Toxicity Testing for Assessment of Environmental Agents Interim Report (2006) / Chapter Skim
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6 New Approaches
6 New Approaches
Pages 149-193
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From page 149... ...
The core of the problem appears to be tension among four objectives of regulatory testing schemes that are difficult to meet simultaneously: depth, providing the most accurate, relevant information possible for hazard identification and dose-response assessment; breadth, providing data on the broadest possible universe of chemicals, end points, and life stages; animal welfare, causing the least animal suffering possible and using the fewest possible animals; and conservation, minimizing the expenditure of money and time on testing and regulatory review (see Figure 6-1)
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From page 150... ...
This chapter and the next review some selected approaches that may ultimately help to move toxicity testing toward one or more of the objectives. In this chapter, the committee summarizes and comments on some strategies proposed by others for near-term improvements in existing toxicity-testing approaches, including the EPA review of toxicity data available for establishing reference doses (RfDs)
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From page 151... ...
testing scheme for existing industrial chemicals. APPROACHES FOR IMPROVING EXISTING TOXICITY-TESTING STRATEGIES Toxicity-testing guidelines and strategies described in the previous chapters are the results of the gradual evolution of testing requirements and risk-assessment approaches that took place as the field of toxicology advanced.
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From page 152... ...
It then identified data gaps with regard to the assessment of life stages, end points, route and duration of exposure, and latency of response and made recommendations to fill the gaps. Options for alternative testing systems were also presented.
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From page 153... ...
FIGURE 6-2 Guideline study designs used to derive the oral reference dose. Life stages during which exposure occurs (gray)
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From page 154... ...
EPA's recommendations address two main objectives for testing strategies -- evaluating a broader array of end points and life stages and increasing information on mechanism or mode of action to improve the human relevance of risk assessment -- and include the following: • Develop a strategy for alternative approaches to toxicity testing, with guidance on how and when to use existing and newly recommended guidelines. • Develop guidelines or guideline study protocols that will provide more systematic information on pharmacokinetics and pharmacodynamics (that is, mechanism or mode of action)
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From page 155... ...
• Develop guidelines or guideline study protocols to assess immunotoxicity, carcinogenicity, and cardiovascular toxicity at different life stages. • Explore the feasibility of setting dermal reference values for direct toxicity, including sensitization, at the portal of entry.
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From page 156... ...
They encourage the development of innovative toxicity-testing protocols, and following EPA's recommendations for any one chemical would enhance the depth of information on pharmacokinetics, life stages, and end points available for hazard identification and dose-response assessment. However, such an intensive toxicity-testing approach would probably be applied to only a small fraction of chemicals in commerce, would increase the number of animals used to study one chemical, and might even reduce the numbers of chemicals tested.
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From page 157... ...
Presence of Data Gaps The committee agrees with EPA that there are numerous data gaps in life stages and end points covered in current testing approaches and in functional assessments of some organ systems. However, there are insufficient data to determine the degree to which those data gaps have practical significance in risk assessment or whether they are primarily of theoretical or academic concern.
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From page 158... ...
It is also important to look beyond animal toxicity data for help in resolving some of the questions. Epidemiologic studies with reliable exposure assessment can shed some light on the likelihood that current toxicity-testing data are missing important end points or are insufficiently sensitive to be applied to life stages not studied.
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From page 159... ...
Before such complex protocols are conducted, acute LD50 studies, repeated-dose toxicity studies, and human data should be evaluated to determine the need for these studies and ultimately to guide the design of such studies. 2 Pharmacokinetics and Pharmacodynamics The committee agrees with EPA that generally little information is available on pharmacokinetics, including possible differences across life stages.
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From page 160... ...
Dermal Portal of Entry The committee considered EPA's conclusion that there is a need to improve the assessment of portal-of-entry effects, especially on the skin, in the risk-assessment process. EPA emphasized dermal effects because oral and inhalation effects are already recognized as important routes of exposure and require specific test data for risk assessments in, for example, its pesticide testing programs.
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From page 161... ...
Taken in isolation, the alternative toxicity study may not fully address all the important data gaps raised by EPA in its analysis of acute toxicity tests, such as reversibility, latency, and endpoint assessment in detail and at different life stages. The animal group size of five is small for conducting hematology, clinical chemistry, and pathology evaluations, and this limits the capacity to detect effects, particularly subtle ones.
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From page 162... ...
