Adverse effect of a sucrose-based semipurified diet on development and postnatal growth of Fischer rats

A commercially prepared semipurified diet (Bio-Serve No. 0006Q) composed of chemically defined ingredients was fed to male and female F344 rats before mating, to females during gestation, and to the offspring after weaning. Compared to rats treated similarly but fed a standard, cereal-based chow (Agway CR RMH 3000), offspring on the semipurified diet exhibited markedly retarded growth. At 12 weeks of age, the deficits in body weight were accompanied by decreased absolute organ weights, increased organ-to-body weight ratios, increased serum cholesterol and triglyceride levels, and development of hepatic periportal lipidosis in both male and female offspring on the semipurified diet. The deficits in body weight are explained, in part, by decreased intake of the semipurified diet, most likely attributable to its high sucrose content. Investigators are cautioned about the inadequacy of certain semipurified diets for development and postnatal growth of F344 rats.     

Lack of carcinogenicity of silicone resin (KS66) in F344 rats.

The carcinogenic potential of silicone resin (KS66), used as an antifoaming food additive, was examined in both sexes of F344 rats. Groups of 50 female and 50 male animals were given diet containing KS66 at doses of 0%, 1.25% and 5.0%. No treatment related effects were noted regarding survival rate, general condition, body weight, food consumption, hematology and organ weight data. Detailed histopathological examination revealed no treatment-related increase in the incidences of any non-neoplastic or neoplastic lesions. The results demonstrate that KS66 is not carcinogenic in F344 rats of either sex.     

Thirteen-week toxicology studies of 1-amino-2,4-dibromoanthraquinone in Fischer 344/N rats and B6C3F1 mice

1-Amino-2,4-dibromoanthraquinone (ADBAQ), an intermediate in the production of commercial dyes for wool, silk, and synthetic fibers, was selected for toxicology and carcinogenesis studies in two rodent species. In advance of the 2-year studies, 13-week studies were conducted in male and female F344/N rats and B6C3F1 mice which were fed a diet containing ADBAQ at concentrations of 0, 0.25, 0.50, 1.00, 2.50, and 5.00%. ADBAQ stained the skin and fur red at all doses in rats and at 1.00% and higher concentrations in mice. Lethargy and emaciation were noted at the 2.50% and higher doses in rats of both sexes. In general, the absolute weight of the liver and the liver/organ weight ratios increased in both sexes and species at all doses. Treated rats developed a chronic toxic hepatitis characterized by hepatocytomegaly, centrilobular vacuolar degeneration and necrosis, regenerative nodules, acute necrotizing cholangitis, bile duct hyperplasia, chronic active inflammation in periportal areas, and focal pigmentation. The hepatopathy occurred at all doses in males and at 0.50% and higher in females and correlated with elevations of serum glutamic-pyruvic and glutamic-oxaloacetic transaminases, leukocytosis, and neutrophilia. Hyaline droplet degeneration in the proximal convoluted tubules of the kidneys occurred in male rats, and uterine atrophy was observed in female rats at 1.00% and higher. Anemia occurred in both sexes of rats at all doses and thymic atrophy was observed in both sexes of high-dose rats. In male mice minimal dose-related lesions in the liver included centrilobular glycogen depletion at 1.00% and higher and pigmentation at all doses. At comparable doses, ADBAQ was considered to be markedly toxic in rats and of minimal nonlife-threatening toxicity in mice.     

Lack of hinokitiol (beta-thujaplicin) carcinogenicity in F344/DuCrj rats

Chronic toxicity and carcinogenicity of hinokitiol (beta-thujaplicin), used as an antibiotic and fungicidal agent of a food additive, was examined in both sexes of F344/DuCrj (F344) rats. In this chronic toxicity study, groups of 10 rats of each sex were given a diet containing hinokitiol at doses of 0, 0.005, 0.015 and 0.05% for 52 weeks. No treatment-related adverse effects were noted in the survival rate, general condition, body weights, food consumption, urinalysis, hematology and clinical chemistry. Slight but significant elevation of spleen and liver weights was noted in both sexes given 0.05% hinokitiol, along with an increase in hemosiderin deposits in male spleens, related to chelator binding of iron, together with slight centrilobular hypertrophy of male hepatocytes. However, these alterations were negligible and not toxicologically significant. In the carcinogenicity study, groups of 50 female and 50 male rats were given a diet containing hinokitiol at doses of 0, 0.005, 0.015 and 0.05% (excluding 0.005% in females). No treatment-related changes in survival rate, general condition, body weight, food consumption, hematology and organ weights were noted. Detailed histopathological examination revealed no treatment-related increase in the incidences of any neoplastic lesions. The results demonstrate that hinokitiol is not carcinogenic in F344 rats of either sex.     

