Carcinogenicity of Potassium Bromate Administered in the Drinking Water to Male B6C3F<sub>1</sub> Mice and F344/N Rats

DeAngelo, Anthony B.; George, Michael H.; Kilburn, Steve R.; Moore, T.; Wolf, Douglas C.

doi:10.1177/019262339802600501

Cited by 180 publications

(112 citation statements)

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“…1,2) Potassium bromate (KBrO 3 ) is a renal carcinogen and is classified as a group 2B (possibly carcinogenic to humans) by the International Agency for Research on Cancer, 3,4) as are bleomycin and carbon tetrachloride, etc. However, KBrO 3 is generally used as an oxidizing agent for the treatment of wheat flour and as a constituent in cold-wave hair solutions.…”

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confidence: 99%

Contribution of Nitric Oxide to Potassium Bromate-Induced Elevation of Methaemoglobin Concentration in Mouse Blood.

Watanabe

Togashi

Fukui

2002

Biological & Pharmaceutical Bulletin

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Bromate is frequently detected in tap water and bottled water, since it is an inorganic oxyhalide disinfection by-product, which is formed when drinking water supplies undergo ozonation, an advanced wastewater treatment technique. 1,2) Potassium bromate (KBrO 3 ) is a renal carcinogen and is classified as a group 2B (possibly carcinogenic to humans) by the International Agency for Research on Cancer, 3,4) as are bleomycin and carbon tetrachloride, etc. However, KBrO 3 is generally used as an oxidizing agent for the treatment of wheat flour and as a constituent in cold-wave hair solutions. Acute exposure to KBrO 3 causes not only kidney failure 5,6) but also neuropathological disorder, such as vertigo, tinnitus, and hearing loss. 7,8) Potassium bromate is known to cause oxidative modification of lipid, protein and DNA bases in the kidney, which has usually been thought to contribute to its renal carcinogenic properties.9,10) Methaemoglobinemia and cyanosis in the incipient stage of renal damage are also known to be caused by KBrO 3 .11) Acquired but not heritable methaemoglobinemia is thought to be caused by the oxidative modification of haemoglobin (Hb) by certain chemicals, such as amyl nitrite and acetanilide, since the iron in the haem rings of Hb is in the Fe 2ϩ state and Hb oxidation is speeded up by the presence of nitrite or certain transition metal ions, especially copper.12) So far, KBrO 3 has been regarded as the direct oxidant of Hb as chlorate 13) but no details of KBrO 3 -induced elevation of methaemoglobin (MetHb) concentration in blood have been examined. Previously KBrO 3 -induced renal oxidative stress and kidney damage were reported to be mainly attributable to the reduction of cytoplasmic glutathione peroxidase (GPx) activity, probably caused by the enhanced production of NO and peroxynitrite (ONOO Ϫ ).14) Therefore, it is possible that KBrO 3 -induced methaemoglobinemia is also related to the change in GPx activity resulting from the enhancement of NO production in blood vessels. In this report, the effects of the GPx mimic ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) on the elevation of MetHb concentration, the enhancement of NO production and the attenuation of GPx activity by KBrO 3 are examined to clarify the significant impact of NO on KBrO 3 -induced methaemoglobinemia. In addition, the effect of ebselen on KBrO 3 -induced renal oxidative stress and kidney damage was comparatively investigated. MATERIALS AND METHODS ChemicalsGlutathione reductase from bakers yeast (EC 1.6.4.2), nitrate reductase from aspergillus species (EC 1.6.6.2), Hb, MetHb, reduced glutathione (GSH) and oxidized glutathione were purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.). 2,4-Dinitrophenylhydrazine (DNPH) was obtained from Tokyo Chemical Industry Co. (Tokyo, Japan). KBrO 3 , potassium cyanide, sodium hydrosulfite and ebselen were purchased from Wako Pure Chemical Industries (Osaka, Japan). 1-Hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7), 3-(4-morpholinyl) sydnonimine hydroc...

