3
Components of the Vision

The committee foresees pervasive changes in toxicity testing and in interpretive risk-assessment activities. The current approach to toxicity testing focuses on predicting adverse effects in humans on the basis of studies of apical end points in whole-animal tests. 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. The use of systems-biology approaches that integrate responses over multiple levels from molecules to organs will enable a more holistic view of biologic processes, including an understanding of the relationship between perturbations in toxicity pathways and consequences for cell and organism function. The central premise of the committee’s vision is that toxicant-induced responses can be quantified with appropriate cellular assays and that empirical or mechanistic models of pathway perturbations



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Toxicity Testing in the 21st Century: A Vision and a Strategy 3 Components of the Vision The committee foresees pervasive changes in toxicity testing and in interpretive risk-assessment activities. The current approach to toxicity testing focuses on predicting adverse effects in humans on the basis of studies of apical end points in whole-animal tests. 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. The use of systems-biology approaches that integrate responses over multiple levels from molecules to organs will enable a more holistic view of biologic processes, including an understanding of the relationship between perturbations in toxicity pathways and consequences for cell and organism function. The central premise of the committee’s vision is that toxicant-induced responses can be quantified with appropriate cellular assays and that empirical or mechanistic models of pathway perturbations

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Toxicity Testing in the 21st Century: A Vision and a Strategy can be used as the basis of environmental decision-making. Combining a fundamental understanding of cellular responses to toxicants with knowledge of tissue dosimetry in cell systems and in exposed human populations will provide a suite of tools to permit more accurate predictions of conditions under which humans are expected to show pathway perturbations by toxicant exposure. 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 decision-making. The regulatory transition from the current emphasis on apical end-point toxicity tests to reliance on perturbations of toxicity pathways will raise many issues. The challenges to implementation and a strategy to implement the vision are discussed in Chapter 5. This chapter discusses individual components of the vision: chemical characterization (component A), toxicity testing (component B), dose-response and extrapolation modeling (component C), population-based and human exposure data (component D), and risk contexts (component E). Component B is composed of a toxicity-pathway component and a limited targeted-testing component. The toxicity-pathway component will be increasingly dominant as more and more high-throughput toxicity-pathway assays are developed and validated. Surveillance and biomonitoring data will be needed to understand the effects of toxicity-pathway perturbations on humans. Finally, the overall success of the new paradigm will depend on ensuring that toxicity testing meets the information needs of environmental decision-making given the risk contexts. COMPONENT A: CHEMICAL CHARACTERIZATION An overview of component A is provided in Figure 3-1. Chemical characterization is meant to address key questions,

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Toxicity Testing in the 21st Century: A Vision and a Strategy FIGURE 3-1 Overview of chemical characterization component. including the compound’s stability in the environment, the potential for human exposure, the likely routes of exposure, the potential for bioaccumulation, the likely routes of metabolism, and the likely toxicity of the compound and possible metabolites based on chemical structure or physical or chemical characteristics. 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. Decisions could be made after chemical characterization about further testing that might or might not be required. For example, if a chemical were produced in such a manner that it would never reach the environment or were sufficiently persistent and biologically reactive, further toxicity evaluation might not be

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Toxicity Testing in the 21st Century: A Vision and a Strategy necessary for regulatory decision-making. Moreover, computational tools for estimating biologic activities and potency could be useful in assessing characteristics of compounds during their development or in a premanufacturing scenario to rule out development or introduction of compounds that are expected to lead to biologically important perturbations in toxicity pathways. In most cases, chemical characterization alone is not expected to be sufficient to reach decisions about the toxicity of an environmental agent. The tools for chemical characterization will include a variety of empirical and computational methods. As outlined in the committee’s first report (NRC 2006a), computational approaches that can and most likely will be used are in the following categories: tools to calculate physical and chemical properties, models that predict metabolism and metabolic products of a chemical, structure-activity relationship (SAR) 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. An array of computational tools is available to calculate physical and chemical properties (Volarath et al. 2004; Olsen et al. 2006; Grimme et al. 2007; Balazs 2007). Tools for assessing metabolic fate and biologic activity are continually evolving, and many of the more accurate and refined examples rely on proprietary technology or proprietary databases. Databases that support the most predictive tools may therefore end up being proprietary and substantially different from those available in the public domain. The committee urges the Environmental Protection Agency (EPA) to consider taking a lead role in ensuring public access to the datasets that are developed for predictive modeling and in providing the resources necessary for the continual evolution of methods to develop SAR, QSAR, and other predictive modeling tools. Many models used to predict hazard are based only on structure and physical and chemical properties and rely on historical datasets. Their reliability is limited by the relevant datasets, which

