Urinalysis Parameters Research Articles

Chronic Toxicity and Oncogenicity Study with Vinyl Acetate in the Rat: In Utero Exposure in Drinking Water

Chronic Toxicity and Oncogenicity Study with Vinyl Acetate in the Rat: In Utero Exposure in Drinking Water. Bogdanffy, M. S., Tyler, T. R., Vinegar, M. B., Rickard, R. W., Carpanini, F. M. B., and Cascieri, T. C. (1994). Fundam. Appl. Toxicol. 23, 206-214. The purpose of this study was to evaluate vinyl acetate for potential chronic toxicity and oncogenicity when given to rats in drinking water from the time of gestation. Target concentrations were 0, 200, 1000, and 5000 ppm (v/v). Drinking water solutions were prepared daily and analyzed at approximately 4-week intervals. F 0 rats were given solutions of vinyl acetate for 10 week and then mated. Offspring (F 1 rats) were culled to equal group sizes of 60 main study rats and 30 rats for satellite groups. F 1 rats were treated for up to 104 weeks with interim kills of satellite groups at 52 and 78 weeks. Body weights and clinical signs of toxicity were monitored in F 0 and F 1 rats. Food and water consumption were measured in F 1 rats. At Weeks 52 and 78 of the test, clinical pathology and urine analysis examinations were conducted on 10 rats per group from satellite animals. A complete gross and histopathological examination of F 1 rats was conducted at the interim kills and on main study rats at Week 104. Average vinyl acetate consumption over the course of the study in male rats of the 200, 1000, and 5000 ppm groups was 10, 47, and 202 mg/kg/day, respectively. Female rats consumed an average of 16, 76, and 302 mg/kg/day, respectively. Compound-related effects observed during the study included a concentration-related decrease in water consumption among rats of the 1000 and 5000 ppm groups. Concurrent body weight decrement was observed only in the 5000 ppm groups. There were no compound-related effects on clinical chemical hematological, or urinalysis parameters. The pathological evaluations revealed no compound-related effects on organ weight, nonneoplastic lesions, or neoplastic lesions. The no-observable-effect level was 200 ppm while the no-observable-adverse-effect level was 1000 ppm. Under the conditions of this study, vinyl acetate showed no evidence of systemic target organ toxicity and was not oncogenic when administered to rats in the drinking water.

The relevance of clinical pathology to toxicology studies

Standardised lists of haematology, clinical biochemistry and urinalysis parameters are monitored during the course of toxicity studies to assess the potential target organ toxicity of pharmaceuticals, medical and surgical devices, agrochemicals, direct and indirect food additives and industrial chemicals. The biological significance and toxicological importance of any changes which are found between the control and test groups have then to be considered in perspective. Although the temporal relationships between clinical pathology findings and histological lesions in target organs or tissues may not be simple the correlations which can be established with clinical pathology findings and post mortem and histopathology observations are crucial if data are to be correctly evaluated. It is also important to understand how factors other than the experimental treatment can modulate the routinely measured parameters. Clinical pathology data are sometimes useful in elucidating the mechanism of toxic responses observed in animals and their extrapolation to humans. Greater thought with respect to the selection of tests, the timing of investigations and the elimination of sources of biological and experimental variation could lead to improvements in the predictive value of animal toxicology studies.

Acute and 2-Week Aerosol Inhalation Studies on 970 and 1700 Molecular Weight Ethylene Oxide/Propylene Oxide (EO/PO) Polymers

