The rate and extent of uptake and depuration of water-born xenobiotics are major determinants of xenobiotic toxicity to fish, as well as most other aquatic life. Environmental factors such as temperature, pH, salinity and dissolved oxygen concentration affect the kinetics of xenobiotic accumulation by fish, but it is generally impossible, even qualitatively, to predict the effect of a change in the environment on the accumulation and toxicity of specfic compounds. Such a predictive capability would be a significant advance in the area of aquatic toxicology. The underlying mechanisms of xenobiotic transport and metabolism in fish are primarily physiological, and environmental effects on fish physiology are relatively well known. The long term objective of this research is the development of physiologically based pharmacokinetic models that can accurately be scaled for fish size and species, and for changes in environmental parameters. These models will improve our understanding of the quantitative relationships among the rate and extent of accumulation of xenobiotics by fish and the dominant transport mechanisms that govern xenobiotic accumulation. Experiments are proposed to characterize the kinetics of accumulation and metabolism of pentachlorophenol, trifluralin, and diethylhexyl phthalate in 4, 20, 100, and 500 g rainbow trout. Compartmental models, that are based on whole-body concentration-time data for the 4, 20, and 100 g trout and on blood concentration-time data for the 500 g fish, will be developed. The concentration of each test compound in several tissues after various times of exposure of 100 g fish will be detemined, along with cardiac output and tissue blood flow rates in 500 g fish. These data and the compartmental models will be used to develop and test physiologically based models that use as model parameters blood flows, tissue masses, and tissue/blood distribution coefficients for the test compounds. The experiments will be performed at water temperatures of 6, 12, and 18 Degrees. The goal is to develop a single model and a consistent set of parameters for each test compound that will predict its pharmacokinetics in the four sizes of fish at each temperature.
NIH ExPorter
NIH ExPorter