Chronic Toxicity and Carcinogenicity Studies of 1-Methylnaphthalene in B6C3F1 Mice

The carcinogenic potential of 1-methylnaphthalene (1-MN), acompound which exists widely in the environment, was investigatedin B6C3F1 mice. Groups of 50 male and 50 female mice were givendiets containing 0, 0.075, or 0.15% 1-MN for 81 weeks. Bothtreatment groups developed pulmonary alveolar proteinosis athigh incidence, with 46.0 and 34.7% of females and 46.0 and38.0% of males, respectively, being affected. Total lipid andphospholipid levels in sera and monocytes in peripheral bloodwere also significantly increased in 1-MN-treated female andmale mice in contrast with control values. The incidences ofbronchiolar/alveolar adenomas in the lungs of male mice givenboth 0.075 or 0.15% 1-MN were 26.0 and 24.0%, respectively,in both cases significantly increased in contrast with the 4.1%observed for control males. However, neither dose dependencenor significant difference in the incidences of bronchiolar/alveolarcarcinomas between 1-MN-treated and control male mice was observed.The incidences of other tumors also were similar in both 1-MN-treatedand control groups. The results of the present experiment thussuggested a possible weak carcinogenic potential of 1-MN tothe lung of male but not female B6C3F1 mice.     

Chronic Toxicity and Carcinogenicity Studies of 2-Methylnaphthalene in B6C3F1 Mice

The toxicity and carcinogenic potential of 2-methylnaphthalene(2-MN) were examined in B6C3F₁ mice. Groups of 50 male and 50female mice were given diets containing 0, 0.075, and 0.15%2-MN for 81 weeks. Both 0.075 and 0.15% 2-MN caused pulmonaryalveolar proteinosis at high incidence: 55.1 and 45.8% in femalesand 42.9 and 46.9% in males, respectively. The incidences oftotal lung tumors, including bronchiolar/alveolar adenomas andcarcinomas, were 20.4 and 12.2% in male mice given 0.075 and0.15% 2-MN, respectively, the former value being significantlyincreased compared with the 4.1% in control males. However,in the respective incidences of the adenomas and carcinomas,neither in-tergroup differences nor dose dependencies were observed.The incidences of other tumors did not differ between mice treatedwith 2-MN and the controls. The results indicated that 2-MNinduces pulmonary alveolar proteinosis but does not possessunequivocal carcinogenic potential in B6C3F₁ mice.     

Chronic Toxicity and Carcinogenicity of Methylmercury Chloride in B6C3F1 Mice

Chronic Toxicity and Carcinogenicity of Methylmercury Chloridein B6C3F1 Mice. MRRSU-MORI, K., HIRANO, M., UEDA, H., MAITA,K., AND SHIRASU, Y. (1990). Fundam. Appl. Toxicol. 14, 179–190.A 2-year feeding study of methylmercury chloride (MMC: 0, 0.4,2, or 10 ppm) was conducted in B6C3F1 mice (60 mice of eachsex/group) to compare chronic toxicity and carcinogenicity resultswith those for ICR mice from our previous study in which malesof the 10-ppm group showed an increased incidence of renal tumorswithout any abnormal in-life parameters. In B6C3F1 mice of the10-ppm group, neurotoxic signs characterized by posterior paralysiswere observed in 33 males after 59 weeks and in 3 females after80 weeks. In males, a marked increase in mortality and a remarkabledecrease in body weight gain were observed after 60 weeks. Toxicencephalopathy consisting of neuronal necrosis of the brainand toxic peripheral sensory neuropathy were induced in bothsexes in this group. Chronic nephropathy, testicular atrophy,and glandular stomach ulcer increased in incidence in the males;chronic nephropathy also increased in incidence in females.In proliferative lesions, there were significant increases inthe incidence of renal adenoma and/or carcinoma (16/60) andtubular cell hyperplasia (14/ 60) in males of the 10-ppm group,as compared to the control group. The incidence of chronic nephropathyalso increased in males of the 2-ppm group. The results of thisstudy indicate that the susceptibility of B6C3F1 mice to renaltoxicity and renal carcinogenicity is comparable to that ofICR mice, and B6C3F1 mice are more sensitive to the chronicneurotoxic effects of MMC than are ICR mice.     

