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3 Components of the Vision
Pages 56-97

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From page 56...
... In the committee's vision, in vitro mechanistic tests provide rapid evaluations of large numbers of chemicals, greatly reduced live-animal use, and results potentially more relevant to human biology and human exposures. As discussed in Chapter 2, toxicity testing can be increasingly reconfigured with the accrual of better understanding of biologic pathways perturbed by toxicants and of the signaling networks that control activation of the pathways.
From page 57...
... The institutional and infrastructural changes required to achieve the committee's vision will include changes in the types of tests that support toxicity testing and how toxicity, mechanistic information, and epidemiologic data are used in regulatory decisionmaking. The regulatory transition from the current emphasis on apical end-point toxicity tests to reliance on perturbations of toxicity pathways will raise many issues.
From page 58...
... Thus, data would be collected on physical and chemical properties, use characteristics, possible environmental concentrations, possible metabolites and breakdown products, initial molecular interactions of compounds and metabolites with cellular components, and possible toxic properties. A variety of computational methods might be used to predict those properties when data are not available.
From page 59...
... and quantitative SAR (QSAR) models that predict biologic activity from molecular structure, and models that predict specific molecular interactions, such as protein-ligand binding, tissue binding, and tissue solubility.
From page 60...
... COMPONENT B: TOXICITY TESTING OF COMPOUNDS AND METABOLITES The long-term vision makes the development of predictive toxicity-pathway-based assays the central component of a broad toxicity-testing strategy for assessing biologic activity of new or existing compounds. The assays will be conducted primarily with cells or cell lines, optimally with human cells or cell lines, and as time passes, the need for traditional apical animal tests will be greatly reduced and optimally eliminated.
From page 61...
... Toxicity pathways are simply normal cellular response pathways that are expected to result in adverse health effects when sufficiently perturbed. For example, in early studies of cancer biology, specific genes that were associated with malignant growth and transformation were called oncogenes (those promoting unrestrained cell replication)
From page 62...
... were found to make oncogenes constitutively active or to cause a great reduction in or loss of activity of suppressor genes. It is the ability of otherwise normal cellular response pathways to be targets for environmental agents that leads to their definition as toxicity pathways.
From page 63...
... . As stated, the committee's long-range vision capitalizes on the identification and use of toxicity pathways as the basis of a new approach to toxicity testing and dose-response modeling.
From page 64...
... 64 Toxicity Testing in the 21st Century medium-throughput assays of more integrated cellular responses, such as cytotoxicity, cell proliferation, and apoptosis. Simpler assays, such as receptor binding or reactivity of compounds with targets (for example, tests of inhibition of cholinesterase activity)
From page 65...
... -- leads to altered homeostasis and alteration in biologic functions that are controlled by the receptors. The biologic revolution now making its way into toxicity testing sets the stage for the design of mechanistic cell-based assays that can be evaluated primarily with high-throughput approaches to testing.
From page 66...
... • To investigate the production of possibly toxic metabolites of new compounds. • To fill gaps in the toxicity-pathway testing strategy to ensure that critical toxicity pathways and end points are adequately covered.
From page 67...
... Although it may become possible to make comprehensive predictions of metabolism of environmental agents, any plan to implement the vision here will probably have to rely on some metabolite-identification studies in whole animals. Another challenge is adequate development of in vitro assays to identify reliably toxicity pathways that are causally related to neurodevelopment and other physiologic processes that depend on timing and patterns of exposure and the interactions of multiple pathways.
From page 68...
... COMPONENT C: DOSE-RESPONSE AND EXTRAPOLATION MODELING The committee's vision includes dose-response and extrapolation modeling modules, which are discussed below; an overview of this component is provided in Figure 3-3. Empirical Dose-Response Modeling As they are currently used in toxicity testing with apical end points, empirical dose-response (EDR)
From page 69...
... In the longrange vision, the committee believes that EDR models will be developed for environmental agents primarily on the basis of data from in vitro, mechanistically based assays described in component B The EDR models would describe the relationship between the concentration in the test medium and the degree of in vitro response; in some cases, they would provide an estimate of some effective concentration at which a specified level of response occurs.
From page 70...
... The main reason for insisting that the in vivo studies have a measure of tissue concentration is to permit comparison with the results from the in vitro assays. In some risk contexts, an EDR model based on in vitro assay results might provide adequate data for a risk-management decision, for example, if host-susceptibility factors of a compound in humans are well understood and human biomonitoring provides good information about its tissue or blood concentrations and about other exposures that affect the toxicity pathway in a human population.
From page 71...
... Models not accessible for review may be useful for many scientific purposes but are not appropriate for regulatory use. Toxicity-Pathway Dose-Response Models Models of toxicity-pathway perturbations need to be developed to interpret results from toxicity tests in a mechanistic rather than simply empirical manner; they should be achievable in the near future.
From page 72...
... The committee recognizes that in the near term there will be continued reliance on default approaches for low-dose extrapolation, such as the linear doseresponse model and application of uncertainty factors to benchmark doses or no-observed-adverse-effect levels. The application of uncertainty and adjustment factors to precursor biologic responses from perturbations will not necessarily involve the same factors as currently used in EPA risk assessments for noncancer end points.
From page 73...
... First, the inactivation of Keap-1 by oxidants and the later formation of the Nrf2-Maf heterodimer are response circuits that can be mathematically modeled to predict low-dose toxic responses. Second, the expression of antioxidantstress proteins and phase 2-detoxifying enzymes can also be modeled to predict low-dose toxic responses.
From page 74...