Developmental programming: Sex‐specific programming of growth upon prenatal bisphenol A exposure

In both human and animals, in utero exposure to bisphenol A (BPA), an endocrine‐disrupting chemical used in the production of plastics and epoxy resins, has been shown to affect offspring reproductive and metabolic health during adult life. We hypothesized that the effect of prenatal exposure to environmentally relevant doses of BPA will be evident during fetal organogenesis and fetal/postnatal growth trajectory. Pregnant ewes were administered BPA subcutaneously from 30 to 90 days of gestation (term 147 days). Fetal organ weight, anthropometric measures, maternal/fetal hormones and postnatal growth trajectory were measured in both sexes. Gestational BPA administration resulted in higher accumulation in male than female fetuses only at fetal day 65, with minimal impact on fetal/maternal steroid milieu in both sexes at both time points. BPA‐treated male fetuses were heavier than BPA‐treated female fetuses at fetal day 90 whereas this sex difference was not evident in the control group. At the organ level, liver weight was reduced in prenatal BPA‐treated female fetuses, while heart and thyroid gland weights were increased in BPA‐treated male fetuses relative to their sex‐matched control groups. Prenatal BPA treatment also altered the postnatal growth trajectory in a sex‐specific manner. Males grew slower during the early postnatal period and caught up later. Females, in contrast, demonstrated the opposite growth trend. Prenatal BPA‐induced changes in fetal organ differentiation and early life growth strongly implicate translational relevance of in utero contributions to reproductive and metabolic defects previously reported in adult female offspring.     

A 90-day oral toxicity study of purple corn color, a natural food colorant, in F344 rats.

A subchronic oral toxicity study of purple corn color (PCC), a natural food colorant, was performed with groups of 10 male and 10 female F344 rats fed the agent at dietary levels of 0%, 0.5%, 1.5% and 5.0% for 90 days. No mortalities occurred during the treatment period. No treatment-related changes in the body weight, food and water consumption, ophthalmology, hematology, organ weight data and histopathology were observed. Regarding general conditions and gross pathology, staining of fur and black feces were noted in rats of the 1.5% and 5.0% diet groups. Moreover, brown urine and black material in the stomach, small and large intestine were evident in rats receiving 5.0%. These changes were considered due to the anthocyanin content. On clinical chemistry analysis, total cholesterol, phospholipid and triglyceride were significantly lowered in both sexes of the 5.0% group, but these were not considered to be toxicologically significant. Thus, the No-observed-adverse-effect-level (NOAEL) was judged to be 5.0% in diet for both sexes (male: 3542 mg/kg/day, female: 3849 mg/kg/day) for PCC under the present experimental conditions.     

Effect of luteinizing hormone releasing hormone (LHRH) agonists on body weight in rats

As the potential clinical applications of LHRH agonists increase, the issue of side effects on nonreproductive organ systems assumes greater significance. LHRH agonists administered continuously or in twice-daily injections accelerated body weight gain in female rats. Two different LHRH agonists produced similar effects on body weight in female rats. When Leuprolide (LHRHa) was given to female rats in twice-daily injections, the adrenal weight increased after 21 days of treatment, whereas administration by osmotic minipumps produced no significant effect on adrenal weight. When another agonist, Zoladex (LHRHz), was given continuously for 52 and 229 days to female rats, the adrenal weight decreased. No change was noted in adrenal weight or body-weight gain of male rats given LHRHz continuously for 51 and 62 days. Reproductive-organ weights were significantly reduced in all LHRH-agonist-treated animals. Serum progesterone in female rats and testosterone in male rats were significantly decreased following treatment with LHRHz. No significant differences were noted in serum prolactin, growth hormone, or corticosterone. The mechanisms and significance of these findings are discussed.     

