The role of fit-for-purpose assays within tiered testing approaches: A case study evaluating prioritized estrogen-active compounds in an in vitro human uterotrophic assay
The role of fit-for-purpose assays within tiered testing approaches: A case study evaluating prioritized estrogen-active compounds in an in vitro human uterotrophic assay
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DOI：
10.1016/j.taap.2019.114774
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发表时间：
2020-01-15
影响因子：
3.8
通讯作者：
Hartman, Jessica K.
中科院分区：
文献类型：
--
作者：
Beames, Tyler;Moreau, Marjory;Hartman, Jessica K.
化学品风险评估依赖于毒性测试，需要大量的动物、时间和成本。对于超过30，000种商业化学品，目前的动物试验规模不足以解决化学品安全问题，因为监管和产品管理方面的考虑不断发展，需要更全面地了解潜在的生物效应、使用条件和相关暴露。我们展示了使用多层次的新方法论（NAMS）战略的危害和风险为基础的优先级，以减少动物试验。使用ToxCast数据，基于雌激素受体（ER）活性和代谢活化的1/2级化学品优先级，选择112种化学品，用于3级人子宫细胞雌激素反应试验（IKA试验）。将3级数据与定量体外至体内外推法（Q-IVIVE）相结合，以支持组织特异性背景下的生物活性测定（作为危害的替代）。使用试验AC（50）s和Q-IVIVE估计人体等效剂量（HED），并将HED与体内衍生出发点（POD）中的啮齿动物子宫营养试验进行比较。对于在体外和体内都有活性的物质，对于19/23种化合物（83%），IKA测定衍生的HED低于或等于体内POD。计算了活性暴露关系，对于所有IKA阳性化合物，IKA测定与啮齿动物子宫营养测定一样或更能保护人体健康。本研究证明了生物学相关的适用性测定的实用性，并支持使用多层次的化学品风险评估策略。
Chemical risk assessment relies on toxicity tests that require significant numbers of animals, time and costs. For the > 30,000 chemicals in commerce, the current scale of animal testing is insufficient to address chemical safety concerns as regulatory and product stewardship considerations evolve to require more comprehensive understanding of potential biological effects, conditions of use, and associated exposures. We demonstrate the use of a multi-level new approach methodology (NAMs) strategy for hazard- and risk-based prioritization to reduce animal testing. A Level 1/2 chemical prioritization based on estrogen receptor (ER) activity and metabolic activation using ToxCast data was used to select 112 chemicals for testing in a Level 3 human uterine cell estrogen response assay (IKA assay). The Level 3 data were coupled with quantitative in vitro to in vivo extrapolation (Q-IVIVE) to support bioactivity determination (as a surrogate for hazard) in a tissue-specific context. Assay AC(50)s and Q-IVIVE were used to estimate human equivalent doses (HEDs), and HEDs were compared to rodent uterotrophic assay in vivo-derived points of departure (PODs). For substances active both in vitro and in vivo, IKA assay-derived HEDs were lower or equivalent to in vivo PODs for 19/23 compounds (83%). Activity exposure relationships were calculated, and the IKA assay was as or more protective of human health than the rodent uterotrophic assay for all IKA-positive compounds. This study demonstrates the utility of biologically relevant fit-for-purpose assays and supports the use of a multi-level strategy for chemical risk assessment.