4
Portal-of-Entry Health Effects

The Environmental Protection Agency (EPA) evaluated an array of health effects associated with formaldehyde exposure. The health effects can be characterized as portal-of-entry effects or systemic effects. The committee defined portal-of-entry effects as those that arise from direct interaction of inhaled formaldehyde with the airways or from the direct contact of airborne formaldehyde with the eyes or other tissue. It defined systemic effects as effects that occur outside those systems.

EPA’s evaluation of portal-of-entry health effects—which are irritation, decreased pulmonary function, respiratory tract pathology, asthma, and respiratory tract cancers—is reviewed in this chapter. The committee determined whether EPA identified the appropriate studies, whether the studies were thoroughly evaluated, whether hazard identification was conducted appropriately according to EPA guidelines, and whether the best studies were advanced for calculation of the reference concentration (RfC) or unit risk.

For two portal-of-entry effects (irritation and decreased lung function), evidence was available from chamber studies that used brief, controlled exposures to assess acute responses and from epidemiologic studies that evaluated chronic exposures primarily in a residential setting and prevalence of symptoms or diseases or the degree of lung-function impairment. Both types of studies have strengths and weaknesses for serving as the basis of candidate RfCs. The chamber studies involve exposures to known concentrations of formaldehyde without the presence of other air contaminants, and outcome measures can be rigorously measured. However, the study populations are selected groups of volunteers, more sensitive people may avoid participation, and the numbers of participants in the studies are generally small, leading to inadequate statistical power to detect biologically significant changes in many of the studies. Furthermore, there is uncertainty about extrapolating from an acute exposure to a chronic exposure, which would be required for derivation of an RfC; and for irritant responses, observations made for a single, brief exposure may not reflect



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4 Portal-of-Entry Health Effects The Environmental Protection Agency (EPA) evaluated an array of health effects associated with formaldehyde exposure. The health effects can be char- acterized as portal-of-entry effects or systemic effects. The committee defined portal-of-entry effects as those that arise from direct interaction of inhaled for- maldehyde with the airways or from the direct contact of airborne formaldehyde with the eyes or other tissue. It defined systemic effects as effects that occur out- side those systems. EPA’s evaluation of portal-of-entry health effects—which are irritation, decreased pulmonary function, respiratory tract pathology, asthma, and respira- tory tract cancers—is reviewed in this chapter. The committee determined whether EPA identified the appropriate studies, whether the studies were thor- oughly evaluated, whether hazard identification was conducted appropriately according to EPA guidelines, and whether the best studies were advanced for calculation of the reference concentration (RfC) or unit risk. For two portal-of-entry effects (irritation and decreased lung function), evidence was available from chamber studies that used brief, controlled expo- sures to assess acute responses and from epidemiologic studies that evaluated chronic exposures primarily in a residential setting and prevalence of symptoms or diseases or the degree of lung-function impairment. Both types of studies have strengths and weaknesses for serving as the basis of candidate RfCs. The chamber studies involve exposures to known concentrations of formaldehyde without the presence of other air contaminants, and outcome measures can be rigorously measured. However, the study populations are selected groups of volunteers, more sensitive people may avoid participation, and the numbers of participants in the studies are generally small, leading to inadequate statistical power to detect biologically significant changes in many of the studies. Fur- thermore, there is uncertainty about extrapolating from an acute exposure to a chronic exposure, which would be required for derivation of an RfC; and for irritant responses, observations made for a single, brief exposure may not reflect 64

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Portal-of-Entry Health Effects 65 the consequences of sustained exposure. There is some indication from acute and short-terms studies that irritant responses to formaldehyde are lessened by acclimatization. The epidemiologic studies considered in the draft IRIS assessment are primarily cross-sectional studies and subject to the general weaknesses that af- fect studies of this design, including the simultaneous measurement of exposure and outcome. Many of the studies involved exposure in residences, and the ex- posure-assessment protocols covered only a brief time window, leaving the pos- sibility that exposures were misclassified. Furthermore, few of the studies took into account potentially confounding exposures, such as secondhand smoke or other air pollutants. The epidemiologic studies do have the advantage of assess- ing the risks of formaldehyde exposures as they are experienced on a chronic basis. The study populations cover the range of susceptibility and, to the extent that the effects of formaldehyde exposure are modified by interactions with other agents, the exposure to formaldehyde is experienced along with exposure to the many other contaminants in indoor air. Given the quite different strengths and weaknesses of the two lines of re- search, the findings from chamber studies and epidemiologic studies should be considered as complementary. The draft IRIS assessment sets aside the chamber studies as less relevant to derivation of candidate RfCs, but the findings from the studies could be useful, and the committee does not concur with EPA's decision to set them aside. Specific recommendations are provided below for the individ- ual health outcomes. IRRITATION Formaldehyde is a reactive gas that has been consistently shown to be an eye, nose, and throat irritant. Sensory irritants act at the sensory fibers of the trigeminal nerve in the nose and upper respiratory tract. Sensory-irritation end points include self-reported sensations of pain, burning, or itching and objective measures of eye-blink counts and lacrimation (Doty et al. 2004). Although EPA’s review focuses on eye, nose, and throat irritation, other types of irritation, such as dermal irritation, have been reported. EPA selected sensory irritation as a candidate critical effect on the basis of concentration-response relationships between formaldehyde and eye irritation observed in three epidemiologic studies of residential populations. Study Identification EPA identified many studies that evaluated sensory irritation in response to formaldehyde exposure in residential, occupational, and clinical settings in humans and in experimental animal studies. Human studies evaluated sensory irritation responses in the eyes, nose, and throat after exposure to formaldehyde at 100-3,000 ppb and for durations ranging from 90 sec in chamber studies to

