Abstract
Physiologically based pharmacokinetic (PBPK) models integrate both chemical- and system-specific information into a mathematical framework, offering a mechanistic approach to predict the internal dose metrics of a chemical and an ability to perform species and dose extrapolations. Bisphenol A (BPA), because of its ubiquitous presence in a variety of consumer products, has received a considerable amount of attention from the public and regulatory bodies. PBPK models using deuterated BPA were developed for immature and adult rats and non-human primates and for adult humans to understand better the dosimetry of BPA. The focus of the present paper is to provide a rationale for interpreting species- and age-related pharmacokinetics of BPA. Gastrointestinal tract metabolism was an important consideration to predict unconjugated BPA serum kinetic profiles in adult and immature rats and monkeys. Biliary excretion and enterohepatic recirculation of BPA conjugates (BPA-c) accounted for the slowed systemic clearance of BPA-c in rats. For monkeys, renal reabsorption was proposed as a mechanism influencing systemic clearance of BPA-c. The quantitative understanding of the processes driving the pharmacokinetics of BPA across different species and life stages using a computational modeling approach provides more confidence in the interpretation of human biomonitoring data and the extrapolation of experimental animal findings to humans.
Highlights
Based pharmacokinetic (PBPK) modeling, with its integration of physiological and biochemical processes, provides a quantitative description of the pharmacokinetics of the parent chemical and its metabolite(s)
Compared with empirical compartmental models that lack physiological and biochemical features, Physiologically based pharmacokinetic (PBPK) models allow for extrapolation of the kinetic behavior of chemicals across routes of exposure, doses and species
PBPK models help reduce the uncertainty associated with extrapolation of toxicity findings in laboratory animals to humans
Summary
Based pharmacokinetic (PBPK) modeling, with its integration of physiological and biochemical processes, provides a quantitative description of the pharmacokinetics of the parent chemical and its metabolite(s). Hepatic conjugation of BPA was determined by fitting serum d6-BPA time course data from i.v. dosing, using a first order metabolic constant (Doerge et al, 2010b).
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