Biosynthetic human growth hormone: subchronic toxicity studies in rats and monkeys

Biosynthetic human growth hormone was injected subcutaneously in rats for 90 days and in cynomolgus monkeys for 30 days. The daily doses were 0.5, 3.3 and 25 IU kg-1 (rats) and 0.3 and 15 IU kg-1 (monkeys). The growth hormone was tolerated well in both rats and monkeys. No drug related deaths occurred and all animals appeared to be normal and also behaved normally throughout the dosing period. Increased body weight gain, increased food utilisation and increased organ weights were seen in the rats in the high and intermediate dose groups. The higher doses of human growth hormone (3.3 and 25 IU kg-1) caused a glandular hyperplasia of the mammary gland in male and female rats with evidence of secretory activity. In the female monkeys secretory activity was seen without any sign of mammary gland hyperplasia. Mucification of the vaginal epithelium and stress induced prostatitis was observed in the rats. Additional treatment related changes in the rats were an increased haematopoietic activity in the spleen and an increase in the amounts of calcium and phosphate excreted in urine. An increase in fasting plasma glucose levels was seen in the male monkeys on the high dose level. The changes observed during the treatment periods presumably represent exaggerated pharmacological effects of the growth hormone.     

A repeated dose 28-day oral toxicity study of extract from cultured Lentinula edodes mycelia in Wistar rats

To evaluate the toxicological safety of extract from cultured Lentinula edodes mycelia (L.E.M.), repeated doses (2,000 mg/kg/day) were administered to male and female Wistar rats for 28 days. No mortality or abnormality in the general status or appearance was observed in rats administered L.E.M extract. Body weight and food consumption decreased slightly, particularly in the case of male rats, although the degree of decrease was not as prominent toward the end of administration. Examination of hematology, serum biochemistry, absolute and relative organ weights, autopsy and histopathology revealed only a few statistically significant differences between the treatment and control groups; these differences suggested no clinically significant changes related to toxicity. Consequently, the no observed adverse effect level (NOAEL) of L.E.M. extract was considered to be more than 2,000 mg/kg/day under the conditions of the present study.     

Comparative study of the sensitivity of male and female rats to methylmercury

Male and female rats were dosed daily by gastric gavage four or five times with 8.0 mg/kg Hg as methylmercury. Treatment lowered the body weight in relation to the body weight of untreated rats to the same extent in male and female rats but when body weight was related to the initial body weight, the effect of methylmercury was more pronounced in females than in males. The importance of differences in growth or loss of body weight is that in spite of the similar whole body clearance mercury concentrations were higher in females than in males. After identical doses the brains of females always contained more mercury than those of males and in both sexes the brain concentration of mercury showed a disproportionate elevation when the number of doses was increased from four to five. However, weight change alone does not explain the sex related difference in the brain concentration of mercury as this was evident even 72 h after a single dose. In agreement with the brain concentration of mercury, female rats developed more intensive co-ordination disorders and after five doses they had more extensive damage in the granular layer of the cerebellum than males.     

Encephalopathy in rats and nephropathy in rats and mice after subchronic oral exposure to benzaldehyde

Male and female Fischer 344 rats and B6C3F1 mice were treated daily (5 days/wk) with benzaldehyde by gavage either in 12 doses of 0 (vehicle control), 100 (rats only), 200, 400, 800, 1600 or (for mice only) 3200 mg/kg body weight/day (followed by 2 days' observation without treatment), or for 90 days in doses of 0, 50, 100, 200, 400 or 800 mg/kg/day (rats) or 0, 75, 150, 300, 600 or 1200 mg/kg/day (mice). In the acute studies, benzaldehyde induced deaths and decreased body-weight gain in both sexes of rats given 800 or 1600 mg/kg/day and caused deaths in both sexes of mice given 1600 or 3200 mg/kg/day. In the 90-day studies, deaths occurred in both sexes of rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Body-weight gain was depressed in male rats on 800 mg/kg/day, in male mice on 600 mg/kg/day and in female mice on 1200 mg/kg/day. Necrotic and degenerative lesions were seen in the cerebellar and hippocampal regions of the brain in both sexes of rats given 800 mg/kg/day, but not in mice. Renal tubular necrosis occurred in male and female rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Mild epithelial hyperplasia or hyperkeratosis of the forestomach was seen in male and female rats on 800 mg/kg/day. In this limited study, the no-observed-toxic-effect doses of benzaldehyde administered by gavage were 400 mg/kg/day in male and female rats, 300 mg/kg/day in male mice and 600-1200 mg/kg/day in female mice.     