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66 Review of EPA’s Draft IRIS Assessment of Formaldehyde chronic residential exposure. They included potentially sensitive members of the population: children less than 4 years old, adults over 65 years old, and people who have asthma. EPA appears to have identified all appropriate exposure-response studies in humans and animals, but the literature review of studies related to the mode of action of sensory irritation associated with formaldehyde exposure should be expanded. The literature on the biologic basis of sensory irritation is more ex- tensive than that included in the draft IRIS assessment and includes studies rele- vant for evaluating the mode of action of formaldehyde in the respiratory sys- tem. Study Evaluation EPA summarized human and animal studies that were identified as having data on formaldehyde concentrations and sensory irritation responses in the eyes, nose, and throat. Population characteristics, exposure assessment, expo- sure-response relationships, and data analysis presented by the study authors were discussed by EPA. However, the committee found that study details (such as age ranges of study participants, sampling durations, and participant-selection processes) and study weaknesses (such as the limitations of the exposure as- sessments performed in the residential and occupational epidemiologic studies) were not thoroughly presented or critically evaluated in a consistent manner by EPA. In some cases, EPA did not give sufficient weight to study weaknesses, such as bias in the selection of participants and the possibility of confounding by other pollutants. Hazard Identification and Use of EPA Guidelines Formaldehyde is a well-recognized reactive and irritant gas. EPA does not have a separate guidance document for evaluating sensory irritation responses. However, the assessment of the available human and animal studies for devel- opment of an RfC for sensory irritation was consistent with the guidance for evaluation of studies in the RfC guidelines (EPA 1994). EPA’s discussion of sensory irritation included direct sensory responses and reflex responses observed in humans and animals. The draft IRIS assess- ment cites the Arts et al. (2006) analysis to support its conclusion that the onset and severity of irritant responses to formaldehyde were observed to be time- dependent and concentration-dependent. However, the results of the Arts et al. (2006) analysis are incorrectly characterized and do not provide strong support for that conclusion.1 The committee evaluated several recent reviews of formal- 1 EPA (2010a) on page 5-4 states that “Arts et al. [2006] reviewed several studies and performed BMD analyses, reporting 10% extra risk BMCL values for reported eye discomfort of 560 and 240 ppb for 3 and 5 hour exposures, respectively. LOAELs of

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Portal-of-Entry Health Effects 67 dehyde sensory irritation and did not identify any studies explicitly designed to characterize the relationship of response, concentration, and exposure duration for sensory irritation for either acute or chronic exposures.2 As noted by EPA, the chamber studies demonstrate that formaldehyde exposure causes sensory irritation in humans; this finding supports the association of increased sensory irritation with increased formaldehyde concentration observed in the residential epidemiologic studies. The potential contribution of sensory irritation to other respiratory health effects was acknowledged during the discussion of other ef- fects, such as lung function, respiratory tract pathology, sensitization, and asthma. Chapter 4.4.1 of the draft IRIS assessment provides a possible mode of ac- tion for sensory irritation: “formaldehyde-induced stimulation of the trigeminal nerve (though whether formaldehyde acts as a direct agonist is unknown)” (EPA 2010a, p. 4-458). Chapter 6 of the draft assessment makes a stronger statement about the same mode of action. Both sections, however, omit discussion of ac- tivity related to the transient receptor potential (TRP) and its association with sensory irritation. Several papers have identified the TRP family of ion channels in sensory neurons as important mediators of response to chemical irritants (Bautista et al. 2006; Macpherson et al. 2007; Bessac and Jordt 2008; Caceres et al. 2009; Bessac and Jordt 2010). Formaldehyde has been shown to activate the TRPA1 ion channel irreversibly by covalent modification—the same as the acti- vation mechanism of other known sensory irritants, such as mustard oil and cin- namaldehyde (Macpherson et al. 2007)—and to act on TRPA1 channels to elicit pain (Macpherson et al. 2007; McNamara et al. 2007). Work by Caceres et al. (2009) provides evidence that TRPA1 plays a critical role in allergic asthmatic responses as a major neuronal mediator of allergic airway inflammation. Other environmental irritants—including the metabolites of naphthalene and styrene, ozone, acrolein, and products of lipid peroxidation resulting from oxidative stress—have been shown to activate TRPA1 (Bautista et al. 2006; Macpherson et al. 2007; Taylor-Clark et al. 2008; Taylor-Clark and Undem 2010; Lanosa et al. 2010). Multiple endogenous and exogenous agents may activate the TRPA1 ion channel simultaneously (Macpherson et al. 2007; Bessac and Jordt 2008). The committee suggests that EPA review this research and consider its potential for improving understanding of the mode of action underlying the irritant effects associated with formaldehyde exposure. 1,000 ppb and 1,700 ppb were reported for 1-2 minute exposures (Bender et al., 1983; Weber-Tschopp et al., 1977). These acute studies support a role for both concentration and duration in the effect level for eye irritation.” However, Arts et al. (2006) use the irritation results collected after 2.5 hr of exposure, not 5 hr, for the BMD analyses be- cause they could not get acceptable model fit using the 5-hr data. 2 The reviews of sensory irritation by Paustenbach et al. (1997), Arts et al. (2006), and Wolkoff and Nielsen (2010) did not identify any studies in which concentration and exposure duration were systematically varied.

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68 Review of EPA’s Draft IRIS Assessment of Formaldehyde Study Selection for Calculation of Reference Concentration and Identification of Point of Departure Three epidemiologic studies—Hanrahan et al. (1984), Ritchie and Lehnen (1987), and Liu et al. (1991)—that evaluated sensory irritation in residents of mobile and conventional homes were advanced as a group by EPA and consid- ered adequate for calculation of candidate RfCs. The studies provided concen- tration-response data on several sensory irritation responses, including irritation of the eyes, nose, and throat, of which eye irritation was identified by EPA as the most sensitive and best characterized. The committee agrees with EPA’s decision to advance the eye irritation effects observed in the residential epide- miologic studies in spite of their limitations. However, it found that EPA set aside the chamber and occupational studies too soon in the process. Although the chamber studies are of acute duration (5-hr maximum single exposure), they are complementary with the residential studies and provide controlled measures of exposure and response. Therefore, the committee strongly recommends that EPA also present the concentration-response data from the occupational, cham- ber, and residential studies on the same graph and include the point estimate and measures of variability in the exposure concentrations and responses. The con- centration-response relationship for eye irritation among the different types of human studies would strengthen EPA’s argument for selection of residential studies for development of candidate RfCs. The strength of the selected epidemiologic studies lies in their evaluation of responses in the general human population who are chronically exposed, their measurement of formaldehyde concentrations in residences, and their assess- ment of effects during or soon after sampling. EPA concluded that potential weaknesses of the studies—use of subjective surveys to collect response infor- mation, short sampling duration, and potential bias in selection of homes—were sufficiently controlled for by the study authors. However, the committee has concerns about the potential weaknesses, especially of the study conducted by Ritchie and Lehnen (1987). There are several general concerns that are relevant to each study: they are cross-sectional in design, the formaldehyde concentration measurements were taken during brief intervals and may not accurately repre- sent usual exposure concentrations, and the investigators considered potential confounding by other pollutants to a varying extent. The committee identified the most serious problems in the study by Ritchie and Lehnen (1987). The committee concluded that the positive attributes of that study—the large sample (2,007) and administration of the survey assess- ing health effects by a technician at the time of sampling—did not outweigh the potential for selection bias in self-selection of participants, who before participa- tion in the study had to meet with a physician for prescreening and have a writ- ten request from the physician to the Minnesota Department of Health (MDH).3 3 The committee notes that the draft assessment omitted from its description that the participants had to meet with a physician as part of the prescreening process. It states on

