National Toxicology Program genetically modified model report最新文献

Senna is used as a stimulant laxative in the management of constipation resulting from opioid use or when treatment with bulking or osmotic agents has failed. Increased use of senna was expected due to the removal of the stimulant laxatives danthron and phenolphthalein from the market. Senna was nominated for study by the Center for Drug Evaluation and Research, United States Food and Drug Administration (FDA) due to the wide use of laxative preparations, positive genotoxicity in vitro for some senna components or metabolites, and unknown carcinogenic potential. Because a 2-year rat study was ongoing by the manufacturer, the FDA requested that the NTP conduct a senna study in the p53(+/-) mouse. In this study, the potential for carcinogenic effects of senna was studied in the C3B6.129F1/Tac-Trp53tm1Brd N12 haploinsufficient (heterozygous F1 p53(+/-)) mouse model as an ongoing goal of the NTP to develop and test model systems for toxicology and carcinogenesis studies, especially those that can provide mechanistic information relative to understanding an agents mode of action. C57BL/6NTac mice were exposed to senna in feed for 5 weeks; heterozygous F1 p53(+/-) mice were exposed to senna in feed for 40 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes.

Unlabelled: Allyl bromide is primarily used as a starting material/chemical intermediate in organic synthesis and as an intermediate in the manufacture of polymers/resins, synthetic perfumes, pharmaceuticals, agricultural chemicals, and other allyl compounds. It has been described as an insecticidal fumigant used in crop protection. Male and female FVB/N and C57BL/6 mice received allyl bromide (greater than 99% pure) by gavage and dermal application, respectively, for 2 weeks, and FVB/N, C57BL/6, Tg.AC hemizygous, and p53 haploinsufficient mice received allyl bromide by gavage for 40 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK STUDIES IN FVB/N MICE: Groups of five male and five female FVB/N mice were dermally administered 0, 7.5, 15, 30, 60, or 120 mg allyl bromide/kg body weight in acetone, 5 days a week for 2 weeks. The survival and mean body weights of all dosed groups of males and females were similar to those of the vehicle controls. There were no increases in the incidences of lesions in dosed mice. 2-WEEK STUDIES IN C57BL/6 MICE: Groups of five male and five female FVB/N mice were administered 0, 7.5, 15, 30, 60, or 120 mg allyl bromide/kg body weight in corn oil by gavage, 5 days a week for 2 weeks. Three 120 mg/kg male mice died prior to the end of the study. Mean body weights of all dosed groups of males and females were similar to those of the vehicle controls. Liver weights of 30 and 60 mg/kg males were significantly greater than those of the vehicle controls. Nonneoplastic lesions of the forestomach, including hyperplasia, inflammation, degeneration, and hyperkeratosis of the forestomach epithelium, were observed in dosed mice. 40-WEEK STUDIES IN FVB/N MICE: Groups of 15 male and 15 female FVB/N mice were administered 0 or 8 mg allyl bromide/kg body weight in corn oil by gavage, 5 days a week for 40 weeks. Survival of dosed mice was similar to that of the vehicle controls. Mean body weights of dosed mice were within 10% of those of the vehicle controls throughout most of the study. There were no chemical-related gross or microscopic findings in dosed mice. 40-WEEK STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 0.5, 1, 2, 4, or 8 mg allyl bromide/kg body weight in corn oil by gavage, 5 days a week for 40 weeks. Survival of dosed mice was similar to that of the vehicle controls. Mean body weights were generally similar between dosed and vehicle control mice throughout the study. In female mice, there were increased numbers of cutaneous and mucocutaneous masses (gross observations) on the body, particularly the vaginal and vulvar area, and these papillomas were observed earlier in the dosed groups. There were positive trends in the incidences of squamous cell papilloma of the vulva and of all skin sites in females. 40-WEEK STUDIES IN C57BL/6 MICE: Groups of 15 male and 15 female

