Kent J. Davis

Effects of prolonged ethylene thiourea ingestion on the thyroid of the rat

Abstract Male and female Charles River rats, approximately 5 wk old, were fed ethylene thiourea (ETU) for 2 yr at levels of 0, 5, 25, 125, 250 or 500 ppm in the diet. Body weights, the weights of the thyroid and other organs, thyroidal uptake of 131 I, haematology and histology were the criteria studied. ETU was found to be a thyroid carcinogen for the rat at the 250 and 500 ppm dietary levels and a thyroid tumorigen at the 125 ppm level; it caused slight thyroid hyperplasia at the 5 and 25 ppm feeding levels. Thyroid hyperplasia was not noticeably reversible in those rats in each group that were changed to control diet after 66 wk on ETU diets. ETU ingestion at the 5 and 25 ppm levels was not biologically deleterious to the rat.

Tumorigenic potential of Aldrin and Dieldrin for mice

Abstract Feeding 10 ppm of Aldrin or Dieldrin to C 3 HeB Fe mice for two years shortened their average life span by two months; significantly increased the incidence of histologically benign liver tumors; decreased the incidence of pneumonia (possibly owing to less cage crowding); and had no discernible effect on the incidence of mesenteric disease, intussusception, and other lesions of less frequent occurrence.

Chronic toxicity of two food colors, Brilliant Blue FCF and Indigotine

Abstract Brilliant Blue FCF (FD & C Blue No. 1) and Indigotine (FD & C Blue No. 2) were fed to groups of 24 Osborne-Mendel rats for two years at dietary levels of 0.5, 1.0, 2.0, and 5.0%. Growth inhibition occurred in the male animals fed Indigotine at the 2.0 and 5.0% levels. No effect was observed on survival, hematology, or organ weights. No significant pathologic changes were observed in animals fed either color. Five beagle dogs received a dietary level of 2.0%, and three dogs a level of 1.0% of Brilliant Blue FCF for one year. One dog died after 17 days on the 2% dietary level and another died after 46 weeks on the 1% level. Indigotine was fed to beagle dogs for periods up to two years at dietary levels of 1.0 and 2.0%. Four of the six dogs at the 2.0% level died during the two years, and one of the four at the 1.0% level was sacrificed in a moribund condition. All the deaths were attributed to intercurrent virus infections. No clinical signs, gross lesions, or microscopic pathology were attributed to intercurrent virus infections. No clinical signs, gross lesions, or microscopic pathology were attributed to ingestion of Brilliant Blue FCF or Indigotine; however, because of deaths from intercurrent virus infections a no-effect level has not been established for Indigotine. Subcutaneous injections of 30 mg of Brilliant Blue FCF or 20 mg of Indigotine into rats weekly for two years produced fibrosarcomas at the site of injection. Other than acute convulsive deaths of some of the test mice immediately after injection, no deleterious effects attributable to the weekly subcutaneous injection of 2.5 mg of Indigotine were observed over a two-year period.

Chronic oral toxicity of Ponceau 3R.

The results of two-year oral toxicity studies with Ponceau 3R using two strains of rats have been presented. Dosage levels were 5.0, 2.0, 1.0, and 0.5% for Osborne-Mendel rats and one dosage level of 2.0% for Bethesda Black rats. Preliminary results of the continuing dog and mouse studies are reported. Ponceau 3R at 5.0, 2.0, 1.0, and 0.5% of the diet produced high mortality, growth inhibition, and increased weight of the liver and kidneys. Malignant liver tumors occurred in both strains of rats at all dietary levels of Ponceau 3R, statistically significant (P < 0.01) in comparison with the controls at the 5.0% level of the Osborne-Mendel rats and the 2.0% level of the Bethesda Black animals. Incidence of benign liver tumors was also significant for all test levels. Marked weight loss and high mortality have been observed in dogs fed Ponceau 3R at dosage levels of 2.0% and 1.0%. After a feeding period of 32 weeks, changes in the liver were the most pronounced tissue changes. Increased mortality of C3HeBFe mice has been observed on 2.0% and 1.0% feeding levels. Hepatic adenomas and carcinomas have been observed on the 2.0% level.

Chronic rat and dog toxicity studies on tartrazine

Rats. Five groups of 24 Osborne-Mendel weanling rats, evenly divided by sex, were fed 5.0, 2.0, 1.0, 0.5, and 0.0% tartrazinemixed in their Purina laboratory chow diet for 2 years. Growth effect was negligible, and there was no effect on survival, hematology, or organ weights. The rats evidenced diarrhea at the 5% dosage level, slight diarrhea at the 2% level, and no diarrhea at the 1% level. The incidence of tumors and of the common incidental diseases was unaffected. No organ pathology attributable to treatment was noted except at the highest dosage level, where the feeding of tartrazine may have influenced the deposition of small amounts of gritty material in the renal pelvis of some of the surviving male rats. Dogs. Three groups of two male and two female beagles each were fed diets containing 2, 1, and 0% tartrazine for 2 years. No clinical symptoms of toxicity or hematologic abnormalities were noted during the study. No gross lesions were noted at autopsy. Histopathology was limited to the usual incidental lesions which, with the possible exception of pyloric gastritis in one high dose level dog, were not attributable to tartrazine toxicity.

