Abstract
LUCS (Light-Up Cell System) is a new live cell test that allows assessment of a cell’s homeostasis and its alteration by a toxic agent. To evaluate the effectiveness of LUCS as an alternative test method for acute oral toxicity, we compared EC50s determined in HepG2 cells treated with 53 chemicals selected from the ACuteTox EU database with corresponding human blood LC50s derived from human acute poisoning cases. Linear regression analysis showed that LUCS results predict human data to 69 %. Rodent oral LD50s and LUCS EC50s were then correlated to human LC50s using shared data sets. Linear regression analyses comparing LUCS and animal data clearly showed that LUCS always predicts human toxicity better than animal data do.These successful prediction values prompted us to simplify the LUCS test, adapting it to regulatory and high throughput applications, resulting in a new protocol with consistent dose-response profiles and EC50s.This study demonstrates that the LUCS test method could be relevant for assessing human acute oral toxicity with a simplified protocol adapted to commercially available fluorescence readers. We suggest that this new alternative method can be used for acute systemic toxicity testing in combination with other tests under European REACH and other regulations, wherever pertinent alternative methods are still lacking.
Highlights
Intensifying demands to address the 3Rs concept (Reduction, Refinement, and Replacement of the use of animals in research) introduced by Russel and Burch [1] has increased the push for new screening strategies into public and private scientific research
This study demonstrates that the LUCS test method could be relevant for assessing human acute oral toxicity with a simplified protocol adapted to commercially available fluorescence readers
We suggest that this new alternative method can be used for acute systemic toxicity testing in combination with other tests under European REACH and other regulations, wherever pertinent alternative methods are still lacking
Summary
Intensifying demands to address the 3Rs concept (Reduction, Refinement, and Replacement of the use of animals in research) introduced by Russel and Burch [1] has increased the push for new screening strategies into public and private scientific research. Despite the 3Rs incorporation into the European legislation (directive 2010 /63) [2], that replaces and repeals 1986’s directive 86/ 609/EEC), and the emergence of a new toxicology paradigm (i.e. more relevant to humans and based on molecular and cellular pathways [3,4,5,6,7,8]), the progress of alternative methods into regulatory use has been slow [9,10]. Acute systemic toxicity data, in particular those required for hazard classification and substance labelling, are informed by animal tests. In Europe, the regulatory requirements for acute toxicity testing of substances are outlined in several regulations: 1) REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals)
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