Bisphenol A is a widely used industrial chemical with many potential sources of human exposure. Bisphenol A is a weak estrogen and has been implicated as an "endocrine disruptor". This term is used for a variety of chemicals encountered in the environment which have estrogenic activity. It has been postulated that human exposure to these chemicals may elicit unwanted estrogenic effects in humans such as reduced fertility, altered development and cancer. Up to now the body burden of bisphenol A in humans is unknown. Therefore, we investigated the metabolism and toxicokinetics of bisphenol A in humans exposed to low doses since systemic bioavailability has a major influence on possible estrogenic effects in vivo. Human subjects (three males and three females, and four males for detailed description of blood kinetics) were administered d(16)-bisphenol A (5 mg). Blood and urine samples were taken in intervals (up to 96 h), metabolites formed were identified by GC/MS and LC-MS/MS and quantified by GC/MS-NCI and LC-MS/MS. d(16)-Bisphenol A glucuronide was the only metabolite of d(16)-bisphenol A detected in urine and blood samples, and concentrations of free d(16)-bisphenol A were below the limit of detection both in urine (6 nM) and blood samples (10 nM). d(16)-Bisphenol A glucuronide was cleared from human blood and excreted with urine with terminal half-lives of less than 6 h; the applied doses were completely recovered in urine as d(16)-bisphenol A glucuronide. Maximum blood levels of d(16)-bisphenol A glucuronide (approximately 800 nM) were measured 80 min after oral administration of d(16)-bisphenol A (5 mg). The obtained data indicate major species differences in the disposition of bisphenol A. Enterohepatic circulation of bisphenol A glucuronide in rats results in a slow rate of excretion, whereas bisphenol A is rapidly conjugated and excreted by humans due to the absence of enterohepatic circulation. The efficient glucuronidation of bisphenol A and the rapid excretion of the formed glucuronide result in a low body burden of the estrogenic bisphenol A in humans following oral absorption of low doses.
Contents of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and of 16 further congeners--polychlorinated dibenzodioxins and dibenzofuranes (PCDD/PCDF)--were determined in lipids of adipose tissue and of livers of 3 stillborns and of 17 infants (0.43-44 weeks old) who died from sudden infant death syndrome. International toxic equivalents (I-TEq) calculated for the sum of TCDD together with all of the 16 congeners (1.55-29.63 ng/kg lipids of adipose tissue, n = 20; 2.05-57.73 ng/kg liver lipids, n = 19) were within the range of or lower than the values published for adults. TCDD concentrations in lipids of breast-fed infants were higher (0.38-4.1 ng/kg lipids of adipose tissue, n = 9; 0.49-3.9 ng/kg liver lipids, n = 8) compared to non breast-fed subjects (0.16-0.76 ng/kg lipids of adipose tissue, n = 8; 0.29-0.71 ng/kg liver lipids, n = 7). Neither I-TEq values nor TCDD concentrations exceeded values published for adults. Since even in stillborns PCDD/PCPF were found (I-TEq, 9.70-10.83 ng/kg lipids of adipose tissue, 6.17-8.83 ng/kg liver lipids; TCDD, 1.3-2.1 ng/kg lipids of adipose tissue, 0.76-1.5 ng/kg liver lipids; n = 3), transplacental exposure has to be deduced. All of the findings concerning TCDD concentrations in the organism become intelligible on the basis of a physiological toxicokinetic model which was developed to describe the body burden of TCDD for the entire human lifetime in dependence of TCDD uptake from contaminated nutrition. The model reflects sex and age dependent changes in the following parameters: body weight, volumes of liver, adipose and muscle tissue, food consumption, and excretion of faeces. TCDD is supposed to be taken up orally, to be distributed freely in lipids of the organism and to be eliminated unchanged by excretion in lipids of faeces as well as by metabolism in the liver. The model was used to predict the half-life of elimination of TCDD (4 months in newborns increasing to approximately 5 years in adults) and concentrations of this compound in lipids of adipose tissue, blood, liver and faeces at different ages. Furthermore, the influence of breast-feeding on the TCDD burden of a mother, her milk and her child was simulated. The model was validated by means of own data gained in adipose tissue and livers of infants and also using a series of values measured by other authors in mother's milk and in tissues and faeces of infants and adults. Predictions as well as experimental findings demonstrate a distinct increase in the TCDD body burden of breast-fed infants. Generally, it can be concluded for the excretion of unchanged, non-volatile, non protein bound highly lipophilic compounds that their half-life is short in infants (approximately 5 months) and increases to approximately 10 years reached between 40 and 60 years of age.
The inhalation pharmacokinetics and the endogenous production of ethylene has been determined in healthy volunteers with respect to the formation of the carcinogen ethylene oxide. Ethylene showed a low degree of accumulation in the body determined in six subjects, the thermodynamic partition coefficient "body/air" being 0.53 +/- 0.23 (mean +/- SD) and the accumulation factor "body/air" at steady-state being 0.33 +/- 0.13 (mean +/- SD). The rate of metabolism was directly proportional to the exposure concentration. Only 2% of ethylene inhaled was metabolized to ethylene oxide, whereas 98% of ethylene was exhaled unchanged. The rate of the endogenous production of ethylene was 32 +/- 12 nmol/h (mean +/- SD), as calculated from exhalation data from 14 subjects. The resulting body burden was 0.44 +/- 0.19 nmol/kg (mean +/- SD). By analyzing published data on ethylene oxide in man its half-life was estimated to be 42 min. Using the pharmacokinetic parameters of ethylene and ethylene oxide, the body burden of ethylene oxide due to the sum of the exposure to environmental ethylene of about 15 ppb and to endogenous ethylene exposure of 0.44 nmol/kg was predicted to be 0.25 nmol/kg. In the blood of five non-smokers and one smoker the hemoglobin adduct resulting from the reaction of ethylene oxide with the N-terminal valine, N-(2-hydroxyethyl)valine, was quantified by gas chromatography/mass spectrometry. The value of 20 +/- 5 pmol/g Hb (mean +/- SD) found in the non-smokers corroborated the steady-state level of 18 +/- 3 pmol/g Hb (mean +/- SD) calculated from the pharmacokinetic approach.
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