General introduction into toxicology of environmental chemicals.
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Animals↗
Biomedical subjects
H Greim
Publications and source records attributed to H Greim.
Correlation between acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and total body fat content in mammals.
Single oral 30-day LD50s of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were correlated with total body fat (TBF) content in various species and strains of laboratory mammals. LD50 values and TBF contents were either obtained from the literature or determined by experiments. A log (LD50) vs. log (TBF) plot yielded a highly significant linear regression equation (r2 = 0.834, P less than 0.001, n = 20). It is suggested that this correlation exists for at least two reasons: (1) increasing TBF content in organisms represents an enhanced capacity to remove TCDD from the systemic circulation and (2) different TBF content reflects a differential role and regulation of fat metabolism for various organisms. Extrapolation of this correlation to man suggests that adult humans are among the less sensitive species to the acute toxicity of TCDD.
Adipose Tissue↗
[The toxicity of dental amalgam fillings].
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Body Burden↗
Centrifugal elutriation of hepatocytes from 2-acetylaminofluorene-treated rats and their characterization by flow cytometry.
Treatment of male Wistar rats with 2-acetylaminofluorene (2-AAF) markedly altered the ploidy distribution of liver cells. Small diploid hepatocytes first appeared after 4-5 weeks feeding of a diet containing 0.02% 2-AAF; after 9 weeks 65-70% of the hepatocytes were diploid. Approximately two-thirds of this new liver cell population persisted after termination of the treatment. The hepatocytes from 2-AAF treated animals were separated according to size and ploidy by centrifugal elutriation and stained for gamma-glutamyltranspeptidase (gamma-GTase). The percentage of gamma-GTase-positive hepatocytes did not significantly differ between the various elutriated cell fractions. Thus gamma-GTase-positive liver cells obtained by feeding of 2-AAF do not represent a distinct size class of hepatocytes. The significance of carcinogen-induced diploid hepatocytes in hepatocarcinogenesis is discussed.
2-Acetylaminofluorene↗
Long-term effects of commercial and congeneric polychlorinated biphenyls on ethane production and malondialdehyde levels, indicators of in vivo lipid peroxidation.
Ethane exhalation was increased in male Sprague-Dawley rats following a single intraperitoneal (IP) injection of Aroclor 1254 (500 mg/kg). In the first 2 weeks following Aroclor 1254 treatment, the increase in ethane exhalation was due to an inhibition of metabolism of endogenous ethane rather than to an increase in ethane production. In weeks 3 and 4 following Aroclor 1254 administration, metabolic clearance of ethane returned to and exceeded control levels, while ethane production increased to approximately twice the control rates (day 30). The HPLC determination of in situ hepatic malondialdehyde levels revealed a 2-fold increase in malondialdehyde content on day 30 following the Aroclor 1254 injection. Further, parallel increases in in situ malondialdehyde levels and ethane production rates were also found 30 days following a single IP injection of 3,3',4,4'-tetrachlorobiphenyl, 2,3,4,4',5-pentachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl (300 mumol/kg). These effects were not reflected in increased diene conjugation. Redox state of the liver was largely unaffected, as evidenced by the relative concentrations of reduced and oxidized NADPH. However, minor changes in reduced and oxidized glutathione were noted.
Animals↗
Inhaled ethylene oxide induces preneoplastic foci in rat liver.
The metabolite of E, EO, has been shown to be an extrahepatic carcinogen in rats in long-term studies. By means of a rat liver foci bioassay with 3 to 4 days old Sprague-Dawley rats, EO showed an initiating capacity in the livers of female, but not of male rats, measured as incidence of foci deficient in ATPase. After inhalation of 55 and 100 ppm EO, 8 h daily, 5 days weekly, and over 3 weeks, 1 week of pause, and another 8 weeks of promotion with polychlorinated biphenyls, foci incidence was generally low. But it was concentration dependently higher than in controls 12 weeks after starting the experiment. A linear concentration-effect relationship existed with a correlation coefficient of r = 0.991. With 33 ppm EO the number of foci was not enhanced significantly. The administration of 10,000 ppm E did not result in an enhanced foci incidence. In general the carcinogenic potential of EO, which has not been shown so far to cause hepatic tumors in rats, could be demonstrated in rat liver using a sensitive rat liver foci bioassay.
