6
Reference Concentrations for Noncancer Effects and Unit Risks for Cancers

Chapter 5 of the draft IRIS assessment discusses the derivation of reference concentrations (RfCs) for noncancer effects and unit risks for cancers. Because estimates of RfCs and unit risks are subject to uncertainty and variation at every stage of the computational process, the committee conducted a thorough appraisal of the Environmental Protection Agency (EPA) process and analysis for calculating the estimates. In this chapter, the committee provides its review of EPA’s derivation of RfCs and unit risks and offers its conclusions and recommendations regarding these two key products of the IRIS assessment.

The committee notes that EPA’s dose-response assessments for cancer and noncancer effects have evaluated some end points for which there may not be adequate evidence to support the conclusion of a causal relationship between that end point and formaldehyde exposure. For example, modes of action for leukemia and Hodgkin lymphoma remain questionable, as noted by the present committee at various places in this report (Chapters 3 and 5). The committee recognizes, however, that EPA has followed its various risk-assessment guidelines (EPA1991, 1998, 2005) in conducting the dose-response assessments. In cancer risk assessment, for example, “dose-response assessments are generally completed for agents considered ‘carcinogenic to humans’ and ‘likely to be carcinogenic to humans’” (EPA 2005). Dose-response assessments include an analysis of all tumor types on the basis of potential causality of the agent and may be conducted to provide a sense of the magnitude and uncertainty of potential risks, especially when the evidence is provided from a well-conducted study (EPA 2005). It is within that framework that the present committee reviewed EPA’s calculation of RfCs for noncancer effects and unit risks for cancer. The review is partly geared toward an analysis of uncertainties associated with the



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6 Reference Concentrations for Noncancer Effects and Unit Risks for Cancers Chapter 5 of the draft IRIS assessment discusses the derivation of refer- ence concentrations (RfCs) for noncancer effects and unit risks for cancers. Be- cause estimates of RfCs and unit risks are subject to uncertainty and variation at every stage of the computational process, the committee conducted a thorough appraisal of the Environmental Protection Agency (EPA) process and analysis for calculating the estimates. In this chapter, the committee provides its review of EPA’s derivation of RfCs and unit risks and offers its conclusions and rec- ommendations regarding these two key products of the IRIS assessment. The committee notes that EPA’s dose-response assessments for cancer and noncancer effects have evaluated some end points for which there may not be adequate evidence to support the conclusion of a causal relationship between that end point and formaldehyde exposure. For example, modes of action for leukemia and Hodgkin lymphoma remain questionable, as noted by the present committee at various places in this report (Chapters 3 and 5). The committee recognizes, however, that EPA has followed its various risk-assessment guide- lines (EPA1991, 1998, 2005) in conducting the dose-response assessments. In cancer risk assessment, for example, “dose-response assessments are generally completed for agents considered ‘carcinogenic to humans’ and ‘likely to be car- cinogenic to humans’” (EPA 2005). Dose-response assessments include an analysis of all tumor types on the basis of potential causality of the agent and may be conducted to provide a sense of the magnitude and uncertainty of poten- tial risks, especially when the evidence is provided from a well-conducted study (EPA 2005). It is within that framework that the present committee reviewed EPA’s calculation of RfCs for noncancer effects and unit risks for cancer. The review is partly geared toward an analysis of uncertainties associated with the 118

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Concentrations for Noncancer Effects and Unit Risks for Cancers 119 underlying risk estimates and is not necessarily an endorsement, for example, of using a specific cancer, such as leukemia, for a consensus risk estimate. The committee’s opinions on mode of action and weight of evidence concerning specific health outcomes are given in Chapters 3-5 of the present report. FORMALDEHYDE REFERENCE CONCENTRATIONS EPA defines an RfC as “an estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human popula- tion (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime” (EPA 2010a). That is, an RfC is a concentration at which exposures would be allowed to occur with sufficient cer- tainty, taking into account susceptibility and variability, that adverse outcomes would not result. RfCs are used by EPA, state agencies, various regulatory agencies, and other entities to develop allowable ambient air concentrations and to evaluate risks posed by current and potential exposures. The draft IRIS assessment proposes several RfCs for formaldehyde that are based on “three studies of related health effects: asthma, allergic sensitiza- tion, pulmonary function, and symptoms of respiratory disease in children from in-home exposure to formaldehyde” (Rumchev et al. 2002; Garrett et al. 1999; Krzyzanowski et al. 1990) (EPA 2010b, p. 5-66). The discussion concludes by presenting a range (1-9 ppb), rather than a specific value, for the RfC. The committee was asked to comment on values of the uncertainty factors used to derive the RfCs that account for human population variability and for deficien- cies in the overall database (see Box 1-1). Chapters 4 and 5 of the present report addressed the health effects asso- ciated with formaldehyde exposure and reviewed the candidate critical effects, relevant studies, and points of departure identified by EPA. EPA’s process for developing the RfC for formaldehyde is illustrated in Figure 6-1. The follow- ing sections briefly summarize EPA’s selection of critical effects and key studies and identification of points of departure for derivation of candidate RfCs. Information that is relevant to evaluating the uncertainty factors pro- posed by EPA is then presented, and the committee provides its recommenda- tions for those factors. Finally, the committee comments on the IRIS process for derivation of RfCs and provides suggestions for improving the process of selecting a final RfC. Selection of Candidate Noncancer Effects Health effects associated with formaldehyde exposure have been studied extensively in people, laboratory animals, and in vitro systems with a variety of study designs. EPA evaluated a broad array of health effects that the committee

