistical analysis; and other considerations, such as exposure levels, contrast, duration of follow-up, and sensitivity of outcome assessment (Appendix A, Section A-233). Figure A-22 states that a total of 38 observational studies and 20 randomized controlled trials on humans were included for sensory irritation. Selection bias receives some attention in the evaluation, given the cross-sectional nature of some of the key observational studies.

TABLE 4-2 Formaldehyde Levels in Outdoor Air Reported in Selected Studies

NOTES:

^a GM = geometric mean.

^b See also Table 6 of this article for additional studies on formaldehyde.

^c SD, Standard deviation.

Evidence Synthesis and Judgment

The 2022 Draft Assessment concludes that there is robust evidence for sensory irritation from controlled human exposure studies, as well as epidemiological studies. It also concludes that robust evidence exists from animal studies, and there are established mechanisms. The 2022 Draft Assessment indicates further that there is robust evidence for a specific mode of action (MOA) underlying the association between inhalation of formaldehyde and sensory irritation. Formaldehyde exposure directly or indirectly stimulates trigeminal nerve endings in the respiratory epithelium, which has been highlighted as the dominant pathway for causing this outcome. The supporting evidence is based largely on animal studies, but EPA’s interpretation is that the suggested MOA identified in animals is also relevant to humans.

Overall Conclusions About the Hazard Descriptor

EPA’s judgment was that, taken together, the evidence demonstrates that inhalation of formaldehyde causes sensory irritation. This judgment was based on four high- and medium-confidence studies of symptom prevalence in humans in residential settings, numerous high- and medium-confidence acute controlled human exposure studies, and numerous high- and medium-confidence occupational studies.

Dose-Response Evaluation

In section 2.1.1 of the Main Assessment (p. 2-2), EPA states that only high- and medium-confidence studies were chosen for POD analysis. This section also reports that emphasis was placed on the characteristics of the study population, the accuracy of formaldehyde exposure, the severity of the observed effects, and the exposure levels. Human epidemiological studies that evaluated groups most representative of the general population were preferred, as were studies that reported complete results and are unlikely to have alternative explanations.

EPA excluded three of the six studies selected for POD derivation: one (Liu et al., 1991) that reported partial results, another (Mueller et al., 2013) that did not observe an exposure–response relationship, and a third (Lang et al., 2008) for which the adverse response level was difficult to define. For the remaining three studies, EPA derived a POD. EPA stated that of these three studies, it had less confidence in those of Kulle et al. (1987) and Andersen and Molhave (1983), which were controlled exposure studies for which the PODs were an order of magnitude higher than that for the study by Hanrahan et al. (1984), which was the final selection.

PULMONARY FUNCTION

Pulmonary function is an important health outcome given the association of level of lung function with mortality, chronic respiratory disease, and coronary heart disease. Small declines in pulmonary function can have a large impact on public health, regardless of whether individual declines are clinically significant (ATS, 2000). Thus, EPA evaluated studies reporting changes in pulmonary function following formaldehyde exposure with changes in spirometric measure outcomes, including FEV₁ (forced expiratory volume in 1 second), FVC (forced vital capacity), their ratio (FEV1/FVC), maximum midexpiratory flow or forced expiratory flow 25–75 percent (FEF_25-75), and peak expiratory flow rate (PEFR). EPA’s review and evaluation focused on experimental and observational studies in humans. Animal studies were not considered because “there were few directly relevant studies in the peer-reviewed literature and the extensive literature on these endpoints in humans was considered adequate to draw a hazard conclusion” (Main Assessment, p. 93, lines 8–11). Thus, animal studies of analogous endpoints were not searched for or cited in the hazard evaluation. However, animal study evidence was used to provide mechanistic support.

Formaldehyde exposure levels differed, mainly as a result of study design. Occupational exposures tended to have time-weighted average (TWA) concentrations above 0.2 mg/m³, with some intermittent peaks at >1 mg/m³, while students in anatomy labs had exposures between 0.1 and >1 mg/m³. Exposures in community settings (residences, schools) were often below 0.1 mg/m³. In controlled human exposure settings, formaldehyde exposures ranged between 0.61 and 3.7 mg/m³.

Literature Identification

Table A-41 in Appendix A summarizes the search terms used for PubMed and Web of Science. Table A-42 (p. 314) summarizes the PECO inclusion and exclusion criteria. Only human studies with indoor inhalation exposure and formaldehyde measurements were included. Outcomes were restricted to FVC, FEV₁, FEF, and PEFR.

A total of 53 studies were identified and evaluated for consideration (Appendix A, p. 313, line 15). This total apparently represents studies rather than individual publications since some studies are described in multiple publications (e.g., Broder et al., 1988a,b,c). Among these 53 studies were 42 observational epidemiology and 11 controlled human exposure studies (Appendix A, Figure A-23). Publication dates for these studies ranged between 1975 and 2015.

Study Evaluation

Methodological issues considered in the evaluation of studies are provided in the Main Assessment (p. 95), as well as in the Assessment Overview (Section 3.2.2). They include pulmonary function measures (with a table of definitions [Table 1-5]); a preference for studies that follow American Thoracic Society (ATS) guidelines or provide detailed protocol and reference equation information; and a preference for pulmonary function measures normalized by race or ethnic origin, gender, age, and height. EPA mentions smoking as a potential confounder and the need to consider a referent group when evaluating change across a work shift or laboratory session. Appendix A presents a table (Table A-43) of criteria used to categorize study confidence for epidemiological studies as high, medium, low, and not informative. This table considers two aspects: (1) exposure, and (2) study design and analysis. Neither the Main Assessment nor the Assessment

Overview references Table A-43. Table A-44 provides EPA’s evaluation of all epidemiological studies of pulmonary function, organized by study type and then alphabetically by author. Some studies have multiple confidence ratings— for example, for preshift versus cross-shift outcomes, longitudinal versus cross-lab change, or comparison with community referents versus change during embalming. Table A-45 covers the controlled human exposure studies. This table is organized by confidence level and then year of publication, with the confidence categories being medium (randomized, with results fully reported) (five publications), low (incomplete reporting of results or blinding not described, with multiple exposure levels) (four publications), and low (no randomization, with blinding not discussed) (two publications).

