Spontaneous Neoplasms in Control Wistar Rats: A Comparison of Reviews

Spontaneous neoplasms in 930 control Wistar rats from five carcinogenicitybioassays conducted between 1990 and 1995 were reviewed andcompared with review findings in studies between 1980 and 1990.Mean survival at 104 weeks was 55% for males and 60% for females,similar to that of the previous review. A total of 1599 neoplasmswas diagnosed in 361 (78%) male and 415 (89%) female rats; 1293(81%) of these were benign and 306 (19%) were malignant (11%with metastases). Sixty-eight percent of all neoplasms werein endocrine and integumentary systems, similar to 74% seenin the previous review. Most common neoplasms (affecting >7%of either sex) were pituitary adenoma (34% of males, 50% offemales), benign adrenal pheochromocytoma (10% of males, 1%of females), thyroid C cell adenoma (6% of males, 8% of females),mammary fibroadenoma (3% of males, 36% of females), keratoacanthoma(11% of males, 0.6% of females), testicular interstitial celltumor (11% of males), uterine stromal polyp (16% of females),pancreatic acinar cell adenoma (13% of males, 0.6% of females),and benign thymoma (3% of males, 8% of females). Seventeen neoplasmsaffecting 2 to 6.9% of either sex included adrenal corticaladenoma, thyroid follicular adenoma, pancreatic islet cell adenoma,pituitary carcinoma, mammary adenoma, mammary adenocarcinoma,fibroma, fibrosarcoma, dermal papilloma, uterine schwannoma,uterine granular cell tumor, pancreatic acinar cell carcinoma,hepatocellular adenoma, lymphoma, granular cell meningioma,renal mesenchymal tumor, and hemangiosarcoma. Remaining neoplasmsoccurred in fewer than 2% of animals. Mean tumor incidence didnot differ significantly between our two reviews. Ratios ofbenign to malignant neoplasms were similar in both reviews andpercentages of survival at 104 weeks were similar. Between thetwo reviews, greater than threefold increase in frequency ofsome neoplasms occurred only in males and included keratoacanthomas,pancreatic acinar cell adenomas/carcinomas, and astrocytomas.Frequencies of remaining neoplasms were within twofold or within10% of previous frequencies. Some neoplasms diagnosed in thisreview but not in the previous review included cardiac schwannoma,pilomatrixoma, parathyroid adenoma, and prostatic adenoma butincidence was approximately 1% any one tumor. Based on thesereviews, Wistar rats appear to have a predilection to pituitaryneoplasms and mammary fibroadenomas (females).     

Spontaneous neoplasms in aged sprague-dawley rats

Incidence of neoplastic lesions in untreated Sprague-Dawley rats (1340 males and 1329 females) used as controls in 17 carcinogenicity studies are tabulated and evaluated. In male rats, the most common neoplasms were benign pheochromocytomas and keratoacanthomas (4.0% in each case) followed by pancreatic islet cell adenomas (3.7%), thyroid parafollicular cell adenomas (3.6%), fibromas and squamous cell papillomas of the skin and hepatocellular adenomas (2.0% in each), malignant lymphoma lymphocytic (1.9%), histiocytic sarcomas (1.4%), and adrenal cortical adenomas (1.2%). In female rats, the most common neoplasms were of mammary gland origin (31.3%: fibroadenoma 19.0%, adenocarcinomas 8.8%, and adenomas 3.5%) followed by thyroid parafollicular cell adenomas (2.9%), uterine endometrial stromal polyps (2.6%), adrenal cortical adenomas (1.9%), malignant lymphoma lymphocytic (1.6%), fibromas in the skin (1.3%), and pancreatic islet cell adenoma (1.1%). Metastases were observed from pheochromocytomas, hepatocellular carcinomas, nephroblastomas, renal pelvis transitional cell carcinoma, interstitial cell tumor and seminoma of the testes, Zymbal's gland adenocarcinomas, and mammary adenocarcinomas.     

Spontaneous tumors in F344/DuCrj rats from 12 control groups of chronic and oncogenicity studies

The types and incidences of spontaneous tumors in F344/DuCrj rats were examined in 960 males and 959 females served as the control groups of separate twelve 2-year chronic and oncogenicity studies carried out during a 1978-1983 period. The major tumors occurred at more than 5% incidence were leukemia (mononuclear cell), testicular interstitial cell tumor, preputial gland adenoma, pituitary anterior adenoma, thyroid C-cell adenoma, adrenal pheochromocytoma and subcutis fibroma for males, and leukemia, uterine endometrial polyp, pituitary anterior adenoma, thyroid C-cell adenoma and mammary gland adenoma/fibroadenoma in females. Analyses on age-related occurrence of tumors revealed that the incidences of most of the major tumors in males attained already to the plateau between 85 and 97 weeks of age while those in females showed a steep rise during the last interval of observation, 98 to 110 weeks of age. An intralaboratory heterogeneity in incidence was observed in the thyroid C-cell adenoma and the adrenal pheochromocytoma for males, and the anterior pituitary adenoma for females.     

The stability of historical control data for common neoplasms in laboratory rats: adrenal gland (medulla), mammary gland, liver, endocrine pancreas, and pituitary gland

Time-related changes in the incidences of spontaneous neoplasms in adrenals (medulla), mamma, liver, pituitary, and (endocrine) pancreas were assessed statistically in Wistar, Sprague-Dawley, and F344 rats employed by BASF, Germany and major European contract research organizations over the last 20 years. Negative trends (7 of 80 cases) were observed for pituitary pars distalis adenomas in Sprague-Dawley males and females, for pancreas islet cell adenomas in BASF Wistar males and females, for benign adrenal pheochromocytomas in Sprague-Dawley males, for malignant pheochromocytomas in F344 males, and for mammary gland fibroadenomas in BASF Wistar females. Positive trends (13 of 80 cases) were observed for benign pheochromocytomas, mammary gland adenocarcinomas, and pancreas islet cell carcinomas in HanWistar females, for malignant pheochromocytomas and islet cell carcinomas in BASF Wistar males, for benign pheochromocytomas and islet cell adenomas in F344 males, for mammary gland fibroadenomas in Sprague-Dawley females, and for benign hepatocellular tumors in HanWistar males and females, and in BASF Wistar and Sprague-Dawley females. In 60 of 80 cases there were no statistically significant trends. These results indicate that the majority of tumor types showed no time trends and that, in each rat strain, certain tumor types are susceptible to slight positive or negative time trends. Accordingly, the validity and use of historical control data should be based on an organ- and strain-specific statistical analysis of tumor incidence over time.     

