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Toxicity Testing for Assessment of Environmental Agents: Interim Report 7 Alternative Approaches and Emerging Technologies There is a coordinated international effort to develop alternatives to animals for toxicity testing of environmental agents. Numerous methods have already been developed and validated to reduce, replace, or refine animal testing, and many more are under development in the United States and Europe. The effort to reduce animal use has generated some additional benefits. For example, some nonanimal methods provide useful mechanistic information that can offer insight into the likely human relevance of observed findings or may offer the ability to predict patterns of toxicity. Furthermore, some approaches that use alternative nonmammalian species allow testing of much larger numbers of organisms, thereby increasing statistical power for evaluating dose-response relationships at the low end of the curve. This chapter reviews approaches specifically focused on alternatives to animal testing that reduce, replace, or refine animal use. The second part discusses some new toxicity-testing approaches (-omics technologies and computational toxicology) that may have longer-term potential for achieving greater depth, breadth, animal welfare, and conservation in toxicity testing. The chapter concludes with a discussion of validation to emphasize the importance of evaluating new toxicity-testing methods to ensure that the information obtained from them is at least as good as, if not better than, conventional mammalian models. Validation, as defined in this chapter, is a formal process that grew out of the experience of the European Centre for the Validation of Alternative Methods (ECVAM), the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and others in evaluating the per-
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Toxicity Testing for Assessment of Environmental Agents: Interim Report formance of new tests. The important point for this report is that validation is now seen as a formal, although flexible, process that new tests must satisfy to be accepted by regulators. The details of validation exercises may vary as one shifts from in vitro and in vivo tests to -omics and computational toxicology techniques. ALTERNATIVES TO CURRENT ANIMAL-TESTING APPROACHES One of the tensions in designing new chemical-testing strategies is between reducing animal use and suffering and regulatory needs for more information on a wider array of chemicals or more detailed information on a smaller group of chemicals. Russell and Burch (1992) provided a framework for addressing that tension. They proposed that scientists pursue techniques and approaches that follow the Three Rs, namely, methods that can replace or reduce animal use in specific procedures or refine animal use to eliminate or decrease animal suffering. Replacement, reduction, and refinement have also come to be known as alternative methods. First proposed in 1959, the Three Rs approach (3Rs) advanced in the 1980s when cosmetics and consumer-product companies began to invest millions of dollars in alternative methods in response to consumer pressure (Stephens et al. 2001). During that same decade, national governments incorporated the Three Rs approach into their animal-protection legislation and in some cases began to fund research on and development of alternatives, academic centers devoted to the alternatives began to be established, the field of in vitro toxicology blossomed, and companies began to market alternative test kits. In the 1990s, government centers devoted to the validation and regulatory acceptance of alternative methods were established in Europe and the United States, alternative tests began to be formally approved and accepted by regulatory agencies, and the triennial World Congresses on Alternatives were inaugurated. There is evidence that, owing in part to the implementation of Three Rs approaches, use of laboratory animals in research and testing in the United States decreased by about 30%1 in the decade after the estab 1 Estimate based on comparison of average number of Animal Welfare Act (AWA)-covered animals used per year in 1994-2003 and average number of AWA-covered animals used per year in 1984-1993. Source: Animal Welfare Reports, USDA/APHIS.
