potassium-bromate and Kidney-Neoplasms

Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive, mainly in the bread-making process. Although adverse effects are not evident in animals fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in rats and nephrotoxic in both man and experimental animals when given orally. It has been demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing both initiating and promoting activities for rat renal tumorigenesis. However, the potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome aberrations both in vitro and in vivo. Glutathione and cysteine degrade KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine in the rat kidney. A wide range of data from applications of various analytical methods are now available for risk assessment purposes.

Topics: Adenocarcinoma; Administration, Oral; Animals; Bread; Bromates; Bromides; Carcinogenicity Tests; Carcinogens; Carcinoma, Renal Cell; Chromosome Aberrations; Cocarcinogenesis; Cricetinae; Cysteine; Dose-Response Relationship, Drug; Fish Products; Food Additives; Food Handling; Glutathione; Hair Preparations; Hearing Loss; Humans; Japan; Kidney Diseases; Kidney Neoplasms; Maximum Allowable Concentration; Mesocricetus; Mesothelioma; Mice; Mutagenicity Tests; Occupational Diseases; Peritoneal Neoplasms; Potassium; Potassium Compounds; Rats; Rats, Inbred F344; Species Specificity; Thyroid Neoplasms; United Kingdom; United States

As susceptibility to carcinogens varies considerably among different strains of experimental animals, evaluation of dose-response relationships for genotoxic carcinogen in different strains is indispensable for risk assessment. Potassium bromate (KBrO(3)) is a genotoxic carcinogen inducing kidney cancers at high doses in male F344 rats, but little is known about its carcinogenic effects in other strains of rats. The purpose of the present study was to determine dose-response relationships for carcinogenic effects of KBrO(3) on N-ethyl-N-hydroxyethylnitrosamine (EHEN)-induced kidney carcinogenesis in male Wistar rats. We found that KBrO(3) showed significant enhancement effects on EHEN-induced kidney carcinogenesis at above 250 ppm but not at doses of 125 ppm and below when evaluated in terms of induction of either preneoplastic lesions or tumors in male Wistar rats. Furthermore, KBrO(3) significantly increased the formation of oxidative DNA damage at doses of 125 and above but not at doses of 30 ppm and below in kidneys. These results demonstrated that low doses of KBrO(3) exert no effects on development of EHEN-initiated kidney lesions and induction of oxidative DNA damage. Taking account of previous similar findings in male F344 rats, it is strongly suggested that a threshold dose exists for enhancement effects of KBrO(3) on kidney carcinogenesis in rats.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Body Weight; Bromates; Carcinogens; Deoxyguanosine; Diethylnitrosamine; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Gene Expression; Kidney; Kidney Neoplasms; Male; Organ Size; Oxidative Stress; Rats; Rats, Wistar; RNA, Messenger

Renal cell tumors were significantly increased in male and female rats given potassium bromate at 250 and 500 mg/L in drinking water. In at least one other study renal cell tumors were produced in male rats at 125 mg/L. Among male mice given 750 mg/L of potassium bromate, there were no significant differences in renal cell tumors between treated and control groups after 88 weeks on test. In oxidative DNA damage tests 8-oxodeoxyguanosine (8-oxodG also referred to as 8-OH-dG) was induced in DNA in the male rat kidney in 1 week, and in females after 3 weeks at 500 mg/L, and also in both male and female rats at 250 mg/L, but not at 125 mg/L. DNA adducts are considered to be an initial step in the carcinogenesis process, however, the administered doses are not always sufficient to cause mutations, possibly due to DNA repair. In the two-step rat renal carcinogenesis model using N-ethyl-N-hydroxyethylnitrosamine (EHEN) as initiator, promotion activity by potassium bromate was measured using the BrdU labeling index. The promoting activity of bromate in male rats was much greater and extended to doses as low as 60 mg/L in male rats, whereas in females the response was limited to 250 and 500 mg/L. Therefore, it was concluded that the mechanisms contributing to cancer in the male rat were more complex than in the female rat. The accumulation of alpha2mu-globulin in the kidneys of male rats exposed to potassium bromate probably accounts for the greater labeling index in the male rat relative to the female rat. Accumulation of alpha(2mu)-globulin as a result of treatment with chemicals is unique to the male rat and does contribute to carcinogenic responses. Neither humans nor female rats display this response. Nevertheless, bromate must be considered carcinogenic because of the response of the female rats. The better correlation between 8-oxodG formation and tumor response indicates that dose-response information from the female rat would be much more relevant to human risk assessment. The fact that an elevation of BrdU-LI in the kidney of the female rat is consistent with the possibility that cell proliferation observed in female rats resulted from oxidative stress and/or cytotoxic responses in the kidney. Therefore, oxidative stress is most likely the mechanism of interest for cancer risk in humans.

