Scientific Studies about Chloramine
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Articles about Chloramine

Chloramine Library

Abstracts of Chloramine Studies

Changes in Blood Lead Levels Associated with Use of Chloramines in Water Treatment Systems
Marie Lynn Miranda; Dohyeong Kim; Andrew P. Hull; Christopher J. Paul; M. Alicia Overstreet Galeano

Background: More municipal water treatment plants are using chloramines as a disinfectant in order to reduce carcinogenic by-products. In some instances, this has coincided with an increase in lead levels in drinking water in those systems. Lead in drinking water can be a significant health risk.

Objectives: We sought to test the potential effect of switching to chloramines for disinfection in water treatment systems on childhood blood lead levels using data from Wayne County, located in the central Coastal Plain of North Carolina.

Methods: We constructed a unified geographic information system (GIS) that links blood lead screening data with age of housing, drinking water source, and census data for 7,270 records. The data were analyzed using both exploratory methods and more formal multivariate techniques.

Results: The analysis indicates that the change to chloramine disinfection may lead to an increase in blood lead levels, the impact of which is progressively mitigated in newer housing.

Conclusions: Introducing chloramines to reduce carcinogenic by-products may increase exposure to lead in drinking water. Our research provides guidance on adjustments in the local childhood lead poisoning prevention program that should accompany changes in water treatment. As similar research is conducted in other areas, and the underlying environmental chemistry is clarified, water treatment strategies can be optimized across the multiple objectives that municipalities face in providing high quality drinking water to local residents.

Haloacetonitriles vs. Regulated Haloacetic Acids: Are Nitrogen-Containing DBPs More Toxic?
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Mark G. Muellner, Elizabeth D. Wagner, Kristin McCalla, Susan D. Richardson, Yin-Tak Woo, and Michael J. Plewa*

College of Agricultural, Consumer and Environmental Sciences, Department of Crop Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, National Exposure Research Laboratory, U.S. Environmental Protection Agency, Athens, Georgia 30605, and Risk Assessment Division, Office of Pollution Prevention and Toxics, U.S. Environmental Protection Agency, Washington, D.C. 20460

Received for review July 21, 2006
Revised manuscript received October 17, 2006
Accepted October 30, 2006

Haloacetonitriles (HANs) are toxic nitrogenous drinking water disinfection byproducts (N-DBPs) and are observed with chlorine, chloramine, or chlorine dioxide disinfection. Using microplate-based Chinese hamster ovary (CHO) cell assays for chronic cytotoxicity and acute genotoxicity, we analyzed 7 HANs: iodoacetonitrile (IAN), bromoacetonitrile (BAN), dibromoacetonitrile (DBAN), bromochloroacetonitrile (BCAN), chloroacetonitrile (CAN), dichloroacetonitrile (DCAN), and trichloroacetonitrile (TCAN). The cytotoxic potency (%C1/2 values) ranged from 2.8 M (DBAN) to 0.16 mM (TCAN), with a descending rank order of DBAN > IAN BAN > BCAN > DCAN > CAN > TCAN. HANs induced acute genomic DNA damage; the single cell gel electrophoresis (SCGE) genotoxicity potency ranged from 37 M (IAN) to 2.7 mM (DCAN). The rank order of declining genotoxicity was IAN > BAN DBAN > BCAN > CAN > TCAN > DCAN. The accompanying structure-activity analysis of these HANs was in general agreement with the genotoxicity rank order. These data were incorporated into our growing quantitative comparative DBP cytotoxicity and genotoxicity databases. As a chemical class, the HANs are more toxic than regulated carbon-based DBPs, such as the haloacetic acids. The toxicity of N-DBPs may become a health concern because of the increased use of alternative disinfectants, such as chloramines, which may enhance the formation of N-DBPs, including HANs. 

