High-dose Males Research Articles

Toxicological evaluation of mu-agonists. Part I: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo-alpha-acetylmethadol HCl (LAAM).

This study evaluated levo-alpha-acetylmethadol hydrochloride (LAAM), a long-acting morphine-like (mu) agonist approved in 1993 to treat opiate dependence. Sprague-Dawley rate (20/sex/group) were gavaged with doses of 3.0-33.5 mg kg-1 for 30 days followed by a 14-day drug-free recovery period. Treatment-related effects included dose-dependent CNS depression, decreased food consumption and body weight gain, reddish urine and abdominal staining. Tolerance developed by day 7. Mortality was dose-dependent; deaths occurred predominantly during the first week. Increased alanine aminotransferase (SGOT, AST) and lactate dehydrogenase (LDH), observed only in high-dose males, were associated with findings in liver. Decreases in spleen/brain weight and increases in brain/body weight ratios were seen in both sexes. Decreases in weights of heart, liver and kidney achieved statistical significance only for high-dose groups. Kidneys of mid- and high-dose groups displayed intertubular mineral/crystal deposition, focal corticomedullary mineralization and focal regenerative tubular epithelium. Centrilobular hypertrophy was observed in livers of high-dose males and mid- and high-dose females. Following the recovery period, decreased body weights and increased brain/body weight ratios occurred in mid-dose males and low-dose females. Weights of liver and kidney and organ/brain weight ratios were decreased in mid-dose males. Histopathological findings observed in kidneys and livers had abated. In summary, acute and repeated administration of LAAM produced a spectrum of activity consistent with its profile as a long-acting pure mu-agonist which stimulates microsomal enzymes in rodents. Renal and hepatic effects seen in initially drug-naive rats treated with morphine-type agonists are not observed in tolerant individuals stabilized on mu-agonists to treat opiate dependence.

Ten and ninety-day toxicity studies of 1,2-dichloroethane in Sprague-Dawley rats.

Male and female Sprague-Dawley rats received 1,2-dichloroethane in corn oil by gavage for 10 or 90 consecutive days. The doses for the 10-day study were 10, 30, 100, and 300 mg/kg; the 90-day study doses were 37.5, 75, and 150 mg/kg. There were ten animals per sex per dose group. In the 10-day study, all female animals died in the high dose group and only 2 of 10 males survived. Final body weights and weight gain along with hematology and clinical chemistry findings were not different from controls. The only relative organ weight which was significantly different was the liver in males exposed to 100 mg/kg. The main histopathological lesion exhibited was multifocal to diffuse inflammation of the mucosal and submucosal layers of the forestomach in the 100 mg/kg dose group. This change was minimal in both males and females. In the 90-day study there were no treatment-related effects pertaining to clinical observations. Body weight gain and total food consumption were significantly decreased in high dose males. There were slight but significant differences in hemoglobin, hematocrit, red blood cell count, platelets, albumin, and alkaline phosphatase values in the 75 and/or 150 mg/kg groups in one or both sexes. In males, relative brain, kidney, and liver weights were significantly increased at 75 and 150 mg/kg. There were also differences in spleen, adrenal, and testes weights (absolute and/or relative). In females, absolute and/or relative kidney and liver weights were significantly increased at 150 mg/kg (liver) and at 75 and 150 mg/kg (kidney). There were no apparent treatment-related effects pertaining to mortality, ophthalmology, gross pathology, or histopathology.

Confirmation study, using nitrobenzene, of the Combined Repeat Dose and Reproductive/Developmental Toxicity Test protocol proposed by the Organization for Economic Cooperation and Development (OECD).