Topics: Administration, Oral; Alpha-Globulins; Animals; Bromates; Carcinogens, Environmental; Carcinoma, Renal Cell; Cell Proliferation; Cocarcinogenesis; Diethylnitrosamine; DNA Adducts; DNA Damage; DNA Repair; Dose-Response Relationship, Drug; Drinking; Female; Japan; Kidney; Kidney Neoplasms; Male; Mice; Mice, Inbred Strains; Mutagenicity Tests; Mutagens; Oxidative Stress; Rats; Rats, Inbred F344; Sex Factors

To clarify the role of 8-OHdG formation as a starting point for carcinogenesis, we examined the dose-dependence and time-course of changes of OGG1 mRNA expression, 8-OHdG levels and in vivo mutations in the kidneys of gpt delta rats given KBrO3 in their drinking water for 13 weeks. There were no remarkable changes in OGG1 mRNA in spite of some increments being statistically significant. Increases of 8-OHdG occurred after 1 week at 500 p.p.m. and after 13 weeks at 250 p.p.m. Elevation of Spi- mutant frequency, suggestive of deletion mutations, occurred after 9 weeks at 500 p.p.m. In a two-stage experiment, F344 rats were given KBrO3 for 13 weeks then, after a 2-week recovery, treated with 1% NTA in the diet for 39 weeks. The incidence and multiplicity of renal preneoplastic lesions in rats given KBrO3 at 500 p.p.m. followed by NTA treatment were significantly higher than in rats treated with NTA alone. Results suggest that a certain period of time might be required for 8-OHdG to cause permanent mutations. The two-step experiment shows that cells exposed to the alteration of the intranuclear status by oxidative stress including 8-OHdG formation might be able to form tumors with appropriate promotion.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Animals, Genetically Modified; Bromates; Carcinogens; Cell Transformation, Neoplastic; Deoxyguanosine; DNA Damage; DNA Glycosylases; Dose-Response Relationship, Drug; Kidney; Kidney Neoplasms; Male; Mutation; Nitrilotriacetic Acid; Oxidative Stress; Precancerous Conditions; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors

Public drinking water treated with chemical disinfectants contains a complex mixture of disinfection by-products (DBPs) for which the relative toxicity of the mixtures needs to be characterized to accurately assess risk. Potassium bromate (KBrO(3)) is a by-product from ozonation of high-bromide surface water for production of drinking water and is a rodent carcinogen that produces thyroid, mesothelial, and renal tumors. The proposed mechanism of KBrO(3) renal carcinogenesis involves the formation of 8-oxoguanine (8-oxoG), a promutagenic base lesion in DNA typically removed through base excision repair (BER). In this study, male Long-Evans rats were exposed via drinking water to carcinogenic concentrations of KBrO(3) (0.4 g/L), 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (0.07 g/L), chloroform (1.8 g/L), bromodichloromethane (0.7 g/L), or a mixture of all these chemicals at the same concentrations for 3 weeks. Half of one kidney was processed for microscopic examination, and the remaining kidney was frozen for isolation of genomic DNA. Levels of 8-oxoG were measured using HPLC with electrochemical detection in DNA samples incubated with formamidopyrimidine-DNA glycosylase. Aldehydic lesions (e.g. abasic sites) in DNA samples were quantitated using an aldehyde-reactive probe slot-blot assay. Treatment with KBrO(3) produced a measurable increase of 8-oxoG in the kidney, and this effect was greater than that produced by treatment with the DBP mixture. No other single chemical treatment caused measurable increases of 8-oxoG. The mixture effect on the amount of 8-oxoG observed in this study suggests an interaction between chemicals that reduced the generation of oxidative DNA damage. No increases in abasic sites were observed with treatment, but a decrease was apparent in the rats treated with the DBP mixture. These data are consistent with previous studies where chronic exposure to this chemical mixture in drinking water resulted in a less than additive carcinogenic response in Tsc2 mutant Long-Evans rats.

