Biomedical subjects

D Neubert

Publications and source records attributed to D Neubert.

At least 19 recordsLinked to original sources

PubMed1995

Enoxacin is an inducer of CYP1A2 in rat liver.

The induction of cytochrome P450 by enoxacin, ciprofloxacin, and ofloxacin was investigated in female Wistar rats. Animals were treated orally with daily doses ranging from 10 to 400 mg enoxacin per kg body wt, 400 mg ciprofloxacin, or 400 mg ofloxacin per kg body wt for up to 7 days. Activities of methoxyresorufin O-demethylase (MROD) and ethoxyresorufin O-deethylase (EROD) were determined fluorimetrically in hepatic microsomes. MROD activity was increased 2.6-fold after treatment with 100 mg enoxacin per kg body wt for 7 days. Lower doses of enoxacin did not induce MROD activity significantly. Antipeptide antibodies directed specifically against different rat cytochrome P450 enzymes demonstrated that CYP1A2, but not CYP1A1, was induced in rats treated with enoxacin. After ciprofloxacin or ofloxacin treatment, no induction of MROD or EROD activity was observed. Neither ciprofloxacin nor ofloxacin caused any change in CYP1A1 or CYP1A2 apoprotein levels. Further investigations with antipeptide antibodies showed that there was no induction of CYP2B1, CYP2B2, CYP2E1, CYP3A1, CYP3A2, CYP4A1, or CYP4A2 following treatment with enoxacin, ciprofloxacin, or ofloxacin. It is concluded that enoxacin, but not ciprofloxacin or ofloxacin, is an inducer of CYP1A2 in rat liver.

Animals↗

PubMed1995

Four generation reproductive toxicity study with 2,3,7,8-tetrachlorodibenzo-P-dioxin (TCDD) in rats. I. Toxicokinetic variations in dams and offspring.

A multigeneration study on the reproductive toxicity of TCDD in rats was conducted. In this paper, the results of extensive pharmacokinetic evaluations are presented. The time course of tissue concentrations within the framework of a multigeneration study was investigated, using radioactive labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a substance with a long elimination half-life. So far, long term exposure to TCDD has generally been conducted by administering the same daily doses via the feed. Since the half-life of TCDD in rats is several weeks, the concentration of the test substance can be predicted to change continuously during such a study. Therefore we intended to expose the animals to a constant tissue concentration by using a loading dose/maintenance dose approach. To achieve this, the animals were treated with initial loading doses of 50, 120 or 250 ng TCDD/kg body wt. Based on the elimination half-life of 3 weeks and a planned dosing interval of 7 days, the weekly maintenance doses were calculated to be 20% of the loading dose. During the postnatal phase of rapid growth, this dosing schedule was insufficient to keep the tissue concentration of TCDD constant. It was necessary to administer a second loading dose and to increase the weekly maintenance dose to 40% of the loading dose. While it was possible to control the tissue concentrations in the F0 generation, a considerably larger variation was observed during the different developmental stages of the F1 generation. The fluctuations could be reduced by using a complex dosing schedule, but even with that it was impossible to achieve completely steady levels in liver and adipose tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1995

Thalidomide and the immune system. 4. Down-regulation of the CD26 receptor, probably involved in the binding of HIV components to T cells in primates.

Thalidomide (Thd) is capable of down-regulating the CD26 receptor on CD4+ lymphocytes after treatment of healthy volunteers. Similar effects are observed when marmosets (Callithrix jacchus) are treated with Thd. The Ta1 epitope of the CD26 receptor has recently been shown to bind the HIV-1 Tat trans-activating protein, and CD26 has also been suggested to be a coreceptor for the binding of the V3 loop of the gp120 HIV envelope protein. This might provide a hint for possible therapeutic interventions.

Animals↗

PubMed1995

Chlorinated dibenzo-p-dioxins and dibenzofurans and the human immune system. 2. In vitro proliferation of lymphocytes from workers with quantified moderately-increased body burdens.

