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K K Rozman

Publications and source records attributed to K K Rozman.

At least 55 records · Page 3Linked to original sources
PubMed1995

Incorporation of first-order uptake rate constants from simple mammillary models into blood-flow limited physiological pharmacokinetic models via extraction efficiencies.

Incorporation of First-Order Uptake Rate Constants from Simple Mammillary Models into Blood-Flow Limited Physiological Pharmacokinetic Models via Extraction Efficiencies. W. L. Roth, L. W. D. Weber, and K. Rozman (1995). Pharm. Res. 263-269. First-order rate constants obtained from classical pharmacokinetic models correspond to mammillary systems in which all of the blood (or plasma) is assumed to be located in a central compartment. In such models the rate at which chemicals are transported out of this pool and into another compartment is the product of the mass of chemical in the central compartment multiplied by a rate constant, which is not limited in magnitude by the blood flow, or the rate at which chemicals from the blood are delivered to the peripheral compartment. Most of the physiologically-based models published to date dispense with some of the information available from mammillary models by assuming that all of the chemical delivered by the flow of blood rapidly equilibrates and can be taken up by the tissue under the control of a "partition coefficient" (Rij = Cj/Ci). We show that the partition coefficient alone does not retain the uptake rate (kji) information available from a classical mammillary model, but that the uptake rate information can be incorporated via unitless extraction efficiency parameters, epsilon j.

Blood Volume↗
PubMed1994

Asbestos in the air of public buildings: a public health risk?

The Environmental Health and Safety Council of the American Health Foundation has examined current estimates of cancer risks associated with the presence of asbestos-containing materials (ACM) in public buildings. The Council finds that even complete removal of asbestos from all of these buildings will provide no measurable benefit to public health. The removal of nonfriable ACM only can be postulated to protect the public against a small hypothetical risk that cannot be measured epidemiologically. Moreover, examination of the assumptions used in the risk assessment calculations leads to the conclusion that these small calculated risks are likely to represent overestimates. In recent surveys, the measured asbestos levels in indoor air cast some doubt on whether occupant exposure to asbestos levels are contributed to significantly by ACM even when some of the material is friable or in bad condition. Furthermore, the models used for cancer risk estimates assume no threshold level for cancer and conclude that any exposure is carcinogenic. This may be unjustified in light of information on the mechanisms for some asbestos-caused disease. Based on the best available data, it is very unlikely that cancer will result from indoor asbestos exposure, especially where ACM is well maintained.

Air Pollution, Indoor↗
PubMed1994

A pharmacodynamically responsive model of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) transfer between liver and fat at low and high doses.

We have constructed a pharmacokinetic model for TCDD in the rat, emphasizing its transfer between plasma, lipid, and cytoplasmic compartments of the liver, white adipose tissue (WAT), and brown adipose tissue (BAT). Volumes of the lipid pools are controlled by a submodel of triglyceride (TG) metabolism and transport that responds via a receptor for TCDD in WAT cytoplasm with a Kd of about 2 nM. This submodel, and one for cytochrome P450IA2 induction, allowed us to simulate binding of TCDD to the induced P450IA2 binding sites at low doses (1 ng/kg to 10 micrograms/kg) independently of the decreased feed intake and hyperlipidemia associated with higher doses (20 to 120 micrograms/kg). In low-dose simulations, the induction of cytochrome P450IA2 binding sites for TCDD dominated the redistribution of TCDD between WAT and liver. When simulations were performed using a partitioning model with constant gastrointestinal flows, increased WAT lipolysis driven by reduced feed intake (from 10 to 120 micrograms/kg) is predicted to result in a decreased WAT volume and a sharp drop in the mass of WAT-associated TCDD, while initially increasing the levels of TCDD in liver. However, the observed concentration of TCDD in WAT increased in rats treated with a high dose (72 micrograms/kg) of TCDD. The rise in tissue concentrations could not be explained without incorporating decreased intestinal flows into the gastrointestinal absorption process, which increased the resorption of TCDD. TCDD concentrations in tissue increased only when the relative tissue volumes decreased more rapidly than the whole-body TCDD elimination rate.

Adipose Tissue↗
PubMed1994

Relationship between acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and disturbance of intermediary metabolism in the Long-Evans rat.