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Contribution of Nitric Oxide to Potassium Bromate-Induced Elevation of Methaemoglobin Concentration in Mouse Blood.

Watanabe

Togashi

Fukui

2002

Biological & Pharmaceutical Bulletin

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“…However, ozone reacts with bromide ions to produce bromate (7). Bromate induces tumors in the rat kidney, thyroid, and mesothelium (8,9) and is a renal carcinogen in the mouse (9). In (12) can be described by a lognormal distribution.…”

Section: Hazard Identificationmentioning

confidence: 99%

“…Exposure to bromate in drinking water is mainly by ingestion; other routes (inhalation and dermal exposure) are not described in the literature. To estimate the excess lifetime risk of renal cell cancer from exposure to bromate, the WHO (1) used data by Kurokawa et (27); data symbolized by diamonds from Kurokawa et al (24); and data symbolized by circles from DeAngelo et al (9) (Figure 1B), mainly because the three experimental dose-response data sets show large differences.…”

Section: Hazard Identificationmentioning

confidence: 99%

“…Other variations in parameter values result in increased estimates of health gain. Increasing CCp RAW or reducing the efficiency of CSF result in health benefits up to [8][9][10][11][12] DALYs/mpy (Figure 7 A, B) unboiled water consumption to 1 L/day increases the net health benefit to 3 DALYs/1 mpy. The results are less sensitive to the total water consumption; to reduce the net health gain to 0 would require per capita consumption of 5 L/day.…”

Section: Risk Characterizationmentioning

confidence: 99%

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Balancing the risks and benefits of drinking water disinfection: disability adjusted life-years on the scale.

Havelaar

Hollander

Teunis

et al. 2000

Environ Health Perspect

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To evaluate the applicability of disability adjusted life-years (DALYs) as a measure to compare positive and negative health effects of drinking water disinfection, we conducted a case study involving a hypothetical drinking water supply from surface water. This drinking water supply is typical in The Netherlands. We compared the reduction of the risk of infection with Cryptosporidium parvum by ozonation of water to the concomitant increase in risk of renal cell cancer arising from the production of bromate. We applied clinical, epidemiologic, and toxicologic data on morbidity and mortality to calculate the net health benefit in DALYs. We estimated the median risk of infection with C parvum as 10-3/person-year. Ozonation reduces the median risk in the baseline approximately 7-fold, but bromate is produced in a concentration above current guideline levels. However, the health benefits of preventing gastroenteritis in the general population and premature death in patients with acquired immunodeficiency syndrome outweigh health losses by premature death from renal cell cancer by a factor of > 10. The net benefit is approximately 1 DALY/million person-years. The application of DALYs in principle allows us to more explicitly compare the public health risks and benefits of different management options. In practice, the application of DALYs may be hampered by the substantial degree of uncertainty, as is typical for risk assessment. Key work: bromate, Cryptosporidium parvum, disinfection, drinkmg water, ozone, quality of life, risk assessment. Environ Health Perspect 108: 315-321 (2000).[Online 21 February 2000] htp:/lle/hpnetl.nie,hs.nih.gov/docs/2OOO/108p315-321havelaar/abstract.htmIThe microbiologic safety of drinking water is of paramount importance to public health (1). Source protection is generally accepted as the primary strategy to obtain microbiologically safe drinking water. However, many sources (surface waters in particular) are highly polluted and need extensive treatment before distribution to the consumer. Chemical disinfection is prominent in these treatment schemes. Highly oxidizing chemicals such as chlorine and ozone kill a variety of pathogenic microorganisms during treatment, and chlorine is applied in many countries as an additional safeguard in the distribution system. An important drawback of the use of these chemicals is the generation of disinfection by-products, which have suspected adverse effects on human health. This situation calls for a formal quantitative framework to compare the positive and negative health effects of drinking water disinfection and to assist in the design and operation of treatment plants (2).Microbiologic risks are expressed as the annual individual probability of infection for a given consumption of drinking water. Chemical risks related to genotoxic carcinogens are usually associated with an increase in cancer incidence attributable to a lifetime exposure. The public health impact of these disease end points is very different and cannot be compared directly. Hen...

