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K K Rozman

Publications and source records attributed to K K Rozman.

At least 37 records · Page 2Linked to original sources
PubMed1998

Quantitative definition of toxicity: a mathematical description of life and death with dose and time as variables.

This manuscript raises some fundamental issues about the role of time as a variable in toxicology, with implications for all biological sciences and also for disciplines dealing with inanimate systems. The dose-response has taken center stage ever since its formulation by Paracelsus. Time-responses have been considered in the past in various contexts such as time to tumor development or half-life of a compound in an organism. However, there has been, to my knowledge, no successful attempt to tie together dose and time in a generalizable theory. This paper describes toxicity by the minimum number of variables (dose and time) from a macroscopic point of view. Interestingly, these fundamental considerations of the dose- and time-dependence of toxicity led to a simple mathematical formulation, which consists of parts previously recognized as valid under specific conditions of experimentation (Haber's Law of Inhalation Toxicology, Druckrey's Law of Cancer Development).

Animals↗
PubMed1997

Cytokines (IL-1beta and TNFalpha) in relation to biochemical and immunological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats.

Previous studies in different strains of rats and mice have shown that the inhibition of gluconeogenesis as a result of reduced liver phosphoenolpyruvate carboxykinase (PEPCK) activity together with appetite suppression play critical roles in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recent immunological studies in rats demonstrated that exposure to low doses of TCDD resulted in an early and enhanced IgG response to immunization with sheep red blood cells (SRBC) and an enhanced delayed-type hypersensitivity (DTH) reaction as well as a positive popliteal lymph node (PLN) response. However, high doses of TCDD suppressed the DTH reaction. This study aimed at examining the involvement of cytokines (IL-1 and TNF) in mediating the above effects. Liver samples from a previous dose-response study on DTH reaction were investigated, in which rats were treated with TCDD (1, 3, 10, 30 and 90 microg/kg) and immunized with an antigen. mRNA levels of IL-1beta were elevated begining at the 1 microg/kg (non-lethal) dosage group with a maximum increase of about 5-fold above controls in the 90 microg/kg (lethal) dosage group. mRNA levels of TNFalpha were also significantly elevated begining at the 30 microg/kg dosage group. These results suggest that at low doses of TCDD, increased IL-1beta could be responsible for immune function stimulation, whereas at high doses of TCDD, greatly elevated TNFalpha and IL-1beta levles may exacerbate or mediate acute toxicity including immune suppression and related biochemical effects. A time course study (60 microg TCDD/kg without immunization) revealed that liver mRNA levels of TNFalpha were significantly elevated starting 24 h, and reaching a maximum 48 h after dosing with TCDD. This change was accompanied by a transient increase of mRNA levels of IL-1beta at day 4 after TCDD dosage. Thus, these data demonstrated that TCDD alone (without immunization) can cause transient increases of mRNA levels of TNFalpha and IL-1beta in liver. Results from these experiments suggest that TCDD-induced cytokine changes may play important roles in various effects of TCDD.

Animals↗
PubMed1997

Evaluation of alternative methods for establishing safe levels of occupational exposure to vinyl halides.

The facts that reduction of occupational vinyl chloride exposures to levels within or below the 0.5-5 ppm range has so far been successful in eliminating vinyl chloride-induced liver angiosarcoma and that humans appear to be less sensitive to the carcinogenic effect of vinyl chloride than rats offered an opportunity to verify or dispute risk assessment extrapolation models used, and proposed, by the U.S. EPA. Safe occupational vinyl chloride exposures were defined as levels associated with an incidence of one angiosarcoma in 100,000 exposed workers, determined from rat bioassay data using default no-threshold (linearized multistage model and benchmark dose approach with linear extrapolation) and threshold (NOEL/LOEL and benchmark dose uncertainty factor approaches) models, and then compared against the likely protective range of 0.5-5 ppm. Safe levels derived using either no-threshold model are equivalent and are two to three orders of magnitude below the 0.5-5 ppm range. Safe levels derived using either threshold model, when applying uncertainty factors which reflect equal or less sensitivity in humans compared to rats, fall within the 0.5-5 ppm range. Similar results were obtained for vinyl bromide and vinyl fluoride. These results undermine the U.S. EPA default assumption of no-threshold for vinyl halides as well as for other DNA-reactive carcinogens while simultaneously supporting the notion that a practical threshold exists. They further suggest that when threshold models are appropriate, the default assumption of greater sensitivity in humans compared to rats should be carefully evaluated.