Unlabelled: Phenolphthalein was commonly used as a laxative for most of the 20th century. The use of phenolphthalein in laxatives has decreased since 1997 when the United States Food and Drug Administration (FDA) proposed to withdraw its classification as an over-the-counter drug (21 CFR, Part 310). Phenolphthalein has been previously evaluated in 2-year carcinogenicity studies by the National Toxicology Program (1996). The major route of human exposure to phenolphthalein is via ingestion, dermal contact, and inhalation of contaminated air originating from process units manufacturing the compound. In this study, the carcinogenic effects of phenolphthalein were studied in the haploinsufficient p16(Ink4a)/p19(Arf) mouse model as an ongoing goal of the NTP is to seek model systems for toxicology and carcinogenesis studies, especially those that can provide mechanistic information relative to understanding an agent's mode of action. Male and female haploinsufficient p16(Ink4a)/p19(Arf) mice were exposed to phenolphthalein (greater than 97% pure) in feed for 27 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 27-WEEK STUDY IN MICE: Groups of 15 male and 15 female mice were exposed to 0, 200, 375, 750, 3,000, or 12,000 ppm phenolphthalein (equivalent to average daily doses of approximately 35, 65, 135, 540, and 2,170 mg phenolphthalein/kg body weight to males and 50, 90, 170, 680, 2,770 mg/kg to females) in feed for 27 weeks. Survival of all exposed groups of male and female mice was similar to that of the control groups. Mean body weights of males in the 12,000 ppm group were less than those of the control group after week 11. No differences in feed consumption were noted between exposed and control groups. Atypical hyperplasia of the thymus, a premalignant change of chemically induced thymic lymphoma, occurred in exposed males and females, and the incidence was significantly increased in 12,000 ppm females. Atrophy of the seminiferous tubules in the testis, hyperplasia of the testicular interstitial (Leydig) cells, and epididymal hypospermia occurred in most 3,000 and 12,000 ppm males. Additionally, the left and right testis weights, the left epididymis weights, sperm motility, the numbers of spermatid heads per testis, and sperm heads per cauda and per gram cauda epididymis were generally significantly less in 3,000 and 12,000 ppm males than in the control group. The incidences of nephropathy were significantly increased in 3,000 and 12,000 ppm males; incidences of hypertrophy of renal tubules were significantly increased in males receiving 750 ppm or greater. Hematopoietic cell proliferation of the spleen occurred in all 12,000 ppm males, and the incidences of this lesion were significantly increased in 375, 750, and 12,000 ppm females.

Genetic toxicology: The frequency of micronucleated erythrocytes was assessed at four time points during the 27-week study in male a

Unlabelled: Glycidol is used as a chemical intermediate in the pharmaceutical industry, as a stabilizer in the manufacture of vinyl polymers, and as an intermediate in the synthesis of glycerol, glycidyl ethers, and amines. Glycidol was nominated for carcinogenicity study by the United States Environmental Protection Agency. Glycidol was selected for study in the haploinsufficient p16(Ink4a)/p19(Arf) mouse because it was found to be carcinogenic in rats and mice in conventional 2-year rodent studies (NTP, 1990), but was negative in a study in p53+/- mice (Tennant et al., 1999). Male and female haploinsufficient p16(Ink4a)/p19(Arf) mice received glycidol (greater than 95% pure) by gavage for 40 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 40-WEEK STUDY IN MICE: Groups of 15 male and 15 female haploinsufficient p16(Ink4a)/p19(Arf) mice were administered 0, 25, 50, 100, or 200 mg glycidol/kg body weight in deionized water by gavage, 5 days per week for 40 weeks. Survival of 200 mg/kg male and female mice was less than that of the vehicle control groups, but the differences were not significant. Mean body weights of 200 mg/kg male mice and 50, 100, and 200 mg/kg female mice were less than those of the vehicle controls. The left testis, left epididymis, and left cauda epididymis weights were significantly decreased in 200 mg/kg males; the number of sperm heads per cauda epididymis were also significantly decreased in this group. Enlarged spleen and foci of discolored liver were observed in 200 mg/kg male mice at necropsy. These findings corresponded to infiltration by histocytic sarcoma or extramedullary hematopoiesis. The incidences of histiocytic sarcoma were increased in dosed groups of males and in females administered 50 mg/kg or greater, and the incidences in 50 and 200 mg/kg males were significantly greater than that in the vehicle control group. In the lung, incidences of alveolar/bronchiolar adenoma were significantly increased in 100 mg/kg males and 200 mg/kg females; multiple adenomas were seen in some dosed males. Squamous cell papillomas of the forestomach were seen in one 200 mg/kg male, one 100 mg/kg female, and three 200 mg/kg females. Significantly increased incidences of epithelial hyperplasia occurred in the forestomach of 200 mg/kg males and females. Neuronopathy, gliosis, and hemorrhage of the brain were observed at various sites in a few 200 mg/kg males and 100 and/or 200 mg/kg females.