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Portal-of-Entry Health Effects 69 That process is likely to have resulted in enrichment of the sample with people who were symptomatic and concerned about formaldehyde exposure. At that time, there was substantial controversy concerning formaldehyde exposure, and people who experienced symptoms and had knowledge of formaldehyde sources in their homes would have been more likely to have sought a test from a physi- cian and have a referral to the MDH. The very high rate (86-93%) of partici- pants who reported eye irritation at concentrations of 300 ppb or greater, par- ticularly in comparison with the prevalence estimates for the middle exposure category, suggests considerable participant selection bias. The draft IRIS as- sessment does not address that issue but comments on recall bias, noting that participants were not aware of formaldehyde concentration when the question- naires were completed. The committee further notes that mothers responded for their children and that the analytic strategy did not account for the data structure (that is, household was the unit of assignment for exposure, but the data were analyzed as though the data from individuals within a household were independ- ent). Thus, the committee recommends that the Ritchie and Lehnen (1987) study not be used to estimate a point of departure for a candidate RfC. Although the contribution of cigarette smoke to sensory irritation was con- trolled for in the residential epidemiologic studies, the absence of evaluation of chemicals other than formaldehyde in the indoor air samples and their potential to confound the association of formaldehyde and sensory irritation is not directly addressed in the draft IRIS assessment. EPA identified a point of departure for each study that was selected for derivation of a candidate RfC for eye irritation: a no-observed-adverse-effect level (NOAEL) of 50 ppb (Ritchie and Lehnen 1987), a lower 95% confidence limit on the benchmark concentration corresponding to a 10% response level (BMCL10) of 70 ppb (Hanrahan et al. 1984), and a lowest observed-adverse- effect level (LOAEL) of 95 ppb (Liu et al. 1991). The committee supports the points of departure selected by EPA for the Hanrahan et al. (1984) and Liu et al. (1991) studies. Although the committee does not recommend that EPA advance the Ritchie and Lehnen (1987) study for calculating a candidate RfC, it is in- cluded in its comments on the point of departure. The draft IRIS assessment appears to use an inconsistent approach for identifying points of departure from studies that present exposure as categories or ranges of concentrations. For example, the Ritchie and Lehnen (1987) and Liu et al. (1991) studies determined points of departure on the basis of the re- sults of three exposure categories. Neither study had a nonexposed reference group for evaluating background response rate. Ritchie and Lehnen reported a 1- 2% prevalence of eye irritation in the lowest exposure group (exposed to for- maldehyde at less than 100 ppb) and a 12-32% prevalence in the middle expo- page 4-2 that “in this cross-sectional study of nearly 2,000 Minnesota residents living in 397 mobile and 494 conventional homes, personal data and formaldehyde samples were collected from residents that had responded to an offer by the state health department to test homes for formaldehyde.”

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70 Review of EPA’s Draft IRIS Assessment of Formaldehyde sure group (exposed at 100-300 ppb). EPA identified less than 100 ppb as the NOAEL and assigned 50 ppb (the midpoint between 0 ppb and 100 ppb) as the NOAEL for calculation of the candidate RfC. In the other case, Liu and co- workers reported a prevalence of eye irritation of 11-13% in the lowest exposure group (exposed at less than 70 ppb; detection limit for a 7-day passive air sam- ple was 10 ppb) and a prevalence of 15-17% in the middle exposure group (ex- posed at 70-120 ppb). EPA selected 70-120 ppb as the LOAEL and 95 ppb (the midpoint of the range) as the LOAEL for calculation of the candidate RfC. The uncertainty associated with the process for selecting a point of departure is not explicitly discussed in the draft assessment. The discussions of uncertainty associated with the points of departure for individual critical studies in Sections 5.1.4.1 and 6.2.1.4.1 of the draft IRIS as- sessment are too limited. For example, the draft assessment does not discuss uncertainty in the points of departure contributed by sources specific to the for- maldehyde database, such as differences in methods used by the critical studies to adjust exposures (such as exposure estimated from samples collected for 7 days vs one or two sample collections of 30 or 60 min each) to reflect chronic exposure and differences in methods of characterizing exposure-response rela- tionships (such as using regression coefficients to estimate a BMC and BMCL for a specific study’s response rate vs using the midpoint of an exposure cate- gory as the estimate of the exposure concentration associated with the study’s response). Conclusions and Recommendations The committee agrees with EPA’s selection of eye irritation as a critical sensory-irritation effect caused by formaldehyde exposure because residential, occupational, and chamber studies have demonstrated that the eyes are more sensitive to irritation from formaldehyde than the nose and throat. The commit- tee supports EPA’s advancement of the residential studies by Liu et al. (1991) and Hanrahan et al. (1984) for derivation of candidate RfCs as adequately con- ducted studies of a randomly selected general population and agrees with the points of departure identified by EPA from these studies: LOAEL = 95 ppb (Liu et al. 1991) BMCL10 = 70 ppb (Hanrahan et al. 1984) The committee recommends that EPA address the following in the revi- sion of the formaldehyde draft IRIS assessment:  Strengthen its critical evaluation of the studies.  Re-evaluate the chamber and occupational studies for calculation of candidate RfCs.