Carcinogenicity and Toxicity of Inhaled Nitrobenzene in B6C3F1 Mice and F344 and CD Rats

The potential carcinogenicity and toxicity of inhaled nitrobenzenewere evaluated following chronic (2-year) exposure in mice andrats. Male and female B6C3F1 mice were exposed to 0, 5, 25,or 50 ppm nitrobenzene, while male and female F344 rats andmale CD rats were exposed to 0, 1, 5, or 25 ppm nitrobenzene.All exposures were for 6 hr/day, 5 days/week excluding holidays,for a total of 505 days over 2 years. Survival was not adverselyaffected by nitrobenzene exposure, and only mild exposure-relateddecreases in body weights (<10% of control) were occasionallynoted. Nitrobenaene exposure resulted in increased incidenceof neoplasia in male B6C3F1 mice (pulmonary alveolar/bronchiolarand thyroid follicular cell neoplasms), female B6C3FI mice (mammarygland neoplasms), male F344 rats (hepatocellular and renal neoplasms),female F344 rats (endometrial stromal neoplasms), and male CDrats (hepatocellu lar neoplasms). In addition, there were marginalincreases in the incidence of hepatocellular neoplasia in femaleB6C3F1 mice and thyroid follicular neoplasia in male F344 rats.Groups of nitrobenzene-exposed mice and rats with increasedincidence of renal and thyroid neoplasia also had increasedincidences of hyperplasia in these tissues. Toxicity resultingfrom chronic inhalation of nitrobenzene was manifested by methemoglobinemia,anemia, and adaptive or degenerative changes in the nose, liver,and testis. The results indicate that inhaled nitrobenzene iscarcinogenic and toxic in mice and rats, and that the spectrumof these responses in animals is dependent on species, sex,and genetic background.     

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).     

Chronic Nephropathy and Renal Carcinogenicity of o-Benzyl-p-chlorophenol in F344/N Rats and B6C3F1 Mice

o-Benzyl-p-chlorophenol, an aryl halide biocide, was evaluatedin male and female F344/N rats and B6C3F₁ mice in a series ofsubchronic and 2-year toxicity and carcinogenicity studies.Kidney was the primary target of toxicity in the 13-week gavagestudies in rats and mice, with increased nephropathy noted aslow as 240 mg/kg in male rats. Considering the nephropathy tobe dose-limiting, the chronic (2-year) study was conducted atlower doses (male rats: 30, 60, or 120 mg/kg; female rats: 60,120, or 240 mg/kg; male and female mice: 120, 240, or 480 mg/kg;in corn oil; n=50/group). Survival and body weights of dosedrats were similar to controls in the 2-year study. Survivalof high-dose male and female mice, and body weights of all dosedmale and mid- and high-dose female mice, were lower than controls.The incidence and severity of nephropathy increased with doseand length of treatment in both rats and mice. There was anincreased incidence of renal tubule adenomas or carcinomas inboth the mid- and high-dose male mice. Despite similar evidenceof nephropathy, however, there were no increased incidencesof neoplasms in female mice or in male or female rats. Thisstudy suggests therefore that while nephrotoxicity may havebeen a necessary component, factors other than the marked nephrotoxicityof o-benzyl-p-chloro-phenol were critical to the developmentof renal carcinogenesis induced in only male mice.     

Styrene Inhalation Toxicity Studies in Mice: I. Hepatotoxicity in B6C3F1 Mice

Studies were conducted to evaluate the toxic effects of short-termrepeated styrene inhalation in B6C3F1 mice. Male and femalemice were exposed to 0, 125, 250, or 500 ppm styrene, 6 hr/day,for up to 14 days. Styrene toxicity was characterized by severecentrilobular hepatic necrosis and deaths after one exposureto 500 ppm or two exposures to 250 ppm. Mortality and hepatotoxicitywere not increased by additional exposures, and in survivingmice, regeneration and repair of initial hepatic injury occurredin spite of continued exposure for 14 days. A marked sex differencewas observed, with male mice significantly more susceptibleto styrene toxicity than females. A nonlinear dose responsewas observed where mortality in male and female mice was greaterin the 250 ppm dose group than that in the 500 ppm dose group.Severe congestion and necrosis of the liver was present in moribundmice; hepatic congestion and serum alanine aminotransferaseand sorbitol dehydrogenase were significantly greater in moribundanimals.     