Chronic Feeding Study of Pyrilamine in Fischer 344 Rats

The antihistamine, pyrilamine maleate, was fed for up to 2 yearsto groups of 57 Fischer 344 (F344) rats of each sex at dietarylevels of 0, 300,1500, or 3000 ppm (free base). Eight or nineof these rats per sex and dose group were killed at 65 weeksto analyze hematology and clinical chemistry in all groups andhistopathology of control and high-dose animals. Histopathologyalso was performed on all dead or moribund rats and on all thatsurvived for 2 years. Average daily exposures were 11 to 150mg/kg pyrilamine compared to human dosages up to 3 mg/kg. Pyrilaminetreatment did not reduce survival. Final body weights were reducedrelative to controls (mid-dose males, 93%, females, 82%: high-dosemales, 82%, females, 70%). The incidences of inflammation ofthe nasolacrimal duct (chronic in females; suppurative in males),liver cytoplasmic vacuolization (males), and the combinationof animals with either liver basophilic or clear cell foci (males)tended to significantly increase with dose. Adrenal pheochromocytomas,mammary gland fibroadenomas, and neoplasms of the clitoral gland,thyroid ccell, and pituitary gland all tended to decrease withincreasing dose in females. In males only preputial gland neoplasmsexhibited a similar negative trend. While two ovarian granulosathecacell benign tumors occurred in high-dose females, these werethought to be a random occurrence. There was no evidence forthe carcinogenicity of pyrilamine in F344 rats in the currentstudy.     

Toxicology and carcinogenesis studies of o-nitrotoluene sulfone (CAS no. 88-72-2) in F344/N rats and B6C3F(1) mice (feed studies)

[structure: see text] o-Nitrotoluene is used to synthesize agricultural and rubber chemicals, azo and sulfur dyes, and dyes for cotton, wool, silk, leather, and paper. o-Nitrotoluene was nominated for study by NIOSH and the NTP based on its considerable human exposure as well as the absence of long-term studies of carcinogenicity in rodents. Male and female F344/N rats and B6C3F1 mice were exposed to o-nitrotoluene (greater than 99% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 2-YEAR STUDY IN RATS: In the core study, groups of 60 male and 60 female rats were fed diets containing 625, 1,250, or 2,000 ppm o-nitrotoluene (equivalent to average daily doses of approximately 25, 50, or 90 mg o-nitrotoluene/kg body weight to males and 30, 60, or 100 mg/kg to females) for 105 weeks. In a 3-month stop-exposure study, groups of 70 male rats were fed diets containing 2,000 or 5,000 ppm o-nitrotoluene (equivalent to average daily doses of approximately 125 or 315 mg/kg) for 13 weeks followed by undosed feed for the remainder of the study. A group of 70 male rats receiving undosed feed served as a control group for both male rat studies; 60 female rats receiving undosed feed were the control group for the female core study. Ten control males and 10 males from each stop-exposure group were sacrificed at 3 months. Survival, Body Weights, and Feed Consumption: All 2,000 ppm core study, all 5,000 ppm stop-exposure, and all but three core study 1,250 ppm male rats died before the end of the studies. Survival of 625 ppm core study and 2,000 ppm stop-exposure males and of 2,000 ppm females was significantly less than that of the controls. Mean body weights of all exposed groups of males except the 625 ppm group were generally less than those of the controls throughout the study. Mean body weights of 2,000 ppm females were less than those of the controls during year 2 of the study. Feed consumption by exposed groups of rats was similar to that by the controls. Biomarkers of Exposure: Three urinary metabolites were followed during the study as biomarkers of exposure. The ratios of o-nitrobenzoic acid to creatinine and of o-nitrobenzylmercapturic acid to creatinine determined at 2 weeks and at 3, 12, and 18 months were linearly related to exposure concentration in males and females. The ratio of o-aminobenzoic acid to creatinine was not related to exposure concentration. Pathology Findings: The incidences of malignant mesothelioma in male rats occurred with positive trends in both the core and stop-exposure studies and were significantly greater in exposed groups than in the controls. Incidences of subcutaneous skin neoplasms (fibroma, fibrosarcoma, and lipoma) were increased in exposed groups of males, while the incidences of fibroma or fibrosarcoma (combined) were increased in exposed females. In all exposed groups of males and females except 2,000 ppm core study males, the incidences of mammary gland fibroadenoma were significantly increased. The incidences of mammary gland hyperplasia were significantly increased in 625 and 1,250 ppm females. Increased incidences of mesothelioma, skin neoplasms, and mammary gland fibroadenoma in the stop-exposure males indicated that 3 months of dosing were sufficient to produce a carcinogenic effect. Liver weights of 5,000 ppm stop-exposure males were significantly greater than those of the controls at 3 months. The incidences of hepatocellular adenoma in 2,000 ppm core study males and females and of hepatocellular adenoma or carcinoma (combined) in 2,000 ppm core study and 5,000 ppm stop-exposure males were significantly increased. Cholangiocarcinoma occurred in three 5,000 ppm stop-exposure males, and a single hepatocholangiocarcinoma occurred in a 625 ppm male and in a 2,000 ppm core study male. Nonneoplastic lesions of the liver included eosinophilic, mixed cell, and clear cell foci in exposed groups of males and females and mixed cell infiltrate in exposed males and basophilic focus in exposed females. The incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in 5,000 ppm stop-exposure males, as were alveolar/bronchiolar hyperplasia in most exposed groups of males and females. The incidences of hematopoietic cell proliferation of the spleen and of hyperplasia of the mandibular lymph node (females) and bone marrow were increased in exposed groups of males at 3 months and/or 2 years and in exposed groups of females at 2 years. The incidences of mononuclear cell leukemia were significantly decreased in all groups of males exposed to 1,250 ppm or greater and in all exposed groups of females; the incidence of testicular interstitial cell adenoma was significantly decreased in 5,000 ppm stop-exposure males. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were fed diets containing 0, 1,250, 2,500, or 5,000 ppm o-nitrotoluene (equivalent to average daily doses of approximately 165, 360, or 700 mg/kg to males and 150, 320, or 710 mg/kg to females) for 105 weeks. Survival, Body Weights, and Feed Consumption: All 2,500 and 5,000 ppm males died before the end of the study. Survival of 1,250 ppm males and 5,000 ppm females was significantly less than that of the controls. Mean body weights of exposed males and 5,000 ppm females were generally less than those of the controls throughout the study, and those of 2,500 ppm females were less during the second year of the study. Feed consumption by 5,000 ppm males was less than that by the controls. Biomarkers of Exposure: Three urinary metabolites were followed during the study as biomarkers of exposure. The ratios of o-nitrobenzoic acid to creatinine determined at 2 weeks and at 3, 12, and 18 months were linearly related to exposure concentration in males and females. The concentrations of o-nitrobenzylmercapturic acid and o-aminobenzoic acid were below the limit of quantitation at most time points. Pathology Findings: The incidences of hemangiosarcoma in all exposed groups of males and in 5,000 ppm females were significantly greater than those in the controls. Large intestine (cecum) carcinomas were observed in all exposed groups except 5,000 ppm males. The incidences of hepatocellular neoplasms were significantly increased in 2,500 and 5,000 ppm females. Nonneoplastic liver lesions including eosinophilic and basophilic foci and minimal to mild necrosis were enhanced in exposed males and females. Also present were focal hepatocyte syncytial alteration in exposed males and hepatocyte necrosis and focal hepatocyte cytoplasmic vacuolization in 5,000 ppm females. Renal tubule pigmentation occurred more frequently in exposed groups of males and in 5,000 ppm females than in the controls. Olfactory epithelial degeneration occurred in every male and female mouse exposed to 2,500 or 5,000 ppm, and the severity of this lesion increased with increasing exposure concentration. GENETIC TOXICOLOGY: o-Nitrotoluene was not mutagenic in any of several strains of S. typhimurium, with or without metabolic activation enzymes (S9). Sister chromatid exchanges were significantly increased in cultured Chinese hamster ovary cells following exposure to o-nitrotoluene in the presence of S9; an equivocal response was seen without S9. o-Nitrotoluene did not induce chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. o-Nitrotoluene did not induce a significant increase in the frequency of micronuclei in bone marrow polychromatic erythrocytes of male rats or male mice when administered by intraperitoneal injection. Results of a peripheral blood micronucleus test were equivocal for male mice and negative for female mice administered o-nitrotoluene in feed for 13 weeks. CONCLUSIONS: Under the conditions of these studies, there was clear evidence of carcinogenic activity* of o-nitrotoluene in male rats based on increased incidences of malignant mesothelioma, subcutaneous skin neoplasms, mammary gland fibroadenoma, and liver neoplasms. The increased incidences of lung neoplasms in male rats were also considered to be exposure related. There was clear evidence of carcinogenic activity of o-nitrotoluene in female rats based on increased incidences of subcutaneous skin neoplasms and mammary gland fibroadenoma. The increased incidence of hepatocellular adenoma in female rats was also considered to be exposure related. There was clear evidence of carcinogenic activity of -o-nitrotoluene in male and female mice based on increased incidences of hemangiosarcoma, carcinoma of the large intestine (cecum), and hepatocellular neoplasms (females only). Exposure to o--nitrotoluene caused increased incidences of nonneoplastic lesions of the mammary gland (females only), liver, bone marrow, spleen, lung, and mandibular lymph node (females only) in male and female rats and of the liver, kidney, and nose in male and female mice. Decreased incidences of mononuclear cell leukemia occurred in exposed groups of rats; the incidence of testicular interstitial cell adenoma was decreased in exposed male rats. [tables: see text]     