A confirmatory familiarization study of the Combined Repeat Dose and Reproductive/Developmental Toxicity Screening (ReproTox) test protocol proposed by the Organization for Economic Cooperation and Development (OECD) was performed using nitrobenzene, a testicular toxicant. The agent was given daily by gavage to groups of 10 male and 10 female Sprague-Dawley rats at doses of 100, 60, 20 and 0 mg/kg body weight. Some of the high dose animals exhibited neurological signs, and two males and 9 females died. Hemolytic anemia due to methemoglobin formation was evident in treated males. Histopathologically, treated males showed atrophy of seminiferous tubules of the testis, reactive changes secondary to hemolytic anemia in the hematopoietic organs, and hepatocellular swelling. Cerebral gliosis was observed in middle and high dose males. Male fertility was not affected. The body weights of pups from treated dams were lowered, and their postnatal loss was increased. Most of the known toxicological properties of this chemical was demonstrated in the present study, with the exception of reduced fertility. Therefore, the ReproTox protocol was concluded as being useful as a screening test of existing high production volume chemicals. It should be noted that while the reproductive toxicity test alone is insensitive for detection of male fertility disturbances associated with testicular toxicity, the latter easily be distinguished on morphological grounds.

Toxicity studies of paclitaxel. (III)--Six-month intermittent intravenous toxicity in rats

Paclitaxel, an antineoplastic agent, was intravenously given to Crj:CD (SD) rats of both sexes at 0 (saline), 0 (vehicle), 0.3 (low dose), 1.0 (intermediate dose) and 3.3 (high dose) mg/kg at seven-day interval over a six-month period (total of 27 doses) to investigate its repeated dose toxicity. The results obtained are summarized as follows: 1. No deaths occurred in this study. Vehicle-related salivation was seen for some high dose and vehicle control rats. Soiling of the perigenital region was observed for some high dose females. 2. Red blood cell count, hemoglobin, hematocrit and white blood cell count were decreased for high dose rats. Reticulocyte count was increased and relative neutrophil count was decreased for high dose males. 3. Relative erythroid and myeloid cell count were decreased for high dose rats in bone marrow smear examinations. 4. Bone marrow hypoplasia and splenic hemosiderosis were observed for high dose rats, and thymic atrophy and lymphoid depletion were seen for some high dose males. Based on the these results, the no-toxic effect dose of paclitaxel was estimated to be 1.0 mg/kg in rats under this study condition.

Chronic effects of corticosteroid oral treatment in rats on blood glucose and serum insulin levels, pancreatic islet morphology, and immunostaining characteristics.

Corticosteroids have for many years proven beneficial in the necessary treatment of diseases and conditions that respond to their anti-inflammatory, immunosuppressive, or hormonal effects. Deflazacort is a derivative of prednisolone and is currently used in humans. Deflazacort was fed in the diet for 1 yr to Crl:CD BR rats at doses from 0.03 to 1.0 mg/kg/day to evaluate its toxic potential. Deflazacort-induced pancreatic islet cell hyperplasia in the 1-yr study was evaluated using subjective and objective methods on routine hematoxylin-and-eosin- or peroxidase-anti-peroxidase-stained preparations of pancreas (islets); the relationship of blood glucose and serum insulin levels to doses of deflazacort administered to rats was also examined. Diagnostic electron microscopy was conducted on similar proliferative islet lesions for a few high-dose males of a parallel carcinogenicity study. This study revealed that proliferative islet lesions were comprised mainly of beta cells (insulin producing) and that the islet area correlated well with hyperplasia grade and dose. However, there were no statistically significant relationships among reductions in blood glucose, serum insulin concentration, and proliferative islet alterations.

Comparison of the toxicity of citral in F344 rats and B6C3F 1 mice when administered by microencapsulation in feed or by corn-oil gavage

