Development and application of simple pharmacokinetic models to study human exposure to di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP)

Abstract

In a published controlled dosing experiment, a single individual consumed 5mg each of labeled di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) on separate occasions and tracked metabolites in his blood and urine over 48h. Data from this study were used to structure and calibrate simple pharmacokinetic (PK) models for these two phthalates, which predict urine and blood metabolite concentrations with a given phthalate intake scenario (times and quantities). The calibrated models were applied to a second published experiment in which 5 individuals fasted over the course of a 48-h weekend (bottled water only), and their full urine voids were captured and measured for DnBP and DiBP metabolites. One goal of this model application was to confirm the validity of the calibrated models — their validity would be demonstrated if a profile of intakes could be found which adequately duplicated the metabolite concentrations measured in the urine. A second goal was to study patterns of exposure for this group. It was found that all metabolites could be duplicated very well with individual-specific “best-fit” intake scenarios, with one exception. It appears that the model predicted much lower concentrations of the metabolite, 3carboxy-mono-propylphthalate (MCPP), than were observed in all individuals. Modeled as a metabolite of DnBP, this suggests that DnBP was not the major source of MCPP in the urine. For all 5 individuals, the reconstructed dose profiles of the two phthalates were similar: about 6 small bolus doses per day and an intake of about 0.5μg/kg-day. The intakes did not appear to be associated with diary-reported activities (personal hygiene and medication) of the participants. The modeled frequent intakes suggested one (or both) of two possibilities: ongoing exposures such as an inhalation exposure, or no exposure but rather an ongoing release of body stores of the phthalate metabolites from past exposures.