Animals↗
PubMed1997

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) increases release of luteinizing hormone and follicle-stimulating hormone from the pituitary of immature female rats in vivo and in vitro.

Recent findings that serum levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were dramatically increased in weanling female Sprague-Dawley (S-D) rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prompted a more detailed study to define the effect and to investigate its mechanism(s). Dose-response and time-course studies were performed in vivo. Single doses (0.03-30 micrograms/kg) of TCDD were administered orally by gastric intubation to 22-day-old female rats. Control animals received vehicle (corn oil) only, whereas naive controls were treated with an empty intubation syringe. Trunk blood was collected after decapitation at various time points during the subsequent 72 hr. Concentrations of LH and FSH were determined in serum by radioimmunoassays (RIA). Two distinct peaks of both hormones were detected. The first, at 1 hr, appeared to be a non-specific response to vehicle as it was present in both vehicle control and TCDD-treated animals, but not in naive control animals. The second peak, at 24 hr, occurred only in animals dosed with TCDD. Gonadotropin levels in these animals were dose-dependently elevated. The ED50 was about 5 micrograms/kg with a maximum elevation of 15- and 20-fold for LH and FSH, respectively. Subsequently, in vitro studies were conducted in cultured pituitary halves and in primary pituitary cell cultures exposed to gonadotropin releasing hormone (GnRH) and/or TCDD. The amount of LH released into the media was measured by RIA. TCDD caused a dose-dependent release of LH from pituitary halves with an ED50 of about 0.1 nM. This effect was abolished in calcium-free medium but was not attenuated by an GnRH antagonist. Further in vitro studies were conducted in primary pituitary cell cultures. Although the cells responded to GnRH very well, no effect of up to 100 nM TCDD on the release of gonadotropins was detected. The results suggest that TCDD induces dose-dependently a brief release of gonadotropins in immature female rats. This effect is at least partially due to an effect of TCDD in the pituitary. Increased release of gonadotropins as a result of TCDD treatment depends on the action of calcium but does not occur via activation of GnRH receptors. However, cells in a primary pituitary culture do not respond to TCDD with increased release of gonadotropins, suggesting that the effect of TCDD in the pituitary is mediated by a factor present in pituitary halves but not in primary cell culture.

Administration, Oral↗
PubMed1997

Subchronic/chronic toxicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) in rats. Part I. Design, general observations, hematology, and liver concentrations.

Groups of 20 male and 20 female adult Sprague-Dawley rats were given five different doses of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD). Total doses for males and females (30.9/18.5, 370/222, 2222/1333, 6667/4000, and 10000/6000 microg/kg) were divided into four daily loading doses and six biweekly maintenance doses. Positive controls were administered 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD, total dose 70/41.9 microg/kg). Liver concentrations, as determined by GC/MS, reflected quite accurately the calculated dose ratios. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest provided with an off-dose period of another 13 weeks. Body weight gain was dose-dependently reduced throughout the study. Mortality occurred dose-dependently, starting on Day 22 and continuing until the end of the off-dose period. Mortality rates at the end of the off-dose period were 90 and 40% for males and 60 and 10% for females in the two highest dose groups. Clinical signs and necropsy findings suggested that the cause of death was related to wasting (early deaths), gastrointestinal and nasal hemorrhage (between Days 64 and 126), or anemia (late deaths, after Day 111). Prothrombin times were prolonged intermittently, mainly at the highest dose of HpCDD. Platelet counts were dose-dependently decreased at the two highest doses of HpCDD and in the TCDD-treated group. This study demonstrates that the relative potency derived from acute toxicity studies is the same as that observed in this subchronic/chronic toxicity study of HpCDD and TCDD, confirming the validity of 0.007 as the toxic equivalency factor (TEF) for HpCDD, which is in good agreement with the international TEF of 0.01.