Monochloramine potently inhibits arachidonic acid metabolism in rat platelets
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Yohko Fujimoto *, Mai Ikeda, Satoru Sakuma
Laboratory of Physiological Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
Received 20 February 2006, Available online 29 March 2006

In the present study, the effects of hypochlorous acid (HOCl), monochloramine (NH2Cl), glutamine-chloramine (Glu-Cl) and taurinechloramine (Tau-Cl) on the formation of 12-lipoxygenase (LOX) metabolite, 12-HETE, and cyclooxygenase (COX) metabolites, TXB2, and 12-HHT, from exogenous arachidonic acid (AA) in rat platelets were examined. Rat platelets (4 · 108/ml) were preincubated with drugs for 5 min at 37 C prior to the incubation with AA (40 lM) for 2 min at 37 C. HOCl (50–250 lM) showed an inhibition on the formation of LOX metabolite (12-HETE, 5–67% inhibition) and COX metabolites (TXB2, 33–73% inhibition; 12-HHT, 27–74% inhibition). Although Tau-Cl and Glu-Cl up to 100 lM were without effect on the formation of 12-HETE, TXB2 and 12-HTT, NH2Cl showed a strong inhibition on the formation of all three metabolites (10–100 lM NH2Cl, 12-HETE, 21–92% inhibition; TXB2, 58–94% inhibition; 12-HHT, 36–92% inhibition). Methionine reversed a reduction of formation of LOX and COX metabolites induced by NH2Cl, and taurine restoring that induced by both NH2Cl and HOCl. These results suggest that NH2Cl is a more potent inhibitor of COX and LOX pathways in platelets than HOCl, and taurine and methionine can be modulators of NH2Cl-induced alterations in the COX and LOX pathways in vivo.

Keywords: Monochloramine; Hypochlorous acid; Arachidonic acid; 12-Lipoxygenase; Cyclooxygenase; Platelet

Evidence that Monochloramine Disinfectant Could Lead to Elevated Pb Levels in Drinking Water
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J A Y A . S W I T Z E R , * V I S H N U V . R A J A S E K H A R A N , S A N S A N E E B O O N S A L E E , E L I Z A B E T H A . K U L P , A N D E R I C W . B O H A N N A N
Department of Chemistry and Graduate Center for Materials Research, University of Missouri, Rolla, Missouri 65409-1170

Many water districts have recently shifted from free chlorine (in the form of HOCl/OCl-) to monochloramine (NH2-Cl) as a disinfectant for drinking water to lower the concentration of chlorinated hydrocarbon byproducts in the water. There is concern that the use of NH2Cl disinfectant may lead to higher Pb levels in drinking water. In this study, the electrochemical quartz crystal microbalance is used to compare the effects of these two disinfectants on the dissolution of Pb films. A 0.5 ím thick Pb film nearly completely dissolves in a NH2Cl solution, but it is passivated in a HOCl/OCl- solution. X-ray diffraction analysis shows that the NH2Cl oxidizes Pb to Pb(II) species such as Pb3- (OH)2(CO3)2, whereas the stronger oxidant, HOCl/OCl-, oxidizes Pb to Pb(IV) as an insoluble PbO2 conversion coating. Although NH2Cl may produce less halogenated organic byproducts than HOCl/OCl- when used as a disinfectant, it may lead to increased Pb levels in drinking water.

The determinants of prevalence of health complaints among young competitive swimmers
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Benoit Levesque, Jean-Francois Duchesne, Suzanne Gingras, Robert Lavoie, Denis Prud’Homme, Emmanuelle Bernard, Louis-Philippe Boulet, Pierre Ernst
Published online: 4 April 2006

Abstract Objectives: Chloramines, which are produced by the reaction of chlorine with the organic matter present in indoor pools, are potential airway irritants in swimmers. The objective of this study was to compare the prevalence of health complaints of young swimmers and young indoor soccer players and to evaluate the relationship between chloramine concentrations and the athletes’ health complaints.

Overall, swimmers exposed to the highest levels of chloramines in the air and water had more respiratory complaints.

Conclusions: Swimmers exposed to chlorination by-products in both the water and air of indoor swimming pools experience frequent respiratory symptoms that could potentially be reduced by limiting exposure to these products.

