Critical evaluation of current developmental toxicity testing strategies: a case of babies and their bathwater

Abstract

This review is the second in a series of four papers emanating from a workshop entitled "Developmental Toxicology-New Directions," which was sponsored by the ILSI Health and Environmental Sciences Institute's (HESI) Developmental and Reproductive Toxicology Technical Committee. The present review analyzes the strengths and weaknesses of current developmental safety testing approaches in an effort to identify those strengths that should be retained in the future versus the weaknesses that should be eliminated. Workshop participants considered the following to be key strengths of current testing approaches: the integrated biology of pregnant animal models including pharmacokinetic and pharmacodynamic processes, the ability to detect low incidence malformations as well as maternally mediated toxicity, and the long history of use coupled with extensive historical data. A number of weaknesses were related to the resource-intensive nature of developmental toxicity testing (e.g., large number of animals, high costs, low throughput, the inability to keep pace with the demand for more toxicity data). Other weaknesses included the use of very high dose levels that often far exceed human exposure levels, the confounding influence of maternal toxicity, sparse understanding of basic developmental mechanisms and genetics of standard animal models relative to mouse or lower organisms, difficulties interpreting low incidence findings, and issues surrounding the interpretation of minor skeletal variations. An appreciation of these strengths and weaknesses is critical for the design of new approaches to developmental toxicity testing in the 21st century.

Optimizing responses to drug safety signals in pregnancy: the example of dolutegravir and neural tube defects

“…However, while negative preclinical reproductive toxicology test results are reassuring, there is no assurance that negative results obtained by testing drugs in animals can definitively predict that a drug will lack teratogenic effects in humans . Similarly, it cannot be concluded that agents teratogenic in animals will necessarily produce teratogenic effects in humans.…”

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

“…Further progress in this area would be accelerated by regulatory steps that preclude the use of in vivo data unless they come from a formally validated model and therefore have a known predictivity (Carney et al, 2011). Uses of the zebrafish assay (Selderslaghs et al, 2011;Padilla et al, 2012;truong et al, 2014), the embryonic stem cell test (eSt) (van Dartel and Piersma, 2011;Seiler and Spielmann, 2011) and further developments on the basis of ReProtect test systems (Piersma, 2010) could immediately fill the gap until assays based on human cells become available.…”

The problem of maternal toxicity in developmental toxicity studies

“…The negative consequences of this practice include unnecessary animal use, cost, and effort as the irrelevant findings generated are further investigated. This testing scheme also can lead to the erroneous classification and labeling of compounds which pose little risk to humans'' (Carney et al, 2011). The second paper (Brannen et al, 2011) is a summary of the discussion of a workshop on developmental toxicology -new directions, held by ILSI and HESI.…”