A Pharmacokinetic Model of the Intracellular Dosimetry of Inhaled Nickel

Abstract

The potential associations between exposure to nickel compounds and cancer have been evaluated in both animal and epidemiological studies of occupationally exposed workers. The results of the epidemiological studies suggest that not all nickel compounds are equally carcinogenic, an observation supported by the animal bioassay results. Given the complexity and the differences in the modes of uptake of different forms of nickel by cells and the subsequent delivery of nickel to the nucleus, it would be expected that some forms of nickel would be more potent than others. A physiologically based pharmacokinetic (PBPK) model would be useful in estimating the cellular exposure to nickel resulting from inhalation of the different forms of nickel. To this end, a preliminary model of a tracheobronchial epithelial cell was developed to describe the differences in the extracellular and intracellular kinetics of the different classes of nickel compounds. Data available in the published literature were used to define the initial model parameters. The resulting cellular dosimetry model was able to describe kinetic data on three forms of nickel (soluble chloride and insoluble sulfide and subsulfide). This preliminary model development effort has identified critical data gaps that could be filled by additional research. The ultimate goal will be to integrate a refined cellular dosimetry model with published lung deposition/clearance and systemic distribution/clearance models for nickel. The use of such an integrated PBPK model would allow for more biologically based risk estimates for the inhalation of the different nickel compounds, as well as mixtures of these compounds.

ISDD: A computational model of particle sedimentation, diffusion and target cell dosimetry for in vitro toxicity studies

“…It is surprising, then, given the growing importance of in vitro studies to chemical and particle risk assessment [10] that few efforts [43,54-56] have been directed at developing computational models of dosimetry for in vitro systems. In part, this oversight may be the result of the incorrect belief that in contrast to in vivo , there are no important kinetic or other processes to consider when addressing the issue of target tissue dose in vitro .…”

Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide

“…Although the precise mode of action for nickel carcinogenesis has not been elucidated, nickel ion is considered to be the ultimate carcinogen. For lung tumor induction, the in vivo intracellular delivery of Ni ions is expected to be dependent on toxicity-limited exposure levels, clearance, cellular uptake, and extra and intracellular particle dissolution (e.g., Benson et al, 1992;Costa and Mollenhauer, 1980;Costa et al, 1981;Goodman et al, 2011;Hack et al, 2007).…”

Evaluation of the Toxic Potency of Selected Cadmium Compounds on A549 and CHO-9 Cells

“…For most heavy metals, there have been reports which indicate that the bioavailability of a metal and, in consequence, its toxic effect, is affected by its physicochemical form and the resulting solubility in water [17,18,19]. The results indicated that solubility in water was not the main factor which affected toxicity of cadmium compounds.…”