Roles of ZO-1, occludin, and actin in oxidant-induced barrier disruption
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Mark W. Musch,* Margaret Mary Walsh-Reitz,* and Eugene B. Chang
The Martin Boyer Laboratories, Inflammatory Bowel Disease Research Center, Department of Medicine, The University of Chicago, Chicago, Illinois
Submitted 1 July 2005; accepted in final form 25 September 2005

Oxidants such as monochloramine (NH2Cl) decrease epithelial barrier function by disrupting perijunctional actin and possibly affecting the distribution of tight junctional proteins. These effects can, in theory, disturb cell polarization and affect critical membrane proteins by compromising molecular fence function of the tight junctions. To examine these possibilities, we investigated the actions of NH2Cl on the distribution, function, and integrity of barrier-associated membrane, cytoskeletal, and adaptor proteins in human colonic Caco-2 epithelial monolayers. NH2Cl causes a time-dependent decrease in both detergent-insoluble and -soluble zonula occludens (ZO)-1 abundance, more rapidly in the former. Decreases in occludin levels in the detergent-insoluble fraction were observed soon after the fall of ZO-1 levels. The actin depolymerizer cytochalasin D resulted in a decreased transepithelial resistance (TER) more quickly than NH2Cl but caused a more modest and slower reduction in ZO-1 levels and in occludin redistribution. No changes in the cellular distribution of claudin-1, claudin-5, or ZO-2 were observed after NH2Cl. However, in subsequent studies, the immunofluorescent cellular staining pattern of all these proteins was altered by NH2Cl. The actin-stabilizing agent phalloidin did not prevent NH2Cl-induced decreases in TER or increases of apical to basolateral flux of the paracellular permeability marker mannitol. However, it partially blocked changes in ZO-1 and occludin distribution. Tight junctional fence function was also compromised by NH2Cl, observed as a redistribution of the -subunit of basolateral Na -K -ATPase to the apical membrane, an effect not found with the apical membrane protein Na /H exchanger isoform 3. In conclusion, oxidants not only disrupt perijunctional actin but also cause redistribution of tight junctional proteins, resulting in compromised intestinal epithelial barrier and fence function. These effects are likely to contribute to the development of malabsorption and dysfunction associated with mucosal inflammation of the digestive tract. oxidants; actin cytoskeleton; tight junctions; transepithelial electrical resistance

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S.D. RICHARDSON National Exposure Research Laboratory, U.S. Environmental Protection Agency, 960 College Station Rd., Athens, GA, USA
Received: 10/01/05 Fax: +706-355-8302
Accepted: 30/03/05 e-mail:

This paper discusses current issues with drinking water disinfection by-products (DBPs), which include emerging (unregulated) DBPs that can be formed at greater levels with alternative disinfectants (as compared to chlorine) and routes of human exposure (which include inhalation and dermal exposure studies, in addition to ingestion). Health effects driving DBP research include the recently observed reproductive/developmental effects (including spontaneous abortion) observed in epidemiologic studies, as well as the discrepancy between the types of cancer observed in animal studies for regulated DBPs (mostly liver cancer) and the types of cancer observed in human epidemiologic studies (mostly bladder cancer). Emerging DBPs discussed in this paper include iodo-acids, bromonitromethanes, iodo-trihalomethanes (THMs), brominated forms of MX, bromoamides, a bromopyrrole, and nitrosodimethylamine (NDMA) and other nitrosamines. Recent toxicity studies have revealed that several of these DBPs are more genotoxic (in isolated cells) than many of the DBPs currently regulated, and new occurrence data have revealed that many of these DBPs can, in some cases, be present at levels comparable to regulated DBPs. Of the alternative disinfectants, chloramination appears to increase the formation of iodo-acids, iodo-THMs, and NDMA and other nitrosamines, relative to chlorine. Preozonation appears to increase the formation of halonitromethanes.

KEYWORDS: Disinfection by-products, DBPs, drinking water, emerging, exposure

Intracellular Ca2 and Zn2 signals during monochloramine-induced oxidative stress in isolated rat colon crypts
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Robert R. Cima,1,2 J. Matthew Dubach,1 Aaron M. Wieland,1 Breda M. Walsh,1 and David I. Soybel1
1Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; and 2Division of Colon and Rectal Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
Submitted 8 November 2004; accepted in final form 25 May 2005

