Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde (2011) / Chapter Skim
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4 Portal-of-Entry Health Effects
4 Portal-of-Entry Health Effects
Pages 64-91
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From page 64... ...
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.
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From page 65... ...
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.
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From page 66... ...
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 extensive than that included in the draft IRIS assessment and includes studies relevant for evaluating the mode of action of formaldehyde in the respiratory system.
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From page 67... ...
Chapter 4.4.1 of the draft IRIS assessment provides a possible mode of action for sensory irritation: "formaldehyde-induced stimulation of the trigeminal nerve (though whether formaldehyde acts as a direct agonist is unknown)
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From page 68... ...
The studies provided concentration-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 epidemiologic studies in spite of their limitations.
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From page 69... ...
study not be used to estimate a point of departure for a candidate RfC. Although the contribution of cigarette smoke to sensory irritation was controlled 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.
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From page 70... ...
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 assessment are too limited. For example, the draft assessment does not discuss uncertainty in the points of departure contributed by sources specific to the formaldehyde 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)
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From page 71... ...
Review research on the TRPA1 and TRPV1 ion channels and use the information to strengthen discussion of the mode of action underlying the sensory 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)
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From page 72... ...
The draft IRIS assessment justifies the choice by stating that "the best single study demonstrating decreased pulmonary function is the moderate residential study by Krzyzanowski et al.
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From page 73... ...
The committee recommends that EPA address the following in the revision 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.
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From page 74... ...
Study Identification The draft IRIS assessment reviews six studies that examined the effects of formaldehyde exposure on the human upper respiratory tract. Two that examined the same worker cohort are identified as the most robust and sensitive and are selected for possible derivation of a candidate RfC (Holmstrom and Wilhelmsson 1988; Holmstrom et al.
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From page 75... ...
The draft IRIS assessment concludes that histopathologic lesions and abnormal mucociliary clearance are equivalent pathologic lesions of the upper respiratory tract. The committee agrees with the statement that "the mucociliary apparatus is an important barrier to infection and exogenous agents and, thus, [a change in mucociliary clearance]
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From page 76... ...
The background formaldehyde exposure of the reference group is not mentioned in the draft IRIS assessment. The group exposed to formaldehyde alone had an increased nasal-resistance score (as measured by rhinomanometry)
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From page 77... ...
Table 5-4 of the draft IRIS assessment lists the point of departure as 240 ppb as a LOAEL for the upper respiratory tract pathology. As noted above, that is the value reported by Holmstrom et al.
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From page 78... ...
However, many well-conducted animal studies have reported noncancer histopathologic lesions of the respiratory tract after formaldehyde inhalation. The committee recommends that EPA address the following in the revision of the formaldehyde draft IRIS assessment: Calculate a candidate RfC from the animal data.
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From page 79... ...
There is also a lack of clarity concerning the health end point considered -- that is, incidence, prevalence, or exacerbation of established asthma. The evidence from epidemiologic studies is summarized as follows: "in conclusion, the epidemiologic studies of formaldehyde exposure
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From page 80... ...
. The ad hoc approach taken in the draft IRIS assessment may reflect inadequate guidance on asthma.
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From page 81... ...
(2002) study was omitted from Table 54 in the draft IRIS assessment that summarizes all studies advanced for candidate RfCs.
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From page 82... ...
Regardless, the approach used in the draft IRIS assessment for identifying a LOAEL is to use the midpoint 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.
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From page 83... ...
Study Identification The draft IRIS assessment appears to have identified all the pertinent studies of formaldehyde and respiratory cancers available at the time of its release. Thus, the draft assessment presents and discusses findings on lung cancer, nasopharyngeal cancer, nasal cancer, and other respiratory cancers from a large number of occupational cohort studies and several population-based case-control studies of adults.
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From page 84... ...
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.)
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From page 85... ...
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 formaldehyde.
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From page 86... ...
. In addition, studies of deposition of formaldehyde in the respiratory tract have demonstrated clearly that the amount of formaldehyde deposited in the lower respiratory tract would be low.
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From page 87... ...
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.
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From page 88... ...
2004. Assessment of upper respiratory tract and ocular irritative effects of volatile chemicals in humans.
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From page 89... ...
1990. Chronic respiratory effects of indoor formaldehyde exposure.
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From page 90... ...
2010. Role of metabolic activation and the TRPA1 receptor in the sensory irritation response to styrene and naphtha lene.
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From page 91... ...
1984. Oc cupational formaldehyde exposure and increased nasal cancer risk in man.
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