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

Abstract

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 predicted by 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 50 and LC 50 -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.

QSAR models of the inhalation toxicity of organic compounds

“…Good single-parameter QSAR models for nonspecific toxicity of aqueous organisms are obtained if logK oct/wa- [9,10]. However, the use of this parameter to describe nonspecific inhalation toxicity did not give any meaningful correlation.…”

“…Such CC usually include hydrocarbons, alcohols, ketones, and alkylbenzenes. Experimental values of the distribution coefficients in octanol-water and water-air systems are used to construct QSAR toxicity models of these compounds [9].…”

A Mini Review of Mammalian Toxicity (Q)SAR Models

“…A number of outliers were detected in the studies, which was attributed to a corresponding proelectrophile mechanism of action. Wolf et al [11] used the lethal narcosis QSARs as taken from Lipnick et al [9] to calculate the baseline toxicity of 108 chemicals retrieved from Register of Toxicology Effects of Chemical Substances (RTECS). On the basis of calculated and experimental RTECS values for acute oral toxicity (LD 50 ) and acute inhalation toxicity (LC 50 ), the toxicity ratio (TR) as the ratio of the calculated baseline toxicity over the experimentally determined value was calculated.…”

“…A TR-value less than one could indicate rapid hydrolysis and/or biotransformation of the parent compound by the organism to non-toxic metabolites. In the study by Wolf et al [11], it was concluded that if baseline toxicity is observed through inhalation exposure, it is also expected to occur through oral exposure. In case of a more specific toxicity, the calculated oral baseline toxicity can be used to determine upper exposure limits.…”

Investigation of Critical Body Residues and Modes of Toxic Action Based on Injection and Aquatic Exposure in Fish

“…The comparison of acute toxicity within and between rat and rainbow trout over various exposure routes shows that they are likely to be based on similar toxicokinetics and interspecies correlations were good, when matched on exposure routes between trout and rats (Delistraty et al 1998). Wolf et al (2004) observed that after establishing a lethal narcosis mechanism through the inhalation exposure route, a compound's oral toxicity can be reliably estimated. The toxicity related with the exposure routes has been observed by many people (Klaassen and Rozman 1991;Delistraty 1999Delistraty , 2000.…”