2
Animal and In Vitro Toxicity Testing

Animals have been used as sentinels for early detection of potential risk to humans or as models to study the causes, pathogenesis, progression, and treatment of diseases. The latter use gave rise to the field of investigative toxicology, wherein animals are used as surrogates to predict possible adverse health effects to humans arising from chemical exposures. That approach is challenged by some people for scientific, ethical, and philosophic reasons, but the use of animal models to assess hazards and risks to humans continues to be the standard for protecting human health. Over the last several decades, scientists have developed standardized protocols for testing potentially hazardous chemicals to ensure sound scientific methods and generation of high-quality data that are critical for assessing human hazards and risks.

Toxicity testing in animals is conducted to identify possible adverse effects resulting from exposure to an agent and to develop dose-response relationships that allow evaluation of responses at other exposures. Toxicity tests are designed to minimize variance, bias, and the potential for false-positive and false-negative results. Those goals, however, are weighed in light of constraints on costs and other resources. The types and extent of human exposure are important considerations in designing toxicity studies for human health risk assessment. An understanding of duration, frequency, intensity, and routes of exposure and an understanding of chemical stability and possible chemical breakdown products are helpful in guiding the selection of the dosing regimen, the test medium, and the test material.



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Toxicity Testing for Assessment of Environmental Agents: Interim Report 2 Animal and In Vitro Toxicity Testing Animals have been used as sentinels for early detection of potential risk to humans or as models to study the causes, pathogenesis, progression, and treatment of diseases. The latter use gave rise to the field of investigative toxicology, wherein animals are used as surrogates to predict possible adverse health effects to humans arising from chemical exposures. That approach is challenged by some people for scientific, ethical, and philosophic reasons, but the use of animal models to assess hazards and risks to humans continues to be the standard for protecting human health. Over the last several decades, scientists have developed standardized protocols for testing potentially hazardous chemicals to ensure sound scientific methods and generation of high-quality data that are critical for assessing human hazards and risks. Toxicity testing in animals is conducted to identify possible adverse effects resulting from exposure to an agent and to develop dose-response relationships that allow evaluation of responses at other exposures. Toxicity tests are designed to minimize variance, bias, and the potential for false-positive and false-negative results. Those goals, however, are weighed in light of constraints on costs and other resources. The types and extent of human exposure are important considerations in designing toxicity studies for human health risk assessment. An understanding of duration, frequency, intensity, and routes of exposure and an understanding of chemical stability and possible chemical breakdown products are helpful in guiding the selection of the dosing regimen, the test medium, and the test material.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Animal toxicity studies conducted for regulatory submission typically are conducted in rats, mice, rabbits, and dogs with greater focus on rats. Testing guidelines generally require that common laboratory strains be used. At least three dose groups and a control group usually are required. For most toxicity tests, the U.S. Environmental Protection Agency (EPA) requires that the highest dose elicit signs of toxicity without compromising survival. EPA strongly recommends that the lowest dose not produce any evidence of toxicity. The numbers of animals required are defined in each study protocol and range from five rats per sex per dose in 28-day toxicity studies to 10 rats per sex per dose in subchronic studies to 50 rats per sex per dose in carcinogenicity assays. For developmental and reproductive studies, the litter is considered the experimental unit, and at least 20 litters per dose are required. The statistical power of a study is determined by the number of animals used and the sensitivity of the end point being evaluated. This chapter provides an overview of consensus-study protocols developed or codified by several organizations, including EPA and the Organisation for Economic Co-operation and Development (OECD). EPA specifies the types and extent of toxicity data that it requires to make regulatory decisions regarding the risks and benefits associated with pesticide products in accordance with the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA). The specific data requirements are listed in the Code of Federal Regulations (CFR), Title 40, Subpart E, Part 158 (40CFR158). EPA also requires testing of industrial chemicals under the Toxic Substances Control Act (TSCA). EPA has harmonized the testing protocols that may be used in support of FIFRA registrations and TSCA test rules and has harmonized the guidelines with those of OECD. Appendix B of this report provides a list of EPA’s harmonized health-effects test guidelines. OECD also develops test guidelines and guidance documents to help to characterize potential hazards associated with new and existing chemicals. The OECD document, Guidelines for the Testing of Chemicals (OECD Guidelines), is a collection of the most relevant internationally agreed-on testing methods used by government, industry, and independent laboratories (OECD 2004a). OECD publishes the guidelines to relieve some of the burden of chemical testing and assessment in multiple countries. Appendix B provides a list of OECD’s health-effects test guidelines.