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Toxicity Testing for Assessment of Environmental Agents: Interim Report lishment of ICCVAM in 1997, which marked the beginning of widespread efforts to implement the Three Rs. In the 21st century, as acceptance and implementation of the Three Rs approach continue to spread, a major challenge in advancing the approach is to harness the potential of new technologies, including -omics, to replace, reduce, and refine animal use. The following sections explore in more detail the refinement, reduction, and replacement alternatives. The replacement of commonly used laboratory animals with less sentient animal species is addressed specifically. Refinement Alternatives Refinement alternatives are changes in existing practices that either decrease animal pain and distress or increase animal welfare. Refinements are best practices, namely, ways of carrying out animal-based procedures and practices that ensure the best practical outcomes with respect to both animal welfare and science. The principle of refinement can be applied to any aspect of laboratory care and use—including anesthesia, analgesia, supportive veterinary care, and euthanasia—and to the more general aspects of animal transport, handling, housing, environmental enrichment, and personnel training (Morton 1995). Refinement approaches of particular relevance to toxicity testing include best practices in dose administration, dose-volume limits, and humane end points (Hendriksen and Morton 1999; ILAR 2000; OECD 2000; Diehl et al. 2001; Stephens et al. 2002). Humane end points in an animal experiment are early indicators of pain, distress, or death and, once validated, can be used to terminate an experiment early to preclude or lessen animal suffering without compromising study objectives (Stokes 2000). The application of humane end points is often associated with frequent monitoring of animals and scoring of their clinical signs. Scoring systems are an important tool for evaluating the efficacy of proposed refinements. In toxicology, refinements include not only modifications of existing tests but also new animal-based tests that result in less pain or distress than conventional procedures or in no pain or distress. For example, historically the guinea pig maximization test (GPMT) was the conventional assay for acute contact dermatitis (ACD). A new procedure, the local lymph node assay (LLNA), assesses ACD by examining local lymph node proliferation instead of the ensuing clinically evident
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Toxicity Testing for Assessment of Environmental Agents: Interim Report allergic reaction. The animals, in this case mice, are euthanized before experiencing the discomfort of ACD. The LLNA can be considered an elaboration of the humane-end-point approach, which was made possible by knowledge of the mechanism of ACD. The LLNA has been accepted by EPA, the Food and Drug Administration (FDA), and the Occupational Safety and Health Administration (OSHA) as a refinement alternative to the GPMT for assessing ACD (NTP 1999). Refinements in toxicology obviously benefit the animals involved in testing, but they can also be advantageous from scientific and societal viewpoints. Pain or distress stemming from poor technique can cloud study outcomes (Morton et al. 2001). Refined approaches, such as the use of humane end points, can lead to earlier completion of testing. Scoring of clinical signs can reveal toxicologic outcomes that might have been overlooked if death were the only outcome noted. Finally, implementing refinement can improve the morale of laboratory personnel and help to satisfy mandates in humane legislation, such as the U.S. Animal Welfare Act, with its emphasis on minimizing pain and distress. Reduction Alternatives Reduction alternatives are methods that use fewer animals than conventional procedures but yield comparable levels of information. They can include methods that use the same number of animals but yield more information so that fewer animals are needed to complete a given project or test (Balls et al. 1995). One of the most dramatic illustrations of reduction is the acute systemic toxicity-testing guidelines of the Organisation for Economic Co-operation and Development (OECD), which apply primarily to industrial chemicals. The number of animals used in OECD’s Test Guideline 401 for the LD50 test dropped from 100 to 25 when the guideline—adopted in 1981—was modified in 1987. OECD also adopted three new guidelines in the 1990s that reflected additional reduction approaches that typically use under 10 animals per test. The new alternatives—the up-and-down procedure, the fixed-dose procedure, and the acute-toxic-class method—led OECD to drop Guideline 401 altogether from its guidelines in 2002 (OECD 2002a). One straightforward way to explore reduction approaches for a given animal test is through retrospective analyses of test data on individual animals. If N is the number of animals conventionally used in a
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Toxicity Testing for Assessment of Environmental Agents: Interim Report test, do (N 1) animals typically yield the same conclusion? Do (N – 2) animals yield the same conclusion? That approach has been applied to the Draize eye-irritancy test to reduce the conventional number of animals used per test from six to three (see EPA 1998). A rigorous application of experimental design and statistical approaches is one of the best ways to pursue reduction in animal numbers (Festing et al. 1998; Vaughan 2004). Statistical aids can yield precise estimates of the number of animals needed to test a hypothesis. Block designs can lead to reduction in animal numbers. And using animals that have genetically defined backgrounds can limit statistical variance and thereby achieve a given level of statistical power with fewer animals (Russell and Burch 1992; Festing 1999). Animal reduction can also be achieved by applying adaptive Bayesian statistical techniques to study design. Such approaches have been used in clinical trials for evaluating new drugs and have resulted in reduced numbers of subjects and early termination in specific arms of clinical trials, reducing ineffective treatments and life-threatening side effects and improving survival (Berry et al. 2002; Giles et al. 2003). The same techniques could be adapted to reduce the numbers of animals used in toxicity testing. Various noninvasive imaging techniques can be used to track the progression of toxic effects or disease in a cohort of animals, eliminating the need for interim killing of animals at selected times. To date, those techniques, such as biophotonic imaging (Contag et al. 1996), have been implemented primarily in biomedical research, as opposed to toxicity testing. If applied to regulatory toxicity testing, they could not only reduce animal numbers in some tests but facilitate the refinement of tests by allowing the monitoring of animals over time to gauge how close they are getting to specified humane end points, such as tumor size. Animal use can also be limited by careful design of testing schemes. For example, EPA modified the testing scheme in its high-production-volume (HPV) chemical testing program after pressure from animal protectionists. The agency called on program participants to take a number of steps intended to reduce animal use, including grouping chemicals into appropriate categories and testing only representative chemicals from a category, avoiding some types of testing of closed-system intermediates, and encouraging a thoughtful, qualitative analysis rather than a rote checklist approach (see EPA 1999). Reducing animal numbers in toxicity tests not only subjects fewer animals to potential suffering but has the potential to lower the cost of testing.