A study of the potential effects of microencapsulation on the toxicity of citral was conducted in 14-day continuous feeding studies with both sexes of F344 rats and B6C3F 1 mice. Toxicity by the feeding route was compared with that from bolus doses of the neat chemical in corn oil administered by gavage. Both sexes of rats and mice were given diet containing 0, 0.63, 1.25, 2.5, 5 and 10% citral microcapsules. These feed formulations were equivalent to daily doses of 0, 142, 285, 570, 1140 and 2280 mg citral/kg body weight for rats and 0, 534, 1068, 2137, 4275 and 8550 mg citral/kg body weight for mice. The daily gavage doses were 0, 570, 1140 and 2280 mg citral/kg body weight for both sexes of rats, and 0, 534, 1068 and 2137 mg citral/kg body weight for both sexes of mice. Citral microcapsules administered in the diet did not cause mortality in mice or rats. Toxicity was confined to decreases in body weight at the 10% concentration in mice, at the 5 and 10% concentrations in rats, and decreases in absolute weights of the liver, kidney and spleen at the 10% concentration in rats. The only histopathological change observed was minimal to mild hyperplasia and/or squamous metaplasia of the respiratory epithelium in the anterior portion of the nasal passages of rats fed 5 or 10% citral microcapsules. By contrast, citral gavage caused mortality in five out of five male and female mice at 2137 mg/kg body weight, and in two out of five male mice at 1068 mg/kg body weight. There were dose-related increases in absolute liver weights of male and female mice. Cytoplasmic vacuolization of hepatocytes occurred in all female mice gavaged with 1068 and 2137 mg citral/kg body weight, and in male mice from the 2137 mg/kg dose group. Necrosis, ulceration and/or acute inflammation of the forestomach occurred in the high-dose mice of both sexes. Inflammation and/or hyperplasia of the forestomach occurred in about half of the male and female mice dosed with 1068 mg citral/kg. Citral gavage at doses that were equivalent to up to 10% in the diet (2280 mg/kg body weight) did not cause toxicity in rats, except for minimal hyperplasia of the squamous epithelium of the forestomach in high-dose males. Microencapsulated citral given in the diet has distinct advantages as an alternative route of administration for long-term studies: the microencapsulation process prevents the normally rapid degradation of the chemical; continual ingestion from the diet mimics the human route of exposure; and higher doses of the chemical can be attained in the animal model to maximize the detection of potential toxic or carcinogenic responses.

Two-year carcinogenicity study with sennosides in the rat: emphasis on gastro-intestinal alterations.

A carcinogenicity study was conducted by administering a purified senna extract via the drinking water to Sprague-Dawley rats of each sex for 2 years. The daily doses received were 0, 5, 15 and 25 mg/kg. Histopathological examination was restricted to tissues from the gastro-intestinal tract, liver, kidneys, adrenals and from tissues with any observed abnormalities or masses. A laxative effect was observed in high-dose females, and in mid- and high-dose males. No significant differences in survival were found between treated and control groups. Mean body weight gain was significantly decreased in high-dose males. Increased kidney weights were noted in mid-dose males and females, and high-dose females. Histopathological examination of control and high-dose rats did not indicate any difference in the incidence of neoplastic lesions. As regards non-neoplastic lesions, a treatment- but not dose-related increase in reactive mesenteric lymph node hyperplasia was observed in preterminally sacrificed rats. However, a corresponding increase was not noted in the terminally sacrificed rats or when preterminal and terminal animals were combined. No ultrastructural changes in the myenteric nerve plexus of the colon and jejunum could be detected in the small number of investigated tissue samples. In conclusion, results from the present investigation do not indicate any relationship between long-term administration of purified senna extract and gastrointestinal, liver, kidney or adrenal tumors in the rat.

Ten and ninety-day toxicity studies of 2,4-dimethylphenol in Sprague-Dawley rats.

Male and female Sprague-Dawley rats received 2,4-dimethylphenol daily by gavage for 10 or 90 consecutive days. The 10-day acute study doses were 0, 60, 120, 600 and 1200 mg/kg; the 90-day subchronic study doses were 0, 60, 180 and 540 mg/kg. Corn oil was used as the vehicle. In the 10-day study, all the high dose animals died. At 600 mg/kg there was a significant increase in relative liver weight in females and several significant alterations in hematologic and clinical chemistry values in both sexes. Histopathological examination revealed changes associated with the forestomach in all dose groups. The 90-day study had numerous compound-related deaths at the 540 mg/kg level. In addition, the final body weight in high dose males and females was significantly less while absolute lung weights and relative liver weights in females, and relative brain, kidney and testes weights in males were also altered. Significant clinical chemistry findings in high dose animals (540 mg/kg) included reduced creatinine and increased cholesterol in both sexes, with increased triglycerides and decreased AST in males only. Histopathologic evaluation revealed hyperkeratosis and epithelial hyperplasia of the forestomach in males and females in the middle and high-dose groups.

