MoBull Consulting

Richland, WA, United States

MoBull Consulting

Richland, WA, United States
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Bull R.J.,MoBull Consulting | Reckhow D.A.,University of Massachusetts Amherst | Li X.,University of Alberta | Humpage A.R.,Australian Water Quality Center a business unit of the South Australia Water Corporation | And 2 more authors.
Toxicology | Year: 2011

Drinking water disinfectants react with natural organic material (NOM) present in source waters used for drinking water to produce a wide variety of by-products. Several hundred disinfections by-products (DBPs) have been identified, but none have been identified with sufficient carcinogenic potency to account for the cancer risks projected from epidemiological studies. In a search for DBPs that might fill this risk gap, the present study projected reactions of chlorine and chloramine that could occur with substructures present in NOM to produce novel by-products. A review of toxicological data on related compounds, supplemented by use of a quantitative structure toxicity relationship (QSTR) program TOPKAT® identified chemicals with a high probability of being chronically toxic and/or carcinogenic among 489 established and novel DBPs. Classes of DBPs that were specifically examined were haloquinones (HQs), related halo-cyclopentene and cyclohexene (HCP&H) derivatives, halonitriles (HNs), organic N-chloramines (NCls), haloacetamides (HAMs), and nitrosamines (NAs). A review of toxicological data available for quinones suggested that HQs and HCP&H derivatives appeared likely to be of health concern and were predicted to have chronic lowest observed adverse effect levels (LOAELs) in the low μg/kgday range. Several HQs were predicted to be carcinogenic. Some have now been identified in drinking water. The broader class of HNs was explored by considering current toxicological data on haloacetonitriles and extending this to halopropionitriles. 2,2-dichloropropionitrile has been identified in drinking water at low concentrations, as well as the more widely recognized haloacetonitriles. The occurrence of HAMs has been previously documented. The very limited toxicological data on HAMs suggests that this class would have toxicological potencies similar to the dihaloacetic acids. Organic N-halamines are also known to be produced in drinking water treatment and have biological properties of concern, but no member has ever been characterized toxicologically beyond bacterial or in vitro studies of genotoxicity. The documented formation of several nitrosamines from secondary amines from both natural and industrial sources prompted exploration of the formation of additional nitrosamines. N-diphenylnitrosamine was identified in drinking waters. Of more interest, however, was the formation of phenazine (and subsequently N-chorophenazine) in a competing reaction. These are the first heterocyclic amines that have been identified as chlorination by-products. Consideration of the amounts detected of members of these by-product classes and their probable toxicological potency suggest a prioritization for obtaining more detailed toxicological data of HQs>HCP&H derivatives>NCls>HNs. Based upon a ubiquitous occurrence and virtual lack of in vivo toxicological data, NCls are the most difficult group to assign a priority as potential carcinogenic risks. This analysis indicates that research on the general problem of DBPs requires a more systematic approach than has been pursued in the past. Utilization of predictive chemical tools to guide further research can help bring resolution to the DBP issue by identifying likely DBPs with high toxicological potency. © 2011 Elsevier Ireland Ltd.


Kolisetty N.,University of Georgia | Bull R.J.,MoBull Consulting | Muralidhara S.,University of Georgia | Costyn L.J.,University of Georgia | And 6 more authors.
Toxicology and Applied Pharmacology | Year: 2013

