Increases In Relative Kidney Weights Research Articles

Protective Effects Of Vitis vinifera And Carica papaya Seed Extracts On Diclofenac-Alcohol Combination Induced Kidney Damage In Albino Rats

Diclofenac is a non-steroidal anti-inflammatory drug commonly used in the treatment of pain and inflammatory conditions in the tropics. Its easy accessibility without prescription has made it a commonly abused medication. The abuse has recently become worrisome as young adults in Nigeria have been observed to concomitantly use diclofenac and alcohol for non-medical purpose. This study was undertaken to study the nephrotoxic effect associated with the combine use of alcohol and diclofenac using animal model, and the protective effect of Vitis vinifera (Grape) seed and Carica papaya (pawpaw) seed. Adult albino rats were divided randomly into groups of six rats each, and each group treated for 90 days with 5% or 45% alcohol with 2mg/kg diclofenac or 10mg/kg diclofenac, and some rats treated with grape seed and/or pawpaw seed concomitantly. Diclofenac and 45% alcohol combination induced nephrotoxicity in rats and oxidative stress characterised by elevated serum urea and creatinine, increased malondialdehyde and decrease in reduced glutathione, catalase and superoxide dismutase in kidney homogenate, as well as moderate interstitial congestion and haemorrhage in rat kidney histology section stained with Haematoxylin and Eosin, which was significantly ameliorated by the grape seed and pawpaw seed. There was a 1.32% increase in relative kidney weight in comparison with control rats. The severity of the nephrotoxicity observed with diclofenac-alcohol combination makes it a very unsafe practice. There is need to explore the nephroprotective benefits of Vitis vinifera seed and Carica papaya seed for maximum benefit to man.

A 90-day subchronic toxicity study of Myrrh in F344 rats

Myrrh is a flavoring agent and food additive. Here, we performed a subchronic toxicity study of Myrrh in male and female F344 rats by feeding at 5,000, 15,000 and 50,000 ppm for 90 days. No deaths or clinical signs were observed. Suppression of body weight gain was observed from the early phase of administration in both males and females in the 50,000 ppm group. Because there were no obvious changes in food intake in any of the Myrrh groups compared with the control group, suppression of body weight gain was considered an adverse effect of Myrrh. Hematology and serum biochemistry parameters with significant changes observed in the Myrrh groups were considered to have no toxicological significance. We observed a significant increase in relative kidney weight in male rats treated with 50,000 ppm Myrrh; this effect was considered to be related to the appearance of hyaline droplets in the epithelium of the proximal tubules histopathologically observed in this group. Immunohistochemical staining with anti-α2u-globulin antibodies suggested that these hyaline droplets were caused by factors other than α2u-globulin deposition. Thus, the no-observed-adverse-effect level of Myrrh was determined to be 15,000 ppm (males: 0.85 g/kg/day, females: 0.95 g/kg/day).

Impact of Chronic Cadmium Exposure on the Nephrotoxicity Sensitivity of Streptozotocin-Induced Diabetic Rats

The present study aimed to assess the role of subchronic cadmium exposure in the development of diabetic nephropathy. Diabetic rats induced by streptozotocin (STZ + Cd) and normal non-diabetic rats (Cd) were exposed to cadmium sulphate in drinking water at a dose of 200 mg / l for 30 days. After 30 days of cadmium poisoning, blood and tissue samples were taken to determine markers of kidney function (urea, uric acid, creatinine, total protein and inorganic ions) and for the achievement histological couples. Cadmium poisoning resulted in an increase in relative kidney weights and a change in biochemical parameters in serum. Histopathological examination of the kidneys revealed degeneration and necrosis of the renal tubules and shrinking of the glomeruli in rats poisoned with Cd. However, our results showed that diabetic rats induced by streptozotocin are more sensitive to nephrotoxicity of cadmium than rats normal. our results suggest that cadmium may be a factor in the development of diabetic nephropathy.