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Portal-of-Entry Health Effects 71  Not advance the Ritchie and Lehnen (1987) study for calculation of a candidate RfC.  Review research on the TRPA1 and TRPV1 ion channels and use the information to strengthen discussion of the mode of action underlying the sen- sory irritation and respiratory effects associated with formaldehyde exposure.  Add a figure that contains all the studies that evaluated eye irritation, include for each study the mean concentration, the concentration range, and the participant response rate, and organize the data by study population (residential, occupational, and chamber). DECREASED PULMONARY FUNCTION Pulmonary function is assessed with spirometry, which measures the amount of air and the speed at which the air is exhaled during a forced exhala- tion after a maximum inhalation. Commonly used measures of pulmonary func- tion include the total amount of air exhaled (forced vital capacity, FVC), the amount of air exhaled in the first second of exhalation (forced expiratory volume in 1 sec, FEV1), the ratio of FEV1 to FVC (FEV1/FVC ratio), and the peak expi- ratory flow rate (PEFR). Pulmonary-function testing is an important tool for the assessment of both asthma and chronic obstructive pulmonary disease. The mode of action of formaldehyde’s effect on pulmonary function may be direct irritation of the airways that result in an inflammatory response or in an asth- matic response in sensitive people. Study Identification Acute and chronic adverse effects of occupational and residential expo- sures to formaldehyde on measures of pulmonary function have been investi- gated in several epidemiologic studies. The study populations have included occupational groups exposed to formaldehyde in various trades and industries, medical students exposed to formaldehyde in anatomy laboratories, and children and adults exposed to formaldehyde in indoor air coming from residential sources. The research approaches have included cross-sectional studies that in- volved testing workers’ lung function before and after work shifts and cohort studies with follow-up ranging from weeks to years. The studies have used stan- dard methods of pulmonary-function testing, including spirometry and peak- flow measurement. There is substantial literature on standardizing the testing methods and guidance on interpreting the findings (Miller et al. 2005). Chamber studies involving brief exposures of volunteers to formaldehyde have also been conducted and have provided mixed findings. The draft IRIS assessment discusses those studies in a descriptive fashion. Deficits in pulmo- nary function due to formaldehyde exposure have been demonstrated in some human experimental studies that included exercise. An adverse effect of formal-

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72 Review of EPA’s Draft IRIS Assessment of Formaldehyde dehyde on pulmonary function has generally not been observed in studies of healthy volunteers who were not exercising. The lack of evidence of an effect of formaldehyde on pulmonary function in many of the chamber studies might be explained by their small samples and by the acute nature of the exposure in the experiments. Because of those issues, the chamber studies are of limited use for estimating an RfC for pulmonary-function loss. However, given the small sam- ples, a more formal analysis that includes a display of the data with appropriate forest plots might be helpful. EPA’s review covered the relevant body of epidemiologic and experimen- tal literature. The evidence is diverse and comes from multiple exposed popula- tions. Many of the studies were performed several decades ago and reflect the substantial public-health concern at the time. The review does not appear to have missed more recent studies. Study Evaluation EPA’s review of epidemiologic studies, toxicologic studies, and experi- mental-chamber studies of formaldehyde and pulmonary function was thorough and appropriate. Here, EPA used tables to summarize the pulmonary function studies; this aided the committee in its review of the information. Hazard Identification and Use of EPA Guidelines EPA concluded that there is extensive evidence that formaldehyde causes decreased pulmonary function in humans (Section 6.1.3.9, EPA 2010a). Al- though the committee agrees with that conclusion, a clear narrative is needed to provide the rationale for it. There are no specific EPA guidelines for evaluating effects of agents on pulmonary function or other respiratory disease outcomes. The most relevant may be EPA’s RfC guidelines (EPA 1994). Inconsistencies in the approach taken by EPA may reflect the lack of adequate guidance for this domain of health outcomes. Study Selection for Calculation of Reference Concentration and Identification of Point of Departure EPA selected the findings in children (6-15 years old) from the Arizona study by Krzyzanowski et al. (1990) as the basis for the development of a candi- date RfC for decreased pulmonary function as measured by PEFR. The draft IRIS assessment justifies the choice by stating that “the best single study dem- onstrating decreased pulmonary function is the moderate residential study by Krzyzanowski et al. (1990)” (EPA 2010a, pp. 5-36 to 5-39). The draft discusses only briefly the possibility of using other studies, such as the Kriebel et al. (1993, 2001) studies of anatomy students exposed to formalin. The committee

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Portal-of-Entry Health Effects 73 notes that the Krzyzanowski et al. (1990) findings are inherently limited by the cross-sectional nature of their study and found that the study design is not suffi- ciently described in the published report. Krzyzanowski et al. (1990) found an effect of formaldehyde in children but not in adults. The findings from the studies by Kriebel et al. (1993, 2001) of anatomy students indicate that the effects of formaldehyde on pulmonary func- tion in adults may be more severe in asthmatics. EPA should provide a more thorough analysis and rationale for its choice to advance only the Krzyzanowski et al. (1990) study but also consider the Kriebel et al. (1993, 2001) studies as additional candidates for its assessment. EPA derived a BMCL10 of 17 ppb as the point of departure on the basis of the study by Krzyzanowski et al. (1990). Regression coefficients were estimated by using a linear mixed-effects regression model, presented in Table 5 in Krzyzanowski et al. (1990), and used by EPA to derive a BMCL10. The PEFR model allowed the effect of formaldehyde exposure to depend on time of day (morning vs bedtime) and asthmatic status. The calculation of a BMCL10 implies the estimation of the dose associated with a particular response level. The model predicts that the dose will vary with the presence of effect modifiers (morning exposure and asthma) of the exposure of interest (formaldehyde). The draft IRIS assessment is unclear about how EPA defined the BMCL10 given the effect modification. Greater elaboration and discussion of how a BMCL10 was based on the model fit are needed. Conclusions and Recommendations EPA’s review and evaluation of the literature on the effects of formalde- hyde on pulmonary function were thorough and appropriate. Although the committee supports EPA’s determination that exposure to formaldehyde may cause a decrease in pulmonary function, EPA should provide a stronger narra- tive to support that conclusion. The committee agrees with the choice of the Krzyzanowski et al. (1990) study as the basis of the derivation of a point of de- parture for a candidate RfC but recommends that other studies also be consid- ered for calculation of an alternative point of departure. The committee recommends that EPA address the following in the revi- sion of the formaldehyde draft IRIS assessment:  Prepare plots of the findings of the chamber studies to assess the utility of pooling their results.  Provide further justification for its choice of the study by Krzyzanowski et al. (1990) for estimating the point of departure.  Consider estimating an alternative point of departure based on the studies by Kriebel et al. (1993, 2001).  Provide a clear description of how the data from the study by Krzyzanowski et al. (1990) were used to estimate the BMCL10.