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120 Review of EPA’s Draft IRIS Assessment of Formaldehyde FIGURE 6-1 Illustration of EPA’s process for deriving a reference concentration for formaldehyde. Abbreviations: ID, identification; RfC, reference concentration; cRFC, candidate reference concentration; POD, point of departure; EPA, Environmental Protec- tion Agency; LOAEL, lowest observed adverse effect-level; NOAEL, no observed ad- verse effect level; and BMCL10, lower 95% confidence limit on the benchmark concen- tration corresponding to a 10% response level. characterized as portal-of-entry or systemic. For portal-of-entry noncancer ef- fects, the draft IRIS assessment concludes that formaldehyde causes sensory irritation, decreased pulmonary function, histopathologic lesions of the upper respiratory tract, and asthma and allergic sensitization. The committee agrees with EPA’s assessment of a causal relationship between formaldehyde and those effects with the exception of incident asthma, which was based on the study by Rumchev et al. (2002). As noted in Chapter 4, the draft IRIS assessment does not sufficiently consider the complexities of the asthma phenotype or the poten- tial role of formaldehyde in causing new cases of asthma as opposed to exacer- bating existing asthma. For systemic noncancer effects, the draft IRIS assessment identifies asso- ciations of formaldehyde exposure with effects on the immune system, the nerv- ous system, the reproductive system, and development. The committee does not find the evidence to be sufficient to support a causal relationship between

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Concentrations for Noncancer Effects and Unit Risks for Cancers 121 formaldehyde exposure and those effects, given the weaknesses of the available evidence. First, the committee agrees that there is evidence indicating possible immune effects, including increased incidence of upper respiratory tract infec- tions, respiratory burst activity in the immune system, and modulation of re- sponses to known allergens, but the evidence is insufficient to conclude that these relationships are causal. Second, the committee finds that the draft IRIS assessment overstates the evidence in concluding that formaldehyde is neuro- toxic; the selected studies are not sufficient for neurotoxicity-hazard identifica- tion, given deficiencies in study design. Third, although the draft IRIS assess- ment concludes that the epidemiologic studies provide evidence of a convincing relationship between formaldehyde exposure and reproductive and developmen- tal effects, the committee concludes that the evidence indicates a suggestive, rather than convincing, relationship. The committee supports EPA’s selection of the following health effects on which to base a candidate RfC: sensory irritation (eye, nose, and throat), upper respiratory tract pathology, decreased pulmonary function, increased asthma and allergic sensitization, and, despite the weak evidence of causality, reproductive and developmental toxicity. However, as described in Chapters 4 and 5 of the present report, the draft IRIS assessment has substantive problems that weaken the arguments related to those outcomes. Selection of Critical Studies The draft IRIS assessment characterizes the approach for study selection for noncancer outcomes as follows: “in general, studies are included where study quality and ability to define exposures are considered adequate for RfC derivation. Whenever possible, greater consideration is typically given to human data from observational epidemiology studies for derivation of an RfC” (EPA 2010b, p. 5-3). The committee views the stated overall approach as reasonable but found no explicit criteria for its application. Similarly, the concept of “ade- quate,” which appears central in decision-making, is left undefined. The draft IRIS assessment offers six general points that were used to evaluate studies: study size, whether the study evaluated humans or animals, whether an epidemi- ologic study was in a residential or occupational setting, whether children were included in the study population in a human study, the accuracy of formalde- hyde concentration measurements, and whether the study evaluated low formal- dehyde concentrations and sensitive end points. The committee agrees that those criteria are appropriate for study selection but notes that no explicit judgments are identified in the draft assessment about how well the individual studies met the criteria. The effects, studies, and points of departure advanced by EPA for candidate RfCs are summarized in Table 6-1. The committee’s comments on the studies selected for the specific outcomes are provided in Chapters 4 and 5 of the present report.

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122 Review of EPA’s Draft IRIS Assessment of Formaldehyde TABLE 6-1 Derivation of Candidate RfCs by EPAa Selected POD End Point Study (range of POD) UFL UFS UFH Respiratory Effects, Asthma, and Sensitization Asthma incidence Rumchev et NOAEL, 33 ppb 1 3 1 or 3 al. (2002) (24-39 ppb) Increased asthma Garrett et LOAEL, 28 ppb 3 1 1 or 3 al. (1999) (16-41 ppb) Pulmonary function— Krzyzanowski et BMCL10, 17 ppb 1 1 3 reduction in PEFR al. (1990) (BMC10, 27 ppb) in children (10%) Sensory Irritation Eye irritation, Hanrahan et al. (1984) BMCL10, 70 ppb 1 1 1 or 3 burning eyes (LOAEL, >100 ppb) Liu et al. (1991) LOAEL, 95 ppb 3 1 1 or 3 (70-120 ppb) Ritchie and NOAEL, 50 ppb 1 1 1 or 3 Lehnen (1987) (0-100 ppb) Reproductive and Developmental Toxicity Decreased fecundability Taskinen et al. (1999) NOAEL, 86 ppb 1 1 10 density ratiob (estimated 8-hr TWA) a All uncertainty factor values are those assigned by EPA. Source: Adapted from Table 5- 6 in EPA (2010b). b Decreased fecundability density ratio is estimated as “the conception rate for exposed women relative to that for unexposed women in each menstrual cycle of unprotected intercourse” (Rowland et al. 1992). Abbreviations: UFL, uncertainty factor for adjustment of LOAEL to NOAEL; UFS, un- certainty factor for adjustment of less than chronic study to chronic duration; UFH, uncer- tainty factor that accounts for human population variability; RfC, reference concentra- tion; POD, point of departure; EPA, Environmental Protection Agency; PEFR, peak expiratory flow rate; LOAEL, lowest observed adverse effect level; NOAEL, no- observed-adverse-effect-level; BMCL10, lower 95% confidence limit on the benchmark concentration corresponding to a 10% response level; and TWA, time-weighted average. Candidate RfCs were derived for the related group of effects occurring in the respiratory system by using three observational epidemiologic studies of children exposed in their homes. The committee agrees with EPA’s assessment that two of the selected studies are sufficient to support derivation of candidate RfCs for decreased pulmonary function (Krzyzanowski et al. 1990) and preva- lence and severity of allergic sensitization and respiratory symptoms (Garrett et al. 1999). However, the committee does not support the selection of the Rum- chev et al. (2002) study because the end point of “incident asthma” is not sup- ported by an understanding of the phenotype of asthma in the age range of par- ticipants in the study.

