Application of QSARs: Correlation of Acute Toxicity in the Rat Following Oral or Inhalation Exposure

Quantitative Structure-Activity Relationships (QSARs) based upon a lethal narcosis mechanism represent baseline or minimum toxicity, i.e. unless a chemical acts by a more specific mechanism, its toxicity will be predictedby such models. Baseline toxicity should be independent of exposure route. A toxicity ratio (TR) is defined as the ratio of the calculated baseline toxicity over the experimentally determined value. A TR-value of approx. 1 indicates baseline toxicity. A TR-value greater than 1 indicates excess toxicity due to the existence of a more specific mechanism of action. We investigated the possibility of extrapolation from the inhalation route to the oral route by applying the above concepts. We report the TR-values for a set of chemicals with measured LD 5 0 and LC 5 0 -values obtained from the Registry of Toxic Effects of Chemical Substances (RTECS) and calculated toxicity values based on a previously developed oral and inhalation baseline-toxicity models. For part of the compounds the reliability of the TR-values may be questionable either due to errors in the measured toxicity values, or due to extrapolation of the baseline-toxicity models outside their range of proven validity. For 47% of the remaining compounds, the TR-value for both exposure routes was approx. 1. For 22% of the remaining compounds a specific mechanism of toxicity was indicated by a TR-value greater than 1, and another 22% appeared to have a specific mechanism of action for only one of the exposure routes. It is concluded that after establishing a lethal narcosis mechanism through inhalation exposure the compound's oral toxicity can be reliably estimated. In case of more specific toxicities, the calculated oral baseline toxicity can be used to determine the upper limits in the toxicity experiment.