Relating Internal BPA Doses to Adverse Effects in Rodent Toxicity Studies

Relatively few literature reports on the biological effects of BPA in experimental animals have evaluated the internal doses achieved.  This information is important to interpret any study toxicity outcomes in relation to human exposure levels.  In cases where these data have been included, the referenced human exposure levels are often at odds with results from controlled pharmacokinetic and clinical studies.  We conducted a subchronic (90 day) study in Sprague-Dawley (SD) rats with the following features: measurement of study material BPA background and serum BPA levels, direct oral dosing of neonates, concurrent reference estrogen (ethinyl estradiol, EE₂) groups, a naïve control, and inclusion of a broad range of in-life endpoints and organ histopathology.  Test articles were orally administered daily in 0.3% carboxymethylcellulose to NCTR SD rats from gestation day 6 until parturition.  Pups were directly dosed from postnatal day 1 (PND 1) because lactational transfer of the test articles is minimal.  BPA doses were 2.5, 8, 25, 80, 260, 840, 2700, 100000, and 300000 μg/kg body weight (bw)/day.  EE₂ doses were 0.5 and 5.0 μg/kg bw/day.  At PNDs 4, 21, and 80, serum was taken at the approximate time of maximal concentration after dosing for measurement of BPA or EE₂.  Unconjugated (bioactive) BPA levels at PND 4 ranged from 0.4 nM at the lowest dose to 49 µM at the highest dose.  At PND 21 and PND 80, the ranges were 0.05 nM - 13.9 µM and 0.02 nM – 0.8 µM, respectively.  Unconjugated BPA was ≤ 5% of total except for the two highest doses at PND 4.  Clear adverse effects of BPA were confined to the two highest dose groups.  BPA affected gestational weight gain at 100,000 μg/kg body weight/day and had multiple reproductive organ and serum clinical chemistry effects in both sexes at 300,000 μg/kg bw/day.  These effects overlapped with EE₂ effects, although toxicities not seen with the reference estrogen were also observed in BPA-treated animals.  In this study, the internal doses of BPA inducing adverse effects were on the order of 10⁶-fold greater than human dietary exposure levels and approximately 10⁴-10⁵ higher than the serum EE₂ levels that produced qualitatively similar effects.  Continuing efforts to detect more subtle effects of BPA at lower doses are underway.