Stantec (ChemRisk), San Francisco, CA, 94104, USA.
Stantec (ChemRisk), Boston, MA, 02116, USA.
Chem Biol Interact. 2023 Sep 1;382:110382. doi: 10.1016/j.cbi.2023.110382. Epub 2023 Feb 7.
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.
作为对丙烯二氯（PDC）的非癌症和癌症危害的系统评价的一部分，重点关注吸入暴露后工人的潜在致癌性，我们确定有必要从作用模式（MOA）的角度来阐述癌症效应。在我们的 MOA 分析中，我们系统地审查了有关 PDC 诱导致癌作用的现有机制证据，并根据国际化学品安全方案（IPCS）-MOA 框架，对生物学上合理的 MOA 途径和关键事件（KEs）进行了映射。对于确定的途径和 KEs，我们评估了生物学一致性、KEs 的必要性、KEs 之间经验观察的一致性、一致性和类比。该分析的结果表明，多种生物学上合理的途径可能导致 PDC 的癌症 MOA，但相关途径因暴露途径和水平、组织类型和物种而异；此外，在高暴露水平下，可能同时发生多种途径。尽管存在一些重要的数据差距，但来自体外机制研究、体内实验动物研究和体外人类肿瘤组织分析的证据表明，主要的 MOA 途径可能涉及细胞色素 p450 2E1（CYP2E1）-谷胱甘肽（GSH）解毒（分子起始事件；MIE）的饱和、CYP2E1-氧化代谢物的积累、细胞毒性、慢性组织损伤和炎症，最终导致肿瘤形成。肿瘤可能通过几个炎症 KEs 子集发生，包括炎症诱导的激活诱导胞嘧啶脱氨酶（AID）的异常表达，这会导致 DNA 链断裂和突变，并可能导致具有职业性胆管癌中发现的特征性突变特征的肿瘤。剂量一致性分析表明，低剂量致突变性（来自任何途径）不是驱动 MOA，并且预计预防靶组织损伤和炎症（与 CYP2E1-GSH 解毒的饱和相关）也将阻止负责肿瘤形成的级联过程。