Alternative Chronic Testing Protocols EPA also presented two chronic protocols that address continuous exposure through all life stages as alternatives to current test procedures. The chronic–carcinogenicity study would evaluate the potentially increased sensitivity of both developing and aging animals to chronic and carcinogenic effects of chemicals.
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From page 163... ...
EPA presented the Unified Screening Study to stimulate ideas on how studies could be combined to limit animal use while expanding the toxicity evaluation across multiple generations to study all life stages and transgenerational effects. Further development will require considerable resources and expertise in the fields addressed by the different arms of the study.
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From page 164... ...
are typically used in toxicity studies, including those of developmental toxicity, reproductive toxicity, and developmental neurotoxicity. Inbred Fischer 344 rats are often used in standard chronic–carcinogenicity studies.
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From page 165... ...
They believed that potential disadvantages of the study outweigh its advantages, especially because it appears to preclude the use of toxicity results from one study to trigger or prevent additional evaluation in other studies in that all studies would be conducted simultaneously. Other members of the committee found that the study protocol could function as a component in a toxicity-testing strategy as applied to either selected chemicals with widespread human exposure or chemicals with initial indications of developmental toxicity.
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From page 166... ...
defines systemic toxicity as "the potential adverse effects of agricultural chemicals on ‘young adults.' " The evaluation of effects of chemicals on different life stages -- including reproduction, development, adolescence, and old age -- is presented in a second paper. The third paper focuses on the acquisition and application of pharmacokinetic data in agriculturalchemical safety assessments.
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From page 167... ...
Today, EPA conducts risk assessments to evaluate a variety of agricultural and residential pesticide exposures of different durations and at different life stages. ILSI-HESI identified the following human exposure durations for which risk assessments may be required: 1 day, 2-28 days, 1-6 months, greater than 60 months, and intermittent.
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From page 168... ...
The 1-year rat study would be conducted as part of an expanded 2-year carcinogenicity assay; an interim kill would occur at 1 year. If the dog is found more relevant, the 90-day dog study would be used to evaluate effect of human exposures over 2 days 4 One important inconsistency between the draft papers is that the life-stages paper appears to eliminate carcinogenicity testing, but the systemic-toxicity paper includes the rat carcinogenicity test in the first tier (see Figures 6-4 and 6-5)
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From page 169... ...
Figure 6-4 shows the tiered-testing strategy proposed by ILSI-HESI. The pivotal studies of the testing strategy are the 28-day rat study and the 90-day dog study.
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From page 170... ...
Life Stages ILSI-HESI proposes a tiered-testing approach for "assessing the potential adverse effects of agricultural chemicals on preconception, embryo/fetal and newborn/pre-weaning life stages and on adults of all ages, including the young and aged" (ILSI-HESI 2004b)
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From page 171... ...
EPA now requires a two-generation rat reproduction study and developmental-toxicity studies in two species. The ILSI-HESI draft paper discusses the potential concerns regarding removal of the secondgeneration part of the multigeneration study and the rat developmentaltoxicity study.
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From page 172... ...
The proposed tiered approach also incorporated an evaluation of margin of exposure with hazard and dose-response assessment to determine whether additional testing would be needed. Finally, the ILSI-HESI draft paper concluded that the intraspecies uncertainty factor of 10 was sufficient to address risks to the elderly on the basis of few toxicity data on aged rats and human data.
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From page 173... ...
In developing its proposal, ILSI-HESI identified some potential omissions and redundancies and possible improvements in existing tests. Recommendations include changing required toxicity-testing durations, removing some currently required guideline studies, modifying other studies to increase end-point coverage, triggering specialized studies on the basis of findings in the core set of toxicity tests, and generating chemical-specific pharmacokinetic data to inform study design and data interpretation.
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From page 174... ...
On the other hand, the proposed extended 28-day rat study, with improvements as discussed above, should provide a better means of assessing short-term exposures than the 90-day rat study and the existing acute toxicity studies used to establish LD50s. The 28-day rat study is also being proposed to assess risks posed by human exposures as long as 6 months.
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From page 175... ...
For example, for the 21 cases in which comparisons could be made, there were eight cases (38%) in which the NOAEL from the 1-year dog study was less by more than a factor of 2 than that from the 90-day dog study.
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From page 176... ...
