Document Detail

Comparative inter-species pharmacokinetics of phenoxyacetic acid herbicides and related organic acids. evidence that the dog is not a relevant species for evaluation of human health risk.
MedLine Citation:
PMID:  15158559     Owner:  NLM     Status:  MEDLINE    
Phenoxyacetic acids including 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxyacetic acid (MCPA) are widely utilized organic acid herbicides that have undergone extensive toxicity and pharmacokinetic analyses. The dog is particularly susceptible to the toxicity of phenoxyacetic acids and related organic acids relative to other species. Active renal clearance mechanisms for organic acids are ubiquitous in mammalian species, and thus a likely mechanism responsible for the increased sensitivity of the dog to these agents is linked to a lower capacity to secrete organic acids from the kidney. Using published data describing the pharmacokinetics of phenoxyacetic and structurally related organic acids in a variety of species including humans, inter-species comparative pharmacokinetics were evaluated using allometic parameter scaling. For both 2,4-D and MCPA, the dog plasma half-life (t(1/2)) and renal clearance (Clr; mL/h) rates did not scale as a function of body weight across species; whereas for all other species evaluated, including humans, these pharmacokinetic parameters reasonably scaled. This exceptional response in the dog is clearly illustrated by comparing the plasma t(1/2) at comparable doses of 2,4-D and MCPA, across several species. At a dosage of 5mg/kg, in dogs, the plasma t(1/2) for 2,4-D and MCPA were approximately 92-106 and 63 h, respectively, which is substantially longer than in the rat (approximately 1 and 6 h, respectively) or in humans (12 and 11 h, respectively). This longer t(1/2), and slower elimination in the dog, results in substantially higher body burdens of these organic acids, at comparable doses, relative to other species. Although these results indicate the important role of renal transport clearance mechanisms as determinants of the clearance and potential toxicity outcomes of phenoxyacetic acid herbicides across several species, other contributing mechanisms such as reabsorption from the renal tubules is highly likely. These findings suggest that for new structurally similar organic acids, a limited comparative species (rat versus dog) pharmacokinetic analysis early in the toxicology evaluation process may provide important insight into the relevance of the dog. In summary, the substantial difference between the pharmacokinetics of phenoxyacetic acids and related organic acids in dogs relative to other species, including humans, questions the relevance of using dog toxicity data for the extrapolation of human health risk.
Charles Timchalk
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Toxicology     Volume:  200     ISSN:  0300-483X     ISO Abbreviation:  Toxicology     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-05-25     Completed Date:  2004-06-29     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0361055     Medline TA:  Toxicology     Country:  Ireland    
Other Details:
Languages:  eng     Pagination:  1-19     Citation Subset:  IM    
Battelle, Pacific Northwest Division, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland, WA 99352, USA.
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MeSH Terms
Acetic Acids / blood,  pharmacokinetics*,  toxicity
Body Weight / drug effects
Glomerular Filtration Rate
Herbicides / blood,  pharmacokinetics*,  toxicity
Kidney / metabolism*
Metabolic Clearance Rate
Risk Assessment
Species Specificity
Tissue Distribution
Reg. No./Substance:
0/Acetic Acids; 0/Herbicides; 122-59-8/phenoxyacetic acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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