Prior aerosol inhalation studies on heavier molecular weight members of this series of ethylene oxide/propylene oxide (EO/PO) polymers have demonstrated that the lung is the primary target organ in rats. These studies extended the toxicological data on the lower molecular weight (MW) members (970 and 1700) of this series. In the present group of studies, the 4-hr acute LC50 value (95% confidence limits) for the 970 MW polymer (U-260) was determined to be 4770 (4260–5350) mg/m3 for the combined sexes of Sprague-Dawley rats. A previous study had determined the LC50 value for the 1700 MW polymer (U-660) to be 4670 (4090–5320) mg/m3 in Wistar rats. Repeated exposure studies were also conducted on both polymers, in which Fischer 344 rats were exposed for 6 hr/day, 5 days/week, for 9 exposures. For U-660, repeated exposure to mean concentrations of 504, 982, or 2460 mg/m3 produced total mortality at 2460 mg/m3, while signs of ocular and nasal irritation, respiratory difficulties, and reduced body weight (BW) and/or BW gain occurred in the 504 and 982 mg/m3 groups. Many of the hematological, serum chemistry, and urinalysis parameters were abnormal for the 504 and 982 mg/m3 groups when compared to controls. Absolute and relative lung weights were increased for the 504 and 982 mg/m3 groups. Of the organs evaluated, only the lung had histopathological lesions, including interstitial pneumonitis, bron-chioalveolar cell hyperplasia, and intra-alveolar macrophage infiltrates. The severity of the lesions was concentration-related. In a subsequent U-660 study with exposure concentrations of 5, 51, 98, and 492 mg/m3, effects observed at 492 mg/m3 were consistent with those observed in the previous U-660 study at 504 mg/m3. The most notable effects of lower concentrations included increases in absolute and relative lung weight observed for male rats of the 51, 98, and 492 mg/m3 groups and female rats of the 98 and 492 mg/m3 groups, as well as increases in absolute and/or relative kidney weights noted for females for the 98 and 492 mg/m3 groups. Additionally, histological evaluation indicated an increased incidence or alveolar histiocytosis for male animals exposed to 51 mg/m3 or higher concentrations of U-660. However, the injury to the lung that resulted from exposure to 492 mg/m3 U-660 completely resolved during a 6-week recovery period. For U-260, repeated exposure to mean concentrations of 5, 52, or 512 mg/m3 produced decreased BW gain in the 52 and 512 mg/m3 groups and increased absolute kidney weights in the 512 mg/m3 group. There were no histopathological lesions in the kidneys or lungs. Thus, despite the similar LC50 value for these compounds, data for the 1700 MW polymer (U-660) indicate that the toxicity is cumulative, while data for the 970 MW polymer (U-260) indicate that, in contrast to other higher MW members of this series, pulmonary toxicity is not produced in rats during a 2-week exposure to concentrations up to 512 mg/m3. Further, a clear no-observed-effect concentration of 5 mg/m3 was established for both U-660 and U-260.

Renal clearance and excretion of endogenous substances in the owl monkey.

The clearance and excretion of creatinine, calcium, phosphorus, sodium, and potassium by the kidney was evaluated in 62 owl monkeys using timed urine collections and quantitative urinalyses. The endogenous clearance of creatinine was determined for each monkey. Urinary electrolyte excretion and fractional electrolyte excretions (FE) were measured. Linear regression analysis was used to calculate the correlation between urinary excretion and FE for each electrolyte. The coefficient of determination for each analyte was significant (P ⩽ .0001). Determination of FE was found to be an appropriate indicator of the renal handling of electrolytes and, when viewed in conjunction with urinalysis and other serum parameters, an aid in evaluating renal function in the owl monkey. © 1992 Wiley-Liss, Inc.

Dietary effects of propylene glycol alginate in humans

Following a 7-day control period, five male volunteers consumed a weight of propylene glycol alginate corresponding to 175 mg/kg body weight for 7 days, followed by 200 mg propylene glycol alginate per kg body weight for a further 16 days. Measurements before and at the end of the 23-day period of dietary supplementation showed that propylene glycol alginate had little effect on faecal parameters (pH, water content, daily wet and dry weights). The dietary transit time remained constant for three volunteers, increased for one, and decreased for one. The ingestion of propylene glycol alginate had no significant effect on (a) haematological indices, (b) plasma biochemistry parameters, (c) urinalysis parameters, (d) blood glucose and plasma insulin concentrations, (e) breath hydrogen concentrations. No allergic responses were reported by, nor observed in, any of the volunteers. The study therefore indicates that the ingestion of propylene glycol alginate at a high level for 23 days caused no adverse dietary or physiological effects; in particular, the enzymatic and other sensitive indicators of adverse toxicological effects remained unchanged.

