Bisphenol A (BPA) is a high production volume industrial chemical to which there is widespread human oral exposure. Guideline studies used to set regulatory limits detected adverse effects only at doses well above human exposures and established a no-observed-adverse-effect level (NOAEL) of 5 mg/kg body weight (bw)/day. However, many reported animal studies link BPA to potentially adverse effects on multiple organ systems at doses below the NOAEL. The primary goals of the subchronic study reported here were to identify adverse effects induced by orally (gavage) administered BPA below the NOAEL, to characterize the dose response for such effects and to determine doses for a subsequent chronic study. Sprague Dawley rat dams were dosed daily from gestation day 6 until the start of labor, and their pups were directly dosed from day 1 after birth to termination. The primary focus was on seven equally spaced BPA doses (2.5-2700 μg/kg bw/day). Also included were a naïve control, two doses of ethinyl estradiol (EE2) to demonstrate the estrogen responsiveness of the animal model, and two high BPA doses (100,000 and 300,000 μg/kg bw/day) expected from guideline studies to produce adverse effects. Clear adverse effects of BPA, including depressed gestational and postnatal body weight gain, effects on the ovary (increased cystic follicles, depleted corpora lutea, and antral follicles), and serum hormones (increased serum estradiol and prolactin and decreased progesterone), were observed only at the two high doses of BPA. BPA-induced effects partially overlapped those induced by EE2, consistent with the known weak estrogenic activity of BPA.
Hemoglobin adducts of 15 aromatic amines were determined in nonsmokers and smokers of blond-or black-tobacco cigarettes living in Turin, Italy. The subjects were all males age 55 or less and were representative of the population previously examined in a case/control study of bladder cancer. 4-Aminobiphenyl adduct levels were found to be significantly different in the three groups, and the differences were approximately proportional to the relative risk of each group. Adjustment for age and cigarette consumption did not materially influence the differences. A significant correlation of adduct levels with cigarette consumption was also observed for all smokers as well as for smokers of blond tobacco. Other amines for which significant differences between smokers and nonsmokers were observed were 3-aminobiphenyl, 2-naphthylamine, o-and p-toluidine, 2,4-dimethylaniline, and 2-ethylaniline. Some of these amines are human bladder carcinogens, and their occurrence in blood as hemoglobin adducts is evidence for their metabolic activation. Thus, by a combination of traditional epidemiological methods and modern chemical analyses, we have provided evidence for a biochemical basis for the often observed association between cigarette smoking and bladder cancer.Cigarette smoking is a major cause of cancer of the urinary bladder. In countries where a long history of cigarette consumption exists, the proportion of bladder cancers attributed to this risk factor is estimated to be about 50% for men and 30% for women (1-3). The relative risk for bladder cancer among cigarette smokers ranges in most reports from 1.5-to 3.0-fold higher than among nonsmokers, with higher values reported in certain populations (4). It has been hypothesized that the carcinogenicity of tobacco smoke for the bladder may be due to the presence of various aromatic amines, including the known human bladder carcinogens 4-aminobiphenyl and 2-naphthylamine (5).Current evidence indicates that aromatic amines exert their carcinogenic effects on the bladder only after a number of metabolic and distribution steps. The critical activation to an electrophilic intermediate is effected in the liver through N-hydroxylation of the parent amine to the hydroxylamine. This is followed by transport to the bladder, where reaction with DNA is thought to initiate tumorigenesis (6-8). We have developed and reported (9-11) a method to quantify the timeweighted average hydroxylamine production over a period of several months from exposure to environmental aromatic amines. The technique depends upon measurement of the covalent sulfinamide adduct of the 83-chain cysteine-93 residue formed by interaction of aromatic hydroxylamines with hemoglobin. Although stable in vivo, this adduct can be broken down in vitro to regenerate the parent amine and a hemoglobin molecule containing cysteine sulfinic acid. Accurate and sensitive quantification of the adduct is accomplished by mass spectrometric analysis of the regenerated amines after separation by gas chromatography. Previous s...
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