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Toxicity Testing in the 21st Century: A Vision and a Strategy are continually evolving and increasing in size and accessibility. That is, the predictive value of the structure-activity rules will depend on the chemicals in the dataset from which they are derived—their prevalence, structures, and whether they have the toxic activity of interest (see, for example, Battelle 2002). Computational approaches for predicting toxicity and molecular interactions are available for only a small number of end points, such as estrogen-receptor binding, and their predictive value can be low (Battelle 2002). As approaches improve with time and experience and as the datasets available for model development become larger and more robust, computational tools should become much more useful for chemical characterization, predicting activity in toxicity pathways, and early-stage decision-making. 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. The overview of component B provided in Figure 3-2 indicates that toxicity testing will include both pathway testing and targeted testing, which are discussed further below. A period of transition is inevitable because of the need to develop the full suite of toxicity-pathway tests that will be required for a comprehensive assessment of toxicity. Challenges related to the transition from the current paradigm oriented to apical end points to that outlined here are addressed separately in Chapter 5.

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Toxicity Testing in the 21st Century: A Vision and a Strategy FIGURE 3-2 Toxicity-testing component, which includes toxicity-pathway testing in cells and cell lines and targeted testing in whole animals. Toxicity Pathways The committee’s vision focuses on toxicity pathways. 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) and tumor-suppressor genes (those restricting replication). Both oncogenes and tumor-suppressor genes were later found to code for proteins that played important roles in normal biology. For example, oncogenes were involved in cell replication, and suppressor-gene products normally halted some key part of

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Toxicity Testing in the 21st Century: A Vision and a Strategy the replication process. However, mutations (such as those which can be induced by some environmental agents) 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. Perturbations of toxicity pathways can be evaluated with a variety of assays, including relatively straightforward biochemical assays, such as receptor-binding or reporter-gene expression, or more integrated cellular response assays, such as assays to evaluate proliferation of an estrogen-responsive cell line after treatment with environmental agents. Cellular responses can be broadly dichotomized as those requiring recognition of the structure of an environmental agent and those occurring because of reactivity of the environmental agent. In the first case, the three-dimensional structure is recognized by macromolecular receptors, as with estrogenic compounds. Accordingly, tests for the structurally mediated responses could be based on binding assays or on integrated cellular-response events, such as proliferation, induction of new proteins, or alteration of phosphorylation status of cells after exposure to environmental agents. In the second case, with reactivity-driven responses, the compound or a metabolite reacts with and damages cellular structures. Reactive compounds have the capacity to be much more promiscuous in their targets in cells, and the initial stress responses to tissue reactivity with these agents may also trigger adaptive changes to maintain homeostasis in the face of increased cellular stress (see Figure 2-2). Biologic systems from single cells to complex plant and animal organisms have evolved many mechanisms to respond to and counter stressors in their environment. Many responses are mediated through coordinated changes in expression of genes in specific patterns, which result in new operational characteristics of affected cells (Ho et al. 2006; Schilter et al. 2006; Singh and DuMond 2007). Many stress-response pathways—such as those

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Toxicity Testing in the 21st Century: A Vision and a Strategy regulated by hsp90-mediated regulation of chaperone proteins, by Nrf2-mediated antioxidant-element control of cellular glutathione, or by steroid-hormone family (for example, PPAR, CAR, and PXR) receptor-mediated induction of xenobiotic metabolizing enzymes—are conserved across many vertebrate species (Aranda and Pascual 2001; Handschin and Meyer 2005; Westerheide and Morimoto 2005; Kobayashi and Yamamoto 2006). Initial responses to stressors represent adaptation to maintain normal function. When stressors are applied at increasingly high concentrations in combination with other stressors, in sensitive hosts, or during sensitive life stages, adaptation fails, and adverse effects occur in the cell and organism (see Figure 2-2). 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. An important question for toxicity-testing strategies concerns the number of pathways that might need to be examined as primary targets of chemical toxicants. For example, in the case of reproductive and developmental toxicity, the National Research Council Committee on Developmental Toxicology listed 17 primary intracellular and intercellular signaling pathways that were then known to be involved in normal development (NRC 2000). Those pathways and the various points for toxic interaction with them are potential targets of chemicals whose structures mimic or disrupt portions of them. Some of the pathways are also important at other life stages, and biologically significant perturbations of them might result in long-lasting effects or effects that are manifested later in life. As discussed in Chapter 5, considerable effort will be required to determine which pathways ultimately to include in the suite of toxicity pathways for testing and what patterns and magnitudes of perturbations will lead to adverse effects. Some examples of toxicity pathways that could be evaluated with high-throughput methods are listed below, where the consequences of pathway activation are also noted. Most tests are expected to use high-throughput methods, but others could include