Lack of carcinogenicity of L-isoleucine in F344/DuCrj rats.

The carcinogenic potential of L-isoleucine, used as a food fortifier, was examined in both sexes of F344 rats. Groups of 50 female and 50 male animals were given diet containing L-isoleucine at concentrations of 0%, 2.5% or 5.0%. No treatment-related changes in the survival rate, general condition, body weight, food consumption, urinalysis, hematology or clinical chemistry data and organ weights were noted. Detailed histopathological examination revealed no treatment-related increase in the incidences of any non-neoplastic or neoplastic lesions. The results indicate that L-isoleucine is not carcinogenic in F344 rats of either sex.     

Short-term toxicity of allyl alcohol in rats

Groups of 15 male and 15 female rats were give 0 (control), 50, 100, 200 or 800 ppm allyl alcohol in the drinking water for 15 weeks. There were no effects attributable to allyl alcohol in the results of the haematological examinations or analyses of serum. There was a dose-related reduction in the fluid intake at all treatment levels in both sexes, while growth and food consumption were reduced in both sexes given 800 ppm and in males give 200 ppm. Males given 100 ppm or above and females given 200 or 800 ppm produced less urine than the controls in a period without water or following a water load. The only changes in organ weight that could be attributed to treatment were increased values for the relative weights of liver, spleen and kidney. All 3 organs were affected in both sexes given 800 ppm and the kidneys were also affected in both sexes given 200 ppm and in females given 100 ppm. No effects attributable to allyl alcohol treatment were seen at autopsy or in the histopathological examination. The no-untoward-effect level established in this study was 50 ppm of the drinking water, a level equivalent to an intake in rats of between 4.8 and 6.2 mg allyl alcohol/kg/day.     

One-year chronic toxicity study of Aloe arborescens Miller var. natalensis Berger in Wistar Hannover rats. A pilot study.

This study was conducted to evaluate the chronic toxicity of Aloe arborescens Miller var. natalensis Berger (ALOE) in the diet at doses of 4.0%, 0.8% or 0.16% to groups of male and female Wistar Hannover rats. No deaths occurred at any dose level throughout the treatment period. Both sexes receiving 4.0% showed diarrhea, with a reduced body weight gain. Increase of WBCs in the male 4.0% group, decrease of Hb in the female 4.0% and 0.8% groups, decrease of IP in the male 4.0% and 0.8% groups and female 4.0% group, and decrease of Ca and ALT in the female 4.0% group were observed. Relative kidney weight showed increase in the female 4.0% group and relative heart and brain weights were decreased in the female 4.0% and 0.8% groups. Histopathologically, both sexes receiving 4.0% showed severe sinus dilatation of ileocecal lymph nodes, and yellowish pigmentation of ileocecal lymph nodes and renal tubules. In conclusion, the no observed adverse effect level (NOAEL) for ALOE was the 0.16% in diet, which is equivalent to 87.7 and 109.7 mg/kg/day in males and females, respectively.     

Single dose oral toxicity study of BMY-28100 in juvenile rats and dogs

In order to investigate the single dose oral toxicity of BMY-28100 in juvenile animals, the drug was administered in single doses to 4-day-old and 14-day-old Crj: CD (SD) rats of both sexes at a dose of 2,000 mg/kg, and to 4-week-old beagle dogs of both sexes at doses of 500, 1,000 and 2,000 mg/kg by oral route. The results obtained are summarized as follows: 1. In rats, decreases of the body weight gain were observed for male and female rats treated with the drug on postnatal day 4 through 5 days and 3 days after dosing, respectively. There were no apparent drug-related toxic signs. No deaths occurred during the observation period. Enlargement of the cecum was found in a few rats of both sexes administered the drug on postnatal day 4 or 14. 2. In dogs, watery-mucous diarrhea observed at 2 to 3 hours after dosing in all dose groups was not dose-related. This finding lasted in some dogs till 4 days after dosing. An increased incidence of emesis was induced in all males at 2,000 mg/kg and all females of all dose groups except one female at 2,000 mg/kg. Body weights increased normally for all dogs, but one male at 1,000 mg/kg showed a transient decrease in food consumption. No drug-related histopathological changes were found. Based upon these results, BMY-28100 at 2,000 mg/kg induced no apparent toxic changes in the present experimental conditions. Therefore, the single dose oral toxicity of the drug in juvenile animals appeared to be very slight and generally similar to that in adults.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatic effects of R-goitrin in sprague-dawley rats

