Accounting for data variability, a key factor in in vivo/in vitro relationships: application to the skin sensitization potency (in vivo LLNA versus in vitro DPRA) example

Journal of Applied Toxicology Volume 36, Issue 12 (2016) 1568-1578

When searching for alternative methods to animal testing, confidently rescaling an  in vitro result to the corresponding  in vivo classification is still a challenging problem. Although one of the most important factors affecting good correlation is sample characteristics, they are very rarely integrated into correlation studies. Usually, in these studies, it is implicitly assumed that both compared values are errorā€free numbers, which they are not. In this work, we propose a general methodology to analyze and integrate data variability and thus confidence estimation when rescaling from one test to another. The methodology is demonstrated through the case study of rescaling the  in vitro Direct Peptide Reactivity Assay (DPRA) reactivity to the  in vivo Local Lymph Node Assay (LLNA) skin sensitization potency classifications. In a first step, a comprehensive statistical analysis evaluating the reliability and variability of LLNA and DPRA as such was done. These results allowed us to link the concept of gray zones and confidence probability, which in turn represents a new perspective for a more precise knowledge of the classification of chemicals within their  in vivo OR  in vitro test. Next, the novelty and practical value of our methodology introducing variability into the threshold optimization between the  in vitro AND  in vivo test resides in the fact that it attributes a confidence probability to the predicted classification. The methodology, classification and screening approach presented in this study are not restricted to skin sensitization only. They could be helpful also for fate, toxicity and health hazard assessment where plenty of  in vitro and  in chemico assays and/or QSARs models are available. 


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