Toxicity of three drug solvents

N,N-dimethylformamide was approximately 10 times as toxic, and N,N-dimethylacetamide (in 50% aqueous solution) was approximately 312 times as toxic as propylene glycol when single doses were administered intraperitoneally in mice. The LD50 values were respectively 1122, 3236, and 11,400 mg/kg.

Chronic toxicity of cubé

Abstract The effects of feeding cube powder to rats for two years at dietary levels of 50, 100, 250, 500, and 1000 ppm, and to dogs for 28 months at levels of 50, 150, and 400 ppm have been presented. Cube at all levels, except 50 ppm, inhibited growth of rats. No histopathologic change attributable to cube ingestion was noted at any level. The incidence of gross mammary tumors, nephritis, and pituitary lesions at the higher levels was less than in the controls. One dog at the 150 ppm level died after 20 months with hepatic pathology not attributed to cube toxicity. No clinical or hematologic effects were noted in the remaining dogs.

Long-term toxicity studies of erythrosine. ii. effects on haematology and thyroxine and protein-bound iodine in rats*

Abstract Erythrosine (FD & C Red No. 3) was administered to male and female Osborne-Mendel rats either by intubation twice weekly for 85 wk or continuously in the diet for 86 wk. No consistent differences in red blood cell counts, haematocrit, haemoglobin, reticulocyte counts or other indications of anaemia were observed. Increased values for protein-bound iodine were attributed to circulating erythrosine in the blood serum; these values had returned to normal 16 wk after erythrosine administration ceased. Thyroxine-iodine levels were not affected in treated rats. No gross nor microscopic pathology was attributed to administration of this dye.

Pathologic changes noted in rats fed D&C Red No. 9 for two years.

Two hundred and fifty 3-week-old Osborne-Mendel rats divided into 5 groups of 50 rats each, each group equally divided by sex, were started on a two-year feeding experiment on D&C Red No. 9, which was mixed into the diet at levels of 1%, 0.25%, 0.05%, 0.01% and 0% (controls) and fed ad libitum. The color had no apparent effect on the growth rate, mortality, or occurrence of tumors in the test rats. Hemoglobin levels were slightly lowered and red blood cell abnormalities were observed in rats on the 1% and 0.25% feeding levels. At autopsy, survivors on the 1% feeding level showed moderate splenomegaly and rats on the 0.25% level showed slight splenomegaly. Rats on these two feeding levels had less chronic nephritis than did either control rats or rats on the two lower feeding levels. Grossly 58% of the rats had pneumonia, 18% had nephritis, 18% had pituitary lesions, and 29% of the females had mammary tumors. Other incidental gross pathologic changes randomly distributed in these 250 rats included lymphosarcoma in 6 rats, epidermal carcinomas in 3 rats, interstitial cell tumors of the testis in 3 males, subcutaneous fibromas in 2 males, and 1 rat each with a thyroid carcinoma, pulmonary adenocarcinoma, cecal fibroma, hepatoma, vaginal tumor, and a uterine polyp. Randomly distributed incidental nonneoplastic gross pathology included adrenal enlargement in 12 rats, uterine or ovarian cysts or abscesses in 11 females, subcutaneous abscesses in 3 rats, foot granulomas in 3 rats, prostatic abcesses in 2 males, mammary hyperplasia in 2 females, and 1 case each of hepatic abscess, pancreatic abscess, mesenteric arteritis, perirenal hemorrhage, and marked testicular atrophy. Histopathologic findings attributable to DC however, pigmentation of the renal tubular epithelium occurred only in rats on these two feeding levels. At 0.05% and 0.01% there were no gross or microscopic pathologic changes attributable to D&C Red No. 9.

Pathologic changes noted in rats fed D&C Red No. 10 [monosodium salt of 2-(2-hydroxy-1-naphthylazo)-1-naphthalenesulfonic acid] for two years

Abstract Two hundred and fifty 3-week-old Osborne-Mendel rats divided into 5 groups of 50 rats each, and each group equally divided by sex, were started on a 2-year feeding experiment on D & C Red No. 10 which was mixed into the diet at levels of 1%, 0.25%, 0.05%, 0.01%, and 0% (controls) and fed ad libitum. The color had no apparent effect on the growth rate of test rats. Percentage of rats surviving on the 2-year test was increased by the addition of the color to the diet. Slight to moderate splenic enlargement was noted in 1% and 0.25% feeding level rats. Grossly 42% of the rats had pneumonia, 17% had nephritis, 17% had pituitary lesions, and 43% of the females had mammary tumors. Other incidental gross pathology randomly distributed among these 250 rats included lymphosarcoma in 7 rats, subcutaneous tumors in 5 males, endometrial sarcomas in 4 females, thyroid tumors in 4 rats, testicular tumors in 3, hepatic tumors in 2, abdominal lipoma in 1, leukemia in 1, ovarian tumor in 1, cystic ovaries in 5, ovarian abscesses in 2, and 1 rat each with a splenic infarct, a large abdominal hematoma, and a foot-pad granuloma. Approximately 800 tissue sections from these 250 rats were prepared for microscopic study. Histopathology attributable to D & C Red No. 10 toxicity occurred only in the spleen and bone marrow. Since survival of the test animals is considered to be more important to these animals than their slight to moderate splenic and bone marrow hyperplasia, it is apparent that D & C Red No. 10 had a beneficial effect in this experiment. However, because of the undesirable side effects of splenomegaly and bone-marrow hyperplasia at the 1% and 0.25% feeding levels, the 0.05% level should be considered the “no-effect” level.