The Integrated Acute Systemic Toxicity Project (ACuteTox) for the Optimisation and Validation of Alternative In Vitro Tests

Abstract

The ACuteTox project is designed to replace animal testing for acute systemic toxicity, as is widely used today for regulatory purposes, by using in vitro and in silico alternatives. In spite of the fact that earlier studies on acute systemic toxicity demonstrated a good correlation between in vitro basal cytotoxicity data (the 50% inhibitory concentration [IC50]) in human cell lines and rodent LD50 values, and an even better correlation between IC50 values and human lethal blood concentrations, very few non-animal tests have been accepted for general use. Therefore, the aim of the ACuteTox project is to adapt new testing strategies, for example, the implementation of new endpoints and new cell systems for toxicity screening, organ-specific models, metabolism-dependent toxicity, tissue absorption, distribution and excretion, and computer-based prediction models. A new database, AcuBase, containing descriptions and results of in vitro tests of the 97 reference chemicals, as well as the results of animal experimentation, and human acute toxicity data, will be generated within the framework of ACuteTox. Scientists from 13 European countries are working together and making efforts to find the most appropriate testing strategies for the prediction of human acute systemic toxicity, and also to select a robust in vitro test battery for cytotoxicity testing of chemicals.

Multiscale modeling reveals inhibitory and stimulatory effects of caffeine on acetaminophen‐induced toxicity in humans

“…A mean toxic dose of APAP (34 g) was identified in literature at a sublethal level, 32,33 whereas the dose level of CAF (4.4 g) was derived from a relative dose ratio of 1000:130, according to therapeutic indications used in drug combination therapy. [8][9][10] Note that APAP and CAF are frequently co-administered because CAF is supposed to enhance the analgesic effect of APAP.…”

Three dimensional cellular microarray platform for human neural stem cell differentiation and toxicology

“…Both of these concentrations, however, are higher than the toxic blood concentrations required to cause hepatotoxic effects (~ 0.2 – 1 mM) (Clemedson et al 2007). As expected, the viability of the cells below the hepatotoxic range of concentrations remains unaffected for both the hNSC line and its progeny, and is consistent with reports in the literature (Breier et al 2008b; Buzanska et al 2009).…”

High-Throughput Toxicity and Phenotypic Screening of 3D Human Neural Progenitor Cell Cultures on a Microarray Chip Platform

“…This included acutely toxic compounds (e.g., paraquat, CdCl 2 ) with IC 50 values consistent with literature values (Breier et al., 2008). Compounds without potent neurotoxicity (e.g., acetaminophen, caffeine, diphenhydramine) were found to have no cytotoxicity at functionally relevant concentrations, and only at concentrations associated with systemic human toxicity did decreases in viability occur (Brent et al., 2011, Clemedson et al., 2007, Radovanovic et al., 2000). PbCl 2 and MnCl 2 did not reduce cell viability for either undifferentiated or differentiating cultures.…”