Evidence Synthesis and Judgments

Section 1.2 of the Main Assessment, “Synthesis of Evidence for the Effects on the Respiratory System,” addresses synthesis between and within evidence streams for all noncancer outcomes. Section 1.2.2, “Pulmonary Function,” begins with an overview providing brief comments on aspects of the literature identification and inclusion, followed by brief summaries of the evidence synthesis, mechanistic support, and hazard evaluation. Detailed synthesis information begins with the unnumbered subsection on PDF p. 96 “Pulmonary Function Studies in Humans.” The synthesis discussion is blended with the study evaluation tables (Tables 1-6 to 1-9) also presented in this section, and the subsection is organized by exposure duration (acute, intermediate, and long-term) and study design features: for acute, controlled human exposure and observational within the work shift or anatomy lab section; for intermediate, anatomy labs; and for long-term, occupational and then residential. Appendix A provides several figures (A-24 to A-26) that show results from studies describing change in pulmonary function measures during a work shift or anatomy lab session, with one figure for each outcome measure (FEF, FEV₁, FVC, etc.). This topic ends with Table A-46, summarizing each of those studies. The following narrative provides specific comments relevant to the synthesis discussion for each study grouping presented in the Main Assessment.

Acute controlled human exposure studies. This subsection notes that while formaldehyde exposure has not been shown to induce pulmonary function deficits in nonexercising healthy volunteers, small but statistically significant deficits have been observed in studies with two or more 15-minute exercise regimens, although not in studies with shorter exercise segments. The overview at the beginning of Section 1.2.2 (Main Assessment, p. 93) indicates that the controlled human exposure studies “consistently did not observe changes.”

Acute epidemiological studies: Changes in pulmonary function across a work shift or anatomy course lab session. This subsection considers studies of work shift changes among multiple occupations (plywood workers, chemical industries, funeral workers), as well as students in anatomy lab sessions. The workers were assumed to have had prior formaldehyde exposure, while the students were not. The text states that many of the studies “observed pulmonary function declines over the course of the workday or lab.” Most studies did not consider change in an unexposed referent group; studies that did include a referent group showed a change in pulmonary function on average in that group, although studies varied with respect to the direction observed, and this additional potentially insightful detail is not provided.

Intermediate-duration exposures (<1 year) among anatomy/pathology students. The discussion of the three panel studies published by two sets of authors highlights that there were different results for spirometry measures (FVC, FEV₁, FEV₁/FVC, and FEF_25-75) in one study versus change in PEFR measures in two other studies. Interpretation of those studies was challenged by intermittent exposures, student absences, and decreasing formaldehyde concentrations over the quarter.

These studies are not mentioned further in any of the summaries (i.e., the beginning of Section 1.2.2 of the Assessment Overview or the integrated summary of evidence in the Main Assessment).

Long-term formaldehyde exposure in occupational settings. This subsection addresses two types of study design: cross-sectional (or prevalence) studies and longitudinal studies. Note that the reference to cross-sectional studies (Main Assessment, p. 102) points to studies under the “prevalence studies” heading in Table 1-7; it is left to the reader to make this connection. EPA concludes that overall, these studies show evidence of decrements in pulmonary function associated with formaldehyde exposure, particularly given that many studies could be biased toward no association.

For the cross-sectional studies, challenges are highlighted in the text: selection bias (healthy worker effect and survivor [lead time] bias), a community-based reference group in one study, higher prevalence of other exposures affecting pulmonary function in the referent group). Nonetheless, EPA notes that most studies observed associations of formaldehyde with deficits in pulmonary function before the work shift at the beginning of the work week.

The discussion of the longitudinal results from three studies with lead authors Nunn, Alexandersson, and Lofstedt (p. 1–47, PDF p. 106), highlights that the four- to six-year duration of these studies, their small sample sizes, and the potential for exposure-related loss to follow-up leading to selection bias are challenges, but notes that nonetheless, some pulmonary function declines were reported. Three studies are mentioned briefly, and then an additional two reference studies are covered (Lee and Fry, 2010; Redlich et al., 2014). They report a formaldehyde-associated age-related decline in FEV₁ among nonsmokers that was 50 percent greater compared with the expected rate of age-related decline. The remainder of the discussion concerns duration of work in an exposed job and its association with pulmonary function. EPA concluded that results “seem to support a conclusion that occupational exposure may result in declines of FEV₁ and FEF over time” (PDF p. 53 of the Assessment Overview), but did not deem them to be consistent across studies.

Residential exposures among adults. This section addresses four studies (covered in seven publications), noting the challenge of comparing them given their different approaches to pulmonary function assessment and reporting. Overall, EPA concluded that “adults in general did not experience declines in pulmonary function at average formaldehyde levels less than 0.05 mg/m³” (PDF p. 117). Much of the discussion in this subsection focuses on Krzyzanowski et al. (1990) because it was rated as having high confidence.

Residential and school exposures among children. This discussion also focuses on Krzyzanowski et al. (1990), whose results for children aged <15 years show a decrease in PEFR associated with increased formaldehyde exposure. Results from this paper are reproduced in Figure 1-6, which shows the modeled decrease in PEFR per unit of formaldehyde exposure; the figure would benefit from a more in-depth discussion given the later use of this study for dose-response analysis. The general discussion highlights the low exposures in these studies and the small exposure contrast in one, although it was difficult to determine the exposure concentration reported by Wallner et al. (2012).

EPA’s synthesis also considers the MOA evidence for decrements in pulmonary function. As summarized in Figure 1-7, the most plausible mechanisms are indirect activation of sensory nerve endings in the lower respiratory tract and/or increases in airway eosinophils. There are also possible changes in the upper respiratory tract that may contribute to this outcome. Table 1-10 summarizes the studies that provide the most informative mechanistic evidence regarding decrements in pulmonary function following formaldehyde exposure.