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report In addition to its guidelines, OECD publishes a monograph series called guidance documents and detailed review documents that provide information on available testing methods and on how to use OECD guidelines in a testing strategy for classification of specific end points.1 They also discuss when such testing is useful or necessary, end points of concern, approaches for statistical analysis, and limitations of tests. The detailed review documents are prepared when it is necessary to assess the state of the art; they reflect a description of scientific progress, an inventory of gaps in the current set of testing guidelines, recommendations of guidelines that need updating, and proposals for developing or updating guidelines. The specific testing requirements developed by EPA and OECD are assumed to have a sound scientific foundation and are generally accepted by interested stakeholders. As indicated, this chapter discusses the consensus protocols focusing primarily on EPA guidelines. It has been organized to present the more general toxicity tests first and then the tests designed to evaluate specific toxicity end points. Thus, the toxicity tests characterized by exposure duration—acute, subchronic, and chronic—are reviewed first; these tests are designed to gain an understanding of systemic effects, given various lengths of exposure, and can be used to guide human health risk assessment for those exposure durations. Toxicity tests designed to evaluate specific end points are discussed next and include tests for reproductive and developmental toxicity, neurotoxicity, immunotoxicity, and genotoxicity. It is important to note that some specialized end points are evaluated by various clinical measures or histopathology conducted in the exposure-duration tests. Results of general toxicity tests often indicate a need to conduct more specialized tests. The chapter concludes with a discussion of metabolism and pharmacokinetic studies. The intent of this chapter is to provide an overview of the rationale for conducting specific toxicity tests, the basic aspects of the study protocols, and the possible shortcomings of currently accepted tests. The descriptions are meant not to be exhaustive but simply to provide a context for evaluating toxicity-testing strategies. Detailed descriptions of study protocols can be found in the cited references. 1   See http://www.oecd.org/document/30/0,2340,en_2649_34377_1916638_1_1_1_1,00.html for a listing of the OECD monographs.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report TOXICITY TESTING CHARACTERIZED BY EXPOSURE DURATION Acute Toxicity Testing Acute toxicity tests evaluate the adverse effects of short-term exposure and are considered by EPA to be an “integral step in the assessment of [a chemical’s] toxic potential under the regulatory framework of its pesticide and toxic substances programs” (EPA 1998a). To be considered an acute exposure, dosing may be done once or may be done several times within or continuously throughout a 24-hour period, but use of a single dose is by far the most common method. The test animals, typically rodents (rats or mice) are observed for a period of several days to 2 weeks after dosing, and observations of deviant behavior, growth, or mortality are recorded. Historically, the primary focus of an acute toxicity test was to determine a chemical’s median lethal dose (LD50), the dose that causes death in 50% of the test animals. Today, acute toxicity tests are used also to determine dosing regimens for longer-term toxicity tests and to evaluate more fully the effects of acute exposure. Acute testing protocols have evolved over the years to conserve animal use, to minimize the pain and discomfort of the test animals, and to obtain more information on the pathogenesis of toxicity. If a chemical is judged to have low toxicity, a limit test is first conducted. The limit test is a sequential test that uses a maximum of five animals with a starting test dose of 5,000 mg/kg (EPA 1998b). If three or more animals survive, the LD50 is considered to be greater than 5,000 mg/kg, and no further testing is conducted. If the substance proves to be more toxic than expected (that is, three or more animals die), the primary test recommended by EPA to assess acute oral toxicity is the up-down procedure (UDP) (EPA 1998b). The UDP uses one animal per exposure, and the animals are dosed sequentially at 48-hour intervals. The first animal is dosed a step below the best estimate of the LD50. If the animal survives, the second animal receives a dose that is higher by a factor of 3.2; if the first animal dies or appears moribund, the second animal receives a dose that is lower by a factor of 3.2. This process continues until death is observed or an upper bound is reached (usually 2,000 or 5,000 mg/kg). EPA has developed a software program that incorporates the data obtained from the UDP to calculate the LD50 and the confidence interval.