Lymphocyte proliferation responses were studied in workers with moderately increased body burdens of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/PCDFs, calculated as International Toxicity Equivalencies [I-TE]). Mitogens (pokeweed mitogen [PWM], phytohemagglutinine [PHA], concanavalin A [Con A]), as well as an anti-human monoclonal antibody against CD3 were used as proliferation stimulators in vitro. Additionally, the feasibility of using the lymphocyte response to tetanus toxoid was assessed, and the response to this recall-antigen was included in this trial. No decrease in the capacity of 3H-thymidine incorporation was observed with any of the proliferation stimulators in the group of volunteers with the increased TCDD-body burden when compared with volunteers exhibiting TCDD-concentrations in blood fat within the reference range. Regression analysis revealed a slight trend towards an increase for 3H-thymidine incorporation during the stimulation with PHA only. It can be concluded from our data that moderate increases in the TCDD- or I-TE-body burdens do not induce any medically significant changes in the capacity for proliferation of lymphocytes, measured as 3H-thymidine incorporation.

Adult↗

PubMed1995

Proliferative capacity of marmoset lymphocytes after tetanus vaccination and lack of 2,3,7,8-tetrachlorodibenzo-p-dioxin to reduce a booster effect.

Marmosets (Callithrix jacchus) were vaccinated with tetanus toxoid and boostered 3 months and 1 year following the initial immunization. During this period, the proliferative response of lymphocytes (3H-thymidine incorporation) to the recall antigen was measured in vitro in blood samples 7 times. The experimental procedure proved to be suitable to monitor a defined but complex function of the immune system, and to assess possible substance-induced alterations with minimal stress or discomfort for the non-human primates. As a first example, a possible interference by a single very small dose (100 ng/kg body weight) of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) given at the time of the second booster was evaluated. No reduction in the in vitro response of the lymphocytes to recall antigen was observed under the experimental conditions used, and the extent of the 3H-thymidine incorporation was not significantly different in the groups. When the ratio of the responses between the first and the second booster was taken as a measure, there was a slight but statistically significant increase in this ratio for the lymphocytes of the TCDD-treated marmosets over that of reference animals. The limitations of these attempts to develop a test system and evaluate a substance-induced effect, and possible improvements of the test, e.g. with multivaccination, are discussed. It is suggested to use this approach also after routine multivaccination in children to assess possible substance-induced effects on immunological variables. This would allow an excellent comparison of experimental and clinical data obtained in primates with an identical technology.

Animals↗

PubMed1994

Long-term interleukin-6 administration stimulates sustained thrombopoiesis and acute-phase protein synthesis in a small primate--the marmoset.

Interleukin-6 (IL-6) has been ascribed significant roles in both hematopoiesis and the immune response, although its contribution to host defence as a whole is poorly understood. Because short-term IL-6 treatment was previously shown to stimulate megakaryocytopoiesis, we investigated the effect of long-term administration of IL-6 on megakaryocytopoiesis and other systemic parameters in nonhuman primates. We chose a small primate, the marmoset (Callithrix jacchus), which enabled long-term administration at high doses. Recombinant human IL-6 (rhIL-6) administered at doses of up to 1,000 micrograms/kg/d over 4 and 9 weeks caused a sustained twofold to threefold increase of thrombocyte counts, peaking at 4 weeks. Thrombocyte counts declined thereafter, despite continuing IL-6 administration. The number of bone marrow megakaryocytes at 4 and 9 weeks was not increased compared with controls, but the ploidy grade was augmented, suggesting that IL-6 effects are restricted to mature megakaryocytes in vivo. An acute-phase protein response was observed within 24 hours after the first IL-6 administration and reached a maximum after 1 week of IL-6 administration at 25 micrograms/kg. Serum C-reactive protein, haptoglobin, and ceruloplasmin were increased, whereas albumin and transferrin levels declined. The acute-phase protein response was not associated with any morphologic evidence of hepatocellular damage. The increased levels of Ig and soluble IL-2 receptor in the serum levels reflected systemic immunostimulation. There was no evidence of renal mesangioproliferative pathology. Antibodies against rhIL-6 developed within 2 weeks, continuously increasing during the course of the study. High titers of neutralizing antibodies appeared concomitantly with the decrease in platelet counts and decline in acute-phase proteins. Therefore, despite the pleiotropic effects of IL-6 observed in vitro, long-term administration of IL-6 caused a selective and sustained stimulation of thrombopoiesis in marmosets that was only ablated by the appearance of neutralizing antibodies, and high doses were well tolerated in marmosets. A long-term targeting of IL-6 to cells of the megakaryocytic lineage, without evoking general toxicity, confirms the potential therapeutic usefulness of rhIL-6 for the chronic treatment of thrombocytopenic patients.

