Citation:

Aschner, M., S. Ceccatelli, M. Daneshian, E. Fritsche, N. Hasiwa, T. Hartung, H. Hogberg, M. Leist, A. Li, W. Mundy, S. Padilla, A. Piersma, A. Bal-Price, A. Seiler, R. Westerink, B. Zimmer, AND P. Lein. Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use. ALTEX. Society ALTEX Edition, Kuesnacht, Switzerland, 34(1):49-74, (2017). https://doi.org/10.14573/altex.1604201

Impact/Purpose:

There is a paucity of information concerning the developmental neurotoxicity hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of-action. To validate these alternative methods for developmental neurotoxicology, positive and negative control chemicals are needed. This workshop addressed this requirement by (i) identifying a sufficient number of chemicals for assay development (about 30 compounds), (ii) defining the clear selection criteria with regards to the published data, and the statistical methods applied to the data reported in these publications; (iii) documenting failures to fulfill the selection criteria, and to communicating considerations concerning the use of this compound set for assay development

Description:

There is a paucity of information concerning the developmental neurotoxicity (DNT) hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of-action. Moreover, the processes modelled by the assays can be linked to toxicity endophenotypes, i.e. alterations in neural connectivity that form the basis for neurofunctional deficits in man. The authors of this review convened in a workshop to define criteria for the selection of positive/negative controls, to prepare recommendations on their use, and to initiate the setup of a directory of reference chemicals. For initial technical optimization of tests, a set of >50 endpoint-specific control compounds was identified. For further test development, an additional “test” set of 33 chemicals considered to act directly as bona fide DNT toxicants is proposed, and each chemical is annotated to the extent it fulfills these criteria. A tabular compilation of the original literature used to select the test set chemicals provides information on statistical procedures, and toxic/non-toxic doses (both for pups and dams). Suggestions are provided on how to use the >100 compounds (including negative controls) compiled here to address specificity, adversity and use of alternative test systems

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