Spontaneous tumors in F-344/Jcl rats

The age-related incidence of spontaneously occurring neoplastic and non-neoplastic lesions in untreated F-344/Jcl rats, used as controls in carcinogenicity testing, were studied from the histological examination of tissues from 469 males and 354 females. The incidence of spontaneous tumors was 83.2% in the males and 71.2% in the females. The most common neoplasms were leukemia (males: 24.3%, females: 24.0%), pituitary adenoma (males: 16.0%, females: 45.2%), pheochromocytoma (males: 14.7%, females: 7.3%), testicular interstitial cell tumor (males: 79.1%), and uterine endometrial stromal polyp(females: 16.4%). The incidence of other tumors of almost all the organs and/or tissues was low. Non-neoplastic lesions generally increased with advancing age of the animals.     

Neoplastic and nonneoplastic lesions in aging osborne-mendel rats

Neoplastic and nonneoplastic lesions in 975 male and 970 female Osborne-Mendel rats used as controls in carcinogenesis tests were tabulated and evaluated. Three types of controls were considered—untreated controls (245 males, 245 females), controls administered corn oil in feed (530 males, 525 females), and controls administered corn oil by gavage (200 males, 200 females). Few neoplasms were seen in rats less than 18 months of age; the incidence of tumors markedly increased between 18 and 24 months of age. The incidence of some of the more common neoplasms, in which the combined incidence was greater than 1%, varied among the control groups, and in most cases the differences in incidences were not statistically significant. Hemangiosarcomas at all sites and C-cell adenomas of the thyroid in female rats were marginally significantly lower in controls given corn oil by gavage than in the other two groups. The occurrence of adenocarcinomas of the mammary gland was significantly higher in male controls given corn oil by gavage than in the other two groups. In untreated controls, the incidences of adrenal cortical adenomas in males and females and of pheochromocytomas in males were significantly higher than in both groups given corn oil. In rats administered corn oil in the feed, the incidences of pituitary adenomas in males and females, follicular cell adenomas of the thyroid in males, and endometrial stromal polyps in females were significantly higher than the incidences in the other two groups. The possible reasons for these differences are discussed. However, the types of tumors seen in the three control groups were morphologically comparable. The tumors observed included two types that had not previously been well characterized in Osborne-Mendel rats—malignant fibrous histiocytomas and lipomatous tumors of the kidney. Incidences of the more common nonneoplastic lesions are reported.     

Toxicology and carcinogenesis studies of androstenedione (CAS No. 63-05-8) in F344/N rats and B6C3F1 mice (gavage studies)

