A simple pharmacokinetic model to characterize exposure of Americans to Di-2-ethylhexyl phthalate

Abstract

A simple pharmacokinetic model to predict concentrations of metabolites of di-2-ethylhexyl phthalate, DEHP, in humans starting from intakes of DEHP was developed and applied. This model predicts serum and urine concentrations of five DEHP metabolites: MEHP, 5oxo-MEHP, 5OH-MEHP, 5cx-MEPP, and 2cx-MMHP. The model was calibrated using data from an individual who dosed himself with 48.5 mg DEHP, and then took blood and urine samples over a 44-h period. The calibrated model was then used in two applications: one on a second set of individuals whose exposure to DEHP was through PVC medical devices in a blood platelet donation procedure, and one on background exposures in the United States (US). Based on 2001/02 NHANES data, median US background urine concentrations of MEHP, 5OH-MEHP, and 5oxo-MEHP are 4.1, 20.1, and 14.0 mg/l, respectively. Creatine and urine volume-correction approaches were used to backcalculate an average daily dose of DEHP in the range of 0.6-2.2 mg/kg per day. A ''background cohort'' including 8 individuals and 57 complete days of urination were assumed to be exposed to1.5 mg/kg per day, spread out in equal doses of 0.3 mg/kg per day at 0900, 1200, 1500, 1800, and 2100 h. The average predicted urine concentrations were 4.6, 15.9, and 9.4 mg/l for MEHP, 5OH-MEHP, and 5oxo-MEHP. These are similar, but the two secondary metabolites are slightly lower than medians found in NHANES. This slight difference between the NHANES results and the background simulations could have been due to differences in metabolism between the individual who provided the calibration data (61-year-old Caucasian male) and the general US population. Another explanation evaluated was that urine concentrations further from the time of exposure may have larger disparities between MEHP and the two secondary metabolites as compared with concentrations measured closer to the time of exposure.

A critical evaluation of the creatinine correction approach: Can it underestimate intakes of phthalates? A case study with di-2-ethylhexyl phthalate

“…On a body weight basis, this 48.5 mg translates to 650 mg/kg. This differs from median intakes determined from urine measurements and the creatinine correction approach that ranges from about 1 mg/kg/day in the United States (Lorber et al, 2010) to 5 mg/kg/day based on urine measurements from German study participants (Wittassek et al, 2007b). As observed, this dose is clearly elevated above background and this is observed also in the urine concentration data.…”

Assessing exposure to phthalates – The human biomonitoring approach

“…Individual variations in (oxidative) metabolism have been discussed as a third possibility for a weaker correlation between MEHP and oxidized metabolites than within the oxidized metabolites [129,147]. However, Lorber et al [147] have shown in their PBPK-model of DEHP that, due to the elimination kinetics of the different DEHP metabolites, depending on the time point of exposure, and the time point of sample collection (morning or afternoon sample), the ratio between MEHP and the oxidized metabolite 5OH-MEHP can vary between 2.89 and 5.4, whereas the ratio between the oxidized metabolites 5OH-MEHP and 5oxo-MEHP varies within a close margin of 1.50-1.78. Therefore, most of the weaker correlation of MEHP with the oxidized metabolites can be explained by differences in elimination kinetics between these metabolites and not inter-individual differences in phthalate metabolism.…”

A biomarker approach to estimate the daily intake of benzene in non-smoking and smoking individuals in Germany

“…Despite its simplicity, a most recent re-evaluation with a more sophisticated model once again accentuated its merits for exposure estimation (Lorber et al, 2009).…”