Dietary effects of sodium alginate in humans

Following a 7-day control period, five male volunteers consumed a weight of sodium alginate corresponding to 175 mg/kg body weight for 7 days, followed by 200 mg sodium alginate per kg body weight for a further 16 days. Measurements before and at the end of the 23-day period of dietary supplementation showed that sodium alginate acted as a faecal bulking agent for all volunteers, giving a significant (p less than 0.01) increase in daily wet weight, and also increases in the water content and daily dry weight, but no change in faecal pH. Although the dietary transit time remained constant for two volunteers, it decreased for two, and increased slightly for one, with little resulting change in the overall mean value. The ingestion of sodium alginate had no significant effect on (a) haematological indices, (b) plasma biochemistry parameters, (c) urinalysis parameters, (d) blood glucose and plasma insulin concentrations, (e) breath hydrogen concentrations. No allergic responses were reported by, nor observed in, any of the volunteers. The study therefore indicates that the ingestion of sodium alginate at a high level for 23 days caused no effects other than those normally associated with a polysaccharide bulking agent; in particular, the enzymatic and other sensitive indicators of adverse toxicological effects remained unchanged.

Renal clearance, urinary excretion of endogenous substances, and urinary diagnostic indices in healthy neonatal foals.

Urine (U) and serum (S) were obtained every 2 hours during a 12- or 24-hour period from eight healthy 96-hour-old pony or horse foals. Dams' milk samples were obtained concurrently. Urine volume was measured during this 12- or 24-hour period. The mean amount of urine produced was 148 +/- 20 ml/kg/day. Baseline urinalyses were evaluated on all foals at two days of age, before any manipulation. Urine generally was dilute (less than 1.008) but the specific gravity was as high as 1.027 in one normal foal. Continuous (12 or 24 hour) urinary catheterization resulted in bacteriuria but not white blood cells in the urine. Prolonged catheterization did not cause foals to become febrile or exhibit clinical signs of cystitis or other illness. Urinary electrolyte excretion, urinary electrolyte clearances, and fractional electrolyte excretions (FE) were measured. When compared with normal values reported in adult horses, excretion, clearance, and FE were similar for sodium (Na) but higher for potassium (K), phosphorus (P), and calcium (Ca). There were no significant differences between data collected during different time periods, and it was concluded that the use of single sample urine/serum estimates of fractional excretion in the neonatal foal was an appropriate indicator of the renal handling of electrolytes, and when viewed in conjunction with urinalysis and other serum parameters, a valuable aid to evaluating renal function.

Effects of Chronic Treatment with the Leukotriene D4 Antagonist Compound LY171883 on Fischer 344 Rats and Rhesus Monkeys

Effects of Chronic Treatment with the Leukotriene D4 Antagonist Compound LY171883 on Fischer 344 Rats and Rhesus Monkeys. HOOVER, D. M., BENDELE, A. M., HOFFMAN, W. P., FOXWORTHY, P. S., AND EACHO, P. I. (1990). Fundam. Appl. Toxicol. 14, 123–130. One-year toxicity studies were done to evaluate potential toxic effects associated with chronic exposure of rats and monkeys to the leukotriene antagonist LY171883. Rats were fed dietary doses of 0.0, 0.01, 0.03, or 0.1%, equivalent to approximately 0, 5, 15, or 50 mg/kg of body weight/day. Monkeys were given daily nasogastric gavage doses of 0, 30, 75, or 175 mg/kg of body weight. No treatment-related effects occurred in physical, behavioral, ocular, food consumption, or uri-nalysis parameters in either species. Mild dose-related hepatotoxicity occurred in rats given approximately 15 or 50 mg/kg of LY 171883. The hepatotoxicity was characterized by liver enlargement associated with induction of hepatic peroxisomal β-oxidation and microsomal drug metabolism. Male rats also had hepatocellular fatty change, centrilobular hypertrophy of hepa-tocytes, and increased levels of serum alanine transaminase and total bilirubin. Other effects in rats included minimal decreases in hematocrit values, decreases in serum triglycerides and cholesterol, and increased kidney weight The monkeys tolerated daily oral doses of LY 171883 up to 175 mg/kg with only minor increases in hepatic microsomal enzyme activity and slightly increased liver and kidney weights in males. No effects occurred in monkeys given 30 mg/kg. There was no induction of hepatic peroxisomal enzymes or pathologic abnormalities in monkeys treated with LY 171883. The peroxisomal inductive effect was apparently a species-related effect separate from the pharmacologic activity of leukotriene antagonism.