Overall Conclusions About the Hazard Descriptor

EPA concluded that, based on moderate human evidence, long-term inhalation of formaldehyde is likely causal for decreases in pulmonary function (i.e., EPA applied the evidence indicates rating). EPA deemed Krzyzanowski et al. (1990) to have the strongest design and methods, providing evidence supported by a more limited study in schools conducted by Wallner et al. (2012). The narrative and table also mention “several studies of workers with long-term exposure to >0.2 mg/m³” without giving references. EPA also concluded that the evidence is inadequate to determine the causal effect of formaldehyde exposure on acute and intermediate-term time scales. This judgment does not give much weight to the evidence that pulmonary function decrements

occurred in controlled human exposure settings among participants who exercised at least 30 minutes (Green et al., 1987, 1989), or that some individuals exhibited clinically significant deficits (Green et al., 1987).

Dose-Response Evaluation

EPA’s confidence in the human study used to derive the POD (Krzyzanowski et al., 1990) was high. This cross-sectional study of residential exposure found a linear relationship between higher formaldehyde exposure and decreased PEFR among children exposed to average concentrations of 0.032 mg/m³ (26 ppb). EPA applied benchmark dose modeling to calculate the concentration at which a 10 percent decrement in pulmonary function would be expected; EPA considered a 10 percent decrement to be the benchmark response (BMR). A benchmark concentration (BMC)₁₀ (0.033 mg/m³) and benchmark concentration lower bound (BMCL)₁₀ (0.021 mg/m³) were subsequently determined from the regression coefficient from a random effects model of PEFR among children reported by the study authors. A single uncertainty factor to account for variability among humans (UF_H) of 3 was applied to the BMCL₁₀ to derive a cRfC of 0.007 mg/m³.

RESPIRATORY PATHOLOGY

Formaldehyde’s effects on the respiratory tract have been studied extensively. Animal studies show that inhaled formaldehyde at 2 ppm or higher is cytotoxic and that increases in epithelial cell proliferation occur after chronic formaldehyde inhalation in mice, rats, and nonhuman primates (Kerns et al., 1983; Monticello et al., 1996). Formaldehyde-induced airway lesions in animals include rhinitis, epithelial dysplasia, and squamous metaplasia. These lesions demonstrate concentration, time, and site dependence, as well as an anterior-to-posterior severity gradient (Kerns et al., 1983; Monticello et al., 1996).

Literature Identification

PubMed search terms related to respiratory tract pathology in humans included hyperplasia, metaplasia, nasal mucosa, occupational diseases, respiratory tract diseases, rhinitis, and mucociliary. Some broad terms (e.g., the MeSH term pathology) were not used in the search for human literature.

A total of 1009 citations were screened (title and abstract) for assessment of respiratory tract pathology in humans, and 12 studies were ultimately included in the review (Appendix A, p. A-390). A total of 1678 citations were screened (title and abstract) for the assessment of respiratory

tract pathology in animals, and 41 toxicology studies were ultimately included in the review (Appendix A, p. A-393).

Study Evaluation

Outcome-specific criteria used to evaluate human studies of formaldehyde-induced respiratory pathology included assessment of the exposure, participant selection and comparability, possibility of confounding, analysis and completeness of results, and study size (Appendix A, Table A-57). EPA evaluated whether studies describing histologic results provided an explanation of how tissues were evaluated and scored. EPA downgraded cross-sectional studies among occupational cohorts since workers may have been less sensitive to the irritant properties of formaldehyde then the general population. EPA considered gender and smoking were considered by EPA to be potential confounders for pathological endpoints.

Outcome-specific criteria used to assess the animal studies included sample size, inadequate reporting of lesion incidence and/or severity, combining of multiple lesions, inadequate sampling of the respiratory tract, and short (<1 year) exposure duration or follow-up. EPA also evaluated the source of the formaldehyde (e.g., commercial grade, paraformaldehyde, or formalin). Coexposure to methanol (found in some formalin products) was not considered to be a major confounding factor for identifying effects of inhaled formaldehyde on respiratory pathology. According to EPA, “a sample size of less than 10 was considered a significant limitation”; however, this criterion was applied to the Holmstrom et al. (1989) study even though this study had 16 animals/group.

Evidence Synthesis and Judgments

EPA identified no high-confidence and four medium-confidence human occupational studies. Histological changes in the respiratory tract seen in the latter four studies were associated with formaldehyde exposures ranging from 0.1 to 2.5 mg/m³ (Table 1-25). EPA downgraded occupational studies for this outcome. EPA’s rationale for this downgrade was that survivor bias impacted studies, specifically, “current workers who likely were less sensitive ‘survivors’ of the long-term respiratory irritant effects of formaldehyde, which would cause survival bias and an attenuation of comparisons between exposed and comparison groups” (pp. 1–153). Although this downgrade was applied, EPA did not critically evaluate whether a healthy worker survivor effect was present in these studies.

EPA’s evaluation of animal studies focused on the incidence of hyperplasia and metaplasia after formaldehyde inhalation. Only studies judged by EPA to be of high and medium confidence are included in the synthesis and evidence tables in the Main Assessment. Long-term studies were also deemed more relevant for the assessment. EPA concluded that “a clear relationship between formaldehyde exposure duration and the development of squamous metaplasia and, to a lesser extent, hyperplasia” (pp. 1–161) could be drawn from the experimental animal studies. EPA characterizes formaldehyde-induced squamous metaplasia in the rat nasal cavity as minimally adverse, with no clear discussion of this determination.

EPA identified a single study conducted in rhesus monkeys as having medium confidence. This study reported hyperplasia and metaplasia in the larynx, trachea, and carina after a 6-week exposure to 7.4 mg/m³ formaldehyde (Monticello et al., 1989). EPA concluded that these data may suggest that the “monkey nose is less efficient than the rodent nose at scrubbing formaldehyde from inhaled air” (pp. 1–160). Although this conclusion is plausible, a more likely explanation relates to differences in breathing patterns between rodents and nonhuman primates (obligatory nasal versus oronasal).

