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Kolisetty N.,University of Georgia | Delker D.A.,University of Utah | Muralidhara S.,University of Georgia | Bull R.J.,MoBull Consulting | And 3 more authors.
Archives of Toxicology | Year: 2013

Bromate (BrO3 -), a by-product of ozonation of drinking water, induces nephrotoxicity in male rats at much lower doses than in female rats. This difference appears to be related to the development of α-2u-globulin nephropathy in males. To determine sex-dependent changes in mRNA and protein expression in the renal cortex attributable to α-2u-globulin nephropathy, we performed microarray and immunohistochemical analyses in proximal renal tubules of male and female F344 rats treated with KBrO3 for 28 days. Particular attention was paid to molecular biomarkers of renal tubular injury. Microarray analysis of male and female rats treated with BrO3 - at low doses (125 mg/L KBrO3) displayed marked sex-dependent changes in renal gene expression. The greatest differences were seen in genes encoding for cellular differentiation, apoptosis, ion transport, and cell proliferation. Differences by sex were especially prominent for the cell cycle checkpoint gene p21, the renal injury protein Kim-1, and the kidney injury and cancer biomarker protein osteopontin. Dose-related nephrotoxicity, assessed by hematoxylin and eosin staining, was greater in males compared to female rats, as was cellular proliferation, assessed by bromodeoxyuridine staining. The fraction of proximal renal cells with elevated 8-oxodeoxyguanosine (8-OH-dG) was only increased at the high dose and did not differ by sex. Dose-dependent increases in the expression of osteopontin were detected immunohistochemically only in male rats and were localized in proximal tubule cells. Similarly, BrO3 - treatment increased clusterin and Kim-1 staining in the proximal tubules; however, staining for these proteins did not differ appreciably between males and females. These data demonstrate both qualitative and quantitative differences in the response of male versus female kidneys to BrO3 --treatment. These sex-dependent effects likely contribute to renal carcinogenesis of BrO3 - in the male rat. © 2013 Springer-Verlag Berlin Heidelberg. Source

Hrudey S.E.,University of Alberta | Bull R.J.,MoBull Consulting | Cotruvo J.A.,Joseph Cotruvo and Associates LLC | Paoli G.,Risk science International | Wilson M.,Risk science International
Risk Analysis | Year: 2013

Some volatile N-nitrosamines, primarily N-nitrosodimethylamine (NDMA), are recognized as products of drinking water treatment at ng/L levels and as known carcinogens. The U.S. EPA has identified the N-nitrosamines as contaminants being considered for regulation as a group under the Safe Drinking Water Act. Nitrosamines are common dietary components, and a major database (over 18,000 drinking water samples) has recently been created under the Unregulated Contaminant Monitoring Rule. A Monte Carlo modeling analysis in 2007 found that drinking water contributed less than 2.8% of ingested NDMA and less than 0.02% of total NDMA exposure when estimated endogenous formation was considered. Our analysis, based upon human blood concentrations, indicates that endogenous NDMA production is larger than expected. The blood-based estimates are within the range that would be calculated from estimates based on daily urinary NDMA excretion and an estimate based on methylated guanine in DNA of lymphocytes from human volunteers. Our analysis of ingested NDMA from food and water based on Monte Carlo modeling with more complete data input shows that drinking water contributes a mean proportion of the lifetime average daily NDMA dose ranging from between 0.0002% and 0.001% for surface water systems using free chlorine or between 0.001% and 0.01% for surface water systems using chloramines. The proportions of average daily dose are higher for infants (zero to six months) than other age cohorts, with the highest mean up to 0.09% (upper 95th percentile of 0.3%). © 2013 Society for Risk Analysis. Source

Bull R.J.,MoBull Consulting | Crook J.,Environmental Consulting Engineer | Whittaker M.,ToxServices LLC | Cotruvo J.A.,Joseph Cotruvo and Associates LLC
Regulatory Toxicology and Pharmacology | Year: 2011

The detection of drugs in drinking water sources has raised questions related to safety. In the absence of regulatory or other official guidance, water utilities are faced with a problem of which drugs should be monitored and the detection limits that should be required. The US FDA summarizes data required for drug approval and post marketing adverse reaction reporting. The use of these data as a means of arriving at concentrations in water where adverse health effects are minimal or non-existent was explored. The minimum therapeutic dose was assumed an appropriate point of departure. Appropriate uncertainty factors could be applied depending upon the qualitative and quantitative nature of the data that are available. Assumptions inherent in US FDA's approval of drugs for use in subsets of the population relative to the broader concerns that arise for exposures of the entire population had to be considered. Additional questions are; whether the drug under consideration is carcinogenic, carries pregnancy and lactation warnings, approval for limited vs. chronic use, exposures to multiple compounds that could act in additive or synergistic ways, and the seriousness of toxicities that are observed. Aside from these considerations, a combined uncertainty factor of 1000 appeared adequate. © 2011 WateReuse Research Foundation. Source

Cotruvo J.,Joseph Cotruvo and Associates LLC
Techniques - Sciences - Methodes | Year: 2010

Standards, directives and guidelines values for drinking water contaminants are a mean, in theory simple, designed for authorities and operators use to ensure the safety of supplied water. Standard derivation hence is an essential step in protection the public health. Adopted values are deliberately conservative, and it must be acknowledged that such values reflect the hypothesis made during the calculation, which in the case of bramâtes, may prove a posterioriwrong. Source

Cotruvo J.A.,Joseph Cotruvo and Associates LLC | Bull R.J.,MoBull Consulting | Pacey G.E.,Miami University Ohio | Gordon G.,Miami University Ohio
Journal / American Water Works Association | Year: 2010

Bromate decomposition kinetics with simulated stomach/gastric juice was studied to contibute to more accurate determination of the risk of environmentally relevant exposures to bromate. Any presystemic reduction in the stomach would yield lower risks. Bromate is rapidly reduced by hydrogen sulfide (H 2S); half-lives were 153 min at zero H 2S and 2,24, and 32 min at 10 -4, 10 -5, and 10 -6 MH 2S, respectively. Half-lives at 10 -4 and 10 -5 Mare biologically relevant for the retention time for water in an empty stomach. Common dietary inorganic reducing agents (ferrous, iodide, and nitrite) generally enhanced bromate reduction with H2S. Oxidizing agents (hypochlorous acid/chlorine, chloramine, and ferric ion) usually modestly reduced decomposition rates with H 2S. Consumption of chlorinated or chloraminated drinking water containing bromate would not materially affect the extent of presystemic brómate reduction. Current studies by the authors are quantifying brómate reduction from the greater systemic liver and blood metabolism, where rapid reactions with glutathione and other reducing agents occur. Source

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