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Epidemiologic data suggest that soy consumption may protect against cancer induction in several tissues in humans. Although the soy components responsible for this activity remain unidentified, isoflavones (e.g., genistein) and protease inhibitors (e.g., Bowman-Birk inhibitor complex [BBIC]) demonstrate chemopreventive activity in several animal cancer models. As part of their preclinical development for cancer prevention, PTI G-2535 (a soy isoflavone mixture containing 45%genistein,23%daidzein, and 4%glycitein) and BBIC were evaluated for oncogenicity in p 53(+/-) mice. In separate studies, groups of 25 p53(+/-) mice/sex received daily gavage exposure to PTI G-2535 (0, 250, 1000, or 2500 mg/kg/day) or BBIC (0, 500, 1000, or 2000 mg/kg/day) for 6 months. The high doses of both PTI G-2535 and BBIC were limited by viscosity. p -Cresidine (400 mg/kg/day) served as a positive-control article in both studies. PTI G-2535 induced no gross toxicity in any animal, but did induce a dose-related suppression of body weight gain in male mice. Modest hematologic alterations and increased liver and spleen weights were seen in both sexes exposed to the isoflavone mixture. BBIC had no significant effect on body weight, food consumption, clinical pathology, or organ weights in either sex. Histopathologic evaluations demonstrated no increases in the incidence of either benign or malignant tumors in any group of p53(+/-) mice exposed to PTI G-2535 or to BBIC. By contrast, the positive-control article, p -cresidine, induced urinary bladder cancers in both studies. Neither PTI G-2535 nor BBIC demonstrates any evidence of oncogenicity in the p53(+/-) mouse model. [ABSTRACT FROM PUBLISHER]

Epidemiologic data suggest that soy consumption may protect against cancer induction in several tissues in humans. Although the soy components responsible for this activity remain unidentified, isoflavones (e.g., genistein) and protease inhibitors (e.g., Bowman-Birk inhibitor complex [BBIC]) demonstrate chemopreventive activity in several animal cancer models. As part of their preclinical development for cancer prevention, PTI G-2535 (a soy isoflavone mixture containing 45% genistein, 23% daidzein, and 4% glycitein) and BBIC were evaluated for oncogenicity in p53 (+/-) mice. In separate studies, groups of 25 p53 (+/-) mice/sex received daily gavage exposure to PTI G-2535 (0, 250, 1000, or 2500 mg/kg/day) or BBIC (0, 500, 1000, or 2000 mg/kg/day) for 6 months. The high doses of both PTI G-2535 and BBIC were limited by viscosity. p -Cresidine (400 mg/kg/day) served as a positive-control article in both studies. PTI G-2535 induced no gross toxicity in any animal, but did induce a dose-related suppression of body weight gain in male mice. Modest hematologic alterations and increased liver and spleen weights were seen in both sexes exposed to the isoflavone mixture. BBIC had no significant effect on body weight, food consumption, clinical pathology, or organ weights in either sex. Histopathologic evaluations demonstrated no increases in the incidence of either benign or malignant tumors in any group of p53 (+/-) mice exposed to PTI G-2535 or to BBIC. By contrast, the positive-control article, p -cresidine, induced urinary bladder cancers in both studies. Neither PTI G-2535 nor BBIC demonstrates any evidence of oncogenicity in the p53 (+/-) mouse model. [ABSTRACT FROM AUTHOR]

Glycerin (CAS no. 56-81-5) and propylene glycol (CAS no. 57-55-6) are commonly used as humectant ingredients in manufactured cigarettes to control and maintain the moisture content of the cut tobacco filler. The potential of these added humectants to affect the toxicity of cigarette smoke was investigated in a subchronic nose-only smoke inhalation study in rats. Filtered test cigarettes were prepared from an American-style tobacco blend containing either glycerin added at 5.1% w/w tobacco, propylene glycol at 2.2% w/w tobacco, or combinations of these humectants totaling 2.3%, 3.9%, and 7.2% w/w tobacco. Other groups of animals were exposed similarly to the smoke of reference cigarettes without added humectants, or to filtered air (sham control). Smoke exposures were conducted for 1 h/ day, 5 days/wk for 13 wk, at target smoke particulate concentrations of 350 mg/m[sup 3]. All smoke-exposed groups had equivalent increases in blood carboxyhemoglobin, serum nicotine, and serum cotinine relative to the air controls. Smoke-associated reductions in body weights and occasional increases in heart and lung weights were generally similar among the various exposure conditions at necropsy. Increases in serum alkaline phosphatase and decreases in serum glucose and cholesterol were observed among smoke-exposed females relative to air controls. However, no significant differences in these parameters were evident between the humectant-containing and reference cigarette smoke exposure groups. Assessments of respiration conducted after 3, 6, 9, and 12 wk of smoke exposure indicated an initial smoke-related but not humectant-related decrease in respiratory rate, tidal volume, and minute volume during the first 20 min of each smoke exposure. Respiratory-tract histopathology was consistent across sexes and smoke groups, comprising (1) diffuse and focal alveolar pigmented macrophages and chronic interstitial inflammation in the lung, (2) laryngeal epithelial hyperplasia, squamous metaplasia, and scab formation, and (3) epithelial hyperplasia in the anterior nose. Smoke-related histopathology resolved substantially during a 6-wk postexposure recovery period. Addition of the tested humectants to cigarettes, singly or in combination, had no meaningful effect on the site, occurrence, or severity of respiratory-tract changes or on the measured indices of pulmonary function. It was concluded that the addition of glycerin and propylene glycol to cigarettes does not significantly affect the biological activity of inhaled cigarette smoke in this rat model. [ABSTRACT FROM AUTHOR]