Dermal Toxicity and Carcinogenicity of 4-Vinyl-1 -cyclohexene Diepoxide in Fischer Rats and B6C3F1 Mice

Dermal Toxicity and Carcinogenicity of 4-Vinyl-1-cyclohexeneDiepoxide in Fischer Rats and B6C3F1 Mice. CHHABRA, R. S., HUFF,J., HASEMAN, J., JOKJNEN, M. P., AND HETJMANCIK, M. (1990).Fundam. Appl. Toxicol 14, 752–763. 4-Vinyl-l-cyclohexenediepoxide (VCHD) is used as a chemical intermediate and as areactive diluent for diepoxides and epoxy resins. Studies wereconducted by administering VCHD in acetone by dermal application,5 days per week for 105 weeks, to groups of 60 rats of eachsex at 0, 15, or 30 mg/animal. Groups of 60 mice of each sexwere administered 0, 2.5, 5, or 10 mg/animal on the same schedulefor up to 103 weeks. Ten animals from each group were humanelykilled, necropsied, and examined histopathologically duringMonth 15. At the 15-month evaluation, 2 of 10 male rats thatreceived 30 mg had a squamous cell carcinoma of the skin ator adjacent to the site of application. Squamous cell papillomasand carcinomas were seen in all mice that received 5 or 10 mg.Two of nine female mice given 10 mg had granulosa cell tumorsof the ovary, and one of nine female mice given 10 mg had anovarian papillary cystadenoma. In the 2-year studies, body weightand survival were lower in high-dose rats and mid- and high-dosemice than in vehicle controls. All high-dose male mice diedby Week 83; remaining high-dose female mice were killed duringWeek 84 for humane reasons. Squamous cell papillomas of theskin in dermally exposed male rats and squamous cell carcinomasand basal cell adenomas or carcinomas of the skin in exposedmale and female rats were increased. The incidence of squamouscell carcinomas of the skin was increased in male and femalemice at all dose levels. Mid- and high-dose female mice hadan increased incidence of benign or malignant granulosa celltumors and of benign mixed tumors of the Ovary.     

Toxicity and Carcinogenicity of {Delta}9-Tetrahydrocannabinol in Fischer Rats and B6C3F1 Mice

⁹-Tetrahydrocannabinol (⁹-THC) was studied for potential carcinogenicityin rodents because it is the principal psychoactive ingredientin marihuana and it has potential medicinal uses. ⁹-THC in cornoil was administered by gavage to groups of male and femaleFischer rats and B6C3F1 mice at 0, 5, 15, 50, 150, or 500 mg/kg,5 days a week for 13 weeks and for 13-week plus a 9-week recoveryperiod, and to groups of rats at 0, 12.5, 25, or 50 mg/kg andmice at 0, 125, 250, or 500 mg/kg, 5 times a week for 2 years.In all studies, mean body weights of dosed male and female ratsand mice were lower than controls but feed consumptions weresimilar. Convulsions and hyperactivity were observed in dosedrats and mice; the onset and frequency were dose related. SerumFSH and LH levels hi all dosed male rats and corticosteronelevels in 25 mg/kg female rats were significantly higher thancontrols at 15 months in the 2-year studies. ⁹-THC administrationfor 13 weeks induced testicular atrophy and uterine and ovarianhypoplasia; the lesions persisted in a 9-week recovery period.In the 2-year studies, survival of dosed rats was higher thancontrols; that of mice was similar to controls. Incidences oftesticular interstitial cell, pancreas and pituitary gland adenomasin male rats, mammary gland fibroadenoma and uterus stromalpolyp in female rats, and hepatocellular adenoma/carcinoma inmale and female mice were reduced in a dose-related manner.Decreased tumor incidences may be at least in part due to reducedbody weights of dosed animals. Incidences of thyroid gland follicularcell hyperplasia were increased in all dosed groups of maleand female mice, and follicular cell adenomas were significantlyincreased in the 125 mg/kg group of males, but there was noevidence of a dose-related trend in proliferative lesions ofthe thyroid. There was no evidence that ⁹-THC was carcinogenicin rats or mice.     

