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...

Maximum contaminant levels are used to control potential health hazards posed by chemicals in drinking water, but no primary national or international limits for aluminum (Al) have been adopted. Given the differences in toxicological profiles, the present evaluation derives total allowable concentrations for certain water-soluble inorganic Al compounds (including chloride, hydroxide, oxide, phosphate and sulfate) and for the hydrated Al silicates (including attapulgite, bentonite/montmorillonite, illite, kaolinite) in drinking water. The chemistry, toxicology and clinical experience with Al materials are extensive and depend upon the particular physical and chemical form. In general, the water solubility of the monomeric Al materials depends on pH and their water solubility and gastrointestinal bioavailability are much greater than that of the hydrated Al silicates. Other than Al-containing antacids and buffered aspirin, food is the primary source of Al exposure for most healthy people. Systemic uptake of Al after ingestion of the monomeric salts is somewhat greater from drinking water (0.28%) than from food (0.1%). Once absorbed, Al accumulates in bone, brain, liver and kidney, with bone as the major site for Al deposition in humans. Oral Al hydroxide is used routinely to bind phosphate salts in the gut to control hyperphosphatemia in people with compromised renal function. Signs of chronic Al toxicity in the musculoskeletal system include a vitamin D-resistant osteomalacia (deranged membranous bone formation characterized by accumulation of the osteoid matrix and reduced mineralization, reduced numbers of osteoblasts and osteoclasts, decreased lamellar and osteoid bands with elevated Al concentrations) presenting as bone pain and proximal myopathy. Aluminum-induced bone disease can progress to stress fractures of the ribs, femur, vertebrae, humerus and metatarsals. Serum Al ≥100 µg/L has a 75-88% positive predictive value for Al bone disease. Chronic Al toxicity is also manifest in the hematopoietic system as an erythropoietin-resistant microcytic hypochromic anemia. Signs of Al toxicity in the central nervous system (speech difficulty to total mutism to facial grimacing to multifacial seizures and dyspraxia) are related to Al accumulation in the brain and these symptoms can progress to frank encephalopathy. There are four groups of people at elevated risk of systemic Al intoxication after repeated ingestion of monomeric Al salts: the preterm infant, the infant with congenital uremia and children and adults with kidney disease. There is a dose-dependent increase in serum and urinary Al in people with compromised renal function, and restoration of renal function permits normal handling of systemically absorbed Al and resolution of Al bone disease. Clinical experience with 960 mg/day of Al(OH)(3) (~5 mg Al/kg-day) given by mouth over 3 months to men and women with compromised renal function found subclinical reductions in hemoglobin, hematocrit and serum ferritin. Following adult males and females with reduced ki...

Polyethylene terephthalate, a copolymer of terephthalic acid (TPA) or dimethyl terephthalate (DMT) with ethylene glycol, has food, beverage, and drinking water contact applications. Di-2-ethylhexyl terephthalate (DEHT) is a plasticizer in food and drinking water contact materials. Oral reference doses (RfDs) and total allowable concentrations (TACs) in drinking water were derived for TPA, DMT, and DEHT. Category RfD and TAC levels were also established for nine C(1)-C(8) terephthalate esters. The mode of action of TPA, and of DMT, which is metabolized to TPA, involves urinary acidosis, altered electrolyte elimination and hypercalciuria, urinary supersaturation with calcium terephthalate or calcium hydrogen terephthalate, and crystallization into bladder calculi. Weanling rats were more sensitive to calculus formation than dams. Calculi-induced irritation led to bladder hyperplasia and tumors in rats fed 1000 mg/kg-day TPA. The lack of effects at 142 mg/kg-day supports a threshold for urine saturation with calcium terephthalate, a key event for calculus formation. Chronic dietary DMT exposure in rodents caused kidney inflammation, but not calculi. Chronic dietary DEHT exposure caused general toxicity unrelated to calculi, although urine pH was reduced suggesting the TPA metabolite was biologically-active, but of insufficient concentration to induce calculi. Respective oral reference doses of 0.5, 0.5, and 0.2 mg/kg-day and total allowable drinking water concentrations of 3, 3, and 1 mg/L were derived for TPA, DMT, and DEHT. An oral RfD of 0.2 mg/kg-day for the terephthalate category chemicals corresponded to a drinking water TAC of 1 mg/L.

Glutathione (GSH), cysteine, and other low-molecular-weight thiols (LMWT) play a vital role in the detoxication of xenobiotics and endogenous chemicals. Differential alterations of LMWT status in various cell types of the developing embryo may underlie cell-specific sensitivity or resistance to xenobiotics and contribute to embryotoxicity. This study describes the spatial and temporal distribution of LMWTs in rat conceptuses and alterations produced by the non-teratogenic GSH modulator, acetaminophen (APAP). Pregnant female rats were given 125, 250, or 500 mg/kg APAP (po) on gestational day 9. Conceptal LMWT was localized histochemically using mercury orange in cryosections, and GSH and cysteine concentrations were measured by HPLC analysis. Mercury orange histofluorescence revealed a non-uniform distribution of LMWT in untreated conceptal tissues, with strongest staining observed in the ectoplacental cone (EPC), visceral yolk sac (VYS), and embryonic heart. Less intense staining was observed in the neuroepithelium. Following treatment with APAP, tissue-associated LMWT decreased dramatically except in the EPC, while exocoelomic fluid LMWT, and LMWT within embryonic lumens, increased. Exposure to 250 mg/kg APAP decreased embryonic GSH after 6 and 24 h by 46% and 38%, respectively. Acetaminophen (500 mg/kg) decreased embryonic and VYS cysteine content by 54% and 83%, respectively, after 24 h. Acetaminophen alters the spatial distribution of LMWT in rat conceptuses, particularly with respect to cysteine. The mobilization of cysteine following chemical insult may influence the ability of conceptal cells to maintain normal GSH status due to reduced availability of cysteine for de novo GSH synthesis.

Due to its high nitrogen content, melamine has been used to adulterate food to increase apparent protein content. In 2008, thousands of Chinese infants consumed reconstituted formula derived from melamine-adulterated milk. Urinary-tract stones (comprised of melamine and uric acid) accumulated in some victims and lead to acute renal failure or death. Premature infants and children (<2 yr) have an increased susceptibility to ingested melamine. Due to incomplete reporting, the human data were inadequate to identify a no-observed-adverse-effect level (NOAEL) for melamine-induced pediatric urolithiasis. Urolithiasis, urinary bladder cystitis, and ulcerations were observed in F344 rats after subchronic or chronic ingestion of melamine at > or =72 mg/kg-d. Bladder epithelial damage was followed by epithelial hyperplasia that progressed to bladder papillomas and carcinomas in male but not female F344 rats or male or female B6C3F1 mice. Short-term assays suggest, at best, weak genotoxic activity, and kinetic data show that melamine is not metabolized. Since reliable exposure information was lacking from the clinical reports, an oral reference dose (RfD) based on urolithiasis in male rats after 13 wk of continuous melamine ingestion was calculated as a 10% benchmark dose (38 mg/kg-d). Incorporation of 10-fold interspecies and intraspecies (for the increased susceptibility of infants) uncertainty factors and a threefold database uncertainty factor (for the lack of immunological, neurological and reproduction toxicity data) yields an oral RfD of 0.13 mg/kg-d. Assuming the 70-kg adult consumes 2 L of drinking water daily, a total allowable concentration of 0.9 mg/L (900 microg/L) was calculated for melamine in drinking water.