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Concentrations for Noncancer Effects and Unit Risks for Cancers 123 Candidate RfCs were derived for sensory irritation of the eye by using three residential epidemiologic studies: Hanrahan et al. (1984), Ritchie and Lehnen (1987), and Liu et al. (1991). Although the committee agrees with EPA’s selection of the Hanrahan et al. (1984) and Liu et al. (1991) studies as the best of those available, it disagrees with EPA’s selection of the Ritchie and Lehnen (1987) study because of the high potential for selection bias among the self-selected participants. A candidate RfC was derived for reproductive effects on the basis of a de- creased fecundability density ratio observed in women occupationally exposed in the epidemiologic study by Taskinen et al. (1999). The committee agrees that the choice of that outcome in the study is justifiable for the reasons provided in the draft IRIS assessment. The committee supports EPA’s decision not to derive candidate RfCs for immunotoxicity and neurotoxicity end points but disagrees with its decision not to calculate a candidate RfC for upper respiratory tract pathology. Many well- documented studies have reported the occurrence of upper respiratory tract pa- thology in laboratory animals, including nonhuman primates, after inhalation exposure to formaldehyde. The dataset is one of the most extensive available, and the committee therefore recommends that EPA use the animal data to calcu- late a candidate RfC for this end point. Uncertainty Factors As defined by EPA (1994, 2010a), uncertainty factors are used to derive an RfC to account for study limitations, uncertainty in required extrapolations, and variability in response:  UFA accounts for uncertainty in animal-to-human extrapolation.  UFH accounts for human population variability and uncertainty in esti- mation of the variability.  UFL adjusts a lowest observed-adverse-effect level (LOAEL) to a no- observed-adverse-effect level (NOAEL).  UFS adjusts a less than chronic study to a chronic duration.  UFD accounts for uncertainty in identifying the critical effect when the database does not evaluate a complete array of health effects. The default value for each uncertainty factor is 10; a factor of 3 (the ap- proximate square root of 10) is used by convention when there is information to support a partial reduction in the uncertainty factor (EPA 1994). Guidance from EPA on when a specific uncertainty factor might be changed from the default value has been provided by the Toxicology Working Group of the 10X Task Force (EPA 1999) and EPA’s RfD/RfC Technical Panel (EPA 2002). As noted above, EPA requested advice from the committee on determining the values of

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124 Review of EPA’s Draft IRIS Assessment of Formaldehyde the uncertainty factors that account for human population variability and data- base completeness. EPA selected study-specific uncertainty factors for each of the candidate RfCs (Table 6-1). All candidate RfCs advanced by EPA are based on observa- tional epidemiologic studies; thus, UFA that accounts for uncertainty in animal- to-human extrapolation is assigned a value of 1. The committee concurs with EPA’s selection of a value of 3 for UFL for the Garrett et al. (1999) and Liu et al. (1991) studies. Although the studies did not report the duration of residence in the homes tested, the exposure period was assumed to correspond to a chronic exposure period of 10% of a lifetime, or 7 years, as defined by EPA. Thus, EPA selected a value of 1 for UFS for all studies except Rumchev et al. (2002) for which a value of 3 was selected because the study participants were exposed for less than 3 years. Two alternative values (1 and 3) are presented in the draft IRIS assessment for UFH in five of the seven studies for which candidate RfCs were developed (see Table 6-1). In defining UFH, EPA specifically considered susceptible popu- lations, including children, and that is consistent with the NRC (1993) report Pesticides in the Diets of Infants and Children, the Food Quality Protection Act (1996), and the EPA (2006) report A Framework for Assessing Health Risk of Environmental Exposures to Children. As noted previously, the committee does not support the use of the Rumchev et al. (2002) and Ritchie and Lehnen (1987) studies for derivation of candidate RfCs. Thus, the focus of the remainder of this discussion will be on uncertainty factors used to derive candidate RfCs for asthma and allergic sensitization (Garrett et al. 1999) and eye irritation (Harahan et al. 1984; Liu et al. 1991). Evaluation of Human Population Variability Variability of the human response to a specific exposure is recognized quantitatively during the development of the RfC through application of the un- certainty factor UFH (EPA 1994). An overarching difficulty in determining the appropriate value for UFH is that the critical underlying parameters—the propor- tion of the population to be protected by an RfC and the definition of apprecia- ble risk—have not been quantitatively articulated by EPA or other risk manag- ers. In fact, the definition of an appreciable risk is a societal matter, and the selected value might depend on the particular material of concern and the con- text (Lowrance 1976; NRC 2009). Furthermore, it is often difficult to determine an appropriate value for UFH because chemical-specific information on mode of action and on characteristics of the sensitive populations is typically sparse. Consequently, descriptions of human variability are often highly imprecise and uncertain. UFH is conceptualized as accounting for population variability that arises from differences in toxicokinetics (variation in the dose to the active site from

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Concentrations for Noncancer Effects and Unit Risks for Cancers 125 the same external exposure) and from differences in toxicodynamics (variation in response to the same dose at the active site) (EPA 1994, 2002). Accordingly, the committee evaluated the data presented in the draft IRIS assessment on toxi- cokinetics, toxicodynamics, mode of action, and attributes of the key studies to consider how well they represent the dose-response data on susceptible popula- tions. The committee found the discussion of potential sources of population variability and uncertainties related to life stages and mode of action in Section 4.6 of the draft assessment to be generally comprehensive. However, sources of uncertainty and variability identified in that section are not integrated into the discussion of the appropriate value of UFH to use with the key studies; instead, the section focuses primarily on the attributes of the study for the specific candi- date RfC. The following sections represent the committee’s synthesis of the available information and the response to its charge question. Toxicokinetics The toxicokinetics of inhaled formaldehyde depend on uptake at the portal of entry and metabolism. Total uptake in the upper respiratory tract might vary from person to person because of different physical characteristics of the upper respiratory tract, breathing patterns (oral vs nasal), and ventilation rate. As noted by EPA, modeling of reactive-gas uptake by Ginsberg et al. (2005) suggests that uptake in the upper respiratory tract is similar in 3-month-old children and adults. That relationship was confirmed by Ginsberg et al. (2010) after reanaly- sis of the models that used the higher ventilation rates in children reported in the updated Child-Specific Exposure Factor Handbook (EPA 2008a). EPA evalu- ated the computational-fluid-dynamics model of Garcia et al. (2009) that models flux (rate of gas absorbed per unit surface area of the nasal lining) of a generic reactive water-soluble gas, which is representative of formaldehyde, in the indi- vidual nasal cavities of five adults and two children, 7 and 8 years old (EPA 2010b, Appendix B). Garcia et al. (2009) report that their simulations of local- ized flux across the nasal epithelium do not predict differences in nasal do- simetry (uptake) between children and adults; average uptake differed by a fac- tor of 1.6 among the seven subjects. Variability in the local gas flux among different regions of the individual nasal passages of the five adults and the two children was larger (a factor of about 3-5). If the effects associated with formal- dehyde exposure are specific to location and cell type in the upper respiratory tract, the variability in local flux could be a contributor to variability in popula- tion response. EPA concluded and the committee agrees that the analysis of in- terindividual flux, although well done, is based on a small sample and involves people whose nasal cavities have a “normal” shape. Consequently, the study probably did not capture the full array of nasal-cavity geometry, and the findings should be generalized with caution. The committee encourages EPA to continue to evaluate the type of data that can aid in characterizing variability in deposited dose in future IRIS assessments.

