关 键 词：

含CAD图纸+文档 淄博市 某区 给水 工程 工艺 设计 CAD 图纸 文档

资源描述：

压缩包内含有CAD图纸和说明书,均可直接下载获得文件，所见所得，电脑查看更方便。Q 197216396 或 11970985

内容简介：

任务书一、原始依据（包括设计或论文的工作基础、研究条件、应用环境、工作目的等。）根据相关设计资料，确定合理的工艺方案，使给水厂出水水质达到生活饮用水卫生标准（GB5749-2006），并安全输配到用户，满足用户的需求。（1）设计水量：满足最高日供水量 10.5 104m3/d；（2）原水水质：各项指标达到地表水环境质量标准（GB 3838-2002)中的类水质标准；（3）气象水文资料：（学生查阅给水排水设计手册（第1册）填写所在城市资料）1）气温：年平均 12.9 ，极端最高_42.1_, 极端最低_-23.0_,最热月月平均最高 32.0 ，最冷月月平均最低 -8.2 。2）降水量：平均年总量 630.3 mm，最大日_179.3_ mm，最大时 64.4 mm。3）相对湿度：最热月平均 76 。4）主导风向： 年最多风向 南西南 ；夏季最多风向：6月 南西南 、7月 南西南 、8月 南 、冬季最多风向：12月 南西南 、1月 南西南 、2月 南西南 、5）风速: 冬季平均： 2.6 m/s、夏季平均 2.3 m/s；6) 平均气压： 1001.0 mbar；7）最大冻土深度： 48 cm；8）最大积雪深度： 33 cm；（4）工程地质资料：土壤承载力满足基建设计要求，地下水水位相对标高 -5.0 m；（5）二泵站输水管起端节点自由水压 50 m。学生在毕业设计过程中熟悉相关的工作方法、工作过程，掌握主体工艺的设计计算和绘图，加强对所学基础知识的应用技能，为日后工作打下坚实基础。二、参考文献1 严煦世、范瑾初主编. 给水工程M. 第4版. 北京：中国建筑工业出版社，19992 中国市政工程东北设计研究院主编. 给水排水设计手册（第1册）常用资料M. 第2版. 北京：中国建筑工业出版社，20003 北京市政工程设计研究总院主编. 给水排水设计手册（第3册）城镇给水M. 第2版. 北京：中国建筑工业出版社，20044 室外给水设计规范（GB500132006）. 中国计划出版社，20065 崔玉川等主编给水厂处理设施设计计算M北京：化学工业出版社，20036 高湘主编给水工程技术及工程实例M北京：化学工业出版社，20027 姜乃昌、陈锦章主编水泵及水泵站M第4版北京：中国建筑工业出版社，19988 张智等主编给水排水工程专业毕业设计指南M北京：中国水利水电出版社，19999 市政工程设计施工系列图集给水排水工程（上、下册），中国建筑工业出版社，200310 王启山主编水工业工程常用数据速查手册M北京：机械工业出版社，200511 严煦世主编给水排水工程快速设计手册（1）给水工程M北京：中国建筑工业出版社，199912 Dr B C Punmia, Ashok Kr Jain, Arun Kr JainWater Supply EngineeringMLaxmi，199513 American Water Works Association，American Society of Civil EngineersWater Treatment Plant Design (4th edition)McGraw-Hill Professional, 200414 其它参考资料三、设计（研究）内容和要求（包括设计或研究内容、主要指标与技术参数，并根据课题性质对学生提出具体要求。）1设计内容要求（1）根据水质、水量、地区条件、施工条件和水厂运行情况、确定净水厂的处理工艺流程；（2）拟定各处理构筑物的设计流量，并根据确定的净水厂位置，选择适宜采用的处理构筑物，确定设计采用的处理构筑物的形式及数量；（3）进行各构筑物的设计计算，确定各构筑物和各主要构件的尺寸并绘制部分计算简图，设计时要考虑到构筑物及其构件施工上的可能性，并符合要求。1）投药及混合根据原水水质、处理要求、货源及其他经济技术条件选定混凝剂品种及投加量，设计溶解池、溶液池，布置加药间及药库，画出草图；确定混合方式，进行混合工艺设计计算和设备选择。2）絮凝、沉淀（或澄清池）絮凝池和沉淀池应同时进行计算和设计，并应注意两者的关系与配合，要使两池之间在高程、水流衔接、深度和池数等方面相互配合。根据设计流量，絮凝池、沉淀池应至少分为独立相同的两组，每组可根据需要分为若干格。也可根据水质情况选用澄清池，并进行设计计算。3）滤池在北方，滤池一般应设在室内，冲洗水泵房应尽可能与滤池合建。4）消毒选定消毒剂并根据水质有关参考资料确定其投加量，投加点应根据水质情况确定。进一步选择投加设备，布置加药间及药库，绘出草图。5）清水池清水池之间要既能互相连通，又能单池运行。清水池应根据水量大小、地形及设计高程而定，由单池容积和设计水深决定水池平面尺寸。（4）根据各构筑物的确定尺寸，确定各构筑物在平面位置上的确切位置，完成平面布置；确定各构筑物间联接管道的位置，管径、长度、材料及附属设施，完成水厂的高程布置。（5）绘制净水厂平面及高程布置图，净水构筑物工艺平、剖面图。（6）二泵站设计计算选泵台数不宜过多，也不宜过少，应能满足各种不同流量及扬程之需要为宜，一般4-7台，尽可能同型号。确定泵站形式，进行泵站设计计算；绘制二泵站工艺图。2设计成果要求（1）设计说明书一份（1.2万字）；参考文献10篇；相关外文文献资料翻译1份（5000汉字）。（2）绘制的图纸折合零号图纸3张，其中至少包括手绘图1张，其内容应满足表1要求。表1 毕业设计绘制图纸要求图纸内容数量及尺寸要求1水厂总平面和高程布置图1张，1号2絮凝和沉淀池平剖面图2张，1号3滤池平剖面图1张，1号4清水池平剖面图1张，1号5送水泵站平剖面图1张，1号指导教师（签字）20xx年 2 月28 日审题小组组长（签字）Humans have altered the nitrogen cycledramatically over the last half-century, and as aresult, nitrate is steadily accumulating in ourwater resources. Globally, human nitrogenproduction has increased rapidly since 1950and currently exceeds nitrogen fixed by naturalsources by about 30% (Fields 2004). This fig-ure compares with pre-1950 human inputs,which were a small fraction of the input fromnatural sources (Lambert and Driscoll 2003).Fertilizer is the largest contributor to anthro-pogenic nitrogen worldwide; other majorsources include animal and human waste,nitrogen oxides from utilities and automobiles,and leguminous crops that fix atmosphericnitrogen (Fields 2004). These organic andinorganic sources of nitrogen are transformedto nitrate by mineralization, hydrolysis, andbacterial nitrification. Under reducing condi-tions, nitrate can be biologically transformedto nitrogen gas through denitrification. Nitratenot taken up by plants or denitrified migratesto streams and groundwater.The U.S. Environmental ProtectionAgency (EPA) maximum contaminant level(MCL) for nitrate in drinking water of10 mg/L nitrate-nitrogen (nitrate-N) (equiva-lent to 45 mg/L as nitrate) and the WorldHealth Organization (WHO) guideline (WHO2004b) of 50 mg/L as nitrate (equivalent to11 mg/L as nitrate-N) were promulgated toprotect against methemoglobinemia, or “bluebaby syndrome,” to which infants are especiallysusceptible. The regulatory level is usually metfor public water supplies, which are routinelymonitored. Much less is known about privatewells, which in the United States are usuallyrequired to be tested only when the well is con-structed or when the property is sold. Somehave suggested recently that the regulatory levelfor nitrate in drinking water is overly conserva-tive (Avery 1999; Lhirondel and Lhirondel2002). However, this discussion of the regula-tory level has not thoroughly considered studiesof other chronic health effects including cancer,adverse reproductive outcomes, and diabetes.Although a causal role for nitrate in these otherhealth outcomes is not conclusive, recent studiesthat indicate possible adverse effects at nitratelevels below the MCL are of concern (Brenderet al. 2004b; DeRoos et al. 2003; Ward et al.1996; Weyer etal. 2001).In recognition of the widespread contam-ination of drinking-water sources by nitrateand the potential for health effects in additionto methemoglobinemia, a symposium titled“Drinking Water Nitrate and Health: RecentFindings and Research Needs” took place atthe annual meeting of the InternationalSociety for Environmental Epidemiology(14 August 2004, New York, New York,USA). Invited experts presented results fromrecent unpublished studies and summarizedthe state of knowledge on exposure andhealth effects of drinking-water nitrate, with afocus on cancer and adverse reproductive out-comes. This article summarizes the sympo-sium discussions and recommends promisingareas for future research. Specifically, we dis-cuss the epidemiologic evidence for drinking-water nitrate and risk of specific cancers,adverse reproductive outcomes, and otherhealth outcomes in the context of the currentregulatory limit for nitrate in drinking water.Nitrate Levels in Groundwaterand Water SuppliesNitrate is the most common chemical contami-nant in the worlds groundwater aquifers(Spalding and Exner 1993). An estimated 42%of the U.S. population uses groundwater as theirdrinking-water supply (Hutson et al. 2004). Inthe United States, total nitrogen in streams