Genetic toxicology: The frequency of micronucleated erythrocytes was monitored in peripheral blood of male and female haploinsufficient p16(Ink4a)/p19(Arf) mice in the 40-week study. No significant increases were observed at 6.5, 13, or 19.5 weeks; small but statistically significant increases were seen in both male and female mice sampled at 26 and 40 weeks.

Conclusions: Under the conditions of this 40-week gavage study, there was clear e

Unlabelled: Benzene is used primarily as a solvent in the chemical and pharmaceutical industries, as a starting material and intermediate in the synthesis of numerous chemicals, and in gasoline. The major United States source of benzene is petroleum. Benzene has been previously evaluated in 2-year carcinogenicity studies by the National Toxicology Program (1986). In this study, the carcinogenic effects of benzene were studied in the haploinsufficient p16 Ink4a/p19 Arf mouse model as part of an ongoing NTP effort to seek improved model systems for toxicology and carcinogenesis studies, especially those that can provide mechanistic information relative to understanding an agent's mode of action. Male and female haploinsufficient p16 Ink4a/p19 Arf mice were administered benzene (greater than 99% pure) by gavage for 27 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 27-WEEK STUDY in MICE: Groups of 15 male and 15 female haploinsufficient p16 Ink4a/p19 Arf mice were administered 0, 25, 50, 100, or 200 mg benzene/kg body weight in corn oil by gavage 5 days per week for 27 weeks. All animals survived until the end of the study except one male administered 200 mg/kg. Mean body weights of males administered 50 mg/kg or greater were generally less than those of the vehicle controls throughout the study, and those of 25 mg/kg males were less after week 13. Mean body weights of 200 mg/kg females were less than those of the vehicle controls after week 17. Treatment-related clinical findings in 25 mg/kg or greater males and 50 mg/kg or greater females included black, brown, or gray discoloration (pigmentation) of the feet. The thymus weights of all dosed groups of males were significantly decreased. At weeks 13 and 27, a dose-related decrease in the erythron occurred in males and females. The erythron decrease was shown by decreases in the hematocrit, hemoglobin, and erythrocyte count values in all dosed males and in the 100 mg/kg or greater females. Decreased leukocyte counts, primarily lymphocyte counts, resulted in a dose-related leukopenia in males and females. In males, segmented neutrophil counts were also decreased. The incidence of malignant lymphoma was significantly increased in 200 mg/kg males compared to the vehicle controls. In the bone marrow, significantly increased incidences of minimal to mild atrophy occurred in the 100 and 200 mg/kg males compared to the vehicle controls. In the spleen, there were significantly increased incidences of lymphoid follicle atrophy in 100 and 200 mg/kg male mice. The incidence of hematopoietic cell proliferation was significantly increased in 200 mg/kg males. The incidences of atrophy of the thymus in the 100 and 200 mg/kg males were significantly greater than those in the vehicle controls. In the lymph nodes, significantly increased incidences of atrophy (mandibular, mediastinal, and mesenteric) occurred in 100 and 200 mg/kg males, and the incidence of