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126 Review of EPA’s Draft IRIS Assessment of Formaldehyde Ventilation rate is another potential contributor to population variability in toxicokinetics and needs to be evaluated because children have higher ventila- tion rates in relation to body weight than do adults. Unlike the oral reference dose, the inhalation RfC is typically used directly without adjustment for differ- ences in exposure conditions (EPA 2009a). As noted by EPA, ventilation rate and age-related variation in oral and nasal breathing patterns probably contribute to variability in dose to specific areas of the upper respiratory tract; higher venti- lation rates and oral breathing decrease absorption of formaldehyde in the nasal cavity and increase the amount of formaldehyde available to the lower respira- tory tract (EPA 2010b). As described in the draft IRIS assessment, formaldehyde is metabolized primarily by alcohol dehydrogenase (ADH3) (EPA 2010b). ADH3 plays a cen- tral role in regulating bronchiole tone and allergen-induced hyperresponsiveness (Gerard 2005; Que et al. 2005) and mediates reduction of S-nitrosoglutathione (GSNO) (Thompson and Grafstrom 2008; Thompson et al. 2010), an endoge- nous bronchodilator and reservoir of nitric oxide activity (Jensen et al. 1998). The ontogeny and regulation of ADH3 among human life stages is not yet un- derstood (Thompson et al. 2009). ADH3 mRNA transcripts have been detected in the third-trimester human fetus, but the relative expression and activity of ADH3 protein at various life stages are not known (Thompson et al. 2009). Polymorphisms in ADH3 have been reported in members of various ethnic groups (Hedberg et al. 2001), and single-nucleotide polymorphisms in ADH3 have been associated with childhood risk of asthma (Wu et al. 2007). As noted in the draft IRIS assessment, the qualitative and quantitative effects of the inter- actions of ADH3 and GSNO on the toxicity of formaldehyde and human popula- tion variability are not understood. Toxicodynamics Toxicodynamics is a potential source of human population variability re- lated to variation in the response to a given dose at the active site. The potential contribution of toxicodynamic differences to population variability is evaluated by considering the mode of action, potential life-stage sensitivities, and the ex- tent to which the study population includes susceptible populations. Although the modes of action of formaldehyde’s effects on the respiratory system are not fully characterized, the committee finds the discussions of the biologic mecha- nisms underlying sensory irritation, asthma, and immunotoxicity in the draft IRIS assessment to be inadequate and not reflective of current scientific under- standing. Formaldehyde has been shown to activate the TRPA1 ion channel ir- reversibly by covalent modification (Macpherson et al. 2007). The TRPA1 ion channel is associated with sensory irritation responses (Bessac and Jordt 2008) and plays a critical role in allergic asthmatic responses as a major neuronal me- diator of allergic airway inflammation (Caceres et al. 2009). The contribution of TRPA1 and the enzymes involved in metabolism or processing of formalde-

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Concentrations for Noncancer Effects and Unit Risks for Cancers 127 hyde—ADH3 (Gerard 2005; Que et al. 2005; Wu et al. 2007; Hedberg et al. 2001) and GSNO (Thompson and Grafstrom 2008)—to population variability in toxicodynamics is not understood. Populations sensitive to effects of formaldehyde exposure include those who have asthma (Krzyzanowski et al. 1990; Kriebel et al. 1993; Garrett et al. 1999) and atopy (Garrett et al. 1999). They may also include those who have acute and chronic inflammatory airway conditions (such as viral infections, asthma, rhinitis, and chronic obstructive pulmonary disease) (Bessac and Jordt 2008) and those exposed to other respiratory irritants that act through related modes of action (Macpherson et al. 2007; Bessac and Jordt 2008). Children may be a susceptible population, given their developing respiratory tract and nervous system (Pinkerton and Joad 2000; Rice and Barone 2000; Ginsberg et al. 2005). On the basis of the toxicokinetic and toxicodynamic data, the committee agrees with EPA’s conclusion that the available data are consistent with some life-stage differences in susceptibility to the effects of formaldehyde. However, there is substantial uncertainty regarding the determinants and the distribution of susceptibility in the population. Values of UFH The committee considered the appropriate value for UFH for the following studies: Garrett et al. (1999), which evaluated the risk of allergy and asthma-like respiratory symptoms in 148 children 7-14 years old; Liu et al. (1991), which evaluated eye irritation in over 1,000 people 4 to over 65 years old; and Hanra- han et al. (1984), which evaluated eye irritation in 61 teens and adults. Criteria described by the RfD/RfC technical report (EPA 2002) regarding when a value of less than 10 could be assigned to UFH guided the committee in its assessment of the appropriate value for UFH (1 or 3). Specifically, “how completely the sus- ceptible subpopulation has been identified and their sensitivity described (vs. assumed)” and whether “the data set on which the POD [point of departure] is based is representative of the exposure/dose-response data for the susceptible subpopulation(s)” (EPA 2002, p. 4-43, 4-44). Identification of Sensitive Populations Children and adults who have asthma and allergic sensitization are suscep- tible populations on the basis of studies that showed increased exacerbation of respiratory and allergic sensitization responses to formaldehyde exposure in people who have asthma (EPA 2010b, p. 4-543). Increased symptoms of upper airway irritation were observed in study participants that also reported chronic respiratory and allergy symptoms; this finding suggests increased susceptibility to irritation (Liu et al. 1991). Subjects who have acute and chronic inflammatory airway conditions (such as viral infections, asthma, rhinitis, and chronic obstruc- tive pulmonary disease) (Bessac and Jordt 2008) may also be susceptible popu-

