Modeling Oral Rat Chronic Toxicity

Abstract

The chronic toxicity is fundamental for toxicological risk assessment, but its correlation with the chemical structures has been studied only little. This is partly due to the complexity of such an experimental test that embraces a plethora of different biological effects and mechanisms of action, making (Q)SAR studies extremely challenging. In this paper we report a predictive in silico study of more than 400 compounds based on two-dimensional chemical descriptors and multivariate analysis. The root mean squared error of the predictive model is 0.73 (in a logarithmic scale) on a leave-one-out cross-validation and is close to the estimated variability of experimental values (0.64). The analysis of the model revealed that the chronic toxicity effects are driven by the bioavailability of the compound that constitutes a baseline effect plus excess toxicity possible described by a few chemical moieties. The results obtained give confidence that this model can be useful for establishing a level of safety concern in the absence of hard toxicological data.

Applicability of QSAR analysis to the evaluation of the toxicological relevance of metabolites and degradates of pesticide active substances for dietary risk assessment

“…72 Mazzatorta et al (2008) reported a regression-based QSAR for rat chronic toxicity (180 or more days). The model was developed by applying multivariate analysis to LOAELs for 445 diverse compounds selected from multiple sources, including the dataset of and various chemical assessment reports (JECFA, JMPR, NCI and NIH).…”

“…Threshold of Toxicological Concern (TTC), TOPKAT, MULTICASE, Lazar (http://www.insilico.de/), Toxtree, in-house models published in the literature Mazzatorta et al, , 2008 and a model developed under contract .…”

“…Exposures lower than the relevant TTC are considered of low safety concern. In case of estimated exposure higher than the relevant TTC, margins of exposure (MoE) between the predicted toxicity values of rat LOAEL obtained from TOPKAT, rat LOAEL calculated by an in-house model (Mazzatorta et al, 2008) and MRTD (Maximum Recommended Therapeutic Doses) model developed using large number (over 1300) of drugs, are calculated.…”

“…Mazzatorta et al (2008) Nestlé Research Center • A multivariate chronic toxicity (LOAEL) model, using 2D descriptors, was built from a dataset of 445 different chemicals.…”

Estudos de QSAR 2D baseados em descritores topológicos e fragmentos moleculares para uma série de derivados azólicos ativos contra Candida albicans

“…impedimentos estéricos), enquanto descritores relacionados com lipofilicidade (nX e MLOGP) têm contribuição positiva (Figura 4). 38,39 É importante ressaltar que outros fatores além da interação ligante-macromolécula influenciam os valores de CIM 80 , portanto, é razoável supor que a contribuição positiva observada no gráfico de vetor de regressão reflita Outra característica importante para atividade antifúngica é a presença de anéis de 5 membros (nR05), representados nesse conjunto de dados pelos anéis triazolona ou triazol, este último comum a todas as moléculas do conjunto de dados. Por outro lado, moléculas potentes (pCIM 80 > 2,0) apresentam anel triazolona, enquanto o mesmo não é observado para moléculas com baixa atividade antifúngica (pCIM 80 < 0,99).…”