Toxicokinetics in infants and children in relation to the ADI and TDI.

Age-dependent developmental changes in toxicokinetics occur in both rats and humans, particularly in relation to renal function and hepatic xenobiotic metabolism. These processes are immature in humans at birth, especially in the pre-term neonate, but mature rapidly over the first months of life. In consequence the duration of immaturity primarily corresponds to the period of suckling. Similar developmental changes occur in the neonatal rat over the first weeks of life. Rat pups start to consume some of the adult diet in the third week of life, prior to weaning, so that there is a potential for consumption of the adult diet during the period of immaturity. There is an extensive database on the pharmacokinetics of therapeutic drugs in infants and children. The elimination/clearance of many drugs is higher in children than in adults and this difference would apply to other xenobiotics. In consequence, children frequently will have lower body burdens than adults for the same daily intake of a chemical when this is expressed on a body weight basis, as used to describe the ADI (Acceptable Daily Intake) or TDI (Tolerable Daily Intake) (e.g. mg/kg body weight/day). Therefore, an increased safety or uncertainty factor for post-suckling infants and children is not required in relation to age-related differences in toxicokinetics. Indeed, the higher clearance of many xenobiotics (toxicokinetics) by children compared with adults may compensate, at least in part, for increased organ sensitivity (toxicodynamics) during development.