Topics: Animals; Bromates; Chloroform; Disinfectants; DNA; DNA Damage; Furans; Guanine; Histocytochemistry; Kidney Neoplasms; Male; Oxidative Stress; Rats; Rats, Long-Evans; Rats, Mutant Strains; Trihalomethanes; Water Purification; Water Supply

We report the modulatory effect of coumarin (1,2-benzopyrone) on potassium bromate (KBrO(3)) mediated nephrotoxicity in Wistar rats. KBrO(3) (125 mg/kg body weight, i.p.) enhances gamma-glutamyl transpeptidase, renal lipid peroxidation, xanthine oxidase and hydrogen peroxide (H(2)O(2)) generation with reduction in renal glutathione content and antioxidant enzymes. It also enhances blood urea nitrogen, serum creatinine, ornithine decarboxylase (ODC) activity and [(3)H]-thymidine incorporation into renal DNA. Treatment of rats orally with coumarin (10 mg/kg body weight and 20 mg/kg body weight) resulted in a significant decrease in gamma-glutamyl transpeptidase, lipid peroxidation, xanthine oxidase, H(2)O(2) generation, blood urea nitrogen, serum creatinine, renal ODC activity and DNA synthesis (P < 0.001). Renal glutathione content (P < 0.01) and antioxidant enzymes were also recovered to significant level (P < 0.001). These results show that coumarin may be used as an effective chemopreventive agent against KBrO(3)-mediated renal oxidative stress, toxicity and tumor promotion response in Wistar rats.

Topics: Animals; Antineoplastic Agents; Blood Urea Nitrogen; Bromates; Catalase; Chemoprevention; Coumarins; Creatinine; DNA; Female; Free Radicals; gamma-Glutamyltransferase; Glucosephosphate Dehydrogenase; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Hydrogen Peroxide; Kidney; Kidney Neoplasms; Lipid Peroxidation; NAD(P)H Dehydrogenase (Quinone); Ornithine Decarboxylase; Oxidative Stress; Rats; Rats, Wistar; Xanthine Oxidase

It is still of importance to investigate renal carcinogenesis by potassium bromate (KBrO3), a by-product of water disinfection by ozonation, for assessment of the risk to man. Five female F344 rats in each group were given KBrO3 at a dose of 300 mg/kg by single i.g. intubation or at a dose of 80 mg/kg by single i.p. injection, and were killed 48 h after the administration for measurements of thiobarbituric acid-reactive substances (TBARS) and 8-oxodeoxyguanosine (8-oxodG) levels in the kidney. Both levels in the treated animals were significantly elevated as compared with the control values. In a second experiment, 5 male and female F344 rats in each group were administered KBrO3 at concentrations of 0, 15, 30, 60, 125, 250 and 500 ppm in the drinking water for 4 weeks. KBrO3 in the drinking water did not elevate TBARS in either sex at any of the doses examined, but 8-oxodG formation in both sexes at 250 ppm and above was significantly higher than in the controls. Additionally, the bromodeoxyuridine-labeling index for proximal convoluted tubules was significantly increased at 30 ppm and above in the males, and at 250 ppm and above in the females. Alpha2u-globulin accumulation in the kidneys of male rats was increased with statistical significance at 125 ppm and above. These findings suggest that DNA oxidation induced by KBrO3 may occur independently of lipid peroxidation and more than 250 ppm KBrO3 in the drinking water can exert a carcinogenic effect by way of oxidative stress.

Topics: Administration, Oral; Animals; Bromates; Carcinogens; Cell Division; Disease Models, Animal; DNA Damage; Dose-Response Relationship, Drug; Female; Humans; Kidney; Kidney Neoplasms; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Inbred F344; Water Purification