EPA reviewed mechanistic data extensively and found robust data for several endpoints, including the binding of formaldehyde to macromolecules, alterations in mucociliary function, epithelial damage or dysfunction in the upper respiratory tract, increased cell proliferation in the upper respiratory tract, and trigeminal nerve stimulation. These data were used to support EPA’s conclusion that epithelial cell injury results in squamous metaplasia in the upper respiratory tract.

Overall Conclusions About the Hazard Descriptor

EPA concluded that there was robust evidence that inhaled formaldehyde exposure can induce histopathologic lesions in the nasal cavity and other portions of the upper respiratory tract. Lesions were dependent on both the formaldehyde concentration and, to a lesser extent, duration of exposure. This conclusion was based on numerous high- and medium-confidence studies of chronic and subchronic exposure duration of multiple experimental animal species. EPA also concluded that the data provide moderate evidence that inhaled formaldehyde induces histopathological lesions in the human upper respiratory tract. This determination was based on four mediumconfidence human epidemiological studies (Ballarin et al., 1992; Boysen et al., 1990; Edling et al.,

1988; Holmstrom et al., 1989). These studies showed that participants exposed to average formaldehyde levels between 0.05 and 0.6 mg/m³ had higher average histopathology scores than those of their respective comparison group. Overall, the strength of the evidence for hyperplasia and squamous metaplasia includes robust evidence from animal studies and moderate human evidence from observational epidemiological studies, and strong support for a plausible MOA based primarily on mechanistic evidence from experimental animals. EPA’s overall conclusion is that the evidence demonstrates that inhalation of formaldehyde causes respiratory tract pathology in humans given the appropriate exposure circumstances.

Dose-Response Evaluation

EPA’s confidence in the two studies used to derive PODs was high. Four human studies EPA judged as having medium confidence provided additional support. The PODs derived by EPA were based on lesions seen at Level 1 in the rat nasal cavity. EPA used lesion incidence data (Woutersen et al., 1989; Kerns et al., 1983) to model the dose-response relationship. EPA found that the 24-month data for Level 1 (Table 1-26) could not be modeled because of the steep dose-response relationship seen in the Kerns et al. (1983) study, so it modeled the 18-month incidence data and obtained a BMCL₁₀ of 0.448 mg/m³ (Table 2-5).

EPA used a computational fluid dynamic (CFD) model (Kimbell et al., 2001) to estimate formaldehyde flux at the Level 1 cross section of the F344 rat nose. EPA found that the average flux in the Level 1 region corresponding to the BMCL₁₀ of 0.448 mg/m³ determined for the Kerns et al. (1983) study was estimated to be 685 pmol/mm²-hr. A human CFD model (Kimbell et al., 2001) was then used to estimate the formaldehyde exposure concentration (0.484 mg/m³) that would result in a similar formaldehyde flux in the human nose (Table 2-5; Appendix B, Section B.1.3). This value was subsequently adjusted for continuous exposure (6 hours/24 hours) × (5 days/7 days) to provide a human POD_ADJ of 0.086 mg/m³.

A human POD_ADJ of 0.094 mg/m³ was obtained for squamous metaplasia at nasal Level 1 using lesion incidence data from Woutersen et al. (1989). Since a CFD model for Wistar rats was unavailable, EPA based the POD for the Woutersen et al. (1989) study on parts per million equivalence (pp. 2–19).

EPA’s confidence in the POD calculation based on Woutersen et al. (1989) was medium, while confidence based on Kerns et al. (1983) was low. EPA stated that it assigned lower confidence to the POD derived from Kerns et al. (1983) because the calculation involved an extrapolation well below the tested formaldehyde concentrations, and the BMC was based on the 18-month exposure rather than the 24-month exposure, where responses were greater in magnitude. EPA did not explain why its confidence in the POD based on the Woutersen et al. (1989) study was medium.

An uncertainty factor (UF)A interspecies uncertainty of 3 was used to account for animal-to-human variation; a UF_H of 10 was used to account for human variation; and a UF_S subchronic uncertainty factor of 3 was applied to account for extrapolation to chronic exposure in the Kerns et al. (1983) study. Incidence data for squamous metaplasia at Level 1 from the Kerns et al. (1983) study are reported in Table 1-26. EPA’s rationale for including a UF_S of 3 rests on its inability to model the 24-month data from the Kerns et al. (1983) study, prompting use of the 18-month data. EPA acknowledges that “a lower POD would have been expected if the 24-month data could have been modeled” (p. 74), and EPA states further that “while exposure duration is important to the development of this lesion, such effects appear to be more dependent on exposure concentration”

(p. 75). In addition, an 18-month study in rats is a chronic-duration study that would not typically necessitate the use of a subchronic UF.

Two cRFCs were calculated for respiratory tract pathology. The first was estimated using data from Woutersen et al. (1989), had a composite UF of 30 (UFA = 3, UF_H = 10), and was 0.003 mg/m³. The second cRFC was estimated using data from Kerns et al. (1983), had a composite UF of 100 (as discussed above), and was 0.0009 mg/m³. EPA chose the organ-specific RfC for respiratory tract pathology of 0.003 mg/m³ based on the Woutersen et al. (1989) study. EPA considered the completeness of the database for respiratory tract pathology to be high.

NONCANCER SYSTEMIC EFFECTS

The potential systemic effects of formaldehyde that are evaluated in the 2022 Draft Assessment include immunotoxicity (allergy and asthma), reproductive toxicity, and neurotoxicity. As noted in Chapter 3 of the present report, systemic bioavailability of inhaled formaldehyde beyond the respiratory tract is unlikely. Thus, systemic responses are unlikely to arise from the direct delivery of formaldehyde to a distant site in the body by mechanisms that could result in injury at sites distal from the respiratory tract.

