Alternative testing strategies for predicting developmental toxicity of antifungal compounds

Promotie

Alternative testing strategies for predicting developmental toxicity of antifungal compounds

Promovendus H (Hequn) Li MSc
Promotor prof.dr.ir. IMCM (Ivonne) Rietjens
prof.dr.ir. B (Bennard) van Ravenzwaay
Copromotor Jochem Louisse
Organisatie Wageningen University, Sub-department of Toxicology
Datum

vr 8 april 2016 11:00 tot 12:30

Locatie Auditorium, building number 362
Generaal Foulkesweg 1
362
6703 BG Wageningen
0317-483592

Summary


For the determination of safe human exposure levels of chemicals in toxicological risk assessments, there is large interest in the development of in vitro and/or in silico test systems as alternatives for animal studies. The aim of the present thesis was to evaluate the applicability of combined in vitro approaches taking toxicokinetic (what the body does to the compound) and toxicodynamic (what the compound does to the body) aspects into account, as well as of an integrated in vitro and in silico approach for prediction of developmental toxicity using a series of antifungal compounds as the model compounds. In this thesis, we show that it is important to take placental transfer of compounds into account when predicting developmental toxicity with in vitro methods. The results obtained also show that in vivo developmental toxicity dose levels can be closely predicted using a PBK modelling-facilitated reverse dosimetry approach. This reverse dosimetry approach could contribute to an increased acceptance and further implementation of in vitro toxicity data in risk assessment procedures. The combined in vitro approaches and the integrated in vitro-in silico approaches appear to be promising for the screening and prioritization of chemicals and to provide reference values, such as BMD10 values, without using animals, therefore contributing to the replacement, reduction and refinement (3Rs) principle of animal testing.