Disinfection of surface water for human consumption results in the generation of a complex mixture of chemicals in potable water. Cancer risk assessment methodology assumes additivity of carcinogenic effects in the regulation of mixtures. A rodent model of hereditary renal cancer was used to investigate the carcinogenic response to a mixture of drinking water disinfection by-products (DBPs). Rats carrying a mutation in the Tsc2 tumor suppressor gene (Eker rats) readily develop renal preneoplastic and neoplastic lesions, and are highly susceptible to the effects of renal carcinogens. Male and female Eker rats were exposed via drinking water to individual or a mixture of DBPs for 4 or 10 months. Potassium bromate, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), chloroform, and bromodichloromethane were administered at low concentrations of 0.02, 0.005, 0.4 and 0.07 g/l, respectively, and high concentrations of 0.4, 0.07, 1.8 and 0.7 g/l, respectively. Low and high dose mixture solutions were comprised of all four chemicals at either low concentrations or high concentrations, respectively, Following necropsy, each kidney was examined microscopically for preneoplastic lesions (atypical tubules and hyperplasias) and tumors. While some of the mixture responses observed in male rats did fall within the range expected for an additive response, especially at the high dose, predominantly antagonistic effects on renal lesions were observed in response to the low dose mixture in male rats and the high dose mixture in female rats. These data suggest that current default risk assessments assuming additivity may overstate the cancer risk associated with exposure to mixtures of DBPs at low concentrations.

Topics: Animals; Bromates; Carcinogenicity Tests; Carcinogens, Environmental; Chloroform; Disinfectants; Dose-Response Relationship, Drug; Drinking; Drug Synergism; Female; Furans; Genes, Tumor Suppressor; Kidney Neoplasms; Male; Precancerous Conditions; Rats; Rats, Long-Evans; Rats, Mutant Strains; Repressor Proteins; Sex Factors; Time Factors; Trihalomethanes; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Water Purification

Potassium bromate (KBrO(3)) is a rat renal carcinogen and a major drinking water disinfection by-product in water disinfected with ozone. Clear cell renal tumors, the most common form of human renal epithelial neoplasm, are rare in animals but are inducible by KBrO(3) in F344 rats. Detection of cytoplasmic periodic acid-Schiff-positive granules in clear cell tumors, indicative of glycogen accumulation, provides evidence of their biochemical similarity to human counterparts. Mutation in the coding region of the von Hippel-Lindau (VHL) gene is frequently detected in human clear cell renal carcinomas. Detection of VHL mutations in KBrO(3)-induced rat renal tumors could enhance the relevancy of these rat renal tumors for human health risk assessment. Formalin-fixed paraffin-embedded control tissues and renal tumors from male F344 rats exposed to KBrO(3) in the drinking water for 2 years were examined microscopically and were microdissected for DNA extraction. The coding sequence and a promoter region of the VHL gene were examined by polymerase chain reaction-single strand conformation polymorphism and/or DNA sequencing. Two of nine clear cell renal tumors carried the same C to T mutation at the core region of the Sp1 transcription factor binding motif in the VHL promoter and one of four untreated animals had C to T mutation outside the highly conserved core region. Mutation in the VHL coding sequence was only detected in one tumor. No VHL mutations were observed in three chromophilic tumors. KBrO(3)-induced rat renal tumors are morphologically similar to their human counterpart but the genetic basis of tumorigenesis is different.

Topics: Adenocarcinoma, Clear Cell; Animals; Bromates; DNA Mutational Analysis; DNA Primers; DNA, Neoplasm; Kidney Neoplasms; Ligases; Male; Mutation; Open Reading Frames; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Promoter Regions, Genetic; Rats; Rats, Wistar; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Von Hippel-Lindau Tumor Suppressor Protein

Potassium bromate (KBrO3), a food additive, induces renal-cell tumors in rats. KBrO3 induced 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG) formation in human leukemia cell line HL-60 as well as in its H2O2-resistant clone, HP100, suggesting no involvement of H2O2. Depletion of GSH by buthionine sulfoximine (BSO) had a little inhibitory effect on KBrO3-induced 8-oxodG formation. However, the amount of 8-oxodG was still significantly higher than that in control, suggesting that intracellular Cys can affect KBrO3 to oxidize DNA, when GSH decreased. KBrO3 caused 8-oxodG in isolated DNA in the presence of GSH (tripeptide; gamma-GluCysGly), gamma-GluCys, CysGly, or Cys. Methional completely inhibited 8-oxodG formation induced by KBrO3 plus GSH, but typical hydroxyl radical scavengers, SOD and catalase, had little or no inhibitory effects. When bromine solution (BrO(-)) was used instead of BrO3(-), similar scavenger effects were observed. Experiments with 32P-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene suggested that KBrO3 induced 8-oxodG formation at 5'-site guanine of GG and GGG sequences of double-stranded DNA in the presence of GSH and that treatment of formamidopyrimidine-DNA glycosylase led to chain cleavages at the guanine residues. ESR spin-trapping studies showed that 1:2:2:1 quartet DMPO (5,5-dimethyl-1-pyrroline N-oxide) spectrum similar to DMPO/hydroxy radical (*OH) adduct, but the signals were not inhibited by ethanol. Therefore, the signal seemed not to be due to *OH but byproduct due to oxidation of DMPO by the reactive species. The signals were suppressed by the addition of dGMP, but not by other mononucleotides, suggesting the specific reactivity with guanine. On the basis of our results and previous literature, it is speculated that reduction of KBrO3 by SH compounds in renal proximal tubular cells yields bromine oxides and bromine radicals, which are the reactive species that cause guanine oxidation, leading to renal carcinogenesis of KBrO3.

