[Show abstract][Hide abstract] ABSTRACT: In the field of environmental toxicology, and especially aquatic toxicology, quantitative structure activity relationships (QSARs) have developed as scientifically-credible tools for predicting the toxicity of chemicals when little or no empirical data are available. A basic and fundamental understanding of toxicological principles has been considered crucial to the continued acceptance and application of these techniques as biologically relevant. As a consequence, 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 assessment of a compound's likely mode of toxic action is critical for a correct QSAR selection; incorrect mode of action-based QSAR selections can result in 10- to 1000-fold errors in toxicity predictions. The establishment of toxicologically-credible techniques to assess mode of toxic action from chemical structure requires toxicodynamic knowledge bases that are clearly defined with regard to exposure regimes and biological models/endpoints and based on compounds that adequately span the diversity of chemicals anticipated for future applications. With such knowledge bases classification systems, including rule-based experts systems, have been established for use in predictive aquatic toxicology applications.
[Show abstract][Hide abstract] ABSTRACT: Simultaneous electrophysiological and behavioral studies were performed on 21–32 day old juvenile medaka (Oryzias latipes) exposed at sublethal concentrations to organic chemicals representing various modes of action. Non-invasive recordings were made of the electrical impulses generated within giant neuronal Mauthner cells, associated interneurons and motoneurons, and axial musculature, all of which initiate the startle or `escape' response in fish. Timing in ms between these electrical sequelae was measured for each fish before and after 24 and 48 h exposure to a chemical. Carbaryl and phenol affected Mauthner cell to motoneuron transmission while chlorpyrifos, carbaryl, phenol and 2,4-dinitrophenol (DNP) showed neuromuscular effects. The variety of neurological effects detected at various concentrations of chemicals tested here suggest that different mechanisms may be responsible. Also noted was the number of startle responses to number of stimuli ratio (R/S); this ratio was affected by most chemicals. Medaka generally appeared to be more susceptible to predation after exposure to chlorpyrifos, carbaryl, fenvalerate, endosulfan, phenol, 1-octanol and DNP. The effects threshold for many of the test compounds was found to be consistent for both the neurophysiological and behavioral endpoints. Consequently, electrophysiological responses of Mauthner cell-initiated startle responses provided a measure of neurological injury that is also directly correlated to a definitive and ecologically relevant behavioral endpoint.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Fathead minnows (Pimephales promelas) were exposed to acutely toxic concentrations of organic chemicals under flow-through conditions at 25°C for 96 h. Changes in behavior and morphology were systematically recorded to develop a plan for classifying these chemicals. On this basis, three behavioral toxicity syndromes were evident. Each syndrome appears to represent a different general mode of toxic action. The hypoactivity syndrome, reflecting narcosis, is characterized by depressed locomotor activity, loss of startle response and very dark body coloration. The hyperactivity syndrome, representing metabolic dysfunction (e.g., uncouplers of oxidative phosphorylation), is characterized by greatly accelerated locomotor activity, overreaction to stimuli and increased ventilatory activity. The physical deformity syndrome, indicative of neurological dysfunction (e.g., AChE inhibition), is characterized by a high incidence of convulsions, tetany, scoliosis/lordosis and hemorrhage in the vertebral area. This classification approach also should be useful to help delineate specific, underlying mechanisms or sites of chemical action.