This study examined the toxicity of 1,2-dithiole-3-thione (D3T) in rats following 14 days of daily oral (gavage) administration. D3T, an extensive inducer of hepatic phase II drug-metabolizing enzymes, has demonstrated cancer preventive efficacy in rodent models of tumorigenesis and is a candidate drug for cancer prevention. Male and female CD rats (5/sex/dose group) received D3T at dose levels of 0 (corn oil vehicle control), 2, 6, 20, and 60 mg/kg/day. Oral administration of D3T for 14 days at ≥20 mg/kg/day resulted in decreased activity, lethargy, rough coat, and piloerection, and toxicologically significant lesions in the stomach, characterized by apoptotic necrosis and hyperplasia of the glandular mucosa. Administration of D3T at 60 mg/kg/day produced anemia in females, decreased body weight gain in males, and increased vacuolation of adrenal cortical cells. Increased liver weights, vacuolation of hepatocytes, and serum chemistry changes, indicative of altered liver function, were observed at ≥ 6 mg/kg/day, which were likely due to a pharmacologic effect of D3T on the liver and not considered to be toxicologically significant. Under the conditions of the study, the no-observed-adverse effect level (NOAEL) was 6 mg/kg/day. [ABSTRACT FROM AUTHOR]

Obese mottled yellow A, lean pseudoagouti A and lean black / (YS×VY) F-1 hybrid female mice were fed diet containing 160 p.p.m. lindane (γ-hexachlorocyclohexane) for 6, 12, 18 or 24 months. Clara cell hyperplasia was present in a majority of the mice after six months of lindane ingestion; however, more yellow mice (77%) than pseudoagouti (50%) or black (56%) mice had developed this lesion. Continued ingestion of lindane increased the incidence of Clara cell hyperplasia and resulted in similar prevalences in the three phenotypes. Lung tumors associated with lindane ingestion for 24 months were found only in yellow (19%) and pseudoagouti (14%) mice but in the black mice. Prevalences of hepatocellular adenomas and carcinomas were very low (<10%) in untreated pseudoagouti and black mice. Lindane ingestion for 24 months resulted in an hepatocellular adenoma prevalence of 12% in pseudoagouti mice and 3% in black mice; comparable hepatocellular carcinoma prevalences were 5% and 1%. Among yellow mice fed lindane diet for 24 months, adenoma prevalence was 35% (9% among untreated controls) but carcinoma prevalence was only 17% (13% among controls). The tumorigenic responses evoked by lindane feeding in the lean pseudoagouti A mice but not in the black / mice indicate, for the first time, that the A gene itself, in the absence of obesity, sensitizes cells to transformation. The greater prevalence of hepatocellular adenomas in obese yellow A than in lean pseudoagouti A mice implicates obesity-associated factors in tumor promotion. Similarly, the increased prevalence of hepatocellular carcinomas in untreated obese yellow A mice, as compared to lean pseudoagouti mice, implicates obesity-associated factors as favoring histiotypic progression of liver tumors. Thus, the A gene not only sensitizes cells to respond to tumorigenic stimuli but also, by the induction of obesity, enhances promotion and progression of transformed cells. [ABSTRACT FROM PUBLISHER]

Mottled yellow and agouti (C3H × VY) F-l hybrid male mice were fed untreated control diet or diet with a target dose of 500 p.p.m. sodium phenobarbital (PB) for 17–19 months. No differences in prevalence of hepatocellular adenomas or carcinomas were found between untreated yellow and agouti mice. PB treatment increased prevalence of adenomas but decreased prevalence of carcinomas. No difference in enhancement of adenoma formation by PB was observed between yellow and agouti mice bearing single adenomas. However, the proportion of PB-treated yellow mice bearing multiple adenomas (66%) was much greater than the proportion of analogous agouti mice (18%). Fatty changes in the peri-portal area of the liver and focal cytoplasmic vacuolization were induced to a much greater extent in PB-treated yellow mice than among treated agoutis. PB increased the prevalence and severity of focal areas of chronic inflammation in the liver considerably more in agouti than in yellow mice. The possible relation of this finding to the altered immune responses of obese yellow mice remains to be determined. The results of this study that the use of yellow and agouti (C3H x VY) F-l hybrid mice in carcinogenicity asays make make it possible to differentiate between weak and strong promoters as well as between promoters and complete carcinogens. Weak promoters should induce hepatocellular adenomas in yellow mice even if they fail to do so in agouti mice. Promoting substances which act similarly to PB may be identified in this system by simultaneously increasing adenoma prevalence and decreasing carcinoma prevalence. Complete carcinogens should increase carcinoma prevalence in the yellow mice even at low dose levels. [ABSTRACT FROM PUBLISHER]