During acute exacerbations of inflammatory bowel diseases, oxidants are generated through the interactions of bacteria in the lumen, activated granulocytes, and cells of the colon mucosa. In this study we explored the ability of one such class of oxidants, represented by monochloramine (NH2Cl), to serve as agonists of Ca2 and Zn2 accumulation within the colonocyte. Individual colon crypts prepared from Sprague- Dawley rats were mounted in perfusion chambers after loading with fluorescent reporters fura 2-AM and fluozin 3-AM. These reporters were characterized, in situ, for responsiveness to Ca2 and Zn2 in the cytoplasm. Responses to different concentrations of NH2Cl (50, 100, and 200 M) were monitored. Subsequent studies were designed to identify the sources and mechanisms of NH2Cl-induced increases in Ca2 and Zn2 in the cytoplasm. Exposure to NH2Cl led to dosedependent increases in intracellular Ca2 concentration ([Ca2 ]i) in the range of 200–400 nM above baseline levels. Further studies indicated that NH2Cl-induced accumulation of Ca2 in the cytoplasm is the result of release from intracellular stores and basolateral entry of extracellular Ca2 through store-operated channels. In addition, exposure to NH2Cl resulted in dose-dependent and sustained increases in intracellular Zn2 concentration ([Zn2 ]i) in the nanomolar range. These alterations were neutralized by dithiothreitol, which shields intracellular thiol groups from oxidation. We conclude that Ca2 - and Zn2 -handling proteins are susceptible to oxidation by chloramines, leading to sustained, but not necessarily toxic, increases in [Ca2 ]i and [Zn2 ]i. Under certain conditions, NH2Cl may act not as a toxin but as an agent that activates intracellular signaling pathways.

Monochloramine induces acute and protracted colitis in the rat: Response to pharmacological treatment
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Isabel Ballestera, Raquel Gonza´leza, Ana Nietob, Antonio Zarzueloa, Fermı´n Sa´nchez de Medinaa,TaDepartment of Pharmacology, School of Pharmacy, University of Granada, Campus de Cartuja s/n, 18071 Granada, Spain bBanco de Lı´neas Celulares de Andalucı´a, Fundacio´n Progreso y Salud, Hospital Virgen de las Nieves, Avda. Fuerzas Armadas s/n, Granada, Spain
Received 24 June 2004; accepted 8 November 2004

Monochloramine is a powerful oxidative molecule that is produced in inflammatory sites. We investigated the effect of intrarectally administered monochloramine (3.2 mg) in the rat. A single enema induced after 24 h an intense inflammatory reaction characterized by mucosal necrosis, submucosal edema, hemorrhage and colonic thickening, as well as induction of nitric oxide synthase and tumor necrosis factor and an increase in the interferon g/interleukin 4 ratio. The inflammatory response peaked 3–5 days after monochloramine administration and then followed a extended recovery phase. At 1 week there was substantial but incomplete mucosal repair, submucosal edema, neutrophil/macrophage infiltration and increased myeloperoxydase and alkaline phosphatase activities. Oxidative stress, as determined by malonyldialdehyde levels, was prominent only in the acute phase (3–5 days). Monochloramine colitis was amenable to pharmacological treatment with sulphasalazine or prednisolone, suggesting that it may be used as an experimental model of inflammatory bowel disease. In conclusion, monochloramine induces acute and protracted colonic inflammation in the rat. Locally produced monochloramine might contribute to the perpetuation of inflammatory bowel disease.

Keywords: Monochloramine; Oxidative stress; Inflammatory bowel disease; Alkaline phosphatase; Myeloperoxidase

Investigation of opportunistic pathogens in municipal drinking water under different supply and treatment regimes
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M. Pryor*, S. Springthorpe**, S. Riffard**, T. Brooks**, Y. Huo**, G. Davis*** and S.A. Sattar*** Pinellas County Utilities Laboratory, Largo, FL, USA
** Centre for Research in Environmental Microbiology, University of Ottawa, ON, Canada (E-mail:
*** Microbial Insights, Rockford, TN, USA