andnitrate in groundwater are highest in agricul-tural areas, followed by urban areas and areaswith mixed land use (Figure 1). The mostrecent data indicate that about 22% of domesticwells in agricultural areas of the United Statesexceeded the MCL (U.S. Geological Survey,unpublished data). In contrast, 3% of publicsupply wells in major aquifers (typical sourcesfor public water supplies) exceed the MCL(U.S. Geological Survey, unpublished data).Environmental Health PerspectivesVOLUME113 |NUMBER11 | November 20051607ResearchAddress correspondence to M.H. Ward, Occupationaland Environmental Epidemiology Branch, Division ofCancer Epidemiology and Genetics, National CancerInstitute, 6120 Executive Blvd., EPS 8104, Bethesda,MD 20892 USA. Telephone: (301) 435-4713. Fax:(301) 402-1819. E-mail: wardmWe thank K. Cantor of the National Cancer Institutefor his review of the manuscript.The authors declare they have no competingfinancial interests.Received 25 February 2005; accepted 23 June 2005.Workgroup Report: Drinking-Water Nitrate and HealthRecent Findings andResearch NeedsMary H. Ward,1Theo M. deKok,2Patrick Levallois,3Jean Brender,4Gabriel Gulis,5Bernard T. Nolan,6and James VanDerslice71Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health andHuman Services, Bethesda, Maryland, USA; 2Department of Health Risk Analysis and Toxicology, University of Maastricht, theNetherlands; 3Institut National de Sant Publique du Qubec and Unit de recherche en sant publique, Centre Hospitalier Universitairede Qubec, Qubec, Canada; 4Department of Health Services Research, Texas State University, San Marcos, Texas, USA; 5Departmentof Health Promotion Research, Southern Denmark University and Department of Public Health, University of Trnava, Slovakia; 6U.S.Geological Survey, Reston, Virginia, USA; 7Washington State Department of Health, Olympia, Washington, USAHuman alteration of the nitrogen cycle has resulted in steadily accumulating nitrate in our waterresources. The U.S. maximum contaminant level and World Health Organization guidelines fornitrate in drinking water were promulgated to protect infants from developing methemoglobine-mia, an acute condition. Some scientists have recently suggested that the regulatory limit fornitrate is overly conservative; however, they have not thoroughly considered chronic health out-comes. In August 2004, a symposium on drinking-water nitrate and health was held at theInternational Society for Environmental Epidemiology meeting to evaluate nitrate exposures andassociated health effects in relation to the current regulatory limit. The contribution of drinking-water nitrate toward endogenous formation of N-nitroso compounds was evaluated with a focustoward identifying subpopulations with increased rates of nitrosation. Adverse health effects maybe the result of a complex interaction of the amount of nitrate ingested, the concomitant ingestionof nitrosation cofactors and precursors, and specific medical conditions that increase nitrosation.Workshop participants concluded that more experimental studies are needed and that a particu-larly fruitful approach may be to conduct epidemiologic studies among susceptible subgroups withincreased endogenous nitrosation. The few epidemiologic studies that have evaluated intake ofnitrosation precursors and/or nitrosation inhibitors have observed elevated risks for colon cancerand neural tube defects associated with drinking-water nitrate concentrations below the regulatorylimit. The role of drinking-water nitrate exposure as a risk factor for specific cancers, reproductiveoutcomes, and other chronic health effects must be studied more thoroughly before changes to theregulatory level for nitrate in drinking water can be considered. Key words: adverse reproductiveoutcomes, methemoglobinemia, neoplasms, nitrate, nitrite, N-nitroso compounds, water pollu-tion. Environ Health Perspect 113:16071614 (2005). doi:10.1289/ehp.8043 available via/ Online 23 June 2005The exposure picture is similar in theEuropean Union. Public water supplies arelargely below the WHO guideline; however, insome countries, private wells in rural areas haveelevated nitrate concentrations reaching1015 times the recommended level (EuropeanEnvironment Agency 2003). Overall, nitratelevels exceeded the guideline in about one-thirdof the groundwater bodies for which data wereavailable (European Environment Agency2003). Several eastern European countriesreport high levels of nitrate contamination in alarge proportion of private wells; for example,in Romania, 20% of 2,000 wells had nitratelevels 23 mg/L as nitrate-N (Jedrychowskiet al. 1997). Studies from other countries,including China, Botswana, Turkey, Senegal,and Mexico, report private well water levels thatexceed the WHO guideline, in some instancesat levels 68 mg/L nitrate-N (WHO 2004a).Fertilizer is the main contributing factor in agri-cultural areas; however, nitrogen from humanwaste appears to be the most important sourcein urban areas lacking centralized water andsanitation systems. Although systematic infor-mation on nitrate levels in groundwater inother parts of the world is more limited, empir-ical modeling approaches have indicated thatusers of shallow wells in areas with high nitro-gen inputs, well-drained soils, and unconsoli-dated rocks are most at risk of consuminghigh-nitrate groundwater (Nolan et al. 2002).MethemoglobinemiaIngested nitrate is reduced to nitrite, whichbinds to hemoglobin to form methemoglobin(MetHb). Methemoglobinemia occurs whenelevated levels of MetHb (exceeding about10%) interfere with the oxygen-carryingcapacity of the blood. Infants are particularlysusceptible to developing methemoglobinemiafor several reasons, including their increasedcapacity to convert nitrate to nitrite and theirlower levels of the enzyme cytochrome b5reductase, which converts MetHb back tohemoglobin. Methemoglobinemia in infantsfed formula made with well water with highnitrate levels was first reported in 1945 byComly (1945). The regulatory level