Estimation of Maximum Tolerated Dose for Long‐Term Bioassays from Acute Lethal Dose and Structure by QSAR

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Abstract
A quantitative structure‐activity relationship (QSAR) model has been developed to estimate maximum tolerated doses (MTD) from structural features of chemicals and the corresponding oral acute lethal doses (LD50) as determined in male rats. The model is based on a set of 269 diverse chemicals which have been tested under the National Cancer Institute/National Toxicology Program (NCI/NTP) protocols. The rat oral LD50 value was the strongest predictor. Additionally, 22 structural descriptors comprising nine substructural MOLSTAC(c) keys, three molecular connectivity indices, and sigma charges on 10 molecular fragments were identified as endpoint predictors. The model explains 76% of the variance and is significant (F= 35.7) at p < 0.0001 with a standard error of the estimate of 0.40 in the log(1/mol) units used in Hansch‐type equations. Cross‐validation showed that the difference between the average deleted residual square (0.179) and the model residual square (0.160) was not significant (t= 0.98).

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