International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes

Abstract

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23–24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.

Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling

“…The two applications are (i) mechanistic markers that give quantitative information on toxicity pathways/adverse outcome pathways (AOP) activated by the compound. This would then help to map AOPs in general for the field of developmental toxicity (Bal Price et al, 2015a), and to judge new potential toxicants from the knowledge of their activation of certain AOPs; (ii) grouping of chemicals within the assay to support read across procedures by additional biological data. Notably, such a grouping might turn out to be dependent on the cell type as well as the toxicity endpoint used for the study.…”

“…Grouping along mechanistic markers has also been done for the ToxCast phase I chemicals (Kleinstreuer et al, 2014). Such information could guide biologically driven read across proce dures in hazard assessment (Bal Price et al, 2015a) to group compounds based on similarities of MoA. This would complement traditional structure based approaches.…”

Literature review on in vitro and alternative Developmental Neurotoxicity (DNT) testing methods

“…They can also be used to clarify DNT-mechanisms and modes-of-action to provide information on human relevance. Alternative testing methods are also needed to complement or replace OECD TG 426 in order to fulfil present requirements of chemicals regulation, including tiered testing approaches to advice regulatory decision making processes (Bal-Price et al, 2015a, Crofton et al, 2011.…”

“…In addition, there might also be room for improvements in terms of procedural development of the regulatory process, including development of text in guidelines and guidance documents. There is also need of a form or forum for continuous contact between knowledge-building and knowledge-using capacities in the DNTarea, like the ISTNET consortium for DNT (Bal-Price et al, 2015a, which focus on regulatory needs, as it is expected that new information and models will become available on a continuous basis.…”

Uncertainties of testing methods: What do we (want to) know about carcinogenicity?

“…It is already broadly recognized that besides ethical and consequent policy concerns with animal testing, there are many practical regulatory needs for 3R methods (for instance NAS, 2007;OECD, 2005;Bal-Price et al, 2015) and many major international scientific conferences and advisory bodies specifically support this aim, including the development of alternatives to the 2-year RCB (e.g., 9 th World Congress on Alternatives and Animal Use in the Life Sciences 1 ; ECHA, 2016; EUROTOX, 2015 2 ; ESTIV, 2016 3 ; EUSAAT, 2016 4 ;COC, 2016). One of the most important goals is to increase the testing throughput in order to improve -the availability of regulatory test data for many chemicals, -the effectiveness of substitution of the more hazardous chemicals by providing reliable data for an ample set of potential alternative chemicals, also in the low tonnage production range or even for green chemical engineering (Maertens et al, 2014), -the assessment of mixture toxicity, -the assessment of environmental media including the use of bio-analytics to complement chemical analytics (Schroeder et al, 2016), -approaches to cross-species extrapolation for ample coverage of environmental toxicity (Groh et al, 2015), -the assessment of the multitude of nanomaterial compositions, forms and size distributions, -the possibility to retest chemicals according to progress in the development of scientific and toxicological understanding.…”