Effect of Levosimendan, an Inodilator, on Streptozotocin‐Induced Diabetic Nephropathy in Rats

Levosimendan, an inodilator, was shown to have a renal protective effect in different models of kidney dysfunction in experimental animals and in patients with heart failure. The aim of this study was to examine the effect of levosimendan on streptozotocin‐induced early diabetic nephropathy. Male Sprague Dawley rats (n = 24, 320–400 g) were randomly distributed into four groups and treated for 6 weeks. Groups 1 and 3 received either vehicle or levosimendan (1 mg/kg/day) for the last three weeks, respectively. Groups 2 and 4 were rendered diabetic by a single i.p. injection of streptozotocin (60 mg/kg) and were treated as in groups 1 and 3, respectively. At the end of the experiment, rats were placed in metabolic cages and urine was collected for biochemical analysis. Rats were then anesthetized and blood samples collected for biochemical analysis. Kidneys were removed for histopathology. In the untreated diabetic group, there was a significant decrease in body weight, polyuria and increased relative kidney weight. There was increased urinary albumin/creatinine ratio (UACR), 24 hour (h) albumin level and N‐acetyl‐β‐D‐glucosaminidase (NAG)/creatinine ratio (UNCR). Streptozotocin did not cause a significant effect on creatinine clearance when adjusted to body weight. In addition, diabetes was associated with increased oxidative stress [reduced plasma total antioxidant capacity (TAC) and catalase activities]. Kidneys from streptozotocin‐treated rats showed focal clear renal tubular cells affecting proximal convoluted tubules and focal mild interstitial fibrosis at the cortico‐medullary junction. Levosimendan significantly attenuated the reduction in body weight, polyuria and the increase in relative kidney weight. In addition, it significantly attenuated the increase in UACR, urinary 24 h albumin level and UNCR in diabetic rats. It also significantly mitigated the decrease in plasma TAC and catalase activities in diabetic rats. Rats in the diabetic group treated with levosimendan showed less clear cell changes but similar interstitial fibrosis when compared with the untreated diabetic group. This study shows that levosimendan ameliorated some of the changes seen in streptozotocin‐induced early diabetic nephropathy in rats. This could be partly due to its antioxidative effects.Support or Funding InformationSupported by an internal grant from Sultan Qaboos University (IG/MED/PHAR/18/01)

RESCUE OF INFLAMMATORY RENAL DAMAGE BY MEDICINAL PLANT EXTRACTS IN DIABETIC RATS

Diabetic nephropathy (DN) is the most critical diabetic complication that leads to renal failure. The purpose of this research was to explore the anti-diabetic effectiveness of Cucumis melo var. flexuosus and/or Phoenix dactylifera fruit aqueous extracts and their mechanisms in alleviating nephropathy in hyperglycemic rats. Diabetes was promoted in rats by injection (i.p.) of a single dose of streptozotocin (STZ). C. flexuosus and P. dactylifera extracts (CFE and PDE respectively) were ingested to diabetic rats for thirty consecutive days. The data revealed that intake of either plant extract or their combination to diabetic rats, significantly diminished the serum glucose and raised the serum insulin concentration. The plant extracts significantly ameliorated the increases in relative kidney weights as well as in renal tumor necrosis factor (TNF-α), serum C –reactive protein (CRP) and renal vascular endothelial factor (VEGF). Serum kidney function markers (creatinine, uric acid and urea) were also decreased in diabetic rats treated with the plant extracts. Histopathological observation was also carried out to confirm the biochemical results. This study has proven that the current plant extracts have potential hypoglycemic effect and could attenuate diabetic inflammatory renal damage in rats. The combination of the two extracts was synergistically the effective one. This result may help in exploring a novel therapy to manage diabetes and its complications.

