| Internal dosimetry models have been developed as a tool to estimate the physiological risks associated with the internalization of radionuclides. The models have progressively improved over time by simulating the results of animal studies and incorporating data collected from limited human exposures. The general approach to developing models is the collection of various tissue data from controlled tracer experiments and applying a set of first-order differential equations to the data. A compartmental representation, or compartmental model, is used to illustrate the relationship between the set of specific mathematical equations.
The focus of this research effort was to develop a physiologically informed, or physiologically based, model of the rat hepatic system for systemic exposure to plutonium. The model structure incorporates known anatomical, physiological and physiochemical behavior of plutonium in mammalian systems and supplements the model with proxy linear kinetics of endogenous and xenobiotic materials. The postulated system explicitly identified transferrin bound plutonium in blood plasma, Kupffer cells, and hepatocytes as the primary investigation compartments. The initial model included 22 physiologically informed fixed transfer rates and six adjustable transfer rates. All transfer rates to and from the plasma and within the liver were fixed a priori based on physiological assumptions. It was assumed plutonium-transferrin would behave similar to Dextran, a xenobiotic surrogate, while plutonium-citrate would behave similar to iron, an endogenous element. The initial model had a reported χ2 = 6.86 and 3.28 for the liver and plasma systems respectively. The p-value statistic was reported as 0.55 for the liver and 0.9156 for the plasma. The initial model indicates that direct physiological kinetics in the rat hepatic system adequately describe the translocation of plutonium citrate between the liver and the vascular system for systemic exposure in rats. A secondary experiment was conducted to examine a limited effort to optimize two transfer parameters that underperformed in the initial model. The structure of the physiologically informed model permitted physiological interpretation of the optimized transfer rates and strengthened the confidence in the optimized parameters. The study supports the premise that physiologically informed a priori transfer rate estimates can be employed in an empirical modeling process.
Key Words: Plutonium, Internal Dosimetry, PBPK, biokinetic model, rat hepatic system, AIC. |