Griffin, R. J., Godfrey, V. B., Kim, Y. C., & Burka, L. T.; “Sex-dependent differences in the disposition of 2,4-dichlorophenoxyacetic acid in Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters;” Drug Metabolism and Disposition, 1997, 25(9), 1065-1071.
2,4-Dichlorophenoxyacetic acid (2,4-D), a widely used broadleaf herbicide, is under investigation in a study of peroxisome proliferators. To supplement that study, male and female rats, mice, and hamsters were dosed with 14C-2,4-D orally at 5 and 200 mg/kg and tissue distributions were determined. Blood, liver, kidney, muscle, skin, fat, brain, testes, and ovaries were examined. At early time points tissues from female rats consistently contained higher amounts of radioactivity than did corresponding tissues from males (up to 9 times). By 72 hr, tissue levels were equivalent and males and females had excreted equal amounts of radioactivity. This sex difference was absent in mice. In hamsters, males had higher tissue levels than females. Taurine, glycine, and glucuronide conjugates of 2,4-D were excreted along with parent. Metabolite profiles differed between species qualitatively and quantitatively; however, differences between sexes were minimal. Plasma elimination curves were generated in male and female rats after iv and oral administration. Kinetic analysis revealed significant differences in elimination and exposure parameters consistent with a greater ability to clear 2,4-D by male rats relative to females. This suggests that at equivalent doses, female rats are exposed to higher concentrations of 2,4-D for a longer time than males and may be more susceptible to 2,4-D-induced toxicity. These sex-dependent variations in the clearance of 2,4-D in rats and hamsters may indicate a need for sex-specific models to accurately assess human health risks. FULL TEXT