Administration, Oral↗
PubMed1997

Subchronic/chronic toxicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) in rats. Part II. Biochemical effects.

Groups of 20 male and 20 female rats were given five different oral doses of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) or one dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) divided into four daily loading doses and six biweekly maintenance doses. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest assigned to an off-dose period of another 13 weeks. At the end of the dosing period, liver ethoxyresorufin O-deethylase (EROD) activity was dose-dependently increased starting at the lowest dose (7- to 10-fold) with maximum induction (50- to 100-fold) at the middle or second highest dose. There was a slight reversibility of this effect in HpCDD-treated rats, particularly at lower doses, and a pronounced reversibility in TCDD-dosed rats, both in accordance with respective toxicokinetics. The activity of phosphoenolpyruvate carboxykinase in liver was dose-dependently decreased (up to 60%) at the two or three highest doses of HpCDD and also in the TCDD dosage group. Liver tryptophan 2,3-dioxygenase activity was decreased at the two highest doses of HpCDD (up to 41%), particularly in females. Serum tryptophan concentrations were elevated in rats found moribund due to wasting. There was a dose-dependent decrease in serum glucose concentrations (up to 30%) at the end of the dosing period. Serum thyroxin (T4) concentrations showed a dose-dependent decrease (78% at the highest dose) beginning in the middle dose for HpCDD and in the TCDD dosage group. Serum triiodothyronine (T3) concentrations were only slightly affected, except that they were somewhat decreased in moribund animals. The results demonstrate that similar biochemical changes occur in rats after single as after multiple dosing with HpCDD and TCDD. Based on these endpoints, the relative potency of HpCDD after subchronic exposure is in agreement with the international toxic equivalency factor (I-TEF) of 0.01 and, more specifically, with a TEF of 0.007 based on LD50 values in the same strain of rats.

Animals↗
PubMed1996

Decreased liver type I 5'-deiodinase and increased brown adipose tissue type II 5'-deiodinase activity in 2,3,7,8-tetrachlorobibenzo-p-dioxin (TCDD)-treated Long-Evans rats.

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was studied on the activity of type I 5'-deiodinase (5' DI) in liver and of type II 5'-deiodinase (5' DII) in brown adipose tissue (BAT) microsomes of Long-Evans rats. TCDD decreased the activity of liver 5' DI and increased that of BAT 5' DII. It also reduced the concentration of serum total thyroxine (T4) without affecting triiodothyronine (T3). These effects of TCDD on 5'-deiodinases and serum thyroid hormones are compatible with partial hypothyroidism. Based on our results, it is not possible to decide unequivocally whether TCDD affects thyroid hormone status and 5'-deiodination by a direct action or a feedback mechanism. However, these data are important because they demonstrate that TCDD affects thyroid status in a tissue-specific manner and that its effects on thyroid hormone metabolism are much more complex than currently assumed.

Adipose Tissue, Brown↗
PubMed1996

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on humoral and cell-mediated immunity in Sprague-Dawley rats.

