Extensive metabolism and route-dependent pharmacokinetics of bisphenol A (BPA) in neonatal mice following oral or subcutaneous administration.

Orally administered bisphenol A (BPA) undergoes efficient first-pass metabolism to produce the inactive conjugates BPA-glucuronide (BPA-G) and BPA-sulfate (BPA-S). This study was conducted to evaluate the pharmacokinetics of BPA, BPA-G and BPA-S in neonatal mice following the administration of a single oral or subcutaneous (SC) dose. This study consisted of 3 phases: (1) mass-balance phase in which effective dose delivery procedures for oral or SC administration of (3)H-BPA to postnatal day three (PND3) mice were developed; (2) pharmacokinetic phase during which systemic exposure to total (3)H-BPA-derived radioactivity in female PND3 mice was established; and (3) metabolite profiling phase in which 50 female PND3 pups received either a single oral or SC dose of (3)H-BPA. Blood was collected from 5 pups/route/time-point at various times post-dosing, the blood plasma samples were pooled by group, and time-point and samples were profiled by HPLC with fraction collection. Fractions were analyzed for total radioactivity and data used to reconstruct radiochromatograms and to integrate individual peaks. The identity of the BPA, BPA-G, and BPA-S peaks was confirmed using authentic standards and LC-MS/MS analysis. The result of this study revealed that female PND3 mice have the capacity to metabolize BPA to BPA-G, BPA-S and other metabolites after both routes of administration. Systemic exposure to free BPA is route-dependent as the plasma concentrations were lower following oral administration compared to SC injection.

Risk assessment for consumer exposure to toluene diisocyanate (TDI) derived from polyurethane flexible foam.

Polyurethanes (PU) are polymers made from diisocyanates and polyols for a variety of consumer products. It has been suggested that PU foam may contain trace amounts of residual toluene diisocyanate (TDI) monomers and present a health risk. To address this concern, the exposure scenario and health risks posed by sleeping on a PU foam mattress were evaluated. Toxicity benchmarks for key non-cancer endpoints (i.e., irritation, sensitization, respiratory tract effects) were determined by dividing points of departure by uncertainty factors. The cancer benchmark was derived using the USEPA Benchmark Dose Software. Results of previous migration and emission data of TDI from PU foam were combined with conservative exposure factors to calculate upper-bound dermal and inhalation exposures to TDI as well as a lifetime average daily dose to TDI from dermal exposure. For each non-cancer endpoint, the toxicity benchmark was divided by the calculated exposure to determine the margin of safety (MOS), which ranged from 200 (respiratory tract) to 3×10(6) (irritation). Although available data indicate TDI is not carcinogenic, a theoretical excess cancer risk (1×10(-7)) was calculated. We conclude from this assessment that sleeping on a PU foam mattress does not pose TDI-related health risks to consumers.

Development of a method for the determination of bisphenol A at trace concentrations in human blood and urine and elucidation of factors influencing method accuracy and sensitivity.

Bisphenol A (BPA) is an industrial chemical used to make polymers including some used in food contact applications. Virtually complete presystemic clearance of orally administered BPA occurs in humans by metabolism to BPA-glucuronide (BPA-G), but some biomonitoring studies report low concentrations of free (parent) BPA in human blood and urine. Trace contamination of BPA from exogenous sources or hydrolysis of BPA-G to free BPA, either during or after biomonitoring specimen collection, may have contributed to the reported concentrations of free BPA. An analytical method for the determination of free BPA in human blood and urine was developed and validated in two independent laboratories, using the latest generation of high-performance liquid chromatography-tandem mass spectrometry instrumentation to ensure the desired high sensitivity and selectivity. The method was designed to account for and/or eliminate background contamination from all sources and demonstrated that contamination could occur from devices used for specimen collection or storage, as well as other sources. The method employed an internal standard (BPA-d(8)) and demonstrated accuracy and reproducibility in both matrices fortified with BPA or a surrogate analyte ((13)C-BPA) at a low quantitation limit (0.1-0.2 ng/mL). For validation, five replicate samples were analyzed to evaluate reproducibility. Importantly, it was demonstrated that the conditions of the method did not result in the hydrolysis of BPA-G to free BPA, another possible source of error in BPA analysis. Application of the principles defined by this method will be critical to assure valid analytical results in any future biomonitoring studies.

Chronic inhalation exposures of Fischer 344 rats to 1,6-hexamethylene diisocyanate did not reveal a carcinogenic potential.

The polyisocyanates of 1,6-hexamethylene diisocyanate (HDI) find widespread commercial use as components of paints and in the formulation of light-stable polyurethane coating materials. This 2-year study assessed the oncogenicity of the diisocyanate monomer HDI in male and female Fischer-344 rats exposed 6 h/day, 5 days/week to mean analytical air concentrations of 0, 0.005, 0.025, and 0.164 ppm HDI. During the in-life phase, transient eye irritation was observed in 0.164 ppm males, and a slight body weight decrease (5%) in the 0.164 ppm females during the second year of exposure. There were no exposure-related effects on mortality. Compound-related, non-neoplastic histopathologic changes were limited to the respiratory tract and changes were characterized by epithelial tissue reaction to the acute irritant properties of HDI vapor. For tissues of the nasal cavity, the major histopathologic findings were degeneration of the olfactory epithelium characterized by destruction of the epithelial architecture often with narrowing or atrophy and occasional focal erosion or ulceration. In addition, there was variable degeneration of the respiratory epithelium with hyperkeratosis of the epithelium, epithelial and mucus secretory cell hyperplasia, squamous metaplasia, chronic-active inflammation, and errosive or ulcerative changes. These tissue effects along with a statistically significant decrease in body weight of female rats demonstrated attainment of a maximum tolerated dose. There was no evidence of progression of these changes in the nasal epithelium to neoplasia nor evidence of any compound-related neoplastic lesions for any of the other tissues examined. Therefore, it is concluded that HDI did not show a carcinogenic potential in this study.