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128 Review of EPA’s Draft IRIS Assessment of Formaldehyde lations. However, the mode of action for formaldehyde’s effects is not suffi- ciently elucidated to understand the influence of such factors as life stage, respi- ratory tract development, latency, underlying disease status (such as chronic respiratory diseases and allergic symptoms), genetic polymorphisms of ADH3 and aldehyde dehydrogenase, and cumulative effects of exposure to chemicals that affect the same targets as formaldehyde. To support a value of 1 for UFH, EPA cites the RfD/RfC technical report, which indicates that a UFH of 1 has been applied in cases in which data are very specific “about the particular vulnerability of infants and children within specific age ranges to an agent” (EPA 2002, p. 4-43). To determine how often EPA has used a UFH of 1 in derivation of reference values and its underlying rationale, the committee searched the IRIS database and identified six RfDs with a value of 1 assigned for UFH (EPA 2010c). The RfDs are those for benzoic acid, beryl- lium, fluorine, manganese, nitrate, and nitrite.1 In contrast with formaldehyde, for example, the RfDs for nitrate and nitrite identified points of departure from studies of the susceptible population (infants) and noted that the duration of sus- ceptibility to the effects of nitrate is short (that is, children are not susceptible after specific points in development are reached). In the view of the committee, the modes of action for formaldehyde effects on the respiratory tract are not suf- ficiently understood to determine all potential susceptible populations, and the factors contributing to susceptibility are not yet adequately described. Thus, the committee does not support the application of a value of 1 for UFH. Representativeness of Exposure and Dose-Response Data For the candidate RfC for asthma and allergic sensitization that was based on the study by Garrett et al. (1999), the draft IRIS assessment assumes that children and adults who have asthma or allergic sensitization are the susceptible populations. As described by EPA, the Garrett et al. (1999) study includes a higher proportion of children that may be predisposed to asthma and allergic sensitization than is found in the general population (53 of the 148 children in the study had a diagnosis of asthma); thus, the study appears to describe re- sponses in susceptible populations (EPA 2010b). Garrett et al. (1999) reported that the children who were most responsive to the effects of formaldehyde had parents or family members who had asthma or atopy; this lends support to the hypothesis that there is a genetic component to the increased sensitivity of these children, but there could also be unrecognized environmental sources that con- tribute to similarities in responsiveness within families. 1 The IRIS database was searched to identify RfCs and RfDs that were derived by us- ing a value of 1 for UFH. A search for a UFH of 1 yielded no results. A search for a com- posite UF of 1 yielded five chemicals for which a UFH of 1 was used to derive RfDs: benzoic acid, fluorine, manganese, nitrate, and nitrite. A search for a composite UF of 3 yielded no results. A search for a composite UF of 10 yielded one chemical (beryllium) for which a UFH of 1 was used to derive an RfD.

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140 Review of EPA’s Draft IRIS Assessment of Formaldehyde and the probability (as approximated by RR) derived from the Poisson model of observing any NPC death in the occupational cohort. Moreover, EPA appears to have used age-specific NPC incidence from SEER to replace age-specific NPC mortality (column D of Appendix C, EPA 2010b). The implication could be an upward inflation of cancer risk because NPC survival rate is high (Lee and Ko 2005). EPA’s computation for R0 and R included all groups under 30 years old. The NCI cohort workers were at least 16 years old when occupational exposure to formaldehyde began, and there was a 15-year lag for NPC mortality in the Poisson regression model. Therefore, the risk of NPC death in the NCI cohort before the age of 30 years is essentially ignored in EPA’s model; nonetheless, EPA includes groups less than 30 years old in computing R0 and R. Some ex- planation of the conversion of cumulative exposure (ppm-year) used in the dose- response model and extra risk to average intensity for EC in R also would be helpful. The committee recognizes the complexity of dose-response and risk- quantification processes for the occupational cohort mortality data and therefore recommends inclusion of adequate description and interpretation to ensure transparency and readability. Specifically, sufficient detail about data, models, methods, and software should be provided in an appendix to any IRIS assess- ment to allow independent replication and verification. Selection of Point of Departure EPA’s carcinogenicity risk-assessment guidelines (EPA 2005) recommend the use of an extra risk of 1-10% for deriving effective concentration, ECx. The recommended range of risk increase is expected to be within the available data range. The draft IRIS assessment makes an unusual choice of 0.05% for NPC and Hodgkin lymphoma. EPA justified the choice on the grounds that NPC death is rare in the general population (background lifetime risk, 2.2 x10-4), so a 1% increase would be well above the observed range of the NCI data and would result in upward extrapolation. The extra risk of 0.05% corresponds to an RR within the model-based RR range for the cohort. If a higher extra risk were used, the uncertainty of low-dose extrapolation would be greater. Given the extreme rarity of NPC and Hodgkin-lymphoma death, EPA’s choice of point of departure is reasonable. Derivation of Unit Risks by Using Linear Extrapolation To derive unit risk estimates for formaldehyde inhalation, EPA relied on the default option of low-dose linear extrapolation. EPA justified its choice on several grounds. First, there is a plausible mutagenic mode of action for NPC and other upper respiratory track cancers. Second, the extra risk appeared linear with exposure below 0.01 ppm on the basis of a comparison of risks that were taken directly from the fitted dose-response models at various exposures. How-

