Pharmacokinetics of bisphenol A in neonatal and adult rhesus monkeys

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Abstract

Bisphenol A (BPA) is a high-production volume industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA in urine of > 90% of Americans aged 6–60 is controversial because of the potential for endocrine disruption, particularly during perinatal development, as suggested by in vitro, experimental animal, and epidemiological studies. The current study used LC/MS/MS to measure serum pharmacokinetics of aglycone (active) and conjugated (inactive) BPA in adult and neonatal rhesus monkeys by oral (PND 5, 35, 70) and intravenous injection (PND 77) routes using d6-BPA to avoid sample contamination. The concentration-time profiles observed in adult monkeys following oral administration of 100 μg/kg bw were remarkably similar to those previously reported in human volunteers given a similar dose; moreover, minimal pharmacokinetic differences were observed between neonatal and adult monkeys for the receptor-active aglycone form of BPA. Circulating concentrations of BPA aglycone were quite low following oral administration (< 1% of total), which reflects the redundancy of active UDP-glucuronosyl transferase isoforms in both gut and liver. No age-related changes were seen in internal exposure metrics for aglycone BPA in monkeys, a result clearly different from developing rats where significant inverse age-related changes, based on immaturity of Phase II metabolism and renal excretion, were recently reported. These observations imply that any toxicological effect observed in rats from early postnatal exposures to BPA could over-predict those possible in primates of the same age, based on significantly higher internal exposures and overall immaturity at birth.

Introduction

Bisphenol A (2,2-bis-(p-hydroxyphenyl)-2-propane, BPA), one of the highest production volume industrial chemicals (> 109 kg/year), is used as the monomer for polycarbonate plastics and as glycidyl ethers in epoxy resins (National Toxicology Program, 2008, Willhite et al., 2008). Shatter-proof polycarbonate plastic is used in many common consumer products, including beverage containers and medical devices. Epoxy resins are used as liners for water pipes, metal cans for food and beverages, and as dental sealants. Hydrolysis or leaching of unreacted monomer can release low levels of BPA that lead to human exposure. Of particular concern are products affecting young children, including infant formula (Ackerman et al., 2010), polycarbonate bottles (Carwile et al., 2009), and medical devices used in neonatal intensive care units (NICU; Calafat et al., 2009). In the U.S. population, urinary biomonitoring indicates that current adult exposure to BPA, estimated at ≤ 1 μg/kg bw/day, is frequent and pervasive (Calafat et al., 2008, Lakind and Naiman, 2010). Children typically have the highest exposures, with daily estimates of from all sources in the range of 0.1–10 μg/kg body weight (bw)/day (NTP, 2008). The U.S. Food and Drug Administration (FDA) has estimated mean exposure for BPA from food contact uses to be 0.3, 0.5 and 0.1 μg/kg bw/day for 0- to 1-year-olds, 1- to 2-year-olds and > 2-year-olds, respectively, with 90th percentiles for these same groups of 0.6, 1.1 and 0.3 μg/kg bw/day, respectively (U.S. FDA, 2010). Children undergoing intensive medical procedures in NICU, which often involve parenteral routes of administration, have estimated exposures an order of magnitude higher than those in the general population (Calafat et al., 2009).

Human exposure to BPA is problematic because a wide body of evidence from in vitro and ex vivo studies, experimental animals, and epidemiological studies has indicated the potential for endocrine disruption in a number of organ systems (reviewed by Richter et al., 2007). The main mechanism of action proposed is alteration of estrogen signaling pathways, although effects on androgen and thyroid hormone systems and epigenetic modifications have also been reported. BPA aglycone is well known to possess weak estrogen agonist activity in vitro (i.e., affinity for and transactivation of ERs α and β in the μM range) whereas its glucuronide conjugate is inactive (Snyder et al., 2000; Matthews et al., 2001). While recycling of BPA-glucuronide to its aglycone through the action of tissue glucuronidases has been proposed in context of fetal exposures (Ginsberg and Rice, 2009), no evidence for significant reentry of aglycone BPA from tissues was observed in the circulation of adult and neonatal rats despite high levels of conjugates (Doerge et al., 2010). Many studies involving chronic oral administration of BPA to rodents have been conducted to standards accepted by international regulatory authorities, and they generally reported a lack of adverse effects except at very high doses (National Toxicology Program, 1982, Tyl et al., 2002, Tyl et al., 2008, Stump et al., 2010). In contrast, numerous research-scale mechanistic investigations have reported evidence for rodent toxicities associated with exposures to low doses (≤ 1 mg/kg bw/day) of BPA during critical periods of perinatal development (reviewed in Richter et al., 2007). However, neither the cited guideline-compliant nor the research-scale studies provided assessments of internal exposure to BPA during the perinatal period. The lack of concordance between research-scale and guideline-compliant studies has led to considerable controversy surrounding issues of reproducibility and methodology (Ryan et al., 2010) and the role each type of study should play in regulatory decision-making (Myers et al., 2009).