Adenosine Triphosphatases↗
Corticosterone modulates acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in male Sprague-Dawley rats.
Bilateral adrenalectomy or adrenal demedullation was performed on male Sprague-Dawley rats by established surgical techniques. Subsequently, the dose-response (mortality and mean time to death) to TCDD was determined in adrenalectomized (10, 20, 40 micrograms/kg TCDD ip in 95:5 corn oil:acetone) or demedullated (15, 30, 60 micrograms/kg TCDD) rats. Adrenalectomy drastically increased mortality and greatly shortened mean time to death after dosing with TCDD. More importantly, adrenalectomized TCDD-treated rats died of hypoglycemic shock without losing much body weight. Conversely, adrenal demedullation had no effect on mortality or mean time to death caused by TCDD when compared to nondemedullated TCDD-treated controls. Thus, it was concluded that the factor(s) modulating the acute toxicity of TCDD resides in the adrenal cortex and not in the medulla. Administration of corticosterone (25 micrograms/ml in drinking water) to adrenalectomized rats returned the toxicity of TCDD to levels seen in nonadrenalectomized rats suggesting that this hormone is another key factor (in addition to the thyroid hormones) in the modulation of the acute toxicity of TCDD. Corticosterone supplementation (25, 50, or 100 micrograms/ml) to nonadrenalectomized rats, or to thyroidectomized-adrenalectomized rats (25 micrograms/ml), resulted in no additional beneficial effect indicating that a factor(s) other than thyroid hormones and corticosterone is also involved in the acute toxicity of TCDD.
Adrenalectomy↗
Laudatio to Herbert Remmer.
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Germany, West↗
Pharmacokinetics of isoprene in mice and rats.
Pharmacokinetic analysis of isoprene inhaled by male Wistar rats and male B6C3F1 mice showed saturation kinetics in both species. Below atmospheric concentrations of 300 ppm in rats and in mice the rate of metabolism is directly proportional to the concentration. The low accumulation of isoprene in the body at low atmospheric concentrations suggests transport limitation of the metabolism. Only small amounts of isoprene taken up are exhaled as unchanged substance (15% in rats and 25% in mice). Its half life in rats is 6.8 min and in mice 4.4 min. At concentrations above 300 ppm the rate of metabolism does not increase further in proportion to the atmospheric concentration. It finally approaches maximal values of 130 mumol/(h X kg) body weight at atmospheric concentrations above 1500 ppm in rats, and 400 mumol/(h X kg) body weight at concentrations above 2000 ppm in mice. This indicates limited production of the two possible mono-epoxides of isoprene at high concentrations. Isoprene is endogenously produced and is systemically available. Its production rate is 1.9 mumol/(h X kg) in rats, and 0.4 mumol/(h X kg) in mice, respectively. Part of the endogenous isoprene is exhaled by the animals but it is metabolized to a greater extent: the rate of metabolism of endogenously produced and systemically available isoprene is 1.6 mumol/(h X kg) (rats) and 0.3 mumol/(h X kg) (mice).
Administration, Inhalation↗
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↗
The effect of mercury chloride and methyl mercury on brain microsomal Na+-K+-ATPase after partial delipidisation with Lubrol.
The microsomal Na+-K+-ATPase of rat brain was inhibited by mercury chloride and methyl mercury. The IC50 was 6.5 X 10(-7) M for mercury chloride and 3.5 X 10(-6) M for methyl mercury. The inhibition was of a non-competitive type with respect to ATP. The non-ionic detergent Lubrol potentiated the inhibitory effect of both mercurials. It is concluded that Lubrol removes the bulk lipids present outside the catalytic center of the enzyme. Consequently, the enzyme will become more sensitive to the inhibition by both mercurials.
Animals↗
D-penicillamine induces rat hepatic metallothionein.
Intraperitoneal injection of D-Penicillamine (D-PA) at a dose range of 20-500 mg/kg increased rat hepatic but not renal and pancreatic metallothionein (MT). Elevated MT predominantly contained Zn. Maximal induction was obtained 18 h after a single injection of 200 mg D-PA/kg resulting in 148 +/- 18 micrograms MT/g liver which was 16.4-times the control level of 9 +/- 2 micrograms MT/g. At 48 h after injection, MT declined to 18 +/- 9 micrograms MT/g liver. At maximal MT increase the content of total hepatic Zn but not of Cu was elevated. Increased amounts of Zn in liver homogenate, cytosol and MT could be detected approximately 4 h after injection of 200 mg D-PA/kg. Concomitantly there was a decrease in Zn bound to cytosolic non-MT ligands. All Zn changes reversed at 18 h. These data show that already single doses of D-PA cause induction of Zn-thionein in rat liver and lead to synchronous redistribution of Zn from endogenous sources to newly synthesized MT.
Animals↗
Application, limitations and research requirements of in vitro test systems in toxicology.
There is increasing application of in vitro-test systems for toxicological evaluation of chemicals, which became possible by increasing understanding of the biological endpoints present in such systems and their capability for metabolic activation and inactivation. This communication focuses on the capacities of metabolic activation and inactivation in mutagenicity test systems, using bacteria, mammalian cells in culture and isolated hepatocytes. Bacterial test procedures with S-9-fraction are specific metabolic activation systems with low inactivation capacity. Mammalian cells are either deficient in metabolic activities or contain only limited activation capacity although special cell lines derived from hepatoma cells express certain metabolic activation as well as inactivation reactions. Isolated hepatocytes contain enzymatic activities similar to those in the intact liver, which however decrease at different rates. It is the goal of present research to construct cell lines with defined and sufficient activities of these enzymes. In isolated hepatocytes chemically induced DNA repair can be readily detected when a clear discrimination between mitochondrial, semiconservative and repair synthesis is provided. In such systems genotoxicity of reactive oxygen species is decreased by physiological concentrations of alpha-keto-acids, pyruvate possessing the highest antioxidant activity. It is concluded that in vitro test systems provide a suitable tool for detecting genotoxic and toxic effects of chemicals. However, many biological parameters such as metabolic activity, degree of differentiation of the cells, cofactor requirement, and composition of the medium affect the reliability of the test system. Thus, only a detailed understanding of the biology and biochemistry of such test allow production of reliable and reproducible results.
Animals↗
Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in cold-adapted rats.
The toxicity of 60 micrograms/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) given IP in corn oil/5% acetone was examined in male Sprague-Dawley rats adapted to 25 degrees C or 4 degrees C ambient temperature. Cold exposure significantly reduced mean time to death and tended to increase mortality. Body weight at the time of death was reduced at both ambient temperatures to about the same extent. Thus, the rate of body weight loss was about twice as fast in non-survivors at 4 degrees C than at 25 degrees C. There was a continuous decrease in feed intake of the non-survivors at 25 degrees C until death. However, no reduction in feed intake occurred in any of the rats at 4 degrees C ambient temperature. At 14 days after dosing all TCDD-dosed animals were hypothyroid in terms of T4 but essentially euthyroid in terms of T3. Oxygen consumption at 10 days after dosing was reduced to the same extent in all TCDD-dosed rats without regard to survival status. By day 20 after TCDD dosage, survivors increased their oxygen consumption at both ambient temperatures to nearly control levels whereas non-survivors were unable to do so. Body temperature of all animals remained within normal range except for the non-survivors, which showed reduced rectal temperature shortly before death.(ABSTRACT TRUNCATED AT 250 WORDS)
Acclimatization↗
Stability of metallothionein in gastric juice.