for nitratein drinking-water supplies was determined aftera survey of infant methemoglobinemia casereports in the United States indicated that nocases were observed at drinking-water nitratelevels 10 mg/L nitrate-N. Nevertheless, few cases ofmethemoglobinemia have been reported sincethe MCL was promulgated.The risk of methemoglobinemia amonginfants depends on many factors other thanthe ingestion of nitrate in drinking water.Some foods and medications contain highlevels of nitrate (Sanchez-Echaniz et al. 2001).Enteric infections, potentially caused by fecalbacteria contamination in wells, may lead tothe endogenous production of nitrite, as evi-denced by numerous published reports ofinfants with diarrhea and methemoglobine-mia but no apparent exposure to exogenousMetHb-forming agents (Charmandari et al.2001; Hanukoglu and Danon 1996; Levineet al. 1998; Wennmalm et al. 1993). Theconsumption of antioxidants such as vitaminC appears to be a protective factor. Finally,polymorphisms in the activity of cytochromeb5 reductase may mediate the effect ofingested nitrate or endogenously producednitrite (Gupta et al. 1999).Studies that have examined the relation-ship between nitrate levels in drinking waterand MetHb levels in infants have producedmixed results (U.S. EPA 1991). The fewexperimental studies are largely negative; how-ever, most of these studies evaluated low levelsof drinking-water nitrate and included fewinfants. Cofactors such as diarrhea and respira-tory diseases reportedly increase MetHb levels(Shearer et al. 1972; Shuval and Gruener1972). An epidemiologic study in SouthAfrica (Super et al. 1981) found an increase inMetHb levels in infants fed water with nitrate 20 mg/L nitrate-N; however, clinical methe-moglobinemia was rarely found. A protectiveeffect of vitamin C intake on MetHb wasnoted (Super et al. 1981). More recently, aretrospective, nested casecontrol study inRomania found an association between nitrateexposure from drinking water and clinicalmethemoglobinemia, but also some evidenceof an association with diarrheal disease(Zeman et al. 2002). Gupta and colleagues(1999) found cytochrome b5 reductase activi-ties to be higher among those consumingwater with high nitrate levels, indicating alevel of adaptation to the consumption of highnitrate waters.Recently, the role of nitrate exposurealone in causing methemoglobinemia hasbeen questioned (Avery 1999; Fewtrell 2004;Hanukoglu and Danon 1996). Clearly, weneed to better understand the interaction offactors that lead to methemoglobinemia toassess the relative importance of each factorand to identify the conditions under whichexposure to nitrate in drinking water poses arisk of methemoglobinemia.Nitrate Intake and EndogenousFormation of N-NitrosoCompoundsNitrate is a precursor in the formation ofN-nitroso compounds (NOC), a class of geno-toxic compounds, most of which are animalcarcinogens. In the human body, nitrate is astable, inert compound that cannot be metab-olized by human enzymes. However, thenitrate-reducing activity of commensal bacte-ria may convert nitrate into nitrite and otherbioactive nitrogen compounds that affectphysiological processes and human health.After ingestion, nitrate is readily absorbedfrom the upper gastrointestinal tract. Up to25% is actively excreted in saliva, where about20% is converted to nitrite by bacteria in themouth (Spiegelhalter et al. 1976). This con-version can occur at other sites including thedistal small intestine and the colon.Under acidic conditions in the stomach,nitrite is protonated to nitrous acid (HNO2),which in turn spontaneously yields dinitrogentrioxide (N2O3), nitric oxide (NO), and nitro-gen dioxide (NO2). NO is a bioactive com-pound known to play a role in vasodilatationand in defense against periodontal bacteria andother pathogens. N2O3,on the other hand, is apowerful nitrosating agent capable of donatingNO+to secondary and tertiary amines to formpotentially carcinogenic N-nitrosamines (Leafet al. 1989). Alternatively, HNO2can be proto-nated to H2NO2, which reacts with amides toform N-nitrosamides. At neutral pH, nitrite canbe reduced by bacterial activity to form NO,which can react with molecular oxygen to formthe nitrosating compounds N2O3and nitrogentetroxide (N2O4). In addition to the acid-cat-alyzed and bacterial-catalyzed formation ofnitrosating agents, inducible NO synthaseactivity of inflammatory cells can also produceNO (Ohshima and Bartsch 1994). Together,these three mechanisms of endogenous nitrosa-tion account for an estimated 4075% of thetotal human exposure to NOC (Tricker 1997).Other sources of human exposure include pre-formed NOC found in preserved meats andfish, beer, certain occupational exposures, andtobacco products (Tricker 1997).Several studies support a direct relation-ship between nitrate intake and endogenousWard et al.1608VOLUME113 |NUMBER11 | November 2005Environmental Health PerspectivesFigure 1. Interquartile range of total nitrogen instreams and nitrate-N in groundwater in agricul-tural, urban, and mixed land use, and undevelopedareas of the United States. Upper bound of bar rep-resents 90th percentile and lower bound represents10th percentile. Along the top of the graph are thenumber of stream sampling stations and groundwa-ter networks (group of wells in an aquifer).12108642095611855573412296UndevelopedAgriculturalUrbanMixedDominant land useConcentration (mg/L)StreamsGroundwaterformation of NOC. High intake of drinking-water nitrate (above the MCL) is associatedwith an increased endogenous capacity tonitrosate proline (Mirvish et al. 1992; Molleret al. 1989). In addition, populations withhigh rates of esophageal and gastric cancerexcrete high levels of N-nitrosoproline(Kamiyama et al. 1987; Lu et al. 1986).Nitrate intake at the acceptable daily intakelevel (3.67 mg/kg body weight, 0.84 mg/kg asnitrate-N) results in increased urinary excre-tion of NOC, particularly in combinationwith increased intake of dietary nitrosatableprecursors (Vermeer et al. 1998). However, aCanadian