The effect of food restriction for 4 weeks on common toxicity parameters in male rats.

A chemical mixed with the diet often interferes with food consumption. As a consequence many biological changes may be induced by underfeeding. Therefore, the effects of food restriction for 4 weeks on common toxicity parameters were studied in male rats. Diet consumptions of 5, 10, and 15 g/day/rat and ad libitum (unrestricted) were used. Body weight gains of all restricted groups were depressed and many absolute organ weights were lower than those of the unrestricted diet group. Relative organ weights of the brain and the testes were increased while that of the liver was decreased in all restricted groups. Leukocyte counts were depressed with decreasing food consumption. The concentrations of triglyceride and inorganic phosphorus in all restricted groups were lower than those of the unrestricted group. The activities of glutamic-pyruvic transaminase and alkaline phosphatase were lower in the restricted groups than in the unrestricted one. The toxicological significance of these findings is discussed.     

Beneficial effect of N-acetylcysteine against organophosphate toxicity in mice

Recent studies showed that oxidative stress could be an important component of the mechanism of organophosphate (OP) compounds toxicity. The aim of present study was to investigate either prophylactic and therapeutic effects of N-acetylcysteine (NAC) against fenthion-induced oxidative stress in mice. Additionally, the effects on survival rates were investigated. Therefore, we determined the changes of the blood levels of glutathione (GSH), malondialdehyde (MDA), nitrite, and nitrate in blood or serum. Additionally, all animals were observed for 6 h and the survival rates were recorded. It was found that fenthion administration increased the levels of MDA, and decreased the levels of GSH, nitrite and nitrate. On the other hand, both prophylactic and therapeutic NAC treatment decreased the levels of MDA, and increased the levels of GSH, nitrite, and nitrate. The results showed that NAC is able to attenuate the fenthion-induced oxidative stress whereby NAC has not only prophylactic but also therapeutic activity in fenthion poisoning. On the other hand, we found that NAC can clearly improve survival rates in mice administered with an acute high dose of fenthion poisoning. In conclusion, NAC can decrease OP-induced oxidative stress and mortality rate, but the exact mechanism of its NAC protective effect needs to be explored further.     

Enhancement of aspirin-induced teratogenicity by food restriction in rats

Forty-nine pregnant rats were apportioned to four groups of similar size. Control rats, Group I, were allowed food ad libitum; rats in Group II were allowed food ad libitum and were treated daily from Days 7 through 10, after mating, with 250 mg/kg of acetylsalicylic acid (aspirin) by gavage. The rats in Group III were on a restricted diet, receiving 6 g daily from Days 6–15 after mating. The rats in Group IV received a restricted diet and were given 250 mg/kg of aspirin/day from Days 7–10. The offspring of rats on an unrestricted diet that were treated with 250 mg/kg of aspirin had a variety of malformations. The offspring of the food-restricted rats showed only slightly more than the normal background incidence of malformations, whereas the offspring of the food-restricted rats that also received aspirin had more than twice the incidence of malformations than those that received aspirin and were on an unrestricted diet.     

Short-term toxicity studies of vanadium in rats

Vanadium (in the form of NaVO3) was given in drinking water to groups of 10 male Sprague-Dawley rats over a period of 3 months at concentrations of 0, 5, 10 and 50 ppm. Vanadium accumulated dose-dependently in the kidneys and spleen. Appearance, behaviour, food and water consumption, growth and mortality of the treated rats of all groups were not affected during the 3-month period. Histopathological investigation showed only mild though dose-dependent lesions in kidneys and spleen. The plasma concentrations of urea and uric acid were increased in the highest exposure groups.     

Beneficial effect of alpha-tocopherol in renal ischemia-reperfusion in rats.

We evaluated the effects of alpha-tocopherol (vitamin E) on the products of lipid peroxidation and serum creatinine levels in a rat model of renal ischemia-reperfusion. The animals were submitted to sham operation or renal ischemia-reperfusion, and they were pretreated with alpha-tocopherol or the vehicle saline. In four groups, we analyzed the lipid peroxidation products by measuring malondialdehyde and chemiluminescence levels. In the other three groups, we studied the serum creatinine levels after the procedures. In our study, the pretreatment with alpha-tocopherol reduced significantly the lipid peroxidation of renal cells and renal dysfunction induced by renal ischemia-reperfusion in rats.     

