G.J. Schieferstein
National Center for Toxicological Research
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Toxicology and Applied Pharmacology | 1982
C.J. Nelson; Karl P. Baetcke; Charles H. Frith; Ralph L. Kodell; G.J. Schieferstein
Abstract Mice were provided ad libitum water containing 0, 30, 60, 120, 200, or 400 ppm benzidine dihydrochloride for 40, 60, or 80 weeks. Initially there were 864 mice of both sexes of two crosses, monohybrid cross and F-1 cross. The monohybrid cross was genetically heterogeneous and was produced from the genetically homogenous F-1 cross. Groups of mice from both crosses and both sexes were terminated at 40, 60, and 80 weeks for pathological evaluation. Statistical analyses of animal weights, water consumption, hepatic cellular alteractions, liver tumor incidence, liver tumor survival, and time-to-first appearance of a liver tumor were performed. Average animal weights decreased as the dose of benzidine increased. There was a corresponding decrease in water consumption with increased dose. Positive associations between incidences of basophilic and acidophilic hepatic foci of cellular alterations, hepatocellular adenomas, and hepatocellular carcinomas were noted in females but similar associations were not noted in males. ED50s calculated from liver tumor incidence for the three termination periods ranged from a low of 54 ppm (F-1 cross and monohybrid cross 80-week females) to a high of 2799 ppm (F-1 cross 40-week males). There were significant differences among the liver tumor survival distributions for all four cross-sex combinations, attributable in all four cases to significant dose-related trends. The estimated time-to-first appearance of a liver tumor was also dose related. The estimated mean time-to-liver tumor ranged from 9 months at 400 ppm to 18 months at 60 ppm in females and 15 months at 400 ppm to 23 months at 60 ppm in males. Five months was estimated for an animal to die of a tumor following the first appearance of the tumor for both sexes and both crosses, irrespective of dose. In all responses mentioned above there were minor differences observed between the two crosses but major differences in response were observed between the sexes for both crosses.
European Journal of Cancer | 1980
Charles H. Frith; K.P. Baetcke; C.J. Nelson; G.J. Schieferstein
Abstract Benzidine dihydrochloride induced hepatic foci of cellular alteration, hepatocellular adenomas and hepatocellular carcinomas in mice. All three lesions occurred more frequently in the female, and all three lesions sometimes occurred in the same liver. The data suggest that the foci of cellular alteration would be precursors for the hepatocellular adenomas which are in turn precursors for the hepatocellular carcinomas.
Toxicology Letters | 1979
Charles H. Frith; Karl P. Baetcke; C.J. Nelson; G.J. Schieferstein
Abstract Benzidine dihydrochloride induced hepatocellular adenomas in male and female mice which appeared to progress to hepatocellular carcinomas as either the length of administration and/or the dose level of benzidine increased. The differentiation of hepatocellular carcinomas also correlated inversely with dose, and poorly differentiated hepatocellular carcinomas metastasized more frequently. These findings support the view that the mouse liver tumor is predictive of carcinogenicity in bioassay studies.
Toxicological Sciences | 1988
G.J. Schieferstein; Winslow G. Sheldon; S.A. Cantrell; G. Reddy
In a 90-day study, CD strain rats were dosed with 1,4-dithiane by daily gavage at 0, 105, 210, and 420 mg/kg/day (30 rats/sex/dose) in order to calculate a suggested drinking water criterion. No overt toxicity, treatment-related mortality, or ophthalmologic changes were found. Treatment-related decreases were found in female amylase, sorbitol dehydrogenase, and reticulocyte count, and in LDH 1 in both sexes, in LDH 3 in the males, and in LDH 5 in both sexes. Treatment-related increases were found in female liver and in male kidney and male thymus weight. A treatment-related decrease in female brain weight was also found. Significant changes in organ weight of dosed animals compared to control organ weight were observed at the 105 mg/kg/day dose in the spleen of both sexes, female brain, and the male kidneys. Three organs showed compound-related anatomic changes: nose, liver, and kidney. Anisotrophic crystals of undetermined chemical composition were deposited in the olfactory nasal mucosa of both sexes. These crystals were not composed of 1,4-dithiane because 1,4-dithiane is very soluble in ethanol and would not have been present after the slide preparation process. The crystals were present in similar amounts in both sexes of the high and intermediate dose groups. In the low dose group, however, the crystals were present in greater amounts in the females. Crystals were not observed in the control animals. The other treatment-related anatomic abnormalities were eosinophilic cytoplasmic granulation of the convoluted renal tubule cells in the high dose males and minimal hypertrophy of the centrilobular region of the liver in the high dose females. The animal no-observed-effect-level was 105 mg/kg/day. This study reports a novel form of toxicity (deposition of anisotrophic crystals in the olfactory mucosa) from 1,4-dithiane administered by gavage. The chemical composition of the crystals and the absorption, distribution, metabolism, and excretion of 1,4-dithiane are unknown at present.