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Although the preceding discussion focused on oral exposure, the route most relevant to potential human exposure (oral, inhalation, or ermal) is typically evaluated. Acute testing protocols are available for inhalation and dermal exposure (EPA 1998c,d). EPA has developed toxicity categories on the basis of LD50 or median lethal concentration (LC50) values (see Table 2-1). OECD (2001a) has a similar ranking system. EPA uses the categories to determine precautionary labeling requirements, personal protective equipment requirements, and restrictions on entry into pesticide-treated areas. Acute toxicity data have benefits beyond toxicity ranking. Acute studies reveal whether frank toxicity is sudden, delayed, time-limited, or continuous. The time to onset and resolution of toxicity can provide insight into the time course of absorption, distribution, and clearance of a toxicant. Acute toxicity data can provide some idea of relative bioavailability by comparing data on various routes of exposure and can provide information on clinical signs potentially relevant for physicians who are treating patients and for scientists who are developing hypotheses about pathogenesis and target organs affected by acute exposures. That is especially important because toxic effects of acute exposure are often different from those of prolonged lower-level exposure. As discussed in greater detail in Chapter 6, acute toxicity tests can be redesigned to provide additional information on more subtle effects than lethality and gross clinical signs. One particular end point that has received increasing attention is cardiovascular toxicity, specifically adverse effects on ion channels in the myocardium that lead to abnormalities in the electrocardiogram, namely prolongation of the QT interval. Changes in the QT interval have been linked with cardiac arrhythmia that can progress to more serious cardiac events, including failure. However, the link has not yet been proven, and many believe that more research is needed on an alternative indicator of cardiac arrhythmia. The pharmaceutical industry TABLE 2-1 EPA Acute-Toxicity Categories Study Category I Category II Category III Category IV Oral LD50 ≤50 mg/kg >50-500 mg/kg >500-5,000 mg/kg >5,000 mg/kg Dermal LD50 ≤200 mg/kg >200-2,000 mg/kg >2,000-5,000 mg/kg >5,000 mg/kg Inhalation (4-h) LC50 ≤0.05 mg/L >0.05-0.5 mg/L >0.5-2 mg/L >2 mg/L   Source: EPA 1998a.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report does evaluate effects on cardiovascular function of potential drug candidates as part of its regulatory process; EPA does not have formal guidelines for evaluating cardiovascular toxicity. Acute toxicity studies are based on the assumption that acute toxicity and lethality in animal models are relevant to humans. For many chemicals, the experience in humans is inadequate to confirm that assumption, but enough examples support it to continue this mode of hazard assessment. However, dose extrapolations from animals to humans are not simple: smaller rodents generally have a far greater rate of metabolism than do humans and therefore clear a chemical more rapidly, reducing total exposure relative to dose. Extrapolations therefore use plasma or tissue concentrations, an adjustment or uncertainty factor, or, as a surrogate for metabolic rate, doses calculated on the basis of body surface area or a quantity equal to body weight raised to the ¾ power. Moreover, metabolic and biologic differences sometimes lead to responses in animals or humans that are absent in the other species, termed species specificity. Knowledge of species differences in toxic responses is critical for extrapolating from animal data to human risk. The scientific consensus remains that assessment of acute toxicity can help scientists to evaluate and manage the risks associated with potential exposure to noxious agents. Acute toxicity tests provide at least one relatively quick and inexpensive tool in testing schemes that screen large numbers of chemicals and identify chemicals that warrant further toxicity testing. Subchronic or Repeated-Dose Toxicity Testing Subchronic studies evaluate the adverse effects of continuous or repeated exposure over a portion of the average life span of experimental animals. They provide information on target-organ toxicity and bioaccumulation potential and are designed to determine no-observed-adverse-effect levels (NOAELs), which are used to establish standards or guidelines for human exposure. Subchronic studies are not designed to assess effects that have a long latency period, such as cancer, but do provide information that can be used in setting doses for chronic toxicity and carcinogenicity studies. The exposure durations for subchronic studies are typically 28 or 90 days (see Appendix B for a list of EPA and OECD guidelines). Administration of the chemical (oral, inhalation, or dermal) is usually deter-

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Toxicity Testing for Assessment of Environmental Agents: Interim Report mined by the route of potential or actual human exposure. Depending on exposure duration, animals are often observed for 2 or 4 weeks after the end of treatment for reversibility, persistence, or delayed occurrence of adverse effects. In 90-day studies, 20 rodents (10 of each sex) or eight nonrodents (four of each sex) are used for each dose group and the control group. Additional animals are included in the control and high-dose groups if satellite groups are used to evaluate effects after termination of treatment. In some cases, the shorter-term studies are conducted with fewer animals, such as five rats per sex per dose, and may evaluate fewer measures than the 90-day studies. Typically, doses in subchronic studies are selected to define a dose-response relationship. The lowest dose should produce no adverse effects, the highest dose should induce toxic effects without compromising survival or inducing severe suffering, and the intermediate dose should produce a gradation of effects. A control group is also included. When a dose of 1,000 mg/kg per day in oral or dermal studies or 1 mg/L in inhalation studies is not toxic, further dosing above these quantities is not required. Oral dosing occurs daily if test material is incorporated