population exposed to nitrate belowthe acceptable daily intake level showed norelationship between nitrate levels in drinkingwater and urinary nitrosamines (Levallois et al.2000).Factors that modulate endogenous nitro-sation. Although intake of high drinking-water nitrate is consistently associated withendogenous nitrosation capacity, intake ofdietary nitrate is less likely to increase nitrosa-tion, because of the presence of nitrosationinhibitors in vegetables, the major contribu-tors to dietary nitrate intake (Bartsch et al.1988; National Academy of Sciences 1981).Dietary compounds that inhibit endogenousnitrosation include vitamin C, which has thecapacity to reduce HNO2to NO, and alpha-tocopherol, which can reduce nitrite to NO.Several epidemiologic studies reported noassociation or inverse associations betweendietary nitrate intake and human cancers(Boeing 1991; Forman 1987; Ward et al.1996), which may be because of the antioxi-dants and nitrosation inhibitors in nitrate-containing foods (Bartsch et al. 1988).Inhibitory effects on nitrosation have alsobeen described with betel nut extracts, ferulicand caffeic acid, garlic, coffee, and green teapolyphenols (Stich et al. 1984). In addition,nondietary factors such as the use of mouth-washes containing chlorhexidine can influ-ence the endogenous nitrosating capacity (vanMaanen et al. 1998).Apart from the level of nitrosating agents,the level of nitrosatable precursors in the diet,which come predominantly from meat andfish, is a crucial factor in endogenous nitrosa-tion. Dietary intakes of red and processedmeat are of particular importance in the for-mation of fecal NOC (Bingham 1999;Bingham et al. 1996, 2002; Cross et al. 2003;Haorah et al. 2001). Higher consumption ofred meat (600 vs. 60 g/day), but not whitemeat, resulted in a 3-fold increase in fecalNOC levels (Bingham et al. 1996). Coloncancer incidence is most consistently associ-ated with consumption of red meat (beef,lamb, and pork), but not with poultry andfish (Bingham 1999). Dietary supplementa-tion of a diet low in red meat with either hemeiron or inorganic iron demonstrated that hemein particular was able to stimulate endogenousnitrosation (Cross et al. 2003), thereby provid-ing a possible explanation for the differences incolon cancer risk between red and white meatconsumption. Additionally, this linkage maybe stronger for processed meat than for freshmeat because of the higher NOC and NOCprecursor levels in processed meat.Endogenous nitrosation can also be stim-ulated by inflammatory and other medicalconditions. For instance, patients with bil-harzia have an increased bladder cancer riskassociated with increased urinary levels ofnitrite and volatile nitrosamines, most likelygenerated by the reaction of inflammation-derived NO with amines present in the urine(Tricker et al. 1989). Inflammatory boweldisease is also related to both increased nitro-sation and cancer risk (Lashner et al. 1988).During inflammatory bowel disease, increasedinducible NO synthase activity can produceexcess NO, which is oxidized to nitrogenoxides and nitrite, which in turn react withnitrosatable precursors in colonic contents toproduce NOC. Indeed, ulcerative colitispatients showed increased levels of inducibleNO synthase in the colonic mucosa (Kimuraet al. 1998) and of NO and nitrite in thecolonic lumen (Lundberg et al. 1997;Roediger et al. 1990). Increased levels of fecalNOC have been found in patients withinflammatory bowel disease and in mice withchemically induced colitis (de Kok et al.2005; Mirvish et al. 2003).Health Effects Associated withDrinking-Water NitrateCancer. NOC are potent animal carcinogens,inducing tumors at multiple organ sitesincluding the esophagus, stomach, colon,bladder, lympatics, and hematopoietic system(Bogovski and Bogovski 1981). NOC causetumors in every animal species tested, and it isunlikely that humans are unaffected (Lijinsky1986). The number of well-designed epidemi-ologic studies with individual exposure dataand information on nitrosation inhibitors andprecursors are few for any single cancer site,limiting the ability to draw conclusions aboutcancer risk.Most studies have been ecologic in design,linking incidence or mortality rates to drink-ing-water nitrate levels at the town or countylevel. The early studies focused on stomachcancer mortality, and most used drinking-water nitrate measurements concurrent withthe period of cancer mortality. Results weremixed, with some studies showing positiveassociations, many showing no association, anda few showing inverse associations (Cantor1997). Recent ecologic studies of stomach can-cer in Slovakia, Spain, and Hungary with his-torical measurements and exposure levels nearor above the MCL have found positive correla-tions with stomach cancer incidence or mortal-ity (Gulis et al. 2002; Morales-Suarez-Varelaet al. 1995; Sandor et al. 2001). Two studiesincluded other cancer sites. In Slovakia, inci-dence of non-Hodgkin lymphoma (NHL) andcolon cancer was significantly elevated amongmen and women exposed to public supplynitrate levels of 4.511.3 mg/L nitrate-N(Gulis et al. 2002); there was no associationwith bladder and kidney cancer incidence. InSpain, there was a positive correlation betweennitrate levels in public supplies and prostatecancer mortality, but no relation with bladderand colon cancer (Morales-Suarez-Varela et al.1995).In the past decade, several casecontroland cohort studies have evaluated historicalnitrate levels in public water supplies (largely 2.46 mg/L nitrate-N)of the long-term average nitrate levels at thecurrent residence. They observed significantinverse associations for uterine and rectal can-cer and no significant associations for NHL,leukemia, colon, rectum, pancreas, kidney,lung, and melanoma. Casecontrol studies ofbladder (Ward et al. 2003), brain (Ward et al.2004), colon and rectum (De Roos et al.2003), and pancreas cancer (Coss et al. 2004)in Iowa found no association between cancerrisk and average nitrate levels