Topics: Animals; Antineoplastic Agents; Bromates; Carcinogens; Cell Transformation, Neoplastic; Cysteine; Deuterium; DNA Damage; Food Additives; Free Radicals; Genes, p53; Genes, ras; Glutathione; Guanine; HL-60 Cells; Humans; Kidney Neoplasms; Rats; Spin Trapping

In order to clarify the role of oxidative stress in carcinogenesis by potassium bromate (KBrO3), 8-hydroxydeoxyguanosine (8-OH-dG) levels and cumulating replicating fractions (CRFs) were measured in the kidneys and livers of F344 rats receiving gavage doses of 100, 200 or 400 mg/kg. We used female rats in this study to allow the potential of KBrO3 for inducing alpha 2u-globulin accumulation--known to result in sustained cell proliferation and eventual promoting activity in males--to be ignored. Additional female rats were given 0.05% N-ethyl-N-hydroxyethylnitrosamine (EHEN) orally for the first 2 weeks as an initiator with subsequent administration of KBrO3 at a dose of 500 p.p.m. in the drinking water for 30 weeks. 8-OH-dG levels in the kidneys were significantly elevated with doses of 200 and 400 mg/kg, and this correlated with increases of the CRFs of proximal tubules. In the livers, however, no significant changes were found. In the promotion bioassay, the mean numbers of atypical tubules, atypical hyperplasias and renal cell tumors per rat in animals treated with KBrO3 after EHEN initiation were significantly higher than those in animals receiving distilled water after EHEN initiation. In contrast, there were no significant differences between groups in terms of liver tumors. The overall data suggest that oxidative stress generated by KBrO3 exposure might be associated with induction of cell proliferation and associated promoting activity.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Bromates; Carcinogens; Deoxyguanosine; DNA; Female; Kidney Neoplasms; Kidney Tubules; Liver; Liver Neoplasms, Experimental; Oxidative Stress; Rats; Rats, Inbred F344

Oxidative damage caused by potassium bromate (KBrO3), a rat renal carcinogen, was investigated using in vitro preparations of rat renal proximal tubules (RPT) and renal nuclear fractions. Release of lactate dehydrogenase and decrease of SH-group content in RPT (1 mg protein/ml) by KBrO3 (0.5-5 mM) in a concentration- and time-dependent manner were observed. Peroxidized arachidonic acid and 8-hydroxydeoxyguanosine (8-OH-dG) levels in RPT were increased after administration of 2 and 5 mM KBrO3. 8-OH-dG formation was observed after incubation of renal nuclei with a lipid-peroxiding system, autooxidized methyl linolenate, or KBrO3. These findings provide support for involvement of lipid peroxidation in producing oxidized DNA damage by KBrO3 directly to RPT, the target site for renal carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Arachidonic Acid; Bromates; Carcinogens; Cell Fractionation; Cell Nucleus; Deoxyguanosine; DNA Damage; In Vitro Techniques; Kidney; Kidney Neoplasms; Kidney Tubules, Proximal; L-Lactate Dehydrogenase; Lipid Peroxidation; Male; Oxidation-Reduction; Rats; Thiobarbituric Acid Reactive Substances

