Thursday, February 25th, 2021
10:00AM – 11:30AM EST
- Martin Scholze, Centre for Pollution Research and Policy, Brunel University London, UK
- Ans Punt, Wageningen Food Safety Research, The Netherlands
Register here: https://zoom.us/webinar/register/WN_wsfqCX7uQciWxA1Lu0xc_A
Martin Scholze, Centre for Pollution Research and Policy, Brunel University London, UK
Quantitative in Vitro to in Vivo Extrapolation (QIVIVE) for Predicting Reduced Anogenital Distance produced by Anti-Androgenic Pesticides in a Rodent Model for Male Reproductive Disorders
Many pesticides can antagonize the androgen receptor(AR) or inhibit androgen synthesis in vitro but their potential to cause reproductive toxicity related to disruption of androgen action during fetal life is difficult to predict. Currently, no approaches for using in vitro data to anticipate such in vivo effects exist, and prioritization schemes that limit unnecessary animal testing are urgently needed. Here I will present a quantitative in vitro to in vivo extrapolation (QIVIVE) approach for predicting in vivo anti-androgenicity arising from gestational exposures and manifesting as a shortened anogenital distance (AGD) in male rats. It is built on a physiologically based pharmacokinetic (PBK) model to simulate concentrations of chemicals in the fetus resulting from maternal dosing. The QIVIVE approach was evaluated by using several well-studied model compounds and then applied to various current-use pesticides, all with in vitro evidence for anti-androgenicity but missing in vivo data. Here the QIVIVE model newly identified fludioxonil, cyprodinil, and dimethomorph as in vivo anti-androgens. With the examples investigated, this approach shows great promise for predicting in vivo anti-androgenicity (i.e., AGD shortening) for chemicals with in vitro activity and for minimizing unnecessary animal testing.
Ans Punt, Wageningen Food Safety Research, The Netherlands
A web-based toolbox to support quantitative in vitro-to-in vivo extrapolations (QIVIVE)
An important aspect within next generation non-animal toxicity testing strategies is the extrapolation of in vitro effect concentrations into (human) dose−response or potency information, also called quantitative in vitro-to-in vivo extrapolation (QIVIVE). Insights in dose-dependent plasma and tissue concentrations of a chemical are required to infer the dose levels that would be needed to reach the in vitro effective concentrations in the body. Physiologically based kinetic (PBK) modelling plays a crucial role in generating such insights. To support PBK-model development we have developed a web-based toolbox (www.qivivetools.wur.nl) that contains generic physiologically based-kinetic (PBK) models for rats and humans, including underlying calculation tools to predict plasma protein binding and tissue:plasma distribution. The PBK models within the toolbox allow to make first estimations of internal plasma and tissue concentrations of chemicals, based on the LogP and pKa of the chemical and values for intrinsic hepatic clearance and intestinal uptake. As case study, the toolbox was used to predict oral equivalent doses of in vitro ToxCast bioactivity data for the food additives methylparaben, propyl gallate, octyl gallate and dodecyl gallate. These oral equivalent doses were subsequently compared with human exposure estimates. The goal of the presentation is to provide a background on PBK model development and QIVIVE, making interactively use of the web-based toolbox.