There is much discussion about the occurrence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced effects on the human immune system. Extensive studies have been conducted in mice, but those results cannot explain some of the epidemiological data obtained in exposed humans. Therefore, studies in other laboratory animal species are needed. The aim of these experiments was to examine effects of TCDD on cell- and humoral-mediated immunity in male Sprague-Dawley (SD) rats. A delayed-type hypersensitivity (DTH) assay was used to examine cell-mediated immunity. A time-course study demonstrated that TCDD treatment on day -5 relative to immunization (day 0) produced the greatest effect on cell-mediated immunity. In a dose-response experiment, rats were treated with 1, 3, 10, 20, 30, 40 and 90 micrograms TCDD/kg The effect of TCDD on cell-mediated immunity displayed an inverted U-shaped dose-response curve, in that low doses enhanced and high doses suppressed this immune function. This is the first study to demonstrate an U-shaped dose-response curve of TCDD on the immune system. Primary antibody response to sheep red blood cells (SRBC) was used as endpoint to study the effect of TCDD on humoral immunity. Serum anti-SRBC IgM and IgG levels were measured using an enzyme-linked immunosorbent assay (ELISA). In the dose range examined (10, 20 and 40 micrograms TCDD/kg), serum IgM levels were not affected by TCDD compared to controls at 7 and 14 days after immunization. In contrast, serum IgG levels were dose-dependently elevated both 7 and 14 days after immunization, with a maximum increase of 59% over controls.

Animals↗
PubMed1996

Toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in two substrains of male Long-Evans rats after intravenous injection.

Toxicokinetics of a nontoxic intravenous dose of 14C-labeled TCDD were studied in two substrains of Long-Evans (L-E) rats with a fivefold difference in sensitivity in terms of TCDD-induced mortality. The Turku/AB Long-Evans rat (T L-E) is the most sensitive rat strain with an oral LD50 of 17.7 microgram/kg, whereas the Charles River Long-Evans rat (CR-L-E) is a more resistant strain (oral LD50 95.2 microgram/kg). Samples of 18 tissues were collected 1, 2, 4, 8, 16, and 32 days after dosing and analyzed for radioactivity. Body weight and fecal and urinary excretion of radioactivity were monitored daily during the 32-day study period. CR L-E rats grew significantly faster than T L-E rats, increasing their body weight by 60% in 32 days compared with only 16% in T L-E rats. This difference was not caused by toxicity, because the weight gain was identical in control and TCDD-treated rats of both substrains. Tissue concentrations of [14CC]TCDD-associated radioactivity and area under the curve (AUC) values were lower in CR L-E than in T L-E rats. The most pronounced differences were found in thymus, white adipose tissue, brown adipose tissue, and adrenals. The decrease of TCDD concentration in tissues was faster in CR L-E than in T L-E rats, whereas fecal and urinary excretion was faster in T L-E than in C L-E rats. Elimination half-life was 20.2 days in T L-E rats and 28.9 days CR L-E rats. Differential toxicokinetics of TCDD in the two L-E substrains provide a likely explanation for the greater sensitivity of the T L-E strain, since observed differences in tissue concentrations and AUC values are in good agreement with the difference in susceptibility. In addition to the more efficient tissue uptake of TCDD in T L-E rats than in CR L-E rats, the major contributing factor to differences in toxicokinetics seems to be a differential growth rate (dilution by growth), which in turn appears to provide an explanation for the difference in susceptibility. More rapid excretion of TCDD in T L-E rats than in CR L-E rats is clearly a result of higher tissue concentrations in T L-E rats. However, this faster excretion rate is not sufficient to counterbalance the much slower dilution by growth in T L-E rats than in CR L-E rats. Thus, dilution by growth can be a more important factor in determining the toxicokinetics and toxicity of TCDD in rodents than is excretion.

Animals↗
PubMed1995

Subchronic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and their reversibility in male Sprague-Dawley rats.