ALLERGY AND ASTHMA

Formaldehyde’s capacity to induce irritation and immune response–driven pathologies in nasopharyngeal and pulmonary organs is related in part to activation or suppression of immune function. As a respiratory toxicant, formaldehyde causes bronchial constriction, but it may also directly impact immune cells in the upper airway, cause formation of modified proteins that are antigenic, and exacerbate existing immune-related pathologies in exposed individuals. Immune-related diseases that are potentially linked to formaldehyde have a variety of mechanisms and pathologies that can be confused without careful diagnosis or validated assessments. Formaldehyde is a very common skin allergen that causes allergic contact dermatitis at a prevalence of 8 percent of the U.S. population (Silverberg et al., 2021). Because EPA was conducting an inhalation-specific assessment, this immune-toxic feature of skin contact formaldehyde is not reviewed in the 2022 Draft Assessment, apart from the capacity of inhaled formaldehyde to aggravate dermatologic conditions. Although EPA reviewed formaldehyde’s impact on lower respiratory tract infections, it does not discuss it in detail, concluding that studies related to this outcome did not provide meaningful evidence for determination of a cRfC.

The primary diagnoses EPA chose to define as immune-related health effects following formaldehyde inhalation are allergy and asthma. This decision led to the convocation of two expert panels (one on allergy and one on asthma) to help EPA define the relevant symptoms, physiology, biomarkers of disease, and specific diagnoses to include for search terms. This approach was unique to this outcome domain because the mechanisms of toxicity for relevant immunopathophysiologies were deemed beyond EPA’s expertise. Since these diseases can be misidentified by self-report, biomarker classifications of disease were favored in evaluating strength of evidence; validated (by the American Thoracic Society) questionnaire information was also favored for highconfidence determinations. Animal studies were viewed as indeterminate for allergy and asthma because of the unsuitability of animal models for evaluation of pathophysiology and mechanisms of these outcomes from formaldehyde exposures.

Literature Identification

EPA’s literature search strategy is described in detail in the 2022 Draft Assessment, and was informed by consultation with the outside experts. Table A-48 in Appendix A describes the PECO criteria. The experts advised EPA on study inclusion/exclusion criteria, diagnosis instruments used for immune outcomes, confidence assessments for specific studies, ages of participants, and disease mechanisms. The use of validated questionnaire instruments (e.g., International Study of Arthritis and Allergies in Children [ISAAC]; Asher et al., 1995) and diagnostic tests (e.g., skin prick) to specify diagnostic quality as criteria to enhance confidence determinations compared with studies without such validated instruments was appropriate. Studies on asthma involving very young (<5 yrs) and elderly (>75 yrs) subjects were excluded or downgraded since outside experts stated that respiratory conditions other than asthma may be the basis of symptoms in these age groups. Thirty-six studies (27 observational and 9 randomized controlled trials) were chosen for toxicological review pertaining to immune conditions.

Study Evaluation

EPA chose to adhere to the recommendations of the outside experts in applying evidence status to those studies that (1) had more robust measures of disease (using appropriate biomarkers and validated questionnaires), (2) included higher exposure levels, or (3) included a prospective study design. The one prospective study (in which formaldehyde exposures preceded disease [Smedje and Norback, 2001]) that was based on low exposure values (many were below the analytical chemical limit of detection) was elevated to medium confidence given its longitudinal, prospective nature. Children were deemed to be “more sensitive” at lower exposures given observed effects, and were carried through the evaluation to yield distinct POD and cRfC values separate from those for adults.

Evidence Synthesis and Judgments

EPA concluded based on a moderate level of human evidence (and slight in animals) that inhalation of formaldehyde causes an increased risk of prevalent allergic conditions and asthmatic symptoms and decreased control of asthmatic symptoms, with evidence from occupational studies in the range of exposure values >0.1 mg/m³ and from schools and homes at 0.03–<0.1 mg/m³. EPA made these judgments after carrying out the synthesis of substantial evidence on allergic conditions, asthma, and lower respiratory tract infections (in young children), with a large number of medium-confidence studies being used to justify them. These studies included 8 studies on allergies in children and/or adults (one high- and three medium-confidence) and 15 studies on asthma in children or adults (2 high- and 13 medium-confidence), which together provide a preponderance of evidence that formaldehyde influences these phenotypes in humans. Two studies on asthma

control (in known asthmatic subjects; pp. 1–112 of the Main Assessment) provided high and medium confidence, respectively, with Venn et al. (2003) showing strong trends. The section on “Controlled Acute Exposure” describes studies of short-term acute exposures to humans.

Regarding animal studies, the synthesis was indeterminate for allergy and asthma outcomes based on the lack of appropriate models that recapitulate the symptoms and physiology of human allergy and asthma conditions. Most of the animal data is based on the ovalbumin (OVA) allergen model, which does not recapitulate the entirety of human pathophysiology. The animal model data did aid in advancing understanding of MOA.

In the section “Evidence on MOA for Immune-related Conditions,” EPA concludes that a definitive MOA could not be identified, but components of the MOA are clear. Formaldehyde is responsible for airway inflammatory changes and remodeling that can contribute to respiratory immune-related conditions. The mechanisms for allergic sensitization are less clear. Reliable human data on changes in production of antibodies to formaldehyde and its protein-adducting metabolites is lacking. Figure 1-12 describes the cascades of immune alterations leading to effector-level changes that result in the pathologic observed formaldehyde hazards. Many of the pathway components have uncertain interrelationships, and the evidence is at moderate to slight levels. These immune mechanisms are complex and largely beyond the scope of the 2022 Draft Assessment, and are described in light of several high- to medium-confidence studies in relation to formaldehyde MOA. These animal studies provide strong evidence for some aspects of formaldehyde’s relevant activities—for example, bronchoconstriction and eosinophil activation via inflammatory mediators such as tachykinins, antibodies, Th2-related cytokines, and white blood cell changes. Summaries of these changes are provided in Tables 1-22 and 1-23, with extensive discussion in Appendix A, Section A.5.6.

Overall Conclusions About the Hazard Descriptor

Overall, based primarily on moderate human evidence as well as slight animal evidence from mechanistic studies supporting biological plausibility (including molecular and cellular inflammatory changes and evidence of hypersensitivity), EPA concluded that the evidence indicates that

inhalation of formaldehyde likely causes increased risk of prevalent allergic conditions and prevalent asthma symptoms, as well as decreased control of asthma symptoms, given appropriate exposure circumstances.

