Interspecies variation in toxicity of cholinesterase inhibitors

The chapter discusses how various species differ in response to anticholinesterases (anti-ChEs), and proposes potential causes, focusing on pharmacokinetics and pharmacodynamics (i.e., how the body handles the compound and the mechanism of action of the compound). Cholinesterase (ChE) inhibition by organophosphorus compounds (OPs), and to a lesser extent carbamates (Cms), has been studied extensively as the primary mechanism of toxicity for these broad-spectrum insecticides. Although several factors must be considered in toxicology testing of anti-ChEs, including the specific compound in question, species, and age, as well as level and duration of exposure, the chapter focuses on interspecies variability. Various species respond differently to anti-ChEs. Response, recovery, and reversal depend on both the species affected and the compound. Abundant studies exist on various species, from the intended target group (insects) to animals vulnerable to unsolicited effects, including fish, amphibians, birds, and mammals. These interspecies comparisons seek to improve species selectivity, and to extrapolate toxicity testing between unrelated species for regulatory purposes. First, to improve selectivity for target species, it would be helpful to exploit the differences between species. Second, similarities among unrelated species provide insight into conserved mechanisms of action and toxicity. The extrapolation of toxic effects from animal testing to humans may impact human health and safety by providing a basis for setting reference dose levels. At present, uncertainty factors are applied to account for interspecies variability from experimental animals to humans, as well as intraspecies variability to account for the sensitive individuals within a species.