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74 Review of EPA’s Draft IRIS Assessment of Formaldehyde NONCANCER RESPIRATORY TRACT PATHOLOGY Formaldehyde-induced effects on the respiratory tract have been studied extensively. Animal studies have clearly shown that inhaled formaldehyde at 2 ppm or higher is cytotoxic and that increases in epithelial cell proliferation occur after chronic formaldehyde inhalation by mice, rats, and nonhuman primates (Kerns et al. 1983; Monticello et al. 1996). The resulting airway lesions include rhinitis, epithelial dysplasia, and squamous metaplasia. Formaldehyde-induced effects on the respiratory tract demonstrate concentration, time, and site depend- ence, and these lesions exhibit an anterior to posterior severity gradient (Kerns et al. 1983; Monticello et al. 1996). The committee concludes that the effects for which a candidate RfC should be calculated are histopathologic lesions of the nasal epithelium. Study Identification The draft IRIS assessment reviews six studies that examined the effects of formaldehyde exposure on the human upper respiratory tract. Two that exam- ined the same worker cohort are identified as the most robust and sensitive and are selected for possible derivation of a candidate RfC (Holmstrom and Wil- helmsson 1988; Holmstrom et al. 1989). The draft assessment also reviews the extensive literature on histopathologic effects in the respiratory tract and effects on mucociliary clearance in laboratory animals that inhaled formaldehyde. There are numerous studies in several species of laboratory animals, including ones using acute, subchronic, and chronic inhalation exposures. Although the committee did not perform its own literature search, it notes that two papers (Schoenberg and Mitchell 1975; Bracken et al. 1985) directly related to formaldehyde exposure and cited by Holmstrom and Wilhelmsson (1988) are not included in the draft IRIS assessment. Despite that oversight, EPA appears to have identified the appropriate animal and human studies. Study Evaluation The review of the literature in the draft IRIS assessment is extensive but is often unfocused and lacks critical evaluation of the studies. The animal studies are presented in detail, and they provide unequivocal evidence that inhalation of formaldehyde by laboratory animals causes histopathologic lesions of the upper respiratory tract. The six studies that evaluated formaldehyde-induced effects in humans all used relatively small samples, and the methods of characterizing exposure were not always discussed. None of the human studies demonstrated that exposure duration was important or that a concentration-response relation- ship was present. The draft assessment appears to give equal weight to all publi- cations of the human and animal studies, and there is no consideration of study quality, of the validity of the measurement of the exposure concentration, or of

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Portal-of-Entry Health Effects 81 asthma should be questioned because current understanding of wheezing ill- nesses in this age range indicates that they are transitory and not likely to repre- sent the onset of asthma. A later report by Rumchev et al. (2004) describes higher concentrations of a number of volatile organic compounds in the homes of the cases compared with those of the controls. The potential for confounding by those other pollutants in assessing the effect of formaldehyde was not ad- dressed. Garrett et al. (1999) carried out a cross-sectional study that was inherently limited with respect to causal inference and establishing the temporality of asso- ciations. The cross-sectional findings of the study are used for three outcome measures: prevalence of atopy, prevalence of asthma, and a respiratory symptom score. A study strength is inclusion of four 4-day measurement periods for for- maldehyde, but the analyses are cross-sectional. The symptom data, which rep- resented symptoms that occurred during the last year, were collected at one time. The draft text related to selection of the two studies (EPA 2010a, p. 5-39) does not compare their characteristics and strengths and weaknesses in relation to others that were not selected. The committee finds that the array of studies considered was too narrow and that an expedient choice was made with little additional explanation for the choice. The study by Rumchev et al. (2002) con- cerned an outcome other than incident asthma and should not have been ad- vanced. The study by Garrett et al. (1999) provides relevant information in spite of its cross-sectional nature. EPA has advanced other cross-sectional studies (for example, Krzyzanowski et al. 1990); thus, that limitation alone does not consti- tute a sufficient reason not to advance a study for RfC calculation. Conse- quently, the committee concurs that Garrett et al. can be advanced in the absence of more informative prospective studies. Two studies are advanced for derivation of candidate RfCs: one for diag- nosis of incident asthma based on Rumchev et al. (2002) and the other for aller- gic sensitization—including critical effects of allergic sensitization, asthma, and respiratory symptoms—based on Garrett et al. (1999). For diagnosis of asthma, two points of departure—a NOAEL of 33 ppb based on Rumchev et al. (2002) and a LOAEL of 28 ppb based on Garrett et al. (1999)—are provided. The committee notes that the Rumchev et al. (2002) study was omitted from Table 5- 4 in the draft IRIS assessment that summarizes all studies advanced for candi- date RfCs. As noted above, however the study by Rumchev et al. (2002) is inap- propriately advanced. For the Rumchev et al. (2002) study, the committee notes that a key deci- sion made in the calculation is not well documented. Figure 4-1 (Figure 5-5 in EPA 2010a) provides the odds ratios according to measured concentrations of formaldehyde in the residences. Only the odds ratio for the highest category is statistically significant. The NOAEL is taken to be 30-49 µg/m3 with the stated rationale that “the next highest exposure category was considered to be part of an exposure-related trend of increasing asthma risk and, therefore, biologically significant” (EPA 2010a, p. 5-46). Although confidence intervals around the two intermediate concentration points overlap, a linear model with a continuous ex-