Effect of food restriction on hepatotoxicity of carbon tetrachloride in rats

Five-week-old Sprague-Dawley rats of both sexes were assigned to two types of feeding condition. One was fed ad libitum (AL) on commercial chow and another was fed a restricted amount of the chow (FR), approximately 75% of that fed in the AL condition. In each feeding condition, animals were orally administered carbon tetrachloride (CCl4) at levels of 0 (control), 0.1 or 0.2 ml/kg 6 days a week for 8 weeks. Lesions of the liver (hepatic cellular degeneration and fibrosis) and of the kidney (proximal tubular vacuolation and glomerular sclerosis) induced by CCl4 were aggravated in the FR group. The FR-control showed a higher metabolic activity of aniline in the liver than the AL-control group. Plasma lipid-peroxide (LPO) level was higher in the AL-control group than in the FR-control group. With CCl4 0.2 ml/kg treatment, however, the plasma LPO level was reversed between the AL and the FR groups. Taking together these somewhat unexpected results, it was concluded that (1) 25% food restriction increases toxicity of repeatedly administered CCl4 in rats, and (2) aggravation of CCl4 toxicity may be partly due to enhanced metabolic activation of CCl4 resulting from food restriction.     

Developmental toxicity studies of four fragrances in rats

Four fragrances, 6-acetyl-1,1,2,4,4,7-hexamethyltetraline (AHTN), 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-gamma-2-ben zopyran (HHCB), musk ketone and musk xylene were tested for developmental toxicity in Sprague-Dawley rats (25/group, 3 groups/fragrance, 2 fragrances/corn oil control). Dosages tested were HHCB: 50, 150, 500 mg/kg per day; AHTN: 5, 15, 50 mg/kg per day; musk ketone: 15, 45, 150 mg/kg per day; musk xylene: 20, 60, 200 mg/kg per day. All dosages tested exceeded multiples of the estimated maximal daily human dermal exposure. Treatment (gavage, 5 ml/kg) occurred on GDs 7-17 and Caesarean-sectioning on GD 20. Based on the results of these studies, none of the four fragrances tested were more toxic in the conceptuses than in the dams. Maternal NOAELs were 50, 5, 15 and 20 mg/kg per day for HHCB, AHTN, musk ketone and musk xylene, respectively (150, 50, 45 and 60 mg/kg per day caused clinical signs and reduced weight gain and feed consumption). Developmental NOAELs were 150, 50, 45 and 200 mg/kg per day for HHCB, AHTN, musk ketone and musk xylene, respectively. No adverse effects on embryo-fetal viability, growth or morphology occurred at the highest dosages of AHTN (50 mg/kg per day) or musk xylene (200 mg/kg per day). Developmental toxicity occurred at the high-dosages of HHCB (axial skeletal malformations at 500 mg/kg per day) and musk ketone (increased postimplantation loss and reduced fetal body weight at 150 mg/kg per day). The results of this study indicate that under conditions of normal use, the tested fragrances do not pose a risk to human conceptuses.     

Subchronic toxicity studies of fenbendazole in rats.

The effects of prolonged exposure of rats to fenbendazole were investigated. Fenbendazole was given daily by gavage for 14 consecutive days. These dosages (3000, 500 or 50 mg/kg/d) produced reductions in body weight gains. Renal tubular hyperemia or hemorrhage and glomerular capsule dilation, increased serum creatinine and hepatocellular granular degeneration occurred at dosages of 500 and 3000 mg/kg/d. Renal tubular epithelial cell granular degeneration and tubular dilation, increased serum glutamic pyruvic transaminase, cardiac hemorrhage and granular degeneration also occurred at 3000 mg/kg/d.     

Quantitative studies of the effect of antagonists on the acute toxicity of organophosphates in rats

1. The subcutaneous acute toxicities of the vinyl phosphate pesticides monocrotophos, dicrotophos, chlorfenvinphos, crotoxyphos, dichlorvos, mevinphos, and of the experimental compounds SD 4455 (cis-2-carboxy-1-methylvinyl dimethylphosphate) and SD 7779 (cis-2-(1-phenylethoxy) carbonyl-1-methylvinyl diethylphosphate) have been determined in female rats.2. The effects on the log dose-probit mortality curves to the vinylphosphates of the therapeutic subcutaneous administration of methylatropine, atropine, N-methylpyridinium-2-aldoxime methanesulphonate and obidoxime have been studied.3. Elevation of the LD50 values by the therapeutic regimens was shown to be an unsatisfactory measure of therapeutic efficiency, while reduction of the effect of a maximally lethal dose (LD90) to less than that of a minimally lethal dose (LD10) provided a better quantitative measure of therapeutic efficiency.4. The combination of atropine sulphate (50 mumol base/kg) with obidoxime (250 mumol/kg) was found to be generally the most effective of the antidotal regimens.     