A 40-week male fertility study of the anticancer agent sulofenur (LY186641) administered orally to rats

Sulofenur was evaluated for fertility effects on rats. Five-week old male rats (20/group) received 0, 5, 30, or 60 mg Sulofenur/kg/day for 14 weeks. Fertility was evaluated five times. Treated males were mated with untreated females at 10 weeks. Half the males from each group were necropsied after the 14-week treatment period and the remainder were mated four additional times during a 26-week posttreatment period. Following each mating, females were killed on gestation-day 20 and examined for evidence of pregnancy. Six weeks after mating trial 5, the remaining males were necropsied. Testes and epididymides were collected, weighed, and examined microscopically. All rats mated in each mating trial, and all control and low-dose animals were fertile. A significant reduction in fertility occurred in the middle- and high-dose males. This was consistent with testicular hypospermatogenesis in these groups. Fertility recovered in the high-dose group following cessation of treatment, but remained reduced in the middle-dose group. Preimplantation and postimplantation loss in mating trial 1 were higher in the middle-and high-dose groups. Abnormal fetuses were present in the high-dose group in mating trial 3, but not in mating trials 4 or 5. In conclusion, male rats given doses of 30 and 60 mg/kg/day of Sulofenur showed hypospermatogenesis and decreased fertility. Spermatogenesis and fertility recovered in the high-dose group. A dose of 5 mg/kg/day did not produce any effect on testes or fertility.

Renal lesions induced by ochratoxin A exposure in the F344 rat.

Groups of 80 male and female F344 rats were exposed by gavage to ochratoxin A, a naturally occurring mycotoxin, at levels of 21, 70, and 210 micrograms/kg body weight for up to 2 years. Ochratoxin A induced non-neoplastic renal tubular epithelial changes consisting of cytoplasmic alteration, karyomegaly, degeneration, and cysts. Exposure-related renal tubular proliferative lesions included focal hyperplasia, tubular cell adenoma, and tubular cell carcinoma. Renal tubular cell adenoma occurred as early as 9 months in 1 high-dose male rat, and both adenomas and carcinomas were seen in males by 15 months. At the terminal sacrifice, renal tubular cell tumors were found in both male and female rats, but the response was more pronounced in the males. The incidence of renal tumors in the high-dose rats was the highest of any National Toxicology Program (NTP) study completed to date. In the high-dose males approximately one-third of the renal carcinomas developed metastases. This study demonstrates that ochratoxin A is a potent renal carcinogen in the F344 rat and suggests that contamination of feedstuff by this mycotoxin may pose a potential hazard to domestic animals and man.

Toxicities of microencapsulated tribromomethane, dibromochloromethane and bromodichloromethane administered in the diet to Wistar rats for one month.

The gelatin-starch syrup microencapsulation method was applied to subacute toxicity studies of tribromomethane (TBM), dibromochloromethane (DBCM) and bromodichloromethane (BDCM). Groups of Wistar rats (7 males and 7 females) both sexes were given diet containing microcapsules of each of these trihalomethanes (THMs) at the following concentrations: TBM, 0.068, 0.204 and 0.612% in males, and 0.072, 0.217 and 0.651% in females; DBCM, 0.020, 0.062 and 0.185% in males, and 0.038, 0.113 and 0.338% in females; BDCM, 0.024, 0.072 and 0.215% in males, and 0.024, 0.076 and 0.227% in females. Suppression of body weight gain was seen in each high-dose males fed TBM or BDCM and females fed DBCM or BDCM. Histopathologically, hepatic lesions such as vacuolization and swelling of liver cells were significantly noted in both sexes of all groups fed TBM, in both sexes of the middle- and high-dose groups fed DBCM, and in males of the high-dose group and in females of the middle- and high-dose groups fed BDCM. In addition, single cell necroses were observed in males and females fed DBCM and in males fed BDCM. Hepatic cord abnormalities were also noted in males of the high-dose group fed BDCM. Although no increases in serum transaminase activities (ASAT, ALAT) were evident in either sex fed any of the THMs, decreases in triglyceride content, cholinesterase and lactate dehydrogenase activity were observed. Renal lesions reported to occur in gavage studies were not found in the present feeding study. Lowest-observed-adverse-effect-level (LOAEL) of TBM and no-observed-adverse-effect-level (NOAEL) of DBCM and BDCM were determined to be 56.4 mg/kg, 18.3 mg/kg and 20.6 mg/kg, respectively, under the present experimental conditions.

