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    
Abstract/OtherAbstract:
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.
Authors:
Charles Timchalk
Related Documents :
6283879 - Inhibition of basal and stimulated gastric acid secretion by an enkephalin analogue.
12420319 - Structure of the tarsi in some stenus species (coleoptera, staphylinidae): external mor...
1899009 - Excitation of neurons in the medullary raphe increases gastric acid and pepsin producti...
6304819 - The role of the asp-32 residue of cholecystokinin in gastric acid secretion and gastrin...
19000699 - Dual role of nitric oxide in gastric hypersecretion in the distended stomach: inhibitio...
7600619 - Synthesis of 4-(phenylamino)quinoline-3-carboxamides as a novel class of gastric h+/k+-...
2770059 - Effects of diltiazem on plasma uric acid level and renal uric acid excretion in rats.
2338079 - Multiple fatty acid binding to albumin in human blood plasma.
22475819 - Net endogenous acid production is associated with a faster decline in gfr in african am...
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    
Affiliation:
Battelle, Pacific Northwest Division, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland, WA 99352, USA. charles.timchalk@pnl.gov
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Acetic Acids / blood,  pharmacokinetics*,  toxicity
Animals
Body Weight / drug effects
Dogs
Glomerular Filtration Rate
Half-Life
Herbicides / blood,  pharmacokinetics*,  toxicity
Humans
Kidney / metabolism*
Metabolic Clearance Rate
Rats
Risk Assessment
Species Specificity
Tissue Distribution
Chemical
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


Previous Document:  Report in Europe of nasal myiasis by Rhinoestrus spp. in horses and donkeys: seasonal patterns and t...
Next Document:  Effects of S-adenosylmethionine on intrabiliary glutathione degradation induced by long-term adminis...