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Concentrations for Noncancer Effects and Unit Risks for Cancers 141 ever, the committee notes that the computation was driven entirely by the fitted Poisson model; the degree to which the model fits the data on NPC, Hodgkin lymphoma, or leukemia is not verified or documented. Third, there is no well- established mechanistic dose-response model. Linear extrapolation entails three steps. First, a dose-response model, often a mathematical function in the absence of reliable information on mode of ac- tion, that fits the observed data appropriately well within the available data range must be identified. In the present case, it is the Poisson models fitted to NPC, leukemia, and Hodgkin lymphoma mortality rates. It is less clear how the model fits the datasets. Second, a point of departure is determined from the fit- ted dose-response model that corresponds to an exposure concentration (ECx) that induces a specified risk increase (x) above that of a reference population. EPA chose a point of departure that corresponds to 0.05% extra risk in lifetime NPC mortality with the risk R(ECx) derived from the Poisson models and the life-table method. Third, the extra risk level is divided by the point of departure (ECx or LECx) to yield a unit risk or slope factor. Applying linear extrapolation to NPC mortality data on exposed workers yields only a unit risk of 5.5 x 10-3 based on 0.05% extra risk and LEC0005 = 0.091 ppm (EC0005 = 0.15 ppm). Adding unexposed workers into the calculation changes the unit risk estimate only slightly. Recognizing the high survival rate of NPC patients, EPA also calculated unit risk by using NPC incidence from the NCI SEER database to replace NPC mortality (that is, replace columns D and I with the SEER NPC incidence data). To be consistent, the calculation would also require the use of cancer-incidence data from the NCI cohort in the Poisson dose-response modeling. However, that was not feasible because cancer- incidence data on the NCI cohort (that is, when new cases were first diagnosed) were not available. Nonetheless, EPA’s exercise resulted in new estimates of unit risk that are twice those based on mortality data. EPA correctly pointed out that the correction was attributable to substantial survivorship after NPC onset but was based on the assumption that the exposure-response relationship be- tween formaldehyde exposure and cancer mortality was the same as the relation- ship between exposure and cancer incidence. That assumption is practical but untestable. EPA also reported unit risk estimates based on Hodgkin lymphoma and leukemia mortality obtained from the extended follow-up of the NCI cohort (Beane-Freeman et al. 2009). The analyses followed the same methods that were used for NPC except that a 2-year lag was used instead of 15 years. The extra risk level at the point of departure was 0.05% for Hodgkin lymphoma mortality but 0.5% for leukemia because of the relatively high leukemia mortality ob- served in the NCI cohort. Unit risk estimates are summarized below in Table 6-2 for the three cancers, using mortality or incidence, including all person-years vs exposed workers only to demonstrate uncertainties and variability as influenced by these factors. EPA’s unit risk estimate for leukemia is greater than that for NPC or Hodgkin lymphoma and reflects the choice of point of departure and the high

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142 Review of EPA’s Draft IRIS Assessment of Formaldehyde background leukemia mortality. Unit risk estimates based on cancer incidence are universally greater than those based on mortality because of the substantial survivorship. Although the range of variation in the unit risk estimates does not incorporate the effect of all sources of variation, EPA’s estimation is consistent with the principle of variability and uncertainty analysis in risk assessment. TABLE 6-2 Cancer Unit Risk Estimates for Formaldehyde ECa LECa (95%) Unit Riskb Person- (ppm-1) Years (ppm) (ppm) Cancer Data 5.5 x 10-3 NPC Mortality Exposed only 0.15 0.091 5.4 x 10-3 All 0.15 0.093 1.1 x 10-2 Incidence Exposed only 0.072 0.045 1.1 x 10-2 All 0.074 0.046 5.7 x 10-3 Hodgkin Mortality Exposed only 0.155 0.088 lymphoma 5.7 x 10-3 All 0.151 0.088 1.7 x 10-2 Incidence Exposed only 0.053 0.030 1.7 x 10-2 All 0.052 0.030 4.0 x 10-2 Leukemia Mortality Exposed only 0.246 0.126 4.1 x 10-2 All 0.224 0.121 5.5 x 10-2 Incidence Exposed only 0.178 0.091 5.7 x 10-2 All 0.162 0.088 Total cancerc 4.5 x 10-2 Mortality All 0.1 8.1 x 10-2 Incidence All 0.1 a Extra risk level = 0.0005 for NPC and Hodgkin lymphoma, 0.005 for leukemia. b Unit risk = extra risk/LEC c Risk associated with total cancer is based on the sum of estimated extra risk of each cancer at an exposure of 0.1 ppm. Abbreviations: NPC, nasopharyngeal cancer; EC, effective concentration; and LEC, lower confidence limit on the effective concentration. Source: EPA 2010a.

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Concentrations for Noncancer Effects and Unit Risks for Cancers 143 EPA further derived an estimate of “total cancer” risk by combining risk of the three cancers. First, EPA estimated the lifetime extra risk of each cancer separately at 0.1 ppm and then added the three estimates and computed the up- per confidence limit of the sum. The upper confidence limit is reported as the unit total cancer risk: 4.5 x 10-2 and 8.1 x 10-2 ppm-1 for mortality and incidence, respectively (see Table 6-3). EPA’s computation amounts to using the sum of risk of each cancer as a conservative approximation of the risk of any (total) cancer and relies on the assumption that the maximum likelihood estimates of the three cancer risks are independent, an assumption that is convenient but needs justification because the estimates were derived from the same sample of person-years of exposure. A statistically sound alternative would be to consider incidence or mortality of any cancer and then follow the same methods for NPC incidence or mortality. That would be a preferred approach but would require EPA to fit a Poisson regression to the total cancer incidence or mortality. Sources of Uncertainty A unit risk estimate is subject to uncertainty and variability attributable to many sources at various stages of the derivation process. Moreover, it is difficult to determine the degree to which each source affects the overall uncertainty and variation in the final estimate. EPA discussed many potential sources of uncer- tainty involved in the derivation of the final unit risk estimates. It not only quali- tatively identified important sources of uncertainty but quantitatively explored the variability and uncertainty with respect to different cancers, points of depar- ture, all person-years vs only exposed person-years, and mortality vs incidence. It also adjusted for susceptibility in earlier-life exposure. Although EPA did a commendable job in evaluating some of the underlying uncertainties, the com- mittee finds that there is room for further improvement, especially in describing and applying systematic inclusion and exclusion criteria for selecting studies and cancer end points and in using alternative dose-response models. Estimating Unit Risks by Using Animal Studies To validate and supplement the unit risk estimates using human data, EPA reanalyzed the nasal squamous cell carcinoma (SCC) incidence data from two long-term bioassays that used F344 rats (Kerns et al. 1983; Monticello et al. 1996). The two bioassays were combined in EPA’s reanalysis to achieve a set of robust dose-response data. The combined dataset has SCC incidences of 0% (n = 341), 0% (n = 107), 0% (n = 353), 0.87% (n = 343), 21.4% (n = 103), and 42% (n = 386) in dose groups of 0, 0.7, 2, 6.01, 9.93, and 14.96 ppm, respectively. EPA conducted a dose-response assessment by using a clonal growth model of the nasal tumor with formaldehyde flux to tissue as the dose metric. The analysis resulted in a unit risk of 1.2 x 10-2 ppm-1 (extra risk, 0.005) and 2.2 x 10-2 ppm-1 (extra risk, 0.01) for humans after interspecies scaling. The estimates are rela-