... Physiologically Based Pharmacokinetic Modeling PBPK models assist in extrapolations of dosimetry among doses, dose routes, animal species, and classes of similar chemicals (Clark et al.
From page 75...
... They will be critical for selecting doses in in vitro and targeted in vivo testing, for interpreting and extrapolating from high-throughput test results, for identifying and understanding toxicity pathways, and for identifying toxic chemical hazards. Figure 3-5 provides an overview of component D, and the following sections discuss how population-based and exposure data can be integrated with toxicity testing.
From page 76...
... In some cases, coordination of the tests will be required; interpretation of toxicity-test results will require an understanding of how human susceptibility factors and background exposures affect the toxicity pathway and how those factors and exposures vary among people.
From page 77...
... Identifying those nodes will allow the potential effects of genotypic variation to be better determined and integrated into chemicaltoxicity assessments. Another example of the interplay between toxicity testing and epidemiology is the generation of potentially important data
From page 78...
... Situations in which toxicity testing is not adequately conducted or fails to identify an important human health risk emphasize the need to integrate population-based studies into any toxicity-testing paradigm and the need to collect human data in a structured manner so that they can be used effectively by the toxicology community.
From page 79...
... The first is information collected by manufacturers, users, agencies, or others on exposures of employees in the workplace or on environmental exposures of the population at large. Such exposure information would be considered in the setting of dose ranges for in vitro toxicity testing and of doses for collecting data in targeted pharmacokinetic studies and in selecting concentrations to use in human PBPK models.
From page 80...
... COMPONENT E: RISK CONTEXTS Toxicity testing is valuable only if it can be used to make more informed and more efficient responses to public-health concerns faced by regulators, industry, and the public. In Chapter 1, the committee identified five broad risk contexts requiring decisions about environmental agents, which are listed in Figure 3-6.
From page 81...
... For example, nanotechnology, which focuses on materials in the nanometer range, will present challenges in toxicity testing that might not be easily addressed with existing approaches (IOM 2005; Borm et al. 2006; Gwinn and Vallyathan 2006; Nel et al.
From page 82...
... Second, because many new commercial chemicals are developed each year, there is a need for a mechanism to screen them rapidly for potential toxicity. With an emphasis on high- and mediumthroughput screens, the committee's vision for toxicity testing accommodates screening a large number of chemicals.
From page 83...
... Third, environmental agents that raise concern in the high-throughput assays could have high priority in population-based studies for evaluation of their potential link to asthma in human populations, such as workers. The high-throughput assays that are based on evaluation of toxicity pathways can survey large numbers of environmental agents and identify those which operate through a mechanism that may be relevant to a disease of interest, as in the case of asthma, and may help to generate useful hypotheses that can then be examined in population-based studies.
From page 84...
... Example 1: Irritant Gas Toxicity Testing and Empirical Dose-Response Analysis • Among a larger group of gases tested in multiple highthroughput assays, the agent caused dose-related responses in test assays for glutathione depletion, Nfr2 oxidative-stress pathway activation, inflammatory pathway responses, and general cytotoxicity. Most other human toxicity-pathway tests had negative results, but the test gas was routinely cytotoxic in systems in which
From page 85...
... The hydrolysis product was tested in a broad suite of toxicity pathways and showed little evidence of pathway specific responses, but consistently showed toxic responses at concentrations much above 1.0 mM. • At nontoxic concentrations, the compound showed no evidence of mutagenicity.
From page 86...
... 86 Toxicity Testing in the 21st Century was used to calculate the exposure concentrations that would yield 0.012 mM hydrolysis product (that is, 0.12 mM/10) in the nose and lungs during a continuous human inhalation exposure.
From page 87...
... To evaluate the results, any increases in activation in the exposed population could be compared with pathway activation in control human populations. Example 2: Estrogenic Agonist Toxicity Testing and Empirical Dose-Response Analysis • A large group of commercial chemicals were tested in multiple high-throughput in vitro assays.
From page 88...
... An alternative assessment would be based on a functional response in a toxicitypathway assay, such as transcriptional activation. • Human PBPK models for the compound would be used to model absorption, distribution to sensitive tissues, and elimination of active parent compound.
From page 89...
... and in 95% to 99% of the exposed general population. The PBPK models could also provide the blood concentration associated with the change in receptor occupancy or transcriptional activation.
From page 90...
... Thus, the committee's vision, outlined in Chapters 2 and 3 of this report, is a shift away from traditional toxicity testing that focuses on demonstrating adverse health effects in experimental animals toward a deeper understanding of biologic perturbations in key toxicity pathways that lead to adverse health outcomes. The committee believes that its vision of toxicity testing would better inform the assessment of the potential human health risks posed by exposure to environmental agents and ensure efficient testing methods.
From page 91...
... 2006. Arsenic exposure is associated with decreased DNA repair in vitro and in individuals exposed to drinking water arsenic.
From page 92...
... 2005. Evaluation of physiologically based pharmacokinetic models in risk assessment: An ex ample with perchloroethylene.
From page 93...
... 1996. Physiologi cally based pharmacokinetic/pharmacodynamic modeling of the toxicology interaction between carbon tetrachloride and kepone.
From page 94...
... 2006. The impact of aryl hydrocarbon receptor signaling on matrix metabolism: Implications for development and disease.
From page 95...
... Components of the Vision 95 Leroux, B.G., W.M. Leisenring, S.H.
From page 96...
... 2006a. Toxicity Testing for Assessment of En vironmental Agents: Interim Report.
From page 97...
... 2003. Utility of physiologi cally based pharmacokinetic models to drug development and rational drug discovery candidate selection.


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