Approaching a closer surrogate for the biologically effective dose with subcellular partitioning-based toxicokinetic models

Abstract

A general concept in risk assessment isthat a threshold of exposure exists abovewhich adverse effects are initiated. Toxicityis related to the target-site concentrationor the biologically active dose. Although itis often a huge challenge to measure thespecific dose metric of metal toxicity, sig-nificant progress has been obtained toapproach closer to the target-site concen-tration. Such developments are reviewedin the present study. In addition, a generalframework to simulate the subcellularmetal partitioning, which is supposed toaccount for the internal metal sequestra-tion, is developed and applied to variousmetals. The framework allows for delineat-ing mechanisms of internal metal sequestration. Moreover, the specificity in these mechanisms,which varies among metals, species, and exposure conditions, might explain the complicated rela-tionship between the internal concentration and metal toxicity. Attention should be paid to thedata requirements as the high number of unknown parameters might be accompanied by poten-tial uncertainties. In addition, future efforts should focus on linking the concentration of metals insensitive fractions and toxicological effects.