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82 Review of EPA’s Draft IRIS Assessment of Formaldehyde posure measure was statistically significant. Regardless, criteria for identifying “an exposure-related trend” are not given. The candidate RfC values derived from the study by Garrett et al. (1999) are based on EPA's interpretation of the trends observed in the categorical analy- ses for the three outcomes (allergic sensitization, asthma, and respiratory symp- toms). The paper provides outcome data by three levels of highest exposure measured (less than 20, 20-50, and greater than 50 ppb). There appears to be an error in the description of the categories: it refers to a middle exposure range of 16-40 ppb and a high category of greater than 40 ppb. Regardless, the approach used in the draft IRIS assessment for identifying a LOAEL is to use the mid- point of the middle exposure category. That approach is not specifically justified and appears to represent a pragmatic attempt to handle data that are provided in the form of an exposure-response relationship without a nonexposed group and no clear NOAEL. Conclusions and Recommendations Asthma is a complex phenotype on whose pathogenesis substantial re- search has been conducted. The discussion of asthma needs to be strengthened to reflect the extensive literature better. The discussion of mode of action needs to be greatly strengthened and grounded in current understanding of pathogene- sis. The current speculative discussion is not satisfactory. In light of the current understanding of wheezing illnesses in early life, the study by Rumchev et al. (2002) cannot be advanced as reflecting “asthma.” The committee agrees that the study by Garrett et al. (1999) can be advanced for calculation of a candidate RfC, but the approach taken for identification of a LOAEL needs better justifi- cation. FIGURE 4-1 Odds ratios for physician-diagnosed asthma in children associated with in-home formaldehyde concentrations in air. This is Figure 5-5 in EPA 2010a. Source: Rumchev et al. 2002. Reprinted with permission; copyright 2002, European Respiratory Society.

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Portal-of-Entry Health Effects 83 The committee recommends that EPA address the following in the revi- sion of the formaldehyde draft IRIS assessment:  Strengthen the discussion of asthma to reflect current understanding of this complex phenotype and its pathogenesis better. There should be greater clarity regarding the outcomes considered: incident asthma (the occurrence of new cases), prevalent asthma (the presence of asthma at the time of study), or exacerbation of established asthma.  Strengthen the discussion of mode of action and cite the extensive rele- vant literature.  Do not advance the study by Rumchev et al. (2002) as pertaining to asthma. That study appears relevant not to the asthma phenotype but rather to early-life wheezing illness.  Develop better the approach taken to identifying the LOAEL in the Garret et al. (1999) study. RESPIRATORY TRACT CANCERS The respiratory tract has been considered to include plausible locations for formaldehyde-induced cancer in humans because it is a site of first contact and because of the observed increased incidence of nasal tumors in laboratory ani- mals exposed to formaldehyde. It is particularly true for cancers of the nose and nasal cavity (International Classification of Diseases, Revision 8 [ICD8] 160) and nasopharynx (ICD8 147) because the dose of formaldehyde is expected to be the greatest at these upper respiratory sites. In contrast, lung cancer (ICD8 162) is a less plausible site because the delivered dose for formaldehyde is ex- pected to be much less in the lower respiratory tract than in the upper respiratory tract. There is extensive evidence from human and experimental studies that the mode of action of the induction of upper respiratory tract tumors by formalde- hyde involves a genotoxic mechanism. It is also likely that the mode of action involves induction of cell proliferation by formaldehyde toxicity. Chapter 3 pre- sents a more extensive discussion of the mode of action of formaldehyde induc- tion of respiratory cancers. Study Identification The draft IRIS assessment appears to have identified all the pertinent stud- ies of formaldehyde and respiratory cancers available at the time of its release. Thus, the draft assessment presents and discusses findings on lung cancer, naso- pharyngeal cancer, nasal cancer, and other respiratory cancers from a large number of occupational cohort studies and several population-based case-control studies of adults. The committee is aware that an update of the National Cancer Institute (NCI) cohort for solid tumors is in progress, and the formaldehyde IRIS

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84 Review of EPA’s Draft IRIS Assessment of Formaldehyde assessment will need to include the update when it becomes available. However, the committee is not recommending that EPA wait until release of the update to complete its assessment. Study Evaluation The draft assessment presents an extensive evaluation of the pertinent studies published before EPA’s review. Particular attention was appropriately given to discussion of the findings of an excess of nasopharyngeal cancer (NPC) in the NCI study of workers employed in formaldehyde industries (Hauptmann et al. 2004). The draft assessment also considers alternative analyses and criti- cisms of the study by Marsh and colleagues (Marsh et al. 1996, 2002, 2007a,b; Marsh and Youk 2005). A primary finding of the NCI study is that the excess of NPC in the cohort was attributable almost entirely to one of the 10 study facili- ties (Marsh et al. 2007a). That facility was one of the largest; this would trans- late into greater statistical power to detect an increase in NPC mortality than some of the smaller facilities, which had fewer cases of this very rare cancer and thus much lower statistical power. The draft assessment suggests that there was also an excess of NPC in a second plant, but this finding was too unstable to be useful given that it was based on only one case and had a very wide confidence interval (standardized mortality ratio, 5.35; 95% confidence interval, 0.13- 29.83). The pooling of results across plants translates into even greater power to detect a formaldehyde-associated excess of NPC. Plant differences other than statistical power may explain differences in observed cancer rates and are worth noting as limitations in interpreting risk estimates based on this study. For ex- ample, a reanalysis of the NCI cohort by Marsh et al. (2007b) provides evidence that the excess of NPC might be explained by other employment in silver- smithing or other metal-working industries in Connecticut. However, there is no evidence from other studies that those industries are associated with an in- creased risk of NPC. The study evaluation would be improved substantially if the EPA frame- work for causal determinations were stated explicitly because it would help to provide structure for the study evaluations and clarify which findings were most relevant to future causal determinations. The committee finds that the review regarding all the other respiratory cancer sites is thorough and appropriate. Hazard Identification and Use of EPA Guidelines The draft IRIS assessment draws inconsistent conclusions about hazard identification in four sections. In the summary of the section “Respiratory Tract Cancer,” the draft concludes that there is sufficient epidemiologic evidence that formaldehyde is causally associated with NPC and sinonasal cancer (EPA 2010a, section 4.1.2.1.5.4.). In the section “Summary: Carcinogenic Hazards in Humans,” the draft concludes that “the weight of the epidemiologic evidence at

