Inter-Species Pharmacokinetic Comparison of Organic Acid Herbicides. Is the Dog a Relevant Species for Evaluation of Human Health Risk?

Abstract

3,5,6-Trichloro-2-pyridinyloxyacetic acid (triclopyr) and 2,4-dichlorophenoxyacetic acid (2,4-D) are widely utilized herbicides that have undergone extensive toxicity and pharmacokinetic analysis. Based on this large data-base, the dog appears to exhibit the lowest No-Observed-Effect Levels (NOEL) relative to other species that have undergone toxicological evaluation. It is proposed that this unique sensitivity of the dog to organic acid herbicides is primarily due to the dog’s low capacity, relative to other species (including humans), to excrete organic acids. The excretion of organic acids, like triclopyr and 2,4-D, in the kidney is the net result of filtration, secretion and reabsorption processes. Although renal clearance mechanisms for organic acids are ubiquitous in mammalian species there are qualitative differences between species that account for observed discrepancies in clearance capacity. The pharmacokinetics and metabolism of triclopyr and 2,4-D are fairly consistent across species (including the dog), these herbicides are rapidly absorbed following oral administration and quickly cleared from the body into the urine predominantly unmetabolized. Aliometric parameter scaling was used to compare the triclopyr and 2,4-D pharmacokinetic parameters across species. The results of this analysis clearly illustrated the decreased capacity of the dog to effectively clear these organic acids relative to other species, including humans. In addition, this decreased clearance capacity of the dog is not compound specific, but is associated with organic acids that share common pharmacokinetic properties: as (1) extensive but reversible plasma protein-binding, (2) weak acids that are highly ionized at physiological pH, (3) limited metabolism of the parent acid, and (4) urinary excretion primarily involving a saturable, active secretion. The most likely mechanism responsible for the lower clearance in the dog, is a low capacity to actively secrete organic acids by the kidney. Other potential mechanisms for the lower clearance such as increased reabsorption from the tubules can not be excluded. This comparative species evaluation of the pharmacokinetics and renal clearance of triclopyr and 2,4-D questions the relevance of using dog toxicity data for the extrapolation of human health risk for these organic acids. Based on the lack of a pharmacokinetic concordance between the dog and other mammalian species it is suggested that the dog is not a reasonable surrogate for humans. Therefore, from a risk assessment perspective, it would seem prudent to utilize toxicity data from other species (e.g. rodents) for extrapolation of human health risk for these organic acid herbicides.