over almost30 years. Each study evaluated the interactionbetween nitrosation inhibitors or NOCprecursors and nitrate intake from drinkingwater. For colon cancer, there was a signifi-cant positive interaction between 10 or moreyears of exposure above 5 mg/L nitrate-N andboth low vitamin C and high meat intake,factors likely to increase endogenous NOCformation (De Roos et al. 2003).A casecontrol study of NHL in Nebraska(USA) (Ward et al. 1996) found a significantpositive association between the average nitratelevel in public water supplies over about40 years and risk among men and women. Inthe highest quartile of nitrate (4.0 mg/Lnitrate-N), risk was elevated 2-fold. However,a recent study of NHL in Iowa with similarexposure levels found no association (Wardet al. 2004). A casecontrol study of NHL inMinnesota (USA) (Freedman et al. 2000) withlower levels of nitrate found an inverse associa-tion among those with the highest level( 1.5 mg/L nitrate-N). Casecontrol studiesin Nebraska (Ward et al. 2004) and Germany(Steindorf et al. 1994) found no associationwith long-term average nitrate levels in publicDrinking-water nitrate and healthEnvironmental Health PerspectivesVOLUME113 |NUMBER11 | November 20051609water supplies and adult brain cancer. TheNebraska study found no evidence of an inter-action with vitamin C intake. A casecohortanalysis of stomach cancer within a cohortstudy in the Netherlands (van Loon et al.1998) found no association with quintiles ofwater nitrate intake determined from publicsupply levels.Specific NOC are transplacental neurocar-cinogens in animal studies. A study of child-hood brain cancer measured nitrate levels inwater supplies using dipstick measurements,often many years after the pregnancy (Muelleret al. 2001). Measured levels of nitrate andnitrite were not associated with risk; however,women in western Washington State, one ofthe three study centers, who used private wellsas their drinking-water source during the preg-nancy had a significantly increased risk ofbrain cancer in their offspring.Adverse reproductive outcomes. In 1961,Schmitz described a possible relationshipbetween high maternal MetHb levels andspontaneous abortion. Since then, at least 10studies have examined the associationbetween drinking-water nitrate and adversereproductive outcomes. Table 2 summarizesthese studies by location, study design, deter-mination of water nitrate, and key findings.Few studies have been published regardingwater nitrate and the outcomes of sponta-neous abortions, stillbirths, premature birth,or intrauterine growth retardation. Results ofthese studies have been inconsistent, possiblyindicating no true effect of water nitrate onreproductive outcomes at the levels evaluatedin these studies. Alternatively, the inconsis-tencies may be due to the differing periodsover which exposure was assessed, differinglevels of water nitrate across studies, or differ-ences in exposure to other cofactors.Results of studies evaluating drinking-water nitrate and congenital malformations inoffspring are also mixed (Table 2). Four stud-ies (Arbuckle et al. 1988; Brender et al. 2004a,2004b; Croen et al. 2001, Dorsch et al. 1984)found positive associations between drinking-water nitrate and congenital malformations,Ward et al.1610VOLUME113 |NUMBER11 | November 2005Environmental Health PerspectivesTable 1. Analytic epidemiologic studies of drinking-water nitrateaand cancer.Study designReference, year,(casecontrol, cohort)Years of cancerCancer sitescountryRegional descriptionascertainmentExposure descriptionaincludedSummary of findingsCoss et al. 2004Population-based casecontrolAverage nitrate level in public suppliesPancreasNo significant associations withUSAIncidence19601987 (highest quartile 2.8 mg/L);quartiles of average nitrate orIowa19861989Years of exposure 7.5 and 10 mg/Lnumber of years 7.5 or 10 mg/LDeRoos et al. 2003Population-based casecontrolAverage nitrate level in public suppliesColonNo association with average level,USAIncidence19601987 categorized into four levelsRectumyears 5 and 10 mg/L;Iowa19861989(lowest: 1.0; highest: 5mg/L);Significantly elevated risk amongYears of exposure 5 and 10 mg/Lsubgroups with below medianvitamin C intake or above medianmeat intake and 10 or moreyears 5 mg/LFreedman 2000Population-based casecontrolAverage nitrate level in publicNon-HodgkinNo increase risk with increasingUSAIncidencewater supplies 19471980 (157 towns)lymphomaexposure level. OR for 1.5 mg/LMinnesota excluding four largestcategorized into three levels: 0.5, 0.5 to(three cases, four controls) wascities19801982 1.5, 1.5 mg/L0.3 (95% CI, 0.10.9).Mueller et al. 2001Population-based casecontrolWater source (private well, public supply)Childhood brainNo overall association with waterUSA19 counties in San Francisco,during pregnancy; dipstick measurementssource. Well use in westernCalifornia, area and westernof nitrate and nitrite for those still livingWashington State increased riskWashington State19841990at residence during pregnancy(OR = 2.6; 95% CI, 1.35.2); well usein Los Angeles inversely associatedwith risk (OR = 0.2; 95% CI, 0.10.8)Steindorf et al. 1994Population-based casecontrolNitrate levels in municipal supplies afterBrainNo association with average nitrateGermanyIncidence1970 (highest quartile: 5.7 mg/L)levelRhein-Neckar-Odenwald area19871988Van Loon et al. 1998Prospective cohortNitrate intake from public supplies inStomachNo association with quintiles ofNetherlandsIncidence1986 and intake of tap water (quintiles;water nitrate intake (highest19861992mean level in highest quintile: 3.7 mg/day)quintile: RR = 0.88)Ward et al. 1996Population-based casecontrolAverage nitrate level in public water suppliesNon-HodgkinSignificant positive trend withUSAIncidence1945early 1980s categorized into quartileslymphomaincreasing quartiles: OR highest66 counties in eastern Nebraska19831986(lowest: 2.46 mg/L)leukemia,quartile OR = 2.83) and ovary19861998colon, rectum,(OR = 1.84) and inverse associationspancreas, kidney,for