Etiology of bromate-induced cancer and possible modes of action-studies in Japan

doi:10.1016/j.tox.2006.01.007

Toxicology

Volume 221, Issues 2–3, 17 April 2006, Pages 154-157

https://doi.org/10.1016/j.tox.2006.01.007 Get rights and content

Abstract

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 α_2μ-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 α_2μ-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.

Section snippets

Carcinogenicity test in rats

Groups of 53 males and 53 females of F344 rats received KBrO₃ for 110 weeks at concentrations of 500 (reduced to 400 ppm at week 60 in the males) and 250 ppm in the drinking water. Incidences of adenomas and adenocarcinomas and their combined incidences as renal cell tumors (RCTs) in the treated rats of both genders were significantly higher than the controls. Tumors of the peritoneum, all diagnosed as mesotheliomas, also occurred at a significantly higher incidence in male rats given 250 or 500

Limited duration study

Groups of 14–20 male F344 rats were given KBrO₃ orally at concentration of 500 ppm for 13, 26, 39 or 52 weeks and maintained untreated up to the end of the experiment, week 104. The results revealed that 13 weeks of exposure was necessary to produce increase in the incidence of RCTs (Kurokawa et al., 1987). Further study confirming initiating potential of 13 weeks exposure to KBrO₃ at various doses is now on-going based on a two-stage renal carcinogenesis model using trisodium nitrilotriacetate

Oxidative DNA damage

Five male and female rats in each group were administered KBrO₃ at a concentration of 500 ppm in the drinking water for 1, 2, 3, 4 and 13 weeks, and then 8-hydroxydeoxyguanosine (8-OH-dG) levels in kidney nuclear DNA were measured using HPLC-ECD system. 8-OH-dG levels were increased at 1, 2, 3, 4 and 13 weeks in kidney DNA of male rats chronically exposed to KBrO₃ at a carcinogenic dose, significant increase also being observed from 3 weeks up to the end of the experiment for females (Umemura et

Summary for the overall

The overall data were summarized in Fig. 1. Carcinogenicity studies demonstrated significantly elevated incidences of renal cell tumors in male and female rats given KBrO₃ at 250 and 500 ppm in the drinking water. A further dose–response study using only male rats showed 125 ppm to also be a carcinogenic dose. However, since another group showed that a dose of 200 ppm failed to induce renal tumors in male rats (Wolf et al., 1998), it seems equivocal whether 125 ppm has a carcinogenic potential.

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There are more references available in the full text version of this article.