The hypothesis tested in this experiment is that effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) show identical dose-responses after subchronic as after acute exposure when the dose is corrected for toxicokinetics. Groups of male Sprague-Dawley (S-D) rats were administered orally a total dose of 0, 0.2, 2.3, 11.5, 35, 70 or 115 micrograms/kg of TCDD over a period of 10 weeks at 4 ml/kg of vehicle. Body weight was recorded weekly. One week after the last dose of TCDD one half of the rats was killed and tryptophan 2,3-dioxygenase (TdO), 7-ethoxyresorufin-O-deethylase (EROD) and phosphoenolpyruvate carboxykinase (PEPCK) activities were measured in livers, whereas tryptophan and total T4 (TT4) were determined in serum. The results show that the dose-response for decreased TdO and PEPCK activity and elevated serum tryptophan levels are similar if not the same as the dose-response for subchronic retardation of body weight increase. They also demonstrate that the dose-responses for the induction of EROD activity and the reduction of serum TT4 occurred at much lower doses than those for decreased TdO and PEPCK activities or elevated tryptophan levels and mortality. After a 6-week recovery period, PEPCK and TdO activities in liver as well as tryptophan in serum returned to near control values, whereas EROD activity and serum TT4 still displayed a dose-dependent induction and reduction, respectively, albeit both shifted to the right in accordance with toxicokinetics. These data support the notion that subchronic dose-responses of TCDD are similar to acute dose-responses when corrected for toxicokinetics and that at least some TCDD-induced effects are reversible also in accordance with toxicokinetics.

Animals↗
PubMed1995

Toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats including placental and lactational transfer to fetuses and neonates.

The toxicokinetics of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in virgin female Sprague-Dawley (S-D) rats, the effects of pregnancy, parturition, and lactation on the distribution and/or redistribution of TCDD, and placental and lactational transfer to fetuses and neonates were investigated. Doses of 5.6 micrograms/kg of 14C-labeled TCDD were given i.v. either to virgin rats or to pregnant rats on Day 18 of gestation and 1 day postparturition, respectively. Virgin females were terminated on Day 1, 2, 4, 8, 16, or 32, pregnant rats on Day 1, 2, 4, or 8, after dosing to collect tissues. Two groups of neonates, which were born either to TCDD-treated or nontreated dams were cross-fostered beginning on the first day after birth to simulate exposure to TCDD either by lactational transfer only or by both placental and lactational transfer. Serum and 18 different tissues were collected from virgin rats to evaluate the kinetic profile of TCDD. Serum and tissue samples from liver, kidney, brown, and white adipose tissue were collected from pregnant and postparturition rats. Liver samples from fetuses and neonates were obtained on Gestational Days 19 and 20, or postnatally on Days 1 and 5. TCDD equivalents were calculated from measurement of radioactivity. The results show that the profile of TCDD distribution in virgin female rats was similar to that in male rats but that the concentration of TCDD in most tissues was higher in females than in males.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Correlation between toxicity and effects on intermediary metabolism in 2,3,7,8-tetrachlorodibenzo-p-dioxin-treated male C57BL/6J and DBA/2J mice.

Male mice were treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by gavage. C57BL/6J (C57) mice received 0.03 to 235 micrograms/kg, DBA/2J (DBA) mice 1 to 3295 micrograms/kg. On Day 8 after dosing blood was collected, and livers and kidneys were removed. Body weights and feed intake were not much affected until Day 8 after exposure. Hepatomegaly developed at doses above 3 and 97.5 micrograms/kg in C57 and DBA mice, respectively. Ethoxyresorufin O-deethylase activity was induced in liver with an ED50 of 1.1 and 16 micrograms/kg and in kidney with an ED50 of 65 and 380 micrograms/kg in C57 and DBA mice, respectively. The activity of phosphoenolpyruvate carboxykinase (PEPCK) in livers of both mouse strains was reduced over the entire dose range, displaying a plateau in the dose response at the onset of acute toxicity of TCDD. This enzyme activity was decreased by as much as 80% at the respective lethal doses. PEPCK activity in kidney was not affected. Glucose-6-phosphatase activity (G-6-Pase) in liver was altered only in the lethal dose range with a maximum reduction of about 50%. Serum glucose concentration was reduced over the entire dose range, but the reduction was significant only at doses in which G-6-Pase activity was affected, reaching levels as low as 3 mmol/liter in DBA mice. Tryptophan 2,3-dioxygenase activity was not lowered at any dose of TCDD in either mouse strain, and no increase in serum tryptophan levels was observed. Serum levels of thyroxine (T4) and triiodothyronine (T3) were dose dependently decreased over most of the dose range administered, with T3 levels exactly paralleling T4 levels in both mouse strains. It is concluded that TCDD causes acute toxicity in male C57 and DBA mice by a severe reduction of gluconeogenesis, but, in contrast to rats, it does not affect tryptophan homeostasis. Following administration of TCDD serum T3 levels in the mouse appear to correlate with T4 levels, whereas in the rat they are independent of each other.