The renal tumour-initiating activity of potassium bromate (KBrO3), a known genotoxic rat renal carcinogen, was investigated in male F344/NCr rats. 6-wk-old rats were given KBrO3 intragastrically as a single dose of 300 mg/kg body weight, which was confirmed by our preliminary toxicity study as a maximum tolerated single dose for this strain of rat. Starting 2 wk after KBrO3 treatment, groups of 39 rats received either a basal diet or a diet containing 4000 ppm barbital sodium (BBNa) as a promoting regimen and were killed at 30, 52, or 104 wk. Control rats received either dietary BBNa (4000 ppm) or the basal diet alone from wk 2 to 52 or 104 wk. Nephropathy was observed in all rats treated with KBrO3 followed by BBNa at 30 wk and in rats receiving BBNa alone, but not in rats exposed to KBrO3 alone. Dysplastic renal tubular cell foci (DTF), putative preneoplastic renal tubular cell lesions were found associated with nephropathy in rats exposed to KBrO3 followed by BBNa from 47 wk. The incidences and multiplicities of DTF and renal tubular cell tumours observed from 31 to 104 wk revealed no initiating effect of KBrO3 treatment. These results indicate that the KBrO3 dose of 300 mg/kg did not initiate renal carcinogenesis.

Topics: Animals; Barbital; Body Weight; Bromates; Carcinogens; Kidney Neoplasms; Male; Organ Size; Rats; Rats, Inbred F344

In order to ascertain the minimum induction time, minimum treatment period and total dose required for development of renal cell tumors, KBrO3 at a concentration of 500 ppm was administered in the drinking water to a total of 232 male F344 rats divided into 14 experimental groups and the development of tumors was examined by two different approaches. In a continued-treatment study, administration of KBrO3 was stopped at week 13, 26, 39, 52 or 104 and rats were immediately sacrificed for comparison with controls given distilled water (DW) alone. Renal cell adenomas were found as early as after 26 weeks of treatment with KBrO3. The yields of dysplastic foci, adenomas and adenocarcinomas of the kidney, follicular cell tumors of the thyroid and mesotheliomas of the peritoneum increased with treatment, the final incidences all being statistically significant after administration of KBrO3 for 104 weeks. To examine the effect of discontinued treatment, on the other hand, the rats were given KBrO3 for the first 13, 26, 39 or 52 weeks and were subsequently maintained on DW alone until sacrifice at week 104. The incidences of tumors in these groups were compared with that of a group continuously administered KBrO3 for 104 weeks. The yields of renal dysplastic foci, adenomas and adenocarcinomas in all discontinued-treatment groups were approximately equal to or even higher than those in the group given KBrO3 continuously for 104 weeks. It is concluded that, under the conditions of this study: the minimum induction time for the development of renal adenomas was 26 weeks and the minimum treatment period and total dose for the induction of renal adenomas and adenocarcinomas were 13 weeks and 4 g/kg, respectively, when the rats were maintained thereafter on DW for 2 years.

Topics: Animals; Body Weight; Bromates; Bromine; Carcinogens; Dose-Response Relationship, Drug; Drinking Behavior; Drug Administration Schedule; Kidney Neoplasms; Male; Rats; Rats, Inbred F344; Thyroid Neoplasms

Following oral administration of a renal carcinogen, potassium bromate (KBrO3), to the rat, a significant increase of 8-hydroxydeoxyguanosine (8-OH-dG) in kidney DNA was observed. In the liver, a non-target tissue, the increase in 8-OH-dG was not significant. The non carcinogenic oxidants, NaCIO and NaCIO2, had no effect on 8-OH-dG formation in kidney DNA. These results suggest that formation of 8-OH-dG in tissue DNA is closely related to KBrO3 carcinogenesis.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Bromates; Bromine; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA; Kidney; Kidney Neoplasms; Rats

Dose-response studies on the carcinogenicity of potassium bromate (KBrO3), a food additive, were undertaken to examine its effects at low doses. A total of 148 6-week-old male inbred F344 rats were divided into 7 groups. They were given KBrO3 orally in their drinking water at doses of 500, 250, 125, 60, 30, 15, and 0 ppm for 104 weeks, at the end of which time all the surviving animals were autopsied and then examined histopathologically. Shortening of the survival times and marked inhibition of body weight increase were observed in a group given 500 ppm KBrO3. The combined incidences of renal adenocarcinomas and adenomas were significantly increased in rats treated with KBrO3 at doses of 500, 250, and 125 ppm in a dose-related manner. The dose-response curve showed a sigmoid appearance. The value for the virtually safe dose (VSD), calculated by the probit model, was 0.950 ppm KBrO3 at a risk level of 10(-6). However, significant increases in the occurrence of dysplastic foci of the kidney were found in groups at doses higher than 30 ppm KBrO3. The VSD value for the dysplastic foci estimated by the gamma-multi-hit model was 0.148 X 10(-3) ppm KBrO3 at a risk level of 10(-6). In a group tested with 500 ppm KBrO3, the combined incidences for follicular adenocarcinomas and adenomas of the thyroid and for mesotheliomas of the peritoneum were shown to be significantly increased.