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8-Hydroxydeoxyguanosine (8-OHdG) is well known not only as an effective biomarker of oxidative stress but also as a mutagenic DNA modification. Incorporation of dAMP at the opposite site of 8-OHdG induces G>T or A>C transversions. However, in vivo analyses of gene mutations caused by potassium bromate (KBrO₃), which can induce 8-OHdG at carcinogenic target sites, showed that G>T was prominent in the small intestines of mice, but not in the kidneys of rats. Because KBrO₃ was a much clearer carcinogen in the kidneys of rats, detailed analyses of gene mutations in the kidney DNA of rats treated with KBrO₃ could improve our understanding of oxidative stress-mediated carcinogenesis. In the current study, site-specific reporter gene mutation assays were performed in the kidneys of gpt delta rats treated with KBrO₃. Groups of 5 gpt delta rats were treated with KBrO₃ at concentrations of 0, 125, 250, or 500 ppm in the drinking water for 9 weeks. At necropsy, the kidneys were macroscopically divided into the cortex and medulla. 8-OHdG levels in DNA extracted from the cortex were dramatically elevated at concentrations of 250 ppm and higher compared with those from the medulla. Cortex-specific increases in mutant frequencies in gpt and red/gam genes were found at 500 ppm. Mutation spectrum and sequence analyses of their mutants demonstrated significant elevations in A>T transversions in the gpt gene and single base deletions at guanine or adenine in the gpt or red/gam genes. While A>T transversions and single base deletions of adenine may result from the oxidized modification of adenine, the contribution of 8-OHdG to gene mutations was limited despite possible participation of the 8-OHdG repair process in guanine deletion.
Combining high resolution mass spectrometry with a halogen extraction code to characterize and identify brominated disinfection byproducts formed during ozonation
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Ozonation is widely used during water treatment but can generate a variety of toxic disinfection byproducts, especially in the presence of bromide. In the present study, our halogen extraction code was extended and modified to identify bromine isotopic patterns and combined with the R package MFAssignR in selectively identifying brominated disinfection byproducts (Br-DBPs) from high resolution mass spectra. In total, 127 Br-DBPs formed from a Suwannee River natural organic matter (SRNOM) solution were successfully detected from tens of thousands of mass spectrometry peaks. Kendrick mass defect analysis and structural characterization identified 17 structures, 15 of which were identified as brominated carboxylic acids and firstly reported here. Computational model predictions indicated that these brominated carboxylic acids may possess high toxic potencies and raise valid concerns. The adapted halogen extraction code described in this study is a powerful tool for a wider application of analyzing Br-DBPs in complex water matrices and provides an effective technique to characterize and identify these compounds in future studies.
Occurrence and spatio-temporal variability of halogenated acetaldehydes in full-scale drinking water systems
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Citation Excerpt :
However, other problems have emerged with the use of these chemicals. For example, ozonation may substantially minimize the formation of THMs and HAAs, but it may lead to the formation of bromate, which is problematic (Moore and Chen, 2006; Umemura and Kurokawa, 2006). Similarly, the formation of nitrosamines, chlorite and chlorate were reported with the use of chloramines or chlorine dioxide (Choi and Valentine, 2002; Padhi et al., 2019).
As the third largest group of identified disinfection by-products (DBPs) by weight, halogenated acetaldehydes (HALs), were monitored for one year at numerous locations in two full-scale drinking water systems applying an ozone-chlorine sequential disinfection strategy. The HALs that were targeted included four trihalogenated acetaldehydes (THALs): chloral hydrate (CH), bromodichloroacetaldehyde (BDCAL), dibromochloroacetaldehyde (DBCAL) and tribromoacetaldehyde (TBAL). Three dihalogenated acetaldehydes (DHALs) were also included: dichloroacetaldehyde (DCAL), bromochloroacetaldehyde (BCAL) and dibromoacetaldehyde(DBAL). In addition to various sampling points in two distribution networks, this study also investigated the formation of HALs during water treatment and for the first time, reports the formation of DBAL before chlorine is applied. Low bromide levels in source waters from both systems resulted in the rare detection of DBAL and TBAL. CH accounted for >50% of total HALs (HAL7) with DHALs accounting for as little as 10% of HAL7, presumably due to the use of ozone-chlorine instead of ozone-chloramine. In the presence of chlorine residuals and with increasing water residence times, most HALs continued to form, more readily in warm water than in cold water. However, the spatial and temporal patterns for each HAL differed depending on speciation (THAL vs. DHAL) and water temperature. Compared to the relatively stable bromine incorporation factor (BIF) of THMs in the distribution systems, the decreasing BIFs of HALs according to water residence time increases suggested that bromine-containing THMs are more stable than their corresponding HALs. Re-chlorination at the extremities of the distribution networks demonstrated a significant impact on the occurrence and speciation of DBPs. In both full-scale systems, water temperature was shown to be the biggest contributing factor to HAL formation. The strong correlations between THM levels and THAL levels make it possible to predict the occurrence of THALs based on THMs.