Protective Effect of Apelin-13 on Kidney and Platelet Functions in Adenine-Induced Chronic Renal Failure in Rats

AbstractBackground: Apelin and angiotensin I receptor-related protein J receptor (APJ) were found to be expressed in the kidney. Also, in cases of Chronic Renal Failure (CRF), platelet function was found to be affected. Apelin-13 treatment effect on both kidney and platelet functions in cases of CRF was not fully understood.Aim of Study: To investigate the possible protective effect of apelin-13 on kidney and platelet function in adenine-induced CRF in rats.Material and Methods: Rats were divided into three groups of eight rats each as follow: Intact control group received a standard diet for 28 days, adenine treated group received a standard diet added to it adenine (0.75% w/w) for 28 days, and adenine + apelin treated group received a standard diet added to it adenine as in the adenine treated group with a concomitant treatment with apelin-13 for 28 days. Apelin-13 was dissolved in saline immediately before use and was given at a dose of 5μg/kg body weight/day subcutaneously. 24-hour urine samples were collected, and 24-hour water intake was estimated on the 28th day of the study, while each rat was kept in a separate metabolic cage. The collected urine samples were measured for volume, total protein, and creatinine levels. After 28 days from the start of the experimental period, rats were fasted overnight, and their blood pressure was measured using the Power Lab. Blood samples were collected and a part of it was placed in heparinized tubes to investigate platelet indices and another part of blood was kept in non-heparinized tubes which were left to clot for 30min at room temperature. Clotted blood was centrifuged at 3000rpm for 15min. The supernatant serum was pipetted off using fine tipped automatic pipettes and stored at –20oC until assayed.Results: Treatment with adenine (0.75%, w/w) for 28 days caused a significant decrease (p<0.001) in Body Mass Index (BMI) and a significant increase (p<0.001) of the relative kidney weight when compared with that of the control group. On concomitant treatment with apelin-13 and adenine significantly mitigated (p<0.001) the adenine-induced reduction in BMI and the increase in relative kidney weight. Water intake and urine output of adenine treated rats were signifi-cantly higher (p<0.001) than that in control rats, while, simultaneous treatment with adenine and apelin-13 signifi-cantly decreased (p<0.001) both in comparison to adenine treated group. Also, in comparison with control group, the serum levels of creatinine, uric acid and urea were enhanced significantly (p<0.001) in adenine treated group, indicating that adenine-induced CRF model has been successfully estab-lished in this experiment. However, these enhancements were significantly decreased (p<0.001) by concomitant treatment with apelin-13. On the other hand, there was a significant decrease (p<0.001) in the creatinine clearance in adenine treated group in comparison to the control one, however, simultaneous treatment with adenine and apelin-13 signifi-cantly deteriorated this effect. Also, in this study, comparing to those of normal group, the Superoxide Dismutase (SOD) and Glutathione Reductase (GR) levels in adenine treated group were significantly decreased (p<0.001) while, Malonal-dehyde (MDA) was significantly increased (p<0.001). The alteration of SOD, GR and MDA serum levels was remarkably reversed by concomitant treatment with apelin-13. A significant increase (p<0.001) in platelet count, Mean Platelet Volume (MPV), Platelet Distribution Width (PDW) and plateletcrit, but a significant decline (p<0.001) in bleeding time in adenine treated group in comparison to the control one. These changes were significantly reversed (p<0.001) by the concomitant treatment with adenine and apelin-13 in comparison to the adenine treated group.Conclusion: Apelin-13 treatment improved both kidney and platelet functions, and may give a promising strategy for slowing the progression of CRF and its complications.