Comparative Toxicity and Carcinogenicity of Two Chlorinated Paraffins in F344/N Rats and B6C3F1 Mice

The toxicity and carcinogenicity of chlorinated paraffins containingC12 with 60% Cl, and C23 with 43% C1, were assessed in prechronicand 2-year gavage studies using F344/N rats and B6C3F1 miceof both sexes. Single administrations of chlorinated paraffinswere nonle thal in rats and mice, but repeated-dose and 2-yearstudies demonstrated toxic responses that differed with theparaffins. The C23,C143% paraffin produced a granulomatous inflammationin the liver of female rats in 13-week studies, while the C12,Cl60% paraffin caused deaths of rats and mice in 16-day studiesand marked liver enlargement in 13-week studies. In 2-year studies,the C23,C143% paraffin caused hepatic and lymphatic granulomatousinflammation and hyper plasia in both sexes of rats, and wasassociated with marginal increases in adrenal medullary pheochromocytomasin female rats and hepatocellular neoplasms in female mice andwith clear increases in malignant lymphomas in male mice. TheCl 2,Cl60% paraffin caused marked liver enlargement in ratsand increased the severity of nephropathy in male rats and theincidence of nephropathy in female rats. Cl2,Cl60% also causedhepatocellular neoplasms in both sexes of rats and mice: kidneytubular cell adenomas and adenocarcinomas in male rats, thyroidfollicular cell neoplasms in female rats and female mice, anda marginal increase in mononuclear cell leukemia in male rats.Thus, the short-chain, heavily chlorinated paraffin appearsto have a greater potential for chronic toxicity and carcinogenicitythan the longer-chain, lightly chlorinated paraffin. Both paraflinshave been reported to be nonmutagenic in bacteria. (NationalToxicology Program (1986) Technical Report, NIH Publications86-2561 and 86-2564).     

Prechronic Toxicity Studies on 2-Ethylhexanol in F334 Rats and B6C3F1 Mice

Data on the subchronic toxicity of 2-ethylhexanol (2EH) wererequired to establish the dose vehicle and dose levels for oncogenicitystudies. In preliminary studies 2EH was given subacutely (11days) to male and female Fischer 344 rats and B6C3F1 mice asan aqueous emulsion by oral gavage (0, 100, 330, 1000, and 1500mg/kg/day). Clinical observations were made, body weights, foodconsumption, clinical chemistries, hematologies, and selectedorgan weights were measured, and gross and micropathologieswere performed. Target organs were the central nervous system,liver, forestomach, spleen, thymus, and kidney in rats and thecentral nervous system, liver, and forestomach in mice. 2EHwas then administered by oral gavage to male and female F344rats and B6C3F1 mice as an aqueous emulsion (0, 25, 125, 250,and 500 mg/kg/day) for 13 weeks. At 500 mg/kg/day in the ratthere was reduced body weight gain (6% male, 7% female), increasedrelative liver (29% male, 15% female), kidney (16% male, 6%female), stomach (11% male, 16% female), and testes (6%) weights,and moderate gross and microscopic changes in the liver andforestomach. There were no behavioral effects or effects onthe spleen or thymus. A no-effect level for target organ effectsin the rat was 125 mg of 2EH/kg/day. At 500 mg of 2EH/kg/dayin the mouse the only effects were increased relative stomachweights in males (13%) and a low incidence of gross and microscopicfindings in the forestomach (male and female) and liver (female).A no-effect level for target organ effects in the mouse was125 mg of 2EH/kg/day. 2EH was a peroxisome proliferator in therat but not in the mouse at subchronic dose levels of 500 mg/kg/day.Dose levels in oncogenicity studies were set at 50 mg/kg/dayfor the absence of treatment-related effects in rats and mice,and 500 and 750 mg/kg/day, respectively, in rats and mice ashigh doses producing minimal toxicity without altering the lifespan.     