Dicyclohexylcarbodiimide is used in industry as a stabilizing agent, coupling agent, and condensing agent. Its widespread use during protein synthesis in the recombinant DNA industry and in the synthesis of polypeptides in the chemical and pharmaceutical industries provides an increasing potential for low-level human exposure. Dicyclohexylcarbodiimide was nominated for study by The National Cancer Institute as a key representative of the carbodiimide chemical class because of its acute toxicity and the absence of data on potential health effects. Male and female F344/N rats and B6C3F 1 mice were administered dicyclohexylcarbodiimide (greater than 98% pure) dermally for 3 or 13 weeks. Female Tg.AC hemizygous and p53 haploinsufficient mice were administered dicyclohexylcarbodiimide dermally for 20 or 27 weeks, respectively. Genetic toxicology studies were conducted in Salmonella typhimurium, male F344/N rat bone marrow cells, and B6C3F 1 mouse peripheral blood erythrocytes. 3-WEEK STUDY IN F344/N RATS Groups of five male and five female rats were dermally administered 0.3 mL ethanol containing 0, 0.6, 1.8, 5.1, 15, or 45 mg dicyclohexylcarbodiimide, 5 days per week for 3 weeks. All males and females in the 15 and 45 mg groups, four 5.1 mg males, and all 5.1 mg females died before the end of the study. Of the surviving groups, final mean body weights were similar to those of the vehicle controls, although the one surviving 5.1 mg male rat lost weight during the study. Histopathologic examination of rats dosed with 5.1 mg dicyclohexylcarbodiimide or less revealed treatment-related lesions of the skin at the site of application including epidermal hyperplasia, epidermal necrosis, or chronic active inflammation in the dermis. 3-WEEK STUDY IN B6C3F 1 MICE Groups of five male and five female mice were dermally administered 0.1 mL of ethanol containing 0, 0.2, 0.6, 1.7, 5, or 15 mg dicyclohexylcarbodiimide, 5 days per week for 3 weeks. One 0.6 mg female mouse and all mice in the 1.7, 5, and 15 mg groups died before the end of the study. Final mean body weights of the 0.6 mg groups were significantly less than those of the vehicle controls, and animals in these groups generally lost weight during the study. Histopathologic examination of mice dosed with 1.7 mg dicyclohexylcarbodiimide or less revealed treatment-related lesions of the skin at the site of application including epidermal hyperplasia, epidermal necrosis, and acute or chronic active dermal inflammation. 13-WEEK STUDY IN F344/N RATS Groups of 10 male and 10 female core study rats were dermally administered 0, 0.75, 1.5, 3, 6, or 12 mg dicyclohexylcarbodiimide/kg body weight in ethanol, 5 days per week for 13 weeks; groups of 10 male and 10 female clinical pathology study rats were administered the same doses for 22 days. All 12 mg/kg male and female core study rats died or were found moribund and sacrificed prior to day 45. Final mean body weight and body weight gain of 6 mg/kg males were

Unlabelled: Bromodichloromethane is a by-product of the chlorination of drinking water. It is formed by the halogen substitution and oxidation reactions of chlorine and naturally occurring organic matter (e.g., humic or fluvic acids) in water containing bromide. Bromodichloromethane was nominated to the NTP by the United States Environmental Protection Agency for toxicology and carcinogenicity studies. Male and female Tg.AC hemizygous mice received bromodichloromethane (at least 98%pure) by dermal application for 26 or 39 weeks, in drinking water for 26 or 42 weeks, or by gavage for 26 or 41 weeks. p53 Haploinsufficient mice received bromodichloromethane in drinking water for 26 or 42 weeks or by gavage for 26 or 41 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 26- and 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were dermally administered 0, 64, 128, or 256 mg bromodichloromethane/kg body weight in acetone, 5 days per week for 26 weeks, and groups of 10 male and 10 female Tg.AC hemizygous mice were dermally administered the same doses 5 days per week for 39 weeks. The survival and mean body and organ weights of all dosed groups of males and females were similar to those of the vehicle controls. There were no statistically or biologically significant increases in the incidences of neoplasms or nonneoplastic lesions. 26- AND 42-WEEK DRINKING WATER STUDIES IN TG.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L bromodichloromethane for 26 weeks (equivalent to average daily doses of approximately 20, 36, or 61 mg bromodichloromethane/kg body weight to males and 31, 61, or 130 mg/kg to females). The survival of exposed males and females was similar to that of the control groups. Mean body weights of males exposed to 350 or 700 mg/L were less than those of the controls during most of the study. Mean body weights of 175, 350, and 700 mg/L females were greater than those of the controls after weeks 10, 22, and 23, respectively. In exposed males, water consumption declined with increasing exposure concentration. Water consumption by exposed females was less at the beginning of the study, but was similar to that by controls at the end of the study. The decreased water consumption was related to poor palatability. Absolute heart and right kidney weights of exposed males were significantly less than those of the control group. The incidences of hepatocyte fatty change and hypertrophy in 350 and 700 mg/L females and cytoplasmic vacuolization in 700 mg/L females were significantly greater than those in the control group. Incidences of renal tubule dilatation in males exposed to 175 mg/L or greater, renal tubule hypertrophy in 350 and 700 mg/L males, and nephropathy and renal tubule degeneration in 700 mg/L males were also increased. Groups of 10 male