Dose-Response Evaluation

EPA deemed six studies on allergic conditions, six studies on asthma, and two studies on control of asthma in asthmatic persons eligible for POD derivation. Two studies with the highest confidence from each of these three categories were ultimately selected for POD identification. No observed adverse effect level (NOAEL) and lowest observed adverse effect level (LOAEL) values were chosen from the highest-quality study in children (as a more sensitive population [Annesi-Maesano et al., 2012]) and the highest-quality study in adults (Matsunaga et al., 2008).

The study in children (Annesi-Maesano et al., 2012) used to derive an allergy POD also provided the NOAEL for asthma along with a second study in children, and the asthma control PODs both pertain to asthma in children. EPA’s final judgments on confidence in these PODs were high for allergy in children and medium for asthma control. No judgments or statements about PODs were derived from studies in adults, who, as noted, are generally less sensitive than children. EPA provides reasoning for not providing a POD for adults given the lack of quantification in the studies evaluated, wide confidence intervals, and dichotomous analyses with variable exposure levels. EPA provides no POD evaluation for contact exposures to formaldehyde.

Uncertainty factors were applied to the PODs to derive cRfCs. Because NOAELs were used for most of the PODs, a LOAEL-to-NOAEL UF (UF_L) of 1 was applied. A UF_H of 3 was generally applied, since most studies assessed exposures and outcomes in potentially sensitive populations such as children or pregnant women. All other uncertainty factors were applied at 1 (apart from a UF_S of 3 that was applied for the one study in which exposure was measured during pregnancy [Matsunaga et al., 2008]).

REPRODUCTIVE AND DEVELOPMENTAL TOXICITY

The 2011 National Research Council (NRC) committee that reviewed EPA’s assessment of formaldehyde-associated reproductive and developmental toxicity (NRC, 2011) disagreed with EPA’s determination that the epidemiologic evidence indicates a convincing relationship between occupational exposure to formaldehyde and adverse reproductive outcomes in women. The 2010 Draft Assessment was based on a single occupational study (Taskinen et al., 1999), and the 2011 NRC committee concluded that the pattern of association based on a small number of studies was suggestive, but not convincing (NRC, 2011).

EPA’s 2022 Draft Assessment considers a range of developmental and female and male reproductive toxicity endpoints in relation to formaldehyde inhalation exposure. A total of 20 studies involved residential and occupational exposures for females and males. The human endpoints of interest spanned a wide range, including fecundity (probability of conception), spontaneous abortion, gestational age, birthweight, congenital malformations, and postnatal growth. Semen quality

parameters were also examined. A total of 30 animal studies included female reproductive toxicity (e.g., ovarian and uterine pathology, ovarian weight, hormonal changes), effects on the male reproductive system, and developmental toxicity (e.g., decreased survival, decreased growth, increased structural anomalies, and development endpoints). Formaldehyde exposure levels in human occupational studies were relatively high (>0.1 mg/m³). Formaldehyde exposure levels in animal studies of medium or high confidence were also high (>5 mg/m³).

Literature Identification

The steps EPA followed in conducting its literature search and PECO assessment for inclusion and exclusion of studies are described in the Main Assessment and the Appendices. The initial search was conducted in October 2012, with yearly updates through September 2016. A systematic evidence map identified literature from 2017 to 2021. Inclusion and exclusion criteria for human and animal studies are summarized in Appendix A, Tables A-89 and A-90, respectively. The text indicates that 20 human and 35 animal studies were identified for inclusion.

Study Evaluation

EPA’s evaluation of human studies of female reproductive or developmental toxicity resulted in two medium-confidence occupational studies of spontaneous abortion, two low-confidence studies of congenital malformations, two medium-confidence studies of decreased birthweight and head circumference, and five low-confidence studies of fecundability and spontaneous abortion. Low-confidence animal studies of female reproductive or developmental toxicity had mixed findings for several outcomes. For male reproductive toxicity, the evaluation included one medium-confidence human occupational study of sperm motility and other outcomes, and one lowconfidence human study of sperm count and morphology. Multiple high-or medium-confidence animal studies using mice or rats contributed to an assessment of histopathological lesions of the testes or epididymes, sperm count, testosterone levels, and organ weight change.

Evidence Synthesis and Judgments

The discussion of reproductive and developmental toxicity in the 2022 Draft Assessment is based on an evaluation of all female reproductive and developmental outcomes combined into a single group. With this treatment as a single group, the mix of human evidence, including mediumconfidence studies (with uncertainty due to random error or bias), would place the evidence within the moderate level based on the framework for strength-of-evidence judgments. The justification for combining outcomes was that it would be difficult to distinguish underlying pathogenic events that could yield a delayed recognized pregnancy or fetal loss. Although this rationale may apply generally for delayed time to pregnancy and spontaneous abortion, the broader category of female reproductive and developmental toxicity also encompasses human studies of other “later” developmental outcomes, such as congenital malformations and birthweight.

Assessment of animal studies revealed indeterminate evidence for developmental toxicity and separately, indeterminate evidence for female reproductive toxicity. All evaluated studies had low confidence with methodological limitations, the majority of which were due to a lack of information about test substance or use of formalin, which can contain methanol, a known developmental and reproductive toxicant. For developmental effects, EPA found no direct evidence of biological plausibility; however, oxidative stress and/or hormone disruption are noted as possible indirect linkages. For female reproductive effects, EPA notes that the biological plausibility of neuroendocrine-mediated mechanisms involving the hypothalamic–pituitary–gonadal–axis is consistent with the alterations of reproductive hormones identified in the low-confidence rodent formaldehyde studies.

For male reproductive toxicity, EPA judged the evidence from human studies to be slight. There was one medium-confidence study, but the sparseness of the available evidence for multiple reproductive and developmental outcomes and the associated uncertainty provided a reasonable basis for the strength-of-evidence judgment as slight.

