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The Importance of Evaluating Specific Myeloid Malignancies in Epidemiological Studies of Environmental Carcinogens.

The authors systematically evaluated the epidemiological literature on the four chemical agents (1,3-butadiene, formaldehyde, benzene, and tobacco smoking, excluding pharmaceutical, microbial and radioactive agents, and pesticides) classified by the International Agency for Research on Cancer as having sufficient epidemiological evidence to conclude that each causes “myeloid malignancies.” The result of the evaluation found that few epidemiological studies present results for specific myeloid malignancies, and those identified were inconsistent across studies of the same exposure, as well as across chemical agents. The authors review illustrates that even for agents classified as having sufficient evidence of causing “myeloid malignancies,” the epidemiological evidence for specific myeloid malignancies is generally limited and inconsistent.

An Updated Mode of Action and Human Relevance Framework Evaluation for Formaldehyde-Related Nasal Tumors.

In this evaluation, the authors review and update the mode of action (MOA) framework for nasal tumors, with particular emphasis on the studies published since 2006. In 2006 a published MOA for formaldehyde-induced nasal tumors in rats concluded that nasal tumors were most likely driven by cytotoxicity and regenerative cell proliferation, with possible contributions from direct genotoxicity. The most recent evaluation found that newer studies published since 2006, further underscore the involvement of cytotoxicity and regenerative cell proliferation and lend additional support for the use of mechanistic data for the derivation of toxicity criteria and/or scientifically supported approaches for low-dose extrapolation for the risk assessment of formaldehyde.

Using Mechanistic Information to Support Evidence Integration and Synthesis: A Case Study with Inhaled Formaldehyde and Leukemia.

This framework, the available evidence relevant to evaluating the postulated mode of actions (MOAs) for leukemia following formaldehyde inhalation exposure is organized in the World Health Organization (WHO)/International Programme on Chemical Safety (IPCS) MOA Framework. The integration of all the available evidence highlighted the limited amount of data that support any of the postulated MOAs and demonstrated a significant amount of research supporting the null hypothesis that there is no causal association between formaldehyde inhalation exposure and leukemia. These analyses result in a lack of confidence in any of the postulated MOAs, increasing confidence in the conclusion that there is a lack of biological plausibility for a causal association between formaldehyde inhalation exposure and leukemia.

A Kinetic Analysis of DNA-Deoxy Guanine Adducts in the Nasal Epithelium Produced by Inhaled Formaldehyde in Rats—Assessing Contributions to Adduct Production From Both Endogenous and Exogenous Sources of Formaldehyde.

Goal here of this work was to adapt the pharmacokinetic (PK) model for formaldehyde PKs developed for 14C-DNA-protein crosslinks (DPX) and describe the production of both endogenous and exogenous formaldehyde-DNA reaction products (eg, adducts) for a diverse suite of studies at inhaled concentrations from 0.001 to 15 ppm. Another contribution of the modeling was to assess whether descriptions with a single well-mixed cellular formaldehyde compartment could describe adduct formation from formaldehyde produced both by endogenous cellular metabolism and delivered exogenously by inhalation. This refined PK model for endogenous and exogenous formaldehyde acetal adducts will assist in updating biologically based dose-response models for formaldehyde carcinogenicity.

Evaluation of Inhaled Low-Dose Formaldehyde-Induced DNA Adducts and DNA–Protein Cross-Links by Liquid Chromatography–Tandem Mass Spectrometry.

In this study, both exogenous and endogenous DNA mono-adduct (N2-HOMe-dG) and DNA–protein crosslinks (dG-Me-Cys) were measured to assess the formation of DNA adducts arising from the inhalation to 1, 30, 300 ppb [13CD2]-formaldehyde in rats for 28 days using ultrasensitive nano liquid chromatography–tandem mass spectrometry. Endogenous formaldehyde-induced DNA mono-adducts and DPCs were measured in all tissues examined and the levels of endogenous adducts were not altered by the exposure of exogenous isotope labeled formaldehyde. Exogenous formaldehyde-induced DNA mono-adducts and DPCs were undetectable in all tissues examined. These novel findings substantiate the threshold mode of action of carcinogenesis of formaldehyde and further improve risk assessment of low formaldehyde exposures in the range of regulatory limit values such as the WHO indoor guidance value of 0.1 mg/m³ (≈ 0.08 ppm) and the EU SCOEL recommendation for workplace exposures of 0.3 ppm.

Considerations for Refining the Risk Assessment Process for Formaldehyde: Results from an Interdisciplinary Workshop.