Subchronic oral toxicity studies with alpha-cyclodextrin in rats

The toxicity of alpha-cyclodextrin (alpha-CD), a cyclic polymer of six alpha-1,4-linked glucopyranosyl units with potential applications as a food ingredient, more specifically a water-soluble dietary fiber, was examined in a 4-week range finding study and a 13-week oral toxicity study in rats. In the 4-week study, the test substance was administered to groups of Bor:WISW(SPF;Cpb) rats at dietary levels of 0, 1, 5, and 15% (5 rats/sex/group). An additional group received a diet with 5% beta-CD. In the 13-week study, groups of Crl:(WI)WU Br rats received diets with 0, 1.5, 5, or 20% alpha-CD. An additional group received a diet with 20% lactose (20 rats/sex/group). Satellite groups of 10 rats/sex were attached to the control, 20% alpha-CD and 20% lactose group. Following the 13-week treatment period, these satellite groups were kept on a standard, cereal-based rodent diet for a 4-week recovery period. Parameters measured during the two studies included clinical signs, body weights, food and water intake, hematological and clinicochemical parameters, and organ weights as well as gross and histopathological observations at necropsy. In the 13-week study, ophthalmoscopic examinations as well as urine and feces analyses were also conducted. There were no treatment-related mortalities in either study. In the 4-week study, persistent diarrhea was the most prominent, treatment-related effect observed in the animals of the 15% alpha-CD group especially in the male animals. In association with this effect, food consumption and food conversion efficiency were decreased. In line with observations from studies with other low-digestible, yet fermentable carbohydrates, the weight of the full and empty cecum was increased significantly in the 5% alpha-CD, 5% beta-CD, and 15% alpha-CD group. The reduced relative liver weights (in males and females) and the significantly increased relative testes weight which were observed in the 15% alpha-CD group, were attributed to the impaired nutritional condition (due to diarrhea) and the reduced body weight of the animals of this group, respectively. Microscopic examination of the main organs did not reveal pathological alterations that could be attributed to the alpha-CD treatment. In the 13-week study, soft stool and infrequent mild diarrhea were observed only during the first 2-3 weeks in the 20% alpha-CD and 20% lactose group (mainly male animals). Accordingly, body weights were reduced in males of the 20% lactose group throughout the study and in the 20% alpha-CD group during the last week of the study. Food intakes were slightly increased in the 20% alpha-CD group and the food conversion efficiency, was significantly reduced in males, but not females, of the 20% alpha-CD and 20% lactose group. There were no treatment-related changes of hematological parameters. In line with similar observations from studies on other low-digestible carbohydrates, the urinary pH was decreased and urinary calcium levels increased in the 20% alpha-CD and 20% lactose group. Similarly, the fecal dry weight and nitrogen output was increased in these groups. At termination of the treatment, significantly in creased cecum weights (full and empty) were observed in the 5 and 20% alpha-CD groups and the 20% lactose group. The relative (not absolute) weight of the spleen was significantly increased in males of the 20% alpha-CD group. In the 20% lactose group, the relative weights of the spleen and liver (females) and the testes, brain, and adrenals (males) were significantly increased. The histopathological examination of these and all other organs and tissues did not reveal any abnormalities that could be attributed to the alpha-CD or lactose treatment. In conclusion, the ingestion of alpha-CD for 13-weeks at dietary levels of up to 20% (corresponding to intakes of 12.6 and 13.9 g/kg bodyweight/d in male and female rats, respectively) did not produce any signs of toxicity or adverse effects.     

Beneficial effect of hyperbaric oxygen pretreatment on lipopolysaccharide-induced shock in rats