Androstenedione is an androgen steroid that is normally synthesized within men and women and may be metabolized to a more potent androgen or estrogen hormone. It was nominated to the National Toxicology Program for study due to concern for adverse health effects associated with its chronic use as a dietary supplement by athletes (prior to the banning of its over the counter sales). In order to evaluate its subchronic and chronic toxicity, male and female F344/N rats and B6C3F1 mice were administered androstenedione (98% pure) by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, rat bone marrow cells, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: groups of five male and five female rats were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 12 days. All rats survived to the end of the study, and the mean body weights of dosed groups were similar to those of the vehicle control groups. The development of cytoplasmic vacuoles within centrilobular hepatocytes in male rats was the only treatment-related effect observed. 2-WEEK STUDY IN MICE: groups of five male and five female mice were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 12 days. One vehicle control female, one 20 mg/kg female, and one 50 mg/kg female died early due to gavage accidents. There were no significant chemical-related histopathological or mean body weight changes. 3-MONTH STUDY IN RATS: groups of 10 male and 10 female core study rats were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 14 weeks; additional groups of 10 male and 10 female clinical pathology study rats received the same doses for 23 days. All rats survived to the end of the study. The mean body weights of the 20 mg/kg female group was significantly greater than those of the vehicle control group and there was significant increased weight gain in the 1, 20, and 50 mg/kg female groups. Female thymus weights were significantly increased in the 20 and 50 mg/kg groups, which may be related to the increase in mean body weight. The numbers of sperm per mg cauda epididymis in the 10, 20, and 50 mg/kg male groups and the total number of sperm per cauda epididymis in 50 mg/kg males were significantly less than those of the vehicle controls. No treatment-related histological lesions were observed in males or females. 3-MONTH STUDY IN MICE: groups of 10 male and 10 female mice were administered 0, 1, 5, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for 14 weeks. Except for one 10 mg/kg female that died early due to a dosing accident, all mice survived to the end of the study. The mean body weights of dosed groups were similar to those of the vehicle control groups. The number of spermatids per mg testis and the total number of spermatids per testis in 20 mg/kg males were significantly greater than those of the vehicle controls. Sperm motility in 50 mg/kg males was significantly lower than that in the vehicle controls. The incidences of x-zone atrophy of the adrenal cortex, an androgen-sensitive endpoint, were significantly increased in females administered 5 mg/kg or greater. There were also significant decreases in the incidences of x-zone cytoplasmic vacuolization in 20 and 50 mg/kg females. The incidences of bone marrow hyperplasia were significantly increased in 5 and 50 mg/kg males. 2-YEAR STUDY IN RATS: groups of 50 male and 50 female rats were administered 0, 10, 20, or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for at least 104 weeks. Survival of 10 mg/kg males was significantly greater than that of the vehicle controls. The mean body weights of 20 and 50 mg/kg females were greater than those of the vehicle controls after weeks 17 and 9, respectively. The incidences of mononuclear cell leukemia were significantly increased in 20 and 50 mg/kg females and significantly decreased in 20 and 50 mg/kg males. Incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in 20 mg/kg males. The incidence of testicular interstitial cell adenoma (including bilateral) was significantly decreased in 50 mg/kg males. In females, the incidences of mammary gland fibroadenoma were significantly decreased in the 20 and 50 mg/kg groups, the incidences of mammary gland hyperplasia were significantly decreased in all dosed groups, and the incidences of mammary gland cyst were significantly decreased in the 10 and 50 mg/kg groups. In the liver of males, the incidences of basophilic focus in all dosed groups, the incidence of clear cell focus in the 20 mg/kg group, and the incidence of eosinophilic focus in the 50 mg/kg group were significantly increased. The incidences of pancreatic islet hyperplasia and atrophy of the exocrine pancreas were significantly increased in 50 mg/kg females. 2-YEAR STUDY IN MICE: groups of 50 male and 50 female mice were administered 0, 2 (females only), 10, 20 (males only), or 50 mg androstenedione/kg body weight in a 0.5% aqueous methylcellulose solution by gavage, 5 days per week for at least 104 weeks. Survival of dosed groups was similar to that of the vehicle control groups. Mean body weights of 10 and 50 mg/kg females were generally less than those of the vehicle controls after weeks 81 and 17, respectively. The incidences of hepatocellular adenoma in males and females were significantly increased in the 50 mg/kg groups. In females, the incidences of hepatocellular carcinoma were significantly increased in all dosed groups. Incidences of hepatocellular adenoma or carcinoma (combined) in males and females were significantly increased in the 50 mg/kg groups. Incidences of hepatoblastoma were marginally increased in dosed males. Incidences of multiple hepatocellular adenomas and carcinomas were significantly increased in 10 and 50 mg/kg males, and there was an increased incidence of multiple hepatocellular adenomas in 50 mg/kg females. The incidence of eosinophilic focus was significantly increased in 50 mg/kg males, and the incidences of mixed cell focus and cytoplasmic vacuolization were significantly increased in 50 mg/kg females. There was a marginally increased incidence of pancreatic islet adenoma in 50 mg/kg males and in 10 and 50 mg/kg females, with an earlier day of first incidence in males. The incidences of clitoral gland hyperplasia and clitoral gland duct dilatation were significantly increased in 10 and 50 mg/kg females. The incidence of glomerular metaplasia of the kidney was significantly increased in 50 mg/kg females, and the incidences of cytoplasmic alteration of the submandibular salivary gland were significantly increased in all dosed female groups. The increased incidences of cytoplasmic alteration of the submandibular salivary gland and glomerular metaplasia of the kidney in female mice indicated a masculinizing effect from androstenedione treatment. In 50 mg/kg females, the incidence of malignant lymphoma was significantly decreased. GENETIC TOXICOLOGY: androstenedione was not mutagenic in either of two independent bacterial mutation assays conducted with and without exogenous metabolic activation. No significant increases in the frequencies of micronucleated polychromatic erythrocytes, indicators of chromosomal damage, were observed in bone marrow of male rats administered androstenedione by gavage once daily for 3 consecutive days. Results of a peripheral blood erythrocyte micronucleus test in mice, in which androstenedione was administered by gavage for 3 months, were negative in males but judged to be equivocal in females due to a small increase (twofold over background) in micronucleated normochromatic erythrocytes observed at the highest dose administered (50 mg/kg). CONCLUSIONS: under the conditions of these 2-year gavage studies, there was equivocal evidence of carcinogenic activity of androstenedione in male F344/N rats based on increased incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined). There was equivocal evidence of carcinogenic activity of androstenedione in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of androstenedione in male B6C3F1 mice based on increased incidences of multiple hepatocellular adenoma and hepatocellular carcinoma and increased incidence of hepatoblastoma. There was clear evidence of carcinogenic activity of androstenedione in female B6C3F1 mice based on increased incidences of hepatocellular adenoma and hepatocellular carcinoma. Increased incidences of pancreatic islet adenoma in male and female mice were also considered chemical related. Androstenedione administration caused increased incidences in nonneoplastic lesions of the liver in male and female rats and mice; pancreatic islets and exocrine pancreas of female rats; and clitoral gland, kidney, and submandibular salivary gland of female mice. Decreases in the incidences of testicular interstitial cell adenoma in male rats, mammary gland fibroadenoma, cysts, and hyperplasia in female rats, and malignant lymphoma in female mice were considered related to androstenedione administration. Synonyms: Andro; androst-4-ene-3,17-dione; 4-androstene-3,17-dione; delta-4-androstene-3,17-dione; delta-4-androstenedione; 3,17-dioxoandrost-4-ene; 17-ketotestosterone; SKF 2170 Trade names: Androtex, Fecundin.     

Toxicity and Carcinogenicity of 2,3-Dibromo-1-propanol in F344/N Rats and B6C3F1 Mice

2,3-Dibromo-1-propanol is a metabolite of the flame retardanttris(2,3-dibromopropyl) phosphate, previously shown to be amutagen and carcinogen in experimental animals. Toxicology andcarcinogenesis studies of 2,3-dibromo-1-propanol were conductedby applying the chemical in 95% ethanol to the interscapularskin of male and female F344/N rats and B6C3F₁ mice 5 days aweek for 13 weeks in the prechronic study and 48–55 weeks(rats) or 36–42 weeks (mice) in the carcinogenicity study.In the 13-week study, 10 rats and 10 mice of each sex receiveddoses of 0, 44, 88, 177, 375, or 750 mg/kg. Deaths associatedwith chemical application occurred only in the high-dose (750mg/kg) male mice. Chemical-related lesions were seen in thekidney of male rats, liver of female rats, and liver and lungof both sexes of mice. Based on the toxicity observed in the13-week study, 50 rats of each sex received doses of 0, 188,or 375 mg/kg and 50 mice of each sex received 0, 88, or 177mg/kg in the carcinogenicity study. The planned 2-year studywas terminated early because of reduced survival of rats relatedto chemical-induced neoplasia and because of the appearanceof antibodies to lymphocytic choriomeningitis virus in sentinelmice. Nearly all dosed rats had malignant neoplasms at one ormore sites, while only one control male and one control femalehad malignant neoplasms. In rats, neoplasms induced by 2,3-dibromo-1-propanoloccurred in the skin, nasal mucosa, Zymbal's gland, oral mucosa,esophagus, forestomach, intestines, liver, kidney, mammary gland(females), clitoral gland (females), spleen (males), and mesothelium(males). In mice, chemical-induced neoplasms occurred in theskin, forestomach, liver (males), and lung (males).     

