Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde (2011) / Chapter Skim
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5 Systemic Health Effects
5 Systemic Health Effects
Pages 92-117
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From page 92... ...
In this chapter, the committee reviews EPA's evaluation of systemic health effects, including immunotoxicity, neurotoxicity, reproductive and developmental toxicity, and lymphohematopoietic cancers. The committee determined whether EPA identified the appropriate studies, whether the studies were thoroughly evaluated, whether hazard identification was conducted appropriately in light of EPA guidelines, and whether the best studies were advanced for calculation of the reference concentration (RfC)
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From page 93... ...
. In the case of formaldehyde, as has been discussed elsewhere in the present report, most of or all the direct effects occur at the point of entry in the upper respiratory tract.
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From page 94... ...
However, the differences in responses may not be relevant for other immunotoxicities, such as respiratory burst activity, sensitivity, and atopy. Study Identification The draft IRIS assessment discusses immunologic end points affected by formaldehyde exposure on the basis of human and animal studies in the compiled database of published studies.
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From page 95... ...
As shown in Table 4-47 of the draft IRIS assessment, peroxide production was increased in response to macrophage activation. If the results of the studies were synthesized, EPA could strengthen its conclusion that formaldehyde exposure affects respiratory burst activity in the immune system.
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From page 96... ...
Although the committee agrees that each type of protocol appropriately replicates a real-world exposure scenario, the section deserves a robust rubric to evaluate the strengths and weaknesses of the studies presented. That is particularly important given that the section "Sensitization and Atopy" of the draft IRIS assessment concludes with a statement that "taken as a whole, the results support the finding that formaldehyde exposure can aggravate a type I hypersensitivity response" (EPA 2010, p.
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From page 97... ...
Conclusions and Recommendations The systemic nature of the immune system and the interplay between the innate and adaptive arms of the immune system provide a plausible potential target of formaldehyde, despite its limited distribution beyond the point of entry. The draft IRIS assessment summarizes many human and animal studies that describe formaldehyde-induced immunotoxicity.
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From page 98... ...
Study Evaluation The evaluation of the epidemiologic studies in the draft IRIS assessment focused on Weisskopf et al.
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From page 99... ...
The draft IRIS assessment indicates that there is some question as to whether formaldehyde should be considered a direct neurotoxicant (EPA 2010)
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From page 100... ...
Furthermore, the available human data have important shortcomings -- such as limited exposure assessments and coexposures to neurotoxic solvents -- that preclude a determination that formaldehyde is neurotoxic to humans. Study Selection for Calculation of Reference Concentration and Identification of Point of Departure EPA concluded that the available epidemiologic studies did not provide sufficient exposure information to permit derivation of a point of departure for use in quantitative dose-response assessment.
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From page 101... ...
Conclusions and Recommendations The committee concludes that the draft IRIS assessment overstates the evidence that formaldehyde is neurotoxic. The selected studies are not sufficiently robust in design to be considered well executed for the purpose of neurotoxicity-hazard identification.
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From page 102... ...
Resolve inconsistencies regarding the concentration at which systemic effects of formaldehyde exposure are expected. The draft IRIS assessment indicates that there is some question as to whether formaldehyde should be considered a direct neurotoxicant, and some portions of the assessment suggest that systemic effects are unexpected at formaldehyde concentrations less than 20 ppm.
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From page 103... ...
The committee disagrees with EPA's overall conclusion regarding the totality of the epidemiologic evidence related to the reproductive and developmental effects of formaldehyde. Specifically, the draft IRIS assessment states that "epidemiologic studies suggest a convincing relationship between occupational exposure to formaldehyde and adverse reproductive outcomes in women" (EPA 2010, p.
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From page 104... ...
Many of the conclusions on developmental and reproductive effects in animal studies provided in Section 6.1.3.7 of the draft IRIS assessment are based on studies that are of questionable quality. The following statement seems to over interpret the results: Nevertheless, a number of animal studies have demonstrated effects of formaldehyde on pre- and postnatal development and on the reproductive system.
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From page 105... ...
Because formaldehyde is a natural metabolic intermediate in humans and other animals, some discussion of the endogenous formaldehyde concentrations in the animal models is needed to put the exposures into context. Hazard Identification and Use of EPA Guidelines The draft IRIS assessment briefly summarizes the evaluation of key epidemiologic studies and touches on issues of bias (EPA 2010, Section 4.4.9)
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From page 106... ...
In evaluating the animal data for reproductive effects, the draft IRIS assessment notes that there are no multigenerational tests for reproductive function (EPA 2010, Section 4.4.9.8)
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From page 107... ...
, and assessment of confounding, such as by occupational exposures. The draft IRIS assessment indicates that the study could be used for three outcomes: miscarriage, endometriosis, and decreased fecundity density ratio (FDR)
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From page 108... ...
Although the draft IRIS assessment explores specific diagnoses -- such as acute myeloid leukemia (AML) , chronic myeloid leukemia (CML)
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From page 109... ...
. Another important topic of discussion in the draft IRIS assessment is that of potential modes of action of formaldehyde as a cause of diverse LHP cancers.
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From page 110... ...
, although intriguing, provides the only positive findings and thus does not contribute to the weight of evidence of causality. Study Identification The draft IRIS assessment comprehensively presents studies available through late 2009 that evaluate formaldehyde exposure and risk of LHP cancers.
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From page 111... ...
. To make the IRIS assessment as timely as possible, inclusion of the recent studies seems warranted in the revision.
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From page 112... ...
In addition, the reliance on the peak-exposure metric to determine causality in that study rather than the more conventional dose metric of cumulative exposure should be further justified, particularly in the absence of established modes of action. Hazard Identification and Use of EPA Guidelines The hazard identification concluded that there is a causal association between formaldehyde exposure and mortality from all LHP cancers, all leukemias as a group, myeloid leukemias, Hodgkin lymphoma, and multiple myeloma.
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From page 113... ...
Conclusions and Recommendations The committee recommends that EPA address the following in the revision of the formaldehyde draft IRIS assessment: Focus on the most specific diagnoses available in the epidemiologic data, such as acute myeloblastic leukemia (International Classification of Diseases [ICD]
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From page 114... ...
2010. Epidemiological studies of formaldehyde exposure and risk of leukemia and nasophryngeal can cer: A meta-analysis.
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From page 115... ...
1988. Respiratory symptoms and pathophysiologi cal effects of occupational exposure to formaldehyde and wood dust.
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2009. Reduced allergic lung inflammation in rats fol lowing formaldehyde exposure: Long term effects on multiple effector systems.
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1989. The effects of maternally inhaled formaldehyde on embryonal and foetal development in rats.
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