Changing regulations to lower disinfectant byproducts in drinking water is forcing utilities to switch disinfection from chlorine to monochloramine. It is generally unknown whether this will impact positively or negatively on the microbiological quality of drinking water. A utility in Florida, using water with relatively high organic carbon levels from deep wells in several wellfields, made the decision to change its disinfection regime from chlorine to chloramine in order to meet the new regulations. To assess the impacts of such a change on the microbiology of its water supplies, it undertook a number of studies before and after the change. In particular, the presence of the opportunistic pathogens Legionella and Mycobacterium, and also the composition of drinking-water biofilms, were examined. A preliminary synthesis and summary of these results are presented here. Legionella species were widely distributed in source waters and in the distribution system when chlorine was the disinfectant. In some samples they seemed to be among the dominant biofilm bacteria. Following the change to monochloramine, legionellae were not detected in the distribution system during several months of survey; however, they remained detectable at point of use, although with less species diversity. A variety of mycobacteria (21 types) were widely distributed in the distribution system when chlorine was the disinfectant, but these seemed to increase in dominance after chloramination was instituted. At point of use, only four species of mycobacteria were detected. Other changes occurring with chloramination included (a) an altered biofilm composition, (b) increased numbers of total coliforms and heterotrophs and (c) nitrification of water storage tanks. The results suggested that consideration should be given to the microbiological effects of changing disinfection regimes in drinkingwater and distribution system biofilms.

Keywords Biofilms; drinking-water disinfection; Legionella; Mycobacterium; opportunistic pathogens

Initiation of Rapid, P53-Dependent Growth Arrest in Cultured Human Skin Fibroblasts by Reactive Chlorine Species
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Glenn F. Vile, Lincoln A. Rothwell and Anthony J. Kettle1
Free Radical Research Group, Department of Pathology, Christchurch School of Medicine, P.O. Box 4345, Christchurch, New Zealand
Received 8 November 1999;  revised 3 January 2000.  Available online 15 April 2002.

Oxidants produced by neutrophils have been implicated in causing cancers associated with chronic inflammation. Hypochlorous acid is the most potent oxidant produced by these cells in appreciable amounts. It reacts with amines to form chloramines, which are weaker oxidants but are mutagenic. Recently, we showed that sublethal doses of hypochlorous acid increased levels of the transcription factor protein 53 (p53) and the wild-type activating fragment-1/cyclin-dependent kinase inhibitory protein-1 (WAF1/CIP1) in cultured human skin fibroblasts. WAF1/CIP1 is an important intermediate in the pathway leading to growth arrest. We now show that low doses of hypochlorous acid and physiological chloramines lead to an inhibition of both DNA synthesis and division of cultured human skin fibroblasts. Inhibition of DNA synthesis occurred within 1 h of hypochlorous acid treatment, was maintained for 24 h, and returned to a normal rate after 48 h. Cell division was inhibited by hypochlorous acid and chloramines for 48 h and returned to normal 72 h after treatment. Growth arrest was dependent on p53 because it was blocked when cells were transfected with a p53-binding oligonucleotide. We propose that reactive chlorine species will initiate WAF1/CIP1-dependent growth arrest that will counteract their mutagenic effects and minimize the possibility of the malignant transformation of cells surrounding sites of inflammation. 

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Department of Pathology, Okayama University Medical School, Faculty of Medicine, Okayama, Japan
(Received 26 September 2000; Accepted 6 February 2001)

Abstract—Monochloramine (NH2Cl) is a physiological oxidant produced by activated neutrophils, and it affects apoptosis signaling. We studied the effects of NH2Cl on the cell death induced by etoposide, a widely used anticancer agent that is directed to DNA topoisomerase II. Jurkat T cells, a human acute T cell leukemia cell line, were pretreated with 70 mM of NH2Cl for 10 min. After 24 h, 5–30 mM of etoposide was added to the NH2Cl pretreated and control cells, and their apoptosis, caspase activity, cell morphology, and cellular DNA contents were measured. NH2Cl pretreatment significantly inhibited apoptosis and caspase activation induced by etoposide or camptothecin, a DNA topoisomerase I poison, but not by staurosporine or Fas stimulation. The apoptosis inhibition actually resulted in the proliferation of the survived cells and, notably, the survived cells showed more aberrant morphology, such as variation in nuclear size, nuclear fragments, and multinucleated cells. DNA content analysis of the survived cells showed an increase in aneuploid nuclei. Cell cycle analysis after 24 h of NH2Cl treatment showed a significant decrease in S phase cells with a concurrent increase in G0/G1 phase cells, which suggested that NH2Cl induced G1 arrest. Using synchronized Jurkat cells, etoposide and camptothecin were found to be particularly cytotoxic to S phase cells, whereas staurosporine and Fas stimulation were not. Thus NH2Cl-induced G1 arrest was a likely cause of the observed resistance to etoposide. These observations suggested that inflammation-derived oxidants may make the tumor cells more resistant to etoposide and increase the risk of tumor progression and the development of secondary tumors by increasing the survival of DNA damage-bearing cells. © 2001 Elsevier Science Inc.