Animals↗
PubMed1995

Reproductive effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in female rats: ovulation, hormonal regulation, and possible mechanism(s).

A previous study has shown that exposure of adult rats to TCDD alters estrous cyclicity and ovulation. To further explore the mechanisms involved we employed the gonadotropin-primed immature female rat model. Single doses (0.3-60 micrograms/kg) of TCDD, dissolved in corn oil, were given orally to 22-day-old rats. Equine chorionic gonadotropin (eCG) (20 IU) was injected 24 hr later to induce follicular development. Rats were killed at various times after eCG, blood was collected, and ovarian weights were obtained. Serum concentrations of estradiol-17 beta (E2), luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin (LTH) were measured by radioimmunoassay. Ovulation was determined 72 hr after injection of eCG by counting ova flushed from oviducts. TCDD reduced dose-dependently the increase in ovarian weight gain induced by eCG and also decreased the number of animals ovulating as well as the number of ova recovered; the ED50 was between 3 and 10 micrograms/kg of TCDD. The increase in serum E2 induced by eCG was enhanced in animals treated with TCDD. Peak serum levels of FSH and LH, but not of LTH, were decreased by TCDD. E2, as expected, decreased dramatically in control animals between 60 and 72 hr after injection of eCG, concomitant with a preovulatory surge in LH. This response was absent in TCDD-treated animals. None of these effects were related to decreased food consumption since they were absent in pair-fed controls. In hypophysectomized immature rats treated with eCG and exogenous LH the percentage of rats ovulating and the number of ova recovered were also significantly reduced by TCDD (10 and 60 micrograms/kg). These results suggest that TCDD alters reproductive function in the immature female rat model via effects on the hypothalamic-pituitary axis as well as by direct effects on the ovary.

Administration, Oral↗
PubMed1995

Tissue-specific effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on the activity of phosphoenolpyruvate carboxykinase (PEPCK) in rats.

Reduced gluconeogenesis due to decreased activity of key gluconeogenic enzymes in liver, together with feed refusal, has been suggested to play an important role in TCDD-induced lethality in rats. In this study the toxicological significance of reduced gluconeogenesis was further analyzed by studying dose responses and time courses of effects of TCDD on the activity of PEPCK in liver and two other tissues with high specific activity, viz. kidney and brown adipose tissue (BAT). Liver PEPCK activity was significantly decreased from 1 to 32 days after dosing (60 micrograms/kg). A clear dose response was present 8 days after dosing, beginning at a dose of 1 microgram/kg. In contrast to liver, TCDD treatment increased PEPCK activity in kidney and BAT, but only at the two highest doses administered (30 and 60 micrograms/kg). PEPCK activity in kidney began to increase slowly, reaching a maximum on Day 16 and declining thereafter, whereas in BAT the activity was significantly increased already on Day 1 and maximally on Day 4 after dosing. A likely explanation for these tissue-specific effects is in part related to toxicokinetics and in part to homeostatic responses of the organism to the toxic insult of TCDD. High concentrations of TCDD in liver and BAT combined with early responses (1 day after dosing) suggest a direct effect in these organs/tissues, whereas very low concentration and delayed response in kidney indicate an indirect effect. This interesting enzymatic constellation suggests that the reduction in gluconeogenesis due to decreased PEPCK activity in liver is partially counterbalanced by increased gluconeogenesis in kidney as a result of induction of PEPCK in this organ. Induction of PEPCK in BAT, where it is a glyceroneogenic enzyme, provides for the first time a plausible explanation for the initial accumulation of fat in BAT of TCDD-treated rats.