The water disinfection byproduct bromate (BrO3 -) produces cytotoxic and carcinogenic effects in rat kidneys. Our previous studies demonstrated that BrO3 - caused sex-dependent differences in renal gene and protein expression in rats and the elimination of brominated organic carbon in their urine. The present study examined changes in renal cell apoptosis and protein expression in male and female F344 rats treated with BrO3 - and associated these changes with accumulation of 3-bromotyrosine (3-BT)-modified proteins. Rats were treated with 0, 11.5, 46 and 308mg/L BrO3 - in drinking water for 28days and renal sections were prepared and examined for apoptosis (TUNEL-staining), 8-oxo-deoxyguanosine (8-oxoG), 3-BT, osteopontin, Kim-1, clusterin, and p-21 expression. TUNEL-staining in renal proximal tubules increased in a dose-related manner beginning at 11.5mg BrO3 -/L in female rats and 46mg/L in males. Increased 8-oxoG staining was observed at doses as low as 46mg/L. Osteopontin expression also increased in a dose-related manner after treatment with 46mg/L, in males only. In contrast, Kim-1 expression increased in a dose-related manner in both sexes, although to a greater extent in females at the highest dose. Clusterin and p21 expression also increased in a dose-related manner in both sexes. The expression of 3-BT-modified proteins only increased in male rats, following a pattern previously reported for accumulation of α-2u-globulin. Increases in apoptosis in renal proximal tubules of male and female rats at the lowest doses suggest a common mode of action for renal carcinogenesis for the two sexes that is independent of α-2u-globulin nephropathy. © 2013 Elsevier Inc.


Bull R.J.,MoBull Consulting | Kolisetty N.,University of Georgia | Zhang X.,University of Georgia | Muralidhara S.,University of Georgia | And 9 more authors.
Toxicology | Year: 2012

Bromate (BrO3 -) is a ubiquitous by-product of using ozone to disinfect water containing bromide (Br-). The reactivity of BrO3 - with biological reductants suggests that its systemic absorption and distribution to target tissues may display non-linear behavior as doses increase. The intent of this study is to determine the extent to which BrO3 - is systemically bioavailable via oral exposure and broadly identify its pathways of degradation. In vitro experiments of BrO3 - degradation in rat blood indicate a rapid initial degradation immediately upon addition that is >98% complete at concentrations up to 66μM in blood. As initial concentrations are increased, progressively lower fractions are lost prior to the first measurement. Secondary to this initial loss, a slower and predictable first order degradation rate was observed (10%/min). Losses during both phases were accompanied by increases in Br- concentrations indicating that the loss of BrO3 - was due to its reduction. In vivo experiments were conducted using doses of BrO3 - ranging from 0.077 to 15.3mg/kg, administered intravenously (IV) or orally (gavage) to female F344 rats. The variable nature and uncertain source of background concentrations of BrO3 - limited derivation of terminal half-lives, but the initial half-life was approximately 10min for all dose groups. The area under the curve (AUC) and peak concentrations (Ct=5') were linearly related to IV dose up to 0.77mg/kg; however, disproportionate increases in the AUC and Ct=5' and a large decrease in the volume of distribution was observed when IV doses of 1.9 and 3.8mg/kg were administered. The average terminal half-life of BrO3 - from oral administration was 37min, but this was influenced by background levels of BrO3 - at lower doses. With oral doses, the AUC and Cmax increased linearly with dose up to 15.3mgBrO3 -/kg. BrO3 - appeared to be 19-25% bioavailable without an obvious dose-dependency between 0.077 and 1.9mg/kg. The urinary elimination of BrO3 - and Br- was measured from female F344 rats for four days following administration of single doses of 8.1mgKBrO3/kg and for 15 days after a single dose of 5.0mgKBr/kg. BrO3 - elimination was detected over the first 12h, but Br- elimination from BrO3 - over the first 48h was 18% lower than expected based on that eliminated from an equimolar dose of Br- (15.5±1.6 vs. 18.8±1.2μmol/kg, respectively). The cumulative excretion of Br- from KBr vs. KBrO3 was equivalent 72h after administration. The recovery of unchanged administered BrO3 - in the urine ranged between 6.0 and 11.3% (creatinine corrected) on the 27th day of treatment with concentrations of KBrO3 of 15, 60, and 400mg/L of drinking water. The recovery of total urinary bromine as Br-+BrO3 - ranged between 61 and 88%. An increase in the fraction of the daily BrO3 - dose recovered in the urine was observed at the high dose to both sexes. The deficit in total bromine recovery raises the possibility that some brominated biochemicals may be produced in vivo and more slowly metabolized and eliminated. This was supported by measurements of dose-dependent increases of total organic bromine (TOBr) that was eliminated in the urine. The role these organic by-products play in BrO3 --induced cancer remains to be established. © 2012 Elsevier Ireland Ltd.