In this 2-year study, the suitability of the Hsd:Sprague-Dawley SD (SD) as a replacement for the Crl:CD BR (CD) rat was assessed by comparing survival rates, palpable mass incidence, body weights, food consumption, clinical laboratory parameters, and necropsy and histopathology observations. At Week 104, survival rates in the CD and SD males were 29 and 49%, respectively. Corresponding survival rates in females were 44 and 63%. The total numbers of animals with palpable masses and animals with neoplasms were similar in the CD and SD rats; however, the total numbers of palpable masses and neoplasms were higher in the CD rats. The incidence of corneal lesions was higher in the SD rats, whereas the incidence of lenticular opacities was higher in the CD rats. Body weights, food and water consumption, and organ weights were significantly lower in the SD rats. In contrast, food intake per kilogram of body weight was slightly higher in the SD rats. Numerous differences in clinical laboratory parameters between the CD and SD rats were observed. Some of these were consistent with the increased prevalence of kidney disease and secondary sequelae in the SD rats. Taken together, the better survival, smaller size, and lower food consumption of the SD rat may make it a better model for chronic bioassays. However, the increased propensity for spontaneous renal disease may limit the utility of the SD rat for studying nephrotoxic compounds. [ABSTRACT FROM AUTHOR]

Triethylenetetramine dihydrochloride (trien-2HCl; CAS No. 38260-01-04), a chelating agent used to treat Wilson's disease patients who are intolerant of the drug of choice, was tested for subchronic toxicity in B6C3F1 mice and F344 rats. Mice and rats received trien-2HCl in the drinking water at concentrations of 0, 120, 600, or 3000 ppm for up to 92 days. Twenty mice and 18 rats of each sex were assigned to each dose group fed either a cereal-based (NIH-31) or a purified (AIN-76A) diet, both containing nutritionally adequate levels of copper. An additional control group of rats and mice received a Cu-deficient AIN-76A diet. This low copper diet resulted in Cu-deficiency symptoms, such as anemia, liver periportal cytomegaly, pancreatic atrophy and multifocal necrosis, spleen hematopoietic cell proliferation, and increased heart weight, together with undetectable levels of plasma copper in rats but not in mice. Trien-2HCl lowered plasma copper levels somewhat (at 600 and 3000 ppm) in rats fed the AIN-76A diet, but did not induce the usual signs of copper deficiency. Trien-2HCl caused an increased frequency of uterine dilatation at 3000 ppm in rats fed AIN-76A diet that was not noted in females fed the Cu-deficient diet. Trien-2HCl toxicity occurred only in mice in the highest dose group fed an AIN-76A diet. Increased frequencies of inflammation of the lung interstitium and liver periportal fatty infiltration were seen in both sexes, and hematopoietic cell proliferation was seen in the spleen of males. Kidney and body weights were reduced in males as was the incidence of renal cytoplasmic vacuolization. There were no signs of copper deficiency in mice exposed to trien-2HCl. The only effect of trien-2HCl in animals fed the NIH-31 diet was a reduced liver copper level in both rat sexes, noted at 3000 ppm. [ABSTRACT FROM AUTHOR]

Following 17 – 19 months of feeding 500 p.p.m. sodium phenobarbital (PB) in the diet to yellow and agouti (C3H x VY) F hybrid male mice, two subgroups differing in responsiveness to PB with respect to promotion of hepato-cellular adenomas and body weight gain were observed within each genotype. In untreated mice of both genotypes, the presence of an adenoma at necropsy was associated with decreased body weight gain during this study. However, PB treatment inverted this association. In treated mice the presence of an adenoma at necropsy was preceded by a greater increase in body weight during the study than when no tumor was present. This increase in average body weight gain was more pronounced among the yellow mice (44%) than among the agouti mice (21%). Among yellow mice PB treatment had no effect on body weight gain unless an adenoma was present at necropsy. However, in those yellow mice in which an adenoma was found, body weight was greater than in untreated yellow controls throughout the study beginning at week 27. The mean body weight curve of treated yellow mice bearing one adenoma was slightly higher than that of treated yellow mice in which no adenoma was found. The mean body weight curve of treated yellow mice bearing multiple adenomas was significantly higher than those of yellow mice with no or only one adenoma. [ABSTRACT FROM PUBLISHER]