Jacobs Miriam Naomi, Kubickova Barbara, Boshoff Eugene
Centre for Radiation, Chemical and Environmental Hazards (CRCE), Department of Toxicology, Public Health England (PHE), Harwell Science and Innovation Campus, Chilton, United Kingdom.
Front Toxicol. 2022 Jun 20;4:880818. doi: 10.3389/ftox.2022.880818. eCollection 2022.
Cytochrome P450 (CYP) enzymes play a key role in the metabolism of both xenobiotics and endogenous chemicals, and the activity of some CYP isoforms are susceptible to induction and/or inhibition by certain chemicals. As CYP induction/inhibition can bring about significant alterations in the level of exposure to CYP substrates and metabolites, CYP induction/inhibition data is needed for regulatory chemical toxicity hazard assessment. On the basis of available human pharmaceutical data, a draft Organisation for Economic Co-operation and Development Test Guideline (TG) for an CYP HepaRG test method that is capable of detecting the induction of four human CYPs (CYP1A1/1A2, 2B6, and 3A4), has been developed and validated for a set of pharmaceutical proficiency chemicals. However to support TG adoption, further validation data was requested to demonstrate the ability of the test method to also accurately detect CYP induction mediated by industrial and pesticidal chemicals, together with an indication on regulatory uses of the test method. As part of "GOLIATH", a European Union Horizon-2020 funded research project on metabolic disrupting chemical testing approaches, work is underway to generate supplemental validated data for an additional set of chemicals with sufficient diversity to allow for the approval of the guideline. Here we report on the process of proficiency chemical selection based on a targeted literature review, the selection criteria and considerations required for acceptance of proficiency chemical selection for OECD TG development (i.e. structural diversity, range of activity, relevant chemical sectors, global restrictions etc). The following 13 proposed proficiency chemicals were reviewed and selected as a suitable set for use in the additional validation experiments: tebuconazole, benfuracarb, atrazine, cypermethrin, chlorpyrifos, perfluorooctanoic acid, bisphenol A, N,N-diethyl-m-toluamide, benzo-[a]-pyrene, fludioxonil, malathion, triclosan, and caffeine. Illustrations of applications of the test method in relation to endocrine disruption and non-genotoxic carcinogenicity are provided.
细胞色素P450（CYP）酶在异源生物和内源性化学物质的代谢中起关键作用，某些CYP同工型的活性易受某些化学物质的诱导和/或抑制。由于CYP诱导/抑制可导致CYP底物和代谢物的暴露水平发生显著变化，因此监管化学毒性危害评估需要CYP诱导/抑制数据。基于现有的人类药物数据，已制定了经济合作与发展组织（OECD）关于CYP HepaRG测试方法的测试指南（TG）草案，该方法能够检测四种人类CYP（CYP1A1/1A2、2B6和3A4）的诱导情况，并针对一组药物熟练度化学品进行了验证。然而，为了支持该测试指南的采用，需要进一步的验证数据来证明该测试方法还能够准确检测由工业化学品和农药化学品介导的CYP诱导情况，并说明该测试方法的监管用途。作为“歌利亚”（GOLIATH）项目的一部分，该项目是欧盟“地平线2020”资助的关于代谢干扰化学物质测试方法的研究项目，目前正在开展工作，以生成另一组化学品的补充验证数据，这些化学品具有足够的多样性，以便该指南能够获批。在此，我们报告基于有针对性的文献综述进行熟练度化学品选择的过程、经合组织测试指南制定（即结构多样性、活性范围、相关化学领域、全球限制等）中接受熟练度化学品选择所需的选择标准和考量因素。对以下13种提议的熟练度化学品进行了评审，并将其选为适用于额外验证实验的一组化学品：戊唑醇、丙硫克百威、莠去津、氯氰菊酯、毒死蜱、全氟辛酸、双酚A、N,N -二乙基间甲苯酰胺、苯并[a]芘、咯菌腈、马拉硫磷、三氯生和咖啡因。还提供了该测试方法在内分泌干扰和非遗传毒性致癌性方面的应用示例。