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Toxicity Testing in the 21st Century: A Vision and a Strategy 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), also could be used as needed. Nrf2 antioxidant-response pathway (McMahon et al. 2006; Zhang 2006). The activation of antioxidant-response element signaling occurs through oxidation of sentinel sulfhydryls on the protein Keap1. Some agents, such as chlorine, activate Nrf2 signaling in vitro, and the oxidative stress likely is the cause of irritation and toxicity in the respiratory tract. Heat-shock-response pathway (Maroni et al. 2003; Westerheide and Morimoto 2005). The activation of protein synthesis by HSP1 transcription factor signaling maintains cellular proteins in an active folded configuration in response to stressors that cause unfolding and denaturation. PXR, CAR, PPAR, and AhR response pathways (Waxman 1999; Handschin and Meyer 2005; Hillegass et al. 2006; Timsit and Negishi 2006; Li et al. 2006). The activation of xenobiotic metabolizing pathways by transcriptional activation reduces concentrations of some biologically active xenobiotics and enhances elimination from the body as metabolites (Nebert 1994); it can also increase the activation of other xenobiotics to more toxic forms. The toxicity and carcinogenicity of some agents, such as polyaromatic hydrocarbons, occur because of production of mutagenic metabolites by inducible oxidative enzymes. Hypo-osmolarity-response pathway (Subramanya and Mensa-Wilmot 2006). Cellular stressors damage the integrity of the cellular membranes and activate p38 MAP kinase-mediated pathways to counter them (Van Wuytswinkel et al. 2000). The p38 MAP kinase functionality for the stress responses is conserved across eukaryotes. DNA-response pathways (Nordstrand et al. 2007). Damage to DNA structures induces repair enzymes that act through

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Toxicity Testing in the 21st Century: A Vision and a Strategy GADD45 (Sheikh et al. 2000) and other proteins. Unrepaired damage increases the risk of mutation during cell division and increases the risk of cancer. Endogenous-hormone-response pathways (NRC 1999; Harrington et al. 2006). Enhancement or suppression of activity of transcriptionally active hormone receptors—including estrogen, androgen, thyroid, and progesterone receptors (Aranda and Pascual 2001)—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. The promise of the novel cell-system assays is becoming apparent in advances in several areas: genomic studies of cellular signaling networks affected by chemical exposures, identification of common toxicity pathways that regulate outcomes in diverse tissues, and understanding of networks that control cell responses to external stressors. To ensure the value of results for use in environmental decision-making, the toxicity-pathway assays should be amenable to measurements of dose-response relationships over a broad range of concentrations. Chemical concentrations should be measured directly in the media used in the toxicity-pathway assays when administered concentrations might not represent the concentrations in vitro (for example, in the case of volatile compounds). Finding new assays for assessing the dose-response characteristics of the toxicity pathways will have high priority for research and standardization. Environmental agents on which animal, human, and cellular evidence consistently demonstrates increased risk of adverse health outcomes could serve as positive controls for evaluation of toxicity-pathway assays. Those controls would serve as standards for the evaluation of the ability of other compounds to perturb the assayed toxicity pathways. Negative controls would also be needed to evaluate the specificity of re-

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Toxicity Testing in the 21st Century: A Vision and a Strategy sponses for the key toxicity pathways. For risk implications in specific populations, interpretation of the studies would consider the results of the assays coupled with information on host susceptibility from other human cell or tissue assays and population-based studies. The research needed to implement the toxicity-pathway approach is discussed further in Chapter 5. Targeted Testing As discussed in Chapter 2, an integral part of the committee’s vision is targeted testing, which would be used to complement toxicity-pathway testing and used in the following circumstances: To clarify substantial uncertainties in the interpretation of toxicity-pathway data. To understand effects of representative prototype compounds from classes of materials, such as nanoparticles, that may activate toxicity pathways not included in a standard suite of assays. To refine a risk estimate when the targeted testing can reduce uncertainty, and a more refined estimate is needed for decision-making. 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. One of the challenges of developing an in vitro test system to evaluate toxicity is the current inability of cell assays to mirror the metabolism of a whole animal (Coecke et al. 2006). For the foreseeable future, any in vitro strategy will need to include a provision to assess likely metabolites with whole-animal testing. The metabolites would also need to be tested in a suite of in vitro as-