90-Day toxicity study of dichloroacetate in dogs

Male and female juvenile beagle dogs were dosed daily for 90 days with dichloroacetate (DCA). The compound was administered orally via gelatin capsules at doses of 0, 12.5, 39.5, and 72 mg/kg/day. Each dose group consisted of five males and five females. The dogs were observed clinically and blood samples were taken at 15-day intervals for hematologic and serum chemistry values. Decreased total erythrocyte count and hemoglobin levels were observed in mid- and high-dose dogs beginning at Day 30. Serum concentrations of LDH were elevated at Days 30 and 45 in females and at Day 75 in males treated with DCA at 72 mg/kg/day. One female of the high-dose group died at Day 50 and two high-dose males died at Days 51 and 74. Hindlimb partial paralysis was observed in many high-dose dogs. Vacuolization of myelinated white tracts of cerebrum, cerebellum, and/or spinal cord was observed in many high-dose dogs as well as some mid- and low-dose subjects. Degeneration of testicular germinal epithelium and syncytial giant cell formation was noted in males of all dose groups. Hepatic vacuolar change and chronic hepatitis appeared only in DCA-treated dogs. In addition, suppurative bronchopneumonia and chronic pancreatitis were noted in many high-dose and some middose subjects. A “no-adverse-effect level” was not determined in this study.

90-Day Toxicity Study of Dichloroacetate in Dogs

90-Day Toxicity Study of Dichloroacetate in Dogs. CICMANEC, J. L., CONDIE, L W., OLSON, G. R., AND WANG, S. R. (1991). Fundam. Appl. Toxrcol. 17,376–389. Male and female juvenile beagle dogs were dosed daily for 90 days with dichloroacetate (DCA). The compound was administered orally was gelatin capsules at doses of 0, 12.5, 39.5, and 72 mg/kg/day. Each dose group consisted of five males and five females. The dogs were observed clinically and blood samples were taken at 15-day intervals for hematologic and serum chemistry values. Decreased total erythrocyte count and hemoglobin levels were observed in mid- and high-dose beginning at Day 30. Serum concentrations of LDH were elevated at Days 30 and 45 in females and at Day 75 in males treated with DCA at 72 mg/kg/day. One female of the high-dose group died at Day 50 and two high-dose males died at Days 51 and 74. Hindlimb partial paralysis was observed in many high-dose dogs Vacuolization of myelinated white tracts of cerebrum, cerebellum, and/or spinal cord was observed in many high-dose dogs as well as some mid- and low-dose subjects Degeneration of testicular germinal epithelium and syncytial giant cell formation was noted in males of all dose groups. Hepatic vacuolar change and chronic hepatitis appeared only in DCA-treated dogs. In ddition, suppurative bronchopneumonia and chronic pancreatitis were noted in many high-dose and some middose subjacts. A “no-adverse-effect level” was not determined In this study.

Cardiovascular and adrenal proliferative lesions in Fischer 344 rats induced by long-term treatment with type III phosphodiesterase inhibitors (postive inotropic agents), isomazole and indolidan

Male and female Fischer 344 rats were treated with the positive inotropic agents, isomazole or indolidan, in the diet for 104 weeks. The doses were 0.0, 11.5, 23.5, or 48.0 mg/kg and 0.0, 0.12, 0.40, or 1.3 mg/kg, respectively. Only 17% of the males treated with 48.0 mg/kg isomazole survived the duration of the study. The male component of the indolidan study was terminated at 22 months, with only 18% of the high-dose males surviving. Sixty-five percent of the males treated with 48.0 mg/kg isomazole and 70% of the males treated with 1.3 mg/kg indolidan were found to have severe periateritis, often with thrombi located mainly in the mesenteric arteries. Fifty-four percent of the male rats treated with 48.0 mg/kg isomazole and 55% of the male rats treated with 1.3 mg/kg indolidan died from cardiovascular disease compared to 1–2% among the control males. Animals in the low- and middle-dose groups of both studies had a lower incidence of cardiovascular disease than did those in the high-dose group. Additional lesions associated with the long-term administration of both drugs were markedly increased incidence of adrenal medullary proliferative lesions (both hyperplasia and pheochromocytomas) and increased incidence of chronic progressive glomerulonephrosis. These lesions, like those in the cardiovascular system, occurred in a dose-dependent manner and were more frequent in males than in females. Treatment-related effects in these studies were judged to be related to the pharmacologic action of these compounds.