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“…An oxidizing reagent, KBrO 3 , which is used as a food additive for wheat flour, is known to induce 8-oxoG in the genomes of rats and mice (12,13). KBrO 3 has also been recognized as a renal carcinogen in rats (14,15). In mammals, three enzymes, mutT homolog 1 (MTH1), 8-oxoguanine glycosylase 1 (OGG1), and mutY DNA glycosylase (MUTYH), play important roles in preventing 8-oxoG-related mutagenesis (10).…”

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BUBR1 Insufficiency in Mice Increases Their Sensitivity to Oxidative Stress

Matsuda

Matsumoto

Honma

et al. 2016

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Abstract. Background Budding uninhibited by benzimidazole-related 1 (BUBR1) is a core component of the spindle assembly checkpoint, which monitors whether or not sister chromatids are correctly separated during mitosis. Dysfunction of BUBR1 provokes chromosomal instability, thus leading to aneuploidy (1). Baker et al. generated mice with BubR1 gene mutation with various decreased expression levels of BubR1 due to combinations of wild-type, null, and hypomorphic BubR1 alleles (2-4). The mice that were homogeneous for the hypomorphic allele showed an early onset of aging phenotypes, such as short lifespan, cachectic dwarfism, lordokyphosis, cataracts, loss of subcutaneous fat, impaired wound healing, and decreased vascular wall elasticity (2,4). Chromosomal instability, such as aneuploidy, frequently occurred in the cells derived from hypomorphic BubR1 mice, but few mice spontaneously died of cancer under normal conditions (2). Notably, Dai et al. reported that mice with the wild-type allele and null allele were susceptible to carcinogen-induced adenocarcinoma in the lungs and intestines (5), suggesting that aneuploidy caused by the decreased expression of BUBR1 might enhance carcinogeninduced tumorigenesis in mammals.We recently generated a new strain of hypomorphic BubR1 mice in which the expression of BUBR1 is reduced to 20% of the normal level. These low BUBR1-expressing mutant mice (termed BubR1 L/L mice) do not display apparent abnormalities, such as progeria, infertility, shortened lifespan, or structural anomaly in the tissue during growth and development, under normal conditions. Therefore, BubR1 L/L mice are particularly suitable for investigating the precise roles of BUBR1 in age-related diseases, including cancer. Using these mice, we previously demonstrated that decreased expression of BUBR1 completely inhibits intimal hyperplasia after carotid ligation by suppressing the 769 Τhis article is freely accessible online.

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Carcinogenicity of Potassium Bromate Administered in the Drinking Water to Male B6C3F₁ Mice and F344/N Rats

Cited by 180 publications

References 34 publications

Contribution of Nitric Oxide to Potassium Bromate-Induced Elevation of Methaemoglobin Concentration in Mouse Blood.

Contribution of Nitric Oxide to Potassium Bromate-Induced Elevation of Methaemoglobin Concentration in Mouse Blood.

Balancing the risks and benefits of drinking water disinfection: disability adjusted life-years on the scale.

BUBR1 Insufficiency in Mice Increases Their Sensitivity to Oxidative Stress

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Carcinogenicity of Potassium Bromate Administered in the Drinking Water to Male B6C3F1 Mice and F344/N Rats

Cited by 180 publications

References 34 publications

Contribution of Nitric Oxide to Potassium Bromate-Induced Elevation of Methaemoglobin Concentration in Mouse Blood.

Contribution of Nitric Oxide to Potassium Bromate-Induced Elevation of Methaemoglobin Concentration in Mouse Blood.

Balancing the risks and benefits of drinking water disinfection: disability adjusted life-years on the scale.

BUBR1 Insufficiency in Mice Increases Their Sensitivity to Oxidative Stress

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Carcinogenicity of Potassium Bromate Administered in the Drinking Water to Male B6C3F₁ Mice and F344/N Rats