The paper summarizes a 2017 workshop held in order to identify relevant approaches and methods for improving how evidence is identified and integrated for formaldehyde risk assessment. The meeting included eleven presentations encompassing an introduction and three sessions: (1) "integrating the formaldehyde science on nasal/nasopharyngeal carcinogenicity and potential for causality"; (2) "integrating the formaldehyde science on lymphohematopoietic cancer and potential for causality; and, (3) "formaldehyde research-data suitable for risk assessment". Here we describe key points from the presentations on epidemiology, toxicology and mechanistic studies that should inform decisions about the potential carcinogenicity of formaldehyde in humans and the discussions about approaches for structuring an integrated, comprehensive risk assessment for formaldehyde.

Peak Exposures in Epidemiologic Studies and Cancer Risks: Considerations for Regulatory Risk Assessment.

Reviews approaches for characterizing "peak" exposures in epidemiologic studies and methods for incorporating peak exposure metrics in dose-response assessments that contribute to risk assessment. The focus was on potential etiologic relations between environmental chemical exposures and cancer risks. The authors review recommended developing uniform definitions of "peak" exposure to facilitate fuller evaluation of dose response for environmental chemicals and cancer risks, especially where mechanistic understanding indicates that the dose response is unlikely linear and that short-term high-intensity exposures increase risk.

Six Years After the NRC Review of EPA's Draft IRIS Toxicological Review of Formaldehyde: Regulatory Implications of New Science in Evaluating Formaldehyde Leukemogenicity.

Evaluates the evolution of new scientific evidence on formaldehyde as a potential human leukemogen. Indicated that overall, the quality and amount of evidence relevant to the understanding of a potential causal relationship between formaldehyde inhalation exposure and risk of lymphohematopoietic malignancies (LHM) has increased substantially. The new evidence been published in each of the major streams of evidence (i.e., human, animal and mechanistic) consistently indicates a lack of a causal association between formaldehyde exposure and LHM, and specifically AML. These new studies have addressed many of the National Research Council (2011) scientific criticisms surrounding the evaluation of a combination of cancer types, as well as increased our understanding of the potential impact of exogenous exposure on endogenous levels, which is critical in attempting to understand the potential hazards or risks from formaldehyde exposure.

Commentary on New Formaldehyde Studies in Trp53 Haploinsufficient Mice: Further Support for Nonlinear Risks From Inhaled Formaldehyde.

The article discusses the relevance of a 2017 final report by the U. S. National Toxicology Program (NTP) that explored the potential involvement of p53 mutation in formaldehyde-induced nasal tumors and lymphohematopoietic cancers. The NTP study demonstrated that inhalation of a maximum tolerated dose of formaldehyde did not cause nasal tumors, did not cause an increased prevalence of leukemia or lymphohematopoietic cancer, and did not cause any other type of cancer in Trp53+/- mice. It provides additional support for utilizing a non-linear threshold model for the dose-response analysis of formaldehyde. The commentary reinforces that the mode of action of inhaled formaldehyde must be foundational for characterizing the hazard and dose-response assessment.

Air Quality and Asthma: Has Unrecognized Exposure to Acrolein Confounded Results of Previous Studies?

The evaluation illustrated that there is no evidence that indicates increased sensitivity to sensory irritation to formaldehyde in people often regarded as susceptible such as asthmatics. Suggest that previous studies on potential risk factors and childhood asthma may be confounded by formaldehyde acting as an unrecognized proxy for acrolein.

Six Years After the NRC Review of EPA's Draft IRIS Toxicological Review of Formaldehyde: Regulatory Implications of New Science in Evaluating Formaldehyde Leukemogenicity.

Evaluates the evolution of new scientific evidence on formaldehyde as a potential human leukemogen. Indicated that overall, the quality and amount of evidence relevant to the understanding of a potential causal relationship between formaldehyde inhalation exposure and risk of lymphohematopoietic malignancies (LHM) has increased substantially. The new evidence been published in each of the major streams of evidence (i.e., human, animal and mechanistic) consistently indicates a lack of a causal association between formaldehyde exposure and LHM, and specifically AML. These new studies have addressed many of the National Research Council (2011) scientific criticisms surrounding the evaluation of a combination of cancer types, as well as increased our understanding of the potential impact of exogenous exposure on endogenous levels, which is critical in attempting to understand the potential hazards or risks from formaldehyde exposure.

Does Occupational Exposure to Formaldehyde Cause Hematotoxicity and Leukemia-Specific Chromosome Changes in Cultured Myeloid Progenitor Cells?

Conducted additional and refined analysis on the key underlying data (including specifically exposure information which had not been previously provided) utilized in a study relied upon in the draft IRIS assessment (e.g. Zhang et al. 2010). The analysis evaluates exposed and unexposed populations and any potential correlations between formaldehyde exposure and aneuploidy among the exposed populations. Results showed that differences in white blood cell, granulocyte, platelet, and red blood cell counts were not exposure-dependent. Additionally, among formaldehyde-exposed workers, no association was observed between individual formaldehyde exposure estimates and frequency of aneuploidy, which the original study authors suggested were indicators of myeloid leukemia risk.