Topics: Adenocarcinoma; Adenoma; Animals; Bromates; Bromine; Dose-Response Relationship, Drug; Food Additives; Kidney Neoplasms; Male; Mesothelioma; Neoplasms, Experimental; Peritoneal Neoplasms; Rats; Rats, Inbred F344; Thyroid Neoplasms

Topics: Administration, Oral; Animals; Bromates; Bromine; Carcinoma, Renal Cell; Cricetinae; Kidney Neoplasms; Male; Mesocricetus

Dose-response studies were undertaken to investigate the enhancing activity of potassium bromate (KBrO3), a food additive, on renal tumorigenesis initiated by N-ethyl-N-hydroxyethylnitrosamine (EHEN). A total of 180 male 6-week-old F344 rats were divided into 12 groups. EHEN was given in the drinking water for the first 2 weeks at a concentration of 500 ppm for initiation of carcinogenesis. Thereafter, the rats were treated orally either with KBrO3 at a concentration of 500, 250, 125, 60, 30 or 15 ppm, or with potassium bromide (KBr) at a concentration of 1750 or 350 ppm for 24 weeks. The mean numbers of kidney dysplastic foci were significantly increased in a dose-related manner in rats treated with more than 30 ppm KBrO3. The mean number of renal cell tumors was significantly higher after treatment with KBrO3 at the highest concentration of 500 ppm. On the other hand, KBr had no effect. It was concluded that KBrO3 at doses higher than 30 ppm in the drinking water has an enhancing effect on renal tumorigenesis.

Topics: Animals; Bromates; Bromine; Carcinogens; Cocarcinogenesis; Diethylnitrosamine; Dose-Response Relationship, Drug; Food Additives; Kidney Neoplasms; Male; Nitrosamines; Rats; Rats, Inbred F344

The carcinogenicity of potassium bromate, a food additive and a neutralizer in permanent waving, was tested by adding it to the drinking water of F344 rats for 110 weeks. Groups of 53 males and 53 females, each, were given solutions of 500 or 250 ppm of potassium bromate or distilled water. A concentration of 500 ppm markedly inhibited an increase of body weight of male rats. The mean survival time was shortest for males given 500 ppm (88.1 +/- 18.1 wk); the survival times of other groups were 101-104 weeks. The percentage survival in week 104 was relatively high in all groups, and it was 77.4% for males and 66.0% for females in the control group. High incidences of renal cell tumors (in males and females given 500 or 250 ppm) and mesotheliomas of the peritoneum (in males given 500 ppm) were observed. The incidences of these tumors in test groups were significantly higher than those in controls (P less than .001). It was concluded that, when orally administered under the conditions of this experiment, potassium bromate was carcinogenic to F344 rats.

Topics: Adenocarcinoma; Adenoma; Animals; Body Weight; Bromates; Bromine; Female; Food Additives; Hair Preparations; Kidney Neoplasms; Male; Mesothelioma; Peritoneal Neoplasms; Probability; Rats; Rats, Inbred F344

The effect of potassium bromate, a food additive, was examined in male F-344 rats based on two-stage renal carcinogenesis with N-ethyl-N-hydroxyethylnitrosamine (EHEN) as an initiator. Average numbers of dysplastic foci and renal cell tumors were significantly increased in rats given potassium bromate after initiation with EHEN. It was concluded that potassium bromate has an enhancing effect on renal tumorigenesis.

Topics: Animals; Bromates; Bromine; Diethylnitrosamine; Food Additives; Kidney Neoplasms; Male; Nitrosamines; Rats; Rats, Inbred F344

Topics: Adenocarcinoma; Administration, Oral; Animals; Bromates; Bromine; Female; Food Additives; Kidney Neoplasms; Male; Neoplasms, Experimental; Rats; Rats, Inbred F344

Topics: Adenocarcinoma; Administration, Oral; Animals; Bromates; Bromine; Female; Food Additives; Hair Preparations; Kidney Neoplasms; Male; Neoplasms, Experimental; Rats