Exploring the explanation of age-related sensitivity to a pyrethroid insecticide deltamethrin, in rats

People can be exposed to insecticides in multiple settings and from a variety of routes. During the last ten years, there has been increasing concern that young animals (including humans), in general, may be more sensitive than adults to the toxicity of some pyrethroid insecticides. This dissertation investigates the age-related toxicity of a pyrethroid insecticide, deltamethrin [(S)-alpha-cyano-3-phenoxybenzyl (1R)-3-(2,2dibromovinyl)-2,2-dimethylcyclopropane-carboxylate], in Long Evans, hooded, male rats. Our hypothesis is that postnatal day 21 (PND 21) rats are more sensitive than adults to deltamethrin toxicity due to pharmacokinetic differences. To investigate this hypothesis: (1) a reliable analytical method was developed to quantify deltamethrin tissue concentration in rats; and (2) time course and dose response studies were performed to assess the degree of toxic signs [i.e., salivation and choreoathetosis (jerky, involuntary movements)] and to measure deltamethrin tissue concentrations in PND 21 and adult animals. Time course and dose response studies indicated that: (1) a markedly lower external dosage of deltamethrin was necessary in PND 21 animals to produce similar levels of toxic signs (salivation and choreoathetosis) as observed in adult animals; (2) an equipotent (assessed by degree of salivation and choreoathetosis) dosage of deltamethrin in PND 21 and adult animals produced similar internal concentrations of deltamethrin in both PND 21 and adult animals, but with longer lasting deltamethrin tissue concentrations in the young animals; (3) the same deltamethrin dosage administered to both age groups produced marked salivation and choreoathetosis in PND 21 animals and virtually no salivation or choreoathetosis in adult animals; and (4) the same dosage of deltamethrin produced higher deltamethrin tissue concentrations in PND 21 animals as compared to adults. Liver metabolism studies were conducted to investigate one possible mechanism for age-related differences in toxicity to deltamethrin: young animals are less efficient at the metabolic breakdown of deltamethrin. In vitro studies revealed that both liver carboxylesterases and cytochrome P450s from adult metabolized deltamethrin faster than the liver metabolism of PND 21 animals. In summary, it appears that PND 21 animals are more sensitive to deltamethrin toxicity principally because PND 21 animals detoxify deltamethrin less efficiently than adult animals.