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Toxicity Testing for Assessment of Environmental Agents: Interim Report Replacement Alternatives Replacement alternatives use nonanimal approaches in lieu of animal-based methods. In toxicology, such nonanimal approaches include physiochemical measures, quantitative structure-activity relationship (QSAR) models, and other methods. Replacement might include substituting invertebrates in testing typically done with vertebrates, for example, the use of Caenorhabditis elegans in chronic toxicity testing. It might also include substituting primary culture of tissues or cells, such as neuromuscular preparations, for whole animals; however, such cultures entail animal use to harvest the tissues that will be cultured and therefore do not truly replace animal use. Some nonanimal methods can serve as screens to limit the number of chemicals that move on to later stages of testing. For example, a simple pH determination can characterize a chemical as highly acidic or alkaline and so almost certainly an eye irritant, thus obviating a Draize eye-irritancy test in rabbits (see OECD 2002b). Such a screen can be labeled a “partial replacement” to distinguish it from a nonanimal method that serves as the definitive test, a “full replacement.” Full replacements clearly are more satisfactory from a humane perspective, but partial replacements do limit animal use and suffering in toxicity tests. Replacement approaches have been successfully implemented over the last several decades for a variety of applications, including culturing viruses, assaying vitamins, diagnosing pregnancy, and preparing monoclonal antibodies (Stephens 1989). In toxicology, in vitro tests have shown great potential as replacement alternatives. The Ames mutagenesis test, developed in 1971, was the first in vitro test used in regulatory toxicology. In vitro tests and other nonanimal methods have since been accepted in regulatory toxicology case by case after the development of the field of validation and the establishment of ICCVAM and ECVAM in the 1990s. In recent years, ICCVAM, ECVAM, and OECD have validated or accepted as validated a number of in vitro tests (see Chapter 2, Table 2-3), including the 3T3 neutral red update phototoxicity test, a skin-absorption assay, cytotoxicity assays for acute systemic toxicity, and skin-corrosivity assays, such as the transcutaneous electrical resistance assay, the Corrositex assay, and the Episkin and Epiderm assays (ICCVAM 2004; ECVAM 2005). Their validations have established the strengths and weaknesses of the assays and in some cases limited their applicability to particular chemical classes or levels within tiered testing strategies.
