A consideration of age-dependent differences in susceptibility to organophosphorus and pyrethroid insecticides

Abstract

Evidence that neonates are more sensitive than adults to organophosphorus (OP) and pyrethroid insecticides is largely based on studies that compare toxicity at acute lethal doses. Under such circumstances, the greater susceptibility of the neonate appears to be due to limited metabolic capacity rather than an inherent difference in the sensitivity of target sites. For purposes of risk assessment with food-use pesticides, the more relevant issue is whether the neonate is more sensitive than the adult to lower levels of exposure, approximating levels used to establish acceptable residue limits (tolerances) on various food products. If infants and children are not more sensitive to environmentally-relevant levels of exposure, then the existing tolerances for dietary exposure will provide adequate protection. If, on the other hand, they may be more sensitive, then additional studies with young animals or an additional uncertainty factor may be needed for added protection. This paper examines two sets of studies that address this issue. The first involves multi-generation reproduction studies with rats that were treated with OP insecticides (coumaphos, fenamiphos, tribufos, trichlorfon, or oxydemeton-methyl) through the diet and examined for effects, including cholinesterase (ChE) inhibition. The second involves rats that were treated by gavage with an acute dose of a pyrethroid (cismethrin, permethrin, deltamethrin or cypermethrin) to establish relative sensitivity to either a lethal dose or to a low, behaviorally-active dose. The results with the OP insecticides support ChE inhibition as the most sensitive measure of exposure and the critical effect (i.e., the lowest NOEL) for each study was based on ChE inhibition in the adult. The magnitude of ChE inhibition in pups (measured on postnatal day (PND) 4 and 21) was consistently less than for adults at a given dietary level. For the representative Type I pyrethroids, there was no evidence that pups are more sensitive than adults at any dose level. For both Type II pyrethroids, young rats were considerably more sensitive than adults to a lethal dose but not to lower doses. Levels of deltamethrin in whole-brain tissue support kinetics as the basis for the greater sensitivity of young rats to a lethal dose, with the immature systems involved with detoxification being overwhelmed at such high dose levels. These findings indicate that young animals are not more sensitive than adults to lower doses of OP or pyrethroid insecticides. This outcome supports the conclusion that infants and children are protected by existing tolerances, without the need for an additional uncertainty factor.