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.

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Inhalation is the most important route of absorption for many volatile substances. The inhaled chemical is distributed via the bloodstream into the organs and tissues. It is eliminated mainly unchanged by exhalation and also via metabolism. The blood concentration can be considered as a surrogate for the body burden of the chemical. It depends on the rate of uptake and on the rate of elimination. The rate of uptake by inhalation is determined by the blood:air partition coefficient of the gaseous compound, the actual concentration of the chemical already in the blood entering the lungs, the blood flow through the lungs, and the alveolar ventilation. The latter is greatly influenced by physical activity, which thus has a crucial impact on the rate of uptake. Consequently, the blood concentration of an inhaled chemical and the resulting alveolar retention, representing the rate of metabolism at steady-state, are dependent on the intensity of physical work. Both parameters can be calculated for steady-state conditions using simple algebraic equations, if one assumes that the rate of metabolic elimination is limited by the blood flow through the metabolizing organs. This assumption is valid for many rapidly metabolized inhaled gases and vapours at low concentrations present under workplace conditions. The derived equations give the theoretical background for the observations presented from a series of experimental studies which demonstrate that physical activity can be a major determinant of the toxicokinetics of inhaled compounds. Practical examples illustrate the procedure. We conclude that workplace-related physical activity should be taken into account for compounds with blood:air partition coefficients above 6 in the determination of occupational limit concentrations in air.

Concern about the carcinogenic potential of styrene (ST) is due to its reactive metabolite, styrene-7,8-oxide (SO). To estimate the body burden of SO resulting from various scenarios, a physiologically based pharmacokinetic (PBPK) model for ST and its metabolite SO was developed. This PBPK model describes the distribution and metabolism of ST and SO in the rat, mouse and man following inhalation, intravenous (i.v.), oral (p.o.) and intraperitoneal (i.p.) administration of ST or i.v., p.o. and i.p. administration of SO. Its structure includes the oxidation of ST to SO, the intracellular first-pass hydrolysis of SO catalyzed by epoxide hydrolase and the conjugation of SO with glutathione. This conjugation is described by an ordered sequential ping-pong mechanism between glutathione, SO and glutathione S-transferase. The model was based on a PBPK model constructed previously to describe the pharmacokinetics of butadiene with its metabolite butadiene monoxide. The equations of the original model were revised to refer to the actual tissue concentration of chemicals instead of their air equivalents used originally. Blood:air and tissue:blood partition coefficients for ST and SO were determined experimentally and have been published previously. Metabolic parameters were taken from in vitro or in vivo measurements. The model was validated using various data sets of different laboratories describing pharmacokinetics of ST and SO in rodents and man. In addition, the influences of the biochemical parameters, alveolar ventilation and blood:air ventilation and blood:air partition coefficient for ST on the pharmacokinetics of ST and SO were investigated by sensitivity analysis.(ABSTRACT TRUNCATED AT 250 WORDS)