Keywords—Reactive oxygen species, Apoptosis, DNA damage, Cell cycle, Drug resistance, Free radicals

Formation of Cyanogen Chloride from the Reaction of Monochloramine with Formaldehyde
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E R I K J . P E D E R S E N I I I , † E D W A R D T . U R B A N S K Y , ‡ B E N I T O J . M A R I N÷ A S , * , § A N D D A L E W . M A R G E R U M * , ‡
School of Civil Engineering and Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, and Department of Civil and Environmental Engineering, University of Illinois, Urbana, Illinois 61801

Methanediol dehydrates to give formaldehyde, which reacts rapidly and reversibly with monochloramine to form N-chloroaminomethanol. Under drinking water conditions, N-chloroaminomethanol undergoes a relatively slow decomposition that eventually leads to the formation of cyanogen chloride (ClCN) in apparently stoichiometric amounts. The following reaction sequence is proposed: CH2(OH)2 / CH2O + H2O; CH2O + NH2Cl / CH2(OH)NHCl; CH2(OH)NHCl f CH2NCl + H2O; CH2NCl f HCl + HCN; CN- + NH2Cl + H+ f ClCN + NH3. These reactions were studied at 25.0 °C and an ionic strength of 0.10 M (NaClO4). Stopped-flow photometry was used to monitor rapid, reversible reactions, and photometry was used to study relatively slow decomposition reactions. Equilibrium and rate constants for the addition of formaldehyde to monochloramine were (6.6 ( 1.5) 105 M-1 and (2.8 ( 0.1) 104 M-1 s-1, respectively. The dehydration ofN-chloroaminomethanol was catalyzed by both H+ and OH-, with respective rate constants of 277 ( 7 and 26.9 ( 5.6 M-1 s-1. Under characteristic drinking water conditions, the decay of N-chloroaminomethanol is the rate-limiting step. N-Chloromethanimine, formed by the dehydration of N-chloroaminomethanol, had a decomposition rate constant of (6.65 ( 0.06) 10-4 s-1. At the relatively high methanediol concentrations used in this study, the intermediary N-chlorodimethanolamine was formed by the rapid and reversible reaction of N-chloroaminomethanol with formaldehyde. N-Chlorodimethanolamine then decayed relatively slowly. The following reaction sequence is proposed: CH2(OH)NHCl + CH2O / {CH2(OH)}2NCl; {CH2(OH)}2NCl f CH2NCl + CH2O + H2O. The equilibrium and rate constants for the addition of formaldehyde to N-chloroaminomethanol were (9.5 ( 2.5) 104 M-1 and (3.6 ( 0.1) 103 M-1 s-1, respectively. The decomposition of N-chlorodimethanolamine was catalyzed by OH-, with a rate constant of 19.2 ( 3.7 M-1 s-1. N-Chlorodimethanolamine would not be present under typical drinking water treatment conditions.

Natural Antioxidant, Chlorogenic Acid, Protects Against DNA Breakage Caused by Monochloramine
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Hitoshi Shibata, Yuji Sakamoto, Mikiko Oka, and The late Yasuhisa Kono
Department of Life Science and Biotechnology, Faculty of Life and Environmental Science
Shimane University, Matsue, Shimane 690-8504, Japan

Received December 1, 1998, Accepted March 27, 1999

Chlorogenic acid prevented a stepwise conversion of plasmid pUC18 DNA, form I--form II -- form III, induced by 3 mM monochloramine with a half inhibition of 67.4 um. Chlorogenic acid reacted with monochloramine in a time-dependent manner, and the reaction rate increased with decreasing pH. These results suggest that chlorogenic acid prevents genotoxicity of monochloramine in gastric mucosa.