Acute-Phase Proteins↗

PubMed1994

Embryotoxic effects of thalidomide derivatives in the non-human primate callithrix jacchus. IV. Teratogenicity of micrograms/kg doses of the EM12 enantiomers.

The dose-response of the teratogenic potency of the thalidomide (Thd) derivative EM12 was evaluated in the common marmoset (Callithrix jacchus). The smallest daily dose found to be effective was 30 micrograms EM12/kg body wt. This is the lowest dose of a Thd derivative ever reported to induce severe skeletal abnormalities. Ten micrograms EM12/kg body wt may be considered the no-observed-adverse-effect-level (NOAEL) under the experimental conditions chosen. The teratogenic potencies of the two EM12 enantiomers were tested at 100 micrograms/kg body wt, the dose which just induces an almost 100% effect in the case of the racemate. The S(-)-EM12 was found to induce typical severe limb abnormalities such as amelia, phocomelia, and radius aplasia, and none of the exposed fetuses were devoid of skeletal defects. In contrast, only few and minor skeletal defects were observed after application of the R(+) enantiomer. Although a pronounced teratogenic potency of the R(+)-EM12 can now largely be excluded, these low-dose studies are not sufficient to completely rule out any teratogenic potential of this enantiomer, since racemisation to small amounts of the S(-) form may occur in vivo. Further studies with Thd derivatives which are unable to racemise are necessary to prove the assumed complete ineffectiveness of the R(+) enantiomers.

Abnormalities, Drug-Induced↗

PubMed1994

Effects of recombinant human interleukin 6 (rhIL-6) in marmosets (Callithrix jacchus). 1. General toxicity and hematological changes.

The physiological and toxicological properties of recombinant human interleukin 6 (rhIL-6) were assessed in marmoset monkeys (Callithrix jacchus). Two experimental series were performed with daily subcutaneous administration: (a) 5 or 1000 micrograms rhIL-6/kg per day for three weeks and (b) 25, 100 or 500 micrograms rhIL-6/kg per day for 3 months. RhIL-6 was well tolerated and did not induce fever or any other non-specific signs of toxicity. The main findings were: (1) A two- to threefold increase in platelet counts at 2-4 weeks, which decreased following further continuous rhIL-6 administration; (2) increase in total white blood cells between 1 and 4 weeks of administration, including an absolute increase in granulocytes (including band forms) and basophils. A change in the number of monocytes was not detected; (3) an increase in total red blood cells, which peaked at 4 weeks, sustained elevation of red cell distribution width and a slight decrease in hemoglobin between week 1 and 4, concurrent with a distinct decrease in mean corpuscular hemoglobin at 4 weeks. This effect persisted for 9 weeks in the 100 micrograms/kg and 500 micrograms/kg groups; (4) decrease in plasma AST activity and increase in plasma protein concentration after 2 weeks of treatment; (5) no clinical or biochemical signs of renal glomerular dysfunction; (6) RhIL-6 after s.c. administration was detectable in the plasma, peak levels (mean values +/- SD) of 9.4 +/- 6.3 and 72.4 +/- 7.7 ng/ml were measured after a single dose of 100 or 1000 micrograms/kg; (7) antibodies against rhIL-6 developed within 2 weeks, increased during administration and neutralized the biological effect of rhIL-6 progressively from 4 to 9 weeks. In conclusion, aside from a mild anemia, rhIL-6 was well tolerated in marmosets and had a profound and sustained effect on thrombopoiesis. Due to the formation of neutralizing antibodies, the chronic biological effect of rhIL-6 is lost in marmosets and studies beyond 4 weeks are rendered less meaningful. The analyses of antibody formation, induction of acute phase proteins, histological changes and alterations on lymphocyte receptors will be reported in two following publications.