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Toxicity Testing for Assessment of Environmental Agents: Interim Report Overall, nonanimal approaches offer several potential advantages over classical animal-based tests. First, they can be less time-consuming and more humane. Second, they can be more mechanistically relevant to human toxicity when they are selected or tailored to reflect a specific biochemical pathway or a chemical receptor that does not occur in a given animal model. Third, they can allow for higher throughput. Because of the technical advantages, such approaches are being evaluated for large-scale testing programs, including HPV chemical testing and endocrine-disruptor testing. As the large-scale testing programs are developed and implemented, nonanimal methods are being incorporated as screens into tier-testing approaches with animal testing being reserved primarily for the highest tiers. Efforts to develop a full array of nonanimal methods to address all end points in some testing programs are under way (Worth and Balls 2002). That approach would rely on mechanistically based assays and, where appropriate, incorporate metabolic activation. Such an approach to toxicity-testing programs might be able to eliminate the need for extrapolation from animals to humans in some cases and to aid in identifying hazards to potentially sensitive human populations. Use of Alternative Species Nonmammalian vertebrates, such as fish, are being used increasingly in human health effects testing. To the extent that such species are less sentient than mammals, their use constitutes an example of refinement. Some nonmammalian species have a high degree of structural and physiologic similarity to higher vertebrates, enhancing the likelihood that similar toxicities would be produced. In addition, nonmammalian species have shorter developmental periods and shorter overall life spans, which are useful characteristics for simulating effects of chronic exposure. And they usually require simpler, less expensive laboratory maintenance than mammals. The effectiveness of alternative models is well illustrated by historically prominent studies that used rainbow trout as a model for carcinogenicity and mechanistic cancer research. Trout have been shown to share many mechanisms of carcinogenesis with mammals, such as pathways of metabolic activation and production of mutagenic DNA adducts. Recently, the low cost and ease of maintenance of trout were taken advantage of to carry out the largest dose-response study of chemical-
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Toxicity Testing for Assessment of Environmental Agents: Interim Report induced carcinogenesis ever conducted (William et al. 2003). The goal of this project, which used 42,000 trout, was to identify the dose at which one additional cancer in 103 animals occurred, an order-of-magnitude increase in sensitivity over the largest mouse study, which used 24,000 mice (Gaylor 1980). The dose-response data deviated significantly from linearity, although a threshold dose could not be statistically established. Studies that use large numbers of animals and thereby have increased sensitivity would have profound implications for modeling human health risk assessment if the animal models used were found to be relevant to humans. Another fish model that is gaining increased attention from toxicology researchers is the zebrafish (Sumanas and Lin 2004). Zebrafish have many features that make them highly desirable as a laboratory model, including small size, high fecundity, and rapid development. The embryos are transparent, and this allows visualization of fundamental developmental processes with a simple dissecting microscope. A generation time of only 3 months makes genetic screening practical. Furthermore, a variety of diseases have been successfully modeled in zebrafish via simple genetic alterations or mutations. Much of the zebrafish genome has been sequenced, and at least two zebrafish oligonucleotide microarrays are available, each containing over 14,000 unique sequences. Transgenic zebrafish that express green fluorescent protein (GFP) under the control of various tissue-specific promoters have also been developed. From a toxicology perspective, zebrafish have been shown to express the aryl hydrocarbon receptor (AhR) and the AhR nuclear translocator (ARNT), two proteins that are responsible for initiating the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and structurally related halogenated aromatic hydrocarbons in mammals (Andreason et al. 2002). Zebrafish respond to TCDD with induction of cytochrome P4501A, a key gene controlled by TCDD-activated AhR in all species examined (Andreason et al. 2002). Scientists at the National Toxicology Program (NTP) are evaluating zebrafish to determine their usefulness in screening chemicals for potential toxicity and carcinogenicity. Because of their genetic uniformity and low rates of spontaneous tumor, the use of zebrafish minimizes the experimental variability normally associated with other alternative animal species. Although nonmammalian models show great promise at both ends of the toxicity-testing spectrum (screening and mechanistic studies), there are obvious limitations on the use and applicability of such non-
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Toxicity Testing for Assessment of Environmental Agents: Interim Report mammalian species in some aspects of toxicity testing. Metabolic differences may be greater between nonmammalian species and humans than between humans and other mammals, so the use of such data for human health risk assessment may be more tenuous. Substantial anatomic and physiologic differences between mammals and other species will also prevent their application to assessment of some toxic end points. EMERGING TECHNOLOGIES Novel -omics technologies and computational toxicology may one day contribute to resolution of much of the current tension around the objectives of toxicity testing. The new fields are developing rapidly, and their integration into traditional testing strategies is being investigated. This section provides an overview of the tools, techniques, and science that show promise for advancing toxicity testing and risk assessment. Genetics Individuals differ in their responses to environmental toxicants, and that variability can be attributed to many factors. One possible factor is the variation in the human genome. Each person’s genome is different, and the differences are thought to influence a person’s response and susceptibility to a chemical exposure. The Human Genome Project at the National Institutes of Health has greatly facilitated the search for susceptibility genes—genes that influence a person’s response to a stimulus or probability of developing a particular disease. In the last decade, researchers have been successful in identifying genes for diseases, such as cystic fibrosis, that are due to mutations in single genes. The effect of such a mutation is large and therefore relatively easy to identify. Identifying the susceptibility genes for complex human traits has been more challenging, but recent molecular and statistical advances stimulated by the Human Genome Project have led to the identification of susceptibility genes for several complex human diseases, such as asthma and Crohn’s disease. Those advances have also led to identification of genetic variations that make some people more and other people less susceptible to environmental toxicants.
