A toxicokinetic model for predicting the tissue distribution and elimination of organic and inorganic mercury following exposure to methyl mercury inanimals and humans. I. Development and validation of the model using experimental data in rats

The objective of this study was to develop a biologically based dynamic mod el for predicting the distribution and elimination of methyl mercury and it s metabolite, inorganic mercury, under a variety of exposure scenarios in r ats. A model is proposed based on a multicompartment approach; each compart ment represents an organ or a group of organs or an excreta. The model tran slates into a set of coupled differential equations taking into account int erorgan rates of exchanges and excretion together with the biotransformatio n process. The free parameters of the model are determined from statistical fits to the experimental data of the Farris ef al. (Toxicol. Appl. Pharmac ol. 119, 74-90, 1993) study on the time profiles of blood and tissue concen trations and cumulative excretions. The vast range of time scales that gove rn tissue absorption, distribution, biotransformation, and excretion served to solve the model step by step. This interplay of time scales in the rate s explains the buildups and slow attrition of inorganic mercury in certain key organs such as the brain and the kidney, which are also the sites of th e more important toxic effects. The model was validated on additional exper imental data provided by Norseth and Clarkson (Arch. Environ. Health 21, 71 7-727, 1970) and Thomas et al. (Environ. Res. 41, 219-234, 1986; Environ. R es. 43, 203-216, 1987), This approach, when adapted to humans, allows the r econstruction of the time course of blood and tissue concentrations, starti ng from easily accessible data on hair, urine, and feces (see companion art icle by Carrier et al. (Toxicol. Appl. Pharmacol. 171, 000-000.) (C) 2001 A cademic Press.