1. We investigated the effect of hyperbaric oxygenation (HBO2) pretreatment on the production of exhaled nitric oxide (ENO) and the expression of lung inducible nitric oxide synthase (iNOS) by Escherichia coli lipopolysaccharide (LPS)-induced shock in an experimental rat model. 2. Rats were randomized into four groups, anaesthetized, mechanically ventilated with room air and infused with normal saline (2 mL/h) through the jugular vein for 5 h. Group 1 (NS) received only normal saline. Group 2 (HBO2-NS) was pretreated with HBO2 at 2.8 absolute atmospheres for 2 h and then received normal saline. Group 3 (LPS) received LPS, 20 mg/kg, i.v., bolus. Group 4 (HBO2-LPS) was pretreated with HBO2 for 2 h, followed by LPS. 3. Arterial blood gases, blood pressure, blood pH and ENO production were measured every 30 min. Plasma nitrite/nitrate (NOx) concentrations were assessed at the beginning (baseline) and at the end of the study. Lung myeloperoxidase (MPO) activity, iNOS expression and histological scores were measured for the evaluation of lung injury. 4. Administration of LPS was associated with decreased blood pressure and pH, increased ENO production, plasma NOx concentrations, lung iNOS expression and MPO activity. 5. Pretreatment with HBO2 significantly alleviated the LPS-induced hypotension, acidosis and decreased ENO production, plasma NOx concentrations, lung MPO activity and expression of iNOS. Hyperbaric O2 had no effect on control rats. 6. Our data show that HBO2 pretreatment has beneficial haemodynamic effects in rats with endotoxin shock. The beneficial effects of HBO2 may be partially mediated by decreased ENO production via reduced LPS-induced lung iNOS expression.     

Dietary Mg and/or K restriction enhances paraquat toxicity in rats

Effect of mineral restriction was studied to clarify which mineral in the diet is most indispensable in preventing paraquat (PQ) toxicosis. ODS rats were chosen as the experimental animal owing to the inability to synthesize vitamin C similarly to humans. Rats were fed with either mineral-adequate or restricted diets dosed with 125 ppm PQ. The mineral-adequate diet was based on the American Institute of Nutrition-76, and the restricted diet was one-half the amounts. Measurements were made on the onset day of PQ toxicosis, body weight changes during the feeding experiment, and changes of two acute phase reactant proteins – cysteine proteinase inhibitor and α1-proteinase inhibitor. The minerals tested were divided into three classes: I, largely needed, Ca, K, Na, and Mg; II, moderately needed, Mn, Fe, Zn, and Cu; and III, minutely needed, Cr and Se, respectively. Rats fed with a Mg-restricted diet showed a severe toxicosis but those with a K-restricted diet, a mild toxicosis. No appreciable effect was observed by restriction of other minerals. A synergistic effect was observed in the restriction of Mg and K. Received: 16 September 1997 / Accepted: 25 February 1998     

The brain-tumour issue in long-term toxicity studies in rats

Problems arise in the measurement of the neurocarcinogenic potential of chemical substances in chronic toxicity studies because of the spontaneous occurrence of neoplasms in the brain and other organs of rats from the age of about 2 yr. Statistical analysis may be equivocal and must be accompanied by a thorough biological analysis, to determine the presence or absence of the following characteristic effects of neurocarcinogenic agents: a reliable and consistent increase in brain-tumour incidence beyond the expected control level, a decrease in the age at which tumours appear and/or in survival, a dose-effect relationship, a greater effect on embryonal and foetal brain cells than on those of adults, a shift to more anaplastic types of tumour and the finding of preneoplastic lesions. These criteria have been met in chronic tests on the neurocarcinogens ethyl- and methylnitrosourea and some have been met in results obtained with the weak carcinogen methyl methanesulphonate. However, none of these criteria were met in the case of a test compound subjected to two 2-yr studies (one involving transplacental exposure), although brain tumours occurred in the controls and in all the experimental groups. The test substance is not considered to be a neurocarcinogenic agent.     

Maternal protein-and-energy restriction reduces the developmental toxicity of cyclophosphamide and hydroxyurea in rats

In this study, we examined the relationship between maternal weight gain deficits induced by protein-and-energy restriction (PER) and pregnancy outcome. We also evaluated whether PER would potentiate the developmental toxicity of cyclophosphamide (CP) and hydroxyurea (HU). Two independent experiments--employing two different methods of inducing protein-and-energy malnourishment-were performed. In the first experiment, well-nourished (fed ad libitum, normal diet, 22% of protein, 11.9 kJ/g) and food restricted (fed approximately half of ad libitum food intake, i.e. 12 g/day) rats received CP (0, 5 and 7.5 mg/kg sc) on pregnancy day 11. In the second experiment, well-nourished (normal diet, 24% of protein, 12.4 kJ/g) and malnourished (protein-and-energy deficient diet, 8% of protein, 6.2 kJ/g) rats received HU (0, 300 and 500 mg/kg ip) on pregnancy day 11. PER alone caused pronounced reductions of pregnancy weight gain and low fetal body weight, but induce no embryolethality and, except for a few sternum anomalies, no malformation. PER attenuated embryolethal and teratogenic effects of CP. PER reduced teratogenicity but did not alter effects of HU on embryolethality and fetal body weight. Therefore severe maternal weight gain deficits are not necessarily associated to embryolethality and terata and PER attenuates the teratogenic effects of CP and HU.     

