Toxicity Testing for Assessment of Environmental Agents Interim Report (2006) / Chapter Skim
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Toxicity testing in laboratory animals provides many of the data needed for risk assessment, such as information on the possible effects of exposure to a substance and the exposure concentrations at which effects might be observed. New directives and initiatives for toxicity testing in the United States and Europe reflect an increased demand for toxicity information to provide a rational basis for regulating environmental agents.
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Therefore, the committee focused on major themes rather than details, and it reviewed the documents primarily to compare various overall testing strategies and to evaluate the potential for the strategies to improve testing of environmental agents. The committee primarily examined toxicity-testing strategies rather than protocols for individual assays.
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Some toxicity tests are designed to evaluate general toxicity resulting from exposures of various durations -- acute, subchronic, and chronic -- and others are designed to evaluate specific health effects, including reproductive and developmental toxicity, neurotoxicity, immunotoxicity, genetic toxicity, and carcinogenicity. Toxicity tests may also be distinguished by their objectives -- to evaluate final outcomes of a specified exposure duration; to characterize the possible modes of action of such outcomes, which can depend on exposure route, concentration, and duration; to characterize dose-response relationships; or to identify a potential hazard, such as carcinogenicity from the results of a genotoxicity assay.
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Human Data Human data usually are not a part of toxicity-testing strategies despite the importance of human responses to potentially toxic agents. Although animal toxicity studies provide relevant information on potential adverse health effects of exposure to an agent, interspecies differences can cause effects relevant to the human population to be missed.
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However, emerging technologies and approaches, such as biomonitoring and molecular and genetic epidemiology, may overcome some of the limitations and will be discussed in greater detail in the committee's second report. Use of Data in Human Health Risk Assessment Data from animal toxicity testing, human studies, and in vitro methods are used in human health risk assessment to identify potential hazards, to characterize effects at different exposure levels, to determine the probability of adverse effects of given human exposure scenarios, and ultimately to establish environmental standards and exposure guidance levels.
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Optimizing further testing to improve the initial characterization of a particular chemical or class of chemicals can be highly context-dependent; however, a general framework and further guidance on developing a testing strategy to improve specific risk assessments would be useful. Proposals to Improve Toxicity-Testing Strategies The committee's review of current toxicity-testing strategies reveals a system that is reaching a turning point.
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EPA Review In its 2002 report A Review of the Reference Dose and Reference Concentration Processes, EPA reviewed its procedures for deriving reference values and specifically the adequacy of the toxicity tests to accomplish that purpose. The committee focused its review on Chapter 3 of the EPA report because that chapter directly addressed toxicity-testing approaches.
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Modest changes in existing protocols could enhance the array of health effects and life stages evaluated, and the resulting findings could trigger more in-depth testing of specific outcomes and life stages where it is warranted. The committee notes that epidemiologic studies with reliable exposure assessments could shed some light on the likelihood that current toxicity tests are missing important health effects or are not adequate for evaluating different life stages.
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Recommendations included changing exposure durations of required toxicity tests, eliminating some required guideline studies, modifying some studies to enhance evaluation of specific health effects, and generating chemical-specific pharmacokinetic data to inform study design and data interpretation. The committee supports the general approach used by ILSI-HESI to tailor testing to meet risk-assessment needs.
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For example, ILSI-HESI proposed removing the rat teratology study and using an extended one-generation study and a rabbit teratology study to evaluate developmental effects. Although the proposed one-generation study substantially improves postnatal evaluation of many nonreproductive outcomes, it is unclear whether it would be as sensitive as a rat teratology study for prenatal developmental-toxicity outcomes or would adequately reveal the potential hazard and trigger a followup study.
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The REACH program has the advantage of generating at least some toxicity data on chemicals that are not now subject to testing in the United States. NTP Roadmap for the Future In its 2004 report The NTP Vision for the 21st Century, the NTP discussed its goals: to refine traditional toxicity assays; to develop rapid, mechanism-based predictive screens for environmentally induced diseases; and to improve the overall use of NTP toxicity-testing assays for public-health decisions.
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• The importance of distinguishing between testing protocols and testing strategies as one considers modifications of current testing practices. • The need to be cautious in adding testing requirements for the sake of theoretical thoroughness.
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Current approaches to toxicity testing include testing batteries, tiered testing, tailored testing, and a combination of the three. The committee finds that there are pros and cons of various approaches but leans toward tiered testing with the goal of focusing resources on the evaluation of the more sensitive adverse effects of exposures of greatest concern rather than full characterization of all adverse effects irrespective of relevance for risk-assessment needs.
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Testing strategies may be evaluated in terms of the value of information they provide in light of the four objectives -- increasing depth of knowledge for more accurate risk assessment; increasing coverage of chemicals, life stages, and end points; preserving animal welfare; and minimizing cost. In evaluating new tests and testing strategies, there remains the difficult question of what is to serve as a "gold standard" for performance.
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