The aim of this study was to examine the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin, (TCDD) in a rat strain other than the Sprague-Dawley (S-D) rat, for which most of our data have been generated thus far. Doses for the biochemical study were selected based on an acute range-finding study, which indicated that Long-Evans (L-E) rats are somewhat less susceptible to TCDD toxicity than are S-D rats. Male L-E rats were dosed orally with 10, 20, 45, 67, 100 and 150 micrograms/kg TCDD. Body weight and feed intake were dose-dependently decreased prior to killing of the animals. Eight days after dosing, animals were killed and tryptophan, total T4 (TT4) and total T3 (TT3) levels were determined in serum, whereas the activities of ethoxy-resorufin-O-deethylase (EROD), phosphoenolpyruvate carboxykinase (PEPCK), gamma-glutamyl transpeptidase (gamma-GT) and tryptophan 2,3-dioxygenase (TdO) were measured in liver. EROD activity was fully induced at all doses studied, indicating that as in S-D rats, Ah-receptor-mediated effects do not seem to play any major role in the acute toxicity of TCDD in this rat strain either. Hepatic PEPCK activity was dose-dependently decreased in a similar dose range as in S-D rats, indicating inhibition of gluconeogenesis. Feed intake was dose-dependently decreased as a result of a dose-dependent elevation in serum tryptophan levels, which in turn were related to reduced liver TdO activity. Hepatic gamma-GT activity was also dose-dependently reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Search for the mechanism of toxicity of dioxins. A lesson in toxicology.

The development of modern toxicology was strongly influenced by parallel evolutions of sister disciplines as well as regulatory requirements. This led to an overemphasis of some areas of toxicology while other aspects of it experienced at least a temporary benign neglect. The author of this paper believes that the few and far between successes in elucidating the mechanism of toxicity of chemicals are related to this uneven approach to a very complex problem. Based on one of the most important and controversial contemporary issues in toxicology, viz. that of dioxins, it is argued that by a systematic step-wise use of methodologies borrowed from sister disciplines, our capabilities of elucidating the mechanism of action of toxicants can be considerably improved.

Animals↗
PubMed1989

Physiological pharmacokinetic model of hexachlorobenzene in the rat.

A physiologically based pharmacokinetic model was developed to describe the distribution of hexachlorobenzene (HCB) in the rat after oral administration or injection. The model was based on flow-limited blood perfusion of HCB to tissues and organs of the body. A set of simultaneous differential equations were solved for the different tissue concentrations as a functions of time. The model allowed for elimination of HCB by excretion. The model also allowed for differential growth of various tissues over the course of an experiment. Computer simulations using the model indicated that growth of animals during the course of dosing experiments can greatly increase the apparent half-life of HCB.

Animals↗
PubMed1989

Rapid [14C]heptachlor clearance from body stores of ovines: ingested mineral oil and parenteral trans-stilbene oxide lack effects.

Recently we reported elimination of radioactivity from [14C]heptachlor from body stores of lactating ovines, mainly into excreta rather than milk, contrasting sharply with bovines. To further assess heptachlor metabolism and clearance by ovines, 12 fine-wool wether lambs (41 +/- 3 kg) housed in metabolism stalls were fed pelleted alfalfa hay (96%) plus molasses (3%) ad libitum and were dosed i.p. once with [14C]heptachlor (1.643 mg/kg body wt; sp. act. = .89 microCi/mg). Feces and urine were collected separately and quantitatively. Light mineral oil was mixed with feed (5 g/100 g) of six lambs and trans-stilbene oxide, an inducer of biotransformational enzymes, was administered i.p. (4 g/hd initially; 2 g/hd daily thereafter) through 20 d to three lambs given each mineral oil treatment, in 2 x 2 factorial arrangement. Feces, urine, blood, bile and body tissues were assayed for total 14C activity. Radioactivity (heptachlor and [or] metabolites) eliminated into excreta during 21 d amounted to 34 to 36% of dose administered, of which 67% appeared in urine and 33% in feces. Biological half-time for elimination into excreta was 11.3 d [Kel = -.061/d], similar to 11.7 d we reported for lactating ewes. Clearance from blood had T1/2 = 14 d. Neither mineral oil nor trans-stilbene oxide altered rate or route of 14C activity excreted or concentrations of 14C activity in blood. Results confirmed that ovines eliminate heptachlor much more rapidly than bovines.

