Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde (2011) / Chapter Skim
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6 Reference Concentrations for Noncancer Effects and Unit Risks for Cancers
6 Reference Concentrations for Noncancer Effects and Unit Risks for Cancers
Pages 118-150
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From page 118... ...
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.
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From page 119... ...
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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From page 120... ...
characterized as portal-of-entry or systemic. For portal-of-entry noncancer effects, 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.
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From page 121... ...
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.
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From page 122... ...
. Abbreviations: UFL, uncertainty factor for adjustment of LOAEL to NOAEL; UFS, uncertainty factor for adjustment of less than chronic study to chronic duration; UFH, uncertainty factor that accounts for human population variability; RfC, reference concentration; POD, point of departure; EPA, Environmental Protection Agency; PEFR, peak expiratory flow rate; LOAEL, lowest observed adverse effect level; NOAEL, noobserved-adverse-effect-level; BMCL10, lower 95% confidence limit on the benchmark concentration corresponding to a 10% response level; and TWA, time-weighted average.
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From page 123... ...
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 welldocumented studies have reported the occurrence of upper respiratory tract pathology in laboratory animals, including nonhuman primates, after inhalation exposure to formaldehyde.
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From page 124... ...
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)
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From page 125... ...
. Accordingly, the committee evaluated the data presented in the draft IRIS assessment on toxicokinetics, toxicodynamics, mode of action, and attributes of the key studies to consider how well they represent the dose-response data on susceptible populations.
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From page 126... ...
. As noted in the draft IRIS assessment, the qualitative and quantitative effects of the interactions of ADH3 and GSNO on the toxicity of formaldehyde and human population variability are not understood.
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From page 127... ...
. Identification of Sensitive Populations Children and adults who have asthma and allergic sensitization are susceptible 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.
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From page 128... ...
(1999) , the draft IRIS assessment assumes that children and adults who have asthma or allergic sensitization are the susceptible populations.
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From page 129... ...
EPA evaluated a broad array of health effects associated with formaldehyde exposure, including those related to asthma, pulmonary function, sensory irritation, respiratory tract pathology, reproductive toxicity, developmental toxicity, neurotoxicity, and immunotoxicity.
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From page 130... ...
The proposed RfC is thus based on subtle effects observed in children who are expected to be a susceptible population for respiratory effects. As discussed in the draft IRIS assessment, the principal deficiencies in the database are the lack of studies that provide a full evaluation of the complete spectrum of end points in the reproductive, developmental, nervous, and immune systems and the absence of a multi-generation animal study that evaluates reproductive function.
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From page 131... ...
Each respiratory tract end point (sensory irritation, upper respiratory tract pathology, decreased pulmonary function, increased asthma, and allergic sensitization) and its associated doseresponse information are considered individually, although the draft assessment acknowledges that they are etiologically and clinically related.
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From page 132... ...
. The Science Advisory Board, which conducted a peer review of EPA's draft IRIS assessment titled "Toxicological Review of Trichloroethylene," commented that "the Panel supported the selection of an RfC and an RfD based on multiple candidate reference values in a narrow range, rather than basing these values on the single most sensitive critical endpoint.
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From page 133... ...
The draft IRIS assessment concludes that 8.1 x 10-2 ppm-1 is a reasonable estimate of unit risk of total cancer. Many sources at various stages of the risk-estimation process contribute to the overarching uncertainty and variation in the final risk estimates.
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From page 134... ...
More important, the NCI studies exhibited positive and statistically significant exposure-response relationships for some exposure metrics and selected cancers, notably NPC, Hodgkin lymphoma, and leukemia. EPA also reviewed other epidemiologic studies but chose not to use them for unit risk estimation.
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From page 135... ...
The committee agrees that EPA's choice of NPC, Hodgkin lymphoma, and leukemia to estimate the unit risk is appropriate given that the use of Hodgkin lymphoma and leukemia primarily supports the assessment of uncertainty and the magnitude of cancer risk where there is a lack of evidence to support the biologic plausibility of a relationship between formaldehyde exposure and the two cancers. The committee also notes that the positive exposure-response findings from the NCI studies support the use of the three cancers for unit risk estimation.
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From page 136... ...
. However, the draft IRIS assessment states that "only all leukemias combined and Hodgkin lymphoma were judged to have exposure-response data adequate for the derivation for unit risk estimates" (EPA 2010b, p.
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From page 137... ...
To conduct risk assessment with the models directly, EPA obtained the regression coefficients of the models from the authors through personal communications because the coefficients were not reported in the published papers. The draft IRIS assessment should provide more details on the models, including, for example, the degree to which the model fits the data.
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From page 138... ...
That analysis is essential because dose-response models used for risk estimation must fit the data well in the low-dose range; this may not necessarily be required for an analysis of the dose-response relationship to establish an association between formaldehyde exposure and a selected cancer. EPA is encouraged to consider the use of alternative extrapolation models, including Cox regression models and nonlinear model forms.
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From page 139... ...
and (c) are complicated, but the draft IRIS assessment provides only the following brief explanation: Extra risk estimates were calculated using the β regression coefficients and a life-table program that accounts for competing causes of death.
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From page 140... ...
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.
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From page 141... ...
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 observed 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.
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From page 142... ...
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.
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From page 143... ...
Although EPA did a commendable job in evaluating some of the underlying uncertainties, the committee 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)
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From page 144... ...
EPA's efforts to conduct independent dose-response assessment 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.
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From page 145... ...
The draft IRIS assessment does not provide adequate narratives regarding selection of studies and end points for derivation of unit risks. The committee strongly recommends that EPA develop, state, and systematically apply a set of selection criteria for studies and cancer end points.
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From page 146... ...
With the full range of variation of risk estimates and other information on preference of key assumptions 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.
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Technical Panel, Risk Assessment Forum, U.S. Environmental Protection Agency, Washington, DC [online]
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From page 148... ...
1999. Increased risk of allergy in children due to formaldehyde exposure in homes.
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From page 149... ...
1990. Chronic respiratory effects of indoor formaldehyde exposure.
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From page 150... ...
2010. Review of the Environmental Protection Agency's Draft IRIS Assessment of Tetrachloroethylene.
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