in food or water or 5 days/week if the test material is administered by gavage (the method typically used for rodents) or capsule (typically used for dogs). In inhalation studies, exposure is usually conducted for a period of 6 hours/day for 5 or 7 days/week. Test guidelines require measurement and evaluation of a number of parameters, including clinical signs (such as changes in skin, fur, eyes, secretions, gait, posture, and response to handling), motor activity, grip strength, sensory reactivity to stimuli, body weight, food consumption, clinical pathology (clinical chemistry and hematology), and ophthalmology. At study termination, a gross necropsy is conducted on all animals, and selected organs are weighed. A full histopathologic analysis is conducted on all animals in the control and high-dose groups, on all animals that were killed or died during the study, and on all gross lesions. Target organs are examined in all animals. Statistical methods are used to evaluate the data. Subchronic studies can provide initial or definitive data for risk-assessment purposes. However, the studies are sometimes limited by the smaller sample size, which reduces the sensitivity of the study to detect adverse effects. They often provide the basis of dose selections for longer-term studies, including chronic toxicity and carcinogenicity studies.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Chronic Toxicity and Carcinogenicity The purpose of chronic toxicity testing is to determine the cumulative adverse effects of repeated daily oral, dermal, or inhalation exposures of test animals to various doses of a chemical for at least 12 months (EPA 1998e). The purpose of carcinogenicity testing is to determine the cumulative neoplastic effects of repeated daily oral, dermal, or inhalation exposures to various doses of test chemicals over most of the life span of the test species (EPA 1998f). EPA provides separate guidelines for chronic toxicity and carcinogenicity, but testing is most often combined for these two end points (EPA 1998g). EPA guidelines (EPA 1998e) for chronic toxicity specify that “testing should be performed with two mammalian species, one a rodent and the other a nonrodent. The rat is the preferred rodent species and the dog is the preferred nonrodent species.” Other species can be used with adequate justification. Dose selection is generally based on results of a 90-day study; the highest dose should be the one that causes only mild signs of toxicity and does not alter the length of the study. The intermediate dose is chosen to produce a gradation of toxic effects, and the lowest dose should produce no evidence of adverse effect and thus should allow determination of a NOAEL. At least three dose groups and a control group should be included with 40 rats (20 of each sex) or eight dogs (four of each sex) in each group. EPA guidelines state that body weights and food consumption should be measured and that clinical pathology (hematology, clinical chemistry, and urinalysis) should be conducted at specified intervals during the study. At the end of the study, all animals should be subjected to gross necropsy, weights of major organs should be determined, and all gross lesions and tissues and organs of the digestive system, nervous system, glandular system, respiratory system, cardiovascular and hematopoietic system, and urogenital system should be preserved for histopathologic examination. Ophthalmologic examinations are also recommended. A full histopathologic analysis should be conducted on all controls and animals in the high-dose group and on gross lesions. If exposure-related changes are detected, the analysis is extended to all treatment groups (EPA 1998e). Carcinogenicity bioassays are conducted with rodents, typically rats and mice, for a minimum of 24 months (rats) and 18 months (mice) and are designed to provide data for cancer-hazard identification and dose-response evaluation. Dose-selection guidelines are similar to those for

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Toxicity Testing for Assessment of Environmental Agents: Interim Report the chronic toxicity studies; however, group sizes are larger (50 rodents of each sex per group), and clinical pathology involves examination of blood smears. At the end of the study, gross necropsy and histopathology are extensive because the primary focus is on detecting neoplasms. The National Toxicology Program (NTP) has conducted over 600 lifetime cancer bioassays and has been at the forefront of developing definitive guidelines for detecting carcinogenic activity in rodents; the carcinogenicity data obtained reside in a public database. EPA guidelines for combined chronic toxicity and carcinogenicity testing (EPA 1998g) combine testing for chronic toxicity and carcinogenicity summarized above. In a combined test, the two species typically used are rats and mice—rats mainly for dosing by oral and inhalation routes and mice for the dermal route. Three dose groups and a control group are used, and at least 100 animals (50 of each sex) are used for each group. Additional animals—at least 20 (10 of each sex)—are included at each dose and in the control group as satellite groups for determination of chronic toxicity after 12 months; end points similar to those described for the chronic toxicity test are used. The minimal duration of daily exposure is 2 years for rats and 18 months for mice, and end points similar to those described for the carcinogenicity test are examined at the end of the study. Considerable effort is being devoted to developing alternative transgenic and knockout animal models for carcinogenicity testing in Europe and the United States. The goal is to develop models that will increase the sensitivity of detection of carcinogenic lesions