uterus (highest quartilebladder, breast,OR = 0.55) and rectal cancerovary, uterine(OR = 0.47)corpus, lungand bronchus,melanomaOR, odds ratio.aNitrate levels presented in the original publications as mg/L nitrate were converted to mg/L nitrate-N. particularly malformations of the central ner-vous system, and specifically neural tubedefects (NTDs). In each of these studies,water nitrate levels associated with increasedrisk of these defects were below the MCL,although the 95% confidence intervals (CIs)for some of the risk estimates were consistentwith unity and varied by the source of water(groundwater, mixed, or surface). Two ofthese studies (Brender et al. 2004b; Croenet al. 2001) also examined dietary intake ofnitrates and nitrates and NTDs and foundDrinking-water nitrate and healthEnvironmental Health PerspectivesVOLUME113 |NUMBER11 | November 20051611Table 2. Studies of the relation between drinking-water nitrateaand reproductive outcomes.Reference,Measurement ofReproductivestudy population, study designwater nitrateoutcomeReported findingsAschengrau et al. 1989Matched maternalSBs throughOR of 0.5 for SB with exposureMassachusetts (USA) residentsresidence at pregnancy27 weeks of gestationto water nitrate levels ofHospital casecontrol studyoutcome to results of0.15.5 mg/L relative totap water samplesnondetectable levelsGrant et al. 1996Wells tested for nitratesSBsWater nitrate above U.S. EPAIndiana (USA)after cluster reportedMCL for women with SBsCluster investigationAschengrau et al. 1993Matched maternalCongenital anomalies,Neither stillbirths nor congenitalMassachusetts (USA) residentsresidence duringstillbirths, neonatalanomalies associated withHospital casecontrol studypregnancy ordeathsdetectable levels of wateroutcome to resultsnitrate (0.24.5 mg/L); smallof tap water samplespositive association betweenwater nitrates and neonatal deaths.Super et al. 1981Water sample takenSpontaneousNo association between waterSouth West Africafrom well used atpremature laborfrom high nitrate regions andCross-sectional studytime of home visitSize of infant at birthprematurity or size of infantBukowski et al. 2001Residential postal codeIUGRDoseresponse relation betweenPrince Edward Island, Canadaat time of deliveryPremature birthnitrate level and ORs for IUGRCasecontrol studylinked to nitrateand prematuritylevel exposure mapScragg et al. 1982Address at deliveryCongenitalElevated OR for anyDorsch et al. 1984linked to sourcesmalformationscongenital malformation (2.8);South Australiaof water and datamalformations of the CNS (3.5);Casecontrol studyon nitratesmusculoskeletal system (2.9) ifprimarily drank groundwater.Elevated ORs for congenitalmalformations associated withnitrate levels 5 mg/L relative tonitrate levels 45 mg/LCasecontrol studycompanies andassociated withdatabasesanencephaly (OR 4.0)but not with spina bifida;increased risks for anencephalyat water nitrate levels belowU.S. EPA MCL amonggroundwater drinkers only;dietary nitrate and nitrite notassociated with NTDsCedergren et al. 2002Linked periconceptionalAny congenitalWeak association (OR 1.2)Ostergotland County, Swedenor early pregnancycardiac defectbetween water nitrateRetrospective cohort studyaddress to water supplies 2 mg/L and cardiacusing a geographicmalformationsinformation systemBrender et al. 2004aUsual periconceptionalNTDsOR of 1.9 if waterBrender et al. 2004bdrinking-water sourcenitrates 3.52 mg/L;Texas (USA)tested for nitratesincreased water nitrateCounties along TexasMexico borderassociated withCasecontrol studyspina bifida (OR 7.8)but not with anencephaly(OR 1.0); slightly inverse relationbetween dietary nitrite, total nitriteintake and NTDsAbbreviations: CNS, central nervous system; IUGR, intrauterine growth retardation; SB, spontaneous abortion.aNitrate units are mg/L as nitrate.minimal or no effect on risk. In a study ofnitrosatable drug exposure and risk of NTDs(Brender et al. 2004b), drinking-water nitratesand dietary nitrites/total nitrites substantiallymodified the risk associated with this drugexposure during the periconceptional period;higher levels of nitrates in food or water signifi-cantly increased the risk of NTDs if womenwere exposed to such drugs.Other health outcomes. Animal studies sug-gest that nitrate at high doses can competitivelyinhibit iodine uptake and induce hypertrophicchanges in the thyroid (Bloomfield et al.1961). In a human biomonitoring study in theNetherlands, consumption of water withnitrate levels at or above the MCL was associ-ated with thyroid hypertrophy (van Maanenet al. 1994) and genotoxic effects (van Maanenet al. 1996). Animal studies provide evidencethat NOC can damage the pancreatic beta cells(Longnecker and Daniels 2001). Three epi-demiologic studies (Kostraba et al. 1992;Parslow et al. 1997; van Maanen et al. 2000)that were ecologic in design found a positivecorrelation between drinking-water nitrate lev-els below the MCL and the incidence of type Ichildhood diabetes, although the associationobserved by van Maanen was not statisticallysignificant. Other studies have found associa-tions between water nitrate exposure andincreased blood pressure (Pomeranz et al.2000) and acute respiratory tract infections inchildren (Gupta et al. 2000).Recommendations for FutureResearchExperimental/human biomonitoring studies.Endogenous nitrosation in humans has beendemonstrated in relation to drinking-waternitrate ingestion at levels above the MCL.However, further studies are needed to deter-mine the extent of endogenous nitrosation atintermediate drinking-water nitrate levels(510 mg/L as nitrate-N) and to clarify therole of nitrate from water versus food sources.Furthermore, the role of precursors and mod-ulators of NOC formation should be morefully investigated. These future studies shouldbe conducted among healthy individuals aswell as individuals with medical conditionsthat increase endogenous nitrosation.In view of the complex kinetics of NOCformation and the organ specificity of severalof these compounds (Hodgson et al. 