PRINCIPLES OF TOXICOLOGY - Biology East Borneo

2.4 DISPOSITION: DISTRIBUTION AND ELIMINATION 49the kidney, or of loss of a volatile chemical in expired air), this steady state should be directlyproportional to both the magnitude of exposure and the biological half-life.If exposure were truly constant, the plateau level would be constant also. More commonly, exposureis intermittent, in which case blood concentrations at steady state will cycle in a way that reflects theabsorption and elimination characteristics of the compound as well as the exposure pattern (Figure2.10). However, on a larger timescale this cycling will take place about a constant mean that ispredictable from the equivalent constant exposure rate and the biological half-life. This is one of thereasons why biological half-life is such an important attribute. Together with exposure rate, itdetermines mean steady-state blood level irrespective of whether exposure is continuous or intermittent.However, the individual exposed to large amounts of a substance at wide intervals will experiencegreater peak concentrations in blood and tissues following each new exposure than will an individualexposed to the same total amount as frequent small exposures. If the large peak concentrations areassociated with toxicity or with saturation of elimination processes, then it becomes important toconsider the pattern of administration as well as the equivalent mean exposure rate.Physiologically Based Kinetic Models Physiologically based kinetic (PBK) models are simplifiedbut anatomically and physiologically reasonable models of the body. Tissues are selected or groupedaccording to their perfusion (blood flow) characteristics and whether they are sites of absorption orelimination (by excretion or metabolism). The model design process is facilitated by reference tocompilations of anatomic and physiologic data, including tissue and organ perfusion rates, that arenow widely available.Within this general structural framework, the kinetic behavior of the selected chemical is modeled.A key question is how the chemical is taken up into tissues. When flow-limited kinetics are assumed,the chemical is presumed to be in equilibrium between each tissue group and the venous blood leaving_Figure 2.10 The relationship between average concentration C(n), calculated for repetitive administation, and thetime course of concentration change during continuous administration of a hypothetical compound. Cmax and Cminare the maximum and minimum concentrations in each time interval between doses, assuming instantaneousdistribution of each successive dose. (Reproduced with permission from O’Flaherty, 1981. Figure 5-4.)