For animal studies of male reproductive toxicity, EPA judged the evidence to be robust based on six medium- or high-confidence studies conducted by three research teams using five cohorts of rats or mice. The text on p. 82 of the Assessment Overview discusses six medium- or high

confidence studies, but Table A-36 in Appendix A lists only five studies because one row combines two studies. Nonetheless, it is reasonable to conclude that these six studies were well conducted, although all used high formaldehyde concentrations (>5 mg/m3). The studies found adverse testes and epididymis histopathology, decreased sperm count, altered sperm motility and morphology, and decreased serum testosterone. In addition, several low-confidence studies produced consistent results on male reproductive toxicity, although they were also conducted with very high formaldehyde levels (most above >12 mg/m³). Evidence on the MOA for formaldehyde and male reproductive toxicity is lacking, but indirect effects of oxidative stress and heat shock protein induction were noted in testes or epididymes of exposed rats in the medium- and high-confidence studies.

Overall Conclusions About the Hazard Descriptor

The judgment that the evidence indicates that inhalation of formaldehyde likely causes increased risk of developmental or female reproductive toxicity in humans (given the appropriate exposure circumstances) was based on moderate human evidence and indeterminate animal evidence for developmental or female reproductive toxicity.

The judgment that the evidence indicates that inhalation of formaldehyde likely causes increased risk of reproductive toxicity in men (given the appropriate exposure circumstances) was based on slight human evidence and robust animal evidence for male reproductive toxicity.

Dose-Response Evaluation

For female reproductive and developmental toxicity, dose-response estimation was based on a single medium-confidence study with a time-to-pregnancy endpoint (Taskinen et al., 1999). The 8-hour time-weighted average (TWA) for the intermediate (middle) exposure group was selected as a NOAEL. A UF_H of 10 was applied to the developmental toxicity POD.

For male reproductive toxicity, dose-response estimation was based on two high-confidence studies in rats exposed to paraformaldehyde for 13 weeks that assessed relative testes weight and serum testosterone endpoints. For decreased testes weight (Ozen et al., 2002), a LOAEL of 12.3 mg/m³ was adjusted for continuous exposure based on the experimental paradigm to yield a POD_ADJ of 2.93 mg/m³. A final uncertainty factor of 3000 was applied to the male reproductive toxicity testes weight POD. For decreased serum testosterone and decreased mean seminiferous tubule diameter likely associated with decreased serum testosterone (Ozen et al., 2005), a BMCL_1SD

of 0.208 mg/m³ was calculated, resulting in a POD_ADJ of 0.05 mg/m³. A final uncertainty factor of 300 was applied to the male reproductive toxicity decreased testosterone POD.

The final uncertainty factors were derived for the two male reproductive endpoints using the following assumptions. First, a UF_A of 3 was applied to both endpoints to account for residual toxicodynamic uncertainties in interspecies extrapolation. Second, a UF_S of 10 was applied to both endpoints to approximate the potential effect of chronic exposure because the studies were conducted over a subchronic duration. Third, a UF_L of 10 was applied to the relative testes weight endpoint, which was based on a LOAEL. Fourth, a UF_H of 10 was applied to both endpoints to account for the limited variability in susceptibility factors encompassed by these typical studies of inbred laboratory animal populations.

NERVOUS SYSTEM

The 2010 Draft Assessment suggested that the available human studies demonstrated potentially concerning nervous system effects following formaldehyde exposure. However, the 2011 NRC committee concluded that EPA’s conclusion regarding nervous system effects was overstated and based on insufficient evidence. In developing the 2022 Draft Assessment, EPA searched for evidence of neurotoxicity in both humans and animals. Outcomes in humans included neurobehavioral (e.g., effects on learning and memory), neurochemical, and neuropathologic effects. Relevant outcomes in animal studies included motor activity, anxiety, habituation, learning and memory, and chemical sensitization.

Literature Identification

The steps EPA followed to conduct its literature search and PECO assessment for inclusion and exclusion of studies are documented in the Main Assessment and the Appendices. A total of 4338 articles were screened for inclusion in the assessment of these outcomes, with 147 being considered for hazard identification (40 human, 60 animal, and 47 in vitro and noninhalation studies) (Appendix A, Figure A-25, p. A-591).

Study Evaluation

Human studies of nervous system outcome-specific criteria were evaluated for strengths and limitations based on principles of epidemiologic study quality, including methods for exposure assessment; windows of exposure; sample size; and potential for selection bias, information bias, and confounding (Tables 1-44 and 1-45; Appendix A, Tables A-84 and A-85). EPA rated some human studies examining neurobehavioral outcomes such as memory impairment and deficits in concentration (Bach et al., 1990; Kilburn et al., 1985, 1987) as having overall low confidence. EPA also examined whether there were associations between formaldehyde and amyotrophic lateral sclerosis (ALS) or mortality from neurological disease. These studies estimated formaldehyde exposure based on estimated job exposures. For these included studies, occupational formaldehyde exposure was based on self-report or job exposure matrix (JEM) estimations of level and probability of exposure according to occupational history from tax records. Furthermore, three of the included studies dichotomized formaldehyde exposure into ever versus never exposed, although each attempted to account for duration and timing of exposure.

In evaluating animal studies, EPA considered several factors, including possible confounding due to coexposure to methanol, especially when high exposures (>10 mg/m³) were involved; the potential influence of irritation or changes in olfaction on behavioral measures, with preference given to behavioral studies with a period of latency between exposure and endpoint testing of at least 2 hours; blinding of the outcome assessors for nonautomated assessments; and a preference for outcomes that were deemed sensitive and specific for nervous system effects (Appendix A, Table A-86). Duration of exposure was also considered; however, studies of short-term or even acute duration were not considered to be less informative. Three animal studies (Aslan et al., 2006; Sarsilmaz et al., 2007; Sorg et al., 1998) were deemed to have medium confidence.

Evidence Synthesis and Judgments

EPA summarizes its evidence synthesis for nervous system effects of formaldehyde in Table 1-50. For ALS, EPA determined that the human evidence was slight, that the animal evidence was

indeterminate, and that an effect of formaldehyde on ALS would be surprising in terms of biological plausibility because of a lack of systemic distribution (and a lack of relevant mechanistic studies in humans). For developmental neurotoxicity, the human evidence was indeterminate, and the animal evidence was considered slight, although some evidence of relevant molecular and neurochemical changes in animals provided biological plausibility. For several types of neurobehavioral effects, the human evidence was considered indeterminate or slight, and the animal evidence was considered slight, with some animal evidence that provided potential biological plausibility.

