Situations with enhanced chemical risks due to toxicokinetic and toxicodynamic factors

Recognizing toxicokinetic and toxicodynamic variability is important in risk assessment of chemicals and may help to explain interindividual differences in susceptibility in exposed populations. Both toxicokinetic and toxicodynamic factors may be influenced by age and disease processes and show genetic polymorphic variation. Decreased metabolic activity in the very young or very old may enhance chemical toxicity caused by the parent chemical. Similarly, disease processes affecting hepatic metabolism and renal excretion may delay inactivation of many xenobiotics. Genetic polymorphisms may enhance toxicity in rapid metabolizers when the toxicity is caused by a reactive intermediate and increase toxicity in slow metabolizers when the toxicity is caused by a parent chemical. Some cells of the developing conceptus are exquisitely sensitive to chemical exposure. Also, organs and tissues of newborns and elderly individuals may show increased responses toward xenobiotics. In addition, disease-induced altered receptor sensitivity and tissue repair may result in enhanced chemical toxicity. Further, tissue antioxidant defense against radical damage may be compromised under nutritional deficiencies and starvation. Hereditary peculiarities in individual responses to environmental chemicals may be due to polymorphic variation of receptor proteins and tissue repair enzymes, although the database for such variation is quite limited.