1. Incorporating new approach methods (NAMs) data in dose–response assessments: The future is now!
- Author
-
Lu, En-Hsuan, Rusyn, Ivan, and Chiu, Weihsueh A.
- Subjects
- *
TEST systems , *BASIC needs , *RISK assessment , *DEFAULT (Finance) , *HUMAN beings - 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, includingin silico ,in vitro , andin 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 improvein 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. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF