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Archives of Toxicology (v.68, #6)

Genotoxic risk for humans due to work place exposure to ethylene oxide: remarkable individual differences in susceptibility by Jürgen Fuchs; Ute Wullenweber; Jan Georg Hengstler; Heinz Günter Bienfait; Gerd Hiltl; Franz Oesch (pp. 343-348).

Single strand breaks of DNA of peripheral mononuclear blood cells from 97 male and female workers occupationally exposed to ethylene oxide were analysed by the alkaline elution method. These individuals were occupied with the sterilization of medical devices in hospitals and in commercial plants. Ethylene oxide in the air of the working areas was detected up to a maximal concentration of 16.5 mg/m³ calculated as 4-h time-weighted average (4h TWA). Mean value was 1.47±0.52 mg/m³ (1 mg/m³ =0.55 ppm). Compared to the mean elution rate of the DNA from non-smoking workers exposed to air concentrations of ethylene oxide below the detection limit of 0.1 mg/m³ (4h TWA) the non-smokers working in rooms with a concentration of ethylene oxide between 0.5 mg/m³ and 2 mg/m³ showed a statistically significant (P<0.05) 119% higher mean elution rate and even for the non-smokers exposed to 0.1–0.5 mg/m³ of ethylene oxide a statistically significant (P<0.05) 53% higher mean elution rate was observed. For smokers a similar tendency was found but the increase in elution rates in response to the external exposure was smaller than in non-smokers and no statistical significance was obtained. According to their sensitivity to ethylene oxide the non-smoking workers could be classified into two subpopulations. In the majority of the non-smokers (67%) approximately 5-fold more DNA strand breaks were induced by ethylene oxide than in the other non-smokers. A lowest detectable effect level could only be specified for non-smokers. For the “higher sensitive” group the lowest detectable effect level in an examination of a single individual was calculated to be 0.6 mg/m³ ethylene oxide in the air (4h TWA). For the “lower sensitive” group a lowest detectable effect level was calculated to be 3.5 mg/m³.

Keywords: Ethylene oxide; Occupational exposure; Sterilization workers; DNA single strand breaks; Individual differences; Smoking habits

Influence of inducers and inhibitors of cytochrome P450 on the hepatotoxicity of hydrazine in vivo by Andrew M. Jenner; John A. Timbrell (pp. 349-357).

Hydrazine hepatotoxicity in vivo, as manifested by triglyceride accumulation, depletion of ATP and reduced glutathione (GSH) was shown to be dose related. The effect of pretreatment of rats with various inhibitors and inducers of cytochrome P450 on these dose-response relationships was investigated. Pretreatment with the inhibitor piperonyl butoxide increased triglyceride accumulation whereas pretreatment with the inducers phenobarbital and β-naphthoflavone (BNF) resulted in reduced triglyceride accumulation. Pretreatment with the inducers acetone and isoniazid also enhanced triglyceride accumulation. Only phenobarbital pretreatment also significantly reduced GSH and ATP depletion. A linear correlation was found between hepatic glutathione and ATP levels in non-pretreated animals given various doses of hydrazine. However, exponential relationships were found between hepatic triglycerides and both hepatic ATP and glutathione. The results suggest that i) the hepatotoxicity of hydrazine can be modulated by inducing or inhibiting particular isoenzymes of cytochrome P450, ii) ATP and GSH depletion may not be directly involved in the development of fatty liver.

Keywords: Hydrazine; Hepatotoxicity; Cytochrome P450; Rat

Use of oligonucleotides containing ethenoadenine to study the repair of this DNA lesion by F. Oesch; C. -M. Weiß; S. Klein (pp. 358-363).

Oligonucleotide duplexes of a defined sequence containing one 1,N ⁶-ethenoadenosine (EA) were synthesized and used as substrates to study the repair of this DNA lesion in cell homogenates of peripheral mononuclear blood cells of 39 male and female workers, exposed to vinyl chloride. These data were compared to data from 39 employees of the same company working in other production plants and to data from a control group of 39 persons, living in an area without vinyl chloride production. After incubation of the 5′- and 3′-labeled oligonucleotide duplex with cell homogenate, a specific nicking activity, releasing the deoxyribosyl phosphate originally carrying the EA, was found. This activity was used to determine the individual and collective repair activities for ethenoadenine. The exposed group showed a mean of 158.5±39.9 (SD) fmol product fragment and did not differ significantly from the mean value of the two control groups with 156.5±42.9 fmol and 161.2±53.6 fmol, respectively. Large interindividual variations were found, ranging from 4.9-fold in the exposed to 8.2- and 7.2-fold in the control groups. The development of an assay for ethenoadenine repair is significant for understanding the role of EA repair in eukaryotic cells.

Keywords: Ethenoadenine; Nicking activity; Peripheral mononuclear blood cells; Repair capacities; Vinyl chloride-exposed workers

Relation between lipid peroxidation and inflammation in the pulmonary toxicity of cadmium by Dino Manca; Anne C. Ricard; Huu Van Tra; Gaston Chevalier (pp. 364-369).

Lipid peroxidation (LPO), measured as thiobarbituric acid reactive substances (TBARS), was evaluated in lungs of rats 24 h after intraperitoneal injection of 50, 250, and 1000 μg Cd/kg body weight as CdCl₂. In order to gain some insight into possible causative factors responsible for these oxidative phenomena, the redox-active elements iron (Fe) and copper (Cu), and total lung protein content (an indication of pulmonary inflammatory processes) were also measured. Results obtained demonstrate a similar dose-related, non-linear evolution of total lung TBARS and total lung protein as a function of increasing lung Cd concentrations. Standardization of total lung TBARS to lung protein content further resulted in a linear relationship with lung Cd concentrations, thus suggesting a possible cause-effect relationship between these parameters. No statistically significant association was observed between the dose-related evolution of lung TBARS, and iron (Fe) and copper (Cu) after Cd exposure. The results obtained provide support for the possible involvement of inflammatory phenomena as the most likely events responsible for the generation of LPO in lung tissue following acute exposure to Cd salts.

Keywords: Cadmium; Lipid peroxidation; Lung; Copper; Iron; Inflammation

Plasma membrane hyperpolarization by cyanide in chromaffin cells: role of potassium channels by M. V. Latha; J. L. Borowitz; G. K. W. Yim; A. Kanthasamy; G. E. Isom (pp. 370-374).

Exposure of rat pheochromocytoma (PC12) cells to cyanide produces elevation of cytosolic calcium, impaired Na⁺−H⁺ exchange, membrane lipid peroxidation and release of neurotransmitters. Since these observations suggested cyanide alters plasma membrane function, the present study examined the effect of NaCN on the membrane potential of undifferentiated PC12 cells in suspension. In PC12 cells loaded with the voltage sensitive fluorescent dye, bis-oxonol, cyanide (2.5–10 mM) elicited an immediate (within seconds), concentration related decrease in fluorescence, indicating hyperpolarization of the plasma membrane. Increasing extracellular K⁺ concentration to 20 mM blocked the effect of cyanide (5 mM), suggesting cyanide increased K⁺ efflux. Pretreatment with quinine blocked the cyanide-induced hyperpolarization, whereas glyburide had little effect, showing the hyperpolarization produced by cyanide was due to activation of Ca²⁺ sensitive K⁺ channels. Removal of Ca²⁺ from the media did not influence cyanide-induced hyperpolarization. However, buffering intracellular Ca²⁺ by loading cells with the Ca²⁺ chelators, Quin II or BAPTA, abolished the cyanide effect, showing cytosolic Ca²⁺ is a key factor. These findings suggest that cyanide mobilizes Ca²⁺ from intracellular stores which leads to hyperpolarization via the activation of Ca²⁺ sensitive K⁺ channels.

Keywords: Cyanide; K⁺ channels; Hyperpolarization; bis-Oxonol

Toxicity of β-blockers in a rat whole embryo culture: concentration-response relationships and tissue concentrations by Stephan Klug; Renate Thiel; Rudolf Schwabe; Hans-Joachim Merker; Diether Neubert (pp. 375-384).

Beta-adrenoceptor blockers are widely used drugs for the treatment of cardiovascular diseases. Since β-blockers cross the placenta, it is essential to consider possible adverse effects on the embryo. Six β-adrenoceptor blockers were tested at various concentrations (10–5000 μM) 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 μM, alprenolol 30 μM, atenolol 4000 μM. Measurements of the concentrations of the various drugs in the cultured embryos at corresponding EC₅₀ levels showed differing values: metoprolol 4.5 μM, propranolol 5.2 μM, alprenolol 8.4 μM, pindolol 9.0 μM, acebutolol 12.5 μM and atenolol 77.0 μM. 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.

Keywords: Whole embryo culture; β-Blocker; Abnormal in vitro development; Tissue concentrations

Prolactin lowering activity of the retinoid Ro 14-9706 affecting lactation and pup survival by Andreas Edelmann; Brigitta Galli; Ulrike Hennes; Andreas Kistler; Herbert Kuhn; Felix Mettler (pp. 385-393).

The arotinoid Ro 14-9706, though devoid of any teratogenic potential, was found to reduce dose dependently the survival of pups when their mothers were treated with toxic doses during days 6–15 of gestation. The increased mortality was primarily seen during early lactation. When pups derived from treated mothers were nursed by control foster mothers unexposed to the drug, their survival was significantly improved indicating that the increased mortality was not solely due to fetal drug exposure. When pups derived from untreated mothers were fostered by dams that were exposed to the arotinoid during pregnancy, a significant pup mortality (p<0.01) was observed, suggesting that the nursing behaviour of lactating dams was seriously affected. This impairment could be linked to a prolactin-suppressive activity of the arotinoid during lactation which was also seen during pregnancy. Other pituitary hormones, however, were not affected by the compound. Although the drug induced pronounced structural alterations in mitochondria of adrenocortical cells, visualized by light microscopy as extended vacuolization in the zona fasciculata and reticularis, this pathological finding did not translate into functional impairment of steroidogenesis. Thus, the arotinoid Ro 14-9706 exhibits in rats a prolactin-suppressive activity which affects lactation and subsequently pup survival. This particular endocrinological interference is a new phenomenon and uncommon for retinoids.

Keywords: Retinoid; Arotinoid; Endocrine and neurochemical effects; Cross fostering; Adrenocortical degeneration

Modifications of liver bile acids pool during modulation of rat hepatocarcinogenesis by phenobarbital and nafenopin by N. M. Delzenne; H. S. Taper; M. Roberfroid (pp. 394-397).

As previously demonstrated, chronic administration of phenobarbital (0.05% in the drinking water) and of nafenopin (0.1% in the diet) increases the incidence and the kinetics of appearance of liver cancers. If bile acids play a key role in liver carcinogenesis, it might thus be expected that treatments like phenobarbital or nafenopin, which positively modulate that process, also modify their hepatic pool. The aim of the present study was to analyze the modifications of the liver bile acid pool during the modulation of liver carcinogenesis by phenobarbital and nafenopin. The animals were submitted to the hepatocarcinogenic initiation-selection (IS) procedure adapted from Solt and Farber. As compared to basal diet, the chronic feeding of phenobarbital significantly increased the total concentrations of liver bile acids both at weeks 9 and 17. That increase was mainly due to a change in the concentration of β-muricholic acid and hyodeoxycholic acid and, to a lesser extent, of chenodeoxycholic acid and α-muricholic acid. In contrast, feeding a diet containing nafenopin led to a significant decrease in the concentration of liver bile acids, due to a complete disappearance of chenodeoxycholic acid and muricholic acid, and a decrease in the concentration of hyodeoxycholic acid. Carcinomas appearing in IS phenobarbital-treated rats contain fewer bile acids than the surrounding parenchyma (because of the decrease in deoxycholic acid and ursodeoxycholic acid) whereas the malignant tumors appearing in IS nafenopin-treated rats have essentially the same pattern of bile acids as the surrounding parenchyma. During modulation of liver carcinogenesis by phenobarbital and nafenopin, changes in bile acid metabolism definitively take place but they are both quantitatively and qualitatively different. Therefore, the perturbations of liver bile acid homeostasis occurring in such a carcinogenic protocol do not seem to be implicated in the positive modulation induced by phenobarbital or nafenopin treatment.

Keywords: Bile acids; Liver carcinogenesis; Metabolic disorder

Toxic effects and excretion in urine of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) in the rat after a single oral dose by Hannu Komulainen; Hannele Huuskonen; Veli-Matti Kosma; Simo Lötjönen; Terttu Vartiainen (pp. 398-400).

Toxic effects and excretion in urine of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), the potent mutagenic compound in chlorinated drinking water, was evaluated in male Wistar rats by the up-and-down method. MX was dosed by gavage in deionized water at doses between 200 mg/kg and 600 mg/kg, for one animal at a time, and effects were observed for 14 days. Urine was collected in metabolism cages up to 72 h after dosing for chemical analysis of MX in urine. The animals receiving 200 mg/kg did not display clear clinical signs but at higher doses the signs of ill effects included dyspnea, laborious, wheezing and gasping breathing, decreased spontaneous motor activity, ataxia, nostril discharges, catalepsia and cyanosis. In necropsy bronchi contained foamy liquid and the lungs appeared edematous and spongy. The stomach cavity was expanded due to accumulation of fluid and gas and the gastrointestinal tract from stomach to caecum was reddish. Microscopically, the main target organ of toxicity was the gastrointestinal tract (diffuse congestion and necrosis in the mucosa). Signs of toxicity were recorded also in lungs (slight edema) and kidneys (dilated tubules, thin tubular epithelium, brownish tubular and interstitial concretion). The LD₅₀ in 48 h was 230 mg/kg. Only 0.03–0.07% of the dose (200 mg/kg or 300 mg/kg) was excreted in urine as intact MX. The results indicate that at high doses MX has a strong local irritating effect in the gastrointestinal tract and it probably increases liquid permeability in lungs. MX may also cause tubular damage in kidneys. Data also indicate that after an oral dose only traces of MX are excreted in urine as intact compound, suggesting that MX is subjected to intense metabolism before excretion, even at lethal doses.

Keywords: 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone; Chlorination; Drinking water; Toxicity; Rat

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Archives of Toxicology (v.68, #6)