Impact/Purpose:

The objective of this research is to provide EPA with predictive tools for prioritization and enhanced interpretation of exposure, hazard identification and dose-response information. The results of this project will provide the Agency with data reviews and guidance documents for data evaluation, for use both within and outside the Agency. The long-term output of this project will demonstrate the capability of in vitro and non-mammalian methods to predict developmental neurotoxicity. The overall goal is to use these methods in a high-throughput screen for developmental neurotoxicity testing. The development of a high-throughput in vitro screening battery will address the OPPTS need for a method that can be applied to a tiered approach for hazard identification and risk assessment of thousands of chemicals with little or no available toxicity data. The in vitro screening battery, along with rapid in vivo testing in a non-mammalian species, will be used as a first tier test for ranking the potential of chemicals to produce developmental neurotoxicity and prioritizing them for further testing. The database that results from data generated by testing the set of known developmental neurotoxicants using high-throughput methods will provide OPPTS with information on the utility and limits of the screening battery, and provide guidance for the interpretation and potential use of data from these alternative methods in a risk assessment context.

Description:

SUMMARY: Mechanistic data should provide the Agency with a more accurate basis to estimate risk than do the Agency’s default assumptions (10x uncertainty factors, etc.), thereby improving risk assessment decisions. NTD is providing mechanistic data for toxicant effects on two major pathways by which environmental contaminants injure the adult and developing nervous system: (1) oxidative stress and (2) disruption of signal transduction. By coordinating in vitro and in vivo approaches, NTD has linked toxicant-induced alterations in these pathways that are detectable at the cellular level to adverse health outcomes associated with several major classes of neurotoxicants, such as PCBs, polybrominated diphenyl ethers (PBDEs), particulate matter, and pesticides. In addition, mechanistic information on these toxicity pathways is being used to identify and develop cell-based assays to categorize and prioritize contaminants with regard to their potential adverse impact on human health. APPROACH: This research program focuses on key issues related to improving the interpretation, reliability and use of the Developmental Neurotoxicity Testing Guideline: 1) criticisms from outside the Agency that the DNT guideline is not a useful screening tool; 2) defining modes-of-action for predictive testing of developmental neurotoxic potential and; 3) use of high throughput in vitro and alternative species models for developmental neurotoxicity testing. To address the first issue, we are developing an unbiased evaluation the data currently being submitted to EPA from registrants in order to evaluate the overall quality and diagnostic value of the procedures. Parameters such as variability, reliability, and sensitivity to positive control compounds will be evaluated across studies and laboratories conducting the tests. The second issue involves a proof-of-concept project to link in vitro screening for biological activity at the GABA receptor to adverse consequences in the developing nervous system. For the last issue, we are developing testing batteries of in vitro cell culture models and alternative species as rapid, low cost methods for screening of large numbers of chemicals. A screening approach using high-throughput cell-based models and alternative species must delineate a strong linkage between responses observed at lower and higher levels of biological organization. This project addresses key questions associated with developing a first tier approach for screening for developmental toxicity including: 1) are there predictive biomarkers of key events in the developing nervous system that can be assessed in vitro?; 2) how do we apply technological advances in high-throughput testing, genomics, and/or proteomics to develop rapid in vitro screening assays?; 3) are there homologous, non-mammalian models of neurodevelopment that can be used as a rapid screen for developmental neurotoxicity?

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