Biological-Mathematical Modeling of Chronic Toxicity.

The objectives of the project Biological-Mathematical Modeling of Chronic Toxicity were to study the factors affecting the fate of inhaled vapors in the body and to develop a mathematical model. The main accomplishments are 1 A general pharmacokinetic model for inhalation administration, based on physiological parameters of the exposed subject and on physical and chemical properties of the inhaled substance, was defined. 2 Information on interspecies differences was extracted from the literature partition coefficients of eight organic solvents were determined for eight tissues of three species man, monkey, rat steady state clearances calculated from pulmonary uptake, and intrinsic clearance determined from vapor distribution in rats were used in the model as elimination rate constants. 3 The models were used to evaluate the effects of the following parameters on uptake, distribution and elimination of inhaled vapors solubility, metabolism, body build, interspecies differences, physical exertion, exposure duration, exposure repetition, and short-term excursion limit. 4 Nonlinear dependence of pulmonary uptake on exposure concentration was observed in the animal model. 5 Reduced pulmonary uptake and quantitative and qualitative changes in elimination were observed if two vapors were inhaled simultaneously.