Animals↗
PubMed1987

Metabolism and distribution of [14C]glucose in rats treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Male Sprague-Dawley rats were given a single, usually lethal, dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 125 micrograms/kg ip in corn oil), or vehicle alone. Twenty-four hours after ip administration of TCDD the animals received an ip injection of 14C-labeled glucose, and the time course and amount of exhalation of 14CO2 were monitored for 8 h continuously and once daily for 20 min for the subsequent 5 d. TCDD treatment reduced the amount of 14CO2 exhaled within 8 h after the injection of [14C]glucose by 33%, as compared to pair-fed controls. Blood levels of radioactivity were affected by TCDD accordingly. No particular organ appeared to act as a sink for the radioactivity not exhaled during these 8 h by the treated animals. TCDD (125 micrograms/kg) induced significant changes in the disposition of radioactivity in heart and brown adipose tissue between 25 and 125 min after the iv injection of [14C]glucose. The areas under the curve of [14C]glucose-derived radioactivity were the same after either iv or ip injection in the blood of TCDD-treated rats, allowing a direct comparison of experiments with iv or ip injection of [14C]glucose. The half-lives of radioactivity in the exhaled air and in feces of treated animals were greatly elevated during the 5 d following administration of [14C]glucose. These results indicate that TCDD induces in rats, within 24 h after dosing, alterations in the metabolism of glucose that preceded changes in insulin homeostasis, because hypoglycemia and hypoinsulinemia in rats do not occur until about a week after TCDD treatment. Since overt signs of acute toxicity (reduced feed intake and body weight loss) are also not noticeable until several days after a lethal dose of TCDD, it is probable that this earlier disturbance of glucose metabolism is part of the biological changes that result in wasting away and eventually in death.

Animals↗
PubMed1985

Effect of thyroidectomy and thyroxine on 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced immunotoxicity.

Radiothyroidectomy protected against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced immunotoxicity in rats as assessed by the spleen anti-SRBC plaque-forming cell assay. Thyroxine (T4) replacement therapy partially reversed the effects of thyroidectomy on T4 and triiodothyronine (T3) serum levels, body weight and immune function as well as restored TCDD-induced immunotoxicity. Thus, hypothyroidism induced by TCDD exposure can be viewed as a protective response of the organism to reduce the insult caused by TCDD.

Animals↗
PubMed1984

Phase II enzyme induction reduces body burden of heptachlor in rats.

Contrary to expectations hexadecane had no significant effect on the body clearance of heptachlor in rats. However, phase II enzyme induction altered the kinetics of heptachlor dramatically, reducing its half-life by about 3-fold. The reduction of half-life was reflected in correspondingly lowered adipose tissue and blood levels.

Alkanes↗
PubMed1984

Comparative decontamination of hexachlorobenzene-exposed rats and rabbits by hexadecane.

The effect of 8 wk of hexadecane (Hex; 5% w/w) in the diet on the disposition of [14C]hexachlorobenzene (HCB) was examined under identical conditions in rats and rabbits. Urine and feces were collected daily. Blood was obtained periodically, HCB was determined in serum, erythrocytes, heart, muscle, lungs, liver, kidney, spleen, fat, skin, and brain, as well as in excreta. The half-life of HCB was similar in the two species examined (rat 24 d; rabbit 32 d). Hex treatment increased by 4-5-fold the daily fecal excretion of HCB, resulting in correspondingly reduced half-lives of HCB in both species (rat 8 d, rabbits 12 d). As a result of Hex treatment, HCB concentrations in fat (major tissue of storage) of rabbits were about 5 times and in rats about 13 times lower than in corresponding controls. In general, the decrease of HCB in other tissues paralleled that in fat. Data indicate that the effect of Hex on the disposition of HCB is very similar in rats and rabbits.

Alkanes↗
PubMed1982

Effect of mineral oil and/or cholestyramine in the diet on biliary and intestinal elimination of 2,4,5,2',4',5'-hexabromobiphenyl in the rhesus monkey.

Addition of mineral oil to the diet (5%) of two rhesus monkeys that were dosed 29 wk earlier with 2,4,5,2',4',5'-hexabromobiphenyl (HBB) produced a 175% increase in fecal excretion of HBB. A third rhesus monkey was provided with a complete biliary bypass, which permitted the reintroduction of the monkey's own bile or the introduction of the same amount of exogenous bile, which was obtained from control donor monkeys. This experimental design made it possible to measure the portion of fecal excretion that was due to biliary elimination and the portion that was due to intestinal elimination. The effect of mineral oil and/or cholestyramine (CSA) on biliary and intestinal elimination of HBB in the rhesus monkey was then investigated. The results show that (1) fecal excretion of HBB and/or metabolites is due to both biliary and intestinal elimination; (2) during the first 2 wk after completion of dosing, mineral oil does not influence fecal excretion of HBB significantly; (3) 6-7 wk after completion of dosing, mineral oil enhances fecal excretion of HBB by 50%; (4) 8 wk after the last dose of HBB, 4% CSA in the diet increases fecal excretion of HBB and/or metabolites by about 50%; (5) mineral oil specifically stimulates intestinal elimination of HBB; and (6) combined administration of mineral oil and CSA results in an additive effect.