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Portal-of-Entry Health Effects 85 this time supports a link between formaldehyde exposure and NPC in humans” but does not mention sinonasal cancer (EPA 2010a, section 4.1.2.3., p. 4-188). In the section “Synthesis and Evaluation of Carcinogenicity: Cancers of the Respiratory Tract,” the text offers the conclusion that “formaldehyde is causally related to cancers of the upper respiratory tract as a group” (EPA 2010a, section 4.5.1., p. 4-486). In the section “Hazard Characterization for Formaldehyde Car- cinogenicity,” the draft states that “human epidemiological evidence is sufficient to conclude a causal association between formaldehyde exposure and naso- pharyngeal cancer, nasal and paranasal cancer” (EPA 2010a, section 4.5.4., p. 4- 535). The inconsistencies in the conclusions obviously need to be resolved. Because the draft IRIS assessment presents no causal framework explic- itly, the committee considered the appropriateness of EPA’s conclusions in the context of EPA’s Guidelines for Carcinogen Risk Assessment (EPA 2005). The guidelines state that for a substance to be a known human carcinogen, there should be “convincing epidemiologic evidence of a causal association between human exposure and cancer” or, exceptionally, if all the following conditions are met: “(a) there is strong evidence of an association between human exposure and either cancer or the key precursor events of the agent’s mode of action but not enough for a causal association, and (b) there is extensive evidence of car- cinogenicity in animals, and (c) the mode(s) of carcinogenic action and associ- ated key precursor events have been identified in animals, and (d) there is strong evidence that the key precursor events that precede the cancer response in ani- mals are anticipated to occur in humans and progress to tumors, based on avail- able biological information” (EPA 2005, p. 2-54). EPA’s conclusion that NPC is causally related to formaldehyde was based on the positive findings of the NCI cohort study (Hauptmann et al. 2004) and on several case-control studies (Olsen et al. 1984; Rousch et al. 1987; West et al. 1993; Vaughan et al. 2000). Although an excess of NPC was not observed in other cohort studies of formaldehyde-exposed workers (Coggon et al. 2003; Pinkerton et al. 2004), the negative findings might be explained by the low sta- tistical power of the studies for these rare tumors. There was a consensus in the committee that it would be consistent with EPA guidelines to draw a causal con- clusion for NPC and formaldehyde on the basis of the combination of the epi- demiologic findings with experimental data and mechanistic data on formalde- hyde. For nasal and paranasal (that is, sinonasal) cancers, EPA found a causal re- lationship with formaldehyde exposure on the basis of three factors: positive findings of several case-control studies (Hayes et al. 1986; Olsen and Asnaes 1986; Luce et al. 2002), stronger associations between formaldehyde and cancer in a neighboring tissue (NPC), and an excess of nasal cancer in rats exposed to formaldehyde (EPA 2010a). The committee concluded that EPA’s causal deter- mination regarding sinonasal cancer is consistent with its cancer guidelines. In Section 4.5.1 of the draft IRIS assessment (EPA 2010a), EPA extends its determination of causality to include all upper respiratory cancers and for- maldehyde. EPA does not define what it means by “all upper respiratory can-

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86 Review of EPA’s Draft IRIS Assessment of Formaldehyde cers,” but it might be taken to include cancers of the oral cavity and larynx, as well as nasopharyngeal and sinonasal cancers. That determination was made even though little evidence about any upper respiratory cancer site other than NPC or sinonasal cancer was offered. The committee does not find that determi- nation to be consistent with EPA’s cancer guidelines. The draft IRIS assessment does not conclude that there is a causal associa- tion between exposure to formaldehyde and cancers of the lung. Only one of the major cohort studies of formaldehyde-exposed workers has reported a signifi- cant excess of lung cancer (Coggon et al. 2003). In addition, studies of deposi- tion of formaldehyde in the respiratory tract have demonstrated clearly that the amount of formaldehyde deposited in the lower respiratory tract would be low. The committee concurs with EPA that there is a lack of sufficient evidence of an increased risk of lung cancer in humans exposed to formaldehyde. Study Selection for Calculation of Cancer Unit Risk EPA selected the study by Hauptmann et al. (2004) as the basis of its ex- posure-response assessment of formaldehyde and NPC. That was the only pos- sible choice because the Hauptmann et al. (2004) study was the only study from which an exposure-response relationship could be derived. Furthermore, that study has a number of strengths for conducting an exposure-response assess- ment. In addition to having individual estimates of formaldehyde exposure, the study had a long period of follow-up, controlled for a number of potential con- founding variables, and used internal comparisons that minimized biases related to the healthy-worker effect. The strengths, however, are offset by a number of weaknesses. First, as noted earlier, the excess of NPC in the study was due to an excess in only one of the 10 study facilities. Although that pattern may be explained by the low statis- tical power of the individual study sites for this rare cancer, it raises concerns about the generalizability of the findings to the other facilities and to other workers exposed to formaldehyde. It also raises the possibility that the results were confounded by other pollutants present at that one facility. Second, the exposure-response findings for NPC were far less significant for cumulative formaldehyde exposure (p = 0.032) than for peak exposures (p < 0.001). Despite that finding, EPA chose to construct a dose-response relationship by using find- ings on cumulative exposure, given that peak exposures could not be used to estimate risks associated with lifetime exposures to environmental concentra- tions of formaldehyde. Finally, a serious concern has been raised about an unex- plained under ascertainment of deaths in the Hauptmann et al. (2004) study (Marsh et al. 2010). In the update of findings on lymphatic and hematopoietic cancers in the NCI cohort, Beane-Freeman et al. (2009) noted that 1,006 deaths that had occurred before 1995 were missing from earlier analyses of the NCI cohort. The Beane-Freeman analysis also extended follow-up of the cohort to 2004. The additional follow-up period resulted in a total of 7,091 additional

