Review of EPA's 2022 Draft Formaldehyde Assessment (2023) / Chapter Skim
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5 Cancer
5 Cancer
Pages 87-120
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From page 87... ...
human carcinogen. The 2022 Draft Assessment concludes that the evidence demonstrates that formaldehyde inhalation causes cancer in humans and identifies nasopharyngeal and sinonasal cancers, as well as myeloid leukemia, as types of cancers with this level of evidence.
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From page 88... ...
Methods and procedures for literature identification and evaluation of each study are presented in several parts of the 2022 Draft Assessment. Chapter 4.1 of the Assessment Overview presents a summary of the process, Sections 1.2.5 and 1.3.3 of the "Toxicological Review of Formaldehyde: Inhalation" provide more granular detail with references to the Appendix for additional information about respiratory tract and nonrespiratory tract cancers.
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From page 89... ...
EPA followed the state of practice for literature review at the time the assessment was being conducted in evaluating studies of cancer outcomes in humans and in animals. For mechanistic evidence, EPA used a narrative review approach for summarizing the volumi nous evidence on mechanistic events that are known to be associated with cancers of the upper respiratory tract and lymphohematopoietic cancers.
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From page 90... ...
• For nasopharyngeal cancer in humans, the 2022 Draft Assessment evaluates 20 pri mary epidemiological studies -- 12 case-control and eight cohort study designs. The text explains confidence level determinations for each individual study (Appendix F, Table 1-32)
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From page 91... ...
, and the National Toxicology Program (NTP) Oro-/Hypo- Pharyngeal Assessment Nasopharyngeal Cancer Sinonasal Cancer Myeloid Leukemia Cancer Multiple Myeloma Hodgkin Lymphoma EPA (2022a, The evidence The evidence The evidence demonstrates The available evidence The available evidence The available evidence Draft demonstrates that demonstrates that that formaldehyde inhalation suggests, but is not suggests, but is not suggests, but is not Assessment)
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From page 92... ...
NTP (2011) Causal: Causality is indicated by consistent findings "no consistent findings of higher risk among the "Because the evidence for these two types of of increased risks of nasopharyngeal cancer, sinonasal individuals with the highest exposure levels" (see also cancer [myeloma and Hodgkin lymphoma]
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From page 93... ...
280) NOTE: a The 2022 Draft Assessment (EPA, 2022a)
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From page 94... ...
The committee concludes that these findings provide plausible mechanistic pathways supporting a relationship between formaldehyde exposure and cancer, even though the potential mechanisms of how formaldehyde may cause such systemic effects are not fully understood. It would be desirable to have a more complete understanding about how formaldehyde exposure may cause systemic effects, but the lack of known mechanisms should not detract from the findings of an association between formaldehyde exposure and myeloid leukemia in epidemiology studies." (pp.
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From page 95... ...
4, 15th RoC) "The mechanisms by which formaldehyde causes toxicity at distal sites are "Inhalation-exposure studies in experimental animals have shown that unknown" (p.
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From page 96... ...
In its overall synthesis of the epidemiological evidence, EPA concluded that the available human studies provide robust evidence of an associa tion consistent with causation between formaldehyde exposure and increased risk of si nonasal cancer. • For other respiratory tract cancers (oropharyngeal/hypopharyngeal and laryngeal)
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From page 97... ...
The Draft Agreement also concludes that the development of these lesions, particularly SCCs, depended on the duration of observation, and, based on an increasing incidence and severity of lesions in animals exposed for longer periods of time, the duration of formaldehyde exposure. Finding: With respect to cancer hazard identification for respiratory tract cancers in animals exposed to formaldehyde, EPA synthesized the current state of the science in a manner con sistent with its state-of-practice methods and presents conclusions based on its expert judg ment with the support of the available scientific evidence.
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From page 98... ...
Finally, the Draft Assessment notes that mechanistic data provide strong and consistent evidence supporting the contribution of both direct genotoxicity and mutagenicity and cytotoxicity-induced regenerative proliferation as primary mechanistic events. EPA concluded that these mechanisms were highly relevant for informing quantification of nasal cancers in experimental animals following chronic formaldehyde exposure.
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From page 99... ...
See Chapter 2 of the present report, Recommendation 2.5. Lymphohematopoietic Cancers For lymphohematopoietic cancers, the 2022 Draft Assessment focuses on clinical diagnoses of Hodgkin lymphoma, multiple myeloma, myeloid leukemia, and lymphatic leukemia in exposed humans, as well as relevant tumor findings in animals and mechanistic evidence.
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From page 100... ...
In the overall synthesis of epidemiological evidence, EPA con cludes that the available epidemiological studies provide robust evidence of an asso ciation consistent with causation between formaldehyde exposure and increased risk of myeloid leukemia. • For lymphatic leukemia in humans, the 2022 Draft Assessment evaluates nine pri mary epidemiological studies -- two case-control and seven cohort study designs.
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From page 101... ...
Overall, EPA concludes that the available epidemiological studies provide slight ev idence of an association consistent with causation between formaldehyde exposure and an increased risk of multiple myeloma, primarily with respect to peak exposure. • For Hodgkin lymphoma in humans, the 2022 Draft Assessment evaluates 15 pri mary epidemiological studies -- one case-control and 14 cohort study designs; only 12 of these studies were deemed informative.
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From page 102... ...