Food and Chemical Toxicology | 1984
David L. Greenman; Ralph L. Kodell; B. Highman; G.J. Schieferstein; M. Norvell
C3H/HeJ and C3H/HeN female mice were fed diets containing targeted concentrations of 320 or 640 ppb diethylstilboestrol (DES) starting at 7 or 11 wk of age and continuing throughout their remaining lifespan. Regardless of the DES concentration there was a faster rate of development and higher final incidence of mammary adenocarcinomas among the C3H/HeN mice than among the C3H/HeJ mice. In C3H/HeN mice started on DES when 11 wk old, mammary tumours developed more rapidly than when treatment was started at 7 wk of age. This was also true for C3H/HeJ mice given 320 ppb DES but not for those treated with 640 ppb DES. Both age at the start of treatment and strain of C3H mice are important factors to be considered in designing experiments to study the tumorigenic activity of oestrogens such as DES.
Toxicological Sciences | 1995
David L. Greenman; Winslow G. Sheldon; G.J. Schieferstein; Richard R. Allen; William T. Allaben
Abstract The antihistamine, triprolidine hydrochloride, was fed at dietary concentrations of 0, 250, 1000, or 2000 ppm (as the free base) to groups of 60 Fischer 344 (F344) rats of each sex for up to 2 years to evaluate its potential carcinogenicity. Up to 12 per sex from each group were killed at 65 weeks, and hematology, clinical chemistry, and histopathology were evaluated. A complete histopatho-logical evaluation was performed on all other animals; survivors were killed at 2 years. Survival was significantly extended in tri-prolidine-treated males and females, particularly at the high dose. At the close of the study high-dose males and females had gained significantly less body weight than controls. Among rats killed at 65 weeks females in the mid- and high-dose groups weighed significantly less than controls, but weights of control and dosed males were not significantly different. The incidences of numerous lesions tended to decrease with increasing triprolidine dose. In females, clitoral gland adenomas, thyroid c-cell hyperplasia and neoplasia, mammary gland hyperplasia and fibroadenomas, and uterine stromal polyps, and in males, anterior pituitary gland adenomas, preputial gland neoplasia, thyroid c-cell hyperplasia, pancreatic islet neoplasia, mononuclear cell leukemia, and the combination of lymphocytic, histiocytic, and undifferentiated cell malignant lymphomas and mononuclear leukemia, all exhibited negative dose trends. Cytoplasmic alterations of the parotid gland and numerous liver lesions tended to be more frequent in treated than in control animals. Liver lesions that exhibited positive dose trends include chronic inflammation and centrilobular fatty change in both sexes, mixed cell foci, and the combination of mixed cell foci and eosinophilic foci in females, and in males, basophilic foci and eosinophilic foci. Triprolidine was not carcinogenic in F344 rats.