Laingam S.,Australian Water Quality Center | Froscio S.M.,Australian Water Quality Center | Bull R.J.,MoBull Consulting | Humpage A.R.,Australian Water Quality Center
Environmental and Molecular Mutagenesis | Year: 2012

Disinfection by-products (DBPs) are of concern to both water industries and health authorities. Although several classes of DBPs have been studied, and there are regulated safe levels in disinfected water for some, a large portion of DBPs are not characterized, and need further investigation. Organic N-chloramines are a group of DBPs, which can be formed during common disinfection processes such as chlorination and chloramination, but little is known in terms of their toxicological significance if consumed in drinking water. Only a few in vitro studies using bacterial assays have reported some genotoxic potential of organic N-chloramines, largely in the context of inflammatory processes in the body rather than exposure through drinking water. In this study, we investigated 16 organic N-chloramines produced by chlorination of model amino acids and amines. It was found that within the drinking water-relevant micromolar concentration range, four compounds were both cytotoxic and genotoxic to mammalian cells. A small reduction of cellular GSH was also observed in the treatment with these four compounds, but not of a magnitude to account for the cytotoxicity and genotoxicity. The results presented in this study demonstrate that some organic N-chloramines, at low concentrations that might be present in disinfected water, can be harmful to mammalian cells. © 2011 Wiley Periodicals, Inc.


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.


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.


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.


Zhao Y.,University of Alberta | Anichina J.,University of Alberta | Lu X.,University of Alberta | Bull R.J.,MoBull Consulting | And 3 more authors.
Water Research | Year: 2012

Consumption of chlorinated drinking water has shown somewhat consistent association with increased risk of bladder cancer in a series of epidemiological studies, but plausible causative agents have not been identified. Halobenzoquinones (HBQs) have been recently predicted as putative disinfection byproducts (DBPs) that might be of toxicological relevance. This study reports the occurrence frequencies and concentrations of HBQs in plant effluents from nine drinking water treatment plants in the USA and Canada, where four common disinfection methods, chlorination, chloramination, chlorination with chloramination, and ozonation with chloramination, are used. In total, 16 water samples were collected and analyzed for eight HBQs: 2,6-dichloro-1,4-benzoquinone (2,6-DCBQ), 2,6-dibromo-1,4-benzoquinone (2,6-DBBQ), 2,6-dichloro-3-methyl-1,4-benzoquinone (2,6-DC-3-MBQ), 2,3,6-trichloro-1,4-benzoquinone (2,3,6-TriCBQ), 2,5-dibromo-1,4-benzoquinone (2,5-DBBQ), 2,3-dibromo-5,6-dimethyl-1,4-benzoquinone (2,3-DB-5,6-DM-BQ), tetrabromo-1,4-benzoquinone (TetraB-1,4-BQ), and tetrabromo-1,2-benzoquinone (TetraB-1,2-BQ). Of these, 2,6-DCBQ, 2,6-DBBQ, 2,6-DC-3-MBQ and 2,3,6-TriCBQ were detected in 16, 11, 6, and 3 of the 16 samples with the method detection limit (DL) of 1.0, 0.5, 0.9 and 1.5 ng/L, respectively, using a solid phase extraction and high performance liquid chromatography-tandem mass spectrometry method. The concentrations were in the ranges of 4.5-274.5 ng/L for 2,6-DCBQ, below DL to 37.9 ng/L for 2,6-DBBQ, below DL to 6.5 ng/L for 2,6-DC-3-MBQ, and below DL to 9.1 ng/L for 2,3,6-TriCBQ. These authentic samples show DCBQ and DBBQ as the most abundant and frequently detectable HBQs. In addition, laboratory controlled experiments were performed to examine the formation of HBQs and their subsequent stability toward hydrolysis when the disinfectants, chlorine, chloramine, or ozone followed by chloramines, reacted with phenol (a known precursor) under various conditions. The controlled reactions demonstrate that chlorination produces the highest amounts of DCBQ, while pre-ozonation increases the formation of DBBQ in the presence of bromide. At pH < 6.8, 2,6-DCBQ was observed to be stable, but it was easily hydrolyzed to form mostly 3-hydroxyl-2,6-DCBQ at pH 7.6 in drinking water. © 2012 Elsevier Ltd.