While some toxic effects from BPA have been noted in adult animals, greater concern comes from exposures during the perinatal period when altered organizational programming can confer increased susceptibility for diseases later in life. Identifying windows of vulnerability is critical to conducting risk assessment for BPA because this is also a function of the ability to rapidly detoxify BPA through Phase II metabolism and excretion. The pharmacokinetics of BPA have been studied extensively in adult, pregnant, lactating, and neonatal rats, mice, non-human primates, and humans (reviewed in Willhite et al., 2008). Unfortunately, limitations in study design often make many of these studies of limited value for risk assessment of low-level human exposures through food contact materials and medical devices. The current study in neonatal and adult rhesus monkeys (Macaca mulatta) uses a similar experimental design to that recently reported on BPA serum pharmacokinetics in neonatal and adult Sprague–Dawley rats (Doerge et al., 2010). Design elements include: use of a dose (100 μg/kg bw) within the linear pharmacokinetic range at a level as close as possible to the range of proposed human exposure, yet high enough to measure both free (i.e., active) and conjugated (i.e., inactive) forms of BPA in serum; use of stable isotope-labeled BPA to avoid possible confounding by background contamination; determinations using sensitive and specific LC/MS/MS methodology; evaluation of oral and intravenous (IV) routes of administration; and comparison between adults and several ages of neonates. The many known similarities to humans in physiology, metabolism, and pharmacology make the developing non-human primate model particularly appropriate to evaluate BPA serum pharmacokinetics and fill important data gaps for risk assessment in children (Chellman et al., 2009).

Section snippets

Reagents

Sigma Chemical Co. (St. Louis, MO) supplied the BPA (> 99.9% purity) and all biochemical reagents. Isotopically labeled 13C12-BPA (99 atom %; Cambridge Isotope Laboratories, Andover, MA) and d6-BPA (99.5 atom %; CDN Isotopes, Pointe-Claire, Quebec) were purchased. Compound purity was determined by LC-UV (200 nm) and full-scan LC-ES/MS. All solvents were HPLC grade and Milli-Q water was used throughout.

Animal handling procedures

Procedures involving care and handling of non-human primates were reviewed and approved by

IV dosing in adult females

Fig. 1 shows plots of log aglycone and total BPA concentrations vs. time (mean ± SD) following administration of an IV dose of 100 μg/kg bw to adult female rhesus monkeys (n = 4). This dosing led to rapid distribution of the parent aglycone from serum (t1/2Distr = 0.63 ± 0.23 h) with a slower terminal elimination phase (t1/2Elim = 3.6 ± 1.3 h). Total BPA (i.e., aglycone plus glucuronide and sulfate conjugates) showed similar (i.e., no significant differences by the t-test) distribution (t1/2Distr = 0.40 ± 0.18 h)

BPA pharmacokinetics in adult monkeys

The pharmacokinetics of aglycone BPA in adult monkeys following IV dosing are characterized by an initial distribution phase (mean half-time 0.4 h), a large volume of distribution (mean 15 L/kg), and elimination (mean half-time 3.6 h). This kinetic profile probably reflects the distribution of lipophilic parent compound out of the circulation into tissues where it is further conjugated before elimination. Elimination half-times for aglycone and total BPA are similar suggesting that there is no

Conclusions

These data in a non-human primate model extend the observations on age-dependence of BPA pharmacokinetics previously reported in rats (Doerge et al., 2010). The opportunity to evaluate the pharmacokinetics of BPA in neonatal monkeys is particularly valuable because such studies are not ethically acceptable in human infants. The experimental design for determining serum pharmacokinetics reported here is identical to that previously reported in rats in that the dose of BPA used is as close as

Acknowledgments

This research was supported in part by Interagency Agreement #224-07-0007 between NCTR/FDA and the National Institute for Environmental Health Sciences/National Toxicology Program. The assistance of Melissa Ferguson (Alpha Genesis Inc.) in conducting the monkey procedures and helpful discussions with Dr. John Young are gratefully acknowledged. This document has been reviewed in accordance with U.S. Food and Drug Administration (FDA) policy and approved for publication. Approval does not signify

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