Toxicology and carcinogenesis studies of methyl isobutyl ketone (Cas No. 108-10-1) in F344/N rats and B6C3F1 mice (inhalation studies)

Methyl isobutyl ketone is used as a denaturant for rubbing alcohol; as a solvent for paints, varnishes, nitrocellulose, lacquers, and protective coatings; in industrial extraction processes; in dry-cleaning preparations; and in the synthesis of methyl isobutyl carbinol. Methyl isobutyl ketone was nominated for study by the National Cancer Institute and the United States Environmental Protection Agency because of its widespread use, the high potential for worker exposure due to its many industrial applications, and its high production volume. Male and female F344/N rats and B6C3F1 mice were exposed to methyl isobutyl ketone (greater than 99% pure) by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. 2-YEAR STUDY IN RATS: Groups of 50 males and 50 females were exposed to methyl isobutyl ketone at concentrations of 0, 450, 900, or 1,800 ppm by inhalation, 6 hours plus T(90) (12 minutes) per day, 5 days per week for 104 weeks. Survival of males exposed to 1,800 ppm was significantly less than that of the chamber controls. The mean body weights of the 900 and 1,800 ppm males were less than those of the chamber controls after weeks 97 and 89, respectively. In the standard evaluation of the kidney, there were slightly increased incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) in males exposed to 900 or 1,800 ppm, and renal tubule carcinoma in males exposed to 1,800 ppm. The incidences of renal tubule hyperplasia were also significantly increased in the 450 and 1,800 ppm males, and the severities were greater than in the chamber controls. Chronic nephropathy occurred in all males exposed to 1,800 ppm and in 70% to 88% of exposed females, and the severity was increased in 1,800 ppm males. The incidences of transitional epithelial hyperplasia of the renal pelvis in males exposed to 900 or 1,800 ppm and mineralization of the renal papilla in all groups of exposed males were significantly increased. In addition, two female rats exposed to 1,800 ppm had renal mesenchymal tumors. In the extended evaluation of the kidney, renal tubule adenomas and renal tubule hyperplasia occurred in all groups of exposed male rats. In the combined single and step section analysis, the incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) were significantly increased in males exposed to 1,800 ppm. The incidences of renal tubule hyperplasia were also significantly increased in all exposed groups of males. There was a positive trend in the incidences of mononuclear cell leukemia in males, and the incidence in the 1,800 ppm group was significantly increased. The incidence of adrenal medulla hyperplasia in the 1,800 ppm males was significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 males and 50 females were exposed to methyl isobutyl ketone at concentrations of 0, 450, 900, or 1,800 ppm by inhalation, 6 hours plus T(90) (12 minutes) per day, 5 days per week for 105 weeks. Survival of males and females was similar to that of the chamber controls. The mean body weights of females exposed to 1,800 ppm were less than those of the chamber controls after week 17. The incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in males and females exposed to 1,800 ppm. The incidences of eosinophilic foci were significantly increased in 450 and 1,800 ppm females. GENETIC TOXICOLOGY: Methyl isobutyl ketone was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 when tested with and without hamster or rat liver metabolic activation enzymes. CONCLUSIONS: Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of methyl isobutyl ketone in male F344/N rats based on increased incidences of renal tubule neoplasms. Increased incidences of mononuclear cell leukemia in 1,800 ppm male F344/N rats may have been related to methyl isobutyl ketone exposure. There was equivocal evidence of carcinogenic activity of methyl isobutyl ketone in female F344/N rats based on the occurrence of renal mesenchymal tumors in the 1,800 ppm group. There was some evidence of carcinogenic activity of methyl isobutyl ketone in male and female B6C3F1 mice based on increased incidences of liver neoplasms. Exposure to methyl isobutyl ketone resulted in nonneoplastic lesions of the kidney characteristic of alpha2u-globulin accumulation in male rats and nephropathy in female rats.     

Lack of immunotoxic effects of repeated exposure to atrazine associated with the adaptation of adrenal gland activation

T cell-dependent IgM antibody production and natural killer cell (NKC) activity were assessed in SD rats orally administered atrazine for 28 days to males (0, 6.5, 25, or 100 mg/kg/day) or females (0, 3, 6, or 50 mg/kg/day), or 30 or 500 ppm in diet (3 or 51 mg/kg/day). Anti-asialo GM1 antibodies (NKC) and cyclophosphamide (antibody-forming cell assay [AFC]) served as positive controls. Pituitary (ACTH, prolactin), adrenal (corticosterone, progesterone, aldosterone), and gonadal (androgens, estrogens) hormones were assessed after 1, 7, and/or 28 days of treatment. Food intake and body weights were significantly reduced in the highest dosed males, and transiently affected in females. Urinary corticosterone levels were not increased in atrazine-treated groups in either sex at any time point measured (10, 22, or 24 days). Corticosterone and progesterone were elevated in males after a single atrazine dose ≥6.5 mg/kg/day, but not after 7, 14, or 28 doses. There were no effects on adrenal, pituitary, or gonadal hormones in females. Atrazine did not suppress the AFC response or decrease NKC function after 28 days in males or females. Atrazine had no effect on spleen weights or spleen cell numbers in males or females, although thymus weights were elevated in males receiving the highest dose. The lack of immunotoxic effect of atrazine was associated with diminished adrenal activation over time in males, and no effects on adrenal hormones in females.     