Effects of chronic treatment with the leukotriene D 4 antagonist compound LY171883 on Fischer 344 rats and rhesus monkeys

One-year toxicity studies were done to evaluate potential toxic effects associated with chronic exposure of rats and monkeys to the leukotriene antagonist LY171883. Rats were fed dietary doses of 0.0, 0.01, 0.03, or 0.1%, equivalent to approximately 0, 5, 15, or 50 mg/kg of body weight/day. Monkeys were given daily nasogastric gavage doses of 0, 30, 75, or 175 mg/kg of body weight. No treatment-related effects occurred in physical, behavioral, ocular, food consumption, or urinalysis parameters in either species. Mild dose-related hepatotoxicity occurred in rats given approximately 15 or 50 mg/kg of LY171883. The hepatotoxicity was characterized by liver enlargement associated with induction of hepatic peroxisomal β-oxidation and microsomal drug metabolism. Male rats also had hepatocellular fatty change, centrilobular hypertrophy of hepatocytes, and increased levels of serum alanine transaminase and total bilirubin. Other effects in rats included minimal decreases in hematocrit values, decreases in serum triglycerides and cholesterol, and increased kidney weight. The monkeys tolerated daily oral doses of LY171883 up to 175 mg/kg with only minor increases in hepatic microsomal enzyme activity and slightly increased liver and kidney weights in males. No effects occurred in monkeys given 30 mg/kg. There was no induction of hepatic peroxisomal enzymes or pathologic abnormalities in monkeys treated with LY171883. The peroxisomal inductive effect was apparently a species-related effect separate from the pharmacologic activity of leukotriene antagonism.

The effects of dietary methylcellulose in man

Following a 7-day control period, five male volunteers consumed, on each of 23 consecutive days, a weight of methylcellulose (MC) equal to ten times the acceptable daily intake (25 mg/kg b.w.) approved by the EEC and the Joint FAO/WHO Expert Committee on Food Additives (JECFA). The MC was well tolerated; no allergic responses were reported. Measurements before and at the end of the test period showed that the ingestion of MC, as a pre-hydrated gel, acted as a bulking agent in terms of increased faecal wet (p less than 0.05) and dry weight, with intestinal transit time increasing for three but decreasing for two of the volunteers. Small changes, well within the normal ranges, occurred in some haematological indices, serum lipids and a few plasma biochemistry parameters. There were no changes in urinalysis parameters or breath hydrogen concentrations. There were small (p less than 0.05) reductions in faecal volatile fatty acids and neutral sterols (mumol/g dry weight). The decreases in blood glucose and plasma insulin after 60 min were also within the normal clinical range. The data provide no indications of any adverse effects of methylcellulose resulting from its ingestion for 23 days at the level of 250 mg/kg b.w.

Pharmacological and toxicological evaluation of orally administered pyridostigmine in dogs

Pyridostigmine bromide, a reversible cholinesterase inhibitor, was administered orally (capsule gavage) to beagle dogs (10–15 months of age) of both sexes once daily at 5, 10, or 20 mg/kg for 14 days; every 8 hr at 2 or 5 mg/kg for 28 days; or every 8 hr at 0.05, 0.5, or 2 mg/kg for 3 months as part of its preclinical safety assessment. A small portion of the dogs receiving pyridostigmine for 3 months were allowed an untreated recovery period of an additional 3 months. Daily doses of 10 or 20 mg/kg were lethal to some of the dogs when given for up to 14 days and caused severe intestinal distress, including diarrhea, emesis, and reddened feces in all animals. The cause of death was intestinal intussusception. Signs of systemic toxicity apparent at these doses included hypersalivation and tremors. Similar but less severe effects were produced by 5 mg/kg per day; plasma cholinesterase activities were inhibited by all three doses in a dose-related manner. Signs of toxicity in the 28-day and 3-month studies were generally limited to the gastrointestinal tract and included diarrhea or soft stools and reddened or mucoid-containing stools; these signs appeared to reverse upon discontinuation of the drug. A single dog at 2 mg/kg every 8 hr developed an apparent intussusception. There were no pathological changes in clinical chemistry, hematology, or urinalysis parameters associated with doses of 0.05, 0.5, or 2 mg/kg every 8 hr for up to 3 months, nor were any drug-related lesions observed upon gross necropsy and microscopic evaluation of the major tissues and organs. Red blood cell (RBC) acetylcholinesterase (AChE) activities in the 3-month study were inhibited by approximately 10, 50, and 70% in the 0.05, 0.5, and 2 mg/kg every 8-hr dose groups, respectively, and these degrees of inhibition were maintained throughout the period of treatment. These data suggest that prolonged oral administration of pyridostigmine at doses sufficient to cause profound and sustained inhibition of RBC AChE activity (i.e., as high as 70%) cause mainly local, gastrointestinal distress related to altered intestinal motility. At the extreme, this can be manifested as a life-threatening intestinal intussusception. Systemic anticholinesterase effects (other than enzyme inhibition) were observed only at doses of 2 mg/kg and greater, while local (gastrointestinal) effects and inhibition of RBC AChE were observed at doses as low as 0.05 mg/kg.

