Estimating Acute Toxicity Based on In Vitro Cytotoxicity: Role of Biokinetic Modelling

In the search for methods to evaluate the toxicological risk of chemicals without employing animal experimentation, much emphasis has been put on the replacement of acute toxicity (LD50) determinations. One important assumption was that acute toxicity is related to a compound’s basal cytotoxicity (Ekwall, 1983). In previous programmes, the feasibility of the use of in vitro cytotoxicity data for the prediction of in vivo lethal doses was tested, e.g. in the MEIC study (Ekwall et al., 1998), and by publication of the Register of Cytotoxicity (Spielmann et al., 1999; Halle., 2003). In these studies it was shown that basal cytotoxicity data resulted in good estimates for about 70% of the compounds, i.e. these chemicals could be classified in the appropriate LD50 classes (Clemedson and Ekwall, 1999). This implies that for about 30% of the cases the estimates on the basis of cytotoxicity data deviated from in vivo findings. These deviations from a simple linear relationship between effective concentrations in vitro and toxic doses in vivo can result from the fact that the effective concentrations in vitro are irrelevant for the concentrations that may cause toxicity at the target site in target organs in vivo. This will in many cases be the result of the biokinetics of the compound under study (Blaauboer, 2002). For instance, the absorption of the compound may be minimal, thus leading to low systemic concentrations. Moreover, the processes of distribution, metabolism and elimination may lead to lower or higher concentrations in target organs than could be expected from an even distribution of the compound in the body. Thus, an important drawback of the use of cytotoxicity data is the difficulty of extrapolating a toxic concentration in the in vitro system to a toxic dose in the in vivo situation (Blaauboer, 2003). The ACuteTox programme aims to improve the estimates for acute toxicity on the basis of non-animal studies (e.g. in vitro cytotoxicity studies). Thus, one of the areas needing attention is the study of the biokinetics of the test compounds. Two work packages in the programme are devoted to this: work package 5 involves studies of absorption, distribution and elimination, while work package 6 is devoted to the role of biotransformaEstimating Acute Toxicity Based on In Vitro Cytotoxicity: Role of Biokinetic Modelling Bas J. Blaauboer, Joop Hermens and Jan van Eijkeren Institute for Risk Assessment Sciences, Utrecht University, The Netherlands; National Institute of Health and the Environment (RIVM), Bilthoven, The Netherlands Session 5.06 In vitro approaches for determining acute systemic toxicity