Toxicity testing in the 21st century: a vision and a strategy

Abstract

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.

FIGURE 1

The exposure-response continuum underlying the current paradigm for toxicity testing.

FIGURE 2

Biologic responses viewed as results of an intersection of exposure and biologic function. The intersection results in perturbation of biologic pathways. When perturbations are sufficiently large or when the host is unable to adapt because of underlying nutritional, genetic, disease, or life-stage status, biologic function is compromised, and this leads to toxicity and disease. Source: Adapted from Andersen et al., 2005a. Reprinted with permission; copyright 2005, Trends in Biotechnology.

FIGURE 3

The committee’s vision for toxicity testing is a process that includes chemical characterization, toxicity testing, and dose-response and extrapolation modeling. At each step, population-based and human exposure data are considered, as is the question of what data are needed for decision making.

FIGURE 4

Overview of chemical characterization component.

FIGURE 5

Toxicity-testing component, which includes toxicity-pathway testing in cells and cell lines and targeted testing in whole animals.

FIGURE 6

Overview of dose-response and extrapolation modeling component.

FIGURE 7

Nrf2 antioxidant-response pathway schematic. Adapted from Motohashi and Yamamoto (2004), with permission from Trends in Molecular Medicine.

FIGURE 8

Overview of population-based and human exposure data component.

FIGURE 9

Overview of risk contexts component.

FIGURE 10

Risk assessment components. End product is development of one or more indicators of risk, such as a reference dose or concentration.

FIGURE 11

Progression of some important science and technology activities during assay development.

FIGURE 12

Screening of chemicals that would otherwise not be tested or be subject to only limited testing. The results of the screening tests would be used to decide the nature of further testing needed, if any.