Klaus Abraham

Intake, Fecal Excretion, and Body Burden of Polychlorinated Dibenzo- p- dioxins and Dibenzofurans in Breast-Fed and Formula-Fed Infants

To assess toxicokinetics of polychlorinated dibenzo-p-dioxins(PCDDs) and dibenzofurans (PCDFs), oral intake and fecal excretion were measured in two breast-fed infants and one formula-fed infant during the 1st y of life. The intake of these compounds was up to 50 times higher in the breast-fed infants. In these children, fecal excretion of the main tetra- to hexachlorinated congeners was less than 9% of the intake at age of 1 and 5 mo, indicating almost complete intestinal absorption during breast-feeding. In contrast, distinctly higher fecal excretion rates were observed for the hepta- and octachlorinated compounds. Despite much lower PCDD/PCDF intake after weaning, concentrations in stool fat did not decrease substantially. We conclude that concentrations in fecal fat more or less reflect those in body fat. Additionally, PCDD/PCDF concentrations were measured in blood fat of all infants (and in a second formula-fed baby) at the age of 11 mo. International toxicity equivalent (1-TEq) concentrations in the formula-fed infants were less than 25% of maternal values and about 10 times lower than in the infants breast-fed for 6-7 mo. In the latter, a distinct accumulation was found for the tetra- to hexachlorinated congeners compared with maternal concentrations. We conclude that accumulation of PCDDs and PCDFs in infants is as high as expected on the basis of intake data and assuming complete absorption and negligible elimination during the 1st y of life.

Severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication: kinetics and trials to enhance elimination in two patients

Abstract. In spring 1998, two women were diagnosed with severe 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) intoxication. Over the following 3 years, TCDD levels were monitored under various attempts to enhance its elimination, and the half-lives were evaluated. Olestra, a non-digestible, non-absorbable dietary fat substitute, was continuously administered to the patients either as pure substance or in potato-chips. Additionally, in the more severely contaminated patient, we studied whether low-density lipoprotein (LDL)-apheresis, an extracorporeal means of blood lipid elimination, was effective in reducing the TCDD body burden. The blood concentrations initially measured in spring 1998 were 144,000xa0pg/g blood fat in patient 1 and 26,000xa0pg/g in patient 2, the highest levels ever measured in adults. In March 2001, concentrations in blood fat were 35,900 and 9,500xa0pg/g, corresponding to overall elimination half-lives of 560 days (1.5 years) in patient 1 and 1050 days (2.9 years) in patient 2, which are considerably shorter than median values of 7–9 years reported for background and moderate exposure levels. Calculations of the TCDD half-lives and measurements of TCDD elimination via different routes allowed the calculation of an unidentified route of elimination, representing 78 and 62% of the overall elimination in patient 1 and 2, respectively, probably due to an induced hepatic metabolism caused by the high TCDD exposure. As previously reported, administration of olestra was found to be effective in increasing the fecal excretion of TCDD. Due to the short half-lives in our patients, the effect of olestra on the overall elimination was relatively small, but is expected to be much greater for normal half-lives. LDL-apheresis was shown to eliminate TCDD, corresponding to the eliminated blood fat. When employed twice a week, the amount of TCDD excreted by this method was comparable to fecal excretion. In view of costs and time involved, LDL-apheresis does not seem to be justified for enhancement of TCDD elimination.

Evaluation of the age-dependent development of lymphocyte surface receptors in children.

Components and functions of the immune system change during postnatal development, not only in the first years of life, but well through adolescence and even into adult life. These age-dependent changes within the immune system greatly complicate any attempt to assess pathological alterations of immunologic variables in children. The need for studies on possible substance-induced changes, including risk assessment of environmental chemicals, has increased the necessity to establish reference ranges for certain immunologic variables against which an abnormal developmental status can be evaluated. In the present study age-related changes of surface receptors on peripheral white blood cells were studied in 82 children, aged between 2 months and 17 years. The blood samples were triple labeled with monoclonal antibodies followed by a whole blood lysis technique and were subsequently analyzed by flow cytometry. Complex statistical analyses were performed in order to determine probability ranges for some immunological variables. In this paper we describe the age-dependent development of components involved in major maturational processes, including the appearance and varying expression of adhesion receptors (CD11a, CD18, CD28, CD29, CD44, CD49d and CD54) on CD4+ helper cells and CD8+ suppressor and cytotoxic cells. A clear-cut increase of high epitope density expression of the integrins on both CD4+ and CD8+ cells was noted. These results suggest that the components of immune T cells for performing adhesion by interacting with other cells and many matrix components are largely acquired during postnatal development. Maximal levels of adhesion receptor expression are reached at different ages depending on the specific T cell subpopulation.

Comparative study on age-dependent development of surface receptors on peripheral blood lymphocytes in children and young nonhuman primates (marmosets).

General conformity was found concerning age-dependent changes in the major subsets (CD4, CD8, CD2, CD20) and the adhesion molecules CD11a and CD29 on peripheral blood lymphocytes in children and young marmosets (Callithrix jacchus). Differences exist in the expression of the surface receptors CD45RA and CD56. Taking the total number of white blood cells into account, an age-related increase in the absolute numbers of peripheral blood lymphocytes was found in marmosets whereas in children, an age-dependent decrease was observed. The definition of reference ranges for different stages of maturation in children and young marmosets may serve as a basis on which comparative risk assessment of possible effects on lymphocyte subsets after pre- or perinatal drug exposure can be estimated.