Adipose Tissue, Brown↗
PubMed1995

Comparative toxicity of four chlorinated dibenzo-p-dioxins (CDDs) and their mixture. IV. Determination of liver concentrations.

Groups of male Sprague-Dawley rats were administered orally the following chlorinated dibenzo-p-dioxins (CDDs) in corn oil/acetone (95/5; v/v): 30-60 micrograms/kg 2,3,7,8-tetrachlorodibenzo-dioxin (tetra-CDD), 160-270 micrograms/kg1,2,3,7,8-pentachlorodibenzo-p-dioxins (penta-CDD), 630-1249 micrograms/kg 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin (hexa-CDD) and 5000-8000 micrograms/kg 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (hepta-CDD) or a mixture of the four homologues such that each was present in the mixture at one quarter of its dose as a single compound. Animals were killed at 2 and 8 days after dosing. Livers were immediately removed, and aliquots frozen in liquid nitrogen. Storage occurred at -80 degrees C until further use. About 0.2 g of each lyophilized rat liver was extracted, the extract purified by column chromatography and analyzed by GC/MS for CDD content. Results obtained suggest that the absorption of CDDs after oral administration decreases in the order of tetra-CDD > or = penta-CDD > hexa-CDD > hepta-CDD, indicating that the dose was an incomplete surrogate of exposure in parts I-III of this publication series (Stahl et al. 1992; Weber et al. 1992a,b). Moreover, data also support the notion that the pharmacokinetics of CDD mixtures at high doses are somewhat different from those expected based on single compound exposures. Our findings suggest that the intrinsic relative potency in terms of toxic equivalents (TEQ) of the higher chlorinated homologues is slightly greater (about a factor of 2) than suggested by Stahl et al.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Short- and long-term biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Long-Evans rats.

The aim of this study was to examine short- and long-term biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in female Long-Evans (L-E) rats. In the short-term study, female rats were dosed orally with 5.3, 12, 18 and 60 micrograms TCDD/kg and sacrificed 4 days after dosing. In the long-term study, rats were dosed with 27, 40 and 60 micrograms TCDD/kg and sacrificed 90 days after dosing. Four days after dosing, ethoxyresorufin O-deethylase (EROD) activity was fully induced at all doses studied, hepatic phosphoenolpyruvate carboxykinase (PEPCK) and gamma-glutamyl transpeptidase (gamma-GT) activities were dose-dependently reduced, whereas hepatic tryptophan 2,3-dioxygenase (TdO) activity was stimulated at low doses but decreased at high doses. Serum total T4 (TT4) levels were dose-dependently decreased, whereas serum total T3 (TT3) and tryptophan levels were unaffected. The short-term effects of TCDD examined in this study indicate only small differences in the response of female L-E rats to TCDD as compared to males. Ninety days after dosing, liver EROD activity revealed considerable reversibility although it was still elevated compared to controls. Hepatic PEPCK activity at this time point was no more different from controls. In contrast to 4 days after dosing, serum TT3, TT4 and hepatic gamma-GT activity were dose-dependently elevated at the 90-day time point. These findings have significant implications for the interpretations of subchronic and chronic effects of TCDD on thyroid homeostasis and on the formation of preneoplastic liver foci.

Animals↗
PubMed1995

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on estrous cyclicity and ovulation in female Sprague-Dawley rats.

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on estrous cyclicity and ovulation in Sprague-Dawley rats was examined. TCDD at a single oral dose of 10 micrograms/kg resulted in irregularity of cycles, characterized mainly as prolonged periods of diestrus. In rats cycling normally this dose of TCDD reduced the ovulatory rate and the number of ova recovered. The results suggest that TCDD is a reproductive toxin also in female rats, the mechanism of which is as yet unknown.

Administration, Oral↗