Pentoxifylline May Restore Kanamycin-Induced Renal Damage in Rats

Background: Kidney damage can be caused by many factors, such as using certain drugs in high doses or over the longterm. The use of one such group of drugs, aminoglycosides, which act as Gram-negative antibacterial therapeutic agents,can lead to nephrotoxicity. It has been hypothesized that aminoglycoside-induced nephrotoxicity might be prevented byusing pentoxifylline, which has antioxidant and anti-inflammatory effects and improves microcirculation. The objectiveof this present research was to determine the protective effects of pentoxifylline on kanamycin-induced kidney damage.Materials, Methods &amp; Results: Thirty-two male Wistar rats were divided into four groups as follows: control, pentoxifylline,kanamycin, and kanamycin + pentoxifylline. The control group received intraperitoneal (IP) injections of 0.5 mL normalsaline solution once a day (d) (SID) for 20 d; the pentoxifylline group received IP injections of 50 mg/kg pentoxifyllinetwice a day (BID) for 20 d, the kanamycin group received subcutaneous (SC) injections of 500 mg/kg kanamycin SID for20 d, and the kanamycin + pentoxifylline group received both SC injections of 500 mg/kg kanamycin SID and IP injectionsof 50 mg/kg pentoxifylline BID for 20 d. At the end of 20 d, blood samples were taken from the heart by cardiac punctureunder general anesthesia. After euthanizing the rats by cervical dislocation under anesthesia, the kidneys were immediatelyremoved, relative kidney weights were calculated, and routine pathologic evaluations were conducted. Hemogramparameters were measured using a blood cell count apparatus and serum biochemical parameters were measured usingan autoanalyzer. Kanamycin also caused (P &lt; 0.05) tubular degeneration and tubular dilatation. Although pentoxifyllinesignificantly reduced the level of kanamycin-induced tubular degeneration (P &lt; 0.05), it did not significantly reduce tubulardilatation. Increases in relative kidney weights (P &lt; 0.05) and in interstitial mononuclear cell (MNC) infiltrates wereobserved in the kanamycin and kanamycin + pentoxifylline groups compared to those in the control and pentoxifyllinegroups. Statistically significant changes were determined in the levels of some hemogram and biochemical parameterswithin reference ranges (P &lt; 0.05).Discussion: In this study, both tubular degeneration and dilatation were observed in the kanamycin group. Pentoxifyllineinhibited (P &lt; 0.05) kanamycin-induced tubular degeneration and appeared to also reduce tubular dilatation, although thisreduction was not significant. Tubular necrosis, epithelial edema of proximal tubules, tubular fibrosis, and perivascularinflammation might also be observed in aminoglycoside-induced nephrotoxicity. In current research, pentoxifylline preventedtubular damage induced by kanamycin, but did not inhibit infiltration by MNCs. Pentoxifylline also amelioratedamikacin- or gentamycin-induced histopathologic changes, especially those associated with tubular structures. The protectiveeffects of pentoxifylline on kanamycin-induced tubular nephrotoxicity in this research might be a result of its stimulatingthe production of prostaglandin, a vasodilator, and of its improving microcirculation. Although the anti-inflammatoryeffects of pentoxifylline have been reported, these did not inhibit kanamycin-induced infiltration by interstitial MNCs inthe present study. These results could indicate that the anti-inflammatory effects of pentoxifylline are not obvious and/orare dose dependent. Statistically significantly changes were determined in the levels of some hemogram and biochemicalparameters in reference ranges. However, these changes were within the reference ranges for rats. These results suggestedthat kanamycin-induced tubular degeneration and dilatation might be prevented by administering pentoxifylline.

Efficacy of feed additives to reduce the effect of naturally occurring mycotoxins fed to turkey hen poults reared to 6 weeks of age

Corn with naturally occurring aflatoxin (AF), wheat with naturally occurring doxynivalenol (DON), and barley with naturally occurring zearalenone (ZEA) were used to make rations for feeding turkey hen poults to 6 weeks of age. Control rations with equal amounts of corn, wheat, and barley were also fed. The control rations did contain some DON while both sets of rations contained ZEA. Within each grain source, there were 4 treatments: the control ration plus 3 rations each with a different feed additive which were evaluated for the potential to lessen potential mycotoxin effects on bird performance and physiology. The additives were Biomin BioFix (2lb/ton), Kemin Kallsil (4lb/ton), and Nutriad UNIKE (3lb/ton). The mycotoxin rations reduced poult body weight (2.31vs. 2.08 ± 0.02kg) and increased (worsened) poult feed conversion (1.47vs. 1.51 ± 0.01) at 6 wk. Feeding the poults the mycotoxin feed also resulted in organ and physiological changes typical of feeding dietary aflatoxin although a combined effect of AF, DON, and ZEA which cannot be dismissed. The feed additives resulted in improved feed conversion to 6 wk in both grain treatment groups. The observed physiological effect of feeding the additives was to reduce relative gizzard weight for both groups and to lessen the increase in relative kidney weight for the birds fed the mycotoxin feed. In conclusion, the feed additives used in this study did alleviate the effect of dietary mycotoxins to some degree, especially with respect to feed conversion. Further studies of longer duration are warranted.