Do Chromosome Changes in Blood Cells Implicate Formaldehyde as a Leukemogen?

Research focused on the critical review and integration of the available peer-reviewed literature addressing the potential genotoxicity of formaldehyde. This publication also addresses the potential involvement of chromosome changes in blood cells suggested to be key events in proposed modes of action for the development of leukemia following formaldehyde exposure. The evaluation found reported genetic changes in circulating blood cells do not provide convincing support for formaldehyde classification as a human leukemogen. Specifically, the evaluation notes that no convincing evidence that exogenous exposures to formaldehyde alone, and by inhalation, induce mutations at sites distant from the portal of entry tissue as a direct DNA reactive mutagenic effect – specifically not in the bone marrow. In addition, recent studies reporting changes in human bone marrow or hematopoietic precursor cells either have had confounding exposures or could not distinguish in vivo from in vitro occurrences.

Measurement of Endogenous Versus Exogenous Formaldehyde-Induced DNA-Protein Crosslinks in Animal Tissues by Stable Isotope Labeling and Ultrasensitive Mass Spectrometry.

The formation, accumulation, and hydrolysis of DNA-protein crosslinks of both exogenous and endogenous formaldehyde. The results show that inhaled formaldehyde only reached rat and monkey noses, but not tissues distant to the site of initial contact.

An Updated Re-Analysis of the Mortality Risk From Nasopharyngeal Cancer in the National Cancer Institute Formaldehyde Worker Cohort Study.

The reanalysis provided little or no evidence to support NCI's suggestion of a persistent association between formaldehyde exposure and mortality from nasopharyngeal cancer. Specifically, the findings led to: (1) reduced standardized mortality ratios and relative risks in the remaining nine study plants in unaffected exposure categories, (2) attenuated exposure-response relations for formaldehyde and nasopharyngeal cancer for all the formaldehyde metrics considered and (3) strengthened and expanded evidence that the earlier NCI internal analyses were non-robust and mis-specified as they did not account for a statistically significant interaction structure between plant group (Plant 1 vs. Plants 2-10) and formaldehyde exposure.

The Bottom-Up Approach to Bounding Potential Low-Dose Cancer Risks From Formaldehyde: An Update.

Updated a previously proposed method (Starr and Swenberg 2013). This approach has useful applications for substances, like formaldehyde, where there is a substantial endogenous exposure in potential target tissues and little or no empirical evidence of a positive dose-response at low exogenous exposure levels. It also provides valid bounding estimates of added risk from exposure to all airborne formaldehyde concentrations up to and including 2 ppm.

Formaldehyde Exposure and Mortality Risks From Acute Myeloid Leukemia and Other Lymphohematopoietic Malignancies in the US National Cancer Institute Cohort Study of Workers in Formaldehyde Industries.

Authors obtained the data from the NCI cohort study via a Technology Transfer Agreement to replicate the findings reported by Beane Freemen et al. (2009) and to conduct additional analysis of associations of specific leukemias and lymphomas, especially acute myeloid leukemia, with formaldehyde exposure. Analyses were conducted including peak exposure as defined by Beane Freeman et al. (2009), as well as using an alternative more standard definition of peak exposure. The findings from this re-analysis fail to support the hypothesis that formaldehyde causes acute myeloid leukemia. Specifically, the results indicated: Acute myeloid leukemia was unrelated to “peak” or any other formaldehyde metric including the conventional cumulative exposure (also as reported in Beane Freeman (2009)). In fact, very few cohort members had any peak exposure within 20 years of death due to AML. There were suggestive associations with peak exposure only for chronic myeloid leukemia, albeit based on very small numbers. No other lymphohematopoietic malignancy was associated with either cumulative or peak exposure.

Contrasting Directions and Directives on Hazard Identification for Formaldehyde Carcinogenicity.

The article examined two separate National Academy of Sciences committee evaluations on whether formaldehyde should be identified as a human carcinogen. It highlighted key differences in the approaches, scientific methods and criteria used by two government agencies in identifying and classifying human carcinogens. It also discussed the importance of clear processes for evaluating science and how the available formaldehyde science illustrates the contrast between the two approaches when evidence is integrated to reach conclusions on hazard.

Formation, Accumulation, and Hydrolysis of Endogenous and Exogenous Formaldehyde-Induced DNA Damage.

Evaluated the plausibility for inhaled formaldehyde to reach distal sites in rat and monkey models. The study indicated that inhaled formaldehyde was found to reach nasal respiratory epithelium, but not other tissues distant to the site of initial contact.

Formaldehyde-Associated Changes in MicroRNAs: Tissue and Temporal Specificity in the Rat Nose, White Blood Cells, and Bone Marrow.

