Sex differences in 4-tert-octylphenol toxicokinetics: Exploration of sex as an effective covariate through an in vivo modeling approach

Abstract

4-tert-octylphenol (4-tert-OP) is a potentially harmful substance, which is found widely in the environment. Nevertheless, information on the in vivo toxicokinetics of 4-tert-OP is lacking, and quantitative risk assessment studies are urgently needed. Therefore, we aimed to quantitatively identify differences in the toxicokinetics of 4-tert-OP and its distribution among tissues between sexes. To this end, following exposure of male and female rats to 10 or 50 mg/kg 4-tert-OP orally and 4 or 8 mg/kg 4-tert-OP intravenously, we conducted a quantitative analysis of samples using ultra-high performance liquid chromatography-tandem mass spectrometry. The results revealed that the 4-tert-OP plasma concentration profiles differed between sexes; however, systemic absorption of 4-tert-OP through the gastrointestinal tract occurred within 0.5 h of exposure in both sexes. Although small, the excretion percentage of 4-tert-OP in urine and feces was lower in males than females (0.06-0.08% vs. 0.82-1.11% of exposure). Significant sex differences were also confirmed in the tissue distribution patterns of 4-tert-OP, and overall, the average tissue distribution in males was lower than that in females. The distribution of 4-tert-OP to liver, adipose, spleen, kidney, brain, and lung in both sexes was predominant. A covariate exploration modeling approach revealed that sex explained the differences in 4-tert-OP toxicokinetics between sexes. These significant differences in the toxicokinetics and tissue distribution of 4-tert-OP between sexes will be important for the scientific precision human risk assessment of 4-tert-OP.

Keywords: 4-tert-octylphenol; Covariate; Modeling; Sex differences; Tissue distribution; Toxicokinetics.