Evaluation and Interpretation of Neurodevelopmental
Endpoints for Human Health Risk Assessment
Goal
The goal of this project is to assess the lessons learned from the implementation of standardized tests for developmental neurotoxicity in experimental animals, such as the U.S. EPA OPPTS Health Effects Test Guideline 870.6300 (Developmental Neurotoxicity Study) and similar protocols, and the subsequent application of test results to human health risk assessment.
Project Rationale
In 1991, the US EPA issued a standardized protocol for evaluation of developmental neurotoxicity (DNT) (final version issued in 1998), and, more recently, OECD has attempted to establish a consensus protocol for inclusion in the OECD Testing Guidelines Program for use by member countries. In the past few years, the U.S. guideline has been used to develop data in response to regulatory requirements. The EPA protocol for the evaluation of developmental neurotoxicity (DNT) in laboratory animals is comprised of (a) tests for evidence of deficits in neurobehavioral function, including auditory startle, habituation, associative learning and memory, (b) monitoring of motor activity, and (c) neuropathologic examination, including simple morphometric analysis. Data generated using the EPA protocol and other similar protocols are complex. Sufficient data have now been generated to support the development of a scientific consensus regarding the endpoints measured in the DNT and their interpretation for human health risk assessment.
Approach
ILSI RF/RSI initially established a steering committee to frame the specific objectives and scope of the project, and to identify the questions that should be answered by an expert working group. Additionally the steering committee provided input on the selection of the expert working group. The expert working group met in April 2004, November 2004, and April 2005 and presented a symposium at the 2005 annual meeting of the Neurobehavioral Teratology Society. The expert working group also presented two posters at the 2007 Society of Toxicology meeting. Click here to view the poster “Evaluation and Interpretation of Neurodevelopmental Endpoints for Human Health Risk Assessment – Positive Control Studies, Normal Variability, and Statistical Issues” and click here to view the poster “Identification and Interpretation of Treatment-Related Effects in Developmental Neurotoxicity Testing”.
Current Status of Project
The expert working group has prepared five manuscripts:
- Application of developmental neurotoxicity testing to public health protection
- Undertaking a positive control study as part of a developmental neurotoxicity testing procedure
- Determining normal variability in a developmental neurotoxicity test
- Statistical issues and techniques appropriate for developmental neurotoxicity testing
- Identification and interpretation of treatment-related effects in developmental neurotoxicity testing
The positive control, statistical issues, and interpretation have been accepted for publication in Neurotoxicology and Teratology and the remaining two papers are currently under review. The five papers are expected to be published in one issue of Neurotoxicology and Teratology in 2007.
This project has been supported financially through a cooperative agreement with the US Environmental Protection Agency, Office of Pesticide Programs.