Selected Aspects of the Toxicokinetics and Bioavailability of Cadmium and Lead in Animal and Cellular ModelsEPA Grant Number: U915637
Title: Selected Aspects of the Toxicokinetics and Bioavailability of Cadmium and Lead in Animal and Cellular Models
Investigators: Evans, Timothy J.
Institution: University of Missouri - Columbia
EPA Project Officer: Louie, Nica
Project Period: May 1, 1999 through May 1, 2002
Project Amount: $81,463
RFA: STAR Graduate Fellowships (1999) RFA Text | Recipients Lists
Research Category: Fellowship - Health , Academic Fellowships , Health Effects
The objectives of this research are to fill in data gaps regarding the subacute toxicokinetics and relative bioavailability of cadmium (Cd), following oral exposure in an animal model, and to study factors that affect trophoblastic uptake of divalent lead [Pb(II)] in an in vitro model. It is hypothesized that Cd blood levels can be measured in orally exposed, juvenile swine and that Cd toxicokinetics in this species are associated with tissue metallothionein (MT) levels, as proposed in rodent species and cellular models. Another hypothesis relating to Cd is that assessment of MT induction in various tissues may be useful in estimating the relative bioavailability of Cd in a soil matrix. With regards to Pb(II), it has previously been proposed that Pb(II) competes with divalent calcium [Ca(II)] for cellular uptake, and this hypothesis will be evaluated with respect to trophoblastic cells.
Male, juvenile swine will be orally dosed with varying doses of Cd as cadmium chloride or in a soil matrix, for up to 2 weeks. On selected days of each study, blood samples will be taken prior to dosing and at hourly intervals after the oral administration of Cd. At the end of each experiment, the pigs will be sacrificed, and tissues will be collected for analysis. Blood and tissue Cd concentrations and tissue levels of MT will be determined for the different Cd doses. The data will be analyzed to make inferences regarding the subacute toxicokinetics of Cd and the possible role of MT in the disposition of Cd. Based on the resulting data, attempts will be made to develop additional techniques of estimating the relative bioavailability of Cd in soil matrices. Undifferentiated and differentiated Rcho-1 cells will be grown in culture, harvested, and incubated with the acetoxymethyl ester of indo-1. Indo-1 fluorescence in these cells will be measured after the addition of varying amounts of Pb(II), in the presence or relative absence of extracellular Ca(II), and following the depletion of intracellular Ca(II) stores by thapsigargin. Future experiments will investigate the effects of a variety of factors on indo-1 fluorescence quench in these and other trophoblastic cells.
It is expected that a consistent pattern of blood and tissue Cd concentrations and tissue MT levels will be observed following subacute, oral administration of Cd, and that recommendations can be made concerning the use of this data in Cd relative bioavailability studies. Increased extracellular Pb(II), decreased extracellular Ca(II), depletion of intracellular Ca(II) stores, and cellular alterations associated with trophoblastic differentiation are expected to enhance trophoblastic uptake of Pb(II) in the proposed in vitro model.