and shorten the time for their appearance; the latter would have the effect of conserving the resources required to test each agent and increase the number of agents that can be tested. Some of the efforts are being coordinated through the International Conference on Harmonization (ICH) Expert Working Group on Safety. That group, in collaboration with the Health and Environmental Sciences Institute (HESI) of the International Life Sciences Institute (ILSI), conducted an evaluation of six animal models for their ability to detect the effects of a group of 21 chemicals, which included genotoxins and carcinogens. The results of those efforts were discussed at a workshop (Cohen et al. 2001) and presented in a special issue of Toxicologic Pathology (Vol. 29, supplement issue, 2001), which also presented detailed information on the models. The conclusion drawn from the evaluations was that some of the models might have use in hazard identification, providing information similar to that obtained from the 2-year combined chronic toxicity and carcinogenicity bioassay,

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Toxicity Testing for Assessment of Environmental Agents: Interim Report in conjunction with data from other sources in a weight-of-evidence approach to risk assessment. Determination of the usefulness of the models is still limited by the amount of comparative data available. Considerable effort is being devoted to broadening the comparison of tumor data from transgenic mouse strains and strains of mice traditionally used in lifetime bioassays. TOXICITY TESTING CHARACTERIZED BY SPECIFIC END POINT Toxicity testing of most chemicals begins with acute testing, progresses to subchronic testing, and, depending on the results, concludes with chronic testing. Evaluation in those studies may indicate the need to obtain more information on specific toxicity end points. The following sections discuss the tests used to evaluate reproductive and developmental toxicity, neurotoxicity, immunotoxicity, and genotoxicity. In vitro tests for cytotoxicity and other end points are also briefly discussed. Reproductive and Developmental Toxicity Reproductive and developmental toxicity testing includes a broader category of end points than other kinds of toxicity testing because of the multiple stages of exposure and the variability of possible effects. Exposures of sexually mature animals can result in sterility or decreased fertility by depleting or affecting ova or sperm or by affecting endocrine functions of organs involved in reproduction. If fertilization occurs, abnormalities of ova and sperm can result in embryonic death, failure of implantation, congenital malformations, embryonic growth retardation, genetic disease, or cancer in the offspring. Exposures during pregnancy can result in embryonic or fetal death, congenital malformations, reversible or irreversible growth retardation, or premature or delayed parturition; they may also have delayed postnatal effects, such as cancer, neurobehavioral effects, growth retardation, and death. Toxicant exposures of neonatal, immature, or adolescent organisms may result in growth retardation or stimulation, endocrine abnormalities, immunologic deficits, neurobehavioral effects, cancer, or death. The general purpose of reproductive and developmental toxicity assays is to evaluate the competence of breeding pairs to produce pheno-

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Toxicity Testing for Assessment of Environmental Agents: Interim Report typically normal offspring. All or most of the reproductive cycle is evaluated. Four types of reproductive and developmental studies are discussed here—screening-level reproductive-toxicity assays, prenatal developmental-toxicity and teratology studies, generational tests, and reproductive assessment with continuous breeding. These assays are conducted because of their assumed relevance for predicting human hazard potential, but the data from such models may or may not be relevant for predicting human risk. Thus, the predictive power of the tests may be limited by differences in the underlying biology. A famous example of how species differences can be important is developmental exposure to thalidomide, to which rats are highly resistant and humans are exquisitely sensitive. The assays described are apical tests—complex experiments that measure complicated end points, each of which is an integrated measure of multiple facets of the machinery necessary for successful reproduction and development. Apical tests provide little insight into the hundreds of molecular events, mechanisms, and targets responsible for toxicant action. Although they are useful for determining whether there is an overall effect, the lack of mechanistic insight is an important limitation. Future advances in testing will probably rely on our ability to discern the individual biologic underpinnings of toxicity, a complicated task in this setting. Screening-Level Reproductive-Toxicity Assays In these assays, animals are dosed with the test chemical for at least 2 weeks before mating and then for a maximum of 2 weeks of breeding. The females are dosed through gestation, and the test is terminated on postnatal day 4. The measurements made provide insight into gonadal function, fertility, pregnancy, parturition, and prenatal and postnatal developmental toxicity. OECD testing guidelines (TG) 421 and 422 (OECD 1995a, 1996) are reproductive and developmental screening tests; however, TG 422 (OECD 1996) is a combined repeated-dose toxicity study in combination with the reproductive and developmental screening test. These are screening-level assays used to make decisions about the need for further testing as part of the OECD screening information dataset (SIDS) program.