Animals↗
PubMedDate not supplied

Subchronic (13-week) toxicity of heptachlorodibenzo-p-dioxin in male Sprague-Dawley rats.

A 13-week oral toxicity study with 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) was performed in Sprague-Dawley rats. Rats received HpCDD at five different dose levels or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at one dose level. The doses were divided into 4 daily loading doses and 6 biweekly maintenance doses. At the end of the 13-week dosing period half of the rats were scheduled for necropsy and the other half after another 13-week off-dose period. This preliminary report contains only data from male rats during the 13-week main study period. At the two highest doses of HpCDD and in the TCDD dosage group the body weight or body weight gain was reduced. Mortality was 15, 50 and 5%, respectively. Wasting syndrome was the primary cause of death, but some rats died of hemorrhage without wasting, which may be related to the dose-dependent decrease in platelet counts. Phosphoenolpyruvate carboxykinase (PEPCK), the rate limiting enzyme of gluconeogenesis, was decreased only at the two highest dose levels of HpCDD and in the TCDD group, all of which also showed mortality. Ethoxyresorufin O-deetylase (EROD) was induced dose-dependently in all treated groups. Serum total thyroxine (T4) concentrations were decreased beginning at the middle dose of HpCDD. The study demonstrates that the toxicity observed after subchronic exposure to HpCDD is very similar to that of TCDD. Most importantly, most of the effects after subchronic and acute dose exposure are identical, confirming the validity of 0.007 as the toxic equivalency factor for HpCDD.

Administration, Oral↗
PubMedDate not supplied

Interaction of estradiol and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in an ovulation model: evidence for systemic potentiation and local ovarian effects.

Immature rats were treated with estradiol cypionate, (ECP, 0, 0.1, 1, or 2 mg/kg s.c.) followed 24 h later by TCDD (0 or 10 microg/kg orally). Follicular development was induced with eCG [5 or 10 IU subcutaneously (s.c.)] followed by an ovulatory dose of hCG (10 IU s. c.). Inhibition of ovulation by TCDD was potentiated by ECP in hypophysectomized but not intact rats. Only hypophysectomized rats exposed systemically to TCDD and ECP exhibited weight loss. Pair feeding mimicked the combined effects of TCDD and ECP in hypophysectomized rats. In another experiment, intact rats received ECP s.c. (0 or 2 mg/kg) and TCDD into the ovarian bursa (0 or 250 ng). Another group of intact rats received TCDD orally (10 microg/kg) and ECP into the ovarian bursa (0 or 1.5 microg). Blockade of ovulation by systemic or local TCDD was alleviated by ECP pretreatment. Estrogen increased the systemic toxicity of TCDD in rats whereas antagonizing its direct ovarian effects.

Administration, Oral↗
PubMedDate not supplied

Impaired ovulation by 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) in immature rats treated with equine chorionic gonadotropin.

Several studies have established that 2,3,7,8 tetrachloro-p-dioxin (TCDD) blocks ovulation. The main purpose of this study was to determine if induced ovulation was delayed temporarily by TCDD. The ovulation model used was that of the gonadotropin-primed intact or hypophysectomized rat. Immature intact female Sprague-Dawley rats (IIR) were given 32 microg TCDD/kg by gavage on day 24 of age. The next day equine chorionic gonadotropin (eCG) (5 IU) was injected sc to stimulate follicular development. The number of ova in the oviducts, the ovulation rate, and steroid concentrations were determined at 72, 96, 120, and 144 h after eCG. Immature female Sprague-Dawley rats (IHR) were hypophysectomized on day 23 of age. On day 26, the IHR were given 20 microg TCDD/kg by gavage. The next day eCG (10 IU) was injected sc to stimulate follicle development and at 52 h after eCG, 10 IU human chorionic gonadotropin (hCG) was given to induce ovulation. The same parameters as in IIR were determined in IHR at 72, 96, and 120 h after eCG. TCDD decreased body and ovarian weight gains in both IIR and IHR. In IIR, TCDD delayed ovulation by 24 to 48 h reducing the number of ova shed as well as the number of animals ovulating at 72 and 96 h after eCG. In IHR, however, TCDD reduced only the number of ova shed but caused no delay in ovulation. The IIR treated with TCDD had low levels of progesterone (P4) at 72 and 96 h after eCG but high levels of estradiol (E2) at the same time points. This sustained high level of E2 production coincided with a transient decrease in serum concentrations of androstenedione (A4). The alteration of steroid hormones by TCDD was restored to normal by 48 h after ovulation in IIR. Serum P4 concentration was not altered by TCDD in IHR at 72 h after eCG but was decreased thereafter. The delay in ovulation induced by TCDD in IIR indicates the disruption of the hypothalamus-pituitary-ovary axis during proestrus. The decrease in number of ova shed in IHR induced by exogenous gonadotropins indicates an additional direct ovarian effect of TCDD in blocking ovulation.