Analysis of Variance↗

PubMed1994

Toxicity of beta-blockers in a rat whole embryo culture: concentration-response relationships and tissue concentrations.

Beta-adrenoceptor blockers are widely used drugs for the treatment of cardiovascular diseases. Since beta-blockers cross the placenta, it is essential to consider possible adverse effects on the embryo. Six beta-adrenoceptor blockers were tested at various concentrations (10-5000 microM) in a rat whole embryo culture. Although inducing a very similar pattern of dysmorphogenetic effects (incomplete flexure, disturbed development of the neural tube, the head, the heart and the tail bud), the compounds exhibited a wide range of embryotoxic potency. Estimation of the EC50 (median-concentration producing dysmorphogenesis in 50% of the embryos) for the six compounds revealed differences of more than two orders of magnitude: propranolol 25 microM, alprenolol 30 microM, metoprolol 100 microM, pindolol 150 microM, acebutolol 500 microM, atenolol 4000 microM. Measurements of the concentrations of the various drugs in the cultured embryos at corresponding EC50 levels showed differing values: metoprolol 4.5 microM, propranolol 5.2 microM, alprenolol 8.4 microM, pindolol 9.0 microM, acebutolol 12.5 microM and atenolol 77.0 microM. With regard to the EC50 and the degree of substance transfer to the embryo it can be stated that propranolol and metoprolol show a much higher intrinsic potency to interfere with normal in vitro embryonic development than, e.g. atenolol.

Acebutolol↗

PubMed1994

Thalidomide and the immune system. 3. Simultaneous up- and down-regulation of different integrin receptors on human white blood cells.

Time-dependent changes in the surface receptor expression of various maturational and integrin receptors on peripheral blood cells were studied in two healthy human volunteers following oral applications of thalidomide (Thd). In each measurement the receptor density was quantified by prior calibration of the flow cytometer with latex beads bearing a determined number of fluorescence molecules. The effects observed in the course of the Thd-treatment were practically identical or at least very similar in both the volunteers during four different trials, and were in accord with previous results obtained in large-scale studies (68 treated animals) with non-human primates. It should be stressed that no clear-cut changes were observed in the percentage or absolute numbers of primary lymphocyte subsets such as CD3, CD4 and CD20. After the first two doses of 7 mg Thd/kg body wt the CD18 (the common beta-chain of the beta 2-integrins) marker already decreased in surface density or was no longer detectable on granulocytes, monocytes and lymphocytes. This effect persisted throughout the treatment period and slowly subsided after discontinuation of treatment. With a few days lag phase, the surface density of CD54 (ICAM-1) on granulocytes increased and many cells previously not bearing this receptor newly acquired such surface markers. On monocytes however, the CD54 receptor was lost on many cells. Within the lymphocyte fraction a loss of the CD54 marker could be noted on CD4 cells but not on CD8 cells, where an increase of the receptor expression could be observed. Other markers, such as the alpha chains of the beta 1 integrins CD49b (VLA alpha 2) and CD49d (VLA alpha 4) showed contrasting reactions to the Thd-treatment. Whereas a pronounced loss of the receptor density of CD49d was observed and only few cells with high epitope density were left in the blood at the end of the complete dosing schedule, no such effect was observable on cells bearing the CD49b epitope. A distinct reduction of the number of receptors was also noticeable on L-selectin (Leu8) bearing cells. On CD4 positive lymphocytes, the majority of the described effects on the integrin and adhesion receptors was seen on cells bearing the CD45R0 maturational epitope. This functional receptor is strongly down-regulated and the pathway of CD45RA to CD45R0 maturation is apparently altered by Thd-treatment. These multiple changes we observed may explain the large variety of therapeutic effects experienced in the treatment with Thd.