In this study, a multi-tiered approach was employed to enable an understanding of the genome-wide miRNA responses to formaldehyde and to establish how these responses relate to alterations in transcriptional profiles over time and in various tissues. This study found that formaldehyde inhalation exposure induces tissue and time-dependent responses at the genomic and epigenomic level. Formaldehyde exposure disrupts miRNA expression profiles within the rat nose and white blood cells but not within the bone marrow.

Issues of Methods and Interpretation in the National Cancer Institute Formaldehyde Cohort Study.

Evaluation concluded that efforts should be made to re-analyze data from the 2004 follow-up of the National Cancer Institute formaldehyde cohort study. The evaluation also recommended that publications resulting from the National Cancer Institute formaldehyde cohort study which contain incorrect data from the incomplete 1994 mortality follow-up should be retracted entirely or corrected via published errata in the corresponding journals.

Response to Crump et al.

Formaldehyde Carcinogenicity Research 30 Years and Counting for Mode of Action, Epidemiology, and Cancer Risk Assessment.

Article reviews the data for rodent and human carcinogenicity, early mode of action studies, more recent molecular studies of both endogenous and exogenous DNA adducts, and epigenetic studies. It goes on to demonstrate the power of these research studies to provide critical data to improve our ability to develop science-based cancer risk assessments, instead of default approaches.

Dosimetry of N 6-Formyllysine Adducts Following [13C2H2]-Formaldehyde Exposures in Rats.

The research found that Exogenous N6-formyllysine was detected in the nasal epithelium, but was not detected in the lung, liver, or bone marrow. Endogenous adducts dominated at all exposure conditions, The results parallel previous studies of formaldehyde-induced DNA adducts.

Formaldehyde Exposure and Leukemia: Critical Review and Reevaluation of the Results From a Study That is the Focus for Evidence of Biological Plausibility.

A critical review of the study, as well as a reanalysis of the underlying data, was performed and the results of this reanalysis suggested factors other than formaldehyde exposure may have contributed to the effects reported. Specifically, in the original study the authors did not follow their stated protocol and evaluation of the other study data indicates that the aneuploidy measured could not have arisen in vivo, but rather arose during in vitro culture. The results of the critical review and reanalysis of the data do not support a mechanism for a causal association between formaldehyde exposure and myeloid or lymphoid malignancies.

Formaldehyde and Epigenetic Alterations: MicroRNA Changes in the Nasal Epithelium of Nonhuman Primates.

Found that Formaldehyde exposure significantly disrupts miRNA expression profiles within the nasal epithelium. These results provide evidence for a relationship between formaldehyde exposure and altered signaling of the apoptotic machinery, likely regulated via epigenetic mechanisms.

A Novel Bottom-Up Approach to Bounding Low-Dose Human Cancer Risks From Chemical Exposures.

Provided a refined approach for conducted risk extrapolations using a bottom up instead of top-down risk calculation. Results indicate that top-down risk extrapolations from occupational cohort mortality data for workers exposed to formaldehyde are overly conservative by substantial margins.

Critical Review and Synthesis of the Epidemiologic Evidence on Formaldehyde Exposure and Risk of Leukemia and Other Lymphohematopoietic Malignancies.

Evaluation found that there is no consistent or strong epidemiologic evidence that formaldehyde is causally related to any of the lymphohematopoietic malignancies. Specifically, the evaluation noted that findings from occupational cohort and population-based case-control studies were very inconsistent for lymphohematopoietic malignancies, including myeloid leukemia. Apart from some isolated exceptions, relative risks were close to the null, and there was little evidence for dose-response relations for any of the lymphohematopoietic malignancies.

Use of LC-MS/MS and Stable Isotopes to Differentiate Hydroxymethyl and Methyl DNA Adducts From Formaldehyde and Nitrosodimethylamine.

Research demonstrated that N(2)-hydroxymethyl-dG is the primary DNA adduct formed in cells following formaldehyde exposure. In addition, the study shows that alkylating agents induce methyl adducts at N(2)-dG and N(6)-dA positions, which are identical to the reduced forms of hydroxymethyl adducts arising from formaldehyde.

Identifying an Indoor Air Exposure Limit for Formaldehyde Considering Both Irritation and Cancer Hazards.

Research found that both exogenous and endogenous adducts were readily detected and quantified in the nasal tissues of both exposure groups, with an exposure dependent increase in exogenous adducts observed. In contrast, only endogenous adducts were detectable in the bone marrow, even though ∼10 times more DNA was analyzed.

Is Exposure to Formaldehyde in Air Causally Associated with Leukemia?—A Hypothesis-Based Weight-of-Evidence Analysis.

In this evaluation the authors review the scientific data relevant to the potential causal association between exposure to formaldehyde in air and leukemia in humans using the structured hypothesis-based weight-of-evidence (HBWoE) approach. The evaluation concluded that the case for a causal association was weak and strains biological plausibility.

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