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Bruner, L.H., G.J. Carr, M. Chamberlain, and R.D. Curren. 1996. Validation of alternative methods for toxicity testing. Toxicol. In Vitro 10(4):479-501. Brusick, D. 2001. Genetic toxicology. Pp. 819-852 in Principals and Methods of Toxicology, 4th Ed, A.W. Hayes, ed. Philadelphia, PA: Taylor and Francis. Clewell, III, H.J. 1995a. Incorporating biological information in quantitative risk assessment: An example with methylene chloride. Toxicology 102 (1-2):83-94. Clewell, III, H.J. 1995b. The application of physiologically based pharmacokinetic modeling in human health risk assessment of hazardous substances. Toxicol. Lett. 79(1-3):207-217. Clive, D., K.O. Johnson, J.F. Spector, A.G. Batson, and M.M. Brown. 1979. Validation and characterization of the L5178Y/TK+/- mouse lymphoma mutagen assay system. Mutat. Res. 59(1):61-108. Cohen, S.M., D. Robinson, and J. MacDonald. 2001. Alternative models for carcinogenicity testing. Toxicol. Sci. 64(1):14-19. Cory-Slechta, D.A., K.M. Crofton, J.A. Foran, J.F. Ross, L.P. Sheets, B. Weiss, and B. Mileson. 2001. Methods to identify and characterize developmental neurotoxicity for human health risk assessment. I: Behavioral effects. Environ. Health Perspect. 109(Suppl.1):79-91. Crespi, C.L., F.J. Gonzalez, D.T. Steimel, T.R. Turner, H.V. Gelboin, B.W. Penman, and R. Langenbach. 1991. A metabolically competent human cell line expressing five cDNAs encoding procarcinogen-activating enzymes: Application to mutagen testing. Chem. Res. Toxicol. 4(5):566-572. Dean, B.J., and N. Danford. 1984. Assays for the detection of chemically-induced chromosome damage in cultured mammalian cells. Pp. 187-232 in Mutagenicity Testing: A Practical Approach, S. Venitt, and J.M. Parry, eds. Oxford: IRL Press. de Kanter, R., M. Monshouwer, D.K. Meijer, and G.M. Groothuis. 2002. Precision-cut organ slices as a tool to study toxicity and metabolism of xenobiotics with special reference to non-hepatic tissues. Curr. Drug Metab. 3(1):39-59. Dorman, D.C., S.L. Allen, J.Z. Byczkowski, L. Claudio, J.E. Fisher, Jr., J.W. Fisher, G.J. Harry, A.A. Li, S.L. Makris, S. Padilla, L.G. Sultatos, and B.E. Mileson. 2001. Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: Pharmacokinetic and pharmacodynamic considerations. Environ. Health Perspect. 109 (Suppl.1):101-111. DTP (Developmental Therapeutics Program). 2005. DTP Human Tumor Cell Line Screen. Screening, Developmental Therapeutics Program, National Cancer Institute [online]. Available: http://www.dtp.nci.nih.gov/branches/btb/ivclsp.html [accessed March 18, 2005].

