Science Inventory

Conference Report: Advancing the Science of Developmental Neurotoxicity (DNT) Testing for Better Safety Evaluation

Citation:

Bal-Price, A. K., S. Coecke, L. Costa, K. M. CROFTON, E. Fritsche, A. Goldberg, P. Grandjean, P. J. Lein, A. Li, R. Lucchini, W. R. MUNDY, S. J. PADILLA, A. M. Persico, A. M. Seiler, AND J. Kreysa. Conference Report: Advancing the Science of Developmental Neurotoxicity (DNT) Testing for Better Safety Evaluation. ALTEX. Society ALTEX Edition, Kuesnacht, Switzerland, 29(2):202-15, (2012).

Impact/Purpose:

There is increasing pressure from a variety of children's health advocacy groups being placed on industry, academia and regulatory bodies to develop (alternative) methods that reliably and efficiently screen large numbers of chemicals for which we currently have little or no information concerning their potential for developmental neurotoxicity

Description:

1. Introduction The 3rd International Conference on Alternatives for Developmental Neurotoxicity Testing (DNT3), organized by the European Centre for the Validation of Alternative Methods (ECVAM), the Joint Research Centre of the European Commission, was held from May 10 -13, 2011 in Varese, Italy. Over 100 experts from 18 different countries attended. DNT3 achieved its primary goal of bringing together diverse stakeholders including research scientists, industry representatives, academia, clinical representatives and experts from regulatory bodies from both Europe and the US. A majority of new participants were from European countries that had not attended the two previous DNT conferences held in the United States in 2006 and 2008. Holding the conference in Europe also facilitated new transAtlantic contacts among researchers interested in DNT. At the regulatory level, there is a recognized need for DNT testing. As early as 1998, the EPA published the Health Effects Test Guidelines OPPTS 8706300 on DNT (US EPA, 1998), and in 2007 the Organization for Economic Cooperation and Development (OECD) endorsed a new OECD DNT Test Guideline 426 (OECD, 2007). These Guidelines are largely based on animal studies and are used as higher tiered tests triggered based on structure activity relationships or evidence of neurotoxicity in standard adult, developmental or reproduction studies (Makris et aI., 2009) Experts at the conference stated that these in vivo tests are unsuitable for screening large number of chemicals, for many reasons including low throughput, high cost, and questions regarding reliability. There was also consensus that, new reliable and efficient screening and assessment tools are needed for better identification, prioritization, and evaluation of chemicals with potential to induce developmental neurotoxicity. The information obtained from these screening studies will likely also help to refine animal tests and to inform epidemiological studies. The conferees confirmed that DNT is an issue of growing, global concern and that damage of the developing brain by chemical exposure results in significant societal as well as individual cost. A particular challenge in DNT is that the neurodevelopmental outcome of exposure to potentially neurotoxic chemicals depends not only on the kind of exposure (dose, duration) but also on the developmental stage at the time of exposure. Participants discussed a variety of alternative methods with this challenge in mind. There is increasing pressure from a variety of children's health advocacy groups being placed on industry, academia and regulatory bodies to develop (alternative) methods that reliably and efficiently screen large numbers of chemicals for which we currently have little or no information concerning their potential for developmental neurotoxicity. In vitro and non-mammalian alternative systems-based models are prime candidates, but also in silico methods and combinations should also be considered. As a first step, methods are needed for identifying the effects of chemicals on developmental processes critical to the formation of a functional nervous system. Alternative test methods must then be refined to meet regulatory requirements for identifying potential developmental neurotoxicants in a fast, affordable, and reliable way, ideally also providing potency information that is needed for risk assessment. Most likely this can only be achieved with non-animal test methods, but where this cannot (yet) be realized, any new approach should respect animal welfare and the 3Rs, i.e. it should aim to refine, reduce and ultimately replace animal experiments. Even before regulator acceptance, scientifically robust methods could be used for prioritizing chemicals for further DNT studies under the EPA and GECD guidelines The required features of alternative test methods that would be capable of screening large numbers of chemicals for their DNT profile were discussed in detail. It was proposed that new data must be produced using batteries of in vitro tests that incorporate different DNT-relevant endpoints in high-throughput systems and test a wide range of concentrations of test chemicals. Higher throughput screening methods should be validated if they are used for regulatory purposes. The applied models must be based on evolutionarily conserved neurodevelopmental processes that are mechanistically relevant for human developmental neurotoxicity. In the next step, these test methods should be validated with the goal of obtaining regulatory acceptance. Moreover, cell-cell and organ-organ interactions must be taken into account for valid DNT screening systems, though this requirement presents major technical challenges to non-animal test systems, but is strength ofthe non-mammalian alternative animal models. There was general agreement that methods for a high-throughput screening battery should be developed using recommendations proposed by Crofton et aI., (2011). The expectation is that test methods developed with these recommendations would generate reliable data that could be evaluated across test methods and across laboratories and would allow comparison of their predictive capacity and efficiency. This comparative approach would be useful for demonstrating that a given test method performs adequately for the intended purpose (validation) and could hence be accepted for regulatory applications. Maximizing the opportunities for reducing, refining or replacing of animal experiments should be kept in mind during this process. However, participants also agreed that there is still a long way to go before we have good models for integrating and interpreting data from in vitro and other alternatives that would be sufficient for assessing human risks. The conference concluded with views of regulatory officials from the European Commission and the US Environmental Protection Agency (EPA). In their closing remarks, Dr. Alan Goldberg (Center for Alternative to Animal Testing (CAATIUS) and Dr. Joachim Kreysa (ECVAM/EU) applauded the progress made since DNT2, but concluded that much work is still needed to develop scientifically robust tests that will provide all stakeholders with the data needed for risk assessment and risk management decisions. Initially identifying those environmental chemicals with the greatest potential to disturb the development of the human brain and central nervous system should receive highest priority. With his final words, Dr. A. Goldberg announced that the 4th conference on DNT will be held in the United States and, in recognition of rapid progress in the field, it will be scheduled within the next two years. This report summarizes the main topics discussed during the meeting and presents conclusions and recommendations made for future directions and priorities.

URLs/Downloads:

ALTEX   Exit EPA's Web Site

Record Details:

Record Type:DOCUMENT( JOURNAL/ PEER REVIEWED JOURNAL)
Product Published Date:09/01/2012
Record Last Revised:12/06/2012
OMB Category:Other
Record ID: 240988