The 2022 Draft Assessment concludes that the underlying MOA for neurotoxicity for inhaled formaldehyde exposures is unknown. Although the text acknowledges that it is not likely that inhaled formaldehyde would be transported directly to the central nervous system, there are several potential indirect mechanisms for formaldehyde to impact the nervous system. Most notable is repeated sensory responses, which is recognized as a neurogenic pathway for immune and respiratory outcomes. However, the inflammatory responses could also elicit nervous system outcomes.

Overall Conclusions About the Hazard Descriptor

The 2022 Draft Assessment notes that evidence on noncancerous nervous system effects is weak and lacking, and thus concludes that the evidence suggests, but is not sufficient to infer that inhaled formaldehyde may lead to adverse neurological outcomes in humans. This assessment is based on limited animal studies having medium confidence and several human studies having medium and high confidence for ALS and low or not informative confidence for neurobehavioral outcomes (e.g., memory, mood changes).

Dose-Response Evaluation

EPA did not derive a POD or cRfC for nervous system effects following formaldehyde inhalation.

DERIVATION OF THE RfC

Section 2.1 of the Main Assessment broadly defines EPA’s approach to the dose-response assessment of noncancer effects due to formaldehyde inhalation. The dose-response assessment followed the selection of studies and endpoints receiving EPA’s rating of evidence demonstrates or evidence indicates. EPA identified three human studies for sensory irritation, one human study

for pulmonary function, two human studies for allergic conditions, two human studies for current asthma, two human studies for asthma control, one human occupational study for a developmental outcome, two animal studies for respiratory tract pathology, and two animal studies for male reproductive toxicity.

These individual studies were then considered for risk estimation in four steps: (1) conducting dose-response modeling when data are adequate and deriving a POD; (2) deriving a cRfC; (3) selecting an organ- or system-specific RfC (osRfC); and (4) selecting an overall RfC. In keeping with prior recommendations from the NRC (NRC 2010, 2011), EPA developed multiple cRfCs.

To determine a POD for each selected study/endpoint, EPA either determined a NOAEL/LOAEL based on reported study data or reanalyzed dose-response data using its Benchmark Dose Software (BMDS) when the exposure-response data were deemed adequate for such reanalysis. EPA often lacked the raw data and extracted secondary data, such as exposure-group or model-predicted means. In the case of benchmark dose (BMD) analysis, EPA then estimated the benchmark concentration lower bound (BMCL) and used it as a POD.

Following its guidelines for derivation of the RfC (EPA’s Review of the Reference Dose and Reference Concentration Processes [EPA, 2002, Section 4.4.5]), EPA applied up to five uncertainty factors to the PODs. These uncertainty factors were UF_A for interspecies uncertainty, UF_H for variability across the human population, UF_L for LOAEL-to-NOAEL uncertainty, UF_S for uncertainty in subchronic to chronic or lifetime exposure extrapolation, and UF_D for database uncertainty. The results of EPA’s derivation of cRfCs for noncancer endpoints are summarized in Table 4-3.

EPA then determined an osRfC for each organ/system by qualitatively weighing the confidence and uncertainty of each cRfC. EPA finally chose an overall RfC by qualitatively weighing uncertainty and variability across all osRfCs. EPA used graphic tools (e.g., Figures 2-2 and 2-3) to aid in the final RfC determination.

TABLE 4-3 Selected Noncancer Studies/Endpoints and Derived Points of Departure (PODs) and Candidate Reference Concentrations (cRfCs)

NOTES:

^a. All UFs not reported have a value of 1.

^b. Q = the committee had concerns about EPA’s approach to deriving the POD; ND = EPA did not derive a cRfC.

^c. EPA extracted means of the original dose-response model of Hanrahan et al. (1984) to refit a logistic regression model with only eight data points (one per exposure level). The resulting model failed to recapture the data variation within each exposure group, leading to artificially smaller standard errors associated with the refitted model and an inappropriate BMCL.

^d. EPA derived BMCL using models reported in Venn et al. (2003).

^e. Dannemiller et al. (2013) report a geometric mean of 54.0 and 34.4 ppb in the “very poor control” group and “all others” group, respectively. EPA was not explicit as to whether the NOAEL of 0.042 (mg/m³) was based on the geometric mean = 34.4 ppb, or whether EPA obtained raw data to derive the arithmetic mean (Table 2-4). The reference in the last row of Table 2-4 should be Dannemiller et al. (2013).

^f. EPA fit an exponential model for relative testes weight (Appendix B, Table B-13 and Figure B-15). EPA used both standard deviation (1 SD and 10% range of data variation as the BMR levels and derived BMCL_1sd = 0.204 and BMCL_10RD = 3.24 (mg/m³), but decided to report the LOAEL from the Ozen (2002) without explanation.

^g. BMR level was defined by serum testosterone weight shift more than 1 SD relative to the comparison group. Abbreviations: BMC= benchmark concentration; BMCL= benchmark concentration lower bound; BMDS= benchmark dose software; BMR= benchmark response; cRfC= candidate reference concentration; HEC= human equivalent concentration; LOAEL= lowest observed adverse effect level; NOAEL= no observed adverse effect level; osRfC= organ or system-specific reference concentration; POD= point of departure; POD_ADJ = adjusted point of departure; RfC= reference concentration; SD= standard deviation; UF= uncertainty factor.

Additionally, EPA should address the following points (Tier 3):

• Handle dose-response modeling of correlated data (e.g., Andersen and Molhave, 1983; Kulle et al., 1987) by standard statistical methods, employing a two-step process that involves first fitting a dose-response model for correlated data using standard statistical methods, and then deriving BMC and BMCL using the fitted model.
• Develop methodology that goes beyond a qualitative display of the variability and uncertainty of cRfCs or osRfCs. The current EPA method has limited reproducibility because of the lack of detail. A meta-analysis approach offers a viable option.

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