Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde (2011) / Chapter Skim
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Pages 3-15
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to conduct an independent scientific review of the draft IRIS assessment and to answer questions related specifically to its derivation of reference concentrations (RfCs) for noncancer effects and unit risk estimates for cancer.
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This summary highlights the committee's substantive comments and recommendations that should be considered in revision of the draft IRIS assessment; more detailed comments and recommendations can be found at the conclusions of individual chapters or following the discussions on individual health outcomes. Toxicokinetics The committee reviewed the extensive discussion on toxicokinetics of formaldehyde in the draft IRIS assessment and focused on several key issues: the implications of endogenous formaldehyde, the fate of inhaled formaldehyde, the systemic availability of formaldehyde, the ability of formaldehyde to cause systemic genotoxic effects, and the usefulness of various models.
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The draft IRIS assessment provides divergent statements regarding systemic delivery of formaldehyde that need to be resolved. Specifically, some parts of the draft assume that the high reactivity and extensive nasal absorption of formaldehyde restrict systemic delivery of inhaled formaldehyde so that formaldehyde does not go beyond the upper respiratory tract, and other parts of the draft assume that systemic delivery accounts in part for the systemic effects attributed to formaldehyde exposure.
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model that has been developed for formaldehyde could be used in the derivation of the unit risk estimates. EPA explored the uncertainties associated with the model and sensitivities of various model components to changes in key parameters and assumptions and, on the basis of those extrapolations, decided not to use the BBDR model in its assessment.
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The draft IRIS assessment speculates that formaldehyde could reach the bone marrow and cause the mutagenic effects that lead to the cancers noted. However, despite the use of sensitive and selective analytic methods that are capable of differentiating endogenous exposures from exogenous ones, numerous studies have demonstrated that systemic delivery of formaldehyde is unlikely at concentrations that do not overwhelm metabolism.
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Although the committee agrees with EPA that the human studies that assessed upper respiratory tract pathology were insufficient to derive a candidate RfC, it disagrees with EPA's decision not to use the animal data. The animal studies offer one of the most extensive datasets on an inhaled chemical, and EPA should use the data to derive a candidate RfC for this outcome.
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However, the draft IRIS assessment does not present a clear framework for causal determinations and presents several conflicting statements that need to be resolved regarding the evidence of a causal association between formaldehyde and respiratory tract cancers. On the basis of EPA cancer guidelines, the committee agrees that there is sufficient evidence (that is, the combined weight of epidemiologic findings, results of animal studies, and mechanistic data)
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The draft IRIS assessment states that epidemiologic studies provide evidence of a "convincing relationship between occupational exposure to formaldehyde and adverse reproductive outcomes in women." The committee disagrees and concludes that a small number of studies indicate a suggestive pattern of association rather than a "convincing relationship." Animal data also suggest an effect, but EPA should weigh the negative and positive results rigorously inasmuch as negative results outnumbered positive ones for some end points, should evaluate study quality critically because some studies of questionable quality were used to support conclusions, and should consider carefully potential confounders, such as maternal toxicity, effects of stress, exposure concentrations above the odor threshold, and potential for oral exposures through licking. Although the epidemiologic studies provide only a suggestive pattern of association, EPA followed its guidelines and chose the best available study to calculate a candidate RfC.
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The committee recommends that EPA focus on the most specific diagnoses available in the epidemiologic data, such as acute myeloblastic leukemia, chronic lymphocytic leukemia, and specific lymphomas. As with the respiratory tract cancers, the draft IRIS assessment does not provide a clear framework for causal determinations.
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Thus, the committee supports the use of a UFH of 3 to calculate candidate RfCs for studies identified in the draft IRIS assessment on reduced pulmonary function, asthma, and sensory irritation, noting that the committee does not support the advancement of the studies by Richie and Lehnen (1987) 10 and Rumchev et al.
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The committee agrees that the NCI studies are a reasonable choice because they are the only ones with exposure and dose-response data sufficient for calculation of the unit risks; however, the studies are not without their weaknesses, which should be clearly discussed and addressed in the revised IRIS assessment. Although there are uncertainties as discussed above regarding the causal relationship of 12 Hauptmann, M., J.H.
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were emphasized in synthesizing the evidence. The committee is concerned about the persistence of problems encountered with IRIS assessments over the years, especially given the multiple groups that have highlighted them, and encourages EPA to address the problems with development of the draft assessments that have been identified.
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Summary 15 formaldehyde assessment to implement a new approach. However, models for conducting IRIS assessments more effectively and efficiently are available, and the committee provides several examples in the present report.
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