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.


PubMed | MoBull Consulting
Type: Journal Article | Journal: Toxicology | Year: 2012

Bromate (BrO(3)(-)) is a ubiquitous by-product of using ozone to disinfect water containing bromide (Br(-)). The reactivity of BrO(3)(-) with biological reductants suggests that its systemic absorption and distribution to target tissues may display non-linear behavior as doses increase. The intent of this study is to determine the extent to which BrO(3)(-) is systemically bioavailable via oral exposure and broadly identify its pathways of degradation. In vitro experiments of BrO(3)(-) degradation in rat blood indicate a rapid initial degradation immediately upon addition that is >98% complete at concentrations up to 66M in blood. As initial concentrations are increased, progressively lower fractions are lost prior to the first measurement. Secondary to this initial loss, a slower and predictable first order degradation rate was observed (10%/min). Losses during both phases were accompanied by increases in Br(-) concentrations indicating that the loss of BrO(3)(-) was due to its reduction. In vivo experiments were conducted using doses of BrO(3)(-) ranging from 0.077 to 15.3mg/kg, administered intravenously (IV) or orally (gavage) to female F344 rats. The variable nature and uncertain source of background concentrations of BrO(3)(-) limited derivation of terminal half-lives, but the initial half-life was approximately 10min for all dose groups. The area under the curve (AUC) and peak concentrations (C(t=5)) were linearly related to IV dose up to 0.77mg/kg; however, disproportionate increases in the AUC and C(t=5) and a large decrease in the volume of distribution was observed when IV doses of 1.9 and 3.8mg/kg were administered. The average terminal half-life of BrO(3)(-) from oral administration was 37min, but this was influenced by background levels of BrO(3)(-) at lower doses. With oral doses, the AUC and C(max) increased linearly with dose up to 15.3mgBrO(3)(-)/kg. BrO(3)(-) appeared to be 19-25% bioavailable without an obvious dose-dependency between 0.077 and 1.9mg/kg. The urinary elimination of BrO(3)(-) and Br(-) was measured from female F344 rats for four days following administration of single doses of 8.1mgKBrO(3)/kg and for 15 days after a single dose of 5.0mgKBr/kg. BrO(3)(-) elimination was detected over the first 12h, but Br(-) elimination from BrO(3)(-) over the first 48h was 18% lower than expected based on that eliminated from an equimolar dose of Br(-) (15.51.6 vs. 18.81.2mol/kg, respectively). The cumulative excretion of Br(-) from KBr vs. KBrO(3) was equivalent 72h after administration. The recovery of unchanged administered BrO(3)(-) in the urine ranged between 6.0 and 11.3% (creatinine corrected) on the 27th day of treatment with concentrations of KBrO(3) of 15, 60, and 400mg/L of drinking water. The recovery of total urinary bromine as Br(-)+BrO(3)(-) ranged between 61 and 88%. An increase in the fraction of the daily BrO(3)(-) dose recovered in the urine was observed at the high dose to both sexes. The deficit in total bromine recovery raises the possibility that some brominated biochemicals may be produced in vivo and more slowly metabolized and eliminated. This was supported by measurements of dose-dependent increases of total organic bromine (TOBr) that was eliminated in the urine. The role these organic by-products play in BrO(3)(-)-induced cancer remains to be established.

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