Review of EPA's 2022 Draft Formaldehyde Assessment (2023) / Chapter Skim
Currently Skimming:
4 Noncancer Health Effects
4 Noncancer Health Effects
Pages 53-86
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 53... ...
Noncancer portal-of-entry effects include sensory irritation, decreased pulmonary function, respiratory tract pathology, and allergies and asthma. Although it is a portal-of-entry effect, the committee's discussion concerning asthma is included in the evaluation of systemic effects, reflecting the broader inflammatory consequences of asthma.
|
From page 54... ...
Using a systematic approach to identify and evaluate relevant studies, EPA identified three studies for POD analysis to derive cRfCs, and chose one study, representing an organ- or system-specific cRfC, for consideration of the overall formaldehyde RfC. Literature Identification In the Main Assessment and Appendices, EPA documents the steps it followed to formulate a population, exposure, comparator, and outcome (PECO)
|
From page 55... ...
Excluding outdoor studies from the 2022 Draft Assessment may skew the evidence pool in the direction of higher exposure studies relative to the levels commonly experienced by the general population. The committee also found unconvincing EPA's argument that studies with lower exposure levels may have a limited ability to detect associations between formaldehyde exposure and health effects.
|
From page 56... ...
The committee could not find a consistent approach in how EPA evaluated the potential for se lection bias, for example, across the range of observed response rates. Finding: The 2022 Draft Assessment described specific aspects of exposure assessment that EPA considered when evaluating individual studies, such as having a measurement protocol, duration of exposure measurement period, number of samples obtained, consideration of temperature and humidity, and percentage of measurements below the limit of detection
|
From page 57... ...
(1989) do not provide a reference for their outcome assessment questionnaire, yet EPA categorized it as well as having a high confidence level (Main Assessment: Table 1-1, pp.
|
From page 58... ...
This judgment was based on four high- and medium-confidence studies of symptom prevalence in humans in residential settings, numerous high- and medium-confidence acute controlled human exposure studies, and numerous high- and mediumconfidence occupational studies. Finding: EPA's overall hazard conclusions are supported by the scientific evidence and are consistent with EPA's state-of-practice methods.
|
From page 59... ...
In controlled human exposure settings, formaldehyde exposures ranged between 0.61 and 3.7 mg/m3. Literature Identification Table A-41 in Appendix A summarizes the search terms used for PubMed and Web of Science.
|
From page 60... ...
93) indicates that the controlled human exposure studies "consistently did not observe changes." Acute epidemiological studies: Changes in pulmonary function across a work shift or anatomy course lab session.
|
From page 61... ...
EPA concludes that overall, these studies show evidence of decrements in pulmonary function associated with formaldehyde exposure, particularly given that many studies could be biased toward no association. For the cross-sectional studies, challenges are highlighted in the text: selection bias (healthy worker effect and survivor [lead time]
|
From page 62... ...
Overall Conclusions About the Hazard Descriptor EPA concluded that, based on moderate human evidence, long-term inhalation of formaldehyde is likely causal for decreases in pulmonary function (i.e., EPA applied the evidence indicates rating)
|
From page 63... ...
Animal studies show that inhaled formaldehyde at 2 ppm or higher is cytotoxic and that increases in epithelial cell proliferation occur after chronic formaldehyde inhalation in mice, rats, and nonhuman primates (Kerns et al., 1983; Monticello et al., 1996)
|
From page 64... ...
Outcome-specific criteria used to assess the animal studies included sample size, inadequate reporting of lesion incidence and/or severity, combining of multiple lesions, inadequate sampling of the respiratory tract, and short (<1 year) exposure duration or follow-up.
|
From page 65... ...
Evidence Synthesis and Judgments EPA identified no high-confidence and four medium-confidence human occupational studies. Histological changes in the respiratory tract seen in the latter four studies were associated with formaldehyde exposures ranging from 0.1 to 2.5 mg/m3 (Table 1-25)
|
From page 66... ...
Overall, the strength of the evidence for hyperplasia and squamous metaplasia includes robust evidence from animal studies and moderate human evidence from observational epidemiological studies, and strong support for a plausible MOA based primarily on mechanistic evidence from experimental animals. EPA's overall conclusion is that the evidence demonstrates that inhalation of formaldehyde causes respiratory tract pathology in humans given the appropriate exposure circumstances.
|
From page 67... ...
questionnaire information was also favored for highconfidence determinations. Animal studies were viewed as indeterminate for allergy and asthma because of the unsuitability of animal models for evaluation of pathophysiology and mechanisms of these outcomes from formaldehyde exposures.
|
From page 68... ...
are not defined, and several studies of school-age children were used to inform the strength-of-evidence determi nation. While age cutoffs of <5 and >75 years are cited in the Assessment Overview and Appendices as exclusion criteria, the Main Assessment does not describe age cutoffs, and it is unclear how these cutoffs were made actionable in study choice as some studies of infants and children <5 feature in asthma evaluations in particular.
|
From page 69... ...
that inhalation of formaldehyde causes an increased risk of prevalent allergic conditions and asthmatic symptoms and decreased control of asthmatic symptoms, with evidence from occupational studies in the range of exposure values >0.1 mg/m3 and from schools and homes at 0.03–<0.1 mg/m3. EPA made these judgments after carrying out the synthesis of substantial evidence on allergic conditions, asthma, and lower respiratory tract infections (in young children)
|
From page 70... ...