Short-term inhalation toxicity studies with peroxyacetyl nitrate in rats

The inhalation toxicity of peroxyacetyl nitrate (PAN) was examined in acute (single exposure), sub-acute (4-week repeated exposure) and subchronic (13-week repeated exposure) studies in rats. The 4-h LC₅₀ was found to be 95 ppm.In the 4-week study rats were exposed to 0, 0.9, 4.1 or 11.8 ppm PAN vapour for 6 h/day, 5 days/week. Exposure to 11.8 ppm caused abnormal behaviour, growth retardation, mortality, elevated haemoglobin contents, haematocrit values and erythrocyte counts, increased lung weights and severe inflammatory changes and epithelial hyper- and metaplasia in the respiratory tract. At 4.1 ppm minimal behavioral disturbance, transient growth depression, slightly increased lung weights and mild histopathological changes in the respiratory tract were found. At 0.9 ppm no treatment-related alterations were detected.In the 13-week study rats were exposed to 0, 0.2, 1.0 or 4.6 ppm PAN vapour for 6.5 h/day, 5 days.week. Exposure to 4.6 ppm resulted in changes similar to those found at 11.8 ppm in the 4-week experiment, but no mortality occurred. At 1.0 ppm minimal irritation of the mucous membranes in the nasal cavity was the only PAN-related effect observed. No treatment- related changes were seen at 0.2 ppm. It was concluded that the no-toxic- effect level is between 0.2 and 1.0 ppm, and very probably close to the upper value.     

Beneficial effect of Amorphophallus paeoniifolius tuber on experimental ulcerative colitis in rats

Context: The tuber of Amorphophallus paeoniifolius (Dennst.) Nicolson (Araceae), commonly called Suran or Jimmikand, has high medicinal value and is used ethnomedicinally for the treatment of different gastrointestinal and inflammatory disorders.

Objective: The present study evaluated the effects of extracts of Amorphophallus paeoniifolius tubers on acetic acid-induced ulcerative colitis (UC) in rats.

Materials and methods: Wistar rats were orally administered methanol extract (APME) or aqueous extract (APAE) (250 and 500?mg/kg) or standard drug, prednisolone (PRDS) (4?mg/kg) for 7 days. On 6th day of treatment, UC was induced by transrectal instillation of 4% acetic acid (AA) and after 48?h colitis was assessed by measuring colitis parameters, biochemical estimations and histology of colon.

Results: APME or APAE pretreatment significantly (p?p?p?Discussion and conclusion: APME and APAE showed a preventive effect on UC, and ameliorated inflammation and oxidative damage in colon. The effects may be attributed to presence of phytochemicals, betulinic acid, β-sitosterol, and glucomannan. In conclusion, the tuber of Amorphophallus paeoniifolius exhibited an anticolitic effect through anti-inflammatory and antioxidant action.     

Beneficial effect of atorvastatin on left ventricular remodeling in spontaneously hypertensive rats

This study was designed to investigate whether atorvastatin has a beneficial effect on left ventricular (LV) remodeling in spontaneously hypertensive rats (SHR), and then explore the underlying mechanisms involved. 12 SHRs were randomized to receive either distilled water (SHR group, n = 6) or atorvastatin (ATV group, n = 6) for 10 weeks. Age-matched Wistar-Kyoto rats (WKY) gavaged by distilled water were used as normal controls (WKY group, n = 6). By using these rats, we observed the effects of atorvastatin on LV hypertrophy and fibrosis, and investigated atorvastatin-induced cell apoptosis and p27 protein expression. In addition, the serum lipid concentration and blood pressure level were also measured in this study. 10 weeks later, a significant decrease in the cardiosomatic ratio, LV weight to body weight ratio and cardiomyocyte transverse diameter, as well as myocardial hydroxyproline and collagen content was observed in the atorvastatin-treated SHR. In addition, atorvastatin increased the positive rate of cell apoptosis and p27 protein expression. A decreased serum lipid concentration and a reduced systolic blood pressure level were also found in the atorvastatin-treated SHR. These findings demonstrated a beneficial effect of atorvastatin on adverse LV remodeling in SHR, and the induction of cell apoptosis and upregulation of p27 protein may serve as the underlying mechanisms of this action.