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.