Abstract-In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible models for predicting the toxicity of chemicals when little or no empirical data are available. In recent years, there has been an evolution of QSAR development and application from that of a chemical-class perspective to one that is more consistent with assumptions regarding modes of toxic action. The objective of this research was to develop procedures that relate modes of acute toxic action in the fathead minnow (Pimephales promelas) to chemical structures and properties. An empirically derived database for diverse chemical structures of acute toxicity and corresponding modes of toxic action was developed through joint toxic action studies, the establishment of toxicodynamic profiles, and behavioral and dose-response interpretation of 96-h LC50 tests. Using the results from these efforts, as well as principles in the toxicological literature, approximately 600 chemicals were classified as narcotics (three distinct groups), oxidative phosphorylation uncouplers, respiratory inhibitors, electrophiles/proelectrophiles, acetylcholinesterase inhibitors, or central nervous system seizure agents. Using this data set, a computer-based expert system has been established whereby chemical structures are associated with likely modes of toxic action and, when available, corresponding QSARs.

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An important aspect of understanding how multiple toxicants jointly act involves defining the primary mode of toxic action for the chemicals of interest. We have explored the use of 96-h acute toxicity tests with juvenile fathead minnows and primarily binary chemical mixtures to define the primary acute mode of toxic action for diverse industrial organic chemicals. Our investigation mainly considered the two special cases of noninteractive joint action known as concentration (simple similar) and response (independent) addition. The different forms of joint toxicity with binary mixtures were graphically illustrated by isoboie diagrams. Designated as the mode of action-specific reference toxicants were 1-octanol, phenol, and 2,4-dinitrophenol. It was observed from binary isobole diagrams that a chemical with a similar primary mode of toxic action to that of a reference toxicant would display a concentration-addition type of joint action with the reference toxicant over the entire mixture ratio range. Dissimilar chemicals with very steep concentration-response curves generally showed an interaction that was less-thanconcentration additive, but consistently demonstrated a joint toxicity that was greater than predicted by the response-addition model. The more-than-concentration additive and complex isoboles that are indicative of interactive toxicity were not commonly observed in our experiments.

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An important aspect of understanding how multiple toxicants jointly act involves defining the primary mode of toxic action for the chemicals of interest. We have explored the use of 96‐h acute toxicity tests with juvenile fathead minnows and primarily binary chemical mixtures to define the primary acute mode of toxic action for diverse industrial organic chemicals. Our investigation mainly considered the two special cases of noninteractive joint action known as concentration (simple similar) and response (independent) addition. The different forms of joint toxicity with binary mixtures were graphically illustrated by isoboie diagrams. Designated as the mode of action‐specific reference toxicants were 1‐octanol, phenol, and 2,4‐dimtrophenol. It was observed from binary isobole diagrams that a chemical with a similar primary mode of toxic action to that of a reference toxicant would display a concentration‐addition type of joint action with the reference toxicant over the entire mixture ratio range. Dissimilar chemicals with very steep concentration‐response curves generally showed an interaction that was less‐than‐concentration additive, but consistently demonstrated a joint toxicity that was greater than predicted by the response‐addition model. The more‐than‐concentration additive and complex isoboles that are indicative of interactive toxicity were not commonly observed in our experiments.