The toxicokinetic determinants of dioxin and related chemicals depend on three major properties: lipophilicity, metabolism, and binding to CYP1A2 in the liver. Lipophilicity increases with more chlorination and controls absorption and tissue partitioning. metabolism is the rate-limiting step for elimination. The persistent compounds are slowly metabolized and eliminated, and therefore bioaccumulate. Induction of CYP1A2, which is partially under the control of the aryl hydrocarbon receptor (Ahr), leads to hepatic sequestration of TCDD. The structure/activity relationships for induction are different from that for binding to CYP1A2. Binding to this inducible hepatic protein results in non-linear dose dependent tissue distribution: as the dose increases, the relative concentration in extra-hepatic tissues decreases while that in liver increases. The induction of this protein occurs in both animals and people and results in a increase in the liver to fat ratio of these compounds. This effect has a minor impact on free TCDD and serum TCDD at the range of environmental exposure.
The basic determinants of pharmacokinetic behaviour are similar in animals and people. Several robust classical and physiologically based models have been used to describe the kinetic behaviour. They have contributed to the understanding that the apparent half-life is not absolute, but may vary with dose, body composition, age, and sex.
Given that these are persistent, bioacumulative compounds, what is the appropriate dose metric to use to equate risk across species? Free concentration in the target tissue would be the most appropriate measure. However, the body burden, which is highly correlated with tissue and serum concentration, integrates the differential half-lives between species. Much higher daily doses are required in rodents to achieve the same body burden, or tissue concentration, as a lower daily dose in people. Body burden is readily estimated in both people and rodents. Therefore, in order to compare risks between humans and animals, the body burden is the metric of choice. It is important to note that predictions of body burden based on lipid concentrations at high exposures may underestimate the total body burden and over- or underestimate specific tissue concentrations because of the hepatic sequestration. Use of PBPK models can readily allow for interconversion of body burden with tissue concentrations, as well as with daily dose. Less complicated models such as a steady state/ body burden models using first order kinetics will give approximately the same results at exposures in the environmental range.
There is a range of apparent half-lives for the various PCDDs, PCDFs, and dioxin-like PCBs. However, the TEQ is driven by a relatively small subset of these compounds. When background exposures are involved, an average half-life similar to that of TCDD may be used, but will underestimate daily exposure in short half-life chemicals and overestimate exposure for those with longer than average half-lives. However, if high levels of exposure are involved, such as in occupational settings, it is important to include the pharmacokinetic data on the individual chemicals.