Toxicological and hematological effects of sicklepod ( Cassia obtusifolia) seeds in Sprague-Dawley rats: A subchronic feeding study

Cassia obtusifolia and its seeds, common contaminants of agricultural commodities, are toxic to cattle and poultry. Toxicity has been attributed to anthraquinones which are major constituents of C. obtusifolia, but studies of the subchronic and chronic toxicity of naturally occurring anthraquinones are limited. To investigate the subchronic ( 30 days) toxicity of C. obtusifolia seed, ten rats/sex were fed diets containing 0, 0.15, 0.50, 1.5 or 5.0% C. obtusifolia seed for 13 weeks. Intermittent mild diarrhea was found in high-dose animals and body weights of high-dose males were decreased to week 10. Myeloid hyperplasia with peripheral leukocytosis, thrombocytosis and mild anemia were found in males and females fed diets containing ≥0.50% C. obtusifolia seed. Leukocytosis resulted from neutrophilia, whereas peripheral lymphocyte counts were unaffected. Lymphoid hyperplasia and/or histiocytosis were found in the mesenteric lymph nodes in groups fed C. obtusifolia seed. Thus, a dietary ‘no observable effect level’ for subchronic ingestion of C. obtusifolia seed in rats was <0.15%.

Fourteen-and Ninety-Day Oral Toxicity Studies of Methyl Tertiary-Butyl Ether in Sprague-Dawley Rats

Male and female Sprague-Dawley rats were gavaged with methyl tertiary-butyl ether (MtBE) for 14 or 90 days to evaluate subacute and subchronic toxicity. Five daily dose levels ranged from 0 to 1428 mg/kg body weight for the 14 day study and 0 to 1200 mg/kg body weight for the 90-day exposure. Controls received the corn oil vehicle. At or above dose levels of 1200 mg/kg, MtBE-induced anesthesia lasted about 2 h, followed by uneventful recovery. Diarrhea was common in all treatment groups, but no deaths were attributed to MtBE toxicity. In the subacute study, lung weights were reduced in high-dose females. Trends in the 14-day exposure also included increased cholesterol in both females and males and decreased blood-urea nitrogen (BUN) and creatinine in females. In the 90-day study, females exhibited elevated cholesterol and decreased BUN, while creatinine was decreased in high-dose males. Microscopic findings in most organs were unremarkable, except for high-dose males where renal changes were compatible with alpha 2-globulin nephropathy and were considered to have little toxicologic significance for humans. Both studies indicated that dose levels below those which induce anesthesia (1200 mg/kg) do not result in significant pathophysiologic changes.

Twenty-six week toxicity study with KASAL® (basic sodium aluminum phosphate) in beagle dogs

Sodium aluminum phosphate in its basic form (KASAL) is a white odorless powder comprised of an autogenous mixture of alkaline sodium aluminum phosphate and dibasic sodium phosphate. KASAL is used primarily as an emulsifier in the production of processed cheese. This food additive constitutes a significant source of dietary aluminum in the USA (Pennington, 1987). Recent studies implicated parenteral administration of aluminum to a variety of maladies including osteomalacia and dialysis dementia (Ellis et al., 1979; Goodman, 1986; Will and Savory, 1985). However, relatively few long-term studies in laboratory animals have been reported. Because sodium aluminum phosphate formulations are potentially important sources of aluminum exposure it was important to study their toxicity and contribution to aluminum deposition in potentially important biological tissues (i.e., bone and brain). In the present study, Beagle dogs were fed diets containing up to 30,000 p.p.m. KASAL for 26 weeks. Mild toxicity was observed in high-dose males. No toxicologically significant increase of tissue aluminum concentrations were observed in KASAL treated dogs.