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Toxicity Testing for Assessment of Environmental Agents: Interim Report Several key developments in addition to the Human Genome Project have advanced the field of genetics. First is the characterization of DNA-sequence polymorphisms, particularly the single-nucleotide polymorphisms (SNPs).2 Three entities—the SNP Consortium (TSC), the International HapMap Project, and the National Institute of Environmental Health Sciences (NIEHS) Environmental Genome Project (EGP)—have identified and characterized millions of SNPs. Specifically, they have provided positional information and allele frequencies and have developed assays for genotyping them. The SNPs identified by TSC and the HapMap Project are distributed across the entire genome and were not selected specifically for their functional significance. The SNPs identified by the EGP reside in environmentally responsive genes, such as genes involved with the cell cycle, DNA repair, and metabolism. The work of all three entities has provided a well-characterized set of SNPs that can be used as genetic “landmarks” to localize genes that influence one’s susceptibility to disease and sensitivity to toxicants. The second advance is the development of technologies for high-throughput genotyping. Although millions of polymorphisms have been identified, genotyping them for routine analysis has been an expensive, labor-intensive task. Until recently, genotyping was performed marker by marker; thus, the throughput was low and the cost high. Several recent developments allow thousands of markers to be genotyped in parallel. Large numbers of genotypes can be generated from DNA samples from many individuals. That advance is particularly important because the effect of each sequence variation is likely to be small, and these small effects would be very difficult to detect without a sample of adequate size. The third advance is the improvement of phenotyping methods. A phenotype is the biochemical, physiological, or physical characteristics of an individual as determined by his or her genetic background and the environment. Defining phenotypes and collecting material for study often present challenges. To determine the genetic basis of a phenotype, one must study how the phenotype is passed along in families; therefore, phenotypic measurements and DNA from family members are often needed for analysis. However, in trying to define a phenotype that would indicate susceptibility to an environmental toxicant, it is difficult or impossible, to identify family members who have been exposed to the same 2 Variations in DNA sequence that occur in more than 1% of the population are considered polymorphisms, and SNPs are polymorphisms that differ by one nucleotide.
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Toxicity Testing for Assessment of Environmental Agents: Interim Report agents under similar circumstances. To circumvent that problem, cell cultures from family members are exposed to environmental agents. The agent and dose are controlled, and a large amount of family material can be evaluated. Those studies have demonstrated that gene expression and phenotypes, such as cellular functions, can be accurately measured in cultured cells (Schork et al. 2002; Yan et al. 2002; Lo et al. 2003). In addition, the phenotypes identified in cultured cells are amenable to genetic analysis (Schadt et al. 2003; Greenwood et al. 2004; Morley et al. 2004). In recent studies, cells from members of large three-generation families were exposed to chemotherapeutic agents, such as cisplatin (Dolan et al. 2004), 5-fluorouracil, and docetaxel (Watters et al. 2004), and the genes that influence chemotherapy toxicity were identified (Dolan et al. 2004; Watters et al. 2004). Improvements in phenotyping methods are important for elucidating the genetics of chemical response and measuring the consequences of genetic variation. Genomics The human genome has been estimated to consist of about 25,000 genes. The gene-expression pattern varies from cell to cell and determines the identity of each cell. Cells induce or repress particular genes in response to environmental stimuli. Changes in gene expression help the cells to adapt to the “new” environment or repair damage resulting from the stimuli. One can identify genes that change in response to exposure by comparing the expression level of genes at baseline to the expression level in response to stimuli. With such technologies as microarrays, the expression levels of tens of thousands of genes can be measured accurately and efficiently. Those genes may serve as biomarkers of exposure and also aid in understanding the mechanism of action of the stimuli and the cellular pathways involved in the response. Several groups, such as ILSI-HESI, have initiated projects to investigate the use of genomic data in risk assessment (Pennie et al. 2004; Hood 2004). Other organizations have initiated programs to investigate the use of genomic and other -omic technologies in toxicology. For example, the NRC Standing Committee on Emerging Issues and Data on Environmental Contaminants, which was convened at the request of NIEHS, currently is focused on toxicogenomics and its applications in environmental and pharmaceutical safety assessment, risk communica-
