Incorporating new approach methods (NAMs) data in dose-response assessments: The future is now!

IF 6.4 2区 医学 Q1 ENVIRONMENTAL SCIENCES
En-Hsuan Lu, Ivan Rusyn, Weihsueh A Chiu
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引用次数: 0

Abstract

Regulatory dose-response assessments traditionally rely on in vivo data and default assumptions. New Approach Methods (NAMs) present considerable opportunities to both augment traditional dose-response assessments and accelerate the evaluation of new/data-poor chemicals. This review aimed to determine the potential utilization of NAMs through a unified conceptual framework that compartmentalizes derivation of toxicity values into five sequential Key Dose-response Modules (KDMs): (1) point-of-departure (POD) determination, (2) test system-to-human (e.g. inter-species) toxicokinetics and (3) toxicodynamics, (4) human population (intra-species) variability in toxicodynamics, and (5) toxicokinetics. After using several "traditional" dose-response assessments to illustrate this framework, a review is presented where existing NAMs, including in silico, in vitro, and in vivo approaches, might be applied across KDMs. Further, the false dichotomy between "traditional" and NAMs-derived data sources is broken down by organizing dose-response assessments into a matrix where each KDM has Tiers of increasing precision and confidence: Tier 0: Default/generic values, Tier 1: Computational predictions, Tier 2: Surrogate measurements, and Tier 3: Direct measurements. These findings demonstrated that although many publications promote the use of NAMs in KDMs (1) for POD determination and (5) for human population toxicokinetics, the proposed matrix of KDMs and Tiers reveals additional immediate opportunities for NAMs to be integrated across other KDMs. Further, critical needs were identified for developing NAMs to improve in vitro dosimetry and quantify test system and human population toxicodynamics. Overall, broadening the integration of NAMs across the steps of dose-response assessment promises to yield higher throughput, less animal-dependent, and more science-based toxicity values for protecting human health.

将新方法(NAMs)数据纳入剂量反应评估:未来就是现在!
监管机构的剂量反应评估传统上依赖于体内数据和默认假设。新方法(NAMs)提供了大量机会,既能增强传统的剂量-反应评估,又能加快对缺乏数据的新化学品的评估。本综述旨在通过一个统一的概念框架来确定新方法的潜在用途,该框架将毒性值的推导划分为五个连续的关键剂量-反应模块(KDMs):(1) 出发点(POD)确定,(2) 试验系统对人类(如物种间)毒物动力学和 (3) 毒力动力学,(4) 人类群体(物种内)毒力动力学变异,以及 (5) 毒物代谢动力学。在使用几种 "传统 "剂量-反应评估来说明这一框架后,对现有的 NAM(包括硅学、体外和体内方法)可能适用于 KDM 的情况进行了综述。此外,"传统 "数据源和 NAMs 派生数据源之间错误的二分法被打破,剂量-反应评估被组织成一个矩阵,每个 KDM 都有精度和置信度不断提高的层级:第 0 层:默认值/通用值,第 1 层:计算预测,第 2 层:替代测量,第 3 层:直接测量。这些研究结果表明,尽管许多出版物都提倡在 KDM 中使用 NAM(1)用于 POD 测定和(5)用于人类毒代动力学,但建议的 KDM 和层级矩阵揭示了 NAM 在其他 KDM 中整合的更多直接机会。此外,还确定了开发 NAM 的关键需求,以改进体外剂量测定并量化测试系统和人群毒物动力学。总之,在剂量-反应评估的各个步骤中扩大对 NAM 的整合,有望产生更高的吞吐量、更少的动物依赖性和更科学的毒性值,从而保护人类健康。
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来源期刊
CiteScore
13.80
自引率
6.90%
发文量
13
审稿时长
>24 weeks
期刊介绍: "Journal of Toxicology and Environmental Health: Part B - Critical Reviews" is an academic journal published by Taylor & Francis, focusing on the critical examination of research in the areas of environmental exposure and population health. With an ISSN identifier of 1093-7404, this journal has established itself as a significant source of scholarly content in the field of toxicology and environmental health. Since its inception, the journal has published over 424 articles that have garnered 35,097 citations, reflecting its impact and relevance in the scientific community. Known for its comprehensive reviews, the journal also goes by the names "Critical Reviews" and "Journal of Toxicology & Environmental Health, Part B, Critical Reviews." The journal's mission is to provide a platform for in-depth analysis and critical discussion of the latest findings in toxicology, environmental health, and related disciplines. By doing so, it contributes to the advancement of knowledge and understanding of the complex interactions between environmental factors and human health, aiding in the development of strategies to protect and improve public health.
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