Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors: Analysis of Their Human Relevance Using the IPCS Framework

Strupp, Christian; Banas, Deborah A.; Cohen, Samuel M.; Gordon, Elliot B.; Jaeger, Martina; Weber, Klaus

doi:10.1093/toxsci/kfs127

Cited by 21 publications

(8 citation statements)

References 42 publications

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“…predominance of Clara cells lining mouse lung epithelium). [50][51][52][53][54] Rats and mice in the NTP database are highly discordant in both the development of tumors and the site of tumor formation, despite their relative phylogenetic closeness. This high discordance begs the question of the potential degree of tumor discordance between humans and rodents.…”

Section: Discussionmentioning

confidence: 99%

The “false-positive” conundrum in the NTP 2-year rodent cancer study database

Smith

Perfetti²

2018

Toxicology Research and Application

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In 1990, Ames and Gold described a conundrum of "too many carcinogens" among chemicals tested in rodent bioassays. Their proposed nongenotoxic carcinogenic mechanism was amplification of the background mutation rate via cytotoxicity induced by high doses of the test chemicals, thereby leading to increases in reparative cellular proliferation rates. Recently, we have statistically and mechanistically analyzed the entire 594-study (470 final reports) NTP 2-year rodent cancer database to better understand the conundrum posed by Ames and Gold. Our analysis provides several lines of evidence that support the contention of Ames and Gold. First, across different routes of administration, relatively phylogenetically similar rats and mice are nonetheless discordant for the development of tumors at similar organ sites. Tumor site concordance across sex within species is higher than tumor site concordance across species. Second, many chemicals negative in the Ames test nonetheless induce tumors in either rats or mice. Third, 11 out of 58 chemicals tested by the inhalation route induce lung tumors in mice and not rats, are negative in the Ames test, and exhibit hyperplasia. In 2017, Tomasetti et al. provided evidence for the clinical relevance in humans of the Ames and Gold mechanism regarding amplification of the background mutation rate by demonstrating that the majority of human tumors result from accumulated mutations due to DNA replication errors.

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Section: Discussionmentioning

confidence: 99%

The “false-positive” conundrum in the NTP 2-year rodent cancer study database

Smith

Perfetti²

2018

Toxicology Research and Application

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“…predominance of CCs lining mouse lung epithelium). [192][193][194][195][196] Rats and mice in the NTP database are highly discordant in both the development of tumors and the site of tumor formation, despite their relative phylogenetic closeness. This high discordance begs the question of the potential degree of tumor discordance between humans and rodents.…”

Section: Section Four: Differences Between Human and Mouse Lung Tumorsmentioning

confidence: 99%

Bronchioloalveolar lung tumors induced in “mice only” by non-genotoxic chemicals are not useful for quantitative assessment of pulmonary adenocarcinoma risk in humans

Smith

Perfetti²,

King

2018

Toxicology Research and Application

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Chemicals classified as known human carcinogens by International Agency for Research on Cancer (IARC) show a low level of concordance between rodents and humans for induction of pulmonary carcinoma. Rats and mice exposed via inhalation for 2 years show a low level of concordance in both tumor development and organ site location. In 2-year inhalation studies using rats and mice, when pulmonary tumors are seen in only male or female mice or both, but not in either sex of rat, there is a high probability that the murine pulmonary tumor has been produced via Clara cell or club cell (CC) metabolism of the inhaled chemical to a cytotoxic metabolite. Cytotoxicity-induced mitogenesis increases mutagenesis via amplification of the background mutation rate. If the chemical being tested is also negative in the Ames Salmonella mutagenicity assay, and only mouse pulmonary tumors are induced, the probability that this pulmonary tumor is not relevant to human lung cancer risk goes even higher. Mice have a larger percentage of CCs in their distal airways than rats, and a much larger percentage than in humans. The CCs of mice have a much higher concentration of metabolic enzymes capable of metabolizing xenobiotics than CCs in either rats or humans. A principal threat to validity of extrapolating from the murine model lies in the unique capacity of murine CCs to metabolize a significant spectrum of xenobiotics which in turn produces toxicants not seen in rat or human pulmonary pathophysiology. Executive summaryIn the text to follow, a number of concepts will be developed and supported including the following:Clinical observations of the carcinogenicity of workplace chemicals predated conduction of the first animal cancer bioassays. Rats and mice exposed via inhalation for 2 years show a low level of concordance in both tumor development and organ site location. Chemicals classified as known human carcinogens by IARC show a low level of concordance between

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“…In all cases, lung tumors were solely observed in mice. Although none of the reports did provide details on the underlying MOA or data from which an underlying MOA could be deduced, literature on 2 of the 15 substances learned that CYP2F2-related metabolism of substances in the lung presents a MOA via which oral exposure to a substance can result in the formation of lung tumors (Strupp et al 2012;Strupp et al 2016;Yamada et al 2017). This MOA is based on the formation of reactive metabolites due to CYP2F2 activity in the Club cells of the lung, leading to cytotoxicity and regenerative proliferation.…”

Section: Observed Moasmentioning

confidence: 99%

Towards a mechanism-based approach for the prediction of nongenotoxic carcinogenic potential of agrochemicals

Heusinkveld

Braakhuis

Gommans

et al. 2020

Critical Reviews in Toxicology

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Chemical substances are subjected to assessment of genotoxic and carcinogenic effects before being marketed to protect man and the environment from health risks. For agrochemicals, the long-term rodent carcinogenicity study is currently required from a regulatory perspective. Although it is the current mainstay for the detection of nongenotoxic carcinogens, carcinogenicity studies are shown to have prominent weaknesses and are subject to ethical and scientific debate. A transition toward a mechanism-based weight-of-evidence approach is considered a requirement to enhance the prediction of carcinogenic potential for environmental (agro)chemicals. The resulting approach should make optimal use of innovative (computational) tools and be less animal demanding. To identify the various mode of actions (MOAs) underlying the nongenotoxic carcinogenic potential of agrochemicals, we conducted an extensive analysis of 411 unique agrochemicals that have been evaluated for carcinogenicity by the United States Environmental Protection Agency (US EPA) and the European Chemicals Agency (ECHA). About one-third of these substances could be categorized as nongenotoxic carcinogens with an average of approximately two tumor types per substance, observed in a variety of organs. For twothird of the tumor cases, an underlying MOA (network) could be identified. This analysis demonstrates that a limited set of MOA (networks) is underlying nongenotoxic carcinogenicity of agrochemicals, illustrating that the transition toward a MOA-driven approach appears manageable. Ultimately the approach should cover relevant MOAs and its associated key events; this will also facilitate the evaluation of the human relevance. This manuscript describes the results of the analysis while identifying knowledge gaps and necessities to achieve a mechanism-based weight-of-evidence approach.

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Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors: Analysis of Their Human Relevance Using the IPCS Framework

Cited by 21 publications

References 42 publications

The “false-positive” conundrum in the NTP 2-year rodent cancer study database

The “false-positive” conundrum in the NTP 2-year rodent cancer study database

Bronchioloalveolar lung tumors induced in “mice only” by non-genotoxic chemicals are not useful for quantitative assessment of pulmonary adenocarcinoma risk in humans

Towards a mechanism-based approach for the prediction of nongenotoxic carcinogenic potential of agrochemicals

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