1980;Suzuki et al. 1999), more studies are neededto evaluate the relationship between nitrateintake and formation, metabolism, and excre-tion of NOC. Ideally, a physiologically basedpharmacokinetic model should be developedas previously recommended (NationalResearch Council 1995) to predict exposureto NOC from all sources of nitrate exposure(exogenous and endogenous), nitrite intake,the transformation of nitrate into nitrite, andantioxidant intake. However, this will requireadditional data on the formation of individualNOC as well as their respective toxicologiccharacteristics. The results of these investiga-tions will reveal the value of different markersof NOC exposure in future epidemiologicstudies. Future studies linking NOC exposureto early markers of effect or to the actual dis-ease will clarify the role of endogenous nitro-sation and NOC exposure as etiologic factors.Because many NOC require -hydroxyla-tion by CYP2E1 for bioactivation and for for-mation of DNA adducts, it is important toinvestigate the influence of polymorphisms inthe gene encoding for this enzyme. One studyfound that specific variants in this gene arelinked to increased rectum cancer risk, particu-larly in subjects with high intake of red andprocessed meat, who are exposed to increasedlevels of NOC (Le Marchand et al. 2002).Moreover, gene expression levels of humanCYP2E1 were related to cytotoxicity and DNAdamage by nitrosamines in pancreatic beta-celllines, suggesting that such gene environmentinteractions are also relevant in type 1 diabetes(Lees Murdock et al. 2004). These promisinglines of research point to a possible interactionbetween drinking-water nitrate exposure andgene expression of and/or genetic variation inCYP2E1, which may also influence the risk ofseveral adverse health outcomes associated withnitrate exposure.Epidemiologic studies. Methods must bedeveloped and validated to improve estimatesof current and historical exposure to nitrate viafood and water, particularly for populationsserved by private wells, which are less likely tobe routinely monitored. Future epidemiologicstudies should integrate a) exposure assess-ment for nitrate intake from drinking water,nitrate and nitrite intake from the diet, andamines and amides from dietary and drugsources, b) endogenous exposure to NOC byanalysis of relevant biological media (e.g.,saliva, urine, feces), and c) reliable health riskmarkers (e.g., biomarkers of genotoxicity) ordiagnosis of actual disease.Future studies should include populationswith well-characterized long-term exposures,including those who use private wells, whichcan have higher nitrate levels than public sup-plies. With the increasing availability of publicwater supply monitoring data (many U.S. stateshave almost 40 years of measurements), furtherdetailed exposure assessment of populationsusing public supplies is also feasible. Drinking-water contaminants that may occur along withnitrate, such as agricultural pesticides, shouldalso be evaluated. Geographic-based modelingefforts to predict the probability of high nitrateconcentrations in groundwater, using informa-tion on nitrogen inputs from agricultural andurban sources (Nolan et al. 2002), is a promis-ing approach for estimating drinking-waternitrate exposure for the population usingprivate wells.Additional studies of drinking-waternitrate and cancer are needed to follow up onthe suggestive positive findings to date and toevaluate other cancer sites in which endoge-nously formed NOC may play a role. Studiesof reproductive outcomes should address theexposure period most relevant for the specificoutcome of interest. Maternal residentialmobility between conception and birth maylead to misclassification of exposure if thewater source at birth is used in studies ofspontaneous abortions and congenital malfor-mations. Studies must be of sufficient size toallow for examination of specific defectsrather than groups of defects by system,because combining different defects mightmask associations. More research is needed onthe relation between water nitrate and thereproductive outcomes of spontaneous abor-tion, fetal death, premature birth, andintrauterine growth retardation.In the design and analysis stage, future epi-demiologic studies should consider factors thatmodulate endogenous nitrosation, as discussedabove, to be able to evaluate potential inter-actions of water nitrate intake with these fac-tors, thus providing stronger evidence for oragainst an association. In particular, studies ofsusceptible populations may be fruitful, andepidemiologic studies should be designed withsufficient power to evaluate risk among poten-tially susceptible subgroups. Such populationsinclude patients with different forms of chronicinflammation (such as inflammatory boweldisease), patients infected with nitrate-reducingbacteria (such as in periodontal disease), thosewith low intake of vitamins and other knownnitrosation inhibitors, or those with a historyof high incidence of potentially NOC-relateddiseases. The people of Linxian County inChina, for example, are known for their persis-tently low intake of several micronutrients andhigh risk of esophageal cancer (Blot et al.1993). Such populations will likely benefitfrom preventive measures taken as a result ofthese investigations.ConclusionsAdverse health effects from drinking-waternitrates are most likely the result of a complexinteraction of the amount of nitrate ingested,the concomitant ingestion of nitrosatingcofactors and precursors, and medical condi-tions of the host that may increase nitrosation.Furthermore, these effects may be attenuatedby inhibitors of endogenous nitrosation suchas vitamin C and alpha-tocopherol. We rec-ommend that future studies take into accountsuch complexities in understanding the rela-tion between drinking-water nitrates and can-cer, adverse reproductive outcomes, and otherhealth outcomes.Ward et al.1612VOLUME113 |NUMBER11 | November 2005Environmental Health PerspectivesSeveral authors (Avery 1999; Lhirondeland