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144 Review of EPA’s Draft IRIS Assessment of Formaldehyde tively consistent with the risk estimates derived from human data from the NCI studies. Moreover, EPA characterized uncertainties attributable to dose-response models (Weibull model with threshold, multistage model for time to tumor, and clonal growth model), extra risk level (1%, 5%, or 10%), and dose metric (flux, DPX). The resulting unit risk estimates are in the range of 1.4 x 10-2 to 1.9 x 10-1 ppm-1. The variation confirms increasing unit risk with increasing extra risk level. Uncertainty remained within less than a factor of 3 between various dose- response models. EPA’s efforts to conduct independent dose-response assess- ment are valuable. CONCLUSIONS AND RECOMMENDATIONS The committee reviewed EPA’s approach to derivation of the RfCs and unit risks for formaldehyde as described in the draft IRIS assessment. The com- mittee’s general conclusions and recommendations to be considered in revision of the draft assessment are provided below.  The committee supports EPA’s selection of effects on which it based candidate RfCs but does not support the advancement of two studies selected by EPA: Ritchie and Lehnen (1987) and Rumchev et al. (2002). Furthermore, the lack of clear selection criteria, inadequate discussion of some modes of action, little synthesis of responses in animal and human studies, and lack of clear ra- tionales for many conclusions weaken EPA’s arguments as presented in the draft IRIS assessment.  The committee disagrees with EPA’s decision not to calculate a candi- date RfC for upper respiratory tract pathology. Many well-documented studies have reported the occurrence of upper respiratory tract pathology in laboratory animals, including nonhuman primates, after inhalation exposure to formalde- hyde, and the committee recommends that EPA use the animal data to calculate a candidate RfC for this end point.  The committee found that EPA dismissed the results of the exposure chamber and other nonresidential studies too readily. Although the exposure durations for the chamber studies are short relative to the chronic duration of the RfC, the studies provide compliementary information that could be used for deriving a candidate RfC.  Regarding the uncertainty factor that accounts for variability in re- sponse of the human population, the committee suggests application of a value of 3 to calculate the candidate RfCs on the basis of the work of Garrett et al. (1999), Hanrahan et al. (1984), and Liu et al. (1991). Those studies included potentially susceptible populations, so the default value of 10 is not necessary. However, uncertainties remain regarding susceptible populations and factors that affect susceptibility, so a value of 1 is not recommended.  Regarding the uncertainty factor that accounts for database complete- ness, the committee suggests that EPA apply its first option as described in the

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Concentrations for Noncancer Effects and Unit Risks for Cancers 145 draft IRIS assessment; that is, apply a value of 1 with the qualification that fur- ther research on reproductive, developmental, neurotoxic, and immunotoxic effects would be valuable.  Overall, the committee found little synthesis of the relationships among the identified noncancer health effects; it appeared that EPA was driven by the need to identify the best study for each health effect rather than trying to inte- grate all the information. The committee strongly recommends the use of appro- priate graphic aids that better display the range of concentrations evaluated in each published study selected for quantitative assessment; the figures may help to identify how findings of studies cluster and especially identify low or high reference values that may be inconsistent with the body of literature. Ultimately, such graphics will improve the ability of the assessment and make a compelling case for the RfC ultimately put forward.  Regarding calculation of unit risks, the committee agrees that the NCI studies and the findings of the two follow-ups are a reasonable choice because they are the only ones with sufficient exposure and dose-response data for risk estimation. However, the studies are not without their weaknesses, and these need to be clearly articulated in the revised IRIS assessment.  The committee agrees that EPA’s choice of NPC, Hodgkin lymphoma, and leukemia data from the NCI studies to estimate a unit risk is appropriate given that the analysis of Hodgkin lymphoma and leukemia primarily supports the assessment of uncertainty and the magnitude of potential cancer risk. How- ever, the mode of action for formaldehyde-induced Hodgkin lymphoma and leukemia has not been clearly established. Moreover, the highly limited systemic delivery of formaldehyde draws into question the biologic feasibility of causality between formaldehyde exposure and the two cancers. Thus, substantial uncer- tainties in using Hodgkin lymphoma and leukemia for consensus cancer risk estimation remain.  Overall, the committee finds EPA’s approach to calculating the unit risks reasonable. However, EPA should validate the Poisson dose-response models for NPC, leukemia, and Hodgkin lymphoma mortality with respect to adequacy of model fit, including goodness of fit in the low-dose range, (log) linearity, and absence of interactions of covariates with formaldehyde exposure. Furthermore, EPA is strongly encouraged to conduct alternative dose-response modeling by using Cox regression or alternative nonlinear function forms.  The draft IRIS assessment does not provide adequate narratives regard- ing selection of studies and end points for derivation of unit risks. The commit- tee strongly recommends that EPA develop, state, and systematically apply a set of selection criteria for studies and cancer end points. The committee recognizes that uncertainty and variability remain critical issues as EPA continues to promote quantitative assessment to improve envi- ronmental regulation. There are still technical gaps in developing and applying quantitative analysis of uncertainty and variability, especially to incorporate

