US EPA

675577 

Journal Article 

Abstract 

Using a PBPK model to explore mechanisms of observed pharmocokinetic differences of phthalates across life-stages in rats 

Clewell, RA; Kremer, JJ; Anderson, M; Borghoff, S 

2006 

1 

Toxicologist
ISSN: 0731-9193 

TOX/6001807 

90 

1-S 

259 

English 

Phthalic acid diesters are ubiquitous environmental contaminants resulting from their use in plastics. Human exposure occurs primarily via water and food consumption, though it can also result from iv treatments and blood transfusions. Dibutyl phthalate (DBP) disrupts male sexual development through testosterone inhibition and fertility through reduced spermatogenesis. Previously, separate PBPK models were developed for serum metabolite kinetics in adult male (Keys et al, Toxicol Sci 53, 173-184) and pregnant female rats. They have now been combined using a common description of in vivo kinetics and life-stage specific physiology. To enhance utility for human extrapolation, descriptions were added for potential biomarkers from each major metabolic route (hydrolysis, glucuronidation, hydroxylation), and enterohepatic recirculation, urinary and fecal excretion, and placental transfer. Parameters were obtained from literature or fitted against data in the male rat. The model successfully describes biliary and fecal excretion (50 and 9% of dose), and serum and urine DBP, monobutyl phthalate (MBP), MBP glucuronide (MBPG) and total 14C after 1 and 10 mg/kg DBP iv. It also reproduces serum MBP after moral MBP (34 mg/kg) adn DBP (43-857 mg/kg) dosing. The model was tested in gestation after adding prenatal growth and placental transfer. From the fit to data (50-250 DBP po, and 10-50 MBP iv), glucuronidation appears to be increased in the pregnant female. Fetal UDPGT and glucuronidase activity leads to increased maternal serum MBP. Phthalate kinetics in both adult and fetus (GD19) are dominated by cycling of metabolites between free and conjugated forms. Extrapolation to the human will be useful in predicting target tissue dosimetry across life-stages and exposures. It could also inform biomonitoring by supporting the estimation of phthalate exposure from readily measured biomarkers, such as urine metabolite levels. 

Pregnancy; Rats; Animals; Female; Models, Biological; Phthalic Acids/PHARMACOKINETICS/TOXICITY; Environmental Pollutants/PHARMACOKINETICS/TOXICITY; Fetal Development/DRUG EFFECTS; Aging/METABOLISM; NO CAS RN