Keywords: chlorogenic acid; DNA damage; gastric injury; monochloramine; natural antioxidant

Monochloramine directly modulates Ca2+-activated K+ channels in rabbit colonic muscularis mucosae
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Madhu Prasad*‡, Jeffrey B. Matthews*, Xue D. He‡, Hamid I. Akbarali‡
Received 5 February 1999; accepted 22 June 1999

Background & Aims: Mesenteric ischemia, infection, and inflammatory bowel disease may eventuate in severe colitis, complicated by toxic megacolon with impending intestinal perforation. Monochloramine (NH2Cl) is a membrane-permeant oxidant generated during colitis by the large amount of ambient luminal NH3 in the colon. Reactive oxygen metabolites can modulate smooth muscle ion channels and thereby affect colonic motility, which is markedly impaired in colitis. Methods: Effects of NH2Cl on ionic currents in the innermost smooth muscle layer of the colon, the tunica muscularis mucosae, were examined using the patch clamp technique. Membrane potential in whole tissue strips was measured using high-resistance microelectrodes. Results: Whole cell voltage clamp experiments showed that NH2Cl (3-30 ?mol/L) enhanced outward currents in a dose-dependent manner, increasing currents more than 8-fold at a test potential of +30 mV. Tail current analysis showed that the currents enhanced by NH2Cl were K+ currents. Inhibition by tetraethylammonium and iberiotoxin suggested that these currents represented activation of large-conductance, Ca2+-activated K+ channels. The membrane-impermeant oxidant taurine monochloramine, however, had no effect on whole cell currents. Single-channel studies in inside-out patches showed that NH2Cl increased open probability of a 257-pS channel in symmetrical (140 mmol/L) K+. In the presence of NH2Cl, the steady-state voltage dependence of activation was shifted by ?22 mV to the left with no change in the single-channel amplitude. The sulfhydryl alkylating agent N-ethylmaleimide prevented NH2Cl-induced channel activation. NH2Cl also hyperpolarized intact muscle strips, an effect blocked by iberiotoxin. Conclusions: NH2Cl, at concentrations expected to be found during colitis, may contribute to smooth muscle dysfunction by a direct oxidant effect on maxi K+ channels.

GASTROENTEROLOGY 1999;117:906-917
Abbreviations: EGTA , ethylene glycol-bis(?-aminoethyl ether)-N,N,N',N'-tetraacetic acid, IBTX , iberiotoxin, MPO , myeloperoxidase, NEM , N-ethylmaleimide, PMN , polymorphonuclear leukocyte, SH , sulfhydryl, TEA , tetraethylammonium, TMM , tunica muscularis mucosae

Monochloramine Inhibits Phorbol Esterinducible Neutrophil Respiratory Burst Activation and T Cell Interleukin-2 Receptor Expression by Inhibiting Inducible Protein Kinase C Activity
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Tetsuya Ogino Dagger , Hirotsugu Kobuchi §, Chandan K. Sen , Sashwati Roy , Lester Packer and John J. Maguire
From the Department of Molecular and Cellular Biology and the ¶ Environmental Energy Technologies Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720
(Received for publication, May 1, 1997, and in revised form, August 3, 1997)

Monochloramine derivatives are long lived physiological oxidants produced by neutrophils during the respiratory burst. The effects of chemically prepared monochloramine (NH2Cl) on protein kinase C (PKC) and PKC-mediated cellular responses were studied in elicited rat peritoneal neutrophils and human Jurkat T cells. Neutrophils pretreated with NH2Cl (30-50 £gM) showed a marked decrease in the respiratory burst activity induced by phorbol 12-myristate 13- acetate (PMA), which is a potent PKC activator. These cells, however, were viable and showed a complete respiratory burst upon arachidonic acid stimulation, which induces the respiratory burst by a PKC-independent mechanism. The NH2Cl-treated neutrophils showed a decrease in both PKC activity and PMA-induced phosphorylation of a 47-kDa protein, which corresponds to the cytosolic factor of NADPH oxidase, p47phox. Jurkat T cells pretreated with NH2Cl (20-70 £gM) showed a decrease in the expression of the interleukin-2 receptor alpha chain following PMA stimulation. This was also accompanied by a decrease in both PKC activity and nuclear transcription factor-kappa B activation, also without loss of cell viability. These results show that NH2Cl inhibits PKC-mediated cellular responses through inhibition of the inducible PKC activity.