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146 Review of EPA’s Draft IRIS Assessment of Formaldehyde from all sources and at all stages into an overall summary. The NRC Committee to Review EPA's Toxicological Assessment of Tetrachloroethylene (NRC 2010) made several recommendations for advancing methodology and promoting ap- plications. Further research is needed to study various approaches. Small (2008) discussed a probabilistic framework. Given a set of options related to a key as- sumption (such as mode of action) or a key choice (such as cancer end point), a preference score (or prior probability) may be assigned to each option. The final risk estimate thus also has a weight or probability attached that combines the preference on all options over each assumption or choice. The overarching weight is the result of propagation of uncertainty in each assumption or choice and aggregation of all assumptions over the risk assessment process tree. The collection of final risk estimates for all permissible combinations of assumption and choice forms an empirical distribution. That distribution quantifies the full range of variation and uncertainty in the risk estimate. With the full range of variation of risk estimates and other information on preference of key assump- tions and choices, regulatory policy can depend less on a single principal study, a single principal dataset, or a principal end point. The risk-management process may use the distributional properties of the risk estimate to choose a final risk estimate in the context of all feasible assumptions and choices. The committee concludes that further development of systematic approaches to quantifying un- certainty and variation will enable EPA to conduct IRIS assessments in a more transparent and objective fashion. REFERENCES 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. Bessac, B.F. and S.E. Jordt. 2008. Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control. Physiology (Bethesda). 23:360-370. Blair, A., P. Stewart, M. O’Berg, W. Gaffey, J. Walrath, J. Ward, R. Bales, S. Kaplan, and D. Cubit. 1986. Mortality among industrial workers exposed to formaldehyde. J. Natl. Cancer Inst. 76(6):1071-1084. Breslow, N.E., and N.E. Day. 1987. Statistical Methods in Cancer Research, Vol. 2. The Design and Analysis of Cohort Study. IARC Scientific Publications No. 82. Lyon: International Agency for Research on Cancer [online]. Available: http://www.iarc. fr/en/publications/pdfs-online/stat/sp82/SP82.pdf [accessed Jan. 25, 2011]. 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. Callas, P.W., H. Pastides, and D.W. Hosmer. 1998. Empirical comparisons of propor- tional hazards, poisson, and logistic regression modeling of occupational cohort data. Am. J. Ind. Med. 33(1):33-47.

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Concentrations for Noncancer Effects and Unit Risks for Cancers 147 EPA (U.S. Environmental Protection Agency). 1991. Guidelines for Developmental Toxic- ity Risk Assessment. EPA/600/FR-91/001. Risk Assessment Forum, U.S. Environ- mental Protection Agency, Washington, DC. December 1991 [online]. Available: http://iccvam.niehs.nih.gov/SuppDocs/FedDocs/EPA/EPA-devtox.pdf [accessed Feb. 28, 2011]. EPA (U.S. Environmental Protection Agency). 1994. Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. EPA/600/B- 90/066F. Office of Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC [online]. Available: http://www.epa.gov/raf/publications/pdfs/RFCMETHODOLOG Y.PDF [accessed Nov. 28, 2010]. EPA (U.S. Environmental Protection Agency). 1998. Guidelines for Neurotoxicity Risk Assessment. EPA/630/R-95/001F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. April 1998 [online]. Available: http://www. epa.gov/raf/publications/pdfs/NEUROTOX.PDF [accessed Feb. 28, 2011]. EPA (U.S. Environmental Protection Agency). 1999. Toxicology Data Requirements for Assessing Risks of Pesticide Exposure to Children’s Health: Report of the Toxi- cology Working Group of the 10X Task Force. Draft Report, April 28, 1999. U.S. Environmental Protection Agency [online]. Available: http://www.epa.gov/scipo ly/sap/meetings/1999/may/10xtx428.pdf [accessed Jan. 25, 2011]. EPA (U.S. Environmental Protection Agency). 2002. A Review of the Reference Dose and Reference Concentration Processes. External Review Draft. EPA/630/P- 02/002A. Reference Dose/Reference Concentration (RfD/RfC) Technical Panel, Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/raf/publications/pdfs/rfdrfcextrevdrft.pdf [accessed Jan. 6, 2010]. EPA (U.S. Environmental Protection Agency). 2005. Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001F. Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC. March 2005 [online]. Available: http://www.epa.gov/raf/publications/pdfs/CANCER_GUIDELINES_FINAL_3- 25-05.PDF [accessed Nov. 24, 2010]. EPA (U.S. Environmental Protection Agency). 2006. A Framework for Assessing Health Risk of Environmental Exposures to Children. EPA/600/R-05/093F. National Cen- ter for Environmrntal Assessment, Office of Research and Development, U.S. En- vironmental Protection Agency, Washington, DC. September 2006 [online]. Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=158363 [accessed Mar. 10, 2010]. EPA (U.S. Environmental Protection Agency). 2008a. Child-Specific Exposure Factors Handbook (Final Report) 2008. EPA/600/R-06/096F. National Center for Envi- ronmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://cfpub.epa.gov/n cea/cfm/recordisplay.cfm?deid=199243 [accessed Jan. 25, 2011]. EPA (U.S. Environmental Protection Agency). 2008b. Toxicological Review of Tetra- chloroethylene (Perchloroethylene) (CAS No. 127-18-4) In Support of Summary Information on the Integrated Risk Information System (IRIS). External Review Draft. EPA/635/R-08/011A. U.S. Environmental Protection Agency, Washington, DC. June 2008 [online]. Available: http://cfpub.epa.gov/ncea/cfm/recordisplay.cf m?deid=192423 [accessed Jan.25, 2011]. EPA (U.S. Environmental Protection Agency). 2009a. Risk Assessment Guidance for Super- fund Volume I: Human Health Evaluation Manual (Part F, Supplemental Guidance for

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