In male and female rats, R-goitrin treatment increased the relative liver weights; in some of the enlarged livers a high incidence of mitotic figures was observed. R-goitrin treatment increased the relative thyroid weight, more in male rats than in females. The thyroids of R-goitrin treated rats were either hyperplastic or had most follicles filled with pale-staining colloid and rarely follicles with normal, well-stained colloid. At certain doses, R-goitrin increased serum triglycerides, cholesterol, total protein, albumin and calcium, but it decreased serum thyroxine and urea. However, most of these changes in serum chemistry were small. R-goitrin caused a temporary increase in urinary ascorbic acid output in both sexes, but the liver ascorbic acid level was increased only in female rats. The duration of pentobarbital-induced sleep was significantly prolonged by R-goitrin pretreatment only in male rats.     

Thirteen-week inhalation toxicity of N,N-dimethylformamide in F344/N rats and B6C3F1 mice.

Male and female F-344 rats and B6C3F1 mice (10/sex/group) were exposed to N,N-dimethylformamide (DMF) by whole body inhalation exposure at 0, 50, 100, 200, 400, or 800 ppm, 6 h/day, 5 days/week, for 13 weeks. A concentration-dependent depression in body weight occurred in rats of both sexes at 400 (6-11%) and 800 ppm (20-22%). In contrast, all weight changes in both sexes of mice were within 10% of controls. No rats died, while 5 mice died from nonexposure-related causes. Relative liver weights were significantly increased at all DMF concentrations in both sexes and both species. Activities of serum sorbitol dehydrogenase (SDH) were statistically increased in male and female rats (200 to 800 ppm) on study days 4, 24, and 91 (13 weeks). Activities of alanine aminotransferase (ALT) and isocitrate dehydrogenase (ICD) were statistically increased in both sexes of rats exposed to 800 ppm DMF at all time points. Cholesterol (CHOL) levels were statistically increased in male and female rats (50-800 ppm) at all sampling time points. Levels of total bile acids (TBA) were statistically increased in both sexes of rats (400-800 ppm) on days 24 and 91. Centrilobular hepatocellular necrosis (minimal to moderate) was seen in rats of both sexes exposed at 400 and 800 ppm, with the lesions more severe in females. Centrilobular hepatocellular hypertrophy (minimal to mild) was found in all groups of DMF-exposed male mice, and in female mice exposed at 100-800 ppm. For male and female rats the no-observed-adverse-effect concentration (NOAEC) for microscopic liver injury was 200 ppm. The NOAEC was 50 ppm for female mice, but an NOAEC based upon the absence of microscopic liver injury was not determined in male mice.     

Chronic toxicity and oncogenic dose-response effects of lifetime oral acrylonitrile exposure to Fischer 344 rats