The dietary effects of gellan gum in humans.

Following a 7-day control period, five female and five male volunteers consumed a weight of gellan gum corresponding to 175 mg/kg body weight for 7 days, followed by 200 mg gellan gum per kg body weight for a further 16 days. Measurements before and at the end of the 23-day test period showed that the gellan gum acted as a faecal bulking agent for the male volunteers and for four of the females. Dietary transit time increased for 2 females and 2 males, and decreased for 3 females and 3 males. Faecal bile acid concentrations increased for 4 females and for 4 males; the average increases were from 0.69 to 0.83 mmol/24 h (females) and from 1.22 to 1.44 mmol/24 h (males). Gellan gum ingestion had no significant effect on (a) plasma biochemistry parameters; (b) haematological indices; (c) urinalysis parameters; (d) blood glucose and plasma insulin concentrations; (e) breath hydrogen concentrations. There were no significant changes in HDL cholesterol, triglyceride or phospholipid concentrations. Serum cholesterol concentrations decreased significantly (P less than 0.1) by 13% on average for females, and by 12%, on average, for males. The data indicate that the ingestion of gellan gum at a high level for 23 days caused no adverse dietary or physiological effects in any of the volunteers. In particular, the enzymatic and other indicators of adverse toxicological effects remained unchanged.

Acute and subchronic toxicology of LY-195115 in rats and dogs

LY-195115 is a new (investigational) inotropic agent. When given orally to either young adult rats or mice, single doses of 2500 or 5000 mg/kg were tolerated with minimal lethality. Clinical signs included muscle weakness, hypoactivity, and evidence of hemorrhage. Dogs and monkeys survived a single oral dose of 10 and 5 mg/kg, respectively; however, there was sinus tachycardia for 6–8 h post dose in both species. Rats (207/sex/group) were fed diets containing LY-195115 in concentrations of 0, 0.005, 0.025, or 0.1% for 3 months. The average daily intake of the compound was approximately 0, 3.5, 17, or 70 mg/kg in both sexes. Deaths occurred only in the high-dose group. Body weight gain, food consumption, and efficiency of food utilization were significantly reduced in males in the 0.1 % dose group and animals of both sexes in this group had changes in hematology, clinical chemistry, and urinalysis parameters indicative of renal damage. Crystals containing LY-195115 were present in the urine of animals from the 0.025% and 0.1 % treatment groups. Secondary hydronephrosis due to kidney stone formation was observed on gross and microscopic pathologic evaluation in the males of the 0.025% group and animals of both sexes in the 0.1% group. In addition, periarteritis was present in the adventitia and muscularis of small and medium-sized arteries in the pancreas, lymph node, kidney, and stomach of some animals in all LY-195115 treatment groups. No overt signs of toxicity were produced in beagle dogs (4/sex/group) given daily oral doses of 0.03, 0.12, or 0.5 mg/kg of LY-195115 for 3 months. The only adverse effect was the occurrence of focal subendocardial fibroplasia in the heart in 2 high-dose male dogs. Thus, subchronic exposure of rats to doses of LY-195115 as high as 70 mg/kg produced minimal mortality, renal toxicity, and mild, limited vascular changes, while dogs tolerated doses up to 0.5 mg/kg with no evidence of any effect of treatment except minimal histological changes in the heart consequent to the expected cardiotonic action of the compound.

Safety evaluation of cimetidine: report at the termination of a seven-year study in dogs.

Cimetidine in tablet form was administered orally daily to eight male and four female beagle dogs at a dose level of 144 mg kg-1 for 385 weeks. Four male and two female control dogs received placebo tablets. Treatment with cimetidine did not affect the clinical condition of the dogs, but was associated with a slightly less rapid weight gain. Five dogs (two cimetidine-treated and three controls) were killed during the course of the study for reasons not related to treatment. Treatment with cimetidine did not affect haematological, clinical chemical, urinalysis or electrocardiographic parameters. Multiple biopsies of gastric mucosa taken at intervals of approximately six months from Week 177 to Week 363 showed no change which could be attributed to treatment with cimetidine. There were no toxic effects on the gastric mucosa of any dog. At necropsy no treatment-related findings were reported except for reduction in prostate size in 6/8 males receiving cimetidine. This was expected in view of previous experience with cimetidine.

