Toxicity Testing in the 21st Century A Vision and a Strategy (2007) / Chapter Skim
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2 Vision
2 Vision
Pages 35-55
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From page 35... ...
Make big plans; aim high in hope and work, remembering that a noble, logical diagram once recorded will never die, but long after we are gone will be a living thing, asserting itself with evergrowing insistency. Daniel Hudson Burnham, Architect Designer of the 1893 Chicago World's Fair The goal of toxicity testing is to develop data that can ensure appropriate protection of public health from the adverse effects of exposures to environmental agents.
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From page 36... ...
Pathways that can lead to adverse health effects when sufficiently perturbed are termed toxicity pathways. Responses of cells to oxidative stress caused by exposure to diesel exhaust particles (DEP)
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From page 37... ...
Thus, changes in toxicity pathways are envisioned as the basis of a new toxicity-testing paradigm for managing the risks posed by environmental agents instead of apical end points from whole-animal tests. This chapter provides an overview of the committee's vision but first discusses the limitations of current toxicity-testing strategies, the design goals for a new system, and the options that the committee considered.
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From page 38... ...
. • Toxicity pathway.
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From page 39... ...
Although intermediate biologic changes and mechanisms of action are considered in the paradigm, they are viewed as steps along the pathway to the ultimate induction of an adverse health outcome. Traditional toxicity-testing strategies undertaken in the context of the above paradigm have evolved and expanded over the last few decades to reflect increasing concern about a wider variety of toxic responses, such as subtle neurotoxic effects and adverse immunologic changes.
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From page 40... ...
They also limit the ability to develop predictions about similar chemicals that have not been similarly tested. The following sections describe several limitations of the current system and describe how a system based on toxicity pathways would help to address them.
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From page 41... ...
In contrast, high doses may cause overt toxic responses that preclude the detection of biologic interactions between the chemical and various signaling pathways that lead to subtle but important adverse effects. The vision proposed in this report offers the potential to obtain direct information on toxic effects at exposures more relevant to those experienced by human populations.
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From page 42... ...
For example, testing of mixtures in animal assays could involve huge numbers of combinations of chemicals and the use of substantial resources in an effort of uncertain value. In contrast, testing based on toxicity pathways could allow grouping of chemicals according to their effects on key biologic pathways.
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Accordingly, it would use primarily in vivo animal toxicity tests to predict human health risks. The difficulties in interpreting animal data obtained at high doses with respect to risks in the heterogeneous human population would not be circumvented.
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From page 44... ...
The tiered approach to toxicity testing entails a stepwise process for screening and evaluating the toxicity of agents that still relies primarily on test results in whole animals. The goal of tiered testing is to generate pertinent data for more efficient assessment of potential health risks posed by an environmental agent, taking into consideration available knowledge on the chemical and its class, its modes or mechanisms TABLE 2-1 Options for Future Toxicity-Testing Strategies Option I Option II Option III Option IV In Vivo Tiered In Vivo In Vitro and In Vivo In Vitro Animal biology Animal biology Primarily human Primarily human biology biology High doses High doses Broad range of Broad range of doses doses Low throughput Improved High and medium High throughput throughput throughput Expensive Less expensive Less expensive Less expensive Time- Less time- Less time- Less timeconsuming consuming consuming consuming Use of relatively Use of fewer Use of substantially Use of virtually no large numbers animals fewer animals animals of animals Based on apical Based on apical Based on Based on end points end points perturbations of perturbations of critical cellular critical cellular responses responses Some screening Screening using Screening using using computational computational computational and in vitro approaches possible; approaches approaches; more limited animal flexibility than studies that focus on current methods mechanism and metabolism
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From page 45... ...
. The increasing complexity of biologic information -- including genomic, proteomic, and cell-signaling information -- has encouraged the use of a more systematic multilevel approach in toxicity screening (Yokota et al.
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From page 46... ...
The committee's vision is built on the identification of biologic perturbations of toxicity pathways that can lead to adverse health outcomes under conditions of human exposure. The use of a comprehensive array of in vitro tests to identify relevant biologic perturbations with cellular and molecular systems based on human biology could eventually eliminate the need for whole-animal testing and provide a stronger, mechanistically based approach for environmental decision-making.
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From page 47... ...
Those challenges require maintenance of some whole-animal tests into the foreseeable future, as indicated in Option III, which includes specific in vivo studies to assess formation of metabolites and some mechanistic studies of target-organ responses to environmental agents and leaves open the possibility that more extensive in vivo toxicity evaluations of new classes of agents will be needed. Like Option IV, Option III emphasizes the development and application of new in vitro assays for biologic perturbations of toxicity pathways.
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From page 48... ...
To implement the new toxicity-testing approach, toxicologists will need to evolve a comprehensive array of test procedures that will allow the reliable identification of important biologic perturbations in key toxicity pathways. And epidemiologists and toxicologists will need to develop approaches to understand the range of host susceptibility within populations.
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From page 49... ...
Chemical characterization involves consideration of physicochemical properties, environmental persistence, bioaccumulation potential, production volumes, concentration in environmental media, and exposure data. Computational tools, such as quantitative structure-activity relationship models and bioinformatics,
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From page 50... ...
may eventually be used to categorize chemicals, predict likely toxicity and metabolic pathways, screen for relative potency with predictive models, and organize large databases for analysis and hypothesis generation. Toxicity testing in the committee's vision seeks to identify the perturbations in toxicity pathways that are expected to lead to adverse effects.
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From page 51... ...
For example, human biomonitoring and surveillance can provide data on exposure to environmental agents, host susceptibility, and biologic change that will be key for dose-response and extrapolation modeling. Throughout, the information needs for risk-management decision-making must be borne in mind because they will to a great extent guide the nature of the testing required.
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From page 52... ...
Much research will be needed to ensure that the new system evaluates the effects of the chemicals and their metabolites fully. Moreover, as we shift from a focus on apical end points to perturbations in toxicity pathways, there will be a need to develop an appropriate science base to support risk-management actions based on the perturbations.
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From page 53... ...
2005. Chemical Regulation: Options Exist to Improve EPA's Ability to Assess Health Risks and Manage its Chemical Review Program.
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2005. Predicting the risk of developmental toxicity from in vitro assays.
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2003. Use of proteomics to demonstrate a hierarchical oxidative stress response to diesel exhaust par ticle chemicals in a macrophage cell line.
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