Carrier Proteins↗

PubMed1994

Evaluation of possible effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other congeners on lymphocyte receptors in Callithrix jacchus and man.

Using fluorescence-labeled monoclonal antibodies and flow cytometry (FACScan analysis) we measured surface receptors on peripheral lymphocytes in marmosets (Callithrix jacchus) treated with TCDD in the lower nanogram per kilogram range. Additionally, some polybrominated congeners were studied as well as a 2,3,7,8-substituted dioxin containing chlorine and bromine in the same molecule. Callithrix was found to be very sensitive to the action of TCDD and the other tetrahalogenated congeners; single doses of 10-30 ng/kg body weight reproducibly induced a decrease in the percentage and absolute number of 'memory' helper T cells [CD4+CD29(bright)] and of B cells (CD20+). Subsequently, according to the hypothesis based on the marmoset data, extensive analyses on surface receptors of white blood cells were performed in workers with moderately increased body burdens of TCDD, and for further hypothesis generation > 60 triple-labeling assays were performed with each of the blood samples. No decrease in typical surface receptors (CD4+CD45R0+CD45RA-CD29(bright) or CD20+) was found in the human adult volunteers studied, but a trend toward an increase was noted. It cannot be decided whether this may be a substance-related effect, or results from a confounder (possibly age differences between the groups).

Adult↗

PubMed1994

Risk assessment for possible effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related substances on components and functions of the immune system.

Numerous reports have been published on the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on components and functions of the immune system of animal species, almost exclusively of rodents. Many of the data, obtained with very different dosing schedules, are conflicting or have not been confirmed. Since the overwhelming majority of evaluations were performed with rodents, it is not possible to perform a reliable quantitative or even qualitative risk assessment for TCDD in man based on immunological data obtained from these experiments and to extrapolate them to the situation in humans. In addition to the fact that the doses needed to induce measurable effects in the different species studied varies from 1- to 10,000-fold, there are intrinsic and general difficulties for extrapolations to human beings in the field of immunotoxicology due to the influence of different individual risk factors, e.g. smoking and drinking as well as the lack of experience and validation in this new field of toxicology. Some immunological variables were studied in populations highly exposed to dioxins. In comparison to the results obtained from nonhuman primates, no convincing evidence for substance-related effects was revealed, however, information on only a few immunological components and functions in exposed adults could be assessed so far. Except for one group of studied persons all other subjects were generally exposed to cocktails of several chemicals, vastly complicating the interpretation with respect to one isolated component of these mixtures. Results from studies on exposed children are not available yet.

Animals↗

PubMed1993

Time-dependent differences in the development of somites of four different mouse strains.

In studies on reproductive toxicity and especially teratogenicity, animals are often treated at defined stages of pregnancy. As a result the exposure to a certain teratogen can lead to striking differences in the formation of abnormalities in different strains of the same species. As a contribution to the discussion about the reasons for these differences, we examined the somite development of four different strains of mice during organogenesis. The embryos of pregnant females of the inbred strains DBA/2J, BALB/cJ, and C57BL/6J and of the outbred strain Han:NMRI were studied on days 9, 10, 11, or 12 of gestation. As a criterion for development the somite pairs were evaluated on the respective days. There were remarkable differences in the somite number, even within one litter. The largest variation (minimum vs. maximum) was 14 pairs of somites. The regression curves did not exhibit major differences in the speed of somite development from day 9 to day 12 between the four strains. We have to conclude from our results that the individual embryonic stages within one litter may vary by nearly 1 day, and that there may be a delay of half a day in the embryonic development between different strains of mice.