Enhancement by monochloramine of the development of gastric cancers in rats: A possible mechanism of Heliobacter pylori-associated gastric carcinogenesis

Hiroyasu Iishi, Masaharu Tatsuta, Miyako Baba, Tomkio Mikuni, Reiko Yamamoto, Kazushige Iseki, Hiroshi Yano, Horoyuki Uehara, and Akihiko Nakaizumi
departments of Gastrointestinal Oncology and Gastroenterology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-3 Nakamichi, Higashinari-ku, Osaka, 537, Japan

The effects of cytotix monochloramine on the development of gastric cancers induced by N-methyl-N-nitro-N-nitrosoguanidine were investigated in Wistar rats. After oral administration of drinking water containing the carcinogen and regular chow pellets for 25 weeks, rats received regular chow pellets or chow pellets containing 20% ammonium acetate, and normal tap water or water containing 30mM sodium hypochlorite, with or without s.c. injection of taurine, until the end of the experiment in week 52. Treatment with both ammonium acetate and sodium hypochlorite significantly increased the incidence of gastric cancers in week 52, while the concomitant use of taurine with ammonium acetate and sodium hypochlorite significantly attenuated the enhanced gastric carcinogenesis. Spectrophotometric examinations revealed that taurine scavenged monochloramine. These findings suggest that Helicobacter pylori-associated gastric carcinogeneiss may be mediated by monochloramine.

Interferences by Monochloramine and Organic Chloramines in Free Available Chlorine Methods. 1. Amperometric Titration
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James N. Jensen' and J. Donald Johnson
Department of Environmental Sciences and Engineering, CB 7400, School of Public Health, University of North Carolina,
Chapel Hill, North Carolina 27599-7400

The free available chlorine (FAC) amperometric titration measurement is subject to interference errors from chloramines. Current measurements from chloramines were as much as 17% of the total chlorine in the presence of a 2:l molar excess of free amine at 0 V vs SCE. Interferences with this method increased as the positive applied voltage on the platinum electrode decreased. This trend was observed with both model compounds and chlorinated process waters. The interference from combined chlorine in one chlorinated and settled drinking water was up to 50% of the FAC response. Current increases after each addition of phenylarsine oxide (PAO) were observed with N-chlorosuccinimide, but not with the other chloramines tested.

Giardia: Drinking Water Health Advisory

Chloramines. Chloramines are less effective than chlorine; Ct values for G. muris cyst inactivation by preformed monochloramine were substantially higher than those for chlorine at pH 7 and 5o C. Jarroll (1988) found G. muris cysts to be more resistant to chloramines at lower pH values; preformed chloramines were less effective than chloramines that are not preformed. 

Type of Disinfectant in Drinking Water and Patterns of Mortality in Massachusetts
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by Sally Zierler,*t Robert A. Danley,* and Lisa Feingold*

Chlorination has been the major strategy for disinfection of drinking water in the United States. Concern about the potential health effects of the reaction by-products of chlorine has prompted use of alternative strategies. One such method is chloramination, a treatment process that does not appear to have carcinogenic by-products, but may have less potent biocidal activity than chlorination. We examined the patterns of mortality of residents in Massachusetts who died between 1969 and 1983 and lived in communities using drinking water that was disinfected either by chlorine or chloramine. Comparison of type of disinfectant among 51,645 cases of deaths due to selected cancer sites and 214,988 controls who died from cardiovascular, cerebrovascular, or pulmonary disease, or from lymphatic cancer showed small variation in the patterns of mortality. Bladder cancer was moderately associated with residence at death in a chlorinated community (mortality odds ratio = 1.7, 95% confidence interval = 1.3-2.2) in a logistic regression analysis using controls who died from lymphatic cancer. A slight excess of deaths from pneumonia and influenza was observed in communities whose residents drank chloraminated water compared to residents from chlorinated communities, as well as to all Massachusetts residents (standardized mortality ratio = 118, 95% confidence interval = 116-120 for chloraminated communities, and standardized mortality ratio = 98, 95% confidence interval = 95-100 for chlorinated communities). These results are intended to be preliminary and crude descriptions of the relationship under study. The serious potential for misclassification of exposure status and errors in death certificate classification of cause of death affect the interpretability of the overall evidence that patterns of mortality are similar according to disinfectant in drinking water.

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