Unlabelled: Dichloroacetic acid was nominated for study by the United States Environmental Protection Agency (EPA) and by the National Institute of Environmental Health Sciences because of its widespread occurrence in drinking water as a by-product of water disinfection using chlorination. It was also nominated because dichloroacetic acid is the most studied representative of the class of haloacetic acids and has been shown to cause liver tumors in both rats and mice. Haloacetic acids are second only to trihalomethanes as a family of disinfection by-products found in many drinking water supplies. Dichloroacetic acid is one of several disinfection by-products being evaluated to determine whether genetically modified mouse models can serve as a more rapid and cost-effective means of evaluating and ranking potential hazards of disinfection by-products. The NTP has explored the use of genetically altered mouse models as adjuncts to 2-year rodent cancer assays. These models may prove to be more rapid, use fewer animals, and provide some mechanistic insights into neoplastic responses. As part of the evaluation of new mouse cancer screening models, dichloroacetic acid was tested for potential toxicity and carcinogenicity in two relatively well-studied models, the Tg.AC hemizygous strain and the p53 haploinsufficient strain. Male and female Tg.AC hemizygous and p53 haploinsufficient mice were exposed to dichloroacetic acid in the drinking water (greater than 98% pure) for 26 or 39 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium strains TA98, TA100, and TA1535 and in mouse peripheral blood erythrocytes. 26- AND 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 31.25, 125, or 500 mg dichloroacetic acid/kg body weight 5 days per week for 26 weeks with additional groups of 10 males and 10 females continued on treatment for 39 weeks. Survival of dosed males and females was similar to that of the vehicle control groups for both studies. Mean body weights of dosed males and females in the 26-week study were similar to those of the vehicle control groups. Mean body weights of dosed males in the 39-week study were similar to those of the vehicle control groups. Mean body weights of the 500 mg/kg females were greater than those of the vehicle controls in the 39-week study. The absolute liver weights were increased by greater than 50% compared to the vehicle controls for the 500 mg/kg males and females in both studies. At the site of application, the incidences of squamous cell papilloma were significantly increased in 500 mg/kg males and females at 39 weeks. In addition, one 125 mg/kg male, two 500 mg/kg males, and two 500 mg/kg females had squamous cell papillomas at 26 weeks. The incidences of epidermal hyperplasia and hyperkeratosis were significantly increased at the site of application in the 125 and 500 mg/kg males and females at 26 weeks.

Unlabelled: Diisopropylcarbodiimide is used as a reagent for a variety of reactions including peptide syntheses. The National Cancer Institute nominated diisopropylcarbodiimide for study as a representative chemical in the alkylcarbodiimide class because of its acute toxicity, widespread low-level human exposure, and the absence of data on health effects. Female Tg.AC hemizygous or p53 haploinsufficient mice were administered diisopropylcarbodiimide (greater than 99% pure) dermally for 20 or 27 weeks, respectively. 20-WEEK STUDY IN Tg.AC HEMIZYGOUS MICE: Groups of 10 female Tg.AC hemizygous mice received dermal applications of 0, 4.38, 8.75, 17.5, 35, or 70 mg diisopropylcarbodiimide/kg body weight in ethanol, 5 days a week for 20 weeks. Twelve animals died or were sacrificed moribund prior to the end of the study; two each from vehicle controls, 4.38, 8.75, and 17.5 mg/kg groups, and four from the 35 mg/kg group. Premature deaths were not associated with chemical-related lesions. Odontoma, a common spontaneous finding in Tg.AC hemizygous mice, resulting in jaw malformation, malocclusion, and loss of body condition, occurred in the majority of control, 4.38, 8.75, and 17.5 mg/kg animals that died prematurely. Of the surviving animals, mean body weights were similar to those of vehicle controls. There were no significant changes in organ weights and no treatment-related clinical findings. No neoplasms or nonneoplastic lesions were attributed to administration of diisopropylcarbodiimide. 27-WEEK STUDY IN p53 HAPLOINSUFFICIENT MICE: Groups of 15 female p53 haploinsufficient mice received dermal applications of 0, 4.38, 8.75, 17.5, 35, or 70 mg/kg diisopropylcarbodiimide in ethanol, 5 days a week for 27 weeks. All animals survived to the end of the study. Mean body weights were similar to those of vehicle controls, and there were no treatment-related clinical findings. At necropsy there were no treatment-related gross lesions. Microscopically, there was a higher incidence of treatment-related, predominantly minimal epidermal hyperplasia at the site of application in 70 mg/kg mice than in vehicle controls. No neoplasms were attributed to the administration of diisopropylcarbodiimide.