Overall, EPA concludes that the available evidence supports some events that could contribute to plausible mechanistic pathways relating formaldehyde exposure to lymphohematopoietic carcinogenesis; however, the database was insufficient to support the evaluation or development of any specific MOA. EPA further concludes that while the available mechanistic database has limitations, this does not detract from the strength of the association between formaldehyde exposure and myeloid leukemia in epidemiological studies.
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From page 103... ...
The 2022 Draft Assessment does not include a third cancer outcome in this evidence category -- sinonasal cancer -- because adequate quantitative data for dose-response analysis were lacking. EPA concluded that the large and diverse body of mechanistic, pharmacokinetic, whole-animal, and human evidence was sufficient to conduct the technically complex dose-response analysis for the nasopharyngeal cancer and myeloid leukemia outcomes.
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From page 104... ...
INHALATION UNIT RISK FOR NASOPHARYNGEAL CANCER FROM EPIDEMIOLOGICAL DATA The 2022 Draft Assessment first presents the unit risk estimates derived from epidemiological data, and then presents the analysis based on animal bioassay data and mechanistic, anatomical, and physiological considerations to support the dosimetry using computational fluid dynamic modeling of dosimetry and biologically based dose-response modeling.
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From page 105... ...
Although the 2022 Draft Assessment also contains a judgment of a causal link (evidence demonstrates) between formaldehyde exposure by inhalation and sinonasal cancer, the latter outcome was not used to conduct a dose-response analysis because the study identifies a total of only five deaths from nose and nasal sinus cancer.
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From page 106... ...
Cumulative exposure was estimated from time in a specific job multiplied by the time-weighted average concentration for that job category. The 2022 Draft Assessment characterizes frequency of peak exposure as highly uncertain because it was estimated based on assumptions made by the exposure assessors for the study.
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From page 107... ...
Because background mortality rates for nasopharyngeal tumors are very low, the 2022 Draft Assessment explains that using a higher extra risk would be inappropriate. For example, using an extra risk of 1 percent, typically used for epidemiological data, would result in a relative risk of 53, an upward extrapolation from the observed data, and using 0.1 percent would yield a relative risk of 6.2, on the high end of the observed range in the Beane Freeman et al.
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From page 108... ...
: EPA should state how the adjustment for the 15-year lag was made for nasopharyngeal cancer mortality, and explain the assignment of zero ex posure in Table B-18. Inhalation Unit Risk for Nasopharyngeal Incidence Because nasopharyngeal cancer has a favorable survival rate (the 2022 Draft Assessment cites 51 percent at five years in the 1990s in the United States)
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From page 109... ...
and indoor (20 ppb) formaldehyde exposure levels as a "reality check" on the inhalation unit risk is a useful exercise that would be improved by acknowl edging some of the possible environmental and other causative factors of nasopharyngeal cancer in the United States.
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From page 110... ...
. This dosimetry of local exposure of formaldehyde inhalation facilitates biologically based dose-response (BBDR)
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From page 111... ...
The relationship between administered dose and the DNA–protein crosslinks and flux dose metrics should also be provided. Given the uncertainties in the dose sur rogates, a dose-response analysis and benchmark concentration calculations using ad ministered concentrations should be provided as a point of comparison.
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From page 112... ...
Selection of a Unit Risk Estimate for Nasal Cancer EPA derived inhalation unit risk estimates using the human nasopharyngeal cancer data and animal SCC data. The inhalation unit risk was 7.4 × 10-3 per mg/m3 based on the nasopharyngeal cancer data and 8.9 × 10-3 to 1.8 × 10-2 per mg/m3 based on the animal SCC data, and these results
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From page 113... ...
: EPA should address technical errors, such as mischar acterization of a trend p-value, with a thorough and technical edit and proofreading. Inhalation Unit Risk for Myeloid Leukemia from Epidemiological Data The methods and rationale for derivation of the unit risk estimate for myeloid leukemia are similar to or the same as those for nasopharyngeal tumors discussed earlier.
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From page 114... ...
EPA used the same approach it used for nasopharyngeal cancer (lifetable, application of regression coefficient, selection of POD, and extra-risk benchmark) to derive inhalation unit risk estimates for myeloid leukemia mortality.
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From page 115... ...
. Uncertainty in the Myeloid Leukemia Inhalation Unit Risk The 2022 Draft Assessment provides a detailed discussion of the uncertainty associated with the myeloid leukemia inhalation unit risks.
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From page 116... ...
. The rationale for adjusting for increased early-life susceptibility was that the mutagenic mode of action was established for nasopharyngeal cancers, and the relative risk from formaldehyde exposure is independent of age within the adult age window.
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From page 117... ...
Confidence in the Unit Risk Estimate EPA assigned the "preferred" unit risk estimate for nasopharyngeal cancer incidence an overall confidence level of medium. The 2022 Draft Assessment acknowledges the substantial uncertainty in the dose extrapolation, especially in light of endogenous formation of the chemical and the possible effect on uptake.
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From page 118... ...
2004. Human respiratory tract cancer risks of inhaled formaldehyde: Dose-response predic tions derived from biologically-motivated computational modeling of a combined rodent and human dataset.
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From page 119... ...
Research Triangle Park, NC: Public Health Service US Department of Health and Human Services, National Toxicology Program.
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From page 120... ...
2016. SCOEL/REC/125 formaldehyde: Rec ommendation from the Scientific Committee on Occupational Exposure Limits.
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