Life-Stage-, Sex-, and Dose-Dependent Dietary Toxicokinetics and Relationship to Toxicity of 2,4-Dichlorophenoxyacetic Acid (2,4-D) in Rats: Implications for Toxicity Test Dose Selection, Design, and Interpretation
| Autor: | Mary Sue Marty, Adam W. Perala, Shakil A. Saghir, Larry Hammond, James S. Bus, Carol L. Zablotny, Barbara H. Neal, Julie K. Passage |
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| Rok vydání: | 2013 |
| Předmět: |
Male
PK medicine.medical_specialty Organic anion transporter 1 Offspring TK 2 4-D Toxicology Rats Sprague-Dawley Sex Factors Pharmacokinetics Internal medicine Lactation Toxicity Tests toxicokinetics medicine Animals Toxicokinetics development perinatal 2 4-dichlorophenoxyacetic acid Dose-Response Relationship Drug biology Body Weight Area under the curve toxicity Feeding Behavior Diet Rats Endocrinology medicine.anatomical_structure Area Under Curve rats Toxicity biology.protein Gestation Female pharmacokinetics Research Article |
| Zdroj: | Toxicological Sciences |
| ISSN: | 1096-0929 1096-6080 |
| Popis: | Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating,2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed ≥ 1200 ppm (63 mg/kg/day) for P1 males and between 200 and 400 ppm (14-27 mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21-35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies. |
| Databáze: | OpenAIRE |
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