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Portal-of-Entry Health Effects 87 deaths, which is nearly double the number that were included in Hauptmann et al. (2004). The effect of that under ascertainment of deaths and the additional follow-up period has important implications for analyses of the NCI cohort and NPC. Given the importance of the NCI study to the formaldehyde assessment, EPA should make an effort to update its assessment once the NCI study findings on NPC become available. EPA also conducted an exposure-response analysis based on the combined findings of an increase in nasal squamous cell carcinoma in two long-term bio- assays in F344 rats (Kerns et al. 1983; Monticello et al. 1996). The results of the exposure-response models were used to estimate risk of nasal cancer and of can- cer of the entire respiratory tract (upper and lower) in humans. The committee concurs with EPA’s decision to use the data as the basis of the development of a model to estimate risk of nasal cancer but has serious doubts about the appropri- ateness of using the study to estimate risks of all respiratory cancers in humans. Those doubts and the lack of evidence from most of the epidemiologic studies of an excess of respiratory cancers other than sinonasal cancer and NPC support the committee’s conclusion that risks of all respiratory cancers (particularly lower respiratory tract cancers) should not be calculated now. Conclusions and Recommendations EPA’s review of the literature on formaldehyde and respiratory cancer was thorough and appropriate. It would be useful if, in the future, EPA could explic- itly state its criteria for evaluation of the evidence of causality based on its own cancer guidelines. Several sections of the draft IRIS assessment contain conflict- ing statements on the evidence of causality that clearly need to be rectified. The committee finds that, on the basis of EPA’s guidelines, there is sufficient evi- dence of a causal association between formaldehyde and cancers of the nose and nasal cavity (ICD8 160) and nasopharynx (ICD8 147) but not other sites of res- piratory tract cancer. The committee agrees that the study by Hauptmann et al. (2004) is an appropriate choice for the derivation of a point of departure and unit risk. Although it is a high-quality study, it is important to recognize some of its deficiencies, such as the apparent inconsistency between the findings in different plants in the study and the weakness of the exposure-response relationship in connection with cumulative exposure. Furthermore, the study was found to be missing deaths in a later update of the cohort for lymphatic and hematopoietic cancers. NCI is updating its cohort for respiratory cancer and other solid tumors. The update not only will include the missing deaths but will extend the follow- up, and this will result in nearly twice the amount of deaths. The committee recommends that EPA address the following in the revi- sion of the formaldehyde draft IRIS assessment:  Revise the document to state clearly the criteria that EPA used to de- termine the causality for cancer.

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88 Review of EPA’s Draft IRIS Assessment of Formaldehyde  Resolve the conflicting statements in the document concerning which upper respiratory cancer sites were found to be causally associated with formal- dehyde exposure.  Update the dose-response analysis in the IRIS assessment when the findings from the update of the NCI cohort on solid cancers become available. However, the committee is not recommending that EPA wait until release of the update to complete its assessment. REFERENCES Arts, J.H., M.A. Rennen, and C. de Heer. 2006. Inhaled formaldehyde: Evaluation of sensory irritation in relation to carcinogenicity. Regul. Toxicol. Pharmacol. 44(2):144-160. Barnes, P.J. 2008. Immunology of asthma and chronic obstructive pulmonary disease. Nat. Rev. Immunol. 8(3):183-192. Bautista, D.M., S.E. Jordt, T. Nikai, P.R. Tsuruda, A.J. Read, J. Poblete, E.N. Yamoah, A.I. Basbaum, and D. Julius. 2006. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124(6):1269-1282. Bessac, B.F., and S.E. Jordt. 2008. Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control. Physiology 23(6):360-370. Bessac, B.F., and S.E. Jordt. 2010. Sensory detection and responses to toxic gases: Mechanisms, health effects, and countermeasures. Proc. M. Thorac. Soc. 7(4):269- 277. Beane-Freeman, L.E., A. Blair, J.H. Lubin, P.A. Stewart, R.B. Hayes, R.N. Hoover, and M. Hauptmann. 2009. Mortality from lymphohematopoietic malignancies among workers in formaldehyde industries: The National Cancer Institute cohort. J. Natl. Cancer Inst. 101(10):751-761. Bender, JR, L.S. Mullin, G.J. Graepel, and W.E. Wilson. 1983. Eye irritation response of humans to formaldehyde. Am. Ind. Hyg. Assoc. J. 44:463-465. Bracken, M.J., D.J. Leasa, and W.K. Morgan. 1985. Exposure to formaldehyde: Relation- ship to respiratory symptoms and function. Can. J. Public Health 76(5):312-316. Caceres, A.I., M. Brackmann, M.D. Elia, B.F. Bessac, D. del Camino, M. D’Amours, J.S. Witek, C.M. Fanger, J.A. Chong, N.J. Hayward, R.J. Homer, L. Cohn, X. Huang, M.M. Moran, and S.E. Jordt. 2009. A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc. Nat. Acad. Sci. 106(22):9099-9104. Cassee, F.R., J.H. Arts, J.P. Groten, and V.J. Feron. 1996. Sensory irritation to mixtures of formaldehyde, acrolein, and acetaldehyde in rats. Arch. Toxicol. 70(6):329-337. Coggon, D., E.C. Harris, J. Poole, and K.T. Palmer. 2003. Extended follow-up of a cohort of British chemical workers exposed to formaldehyde. J. Natl. Cancer Inst. 95(21):1608-1615. Cohn, L., J.A. Elias, and G.L. Chupp. 2004. Asthma: Mechanisms of disease persistence and progression. Annu. Rev. Immunol. 22:789-815. Doty, R.L., J.E. Cometto-Muniz, A.A. Jalowayski, P. Dalton, M. Kendal-Reed, and M. Hodgson. 2004. Assessment of upper respiratory tract and ocular irritative effects of volatile chemicals in humans. Crit. Rev. Toxicol. 34(2):85-142. EPA (U.S. Environmental Protection Agency). 1994. Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. EPA/600/8-

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