Differences in sensitivity of children and adults to chemical toxicity: the NAS panel report

The National Academy of Sciences (NAS) Committee on Pesticides in the Diets of Infants and Children worked for some 4 years to evaluate the extent and the health-related consequences of exposure of infants and children to pesticides. The focus of this paper is on deliberations and recommendations of the committee relevant to protection of infants and children from toxic effects of pesticides. The most comprehensive data available for contrasting the toxicity of chemicals in the young and adults were compilations of rodent mortality studies. Age-dependent differences in chemical lethality were less than 1 order of magnitude and usually varied no more than 2- to 3-fold. Findings in studies of pesticides and other chemicals revealed that toxicity was age- and compound-dependent. The younger and more immature the subject, the more different its response from that of an adult. Substantial anatomical, biochemical, and physiological changes occur during infancy, childhood, and adolescence. These maturational changes can substantially affect the absorption, distribution, metabolism, and elimination of chemicals. The net effect of immaturity on pharmacokinetics and pharmacodynamics is difficult to predict. Measurements of physiological functions in different age groups can be made and input into physiologically based pharmacokinetic (PBPK) models. The committee felt that PBPK models could be effectively utilized for different exposure scenarios, to predict the time course of potentially toxic chemicals and metabolites in different organs of children. The committee recognized that maturing organ systems of infants and children may be susceptible to injury by chemicals. There may be developmental periods (i.e., windows of vulnerability) when the endocrine, reproductive, immune, visual, or nervous systems are particularly sensitive to certain chemicals. The committee recommended early assessments using sensitive indices of injury to these organ systems of test animals. Only limited information was available on the therapeutic efficacy and toxicity of drugs in pediatric populations. The most definitive data were maximally tolerated doses (MTDs) of chemotherapeutic agents. MTDs were frequently higher for children than adults, though the differences between age groups were usually < or =2. It was concluded by the NAS committee that immaturity does not necessarily entail greater sensitivity to chemical toxicity; age-dependent toxicity is chemical-dependent; and the existing 10-fold interspecies uncertainty factor provides adequate protection of infants and children, based on current knowledge.