Metallothionein (MT), is presumably the major Cd-binding component of human food. It is not or only partially destroyed by cooking. To study whether MT is stable in gastric juice MT was incubated at various pH values with pepsin and human gastric juice in vitro. Above pH 3.5 nearly all Cd remained bound to the protein and Cd-MT was resistant towards proteolysis. At pH values of 2.5 and 1.7 the protein was digested to 80% and 100%, respectively. At pH 2.5 two Cd-containing peptides with 25-30 amino acids similar to the alpha-domain of the protein were detected. At pH 1.7 these fragments were further degraded to smaller peptides. The results indicate that the pH-dependent proteolytic degradation of Cd-MT depends on the metal content of the protein. Furthermore, the identical results obtained with pepsin and human gastric juice suggest that Cd-MT proteolysis occurs in vivo and will affect Cd resorption.
Amino Acids↗
Environmental chemicals in hepatocarcinogenesis: the mechanism of tumor promoters.
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Animals↗
Thyroid hormones modulate the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
These experiments examine the role of thyroxine (T4) and triiodothyronine (T3) on the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The first experiment is continuation of a study reported previously (Rozman et al., 1984). In this experiment, 60 male Sprague-Dawley rats were divided into 6 equal groups. Four groups of rats were thyroidectomized by 3 mCi Na131 l/kg rat. Five weeks later 2 of the thyroidectomized and 1 of the nonthyroidectomized groups of rats received ip 100 micrograms TCDD/kg body weight in corn oil/acetone, whereas 3 corresponding groups of rats served as vehicle controls. Two days after dosing and every 7 d thereafter, 1 thyroidectomized control group and 1 thyroidectomized TCDD-dosed group were given ip 105 micrograms T4/kg body weight. Mortality and body weight were monitored. The course of TCDD toxicity was similar in nonthyroidectomized and thyroidectomized T4-treated rats but was different in thyroidectomized animals without T4 replacement therapy. At d 90 after TCDD dosage, mortality was still lower and the mean time to death was increased (p less than 0.01) in this group of rats compared to nonthyroidectomized or thyroidectomized T4-treated rats. However, administration of T4 starting at d 91 after dosing with TCDD resulted within 2 wk in the same final mortality in thyroidectomized rats as in nonthyroidectomized or thyroidectomized T4-treated animals, indicating that thyroid hormones modulate the time course of the wasting syndrome but do not affect the ultimate mortality figure. Body weight loss was much slower in thyroidectomized (approximately 1 g/d) than in nonthyroidectomized or thyroidectomized T4-treated rats (approximately 8 g/d). In the second experiment the three vehicle control groups of the first experiment were used. Nonthyroidectomized vehicle controls and thyroidectomized T4-treated controls were maintained as before, whereas thyroidectomized controls received T3 at 5 micrograms/kg daily. One month later each rat was dosed with TCDD at 100 micrograms/kg in corn oil/acetone. Toxicity of TCDD was similar in nonthyroidectomized, thyroidectomized T4-treated, and thyroidectomized T3-treated rats as judged by mortality, body weight, and food intake, indicating no difference between T3 and T4 in the modulation of TCDD toxicity.
Animals↗
Pathology of chronic polychlorinated biphenyl (PCB) feeding in rats.
The hepatocarcinogenic effect of Clophen A 30 and Clophen A 60 was tested in male weanling rats by long-term feeding over a period of 832 days. The mortality rate was investigated in 100-day intervals. In the first 800 days liver carcinoma accounted for 21% of necropsies in the Clophen A 60 group but only 2% of the necropsies in the Clophen A 30 group and none in the control animals. The tumors were first observed after 700 days. After 800 days hepatocellular carcinoma was the most common lesion observed in the Clophen A 60 animals (61%) whereas it was only observed in 3% of animals in the Clophen A 30 group and 2% in the controls. Preneoplastic lesions, such as foci of hepatocellular alterations and neoplastic nodules, were first observed after Day 500. The incidence of foci predominated in all time intervals, but an increase in neoplastic nodules and hepatocellular carcinomas was observed with increased time. There was a marked trend from foci to neoplastic nodule to hepatocellular carcinoma with time. The total mortality rate and the incidence of thymoma, inflammatory lesions of the urogenital tract, in the experiment were significantly reduced by Clophen administration. Whether this protective effect could be induced by polychlorinated biphenyls (PCBs) is discussed.
Administration, Oral↗