Oral toxicity of trichlorobenzyl chloride and its acid derivative.

The acute rat oral LD50 of 2,4,6-Trichlorobenzyl chloride (TCBC) was determined to be 3075 mg/kg. When male and female rats were administered 1500 and 3000 ppm TCBC in the diet for 3 weeks, marked retardation in weight gain was observed. Reductions in food consumption were noted in both groups of treated male, but not female, rats. All blood chemistry and urinalysis parameters including those indicative of liver injury, were within the range of normal limits. Gross necropsy revealed pale livers in all high-dose rats and the majority of low-dose animals. Gross observations correlated with observation of degenerative hepatic changes (irregularity of cell and nuclear size, cord pattern, edema and cytoplasmic alterations) following microscopic evaluation. Rats and dogs administered up to 100 ppm trichlorobenzoic acid (TCBA) in the diet for 90 days exhibited no effects considered related to treatment.

The dietary effects of xanthan gum in man

Following a 7-day control period, 5 male volunteers consumed, on each of 23 consecutive days, a weight of xanthan gum equal to 15 times the current acceptable daily intake (10 mg/kg b.w.) approved by the EEC and by the Joint FAO/WHO Expert Committee on Food Additives; thus, the lightest and heaviest of the volunteers consumed 10.4 g and 12.9 g respectively of xanthan daily. Measurements before and at the end of the test period showed that the ingestion of xanthan, as a pre-hydrated gel, acted as a bulking agent in terms of its effects on faecal wet and dry weight and intestinal transit time but had no significant effect on plasma biochemistry, haematological indices, urinalysis parameters, glucose tolerance and insulin tests, serum immunoglobulins, triglycerides, phospholipids and HDL cholesterol, breath hydrogen and breath methane concentrations. There was a moderate (10%) reduction in serum cholesterol and a significant increase in faecal bile acid concentrations. The data indicate that the ingestion of xanthan caused no adverse dietary nor physiological effects in any of the subjects. In particular, all of the enzymatic and other parameters that act as sensitive indicators of adverse toxicological effects remained unchanged.

Prechronic toxicity of o-benzyl- p-chlorophenol in rats and mice

o-Benzyl- p-chlorophenol (BCP) is a major household and industrial germicide. Its prechronic toxicity was evaluated in male and female F344 rats and B6C3F1 mice. Treatment was by gavage in corn oil. BCP was slightly toxic after acute oral exposure, with high mortality at 4000 and 2000 mg/kg in rats and mice. Exposure to 12 oral doses of BCP at 1000, 500, 250, 125, 62.5, or 0 mg/kg body wt resulted in dose-related cecal dilatation and nephrosis in both rats and mice. Doses for the subchronic studies were based on the results of the 2-week studies. Ten animals were treated per dose per sex. Rats received 480, 240, 120, 60, 30, or 0 mg BCP/kg. Mice were treated with 1000, 800, 650, 500, or 0 mg BCP/kg. Animals were dosed 5 days per week for 13 weeks. Clinical signs related to dosing included urogenital staining in rats and rough/oily haircoats in mice. No effects on growth rate were seen in rats, but growth was retarded at the higher doses used in mice. Kidney weights increased in rats, and liver weights increased in mice. A decrease in thymus weight accompanied by a depletion in thymic lymphocytes (rats) or thymic necrosis (mice) occurred only in a high-dose animals. In both species, the kidney was the major target organ. In rats, there was an increase in incidence and severity of nephropathy and renal tubule regeneration. The lesions in mice primarily involved the renal cortex and included necrosis, casts, chronic inflammation, and regeneration of the renal tubules. No effects of BCP exposure in rats were seen in a broad spectrum of hematology or urinalysis parameters. Minor decreases in blood urea nitrogen, creatinine, and alanine amino transferase were detected in male and female rats. There were no biologically significant neurobehavioral effects in rats or immunotoxic effects in mice due to exposure to BCP. Thus, the kidney is the major target organ for BCP.