Acrylonitrile (AN) was administered in the drinking water for approximately 2 years to groups of 100 male and 100 female Fischer 344 rats at nominal concentrations of 1, 3, 10, 30, and 100 ppm. Two groups, each of 100 males and 100 females, were used as untreated controls. Average daily intake was 0.1, 0.3, 0.8, 2.5 or 8.4 mg AN per kg body weight per day, respectively, for treated male rats and 0.1, 0.4, 1.3, 3.7, or 10.9 mg AN per kg per body weight per day, respectively, for dosed females. Clinical biochemistry, interim necropsies, organ weights and microscopic evaluation of tissues and organs were performed on groups of ten rats per sex per group at months 6, 12, and 18 and at study termination. Females were sacrificed in the 24th month and males were terminated after 26 months of dosing. A consistent decrease in survival, lower body weight and reduced water intake, as well as small reductions in hematological parameters, were observed in both sexes of the 100 ppm group. Elevated numbers of early deaths were observed in groups of males receiving 10 ppm AN and females receiving 30 ppm AN. Organ:body weight ratios at various study intervals were consistently elevated in the high dose group and likely were related to lower body weights. At these same intervals, mean absolute weights were either comparable to controls or only slightly elevated and few changes in weight ratios were seen when organ weights were compared with brain weights. No biochemical changes suggested a treatment-related effect. An increase in urine specific gravity in 100 ppm male rats was reflective of a decrease in liquid intake at this level. The only significant non-neoplastic finding observed histologically was a dose-related increase in hyperplasia/hyperkeratosis in squamous cells of the forestomach in male and female rats given 3 ppm and higher AN. This observation correlated with the induction of treatment-related squamous cell tumors (papillomas and carcinomas) of the forestomach seen primarily in rats at 3 ppm AN and higher. Mammary gland carcinomas were observed only in female groups. Both sexes given 10 ppm AN or more in their drinking water for their lifetime had astrocytomas of the brain/spinal cord and adenomas/carcinomas of the Zymbal's gland.     

Toxicological evaluation of New Zealand deer velvet powder. Part I: acute and subchronic oral toxicity studies in rats.

Potential toxic effects of acute and subchronic dosage regimens of deer velvet powder have been assessed in rats following OECD guidelines. In the acute study, rats of both sexes were exposed to a single dose of 2 g/kg body weight. There was no mortality or other signs of toxicity during 14 days' observation. Furthermore, no significant alteration either in relative organ weights or their histology was discernible at terminal autopsy. In the 90-day subchronic study, deer velvet was administered in 1 g/kg daily doses by gavage to rats. A control group of rats received water only. There was no effect on body weight, food consumption, clinical signs, haematology and most parameters of blood chemistry including carbohydrate metabolism, liver and kidney function. No significant differences were seen between the mean organ weights of the adrenal, kidney and brain in rats treated with deer velvet and control rats. However, there was a significant difference (P<0.05) in the group mean relative liver weight (3.52 +/- 0.30 vs 3.81 +/- 0.26 g/100 g body weight) of deer velvet-treated and control male rats. The gross necropsy and pathological examination of rats treated with deer velvet did not reveal any abnormalities in tissue morphology. Based on these results, it may be concluded that rats had no deer velvet treatment-related toxicological and histopathological abnormalities at the doses administered, despite the observed minor changes in liver weight.     

Toxic responses to acute, subchronic, and chronic oral administrations of monochlorobenzene to rodents

Acute (single exposure), 14-d repeated exposure, 91-d subchronic, and 103-wk chronic toxicity studies of orally administered (gavage, in corn oil) monochlorobenzene were conducted in male and female Fischer-344 rats and B6C3F1 hybrid mice. A single exposure to 4000 mg/kg was lethal to male and female rats, while a single exposure to a dose as low as 1000 mg/kg was lethal to mice. Fourteen daily exposures to 1000 mg/kg caused death in rats of both sexes, but neither survival nor clinical health were compromised at 500 mg/kg in rats or mice. In the 91-d studies, wherein monochlorobenzene was administered once daily, 5 d/wk, survival was reduced by doses of 500 mg/kg and higher in rats, and by doses of 250 mg/kg and higher in mice. Dose-dependent necrosis of the liver (hepatocytes), degeneration or focal necrosis of the renal proximal tubules, and lymphoid or myeloid depletion of the spleen, bone marrow, and thymus (mild to severe) were produced by doses of 250 mg/kg or greater of monochlorobenzene in both sexes of rats and mice, although the incidences of these lesions varied considerably by sex and species. Consistent changes in the circulating blood components were not observed, but a mild porphyrinuria was detected at the higher doses. No toxic effects were observed at doses of 125 mg/kg or less. In the 2-yr studies, wherein monochlorobenzene was administered once daily, 5 d/wk, doses of 30 or 60 mg/kg in male mice and 60 or 120 mg/kg in female mice and male and female rats did not produce any evidence of toxicity. Doses of 60 or 120 mg/kg caused slight (statistically significant at 120 mg/kg; p less than 0.05) increases in the frequencies of male rats with neoplastic nodules of the liver. Increased tumor frequencies were not observed in female rats or in male or female mice receiving monochlorobenzene.