Animals↗

PubMed1992

Effect of lithium on rat embryos in culture: growth, development, compartmental distribution and lack of a protective effect of inositol.

Lithium chloride (LiCl) was tested at various concentrations (50, 100, 150 and 200 micrograms/ml) using a rat whole-embryo culture system beginning on gestation day 9.5 (headfold stage) in order to establish a concentration-response relationship. Open neural tubes--as described in former publications (Tesh 1988)--were not induced by lithium. A significant reduction of embryonic growth and development occurred at the lowest concentration tested (50 micrograms/ml). Clear-cut dysmorphogenetic effects (absence of the eye cup, kink in the spinal anlage, "bleb" at the rostral head region) occurred at a concentration of 150 micrograms/ml LiCl. LiCl concentrations in the embryo, visceral yolk sac, exocoelomic fluid and medium were determined after the embryos had been cultured for 48 h in the presence of a moderately embryotoxic dose of LiCl (3.5 mEq/l or 150 micrograms/ml). Medium supplementation with myo-inositol in different concentrations was ineffective in antagonizing the embryotoxicity induced by LiCl.

Animals↗

PubMed1992

Abnormal thymus development and impaired function of the immune system in rats after prenatal exposure to aciclovir.

Aciclovir (synonym: acyclovir) causes abnormal thymus development in rats. After treatment on day 10 of gestation a weight reduction of the organ is obvious in 21-day-old fetuses which persists postnatally. Adult male rats exposed in utero to one or three injections of 100 mg aciclovir/kg body wt given to the dam on day 10 of pregnancy showed a reduction of the thymus weight to 333 +/- 158 mg and 276 +/- 61 mg (control: 428 +/- 92 mg; n = 10). Corresponding alterations were detectable in female offspring. Liver weight was also decreased and spleen weight (in relation to body wt) was significantly increased in the offspring after the three exposures. In a host resistance model with Trichinella spiralis the function of the immune system of rats prenatally exposed to aciclovir was examined. Six weeks postnatally 10-12 randomly selected male rat offspring of one control and two treatment groups (1 or 3 injections of 100 mg aciclovir/kg body wt on day 10 of gestation) were infected orally with 500 Trichinella spiralis muscle larvae. Before and several times after the infection blood was taken from a tail vein or obtained by decapitation for examination of the antibody titers (IgM, IgG, IgA, IgE) to antigens of T. spiralis. Six weeks after the infection the weight of relevant organs was determined and tongue preparations were used for T. spiralis muscle larvae counting. Aciclovir exposed animals showed a different immune response than control rats. IgM titers in both treatment groups were higher than in controls two weeks after the infection but not different by the end of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyclovir↗

PubMed1992

Reproductive toxicity and toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin. 3. Effects of single doses on the testis of male rats.

The effects of a single dose of TCDD on the testis were studied in rats. The animals were treated (subcutaneously) once with TCDD doses of 0, 0.5, 1.0, 3.0, 5.0 micrograms/kg body weight. Doses of 3.0 or 5.0 micrograms TCDD/kg reduced the number of spermatids/testis significantly (60% of the controls). Electron microscopic inspection revealed that both doses led to a dissolution on the germinal epithelium. Altered germ cells at all developmental stages occurred in all testes evaluated. Doses of 0.5 or 1.0 micrograms TCDD/kg did not induce any effects in the testis; therefore, under these experimental conditions of single exposure to rats the dose of 1.0 micrograms TCDD/kg can be considered as NOAEL.

Animals↗

PubMed1992

Effects of a single haloperidol application to neonatal and early postnatal rats on the neurotransmitter content in the corpus striatum.