Triprolidine: 104-Week Feeding Study in Rats

The antihistamine, triprolidine hydrochloride, was fed at dietaryconcentrations of 0, 250, 1000, or 2000 ppm (as the free base)to groups of 60 Fischer 344 (F344) rats of each sex for up to2 years to evaluate its potential carcinogenicity. Up to 12per sex from each group were killed at 65 weeks, and hematology,clinical chemistry, and histopathology were evaluated. A completehistopatho-logical evaluation was performed on all other animals;survivors were killed at 2 years. Survival was significantlyextended in tri-prolidine-treated males and females, particularlyat the high dose. At the close of the study high-dose malesand females had gained significantly less body weight than controls.Among rats killed at 65 weeks females in the mid- and high-dosegroups weighed significantly less than controls, but weightsof control and dosed males were not significantly different.The incidences of numerous lesions tended to decrease with increasingtriprolidine dose. In females, clitoral gland adenomas, thyroidc-cell hyperplasia and neoplasia, mammary gland hyperplasiaand fibroadenomas, and uterine stromal polyps, and in males,anterior pituitary gland adenomas, preputial gland neoplasia,thyroid c-cell hyperplasia, pancreatic islet neoplasia, mononuclearcell leukemia, and the combination of lymphocytic, histiocytic,and undifferentiated cell malignant lymphomas and mononuclearleukemia, all exhibited negative dose trends. Cytoplasmic alterationsof the parotid gland and numerous liver lesions tended to bemore frequent in treated than in control animals. Liver lesionsthat exhibited positive dose trends include chronic inflammationand centrilobular fatty change in both sexes, mixed cell foci,and the combination of mixed cell foci and eosinophilic fociin females, and in males, basophilic foci and eosinophilic foci.Triprolidine was not carcinogenic in F344 rats.     

Toxicology and carcinogenesis studies of benzophenone (CAS No. 119-61-9) in F344/N rats and B6C3F1 mice (feed studies)

Benzophenone is used as a photoinitiator, a fragrance enhancer, an ultraviolet curing agent, and occasionally as a flavor ingredient; it is also used in the manufacture of insecticides, agricultural chemicals, and hypnotics, antihistamines, and other pharmaceuticals; and it is used as an additive in plastics, coatings, and adhesive formulations. Benzophenone was nominated for study by the National Institute of Environmental Health Sciences based on its potential for occupational and consumer exposure and the lack of long-term toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to benzophenone (greater than 99% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse bone marrow cells, and mouse peripheral blood erythrocytes. Results of 14-week toxicity studies in F344/N rats and B6C3F1 mice were reported earlier (NTP, 2000). 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 312, 625, or 1,250 ppm benzophenone (equivalent to average daily doses of approximately 15, 30, and 60 mg benzophenone/kg body weight to males and 15, 30, and 65 mg/kg to females) for 105 weeks. Survival of 1,250 ppm males was significantly less than that of controls. Mean body weights of 1,250 ppm males were markedly less than those of the controls during year 2 of the study, and weights of exposed females were consistently less than controls throughout the study. Feed consumption by 1,250 ppm males was less than that by the controls after week 70; feed consumption by 1,250 ppm females was generally less than that by the controls throughout the study. There was a positive trend in the incidences of renal tubule adenoma in males, and the incidences in 625 and 1,250 ppm males exceeded the historical control range for all routes; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Due to these findings, additional kidney sections were evaluated; results indicated additional renal tubule adenomas in all groups of males and renal tubule hyperplasia in all groups of males and females. The incidences of pelvic transitional epithelium hyperplasia and the severity of nephropathy were significantly increased in all exposed groups of male rats. Increased incidences of mononuclear cell leukemia in all exposed groups of females exceeded the historical control range from feed studies, and the incidence in 625 ppm females was significantly greater than that in the controls. Male rats exposed to 312 or 625 ppm had significantly increased incidences of mononuclear cell leukemia. One 625 ppm female and two 1,250 ppm females had histiocytic sarcomas, and the incidence in the 1,250 ppm group exceeded the range in the historical controls. Liver lesions included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of males and females, cystic degeneration in 625 and 1,250 ppm males, and bile duct hyperplasia in all exposed groups of females. Incidences of mammary gland fibroadenoma in females exposed to 625 or 1,250 ppm were lower than expected after adjusting for body weight. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 312, 625, or 1,250 ppm benzophenone (equivalent to average daily doses of approximately 40, 80, and 160 mg/kg body weight to males and 35, 70, and 150 mg/kg to females) for 105 weeks. Survival of all exposed groups of mice was generally similar to that of the control groups. Mean body weights of exposed females were less than vehicle controls. Feed consumption by exposed males and females was similar to that by the controls. In male mice, there were significantly increased incidences of hepatocellular adenoma in the 625 and 1,250 ppm groups, and these incidences exceeded the historical control range. All hepatocellular neoplasms combined occurred with a positive trend. In female mice, the incidences of hepatocellular adenoma in the 625 and 1,250 ppm groups were higher than expected after adjusting for the lower body weights in these groups. Incidences of centrilobular hepatocyte hypertrophy were significantly increased in all exposed groups of males and females. All exposed groups of male mice had significant increases in the incidences of multinucleated hepatocytes and chronic active inflammation. The incidences of cystic degeneration of hepatocytes in 625 and 1,250 ppm males were significantly increased. The incidence of histiocytic sarcoma in 625 ppm females was significantly increased and exceeded the historical control range. The incidences of kidney nephropathy and mineralization in exposed groups of females and the severity of nephropathy in exposed groups of males were significantly increased. The incidences of metaplasia of the olfactory epithelium were significantly increased in 1,250 ppm males and females. The incidences of hyperplasia of lymphoid follicles in the spleen were significantly increased in all exposed groups of males and in 312 and 625 ppm females. GENETIC TOXICOLOGY: Benzophenone was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without hamster or rat liver activation enzymes. No significant increases in the frequencies of micronucleated polychromatic erythrocytes were seen in bone marrow samples from male mice administered benzophenone three times by intraperitoneal injection. In addition, no increases in micronucleated normochromatic erythrocytes were noted in peripheral blood of male or female mice administered benzophenone for 14 weeks in dosed feed. CONCLUSIONS: Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of benzophenone in male F344/N rats based on increased incidences of renal tubule adenoma; mononuclear cell leukemia in male F344/N rats may have been related to benzophenone exposure. There was equivocal evidence of carcinogenic activity of benzophenone in female F344/N rats based on the marginally increased incidences of mononuclear cell leukemia and histiocytic sarcoma. There was some evidence of carcinogenic activity of benzophenone in male B6C3F1 mice based on increased incidences of hepatocellular neoplasms, primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in female B6C3F1 mice based on increased incidences of histiocytic sarcoma; the incidences of hepatocellular adenoma in female B6C3F1 mice may have been related to benzophenone exposure. Administration of benzophenone in feed resulted in increased incidences and/or severities of nonneoplastic lesions in the kidney and liver of male and female rats and in the liver, kidney, nose, and spleen of male and female mice. Decreased incidences of mammary gland fibroadenoma in female rats were related to benzophenone exposure.     