Administration, Oral↗
PubMedDate not supplied

The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on weight gain and hepatic ethoxyresorufin-o-deethylase (EROD) induction vary with ovarian hormonal status in the immature gonadotropin-primed rat model.

Immature female rats received 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during an induced proestrus or diestrus. The inhibitory effect of TCDD on acute weight gain and the induction of hepatic ethoxyresorufin-o-deethylase (EROD) activity by TCDD were greatest during proestrus. In a second experiment, ovariectomized rats received estradiol cypionate (ECP) or progesterone followed by TCDD. TCDD and estradiol each alone significantly inhibited weight gain. Progesterone potentiated the effects of TCDD on weight gain. The highest dose of ECP was associated with greater induction of hepatic EROD activity by TCDD than seen with TCDD alone. Estradiol modulates the induction of hepatic EROD activity by TCDD. Differential effects of TCDD on acute weight gain during proestrus vs. diestrus in this model do not mimic changes induced by estrogen alone. Hepatic responses to TCDD may vary according to phase of the female reproductive cycle.

Animals↗
PubMedDate not supplied

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) blocks ovulation by a direct action on the ovary without alteration of ovarian steroidogenesis: lack of a direct effect on ovarian granulosa and thecal-interstitial cell steroidogenesis in vitro.

The main purpose of this study was to investigate the direct effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on ovarian function including ovulation and steroidogenesis. In vivo effects of TCDD were investigated on ovulation and alteration of circulating and ovarian steroid hormones in immature hypophysectomized rats (IHR) primed with equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG). In addition, in vitro effects of TCDD on the steroidogenesis of granulosa cells (GC), theca-interstitial cells (TIC), and whole ovarian dispersates derived from the ovary of IHR were investigated. In the ovulation model, rats were hypophysectomized on Day 23 of age. On Day 26, the IHR were given 20 microg TCDD/kg by gavage. The next day eCG (10 IU) was injected sc to stimulate follicular development. Fifty-two hours after eCG, 10 IU hCG was given to induce ovulation. TCDD (20 microg/kg) blocked ovulation and reduced ovarian weight in IHR. Concentrations of progesterone (P4), androstenedione (A4), and estradiol (E2) in sera and ovaries were not altered by TCDD at 12, 24, 48, and 72 h after eCG. except for a two-fold increase in ovarian concentration of A4 at 48 h after TCDD. However, this higher concentration of A4 at 48 h after TCDD did not reflect that of A4 in sera and did not correlate with E2 in either sera or ovaries. In isolated GC from untreated IHR, TCDD (0.1 to 100 nM) had no significant effect on P4 and E2 after stimulation by LH or FSH. In TIC and whole ovarian dispersates containing GC, TIC, and other ovarian cells, TCDD (0.1 to 800 nM) had no effect on A4 and P4 secretion stimulated by LH. Using RT-PCR, AhR mRNA was shown to be expressed constitutively in the whole ovary of IHR with maximum down-regulation at 6 h after TCDD (20 microg/kg). Ovarian CYP1A1 was induced maximally at 6 h after TCDD, whereas CYP1B1 could not be detected. The induction of AhR related genes by TCDD in the ovary implies the existence of AhR-mediated signal transduction pathways. In summary, these results indicate that TCDD does not affect ovulation in IHR by altering ovarian steroidogenesis. It seems that inhibition of ovulation by TCDD is due to processes related to follicular rupture.

Animals↗