Safety assessment of freeze-dried powdered Cassiae Semen : evaluation of chronic toxicity (26-week) in Sprague-Dawley rats

There is a lack of safety assessment data regarding the long-term consumption of Cassiae Semen (Leguminosae, the seeds of Cassia obtusifolia L. and Cassia tora L.). Thus, we evaluated the toxicity of freeze-dried powdered Cassiae Semen in male and female Sprague-Dawley rats. Rats were intragastrically administered freeze-dried powdered Cassiae Semen at a dose of 0.5, 2.2, or 10.0 g/kg body weight/day for 26 weeks; several variables were assessed after 13 and 26 weeks as well as after a 4-week recovery period. No mortality was observed in the treated animals, and body weight increased in a dose-dependent manner. The total bilirubin (TBIL) levels also displayed a dose-dependent relationship. In males, at 26 weeks, there were significant increases in relative kidney weights in the 2.2 and 10.0 g/kg groups compared with that in the negative control group (p < 0.05 or p < 0.01). Pigment deposition in the epithelial cells of the renal proximal convoluted tubules and atrophy or regeneration of renal tubules were observed in the 10.0 g/kg group after 26 weeks, and these changes were not fully reversed after the 4-week recovery period. Under the studied conditions, the primary toxicity organs for freeze-dried powdered Cassiae Semen in the 10.0 g/kg group were the kidneys.

Iron increases diabetes-induced kidney injury and oxidative stress in rats.

Diabetic nephropathy is both a common and a severe complication of diabetes mellitus. Iron is an essential trace element. However, excess iron is toxic, playing a role in the pathogenesis of diabetic nephropathy. The present study aimed to determine the extent of the interaction between iron and type 2 diabetes in the kidney. Male rats were randomly assigned into four groups: control, iron (300-mg/kg iron dextran), diabetes (a single dose of intraperitoneal streptozotocin), and iron + diabetes group. Iron supplementation resulted in a higher liver iron content, and diabetic rats showed higher serum glucose compared with control rats, which confirmed the model as iron overload and diabetic. It was found that iron + diabetes group showed a greater degree of kidney pathological changes, a remarkable reduction in body weight, and a significant increase in relative kidney weight and iron accumulation in rat kidneys compared with iron or diabetes group. Moreover, malondialdehyde values in the kidney were higher in iron + diabetes group than in iron or diabetes group, sulfhydryl concentration and glutathione peroxidase activity were decreased by the diabetes and iron + diabetes groups, and protein oxidation and nitration levels were higher in the kidney of iron + diabetes group as compared to iron or diabetes group. However, iron supplementation did not elevate the glucose level of a diabetic further. These results suggested that iron increased the diabetic renal injury probably through increased oxidative/nitrative stress and reduced antioxidant capacity instead of promoting a rise in blood sugar levels; iron might be a potential cofactor of diabetic nephropathy, and strict control of iron would be important under diabetic state.

Acute and subchronic toxicity studies of pyrroloquinoline quinone (PQQ) disodium salt (BioPQQ™) in rats

The potential use of pyrroloquinoline quinone disodium salt (BioPQQ™), as a supplemental food ingredient, was evaluated in a range of oral toxicity studies in rats including an acute study, a 14-day preliminary and a 28-day repeated-dose study, and a 13-week subchronic study. The median lethal dose of BioPQQ™ was shown to be 1000–2000mg/kg body weight (bw) in male and 500–1000mg/kgbw in female rats. In the 14-day study, high doses of BioPQQ™ resulted in increases in relative kidney weights with associated histopathology in female rats only, while a follow-up 28-day study in female animals resulted in increases in urinary protein and crystals. These findings were reversible, and resolved during the recovery period. In the 13-week study, a number of clinical chemistry findings and histopathological changes were noted, which were deemed to be of no toxicological significance, as the levels were within the historical control range, were not dose-dependent, occurred at a similar frequency in control groups, or only occurred in the control group. Based on these findings, a no-observed-adverse-effect level of 100mg/kgbw/day was determined for BioPQQ™ in rats, the highest dose tested in the 13-week study.