Conclusions: Under the conditions of this 27-week study, there was no evidence of carcinogenic activity of diisopropylcarbodiimide in female p53 haploinsufficient mice administered 4.38, 8.75, 17.5, 35, or 70 mg/kg in ethanol. There were no treatment-related neoplasms or nonneoplastic lesions in female Tg.AC hemizygous mice administered 4.38, 8.75, 17.5, 35, or 70 mg/kg in ethanol for 20 weeks. Synonyms: 1,3-Diisopropylcarbodiimide; N,N'-diisopropylcarbodiimide; N,N'-methanetetraylbis (2-propanamine).

Unlabelled: Bromate is a drinking water disinfection by-product formed during the ozonation of source water containing bromide. Sodium bromate is also used as an analytical reagent, in the oxidation of sulfur and vat dyes, and for cleaning boilers. As a mixture with sodium bromide, it is used for dissolving gold from its ores. The cosmetic industry uses sodium bromate and potassium bromate as neutralizers or oxidizers in hair wave preparations. Sodium bromate was nominated for toxicity and carcinogenicity studies in transgenic mouse models by the United States Environmental Protection Agency and the National Institute of Environmental Health Sciences. Male and female Tg.AC hemizygous mice received sodium bromate by dermal application for 26 or 39 weeks and by exposure in drinking water for 27 or 43 weeks. Male and female p53 haploinsufficient mice were exposed to sodium bromate (at least 99% pure) in drinking water for 27 or 43 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 26- and 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice received dermal applications of 0, 64, 128, or 256 mg sodium bromate/kg body weight in ethanol/water, 5 days per week for 26 weeks. Additional groups of 10 male and 10 female Tg.AC hemizygous mice were dermally administered the same doses for 39 weeks. Survival of dosed groups was similar to that of vehicle control groups at 26 and 39 weeks. Mean body weights of 256 mg/kg males were less than those of the vehicle control group in both studies. Mean body weights of all dosed groups of females were less than those of the vehicle controls at 39 weeks. Minimal decreases in hematocrit and hemoglobin concentration values occurred in 128 mg/kg females and 256 mg/kg males and females at 26 weeks. A minimal decrease in erythrocyte count also occurred in 256 mg/kg males. These decreases in erythron were accompanied by a minimal decrease in mean cell hemoglobin and mean cell hemoglobin concentration values, primarily in the females. Reticulocyte counts were significantly increased in 128 mg/kg females and 256 mg/kg males and females. There were no increased incidences of neoplasms in male or female Tg.AC hemizygous mice exposed to sodium bromate dermally. Relative kidney weights were significantly increased in 256 mg/kg males at 26 weeks and in all dosed groups of males at 39 weeks. Absolute testis weights in 256 mg/kg males and absolute kidney weights in 256 mg/kg females were decreased at 39 weeks. Nephropathy occurred in 14 of 15 males receiving 128 and 256 mg/kg at 26 weeks and in all 256 mg/kg females in both studies. In the thyroid gland, the incidences of follicular cell hypertrophy in all dosed groups of males and females, follicular secretory depletion in 128 and 256 mg/kg females, and lymphocytic cellular infiltrate in 256 mg/kg females were significantly increased in both studies. Splenic hematopoietic cell