A novel polyoxometalate-encapsulating 3D polycatenated metal-organic framework
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Bromate (BrO3−), a disinfection by-product, is formed when ozone (used to disinfect drinking-water) reacts with naturally occurring bromide in drinking water [41]. BrO3− ions are suspected to act as carcinogens that may cause a range of cancers [42]. Solid state electrochemistry was carried out by entrapping the compound in a GCE.
A novel polyoxometalate-encapsulating polycatenated metal-organic framework, (bib)_0.5[Cu₂(bib)_3.5(GeW₁₂O₄₀)]·H₂O (1) (bib = 1,4-bis(1-imidazol-yl)-2,5-dimethyl benzene), has been synthesized under hydrothermal conditions. In compound 1, 1D molecular ladders and 2D square grid layers is further catenated to the two adjacent such motifs in inclined fashion to give an 1D+2D→3D polycatenaned metal-organic framework with nanotube channels, in which nanosized Keggin anions as guests are encapsulated for the first time. Compound 1 represents a first case of Keggin-type polyoxometalate-encapsulating 1D+2D→3D polycatenated metal-organic framework. The electrochemical studies show that modified electrode of 1 exhibits highly efficient electrocatalytic activity toward reduction of inorganic molecule bromate (BrO₃^-). The electrocatalytic reaction mechanism of 1-GCE toward reduction of BrO₃^- has been illuminated. The photoluminescence property of 1 was also investigated.
Underestimated risk from ozonation of wastewater containing bromide: Both organic byproducts and bromate contributed to the toxicity increase
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Ozonation is widely used in wastewater treatment but the associated byproduct formation is a concern. When ozonation is used in the presence of bromide, bromate is generally considered as a major byproduct, and few studies have examined the toxicity of organic byproducts. This study was designed to investigate the cytotoxicity, genotoxicity and DNA/RNA oxidative damage to Chinese hamster ovary (CHO) cells of organic extracts from ozonated wastewater in the absence or presence of bromide. Ozonation effectively detoxified secondary effluents containing no bromide. However, ozonation significantly increased the cytotoxicity and genotoxicity of the effluents spiked with a bromide concentration as low as 100 μg/L, compared with the bromide-free effluent. When the bromide concentration in the effluent was increased to 2000 μg/L, ozonation resulted in 1.4–1.5 times the cytotoxicity and 1.5–5.0 times the genotoxicity of the non-ozonated secondary effluent. Besides, the oxidative stress (including reactive oxygen species and reactive nitrogen species) and DNA/RNA oxidative damage also became more severe and a high level of 8-hydroxy-(deoxy)guanosine was detected in the CHO cell nucleus in the presence of bromide. Cytotoxicity and genotoxicity were found to increase with the formation of total organic bromine (TOBr). When the CHO cells were exposed to both the organic byproducts and bromate formed from wastewater containing 500 and 2000 μg/L bromide, bromate significantly increased oxidative stress and DNA/RNA oxidative damage at relatively high concentration factors, suggesting both organic byproduct and bromate can contribute to toxicity increase. During ozonation of the effluent containing bromide, particular attention should be paid to the organic byproducts such as TOBr.
Subchronic toxicity evaluation of potassium bromate in Fischer 344 rats
2013, Environmental Toxicology and Pharmacology
Male F344 rats were exposed to potassium bromate (KBrO₃) in drinking water at concentrations of 0, 5, 20, 100, 200, or 400 mg/L for 2 or 13 weeks. Endpoints evaluated included clinical observations, body weights, serum chemistry, gross pathology, organ weights, and select tissue histopathology (kidney, lung, liver, thyroid, and tunica vaginalis). Weekly body weight and water consumption means were similar between KBrO₃ and control groups throughout the study. Increases in kidney weights were observed in rats of the 400 mg/L group following 2- or 13-weeks exposure. Hyaline droplets were observed in renal tubules of rats of the 200 and 400 mg/L groups following 2 weeks exposure and in rats of the 400 mg/L group at 13 weeks. There were no KBrO₃-related microscopic findings in the lung, liver, thyroid, and tunica vaginalis at the 2- and 13-week time points. A no observed effect level of 100 mg/L KBrO₃ (8.1 mg/kg/day) was selected based on the absence of microscopic alterations in the kidney.

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Etiology of bromate-induced cancer and possible modes of action-studies in Japan

Abstract

Section snippets

Carcinogenicity test in rats

Limited duration study

Oxidative DNA damage

Summary for the overall

Carcinogenicity of potassium bromate administered orally to F344 rats

J. Natl. Cancer Inst.

Dose-related enhancing effect of potassium bromate on renal tumorigenesis in rats initiated with N-ethyl-N-hydroxyethylnitrosamine

Jpn. J. Cancer Res.

Dose–response studies on the carcinogenicity of potassium bromate in F344 rats after long-term oral administration

J. Natl. Cancer Inst.

Relationship between the duration of treatment and the incidence of renal cell tumors in male F344 rats administered potassium bromate

Jpn. J. Cancer Res.

Toxicity and carcinogenicity of potassium bromate: a new renal carcinogen

Environ. Health Perspect.