Modulator effects of meloxicam against doxorubicin-induced nephrotoxicity in mice.

Doxorubicin-induced renal toxicity overshadows its anticancer effectiveness. This study is aimed at assessing the possible modulator effects of meloxicam, a cyclooxigenase-2 inhibitor, on doxorubicin-induced nephrotoxicity in mice and exploring some of the modulator mechanisms. Forty male mice were divided for treatment, for 2 weeks, with saline, meloxicam (daily), doxorubicin (twice/week), or both meloxicam and doxorubicin. Doxorubicin induced a significant increase in relative kidney weight to body weight, kidney lipid perooxidation, plasma levels of interleukin-6 and tumor necrosis factor-α, kidney caspase-3 activity, and kidney prostaglandin E2 (PGE2) content. Doxorubicin disturbed kidney histology, abrogated renal function tests (serum creatinine, uric acid, and blood urea nitrogen), induced a significant decrease in antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and catalase) and reduced glutathione (GSH) content. The administration of meloxicam with doxorubicin mitigated all doxorubicin-disturbed parameters. Meloxicam ameliorated doxorubicin-induced renal injury via inhibition of inflammatory PGE2, inflammatory cytokines, caspase-3 activity, antioxidant effect, and free radical scavenging activity.

Resveratrol, melatonin, vitamin E, and PBN protect against renal oxidative DNA damage induced by the kidney carcinogen KBrO 3

Free radical scavengers can protect against the genotoxicity induced by chemical carcinogens by decreasing oxidative damage. The protective effect of the antioxidants melatonin, resveratrol, vitamin E, butylated hydroxytoluene and 2-mercaptoethylamine, and the spin-trapping compound α-phenyl-N-tert-butyl nitrone (PBN) against oxidative DNA damage was studied in the kidney of rats treated with the kidney-specific carcinogen potassium bromate (KBrO 3). KBrO 3 was given to rats previously treated with melatonin, resveratrol, PBN, vitamin E, butylated hydroxytoluene, or 2-mercaptoethylamine. Oxidative damage to kidney DNA was estimated 6 hours afterwards by measuring 8-oxo-7,8-dihydro-2 ′-deoxyguanosine (oxo 8dG) referred to deoxyguanosine (dG) by means of high performance liquid chromatography with electrochemical-coulometric and ultraviolet detection. Levels of oxo 8dG in the renal genomic DNA significantly increased by more than 100% after the KBrO 3 treatment. This increase was completely abolished by the treatment with resveratrol and was partially prevented by melatonin, PBN and vitamin E. Resveratrol and PBN also prevented the increase in relative kidney weight induced by KBrO 3. These results show that various different antioxidants and a free radical trap, working in either the water-soluble or the lipid-soluble compartments, can prevent the oxidative DNA damage induced in the kidney by the carcinogen KBrO 3.

Effects of polyethylene glycol 400 (PEG 400) following 13 weeks of gavage treatment in fischer-344 rats

Fischer-344 rats (10/group/sex) were administered polyethylene glycol 400 (PEG 400) by gavage at 1.0, 2.5 or 5.0 ml/kg (1.1, 2.8 and 5.6 g/kg, respectively) body weight/day 5 days/wk for 13 wk. Animals in the control group received water by gavage (5.0 ml/kg body weight/treatment day). An additional 10 rats/sex/group were assigned to the control and high-dose groups for a 6-wk recovery period. Evaluation of potential renal toxicity was identified as a primary objective. There was no mortality or changes in haematology or clinical chemistry measurements attributed to PEG 400 toxicity. Loose faeces in the mid- and/or high-dose group of both sexes were attributed to bulk cathartic effects of PEG 400. Slight decreases in food consumption and body weights in the mid- and/or high-dose group of male rats and female rots were attributed to the physical presence of PEG 400 in the intestinal tract. However, a direct effect of PEG 400 on the intestinal tract was not ruled out. Increased water consumption was attributed to a possible increase in serum osmolality due to the absorption of the PEG 400 or a reflection of the water dosing received by the control animals. Increased urinary concentration and decreased urinary pH were at least partially attributed to absorption, possible metabolism, and urinary excretion of PEG 400. Small increases in absolute and/or relative kidney weights, observed in many dose groups, were attributed to the osmotic effect of the test substance and/or metabolites in the urine. The significance of a slight increase in relative kidney weights in female rats following the recovery period was unknown. Although no microscopic changes were observed in the kidneys or urinary bladder, a slight, reversible renal toxicity may have resulted in male rats treated by gavage with 2.5 ml/kg/day and rats of both sexes treated by gavage with 5.0 ml PEG 400 kg/day. This was based on the increased concentration of protein and bilirubin, urinary vascular cell findings and N-acetyl-β- d-glucosaminidase activity.