Subchronic Studies of Doxylamine in B6C3F1 Mice

Subchronic Studies of Doxylamine in B6C3F, Mice. JACKSON, C.D. AND BLACKWELL, B.-N. (1988). Fundam. Appl. Toxicol. 10, 254-261.Doxylamine succinate, a histamine (HI) antagonist (antihistamine),was administered as an admixture in the feed to male and femaleB6C3F, mice for 14 or 90 days. Dose levels of 0,100,250, 500,1000, and 2000 ppm doxylamine were administered to males andfemales in the 14-day study while dose levels of 0, 80, 162,325, 750, and 1500 ppm were administered to both sexes in the90-day study. Little toxicity was seen in the 14-day study.Final body weights in the highest dose group were reduced 4.0and 7.3% in males and females, respectively. Treatment-relatedhistopathological changes in the 14-day study were limited toa very low incidence of hepatic necrosis in both sexes. Therewas little toxicity observed in the 90-day study and no cleardose response relative to weight gain was observed. Histologically,the liver was the only organ affected by doxylamine administration.The liver lesions consisted of hepatic cell cytomegaly and/orkaryomegaly which varied from mild to severe and a possibledose-related hepatic necrosis.     

Inhalation Toxicity Studies of Cobalt Sulfate in F344/N Rats and B6C3F1 Mice

Inhalation Toxicity Studies of Cobalt Sulfate in F344/N Ratsand B6C3F1 Mice. BUCHER, J. R., ELWELL, M. R., THOMPSON, M.B., CHOU, B. J., RENNE, R., AND RAGAN, H. A. (1990). Fundam.Appl. Toxicol. 15, 357–372. Groups of 10 F344/N rats andB6C3F1 mice of each sex were exposed to cobalt sulfate heptahydrateaerosols of 0, 0.3, 1.0, 3.0, 10, or 30 mg/m3, 6 hr per day,5 days per week, for 13 weeks. All rats and female mice andall but 2/10 male mice exposed at the top concentration survivedto the end of the studies. Polycythemia was observed in exposedrats but not in mice. Sperm motility was decreased in mice exposedat 3 mg/m3 (the lowest concentration evaluated) and at higherconcentrations, and increased numbers of abnormal sperm anddecreased testis and epididymal weights occurred in mice exposedto 30 mg/m3. Cobalt content in the urine of rats increased withincreasing atmospheric cobalt exposure. Primary histopathologiceffects were limited to the respiratory tract. Lesions in ratsand mice included degeneration of the olfactory epithelium,squamous metaplasia of the respiratory epithelium, and inflammationin the nose; inflammation, necrosis, squamous metaplasia, ulcers(rats), and inflammatory polyps (rats) of the larynx; metaplasiaof the trachea (mice); and fibro-sis, histiocytic infiltrates,bronchiolar epithelial regeneration, and epithelial hyperplasiain the alveoli of the lung. The most sensitive tissue was thelarynx, with squamous metaplasia observed in rats and mice atthe lowest exposure concentration of 0.3 mg/m3. Thus, a no-observed-adverse-effectlevel was not reached in these studies     

Carcinogenicity study of cochineal in B6C3F1 mice

The carcinogenicity of cochineal, a red colouring used in food and other products, was studied in a 2-yr bioassay in B6C3F1 mice. Groups of 50-55 mice of each sex were given 0, 3 or 6% cochineal in the diet for 2 yr. Mice of all groups developed tumours including hepatocellular adenomas or carcinomas, pulmonary adenomas or adenocarcinomas and lymphomas or lymphatic leukaemias, and the incidences of these tumours were not significantly different in treated and control groups. The results indicate that cochineal lacks carcinogenicity in mice and are consistent with those of in vitro short-term assays of cochineal and of carminic acid, an active principle of cochineal.     

Styrene Inhalation Toxicity Studies in Mice: II. Sex Differences in Susceptibility of B6C3F1 Mice

