The article "Toxicity Testing in the 21st Century: A Vision and a Strategy" outlines a significant shift in the approach to toxicity testing, aiming to enhance efficiency and reduce animal usage. The U.S. National Academy of Sciences' 2007 report envisions transitioning from expensive and lengthy in vivo testing to in vitro toxicity pathway assays on human cells or cell lines, using high-throughput robotic screening with mechanistic quantitative parameters. This shift would focus risk assessment on avoiding significant perturbations in toxicity pathways and use computational systems biology models to determine dose-response relationships. Extrapolation of in vitro results to in vivo human conditions would be based on pharmacokinetic models. The report emphasizes the need for a broad discussion and necessary resources to implement this new paradigm, which is currently feasible with existing tools. The historical perspective of regulatory toxicology is discussed, highlighting the evolution of testing strategies for drugs, foods, pesticides, and industrial chemicals. The current system is criticized for its inefficiency, high costs, and limited coverage, particularly in addressing the diverse needs of human health risk assessment. The report identifies key challenges, such as low-dose extrapolation from high-dose data, animal-to-human extrapolation, and the inability to consider mixtures of chemicals. The committee's vision for a new toxicity testing paradigm is outlined, emphasizing broader coverage, reduced costs and time, minimal animal use, and a more robust scientific basis for risk assessment. The report explores four options for a new paradigm, including the baseline option of continuing current practices, expanded tiered testing, and a more comprehensive approach that leverages recent scientific advances. The committee concludes that a more systematic and integrated approach is needed to address the challenges and opportunities in toxicity testing.The article "Toxicity Testing in the 21st Century: A Vision and a Strategy" outlines a significant shift in the approach to toxicity testing, aiming to enhance efficiency and reduce animal usage. The U.S. National Academy of Sciences' 2007 report envisions transitioning from expensive and lengthy in vivo testing to in vitro toxicity pathway assays on human cells or cell lines, using high-throughput robotic screening with mechanistic quantitative parameters. This shift would focus risk assessment on avoiding significant perturbations in toxicity pathways and use computational systems biology models to determine dose-response relationships. Extrapolation of in vitro results to in vivo human conditions would be based on pharmacokinetic models. The report emphasizes the need for a broad discussion and necessary resources to implement this new paradigm, which is currently feasible with existing tools. The historical perspective of regulatory toxicology is discussed, highlighting the evolution of testing strategies for drugs, foods, pesticides, and industrial chemicals. The current system is criticized for its inefficiency, high costs, and limited coverage, particularly in addressing the diverse needs of human health risk assessment. The report identifies key challenges, such as low-dose extrapolation from high-dose data, animal-to-human extrapolation, and the inability to consider mixtures of chemicals. The committee's vision for a new toxicity testing paradigm is outlined, emphasizing broader coverage, reduced costs and time, minimal animal use, and a more robust scientific basis for risk assessment. The report explores four options for a new paradigm, including the baseline option of continuing current practices, expanded tiered testing, and a more comprehensive approach that leverages recent scientific advances. The committee concludes that a more systematic and integrated approach is needed to address the challenges and opportunities in toxicity testing.