Biological and physiological factors involved in disposition of dioxin and related compounds

Over the past several years there has been renewed interest in developing physiologically-based pharmacokinetic models for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related chemicals in various animals and people. These models have improved our understanding of the quantitative relationships among the various factors that regulate TCDD disposition. While certain aspects of disposition are well established, other observations raise a number of issues that have to be addressed in developing a more comprehensive model description. This contribution discusses certain of these issues. (1) Are there specific binding sites for TCDD in tissues other than the liver and does TCDD exposure alter the concentration of these binding sites? (2) In what manner does direct toxicity of TCDD alter tissue disposition? (3) What is the expected impact of physiological changes associated with normal growth and aging on TCDD tissue disposition? The effort to create a more integrated, physiologically-based biologically-realistic model of TCDD dosimetry suggests a number of experiments. These include examining changes in the biological determinants of disposition over time and evaluating factors involved in the tissue dosimetry of TCDD in non-hepatic tissues.