Rethinking developmental toxicity testing: Evolution or revolution?

Abstract

Background Current developmental toxicity testing adheres largely to protocols suggested in 1966 involving the administration of test compound to pregnant laboratory animals. After more than 50 years of embryo‐fetal development testing, are we ready to consider a different approach to human developmental toxicity testing? Methods A workshop was held under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute to consider how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques (revolution). We first consider what changes to the current protocols might be recommended to make them more predictive for human risk (evolution). Results The evolutionary approach includes modifications of existing protocols and can include humanized models, disease models, more accurate assessment and testing of metabolites, and informed approaches to dose selection. The revolution could start with hypothesis‐driven testing where we take what we know about a compound or close analog and answer specific questions using targeted experimental techniques rather than a one‐protocol‐fits‐all approach. Central to the idea of hypothesis‐driven testing is the concept that testing can be done at the level of mode of action. It might be feasible to identify a small number of key events at a molecular or cellular level that predict an adverse outcome and for which testing could be performed in vitro or in silico or, rarely, using limited in vivo models. Techniques for evaluating these key events exist today or are in development. Discussion Opportunities exist for refining and then replacing current developmental toxicity testing protocols using techniques that have already been developed or are within reach.

Use of smoking cessation pharmacotherapies during pregnancy is not associated with increased risk of adverse pregnancy outcomes: a population-based cohort study

“…Studies in rats and rabbits did not find a teratogenic effect of varenicline, even with administered dosages 23 and 50 times higher, respectively, than the maximum recommended human daily dose [47]. However, it has been long established that animal studies are seriously limited in their ability to predict human teratogenesis [48,49]. Overall, this is the most rigorous study to assess safety of bupropion for smoking cessation in pregnancy.…”

Workshop on the validation and regulatory acceptance of innovative 3R approaches in regulatory toxicology – Evolution versus revolution

“…(Aldert H. Piersma, RIVM) Following up from the first BfR-RIVM workshop (Piersma et al, 2018a), the scene of this workshop was set by introducing the concept of evolution versus revolution in innovating toxicity testing (Scialli et al, 2018). The historic sequence of human safety testing has proceeded through the introduction of animal methods in the mid-20 th century, followed by development of in vitro alternatives in later decades.…”

“…The integration of this toxicodynamic model with kinetic models for compound absorption, distribution, metabolism and excretion (ADME), and quantitative in vitro to in vivo extrapolation (Fragki et al, 2017) is necessary to complete the model for computational hazard and risk assessment. A change in paradigms and methodology for risk assessment and validation (Zurlo, 1994), (Davis et al, 2013), (Hartung, 2008), (Leist et al, 2008), (Scialli et al, 2018) is already well on the way -even without the need for a revolution (Monosson, 2005). Classical toxicological assessment, especially for regulatory purposes, is subjected to rigid rules and relies heavily on data obtained from pre-defined lists of standarized (mainly animal) studies described in OECD test guidelines (http://www.oecd.org/env/ehs/testing/section4-health-effects.htm) as exemplified in the REACh Annexes (EU, 2006), or the Classification, Labelling and Packaging (CLP) regulation (EU, 2008)).…”

Integration of Consortia Recommendations for Justification of Animal Use Within Current and Future Drug Development Paradigms

“…Such reviews are arguably conducted most effectively when pharmaceutical companies work in concert, and there is a long history of companies working together to share and critically review the available data and to recommend realistic changes in practices and regulations. [1][2][3][4] Some of these consortia have also highlighted opportunities for the more appropriate use of animals for the safety assessment of novel drugs and biopharmaceuticals. [5][6][7][8] The work of these consortia is not a trivial undertaking.…”