Ninety-Day Oral Toxicity Study of Dibromochloromethane in Sprague-Dawley Rats

Male and female Sprague-Dawley rats received dibromochloromethane daily by gavage to evaluate its subchronic toxicity. Dose levels were 0, 50, 100, and 200 mg.(kg-day)-1, with 10 animals/sex/group for 90 consecutive days. Corn oil was used as the vehicle. No changes were found in mortality, clinical signs, ophthalmoscopic examinations, or hematology that were considered to be related to treatment. Mean final body weight and body weight gain (weeks 0-13) were significantly decreased in male and female high dose animals relative to the vehicle control. Food consumption was decreased in males in a dose-related fashion, reaching statistical significance at the highest treatment level. Indications of hepatotoxicity in the clinical chemistry included elevated alanine amino-transferase (mid and high dose males) and alkaline phosphatase (high dose males and females). Increased serum creatinine (mid- and high dose males and high dose females) and decreased potassium (high dose males) were considered to be suggestive of nephrotoxicity. Absolute and relative weights of several organs in male and female animals were depressed and were related to the decreased body weights. The decreases in brain and thymic weights, and increases in liver and kidney weight (female only) were considered to be treatment related. Histopathological changes included findings of lipidosis of the liver and slight to moderate degenerative changes within the proximal tubular cells of the kidney. Based on the results of this study, the (LOAEL) lowest observed adverse effect level for DCBM when administered to Sprague-Dawley rats in corn oil gavage was 50 mg.(kg-day)-1.

Toxicological evaluation of morning glory seed: Subchronic 90-day feeding study

Diets containing 0.8, 2.53 and 8.0% field variety morning glory seed were fed to male and female rats (20 per group) in a 90-day subchronic feeding study. Gross clinical observations, body weight, and feed and water intake were recorded weekly. At 90 days, all surviving rats were autopsied, organs were weighed, and blood chemistry analyses, haematology, and bone-marrow evaluation for evidence of clastogenic effects were performed. Tissues from control (0% seed) and high-dose (8.0% seed) rats were examined histologically. Effects of morning glory seed were noted mainly in the high-dose group of both sexes. These included increases in mortality, feed consumption (on a body-weight basis), water consumption, serum alkaline phosphatase and potassium, white blood cell count, and brain and liver weights (as a percentage of body weight); body-weight gain and serum glucose were decreased. Significant changes seen in high-dose females alone were: increased haemoglobin, serum constituents (urea nitrogen, glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, and ornithine carbamyl transferase), and organ weights (heart, kidney, spleen and pancreas as a percentage of body weight), and decreases in serum albumin, total protein, albumin:globulin ratio, and calcium. Significant changes occurring in high-dose males alone were: increased testicular weight (as a percentage of body weight), increased serum phosphorus, and decreased serum cholesterol. Liver degeneration in the high-dose females was greater than that in the controls. Mortality at 8.0% seed in the diet was 40% in males and 10% in females. At 0.8% seed, the only parameter that differed significantly from that of the controls was a final body-weight reduction in females without a corresponding reduction in feed consumption.

Prenatal reserpine exposure alters cardiovascular parameters in rat offspring

Electrocardiograms (ECGs) and blood pressures (BPs) were recorded and evaluated in postnatal rats that had been exposed in utero to 0.375 or 0.75 mg reserpine/kg/day sc on Gestational Days (GD) 12–15. These doses caused reduced maternal weight gain during pregnancy and decreased pup body weight at birth, as well as reduced heart weight during the preweaning period. There were no changes in other maternal parameters or in litter size. During the postweaning period, pup body weight was reduced only at the highest dose at Postnatal Days (PND) 30 and 60. By PND 342, the weight reduction was no longer significant when compared to controls. Lead II ECGs were recorded in conscious animals on PND 30, 60, and 342; BPs were recorded in anesthetized animals on PND 346. Several ECG parameters were attenuated by prenatal reserpine exposure: R wave and S wave amplitudes and the QRS interval in males, and the PR interval in females. The BP recordings showed that low-dose males had significantly higher pulse pressures than did high-dose males, but neither group was significantly different from controls. Following an intraarterial norepinephrine challenge, resultant peak pulse pressure was greater in high-dose females than in controls. These results indicate that subtle, long-term, sex-specific alterations in cardiovascular parameters were produced by prenatal reserpine treatment at doses that altered body weight in young animals at PNDs 30 and 60, but this change was no longer apparent at PND 342.