Silva Marilyn, Kwok Ryan Kin-Hin
Retired from California Environmental Protection Agency with a Career in Toxicology and Risk Assessment, United States.
Independent Researcher, United States.
Curr Res Toxicol. 2022 Feb 7;3:100064. doi: 10.1016/j.crtox.2022.100064. eCollection 2022.
Currently, there is a lack of knowledge about the effects of co-exposures of cannabis, contaminated with pesticides like chlorpyrifos (CPF) and the toxic metabolite CPF-oxon (CPFO). CPF/CPFO residues, and Tetrahydrocannabinol (THC), the main component in cannabis, are known to disrupt the endocannabinoid system (eCBS) resulting in neurodevelopmental defects. Although there are data characterizing CPF/CPFO and THC, there are mechanistic data gaps and deficiencies. In this study, an investigation of open access CompTox tools and ToxCast/Tox21 data was performed to determine targets relating to the modes of action (MOA) for these compounds and, given the available biological targets, predict points of departure (POD). The main findings were as follows: 1) PODs for each chemical were from open literature, 2) Concordance between ToxCast/Tox21 assay targets and known targets in the metabolic and eCBS pathways was evaluated, 3) Human Equivalent Administered Dose (EAD) PODs showed the High throughput toxicokinetic (HTTK) 3 compartment model (3COMP) was more predictive of PODs than the PBTK model for CPF, CPFO and THC, 4) Age-adjusted 3COMP HTTK-Pop EAD, with CPF and CPFO ToxCast/Tox21 AC values as inputs were predictive for ages 0-4 when but not THC compared to PODs. 5) Age-related refinements for CPF/CPFO were primarily from ToxCast/Tox21 active hit-calls for nuclear receptors, CYP2B6 and AChE inhibition (CPFO only) associated with the metabolic pathway. Only one assay target (arylhydrocarbon hydroxylase receptor) was common between CPF/CPFO and THC. While computational refinements may select some sensitive events involved in the metabolic pathways; this is highly dependent on the cytotoxicity limits, availability of metabolic activity in the ToxCast/Tox21 assays and reliability of assay performance. Some uncertainties and data gaps for THC might be addressed with assays specific to the eCBS. For CPF, assays with appropriate metabolic activation could better represent the toxic pathway.
目前，对于大麻与毒死蜱（CPF）等农药以及有毒代谢物CPF-氧磷（CPFO）共同暴露的影响缺乏了解。已知CPF/CPFO残留以及大麻中的主要成分四氢大麻酚（THC）会破坏内源性大麻素系统（eCBS），导致神经发育缺陷。尽管有关于CPF/CPFO和THC的数据，但在作用机制数据方面仍存在差距和不足。在本研究中，对开放获取的CompTox工具和ToxCast/Tox21数据进行了调查，以确定与这些化合物作用模式（MOA）相关的靶点，并根据可用的生物学靶点预测起始点（POD）。主要研究结果如下：1）每种化学物质的POD均来自公开文献；2）评估了ToxCast/Tox21检测靶点与代谢和eCBS途径中已知靶点之间的一致性；3）人体等效给药剂量（EAD）POD显示，对于CPF、CPFO和THC，高通量毒物动力学（HTTK）三室模型（3COMP）比生理药代动力学（PBTK）模型更能预测POD；4）以CPF和CPFO的ToxCast/Tox21活性命中值作为输入的年龄调整后3COMP HTTK-Pop EAD，对于0至4岁的年龄组可预测POD，但对于THC则不然；5）CPF/CPFO与年龄相关的细化主要来自ToxCast/Tox21对核受体、CYP2B6和乙酰胆碱酯酶抑制（仅CPFO）的活性命中调用，这些与代谢途径相关。CPF/CPFO和THC之间只有一个检测靶点（芳烃羟化酶受体）相同。虽然计算细化可能会选择代谢途径中一些敏感事件，但这高度依赖于细胞毒性限度、ToxCast/Tox21检测中代谢活性的可用性以及检测性能的可靠性。THC的一些不确定性和数据差距可能通过针对eCBS的检测来解决。对于CPF，具有适当代谢激活的检测可以更好地代表毒性途径。
