A STRATEGY FOR RANKING ENVIRONMENTALLY OCCURRING CHEMICALS. PART V: THE DEVELOPMENT OF TWO GENOTOXICITY QSARs FOR HALOGENATED ALIPHATICS

Abstract

A s4trategy for systematic analysis and priority ranking of chemicals was applied to a class of 58 saturated halogenated aliphatics. The training set, selected by statistical design, was subjected to biological testing in an assay (the DNA precipitation assay) estimating DNA damage in V79 Chinese hamster (cells. The obtained genotoxicity data were modeled by construction of two multivariate quantitative structure-activity relationships (QSARs). To experimentally validate the two derived QSAR models, a validation set of chemicals was chosen (also according to statistical design). Predictions were made for the validation set compounds, and they were found to compare well with the observed data. Thus, the two QSARs were utilized to predict the genotoxicity of 36 nontested compounds belonging to the examined class. In addition, it was found that the genotoxicity data required a multitude of chemical and structural descriptors in order to be modelable, and that log P in particular was an informative descriptor variable. Keywords-H[alogenated aliphaticsMultivariate QSAR Statistical design PLS Hazard ranking 5-86L. ERIKSSON ET AL.

Quantitative Structure-Activity Relationships for Predicting the Toxicity of Pesticides in Aquatic Systems With Sediment

“…Log KO, has been used to predict both fate [4,29] and toxicity [8,30] of a large number of neutral, lipophilic chemicals with a nonspecific, narcosis-type toxicity. Like MV, which is correlated with log KO, for nonpolar compounds, log KO, was insufficient to describe the toxicity of the studied insecticides, as might be expected as the insecticides were inhibitors of AChE and not primarily indifferent narcotics.…”

“…Our group of test chemicals included not only OP chemicals of various types but also carbamates of different structural classes. It has been shown elsewhere that the descriptive value of many unidimensional QSAR parameters is reduced when chemicals of different classes are analyzed simultaneously [8].…”

“…Hydrophobic compounds passively accumulate in aquatic organisms by passage through lipid membranes and exert a nonspecific narcosis by solubilization in lipids of the myelin sheath surrounding axons. Because all aspects of exposure and intoxication depend on waterjlipid partitioning, it is not surprising that log KO, of hydrophobic, nonpolar chemicals can be used to predict the fate [6,7] and toxicity [8,9] of these compounds. This relationship has facilitated hazard assessment by providing a means of predicting toxicity and, therefore, environmental hazard in an inexpensive, time-effective manner.…”

“…In contrast to the nonspecific narcosis produced by hydrophobic, nonpolar compounds, cholinergic insecticides exert their toxicity through inhibition of a specific nervous system enzyme, acetylcholinesterase (AChE) [ 131. AChE inhibitors are also subject to oxidative metabolism, which can potentially activate and/or detoxify the molecules [ 141, whereas hydrophobic, nonpolar chemicals are frequently not metabolized [8,9].…”