To ensure study relevance, both EPA and ILSI-HESI schemes emphasize an iterative process of data collection and use of data analysis in designing pharmacokinetic studies for specific compounds; no single prescribed series of studies is likely to provide necessary and adequate pharmacokinetic datasets on every compound. The possibility of increases in susceptibility to cancer at particular life stages was acknowledged.
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From page 177... ...
Still, although using exposure to guide selection of studies may work well for chemicals to which exposure can be relatively well defined, it may not work as well for industrial chemicals, because the degree and circumstances of human exposures can be difficult to predict or adequately assess. To conclude, the proposed changes in the scheme for pesticide testing may affect the probability of finding some effects and change the volume of evidence available to an assessor in judging the presence or importance of an effect.
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From page 178... ...
The REACH program has four major components (EU 2004)
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From page 179... ...
The exposure route is generally specified to be the one most relevant for potential human exposure. Toxicity testing to be conducted is based primarily on the quantity of chemical manufactured or imported, with cutoffs at 1, 10, 100, and 1,000 metric tons.
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The European Centre for the Validation of Alternative Methods (ECVAM) is involved in facilitating the implementation of the REACH program, which calls for the use of alternative testing strategies where feasible.
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From page 181... ...
REACH has the advantage of generating at least some toxicity data on chemicals that in the United States are not subject to testing requirements. National Toxicology Program: Roadmap for the Future Since its inception in 1979, the NTP has provided data for identifying the health hazards posed by environmental agents, and the data have been used extensively by regulatory agencies in risk assessment.
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From page 182... ...
Future workshops will address other cancerbioassay design issues. Reviews of noncancer assays -- such as developmental toxicity, immunotoxicity, and neurotoxicity studies -- are expected within the next 3 years.
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From page 183... ...
The NTP Roadmap notes, however, the time-consuming and resourceintensive nature of traditional toxicity testing and the consequently large volume of newly introduced and existing chemicals in commerce that have been inadequately assessed for toxicity. The Roadmap outlines the NTP's long-range research strategy to develop rapid screening systems for providing toxicity information on large numbers of chemicals.
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From page 184... ...
The NTP's near-term efforts to refine and extend its toxicity tests and to improve the generation and use of pharmacokinetic and mechanistic data promise to increase the depth of toxicity information on chemicals assayed and to provide greater insight in applying test findings to humans. Furthermore, the NTP's stated objective of reducing animal use and increasing efficiency may be partly realized.
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From page 185... ...
EPA evaluated its testing requirements for pesticides and toxic substances in the context of establishing RfDs and RfCs, found substantial data gaps in life stages studied and end points assessed, and made recommendations for improvements in the near term by using existing toxicity-testing methods and techniques. ILSI-HESI convened a panel of scientists to evaluate EPA's approaches to toxicity testing for pesticides and developed its own set of recommendations.
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From page 186... ...
. The REACH approach includes greater depth of information and coverage of end points and life stages than the current EPA approach to testing of existing or new industrial chemicals under the Toxic Substances Control Act.
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From page 187... ...
That is in part understandable in that some of the NTP effort involves technology transfer and the development and validation of new approaches; the changes are not yet sufficiently well defined to be incorporated into mandated test requirements, such as the EPA pesticide test guidelines. However, specific study designs and protocols should be given consideration for such purposes as they emerge from the NTP program.
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From page 188... ...
This concept is embedded in several existing and proposed strategies. In some strategies, production volume is the primary measure of potential human exposure.
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From page 189... ...
As a result, such extrapolations are often made with little scientific justification, and conventional uncertainty factors are used to bridge the gaps. Current approaches to toxicity testing could be enhanced in some cases by the use of pharmacokinetic data from basic ADME studies to derive dose information before embarking on toxicity testing and by the judicious use of some pharmacokinetic data to aid in extrapolation.
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From page 190... ...
The committee recommends toxicity screening of every agent to which there is a strong potential for human exposure. A well-designed tiered strategy could help to set priorities among environmental agents for screening and could identify end points or mechanisms of action that would trigger more in-depth testing for various end points or in various life stages.
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From page 191... ...
2006. A tiered approach to life stages testing for agricultural chemical safety assessment.
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From page 192... ...
1998f. Health Effects Test Guidelines OPPTS 870.3100.
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From page 193... ...
Life Stages Task Force, Technical Committee on Agricultural Chemical Safety Assess ment, ILSI Health Sciences Institute, Washington, DC. November 2, 2004.
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