These immune mechanisms are complex and largely beyond the scope of the 2022 Draft Assessment, and are described in light of several high- to medium-confidence studies in relation to formaldehyde MOA. These animal studies provide strong evidence for some aspects of formaldehyde's relevant activities -- for example, bronchoconstriction and eosinophil activation via inflammatory mediators such as tachykinins, antibodies, Th2-related cytokines, and white blood cell changes.
|
From page 71... ...
. EPA's 2022 Draft Assessment considers a range of developmental and female and male reproductive toxicity endpoints in relation to formaldehyde inhalation exposure.
|
From page 72... ...
Study Evaluation EPA's evaluation of human studies of female reproductive or developmental toxicity resulted in two medium-confidence occupational studies of spontaneous abortion, two low-confidence studies of congenital malformations, two medium-confidence studies of decreased birthweight and head circumference, and five low-confidence studies of fecundability and spontaneous abortion. Low-confidence animal studies of female reproductive or developmental toxicity had mixed findings for several outcomes.
|
From page 73... ...
Assessment of animal studies revealed indeterminate evidence for developmental toxicity and separately, indeterminate evidence for female reproductive toxicity. All evaluated studies had low confidence with methodological limitations, the majority of which were due to a lack of information about test substance or use of formalin, which can contain methanol, a known developmental and reproductive toxicant.
|
From page 74... ...
was based on moderate human evidence and indeterminate animal evidence for developmental or female reproductive toxicity. Finding: The conclusion that the evidence indicates that inhalation of formaldehyde likely causes increased risk of developmental or female reproductive toxicity in humans is con sistent with EPA's state-of-practice methods.
|
From page 75... ...
NERVOUS SYSTEM The 2010 Draft Assessment suggested that the available human studies demonstrated potentially concerning nervous system effects following formaldehyde exposure. However, the 2011 NRC committee concluded that EPA's conclusion regarding nervous system effects was overstated and based on insufficient evidence.
|
From page 76... ...
Finding: Regarding animal studies, study quality criteria were consistent with EPA's state of-practice methods. Evidence Synthesis and Judgments EPA summarizes its evidence synthesis for nervous system effects of formaldehyde in Table 1-50.
|
From page 77... ...
, along with medium confidence for animal studies on developmental neurotoxicity, the basis for the overall evidence judgment is not well articulated. The 2022 Draft Assessment concludes that the underlying MOA for neurotoxicity for inhaled formaldehyde exposures is unknown.
|
From page 78... ...
: EPA should carefully address the following points re garding the derivation of the RfC: • Fully disclose data extracted from original study reports using HERO or other means. • Cite relevant guidance documents regarding the use of a mean versus median and arithmetic mean versus geometric mean to estimate a lowest observed ad verse effect level or no observed adverse effect level.
|
From page 79... ...
Benchmark concentration lower bound (BMCL) 10 = 0.021 Immune System: Allergic Conditions Annesi-Maesano et al.
|
From page 80... ...
(1999) Time to pregnancy NOAEL = 0.106 LOAEL = 0.278 No UfH = 10 0.01 Yes Male Reproductive Toxicity (animal studies)
|
From page 81... ...
Abbreviations: BMC= benchmark concentration; BMCL= benchmark concentration lower bound; BMDS= benchmark dose software; BMR= benchmark response; cRfC= candidate reference concentration; HEC= human equivalent concentration; LOAEL= lowest observed adverse effect level; NOAEL= no observed adverse effect level; osRfC= organ or system-specific reference concentration; POD= point of departure; PODADJ = adjusted point of departure; RfC= reference concentration; SD= standard deviation; UF= uncertainty factor.
|
From page 82... ...
: EPA should carefully address the following points regarding the derivation of the RfC: • To ensure that the resulting benchmark concentration lower bound is not arti ficially overestimated, better account for within-group variability in the dose response analysis of Hanrahan et al.
|
From page 83... ...
1988b. Comparison of health of occupants and characteristics of houses among control homes and homes insulated with urea formaldehyde foam.
|
From page 84... ...
2008. Formaldehyde and chemosensory irritation in humans: A controlled human exposure study.
|
From page 85... ...
2007. Effects of postnatal formaldehyde exposure on pyramidal cell number, volume of cell layer in hippocampus and hemisphere in the rat: A stereological study.
|
From page 86... ...
1998. Repeated low-level formaldehyde exposure produces cross-sensitization to cocaine: Possible relevance to chem ical sensitivity in humans.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.