We investigated the influence of the dopamine antagonist haloperidol on the neurotransmitter content in the developing rat brain. Dopamine (DA), serotonin (5-HT) and the corresponding metabolites dopac, HVA and HIAA were determined in the corpus striatum of the rat between day 1 and day 21 pn by HPLC with electro-chemical detection. A consistent increase in the content of dopamine was found during postnatal development. The concentrations (ng/g wet tissue; mean +/- standard deviation) increased from 793 +/- 237 on day 1 pn to 4584 +/- 581 on day 21 pn, but remained still lower than in adult animals (9763 +/- 494). Similar results were found for the metabolites dopac and HVA. The content of dopac increased from 59 +/- 22 (day 1 pn) to 551 +/- 59 (day 21 pn) and the content of HVA from 53 +/- 18 (day 1 pn) to 419 +/- 41 (day 21 pn). Both metabolites were also about two times lower than in adult animals (dopac 1090 +/- 282, HVA 744 +/- 206). In contrast to dopamine and its metabolites we found no age-dependent changes in the content of 5-HT from day 1 pn (99 +/- 11) to day 14 pn (121 +/- 21). A remarkable increase in the content of 5-HT was seen from day 14 pn to day 21 pn (438 +/- 56), reaching almost adult levels (570 +/- 92). The metabolite HIAA was nearly three times higher on day 21 pn (610 +/- 123) than on day 14 pn (223 +/- 28) and two times higher than in adults (321 +/- 58).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Polyhalogenated dibenzo-p-dioxins and dibenzofurans and the immune system. 4. Effects of multiple-dose treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on peripheral lymphocyte subpopulations of a non-human primate (Callithrix jacchus).

Non-human primates (Callithrix jacchus) were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) over a period of 30 weeks, and lymphocyte subpopulations of venous blood were monitored using monoclonal antibodies and flow cytometry (FACScan). There was no clear-cut change in the total lymphocyte population during this study. In the first part of the study the new-world monkeys (marmosets) were treated for 24 weeks with a weekly dose of 0.3 ng TCDD/kg body wt. At the end of this treatment period a level corresponding to an actual cumulative dose of about 2.5-2.7 ng TCDD/kg body wt was expected. The percentage and the absolute number of the CD4+CDw29+ cells ("helper inducer" or "memory" cells) surmounted the physiologically occurring increase. Concomitantly the percentage of the CD4+CD45RA+ cells ("suppressor-inducer" or "naive" cells) decreased. There was, at the same period, no change in the total T cell population (CD2+ cells) or in the cells carrying the CD8 or the CD4 epitope. When increasing the weekly dose to 1.5 ng TCDD/kg body wt, a transient increase in the percentage and the absolute number of the CD8+CD56+ cell population ("cytotoxic T cells") was observed 3 weeks after the increase in dosing. At this time the expected decrease in the percentage or the absolute number of CD4+CDw29+ cells was just detectable and this decline was at its maximum 6 weeks after switching to the higher weekly doses. The reduction in the percentage and the absolute number of CD4+CDw29+ cells persisted 5 weeks after discontinuation of the dosing, but this cell population was again within normal limits 7 weeks later. Because the two subpopulations are changed in opposite directions, the ratio CD4+CDw29+/CD4+CD45RA+ is a very sensitive measure of the effect induced by TCDD. There was a pronounced decrease in the percentage of the CD20+ cells (B1 cells), but their percentage and number rapidly normalized, in contrast to the CD4+CDw29+ cells, when the dosing was discontinued. At the end of the treatment period the apparent body burden was calculated to correspond to an actual dose of about 9-10 ng TCDD/kg body wt. Such an actual dose level might be assumed to be reached under steady-state conditions in chronic experiments with daily doses of about 135 pg TCDD/kg body wt (assuming a half-life for TCDD in the marmoset of 6-8 weeks). Extrapolations of the results obtained at higher doses to very low exposures is not justified with respect to the effects induced by TCDD on the immune system of marmosets. At lower doses the effect is clearly reversed.

Animals↗