Styrene is a commercially important chemical used in the productionof plastics and resins. In initial short-term styrene inhalationstudies, toxicity was significantly greater in male B6C3F1 micethan in females, suggesting that males may metabolize styrenemore extensively and/or may be less able to detoxify reactivemetabolites. In addition, a nonlinear dose-response was observedwhere toxicity and mortality were greater in mice exposed to250 ppm than in those exposed to 500 ppm. These studies wereconducted to investigate potential mechanism(s) for sex differencesand the nonlinear dose-response in styrene toxicity by evaluatingthe effects of repeated styrene exposure on styrene oxide production,hepatic GSH availability, and hepatotoxicity in male and femaleB6C3F1 mice. Mice (36/sex/dose) were exposed to 0, 125, 250,or 500 ppm styrene 6 hr/day for up to 3 days. Styrene exposurecaused increased mortality and hepatotoxicity (centrilobularnecrosis, increased serum liver enzymes) in males and femalesafter one or two exposures to 250 and 500 ppm. Hepatic GSH levelswere decreased in a dose-dependent manner in males and females.After one exposure, GSH levels in males rebounded above controlsin all dose groups. After three exposures to 125 or 250 ppmmales appeared to maintain GSH levels; GSH was still decreasedin the 500 ppm group. GSH levels in females were decreased aftereach exposure in all dose groups to lower levels than in males,and did not rebound above controls. Male mice had significantlygreater blood styrene levels than females after one exposureto 500 ppm; however, there were no significant sex differencesin blood styrene after subsequent exposures. Levels of SO inblood were not significantly greater in male mice than femaleswithin a dose group, and did not change significantly with repeatedstyrene exposures for 3 days. Blood styrene and SO levels weresignificantly higher at 500 ppm than at 250 ppm indicating thatstyrene uptake and metabolism are greater at 500 ppm than at250 ppm. The higher incidence of mortality in male mice andthe nonlinear dose-response to styrene cannot be explained bygender- or dose-related differences in hepatotoxicity, GSH depletion,or blood styrene or SO levels.     

Subchronic Toxicity of Triethylenetetramine Dihydrochloride in B6C3F1 Mice and F344 Rats

Triethylenetetramine dihydrochloride (trien-2HCl; CAS No. 38260-01-04),a chelating agent used to treat Wilson's disease patients whoare intolerant of the drug of choice, was tested for subchronictoxicity in B6C3F1 mice and F344 rats. Mice and rats receivedtrien-2HCl in the drinking water at concentrations of 0, 120,600, or 3000 ppm for up to 92 days. Twenty mice and 18 ratsof each sex were assigned to each dose group fed either a cereal-based(NIH-31) or a purified (AIN-76A) diet, both containing nutritionallyadequate levels of copper. An additional control group of ratsand mice received a Cu-deficient AIN-76A diet. This low copperdiet resulted in Cu-deficiency symptoms, such as anemia, liverperiportal cytomegaly, pancreatic atrophy and multifocal necrosis,spleen hematopoietic cell proliferation, and increased heartweight, together with undetectable levels of plasma copper inrats but not in mice. Trien-2HCl lowered plasma copper levelssomewhat (at 600 and 3000 ppm) in rats fed the AIN-76A diet,but did not induce the usual signs of copper deficiency. Trien-2HClcaused an increased frequency of uterine dilatation at 3000ppm in rats fed AIN-76A diet that was not noted in females fedthe Cu-deficient diet. Trien-2HCl toxicity occurred only inmice in the highest dose group fed an AIN-76A diet. Increasedfrequencies of inflammation of the lung interstitium and liverperiportal fatty infiltration were seen in both sexes, and hematopoieticcell proliferation was seen in the spleen of males. Kidney andbody weights were reduced in males as was the incidence of renalcytoplasmic vacuolization. There were no signs of copper deficiencyin mice exposed to trien-2HCl. The only effect of trien-2HClin animals fed the NIH-31 diet was a reduced liver copper levelin both rat sexes, noted at 3000 ppm.     

Carcinogenicity study of gamma-oryzanol in B6C3F1 mice.

The carcinogenic potential of gamma-oryzanol, a drug mainly used for the treatment of hyperlipidaemia, was studied in B6C3F1 mice. Groups of 50 males and 50 females were fed a diet containing 0 (control), 200, 600 or 2000 mg gamma-oryzanol/kg body weight/day for 78 wk. No treatment-related changes were observed in general condition, body weight, food consumption, mortality, organ weight or haematology. Histopathological examinations showed various tumours in all groups, including the control group. In the control and 2000-mg/kg groups, relatively high tumour incidences were observed in the liver of males and in the haematopoietic organs of females. However, there was no statistically significant difference in the incidence of any tumours between the control and the 2000-mg/kg groups. The findings indicate that under the experimental conditions described gamma-oryzanol was not carcinogenic in B6C3F1 mice.     

