The chlorophenoxy herbicide MCPA: a mechanistic basis for the observed differences in toxicological profile in humans and rats versus dogs.

Metabolism data for MCPA in rat, dog and human shows a single oral dose is quantitatively and rapidly absorbed with evidence of non-linear kinetics at >100 mg/kg bw. The extent of metabolism is low and consistent between rat and human, with substantially higher metabolic conversion in dog. Parent accounts for 50%-67% dose in rat, ∼40% in human and 2%-27% in dog. No dog specific metabolite is apparent.In rat and human, MCPA and metabolites are rapidly eliminated in urine (65%-70% within 24 h) but in dog, excretion is via urine and faeces (20%-30% within 24 h), with renal excretion saturating between 5 and 100 mg/kg bw.The species difference in excretion is reflected in pharmacokinetics. Terminal half-life is similar in rat and human (15-17 h) but higher in dog (47 h). Modelling shows species differences in single dose kinetics profoundly affect systemic exposure following repeat dosing.The difference in renal excretion and systemic exposure of MCPA between dogs and rats has been attributed to species differences in active transporters (OAT1/OAT3). A new in vitro flux study in renal proximal tubules supports this hypothesis with net secretion in rat and human of a similar magnitude but significantly less in dog.

Potential impact of ABCB1 (p-glycoprotein) polymorphisms on avermectin toxicity in humans.

Several members of the ATP binding cassette (ABC) transporter protein superfamily perform xenobiotic efflux functions in mammals, limiting gut absorption, mediating excretion, and controlling entry of a wide range of chemicals to sensitive compartments such as brain, testes and foetus. Perhaps the best characterised of these is p-glycoprotein (gene name ABCB1/MDR1), a barrier epithelia expressed protein with structurally diverse substrates, including the avermectin pesticides. In specific mouse and dog strains, ABCB1 mutations have been identified that result in loss of p-glycoprotein function in the blood brain barrier (BBB) and increased susceptibility to avermectin neurotoxicity. As yet no large rearrangements of the human ABCB1 gene analogous to those in the mouse and dog have been identified. However, numerous human ABCB1 single nucleotide polymorphisms (SNPs) have been identified, the allelic frequencies of which vary with ethnicity. There is no clear consensus on whether or not SNPs, or combinations of SNPs, reduce human p-glycoprotein functionality. However, recent in vivo human data indicate that the two commonest ABCB1 haplotypes both exhibit full BBB functionality. We discuss here the role of p-glycoprotein in limiting brain absorption of avermectin pesticides, as well as the potential impact of the reported functional effects and population frequencies of known ABCB1 polymorphisms on avermectin pesticide risk assessments.