Mode of action assessment for propylene dichloride as a human carcinogen.

Autor: Kozal JS; Stantec (ChemRisk), San Francisco, CA, 94104, USA. Electronic address: jordan.kozal@stantec.com., Lynch HN; Stantec (ChemRisk), Boston, MA, 02116, USA., Klapacz J; Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, 48674, USA., Schoeny RS; Rita Schoeny LLC, Washington DC, 20002, USA., Jean PA; Olin Corporation, Clayton, MO, 63105, USA., Maier A; Stantec (ChemRisk), Cincinnati, OH, 45242, USA.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2023 Sep 01; Vol. 382, pp. 110382. Date of Electronic Publication: 2023 Feb 07.
DOI: 10.1016/j.cbi.2023.110382
Abstrakt: As part of a systematic review of the non-cancer and cancer hazards of propylene dichloride (PDC), with a focus on potential carcinogenicity in workers following inhalation exposures, we determined that a mode of action (MOA)-centric framing of cancer effects was warranted. In our MOA analysis, we systematically reviewed the available mechanistic evidence for PDC-induced carcinogenesis, and we mapped biologically plausible MOA pathways and key events (KEs), as guided by the International Programme on Chemical Safety (IPCS)-MOA framework. For the identified pathways and KEs, biological concordance, essentiality of KEs, concordance of empirical observations among KEs, consistency, and analogy were evaluated. The results of this analysis indicate that multiple biologically plausible pathways may contribute to the cancer MOA for PDC, but that the relevant pathways vary by exposure route and level, tissue type, and species; further, more than one pathway may occur concurrently at high exposure levels. While several important data gaps exist, evidence from in vitro mechanistic studies, in vivo experimental animal studies, and ex vivo human tumor tissue analyses indicates that the predominant MOA pathway likely involves saturation of cytochrome p450 2E1 (CYP2E1)-glutathione (GSH) detoxification (molecular initiating event; MIE), accumulation of CYP2E1-oxidative metabolites, cytotoxicity, chronic tissue damage and inflammation, and ultimately tumor formation. Tumors may occur through several subsets of inflammatory KEs, including inflammation-induced aberrant expression of activation-induced cytidine deaminase (AID), which causes DNA strand breaks and mutations and can lead to tumors with a characteristic mutational signature found in occupational cholangiocarcinoma. Dose concordance analysis showed that low-dose mutagenicity (from any pathway) is not a driving MOA, and that prevention of target tissue damage and inflammation (associated with saturation of CYP2E1-GSH detoxification) is expected to also prevent the cascade of processes responsible for tumor formation.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jordan S. Kozal reports financial support was provided to Stantec (ChemRisk) by American Chemistry Council. Heather N. Lynch reports financial support was provided to Stantec (ChemRisk) by American Chemistry Council. Andy Maier reports financial support was provided to Stantec (ChemRisk) by American Chemistry Council. Rita S. Schoeny reports financial support was provided to Rita Schoeny, LLC by American Chemistry Council. Joanna Klapacz reports a relationship with The Dow Chemical Company that includes: employment. Paul A. Jean reports a relationship with Olin Corporation that includes: employment. Jordan S. Kozal, Heather N. Lynch, and Andy Maier are employees of Stantec (ChemRisk), and Rita S. Schoeny is an independent consultant at Rita Schoeny, LLC; both firms provide services to clients such as governments, corporations, law firms and various scientific/professional organizations. Joanna Klapacz is an employee of The Dow Chemical Company and Paul A. Jean is an employee of Olin Corporation, both producers of PDC. The content and the conclusions of the manuscript are exclusively those of the authors. This manuscript was supported by funding from the American Chemistry Council, an industry trade association.
(Copyright © 2023. Published by Elsevier B.V.)
Databáze: MEDLINE
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