Hepatic and Renal Assessment of Acute Exposure to Inhaled Epichlorohydrin: Toxicological Evaluation and Exposure Modeling

To examine the hepatic and renal effects of acute exposure to inhaled epichlorohydrin (ECH), male F344 rats were exposed either to 0 or 100 ppm ECH by inhalation for 4 h. Hepatic and renal toxicity were assessed at the termination of exposure and on days 1, 2, and 3 postexposure. Exposure to inhaled ECH caused no histopathological evidence of hepatic or renal toxicity and had no effect on serum indicators of hepatic toxicity, or hepatic cytochrome P-450 and glutathione concentrations. Exposure to inhaled ECH resulted in an increase in relative kidney weight in rats that were either 65 ± 2 days old or 73 ± 2 days old on the day of inhalation exposure (young adult rats) but not in rats that were 96 ± 2 days old on the day of inhalation exposure (adult rats), and a decrease in absolute and relative liver weight in adult rats but not young adult rats. Blood urea nitrogen/creatinine (BUN/CREAT) was decreased in young adult rats on day 0, and BUN was slightly increased in adult rats on days I, 2 and 3. These observations indicate that acute exposure to 100 ppm ECH did not produce consistent alterations in indicators of hepatic and renal toxicity. Ambient impact assessment modeling (AIAM), a methodology for estimation of exposure over short time periods and comparison of these predicted ambient concentration levels to short-term toxicological threshold values, was conducted for three typical industrial sources of ECH pollution. The results of these analyses illustrated the interdependence of toxicological evaluation and exposure modeling in short-term non-cancer risk assessment and demonstrated the usefulness of AIAM in prioritizing chemicals for additional toxicological evaluation.

Acute inhalation toxicity of high concentrations of silane in male ICR mice.

In order to examine the toxicity of silane, male ICR mice were exposed to silane for 30 min (n = 8), 1 or 4 h (n = 12) at concentrations of 2500, 5000, 7500 (30-min experiment only) or 10,000 ppm. In the 1- and 4-h experiments, 12 mice were divided into two sub-groups: four for 2-day observation and eight for 2-week observation. The mortality was six deaths out of eight mice exposed to 10,000 ppm for 4 h. No deaths occurred in any of the other experiments. In the mice sacrificed 2 days after the exposure, acute renal tubular necrosis was observed at 10,000 ppm (1-h exposure) or at 2500 ppm or more (4-h exposure). Reduction in body weight, increase in relative kidney weight and blood urea nitrogen (BUN) level, and splenic atrophy and inflammatory changes of the nasal mucosa were also seen in the 10,000 ppm-4 h exposure group. In the mice sacrificed 2 weeks after the exposure, tubulo-interstitial nephritis (TIN) developed at 7500 ppm or more (30-min exposure) or at 5000 ppm or more (1- and 4-h exposure). BUN increased in a dose-dependent manner, and BUN in TIN positive mice was significantly higher than that in TIN negative mice (1- and 4-h exposure). No histopathological changes were observed in the glomeruli. These results indicate that the LC50 of silane in mice is between 5000 and 10,000 ppm for 4-h exposure and is greater than 10,000 ppm for 1-h or 30-min exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Subchronic oral toxicity of 4-chloro-α,α,α-trifluorotoluene in sprague-dawley rats

