Assessment of the health effects of chemicals in humans: I. QSAR estimation of the maximum recommended therapeutic dose (MRTD) and no effect level (NOEL) of organic chemicals based on clinical trial data.

The primary objective of this investigation was to develop a QSAR model to estimate the no effect level (NOEL) of chemicals in humans using data derived from pharmaceutical clinical trials and the MCASE software program. We believe that a NOEL model derived from human data provides a more specific estimate of the toxic dose threshold of chemicals in humans compared to current risk assessment models which extrapolate from animals to humans employing multiple uncertainty safety factors. A database of the maximum recommended therapeutic dose (MRTD) of marketed pharmaceuticals was compiled. Chemicals with low MRTDs were classified as high-toxicity compounds; chemicals with high MRTDs were classified as low-toxicity compounds. Two separate training data sets were constructed to identify specific structural alerts associated with high and low toxicity chemicals. A total of 134 decision alerts correlated with toxicity in humans were identified from 1309 training data set chemicals. An internal validation experiment showed that predictions for high- and low-toxicity chemicals were good (positive predictivity >92%) and differences between experimental and predicted MRTDs were small (0.27-0.70 log-fold). Furthermore, the model exhibited good coverage (89.9-93.6%) for three classes of chemicals (pharmaceuticals, direct food additives, and food contact substances). An additional investigation demonstrated that the maximum tolerated dose (MTD) of chemicals in rodents was poorly correlated with MRTD values in humans (R2 = 0.2005, n = 326). Finally, this report discusses experimental factors which influence the accuracy of test chemical predictions, potential applications of the model, and the advantages of this model over those that rely only on results of animal toxicology studies.