Carcinogenicity study of methyl hesperidin in B6C3F1 mice

A long-term carcinogenicity study of methyl hesperidin, a compound of the vitamin P group, was carried out in B6C3F1 mice receiving dietary concentrations of 0, 1.25 or 5%. Administration was continued for 96 wk and then the mice were maintained on basal diet for an additional 8 wk. Growth retardation during the experiment with final changes in organ weights were observed in females given the 1.25% dose of methyl hesperidin and in both sexes receiving the 5.0% treatment. However, no biologically significant effects were evident with respect to mortality or clinical signs. Furthermore, treatment with methyl hesperidin did not result in any changes in haematology, clinical chemistry and urinalysis data. On histological examination, no significant alteration of non-neoplastic and neoplastic lesion incidence was observed in treated mice. The results thus demonstrated that methyl hesperidin lacked any carcinogenicity for B6C3F1 mice in the 96-wk feeding regimen used in this study.     

Carcinogenicity of Chloroform in Drinking Water to Male Osborne-Mendel Rats and Female B6C3F1 Mice

Carcinogenicity of Chloroform in Drinking Water to Male Osborne-MendelRats and Female B6C3F1 Mice. JORGENSON, T. A., MEIERHENRY, E.A., RUSHBROOK, C. J., BULL, R. J.AND ROBINSON, M. (1984). Fundam.Appl. Toxicol. 5, 760–769. The carcinogenic activity ofchloroform administered at 0, 200, 400, 900, and 1800 mg/literin drinking water was studied in male Osborne-Mendel rats andfemale B6C3F1 mice. A second control group was included in thestudy and was restricted to the water consumption of the high-dosegroup. Animals were maintained on study for 104 weeks. Groupsizes were adjusted at low doses such that a detectable tumorresponse would result at the lowest dose if there was a linearrelationship with dose, and the higher doses produced responsessimilar to previous carcinogenesis bioassays of chloroform.The primary finding was that chloroform increased the yieldof renal tubular adenomas and adenocarcinomas in male rats ina dose-related manner. For the high-dose group, which correspondedto a time-weighted average dose of 160 mg/kg per day for 104weeks, there was a 14% incidence of renal tubular adenomas andadenocarcinomas, vs 1% in the control group. This compares toa 24% incidence observed when 180 mg/kg per day of chloroformwas administered for 78 weeks in earlier studies. In contrast,chloroform in the drinking water of mice failed to increasethe incidence of hepatocellular carcinomas in female B6C3F1mice. The highest dose group received a time-weighted averagedose of 263 mg/kg for 104 weeks, resulting in a 5% combinedincidence of hepatocellular adenoma and carcinoma relative toa 6% incidence in the control groups. In a prior National CancerInstitute study an 80% incidence of hepatocellular carcinomaswas observed at 270 mg/kg per day for 78 weeks. These data indicatethat chloroform administered in drinking water is capable ofinducing cancer in the rat kidney. However, the lack of responsein the mouse liver when chloroform is supplied in the drinkingwater suggests that earlier reports of chloroform hepatocarcinogenesismay be related to some interaction with the mode of administration(corn oil gavage).     

Toxicity and Carcinogenicity of Rotenone Given in the Feed to F344/N Rats and B6C3F1 Mice for up to Two Years

ABSTRACT

Toxicity and carcinogenicity studies of rotenone were conducted in F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were given rotenone in their diet for up to 103 weeks. The doses were 0, 38, and 75 ppm for rats and 0, 600, and 1,200 ppm for mice. Reduction in body weight gain occurred in male and female mice given rotenone. No effects on survival were observed for rats of either sex or female mice. Survival of male mice at 1,200 ppm was significantly greater than that of controls (47/50 vs. 29/50). There were no observed nonneoplastic effects due to rotenone, and for male and female mice no neoplasms were induced by rotenone. Parathyroid adenomas occurred at a higher incidence (4/44) in male rats at 75 ppm than in the controls (1/41). Because these tumors are rare (historical rate in NTP studies is 0.3%), the increase in the incidence of these benign tumors may have been related to rotenone administration. Hepatocellular neoplasms were reduced (p<0.01) in males receiving 1,200 ppm 1/50 relative to controls 12/47. Because this low rate of liver tumors is unusual in male B6C3F1 mice, this decrease was considered to be related to rotenone administration.