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Toxicity Testing for Assessment of Environmental Agents: Interim Report ECVAM (European Centre for the Validation Alternative Methods). 2005. Scientifically Validated Methods [online]. Available: http://ecvam.jrc.cec.eu.int/index.htm [accessed March 16, 2005]. EPA (U.S. Environmental Protection Agency). 1996. Microbial Pesticide Test Guidelines OPPTS 885.3000. Background-Mammalian Toxicity/Pathogenicity/Infectivity. EPA 712-C-96-314. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/885_Microbial_Pesticide_Test_Guidelines/Series/885-3000.pdf [accessed March 14, 2005]. EPA (U.S. Environmental Protection Agency). 1998a. Health Effects Test Guidelines OPPTS 870.1000. Acute Toxicity Testing-Background. EPA 712-C-98-189. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-1000.pdf [accessed October 7, 2005]. EPA (U.S. Environmental Protection Agency). 1998b. Health Effects Test Guidelines OPPTS 870.1100. Acute Oral Toxicity. EPA 712-C-98-190. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-1100.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998c. Health Effects Test Guidelines OPPTS 870.1300. Acute Inhalation Toxicity. EPA-712-C-98-193. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-1300.pdf [accessed October 7, 2005]. EPA (U.S. Environmental Protection Agency). 1998d. Health Effects Test Guidelines OPPTS 870.1200. Acute Dermal Toxicity. EPA 712-C-98-192. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-200.pdf [accessed October 7, 2005]. EPA (U.S. Environmental Protection Agency). 1998e. Health Effects Test Guidelines OPPTS 870.4100. Chronic Toxicity. EPA 712-C-98-210. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-4100.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998f. Health Effects Test Guidelines OPPTS 870.4200. Carcinogenicity. EPA 712-C-98-211. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-4200.pdf [accessed March 15, 2005].

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Toxicity Testing for Assessment of Environmental Agents: Interim Report EPA (U.S. Environmental Protection Agency). 1998g. Health Effects Test Guidelines OPPTS 870.4300. Combined Chronic Toxicity/Carcinogenicity. EPA 712-C-98-212. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-4300.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998h. Health Effects Test Guidelines OPPTS 870.3800. Reproduction and Fertility Effects. EPA 712-C-98-208. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-3800.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998i. Guidelines for Neurotoxicity Assessment. EPA/630/R-95/001F. National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/ncea/raf/pdfs/neurotox.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998j. Health Effects Test Guidelines OPPTS 870.3700. Prenatal Developmental Toxicity Study. EPA 712-C-98-207. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-3700.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998k. Health Effects Test Guidelines OPPTS 870.6200. Neurotoxicity Screening Battery. EPA 712-C-98-238. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-6200.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998l. Health Effects Test Guidelines OPPTS 870.6300. Developmental Neurotoxicity Study. EPA 712-C-98-239. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-6300.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998m. Health Effects Test Guidelines OPPTS 870.6100. Acute and 28-Day Delayed Neurotoxicity of Organophosphorus Substances. EPA 712-C-98-237. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-6100.pdf [accessed March 15, 2005].

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Toxicity Testing for Assessment of Environmental Agents: Interim Report EPA (U.S. Environmental Protection Agency). 1998n. Health Effects Test Guidelines OPPTS 870.6500. Schedule-Controlled Operant Behavior. EPA 712-C-98-240. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-6500.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998o. Health Effects Test Guidelines OPPTS 870.6850. Peripheral Nerve Function. EPA 712-C-98-241. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-6850.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998p. Health Effects Test Guidelines OPPTS 870.6855. Neurophysiology: Sensory Evoked Potentials. EPA 712-C-98-242. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-6855.pdf [accessed March 15, 2005]. EPA (U.S. Environmental Protection Agency). 1998q. Health Effects Test Guidelines OPPTS 870.7800. Immunotoxicity. EPA 712-C-98-351. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-7800.pdf [accessed March 9, 2005]. EPA (U.S. Environmental Protection Agency). 1998r. Health Effects Test Guidelines OPPTS 870.5100. Bacterial Reverse Mutation Test. EPA 712-C-98-247. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-5100.pdf [accessed February 18, 2005]. EPA (U.S. Environmental Protection Agency). 1998s. Health Effects Test Guidelines OPPTS 870.5300. In Vitro Mammalian Cell Gene Mutation Test. EPA 712-C-98-221. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-5300.pdf [accessed February 18, 2005]. EPA (U.S. Environmental Protection Agency). 1998t. Health Effects Test Guidelines OPPTS 870.5380. Mammalian Spermatogonial Chromosome

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Toxicity Testing for Assessment of Environmental Agents: Interim Report Aberration Test. EPA 712-C-98-224. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-5380.pdf [accessed March 14, 2005]. EPA (U.S. Environmental Protection Agency). 1998u. Health Effects Test Guidelines OPPTS 870.5385. Mammalian Bone Marrow Chromosome Aberration Test. EPA 712-C-98-225. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-5385.pdf [accessed February 18, 2005]. EPA (U.S. Environmental Protection Agency). 1998v. Health Effects Test Guidelines OPPTS 870.5450. Rodent Dominant Lethal Assay. EPA 712-C-98-227. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-5450.pdf [accessed February 18, 2005]. EPA (U.S. Environmental Protection Agency). 1998w. Health Effects Test Guidelines OPPTS 870.5460. Rodent Heritable Translocation Assays. EPA 712-C-98-228. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-5460.pdf [accessed February 18, 2005]. EPA (U.S. Environmental Protection Agency). 1998x. Health Effects Test Guidelines OPPTS 870.5500. Bacterial DNA Damage or Repair Tests. EPA 712-C-98-229. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-5500.pdf [accessed February 18, 2005]. EPA (U.S. Environmental Protection Agency). 1998y. Health Effects Test Guidelines OPPTS 870.7485. Metabolism and Pharmacokinetics. EPA 712–C–98–244. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://www.epa.gov/opptsfrs/OPPTS_Harmonized/870_Health_Effects_Test_Guidelines/Series/870-7485.pdf [accessed June 15, 2005]. EPA (Environmental Protection Agency). 1999. Toxicology Data Requirements for Assessing Risks of Pesticide Exposure to Children’s Health. Draft Report of the Toxicology Working Group of the 10x Task Force, U.S. Environmental Protection Agency. April 28, 1999 [online]. Available: http://www.epa.gov/scipoly/sap/1999/may/10xtx428.pdf [accessed October 24, 2005].

