human blood esterases (Ecobichon and Stephens, 1973). Erythrocyte acetylcholinesterase and plasma pseudocholinesterase and arylesterase activities were measured in premature newborns of varying gestational age as well as in full-term newborns, children of different ages, and adults. Apparent Km values for the three enzymes did not vary significantly with age for a variety of substrates, indicating that the enzyme properties were similar in all age groups. Enzymatic activity, however, did vary significantly with age. Levels of all three enzymes progressively increased during gestation, then rose markedly during the first year of life. Thereafter, erythrocyte cholinesterase and pseudocholinesterase activities increased gradually to adult levels. If one were to assume that one of these peripheral enzymes (e.g., erythrocyte cholinesterase) reflects brain acetylcholinesterase levels, then the most pronounced effects of cholinesterase inhibitors may be expected to occur in newborns, neonates, and infants, since a chemically induced depression of enzymatic activity may be more apparent when baseline cholinesterase levels are relatively low. Ecobichon and Stephens (1973) provided evidence of another mechanism of increased susceptibility of newborns—namely, diminished detoxification capacity (i.e., significantly lower plasma arylesterase and paraoxon hydrolysis activities). Children 2 to 8 years old had slightly lower activities than adults, suggesting that younger children may be somewhat more susceptible to cholinesterase inhibitors. The consequences of brain acetylcholinesterase inhibition on nervous system development and postnatal function remain largely unexplored.

Because of the paucity of data on the age-dependency of acute toxicity of pesticides in humans, the remainder of this section focuses on relative effects of therapeutic agents in pediatric and adult populations. Substantially more information should be available on drugs, due to their common use in all age groups and stringent requirements by the Food and Drug Administration (FDA) for demonstration of safety and efficacy. Data from well-controlled, parallel studies in infants, children, and adults, however, are quite limited for most drugs.

Done et al. (1977) reported what was termed a therapeutic orphan problem—namely, that safety and efficacy for children had not been proved for 78% of new drugs then marketed in the United States. A 1990 survey by the American Academy of Pediatrics revealed that the labeling of 80% of new drugs approved by the FDA between 1984 and 1989 did not include information on pediatric use. The FDA's policy has allowed the marketing of drugs that have been approved for adults but not studied in children, as long as labeling included disclaimers and no instructions about pediatric use. Without adequate information, physicians commonly prescribe such medications for children, possibly placing pediatric populations at increased risk of uncertain efficacy or adverse reactions.



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