Food and Chemical Toxicology | 1987
David L. Greenman; Ralph L. Kodell; B. Highman; G.J. Schieferstein; M. Norvell
C3H/HeN-MTV+ female mice were fed diets containing 320 or 640 ppb diethylstilboestrol (DES). DES feeding was started at 3 wk of age and was either continued throughout life or discontinued after 4, 8 or 26 wk of administration. A control group consisted of mice fed the same diet without DES, for the duration of the experiment. Mice were killed when palpable body masses (presumed to be mammary adenocarcinomas) reached a diameter of 1 cm. Adenocarcinomas developed in 79% of control mice and 96% of the mice exposed to DES for 26 wk, irrespective of the dose. The frequency and rate of removal of tumour-bearing mice were not increased further with lifetime exposure at a given dose. The time at which the first tumour occurred was largely dependent on the duration of exposure, not dose. The rate of occurrence of subsequent tumours was dependent on dose and duration of exposure; the rate of removal of mice with mammary adenocarcinomas was significantly greater at 640 ppb than at 320 ppb DES. Tumour frequency was 83% in mice exposed to 320 ppb DES for 8 wk and in those exposed for 4 wk; however, tumours developed at a faster rate in mice exposed for 8 wk. Tumour frequency was 94-96% in mice exposed to 640 ppb DES for 4 wk and 8 wk, and tumours developed more rapidly in mice exposed for 8 wk than in those exposed for 4 wk. When data were plotted as log-dose v. log-t50 (time to a probability that half the mice would be removed with mammary tumours) linear extrapolation to the control log-t50 gave an estimate of the no-effect level of exposure to DES. This estimate was remarkably consistent for all data sets (40-93 ppb) and was independent of the duration of exposure.
Toxicological Sciences | 1995
David L. Greenman; Winslow G. Sheldon; G.J. Schieferstein; Richard R. Allen; William T. Allaben
Triprolidine hydrochloride was fed to groups of 60 B6C3F1 mice per sex at dietary levels of 0, 500, 2000, or 4000 ppm (as the free base) for up to 2 years. Up to 12 mice of each sex and dose group were terminated after 65 weeks for hematology and clinical chemistry. The control and high-dose groups were examined histologically. A complete histopathological examination was performed on the remaining 48 mice from each dose group when removed from study due to moribund condition, early death, or terminal euthanization at 105 weeks. Triprolidine did not significantly alter the survival of either sex. High-dose male and mid- and high-dose female body weights were significantly less than controls at the end of the study. Significant trends toward lower frequency with increasing dose were noted in females for fatty change in the liver and lymphomas (combination of lymphocytic, mixed, and histiocytic lymphomas). Similar negative trends in males were for lymphocytic cellular infiltration in multiple organs and lung alveolar/bronchiolar adenomas or the combination of alveolar/bronchiolar adenomas or carcinomas. Significant trends toward increased frequency with increasing dose were found in female mice for lymphocytic infiltration in multiple organs and cytoplasmic alterations of the acinar cells of the parotid gland. Similar positive trends were found in males for cytoplasmic alterations of the parotid gland and various hepatocellular changes (e.g., hypertrophy and altered foci). While there was a positive dose response trend for hepatocellular adenomas in males the combination of these and hepatocellular carcinomas eliminated the significant trend, and it was concluded that there was no evidence of a carcinogenic response to triprolidine in B6C3F1 mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Toxicologic Pathology | 1981
Charles H. Frith; Karl P. Baetcke; C.J. Nelson; G.J. Schieferstein
The incidence of liver tumors induced in mice with benzidine dihydrochloride was highest in the left lateral lobe, intermediate in the right lateral and central lobes and lowest in the caudate lobe. The distribution of liver tumors was related to lobe volume and weight.
Food and Chemical Toxicology | 1985
David L. Greenman; B. Highman; Ralph L. Kodell; G.J. Schieferstein; M. Norvell
C3H/HeN-MTV+ female mice were fed diets containing targeted concentrations of 320 or 640 ppb diethylstilboestrol (DES) starting at 3, 5, 7 or 11 wk of age and continuing throughout their remaining lifespan. Mice were housed in either a single-corridor conventional animal room or in a double-corridor barrier-type animal room. Mice housed in the conventional animal room and started on DES at 7 or 11 week of age developed palpable mammary tumours somewhat sooner than the corresponding groups of mice kept in the barrier animal room. In mice housed in the barrier animal room and exposed to a given DES concentration, there was very little difference between mice started on DES at 3, 5 or 7 wk of age in the exposure time required for the development of palpable mammary tumours. There was a striking difference, however, between mice started on DES at 7 wk and those started at 11 wk of age in the exposure time needed before mammary tumours appeared. Mice started at 11 wk of age developed tumours with, on average, about 4 wk less exposure than did those started at 7 wk. This suggests that treatment between 7 and 11 wk of age had little or no effect on mammary tumour development. In conclusion, both animal-room environment and age at the start of DES treatment influenced the mammary tumour response in female C3H/HeN-MTV+ mice.