ABSTRACT
The use of animals to evaluate the potential adverse effects of xenobiotics (environmental chemicals or therapeutic agents) is required as an essential component of safety and risk assessment to ensure human health. However, many traditional study designs have used direct dosing in adult animals to provide safety data with which to extrapolate for human risk assessment, a practice that provides less than adequate safety data for the pediatric population. The predictive value of the study designs for purposes of risk assessment following direct dosing of xenobiotics to juvenile animals has lagged far behind that of risk assessment based on direct dosing in adult animals or prenatal exposure. Although a considerable volume of material has been written on juvenile or pediatric pharmacokinetics (1), less attention has been given to juvenile or pediatric toxicity studies that employ direct administration of xenobiotics during critical periods of development. Because many nonclinical safety evaluations of therapeutic agents have been conducted in adult animals, many drugs approved for use in the adult human population are still not adequately labeled for use in the pediatric population. Physicians continue to prescribe therapeutic agents off-label for children to treat ailments such as depression, epilepsy, severe pain, gastrointestinal problems, allergies, high blood pressure, and attention deficit hyperactivity disorders (ADHD). Even though many of the drugs prescribed for these indications have been extensively evaluated in adults, the availability of safety or efficacy data obtained from controlled studies in juvenile animals or clinical trials in children continues to lag behind. Historically, physicians have determined the dosage of
therapeutics for use in children based upon professional experience and the child’s body weight. The problems with this approach are that children are not just “little adults,” and the differences in sensitivity between children and adults can be chemical specific. Developing organs or organ systems and metabolic pathways in children and fully developed adult systems can react very differently to drugs. Because of their small stature, infants, and/or children are often assumed to be more susceptible to the toxic effects of drugs or to chemicals in the environment. However, their susceptibility depends on the substance and the exposure situation (e.g., timing of exposure during critical developmental periods). In some cases, there may be no difference in response between children and adults. In other cases, different physiologic and metabolic factors, pharmacokinetics, and behavioral patterns can render children either more or less sensitive than adults.
