Regular Article
A Toxicokinetic Model for Predicting the Tissue Distribution and Elimination of Organic and Inorganic Mercury Following Exposure to Methyl Mercury in Animals and Humans. I. Development and Validation of the Model Using Experimental Data in Rats

https://doi.org/10.1006/taap.2000.9112Get rights and content

Abstract

The objective of this study was to develop a biologically based dynamic model for predicting the distribution and elimination of methyl mercury and its metabolite, inorganic mercury, under a variety of exposure scenarios in rats. A model is proposed based on a multicompartment approach; each compartment represents an organ or a group of organs or an excreta. The model translates into a set of coupled differential equations taking into account interorgan rates of exchanges and excretion together with the biotransformation process. The free parameters of the model are determined from statistical fits to the experimental data of the Farris et al. (Toxicol. Appl. Pharmacol. 119, 74–90, 1993) study on the time profiles of blood and tissue concentrations and cumulative excretions. The vast range of time scales that govern tissue absorption, distribution, biotransformation, and excretion served to solve the model step by step. This interplay of time scales in the rates 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 the more important toxic effects. The model was validated on additional experimental data provided by Norseth and Clarkson (Arch. Environ. Health 21, 717–727, 1970) and Thomas et al. (Environ. Res. 41, 219–234, 1986; Environ. Res. 43, 203–216, 1987). This approach, when adapted to humans, allows the reconstruction of the time course of blood and tissue concentrations, starting from easily accessible data on hair, urine, and feces (see companion article by Carrier et al. (Toxicol. Appl. Pharmacol. 171, 000–000.)

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    Low molecular weight, thiol-containing molecule – HgII complexes are thought to be transported into target cells, where some HgII binds to proteins such as metallothionein and glutathione, resulting in HgII accumulation in target tissues such as the kidney (Bridges and Zalups, 2010). The highest total Hg concentrations are typically found in the liver of mature marine mammals (Arai et al., 2004; Frodello et al., 2000; Woshner et al., 2002) and the kidney of terrestrial mammals (Carrier et al., 2001b; Dietz et al., 2013; Young et al., 2001). Nephrotoxicity is an endpoint of relevance to apex predators in aquatic ecosystems, for example, mature polar bear kidney total Hg concentrations have been observed that exceed the established toxicity threshold for terrestrial mammals of 30 μg g−1 w.w. (Dietz et al., 2013; Sonne et al., 2007).

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