Toxicology and carcinogenesis studies of sodium dichromate dihydrate (Cas No. 7789-12-0) in F344/N rats and B6C3F1 mice (drinking water studies)

Sodium dichromate dihydrate is one of a number of inorganic compounds containing hexavalent chromium (Cr VI) found in drinking water source supplies as a contaminant resulting from various industrial processes including electroplating operations, leather tanning, and textile manufacturing. Because of the lack of adequate experimental data on the toxicity and carcinogenicity of hexavalent chromium ingested orally and because hexavalent chromium has been found in drinking water source supplies, the California Congressional Delegation, the California Environmental Protection Agency, and the California Department of Health Services nominated hexavalent chromium to the National Toxicology Program for study. Results of 3 month toxicity studies in F344/N rats and B6C3F1, BALB/c, and am3-C57BL/6 mice were reported earlier in NTP Toxicity Report 72. In the current study, male and female F344/N rats and B6C3F1 mice were exposed to sodium dichromate dihydrate (greater than 99.7% pure) in drinking water for 2 years. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 20, 60, or 180 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 0.6, 2.2, 6, or 17 mg sodium dichromate dihydrate/kg body weight for males and 0.7, 2.7, 7, or 20 mg/kg for females). Survival of exposed groups was similar to that of the control groups. Mean body weights of 516 mg/L males and females were less than those of the controls throughout the study. The lower body weights were partly attributed to poor palatability of the dosed water and consequent reductions in water consumption. Water consumption by 172 and 516 mg/L rats was less than that by the controls throughout the study. Exposure to sodium dichromate dihydrate caused a microcytic hypochromic anemia in rats that ameliorated with time. Exposure to sodium dichromate dihydrate resulted in the development of neoplasms of the squamous epithelium that lines the oral mucosa and tongue. The incidences of squamous cell carcinoma in the oral mucosa of 516 mg/L male and female rats were significantly greater than those in the controls. The incidence in 172 mg/L females exceeded the historical control ranges for drinking water studies and for all routes of administration. The incidences of squamous cell papilloma or squamous cell carcinoma (combined) of the oral mucosa or tongue of 516 mg/L male and female rats were significantly greater than those in the controls. Exposure concentration-related nonneoplastic liver lesions were observed in males and females exposed to 57.3 mg/L or greater. These included histiocytic cellular infiltration, chronic inflammation, fatty change (females), basophilic focus (males), and clear cell focus (females). Increased incidences of histiocytic cellular infiltration also occurred in the small intestine (duodenum), mesenteric lymph node, and pancreatic lymph node of males and/or females exposed to 57.3 mg/L or greater. 2-YEAR STUDY IN MICE: Groups of 50 male mice were exposed to drinking water containing 0, 14.3, 28.6, 85.7, or 257.4 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 10, 30, or 90 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 1.1, 2.6, 7, or 17 mg sodium dichromate dihydrate/kg body weight). Groups of 50 female mice were exposed to drinking water containing 0, 14.3, 57.3, 172, or 516 mg/L sodium dichromate dihydrate (equivalent to 0, 5, 20, 60, or 180 mg/L chromium) for 2 years (equivalent to average daily doses of approximately 1.1, 3.9, 9, or 25 mg/kg). Survival of exposed groups was similar to that of the control groups. Mean body weights of 257.4 mg/L males were less than those of controls from months 2 through 6 of the study, but by the end of the study, the mean body weight of 257.4 mg/L males was only slightly less than that of the control group. Mean body weights of 172 mg/L females were less than those of the controls from months 3 through 12 of the study, and mean body weights of 516 mg/L females were less than those of the controls from month 2 until the end of the study. By the end of the study, the mean body weight of 172 mg/L females was 8% less than that of the controls, and the mean body weight of 516 mg/L females was 15% less than that of the controls. The lower body weights were partly attributed to poor palatability of the dosed water and consequent reductions in water consumption. Water consumption by 85.7 and 257.4 mg/L males and 172 and 516 mg/L females was less than that by the controls throughout the study. A treatment-related microcytosis occurred in exposed mice; the mice were less affected than the rats. The incidences of neoplasms of the small intestine (duodenum, jejunum, or ileum) were increased in exposed groups of male and female mice. The incidences of adenoma of the duodenum in 257.4 mg/L males and 172 and 516 mg/L females were significantly greater than those in the controls. The incidence of carcinoma of the duodenum was significantly increased in 516 mg/L females. The incidence of adenoma of the jejunum in 516 mg/L females was significantly increased compared to that in the controls. When the incidences of adenoma and carcinoma were combined for all sites of the small intestine, the incidences were significantly increased in 85.7 and 257.4 mg/L males and 172 and 516 mg/L females compared to those in the controls. The incidences in 57.3 mg/L females exceeded the historical control ranges for drinking water studies and for all routes of administration. The incidences of diffuse epithelial hyperplasia were significantly increased in the duodenum of all exposed groups of male and female mice. The incidences of histiocytic cellular infiltration were significantly increased in the duodenum of 85.7 and 257.4 mg/L males and in 172 and 516 mg/L females. In the jejunum, the incidences of diffuse epithelial hyperplasia and histiocytic cellular infiltration were significantly increased in 516 mg/L females. The incidences of histiocytic cellular infiltration of the liver in all exposed groups of females, of the mesenteric lymph node in all exposed groups of males and females, and of the pancreatic lymph node of 85.7 and 257.4 mg/L males and 172 and 516 mg/L females were significantly increased. Tissue distribution studies showed that total chromium concentrations tended to increase with increasing exposure concentration and duration of exposure. CONCLUSIONS: Under the conditions of these 2-year drinking water studies, there was clear evidence of carcinogenic activity of sodium dichromate dihydrate in male and female F344/N rats based on increased incidences of squamous cell neoplasms of the oral cavity. There was clear evidence of carcinogenic activity of sodium dichromate dihydrate in male and female B6C3F1 mice based on increased incidences of neoplasms of the small intestine (duodenum, jejunum, or ileum). Exposure to sodium dichromate dihydrate resulted in histiocytic cellular infiltration in the liver, small intestine, and pancreatic and mesenteric lymph nodes of rats and mice and diffuse epithelial hyperplasia in the small intestine of male and female mice.     

Carcinogenic effects of antimony trioxide and antimony ore concentrate in rats

This study was initiated because of a suspected increase in incidence of lung cancer in antimony smelter workers in England. Three groups of 8-mo-old Wistar-derived rats (90 males and 90 females per group) were exposed by inhalation to either Sb2O3 [time-weighted average (TWA) 45 mg/m3], Sb ore concentrate (TWA 36 + 40 mg/m3), or filtered air (controls) for 7 h/d, 5 d/wk, for up to 52 wk and sacrificed 20 wk after terminating exposures. Serial sacrifices (5 rats/sex/group) were performed at 6, 9, and 12 mo. Autopsies and histopathological examinations were performed on all animals. The dusts and animal tissues were analyzed for Sb, arsenic, and other inorganic elements by atomic absorption and proton-induced X-ray emission methods. The most significant findings were the presence of lung neoplasms in 27% of females exposed to Sb2O3 and 25% of females exposed to Sb ore concentrate (p less than 0.01). None of the male rats in any group or the female controls developed lung neoplasms. There were no significant differences in incidences of cancer of other organs between exposed and control rats. These results were compared with other published results, including an animal inhalation study with Sb2O3 in which lung tumors were also induced. Higher concentrations of arsenic were found in tissues from female rats than from male rats. For example, arsenic levels in blood of control males, control females, Sb2O3 males, Sb2O3 females, Sb ore males, and Sb ore females were 60, 123, 115, 230, 71, and 165 micrograms arsenic/g dry blood, respectively, 9 mo after initiating exposures.     

