Developmental toxicity testing for safety assessment: new approaches and technologies

Abstract

The ILSI Health and Environmental Sciences Institute's Developmental and Reproductive Toxicology Technical Committee held a 2-day workshop entitled "Developmental Toxicology-New Directions" in April 2009. The fourth session of this workshop focused on new approaches and technologies for the assessment of developmental toxicology. This session provided an overview of the application of genomics technologies for developmental safety assessment, the use of mouse embryonic stem cells to capture data on developmental toxicity pathways, dynamical cell imaging of zebrafish embryos, the use of computation models of development pathways and systems, and finally, high-throughput in vitro approaches being utilized by the EPA ToxCast program. Issues discussed include the challenges of anchoring in vitro predictions to relevant in vivo endpoints and the need to validate pathway-based predictions with targeted studies in whole animals. Currently, there are 10,000 to 30,000 chemicals in world-wide commerce in need of hazard data for assessing potential health risks. The traditional animal study designs for assessing developmental toxicity cannot accommodate the evaluation of this large number of chemicals, requiring that alternative technologies be utilized. Though a daunting task, technologies are being developed and utilized to make that goal reachable.

Consensus report on the future of animal-free systemic toxicity testing

“…Reproductive toxicology, including developmental toxicology, is a particularly difficult field as far as animal-to-human predictions are concerned (Knudsen et al, 2011;Makris et al, 2011). Reproductive toxicity aims to assess possible hazard to the reproductive cycle, with a high interest in the early stages of embryonic development (embryotoxicity).…”

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

“…Less than 5% of dossiers in the US EPA HPV database or the EU New Chemical Database (not public) contain any data in this field (Bremer et al, 2007a). Knudsen et al, have analyzed available data (Knudsen et al, 2011) …”

“…In order to move towards transcriptomics read-outs, PCR was employed to monitor specific gene expression (Pellizzer et al, 2004). Knudsen and colleagues (Knudsen et al, 2011) demonstrated the mEST's ability to capture data on disruption of developmental signaling pathways as a potential alternative for assessing developmental toxicity. "His example focused on the expression of genes for the 17 + 2 conserved signaling pathways critical to early development (National Research Council, 2000) The EC report (Adler et al, 2011) (cited literature there) gives a comprehensive overview on variants of the embryonic stem cell tests with respect "... to their readouts but also in the target cell differentiation (Peters et al, 2008;Zur Nieden et al, 2004).…”

Acetyl l-carnitine protects motor neurons and Rohon-Beard sensory neurons against ketamine-induced neurotoxicity in zebrafish embryos

“…This is particularly intriguing given their small size, prolific reproductive capacity and ease of maintenance thus making it an ideal model for safety assessment of drugs de Esch et al, 2012;Knudsen et al, 2011). Moreover, detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes, the largest gene set of any vertebrate so far sequenced, while comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue (Howe et al, 2013).…”