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Toxicity Testing in the 21st Century: A Vision and a Strategy Estimates of cumulative risk should be considered for situations with simultaneous exposures to the irritant gas and other gases that affect Nrf2 signaling. Human Surveillance Surveillance studies of workers or other human populations potentially exposed to the irritant gas could test for evidence of Nfr2 oxidative-stress pathway activation and inflammatory pathway responses, possibly using induced sputum samples. 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. One of them triggered dose-related activation of estrogenic signaling in receptor-binding as-says and increased DNA replication—indicative of cell proliferation—in human breast-cancer cells in vitro. Binding assays for this compound had the lowest ED10 values; assay indicators of gene transcription and DNA replication occurred at much higher concentrations. QSAR methods also predicted an estrogenic effect on the basis of a library of tested compounds. All other human toxicity-pathway tests were negative or showed responses at much higher concentrations. The test compound had low cytotoxicity in most screens and produced estrogen-receptor activation at concentrations one-tenth of those which produce signs of cell toxicity.

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Toxicity Testing in the 21st Century: A Vision and a Strategy A short-term, mechanistic in vivo study with ovariectomized female rats confirmed mild estrogenic action in vivo and moderate evidence of gene expression for responses in utero or in breast tissues. Predicted conjugated metabolites of the compound were without activity in those assays. Extrapolation Experience with estrogen and other estrogenic chemicals indicates the existence of susceptible populations—such as pubescent girls, fetuses, and infants—that require additional protection and attention. In addition, chemicals that bind to and activate the estrogen receptor may act additively with one another. The extrapolation needs to consider the compound uses, subpopulations that are likely to be exposed to it, other background exposures to estrogenic agents in these subpopulations, and the estimated tissue dose in pregnant and nonpregnant women, fetuses, and infants. Research on estrogen and estrogen agonists reveals that if receptor occupancy in the most sensitive tissues in susceptible humans is increased by less than x % by this exposure or any combined exposure to estrogenic compounds, an appreciable activation of downstream responses or a biologically significant increase in their activation would be unlikely. An alternative assessment would be based on a functional response in a toxicity-pathway 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. The models (for example, Markov Chain Monte Carlo PBPK model) would be designed to account for human variability in pharmacokinetics and modeling un-

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Toxicity Testing in the 21st Century: A Vision and a Strategy certainty. The PBPK models could generate a point-of-departure exposure concentration or a daily intake at which there would be less than x % increase in receptor occupancy or less than x % change in transcriptional activation in susceptible populations (for example, fetuses) 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. That blood concentration could be expressed in units of “estrogen equivalence” to simplify comparisons with estrogen and similarly acting estrogen agonists. Also, on the basis of estrogen equivalence, the models could be used to assess the effects of cumulative exposure to exogenous estrogenic compounds and could be checked against biologic monitoring data in the human population for validity and to ensure that the point of departure is not overestimated. Risk-Assessment Guidance Reference doses and concentrations used in decision-making could be based on a point of departure derived as described above. The reference dose would consider factors, such as susceptibility, that could be altered by polymorphisms in critical portions of downstream estrogen-response pathways or in conjugation with enzymes that clear the compound before it reaches the systemic circulation. Human Surveillance Human surveillance of workers exposed to the compound could detect subtle indications of early effects in humans if they were to occur.

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Toxicity Testing in the 21st Century: A Vision and a Strategy TOXICITY TESTING AND RISK ASSESSMENT A major application of the results of toxicity testing is in the risk assessment of environmental agents. As illustrated in Figure 3-7, the committee’s vision for toxicity testing is consistent with the risk-assessment paradigm originally put forward by the National Research Council in 1983. Chemical characterization and toxicity-pathway evaluation would be involved in hazard identification. Pharmacokinetic models would be used to calibrate in vitro and human dosimetry and thereby facilitate the translation of dose in cellular systems to dose in human organs and tissues. Population-based studies would be used to confirm or explore effects observed in cellular systems to suggest biologic perturbations that require clarification in in vitro tests and to interpret findings in in vitro studies in the context of human populations. All would work together to permit establishment of human exposure guidelines based on risk avoidance, which could be used to enforce scientifically based regulatory standards or support non-regulatory risk-management strategies. Mode-of-action information is important for informing the dose-response component of the risk-assessment paradigm. A deep understanding of mode of action involves studying the mechanistic pathways by which toxic effects are induced, including the key molecular and other biologic targets in the pathways. 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.

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