2,4-Pentanedione: 9-Day and 14-week vapor inhalation studies in Fischer-344 rats

Fischer-344 rats, in groups of 10 males and 10 females, were exposed for 9 days (6 hr/day) to 2,4-pentanedione (2,4-PD) vapor at mean concentrations of 805, 418, 197, and 0 (control) ppm. No deaths occurred, and the only adverse signs were of sensory irritation (partial closure of eyelids, periocular and perioral wetness) at 805 ppm. Also at 805 ppm were decreased body and organ weights, lymphocytosis, and moderate inflammation of the nasal mucosa. At 418 ppm there was a decrease in body weight gain and mild inflammation of the nasal mucosa. Apart from minimal nasal mucosal inflammation, there were no effects at 197 ppm. In the subchronic (14-week) study, rats were exposed (6 hr/day; 5 days/week) to 650, 307, 101, and 0 (control) ppm of 2,4-PD vapor, using groups containing 20 males and 20 females, with half being sacrificed at the end of the exposure period and the remainder kept for a 4-week postexposure recovery period. An additional 10 males were added to the 650 and 0 ppm groups for glutaraldehyde perfusion and subsequent electron microscopic examination of sciatic nerves. At 650 ppm, all females and 10 of 30 males died between the second and sixth weeks of exposure. These animals had acute degenerative changes in the deep cerebellar nuclei, vestibular nuclei and corpora striata, and acute lymphoid degeneration in the thymus. Seven of 15 male survivors of the 650 ppm group (combined 14-week and recovery sacrifices) had gliosis and malacia in the same brain regions, minimal squamous metaplasia in the nasal mucosa, decreased body and organ weights, lymphocytosis, and minor alterations in serum and urine chemistries. No ultrastructural evidence of peripheral neuropathy was observed. Except for central neuropathy, many of the adverse effects at 650 ppm were less marked in the 4-week recovery animals. No deaths occurred at 307 ppm, but females had slightly decreased body weight gains, and in both sexes there were minor alterations in hematology, serum chemistry, and urinalysis parameters, which were not present in the 4-week recovery animals. Rats exposed to 101 ppm showed no differences from the control rats. Subchronic exposure to 650 ppm of 2,4-PD vapor causes serious adverse biological effects. Under these study conditions, the minimum-effects concentration was 307 ppm, and the no-adverse effects concentration was 101 ppm.

The subchronic toxicity of tetrachloroethylene (perchloroethylene) administered in the drinking water of rats

This study provides data on the effects of tetrachloroethylene in drinking solutions. The acute oral LD50 in male and female Charles River rats was found to be 3835 mg/kg for males and 3005 mg/kg for females. Male and female rats received theoretical daily doses of 14,400, and 1400 mg tetrachloroethylene/kg body wt/day for 90 consecutive days. There were no compound-related deaths. Body weights were significantly lower in male and female rats at the higher doses. There were no consistent dose-related effects on any of the hematological, clinical chemistry, or urinalysis parameters. 5′-Nucleotidase activity was increased in a dose-dependent manner, suggesting possible hepatotoxicity; however, other serum indicators of hepatic function were unaffected by the treatment. There were no gross pathological effects observed. Liver and kidney body weight ratios, but not brain weight ratios, were elevated at the higher doses. There was no other evidence of compound-related toxicity. These data suggest that exposure of humans to reported levels of tetrachloroethylene in drinking water (approximately 1 μg/liter) does not constitute a serious health hazard.

Effects of cyclosporin A administration in cats

Cyclosporin A was administered orally to 10 cats for 28 consecutive days at a dosage of 20 mg/kg body weight daily divided into 2 equal doses. Serum trough CyA concentrations ranged from 134 to 902 ng/ml with a mean of 567 ± 249 ng/ml ( X ± SD ). Immunosuppression by CyA was suggested in 5 cats by significantly depressed lymphoblast transformation responses. Various hematologic, serum chemical, and urinalysis parameters were monitored on a weekly basis in 10 cats. Serum urea nitrogen concentration increased significantly from baseline values on days 7, 14, and 21, but not on day 28. Urine concentrating ability was unimpaired. Alanine aminotransferase activity was decreased significantly from baseline values at each sample period during CyA administration. Drug-related side effects were minor; one cat developed gingival hypertrophy which regressed within 21 days of CyA withdrawal.