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Toxicity Testing for Assessment of Environmental Agents: Interim Report EPA (U.S. Environmental Protection Agency). 2003. Health Effects Test Guidelines OPPTS 870.2600. Skin Sensitization. EPA 712-C-03-197. Office of Prevention, Pesticides, and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC [online]. Available: http://iccvam.niehs.nih.gov/docs/EPA/870r_2600.pdf [accessed March 16, 2005]. FDA (U.S. Food and Drug Administration). 2000a. Short-term tests for genetic toxicity. Section IV.C.1 in Redbook 2000, Toxicological Principles for the Safety Assessment of Food Ingredients, Office of Food Additive Safety, U.S. Food and Drug Administration [online]. Available: http://www.cfsan.fda.gov/~redbook/red-ivc1.html [accessed March 14, 2005]. FDA (U.S. Food and Drug Administration). 2000b. Mammalian erythrocyte micronucleus test. Section IV.C.1.d. in Redbook 2000, Toxicological Principles for the Safety Assessment of Food Ingredients, Office of Food Additive Safety, U.S. Food and Drug Administration [online]. Available: http://www.cfsan.fda.gov/~redbook/redivc1d.html [accessed February 18, 2005]. FDA (U.S. Food and Drug Administration). 2002. Guidance for Industry: Immunotoxicology Evaluation of Investigational New Drugs. Center for Drug Evaluation and Research, Food and Drug Administration, U.S. Department of Health and Human Services [online]. Available: http://www.fda.gov/cder/guidance/4945fnl.PDF [accessed March 16, 2005]. Flamm, W.G., W. d’Aguanno, L. Fishbein, S. Green, H.V. Malling, V. Mayer, M. Prival, G. Wolff, and E. Zeiger. 1977. Approaches to determining the mutagenic properties of chemicals: Risk to future generations. J. Environ. Pathol. Toxicol. 1(2):301-352. Garman, R.H., A.S. Fix, B.S. Jortner, K.F. Jensen, J.F. Hardisty, L. Claudio, and S. Ferenc. 2001. Methods to identify and characterize developmental neurotoxicity for human health risk assessment. II: Neuropathology. Environ. Health Perspect. 109(Suppl. 1):93-100. Gebhardt, R., J.G. Hengstler, D. Muller, R. Glockner, P. Buenning, B. Laube, E. Schmelzer, M. Ullrich, D. Utesch, N. Hewitt, M. Ringel, B.R. Hilz, A. Bader, A. Langsch, T. Koose, H.J. Burger, J. Maas, and F. Oesch. 2003. New hepatocyte in vitro systems for drug metabolism: Metabolic capacity and recommendations for application in basic research and drug development, standard operation procedures. Drug Metab. Rev. 35(2-3):145-213. Generoso, W.M., J.B. Bishop, D.G. Gosslee, G.W. Newell, C.J. Sheu, and E. von Halle. 1980. Heritable translocation test in mice. Mutat. Res. 76(2): 191-215. Green, S., A. Auletta, J. Fabricant, R. Kapp, M. Manandhar, C.J. Sheu, J. Springer, and B. Whitfield. 1985. Current status of bioassays in genetic toxicology—the dominant lethal assay. A report of the U.S. Enviromental Protection Agency Gene-Tox Program. Mutat Res. 154(1):49-67.

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