The subchronic oral toxicity of 4-chloro-α,α,α-trifluorotoluene (CTT) was assessed in Sprague Dawley rats. Four groups of six male and six female rats were treated daily for 28 days, by gavage, with doses of 0, 10, 100 and 1000 mg CTT/kg body weight using olive oil as a vehicle. No clinical signs were observed, other than salivation in the high-dose group in the last week. The males of this group showed a significant decrease in body-weight gain without a concurrent decrease in food consumption. In males, there were significant dose-dependent increases in blood cholesterol and triglycerides, suggestive of alterations in lipid metabolism. The females showed only a small dose-related increase in serum lactate dehydrogenase. Specific histological alterations were found in the males given 1000 mg/kg/day, namely hyaline droplet nephrosis, along with a significant increase in relative kidney weight, and an increase in lipid vacuoles in the adrenal cortex. Slight nephrosis was also observed in males given 100 mg/kg. Both male and female rats showed a significant increase in relative liver weight at a dose of 1000 mg CTT/kg. CTT appears to have a low subchronic oral toxicity. Neither pathological nor biochemical alterations were found at 10 mg/kg body weight/day and this can be defined as the no-observable-effect level (NOEL).

A subacute oral toxicity study of T-2588 in juvenile rats

A subacute toxicity study on T-2588 was carried out in juvenile rats (6 days-old 48 males and 48 females) by oral administrations at dose levels of 250, 500 and 1,000 mg/kg/day for 1 month. The results obtained were summarized below. During the study, there were no clinical signs considered to be related to the treatment. There were no T-2588-related abnormalities in urinalysis, hematological examinations, biochemical examinations and ophthalmological examinations. Slight increases in relative liver and kidney weights were observed in the 1,000 mg/kg-treated group and slight increases in relative kidney weight were detected in the 500 mg/kg-treated female group. Histologically, however, T-2588-related abnormality was not observed. The maximum safety dose of T-2588 was estimated to be 250 mg/kg/day. In addition to the above examinations, male reproductive performance was examined in the group administered with a dose level of 1,000 mg/kg/day. No adverse effects were observed in male fertility and F1 generation.

Cephaloridine nephrotoxicity in aging male fischer-344 rats

Age-related differences in susceptibility to cephaloridine nephrotoxicity were evaluated in male Fischer-344 rats. Rats, 2.5, 4, 10–12 and 27–29 months old, were administered a single intraperitoneal dose of cephaloridine and renal function evaluated 24 h later. Susceptibility to cephaloridine-induced nephrotoxicity was age-related. Older rats (10–12 and 27–29 months) were the most susceptible to cephaloridine nephrotoxicity as indicated by a dose-related increase in relative kidney weight, elevation in blood urea nitrogen concentrations and a diminished capacity of renal cortical slices to accumulate the organic anion, p-aminohippurate (PAH) and the organic cation, tetraethylammonium (TEA). Impaired renal function following cephaloridine treatment was not detected in 2.5-months-old, apparent to a slight extent in 4-month-old, and most pronounced in 10–- and 27–29-month-old rats. Serum and renal cortical concentrations of cephaloridine tended to be greater in old rats compared to that of young adults. Thus, the enhanced susceptibility of older rats to cephaloridine nephrotoxicity may be related in part to the increased renal cortical accumulation of cephaloridine.

Short-term toxicity of 2,6-dimethylhept-5-en-1-al in rats

Groups of 15 male and 15 female rats were fed for at least 90 days on diets that provided 2,6-dimethylhept-5-en-1-al (DMH) at average intakes of 0 (control), 9, 37 and 150 mg/kg body weight/day. Steps were taken to limit loss of DMH during diet mixing, storage and feeding. No effects attributable to treatment were encountered in body weight, food intake, water intake, haematology (at wk 6 and 13) or the gross and microscopic pathological examinations. At the highest dose level there was a slight reduction in renal concentrating ability at wk 6 in males and wk 14 in females, together with a small increase in relative kidney weight and liver weight in females. The serum-glucose concentrations of both sexes on the highest dose were elevated compared with the controls. It was concluded that the intermediate dose, providing an intake of 37 mg/kg/day, was the no-untoward-effect level.