Derivation of a Bisphenol a Oral Reference Dose (RfD) and Drinking-Water Equivalent Concentration∗

Abstract

Human exposure to bisphenol A (BPA) is due to that found in the diet, and BPA and its metabolites were detected at parts per billion (or less) concentrations in human urine, milk, saliva, serum, plasma, ovarian follicular fluid, and amniotic fluid. Adverse health effects in mice and rats may be induced after parenteral injection or after massive oral doses. Controlled ingestion trials in healthy adult volunteers with 5 mg d16-BPA were unable to detect parent BPA in plasma despite exquisitely sensitive (limit of detection = 6 nM) methods, but by 96 h 100% of the administered dose was recovered in urine as the glucuronide. The extensive BPA glucuronidation following ingestion is not seen after parenteral injection; only the parent BPA binds plasma proteins and estrogen receptors (ER). The hypothesis that BPA dose-response may be described by a J- or U-shape curve was not supported by toxicogenomic data collected in fetal rat testes and epididymes (after repeated parenteral exposure at 2-400,000 microg/kg-d), where a clear monotonic dose-response both in the numbers of genes and magnitude of individual gene expression was evident. There is no clear indication from available data that the BPA doses normally consumed by humans pose an increased risk for immunologic or neurologic disease. There is no evidence that BPA poses a genotoxic or carcinogenic risk and clinical evaluations of 205 men and women with high-performance liquid chromatography (HPLC)-verified serum or urinary BPA conjugates showed (1) no objective signs, (2) no changes in reproductive hormones or clinical chemistry parameters, and (3) no alterations in the number of children or sons:daughters ratio. Results of benchmark dose (BMD10 and BMDL10) calculations and no-observed-adverse-effect level (NOAEL) inspections of all available and reproducible rodent studies with oral BPA found BMD and NOAEL values all greater than the 5 mg/kg-d NOAELs from mouse and rat multigeneration reproduction toxicity studies. While allometric and physiologically based pharmacokinetic (PBPK) models were constructed for interspecies scaling of BPA and its interaction with ER, multigeneration feeding studies with BPA at doses spanning 5 orders of magnitude failed to identify signs of developmental toxicity or adverse changes in reproductive tract tissues; the 5-mg/kg-d NOAELs identified for systemic toxicity in rats and mice were less than the oral NOAELs for reproductive toxicity. Thus, it is the generalized systemic toxicity of ingested BPA rather than reproductive, immunologic, neurobehavioral, or genotoxic hazard that represents the point of departure. Using U.S. Environmental Protection Agency (EPA) uncertainty factor guidance and application of a threefold database uncertainty factor (to account for the fact that the carcinogenic potential of transplacental BPA exposure has yet to be fully defined and comprehensive neurobehavioral and immunotoxicologic evaluations of BPA by relevant routes and at relevant doses have yet to be completed) to the administered dose NOAEL resu...

Letter to the Editor

“…The relatively few regulatory testing guidelines of large multigeneration reproductive toxicology studies are under governmental guidelines and GLPs, with oral routes of administration, a larger number of groups (minimum 4), large numbers of animals/group, and validated endpoints (e.g., Myers et al, 2008;Tyl, 2009). The dietary BPA multigeneration studies (under EPA and OECD testing guidelines and GLPs) in CD (SD) rats (Tyl et al, 2002) and CD-1 (Swiss) mice (Tyl et al, 2008c) Gray et al (2004), Goodman et al (2006), Willhite et al (2008, and others. The Tyl studies reported no systemic effects at or below 5 mg/kg/day (down to less than 1 μg/kg/day) and no reproductive/developmental effects at or below 50 mg/kg/day in either species.…”

Bisphenol-A in Canned Food Products: Is it Really Required?

“…In contrast, there are research studies that do not agree with the above conclusions and indicate that there is no immunologic, neurologic, genotoxic or carcinogenic risk for humans by oral ingestion of BPA (15).…”

Courage for simplification and imperfection in the 21st century assessment of “Endocrine disruption”

“…thus beyond the controversial association of higher risk for disease in humans and the even more controversially discussed results of animal studies, the historical approach of toxicological risk assessment, including allometric scaling and pharmacologically based pharmacokinetic (PBPK) models with interspecies scaling, interaction with the eR, determination of actual human exposure, use of safety factors (NRC, 2000), etc., would not provide for an increased endocrine disruptive health risk for humans via exposure to BPA (Goodman et al, 2006;Chapin et al, 2008;Willhite et al, 2008;Goodman et al, 2009). the latter view is presently shared by all expert teams of national authorities involved in human risk assessment of BPA.…”