Spontaneous neoplasms in aged CD-1 mice.

Spontaneous neoplasms in untreated control CD-1 mice (725 males and 725 females) used in carcinogenicity studies were evaluated and tabulated. The most common neoplasms in male mice were alveolar-bronchiolar adenomas (19.3%) followed by hepatocellular adenomas (11.0%), lymphoreticular neoplasms (6.8%), hepatocellular carcinomas (5.7%), Harderian gland adenomas (2.9%), alveolar-bronchiolar carcinomas (2.5%), and testicular interstitial cell tumors (1.9%). In the females, the most frequently occurring neoplasms were lymphoreticular neoplasms (16.4%) followed by alveolar-bronchiolar adenomas (12.3%), uterine endometrial polyps (4.3%), uterine leiomyomas (3.5%), mammary adenocarcinomas (2.5%), hepatocellular adenomas (1.8%), hemangiomas (1.7%), Harderian adenomas (1.7%), alveolar-bronchiolar carcinomas (1.5%), and pituitary adenomas (1.1%). Tumors in other various organs were found at a low incidence.     

Toxicologic and Reproductive Effects of Inhaled 1,2-Dibromo-3-chloropropane in Rats

Toxicologic and Reproductive Effects of Inhaled 1, 2-Di-bromo-3-chloropropanein Rats. Rao, K.S., Burek, J.D., Murray, F.J., John, J.A., Schwetz,B.A., Bell, T J., Potts, W.J. and Parker, CM. (1983). Fundam.Appl. Toxicol. 3:104-110. Groups of 30 male and 30 female Sprague-Dawleyrats were exposed by inhalation to 0, 0.1, 1.0 or 10 ppm of1,2-dibromo-3-chloropropane (DBCP) vapor for 6 hr/day, 5 days/weekfor 14 weeks followed by recovery periods of up to 32 weeks.The fertility of male rats was evaluated by mating trials withunexposed females. The exposed female rats were mated to unexposedmale rats at the end of the 14-week exposure period and againduring post-treatment and were allowed to deliver. Five rats/sex/exposure level were killed after 4 weeks and after 14 weeksof exposure; remaining rats were sacrificed at the end of therecovery period. DBCP did not affect the ability of males toimpregnate females; however, a dominant lethal effect was evidentat 10 ppm which tended to reverse by 5 weeks after terminationof exposure. Moderate testicular atrophy (males) and focal aggregatesof altered cells in the adrenal cortex (males and females) wereobserved in rats sacrificed immediately after exposure to 10ppm for 14 weeks, but not in those exposed to 1.0 or 0.1 ppm.Pathologic evaluation of the rats from the recovery portionof the study showed treatment-related alterations in males andfemales In the 10 and 1.0 ppm exposure groups, but not in thegroups exposed to 0.1 ppm. The testicular alterations that werepresent in the 10 ppm males after the 14-week exposure periodwere tending to reverse by the end of the recovery period. Lesionswere observed in the adrenal cortex of recovery males and femalesfrom the 10 ppm exposure level; females exposed to 1 ppm hadslight adrenal cortical lesions at the end of the recovery period.In addition, increased numbers of ovarian cysts were presentin recovery females from the 10 ppm exposure level. Brain effectsconsisting of focal or multifocal mineralized deposits werepresent in males and females in the 10 ppm exposure level. Notreatment-related alterations were recognized in any of therats from the 0.1 ppm recovery groups.     

1,2,3-Trichloropropane: A Multisite Carcinogen in Rats and Mice

1,2,3-Trichloropropane was evaluated in 2-year toxicology andcarcinogenesis studies by the National Toxicology Program. Theselection of this chemical for study was based on the potentialfor human exposure, its positive in vitro genotoxicity, andthe carcinogenicity of structurally related chemicals. Duringthe 2-year study 1,2,3-trichloropropane was administered incorn oil by gavage 5 days per week; groups of 60 F344/N ratsreceived 0, 3, 10, or 30 mg/kg, while groups of 60 B6C3F1 micereceived 0, 6, 20, or 60 mg/kg. Because of reduced survivalassociated with the development of chemical-related neoplasms,rats that received 30 mg/kg were terminated at 65 weeks (females)or 76 weeks (males). Similarly, mice that received 60 mg/kgwere terminated at 73 weeks (females) or 79 weeks (males), whilegroups of mice that received 20 mg/kg were terminated at 88weeks. 1,2,3-Trichloropropane induced benign and/or malignantneoplasms at multiple sites in both rats and mice; this includedincreased incidences of benign and malignant neoplasms of thesquamous epithelium of the oral mucosa and forestomach of maleand female rats, benign neoplasms of the kidney and pancreasand benign or malignant neoplasms of the preputial gland inmale rats, malignant neoplasms of the mammary gland, and benignor malignant neoplasms of the clitoral gland in female rats.In mice, 1,2,3-trichloropropane induced a low incidence of malignantneoplasms of the oral mucosa in females, high incidences ofbenign and malignant neoplasms of the forestomach in males andfemales, benign neoplasms of the liver and harderian gland ofmales and females, and uterine neoplasms in females.     

Influence of food intake and sexual segregation on longevity, organ weights and the incidence of non-neoplastic and neoplastic diseases in rats

In a small-scale experiment the effects of four variables were investigated in male and female Wistar rats fed on a standard laboratory chow and not deliberately exposed to any carcinogen. The variables investigated were (i) diet restriction by limiting access to food to 6.5 hr/day instead of 24 hr/day; (ii) housing males in a single-sex room as distinct from a mixed-sex room; (iii) life-long segregation of males from females, as distinct from access to one virgin female for 5 days during each alternate week; and (iv) uniparity in females versus life-long virginity. The endpoints compared were body-weight gain, longevity, visible and palpable swellings, absolute and relative organ weights, microscopically confirmed malignant neoplasms that contributed to death before the end of the study at 2 yr, incidence of other neoplasms in decedents and rats killed at the end of the study, and the incidence of various non-neoplastic conditions including myocardial inflammation and fibrosis, chronic progressive nephropathy, liver glycogen storage and fatty degeneration, mammary gland hyperplasia and secretory activity, pancreatic polyarteritis, radiculoneuropathy and certain testicular changes. The results indicated major beneficial effects of dietary restriction on most of the endpoints. By comparison the other variables had only marginal effects. Leydig-cell hyperplasia and neoplasia occurred at significantly higher incidences in males housed intermittently with females than in permanently segregated males. No convincing differences were seen between females that littered once and those that remained virgins. The relevance of these findings to the prediction of cancer mortality risk in man and to the design of rodent carcinogenicity studies is discussed.