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Toxicity Testing for Assessment of Environmental Agents: Interim Report human data, ICCVAM and similar entities consider the existing test to be the default standard and judge the new test against it. A challenge arises when the reference tests, typically animal-based, have considerable variability across laboratories. Such variability makes it difficult to show correlations between the results of the new test method and those of the reference test. One way to address this challenge is to make greater efforts to collect available human data as the true standard for comparison. In the absence of such data, however, approaches need to be developed to account for the inherent variability in some animal tests when conducting validation assessments. New test methods are not always stand-alone substitutes for existing test methods. New test methods that prove to be inadequate in head-to-head comparisons with existing test methods might pass muster when combined with complementary approaches into tiered or battery approaches. Consequently, ICCVAM might benefit from providing greater guidance on developing and validating such approaches, rather than relying on one-for-one correspondence between the new and existing test methods. Another challenge facing ICCVAM is helping to ensure a steady flow of new test methods into its validation pipeline. Without such candidate methods, ICCVAM would have nothing to validate or assess. ICCVAM or its parent agency should consider funding research to identify biomarkers or mechanisms of toxicity that could be incorporated into test methods and channeled into the ICCVAM pipeline for validation. Meeting the challenges discussed above would enable ICCVAM to be more productive and efficient in assessing new test methods for their suitability for regulatory toxicology. In addition to its guidance on validation principles, ICCVAM and the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) have issued practical guidance on submitting validation data for assessment and nominating promising test methods for further development or validation (ICCVAM/NICEATM 2004). Several new or revised tests have gone through the ICCVAM process and have been assessed according to its validation and regulatory acceptance criteria. For example, in 1998, after a submission by industry representatives, ICCVAM established an independent peer-review panel to review the validation status of the local lymph node assay (LLNA), a reduction and refinement alternative to the guinea pig maximization test
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Toxicity Testing for Assessment of Environmental Agents: Interim Report (GPMT) test for allergic contact dermatitis. The panel judged the LLNA to be an adequate substitute for the GPMT according to the ICCVAM validation criteria. ICCVAM forwarded the results of the review to relevant federal agencies, which accepted the LLNA as a validated test for allergic contact dermatitis. The ICCVAM-NICEATM validation and submission criteria are intended to help industry and the federal government to update and enhance the inventory of chemical testing methods. New or revised methods can be reviewed by ICCVAM and NICEATM, and the resulting recommendations can be sent to individual agencies for their consideration. Thus, the guidelines can help stakeholders to meet the challenges posed by new testing programs or needs. For example, EPA has contracted with ICCVAM and NICEATM to validate receptor-binding assays for its endocrine-disruptor program, and it is using ICCVAM and NICEATM criteria to validate some animal-based tests for the program. It should be emphasized that the formal validation process applies to methods intended for immediate regulatory testing. It is not intended for methods that, for example, are used only inhouse in industry or are purely investigational or newly emerging. REFERENCES Abagyan, R., and M. Totrov. 2001. High-throughput docking for lead generation. Curr. Opin. Chem. Biol. 5(4):375-382. Accelrys. 2005. Products and Services. Accelrys Software Inc. [online]. Available: http://www.accelrys.com [accessed April 12, 2005]. Andreasen, E.A., J.M. Spitsbergen, R.L. Tanguay, J.J. Stegeman, W. Heideman, and R.E. Peterson. 2002. Tissue-specific expression of AHR2, ARNT2, and CYP1A in zebrafish embryos and larvae: Effects of developmental stage and 2,3,7,8- tetrachlorodibenzo-p-dioxin exposure. Toxicol. Sci. 68 (2):403-419. Aronov, A.M., and B.B. Goldman. 2004. A model for identifying HERG K+ channel blockers. Bioorg. Med. Chem. 12(9):2307-2315. Astex Technology. 2005. Current Portfolio. Astex Technology, Cambridge, UK [online]. Available: http://www.astex-technology.com/current_portfolio.html [accessed April 12, 2005]. Baggerly, K.A., J.S. Morris, and K.R. Coombes. 2004. Reproducibility of SELDI-TOF protein patterns in serum: Comparing datasets from different experiments. Bioinformatics 20(5):777-785. Balls, M., P. Botham, A. Cordier, S. Fumero, D. Kayser, H. Koëter, P. Koundakjian, N.G. Lindquist, O. Meyer, L. Pioda, C. Reinhardt, H. Rozemond,
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