Developmental neurotoxicity study of dietary bisphenol A in Sprague-Dawley rats.

This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F(1) offspring from dietary exposure during gestation and lactation according to the Organization for Economic Cooperation and Development and U.S. Environmental Protection Agency guidelines for the study of developmental neurotoxicity. BPA was offered to female Sprague-Dawley Crl:CD (SD) rats (24 per dose group) and their litters at dietary concentrations of 0 (control), 0.15, 1.5, 75, 750, and 2250 ppm daily from gestation day 0 through lactation day 21. F(1) offspring were evaluated using the following tests: detailed clinical observations (postnatal days [PNDs] 4, 11, 21, 35, 45, and 60), auditory startle (PNDs 20 and 60), motor activity (PNDs 13, 17, 21, and 61), learning and memory using the Biel water maze (PNDs 22 and 62), and brain and nervous system neuropathology and brain morphometry (PNDs 21 and 72). For F(1) offspring, there were no treatment-related neurobehavioral effects, nor was there evidence of neuropathology or effects on brain morphometry. Based on maternal and offspring body weight reductions, the no-observed-adverse-effect level (NOAEL) for systemic toxicity was 75 ppm (5.85 and 13.1 mg/kg/day during gestation and lactation, respectively), with no treatment-related effects at lower doses or nonmonotonic dose responses observed for any parameter. There was no evidence that BPA is a developmental neurotoxicant in rats, and the NOAEL for developmental neurotoxicity was 2250 ppm, the highest dose tested (164 and 410 mg/kg/day during gestation and lactation, respectively).

Two-generation reproductive toxicity study of dietary bisphenol A in CD-1 (Swiss) mice.

Dietary bisphenol A (BPA) was evaluated in a mouse two-generation study at 0, 0.018, 0.18, 1.8, 30, 300, or 3500 ppm (0, 0.003, 0.03, 0.3, 5, 50, or 600 mg BPA/kg/day, 28 per sex per group). A concurrent positive control group of dietary 17beta-estradiol (0.5 ppm; 28 per sex) confirmed the sensitivity of CD-1 mice to an endogenous estrogen. There were no BPA-related effects on adult mating, fertility or gestational indices, ovarian primordial follicle counts, estrous cyclicity, precoital interval, offspring sex ratios or postnatal survival, sperm parameters or reproductive organ weights or histopathology (including the testes and prostate). Adult systemic effects: at 300 ppm, only centrilobular hepatocyte hypertrophy; at 3500 ppm, reduced body weight, increased kidney and liver weights, centrilobular hepatocyte hypertrophy, and renal nephropathy in males. At 3500 ppm, BPA also reduced F1/F2 weanling body weight, reduced weanling spleen and testes weights (with seminiferous tubule hypoplasia), slightly delayed preputial separation (PPS), and apparently increased the incidence of treatment-related, undescended testes only in weanlings, which did not result in adverse effects on adult reproductive structures or functions; this last finding is considered a developmental delay in the normal process of testes descent. It is likely that these transient effects were secondary to (and caused by) systemic toxicity. Gestational length was increased by 0.3 days in F1/F2 generations; the toxicological significance, if any, of this marginal difference is unknown. At lower doses (0.018-30 ppm), there were no treatment-related effects and no evidence of nonmonotonic dose-response curves for any parameter. The systemic no observable effect level (NOEL) was 30 ppm BPA (approximately 5 mg/kg/day); the reproductive/developmental NOEL was 300 ppm (approximately 50 mg/kg/day). Therefore, BPA is not considered a selective reproductive or developmental toxicant in mice.

Subacute inhalation exposure of rats to 1,6-hexamethylene diisocyanate with recovery period.

In this subacute inhalation toxicity study of 1,6-hexamethylene diisocyanate (HDI), groups of 10 male and 10 female Sprague-Dawley rats were exposed to 0, 0.005, 0.0175, or 0.150 ppm HDI vapor, 5 h/day, 5 days/wk for 15 exposure days and included animals sacrificed 2 wk postexposure. The purpose was to characterize the HDI-induced effects and their reversibility, and to determine a no-observed-adverse-effect level (NOAEL). No compound-related effects were found for body weights, clinical chemistry, urinalysis, hematology, and organ weights. Thus, no evidence of systemic toxicity was found in this study. The exposure-related findings were restricted to the portal of entry, the respiratory tract. Transient signs of sensory irritation were observed after the daily exposure periods, but the principal findings were the histopathologic changes of the nasal epithelium. Generally, an anterior to posterior gradient of incidence and severity was found, and the changes were characterized as acanthosis, erosion, hyperkeratosis, epithelial cell hyperplasia, chronic active inflammation, squamous metaplasia, ulceration, transitional epithelial cell degeneration, goblet-cell hyperplasia, and degeneration of the olfactory epithelium. Varying degrees of concordance between exposure concentration and incidence and/or severity of the histopathologic changes were found. During a 2-wk recovery period, a tendency toward recovery was evident for tissue changes in the nasal cavity. A NOAEL of 0.0175 ppm HDI was determined.