Lhirondel 2002) have questioned theimportance of nitrate in drinking water as arisk factor for methemoglobinemia and havesuggested that the current nitrate standardmight be safely raised to 1520 mg/L nitrate-N with no increase in methemoglobinemiacases. A better understanding of the condi-tions under which nitrate in drinking waterposes a risk of methemoglobinemia is clearlyneeded, particularly in light of recent cases ofmethemoglobinemia associated with wellwater levels between 20 and 30 mg/L nitrate-N (Knobeloch et al. 2000). Most importantly,the role of nitrate as a risk factor for cancerand adverse reproductive outcomes must bemore thoroughly explored before changes tonitrate water quality standards are considered.REFERENCESArbuckle TE, Sherman GJ, Corey PN, Walters D, Lo B. 1988.Water nitrates and CNS birth defects: a population-basedcase-control study. Arch Environ Health 43:162167.Aschengrau A, Zierler S, Cohen A. 1989. Quality of communitydrinking water and the occurrence of spontaneous abor-tion. Arch Environ Health 44:283290.Aschengrau A, Zierler S, Cohen A. 1993. Quality of communitydrinking water and the occurrence of late adverse preg-nancy outcomes. Arch Environ Health 48:105113.Avery AA. 1999. Infantile methemoglobinemia: reexamining therole of drinking water nitrates. Environ Health Perspect107:18.Bartsch H, Ohshima H, Pignatelli B. 1988. Inhibitors of endoge-nous nitrosation. Mechanisms and implications in humancancer prevention. Mutat Res 202:307324.Bingham SA. 1999. High-meat diets and cancer risk. Proc NutrSoc 58:243248.Bingham SA, Hughes R, Cross AJ. 2002. Effect of white versusred meat on endogenous N-nitrosation in the humancolon and further evidence of a dose response. J Nutr132:3522S3525S.Bingham SA, Pignatelli B, Pollock JR, Ellul A, Malaveille C,Gross G, et al. 1996. Does increased endogenous forma-tion of N-nitroso compounds in the human colon explainthe association between red meat and colon cancer?Carcinogenesis 17:515523.Bloomfield RA, Welsch CW, Garner GB, Muhrer ME. 1961. Effectof dietary nitrate on thyroid function. Science 134:1690.Blot WJ, Li J, Taylor PR, Guo W, Dawsey S, et al. 1993. Nutritionintervention trials in Linxian, China: supplementation withspecific vitamin/mineral combinations, cancer incidence,and disease-specific mortality in the general population.J Natl Cancer Inst 85:14831491.Boeing H. 1991. Epidemiological research in stomach cancer:progress over the last ten years. J Cancer Res Clin Oncol117:133143.Bogovski P, Bogovski S. 1981. Animal species in which N-nitrosocompounds induce cancer. Int J Cancer 27:471474.Brender J, Olive J, Felkner M, Suarez L, Hendricks K,Marckwardt W. 2004a. Intake of nitrates and nitrites andbirth defects in offspring Abstract. Epidemiology 15:S184.Brender JD, Olive JM, Felkner M, Suarez L, Marckwardt W,Hendricks KA. 2004b. Dietary nitrites and nitrates, nitrosatabledrugs, and neural tube defects. Epidemiology 15:330336.Bukowski J, Somers G, Bryanton J. 2001. Agricultural contami-nation of groundwater as a possible risk factor for growthrestriction or prematurity. J Occup Environ Med 43:377383.Cantor KP. 1997. Drinking water and cancer. Cancer CausesControl 8:292308.Cedergren MI, Selbing AJ, Lofman O, Kallen BAJ. 2002.Chlorination byproducts and nitrate in drinking water andrisk for congenital cardiac defects. Environ Res 89:124130.Charmandari E, Meadows N, Patel M, Johnston A, Benjamin N.2001. Plasma nitrate concentrations in children with infec-tious and noninfectious diarrhea. J Pediatr GastroenterolNutr 32:423427.Comly H. 1945. Cyanosis in infants caused by well water. JAMA129:112116.Coss A, Lynch C, Cantor KP, Ward MH. 2004. Pancreatic can-cer and drinking water and dietary sources of nitrate andnitrite. Am J Epidemiol 159:693701.Croen LA, Todoroff K, Shaw GM. 2001. Maternal exposure tonitrate from drinking water and diet and risk for neural tubedefects. Am J Epidemiol 153:325331.Cross AJ, Pollock JR, Bingham SA. 2003. Heam, not protein orinorganic iron, is responsible for endogenous intestinal N-nitrosation arising from red meat. Cancer Res 63: 23582360.De Kok TM, Engels LG, Moonen E, Kleinjans JC. 2005.Inflammatory bowel disease stimulates formation of car-cinogenic N-nitroso compounds. Gut 54:731.DeRoos AJ, Ward MH, Lynch CF, Cantor KP. 2003. Nitrate inpublic water systems and the risk of colon and rectumcancers. Epidemiology 14:640649.Dorsch MM, Scragg RKR, McMichael AJ, Baghurst PA, DyerKF. 1984. Congenital malformations and maternal drinkingwater supply in rural South Australia: a case-controlstudy. Am J Epidemiol 119:473486.Ericson A, Kallen B, Lofkvist E. 1988. Environmental factors in theetiology of neural tube defects: a negative study. EnvironRes 45:3847.European Environment Agency. 2003. Europes Environment:The Third Assessment. Environmental Assessment ReportNo. 10. Copenhagen:European Environment Agency.Fewtrell L. 2004. Drinking-water nitrate, methemoglobinemia,and global burden of disease: a discussion. Environ HealthPerspect 112:13711374.Fields S. 2004. Global nitrogen: cycling out of control. EnvironHealth Perspect 112:A557A563.Forman D. 1987. Dietary exposure to N-nitroso compounds andthe risk of human cancer. Cancer Surv 6:719738.Freedman DF, Cantor KP, Ward MH, Helzlsouer K. 2000. Nitratesin drinking water and non-Hodgkins lymphoma: a popula-tion-based case-control study of men in Minnesota. ArchEnviron Health 55:326329.Grant W, Steele G, Isiorho SA. 1996. Spontaneous abortionspossibly related to ingestion of nitrate-contaminated wellwaterLaGrange County, Indiana, 19911994. MMWRMorb Mortal Wkly Rep 45:569572.Gulis G, Czompolyova M, Cerhan JR. 2002. An ecologic study ofnitrate in municipal drinking water and cancer incidencein Trnava District, Slovakia. Environ Res 88:182187.Gupta SK, Gupta RC, Gupta AB, Seth AK, Bassin JK, Gupta A.2000. Recurrent acute respiratory infections in areas withhigh nitrate concentrations in drinking water. EnvironHealth Perspect 108:363366.Gupta SK, Gupta RC, Seth AK, Gupta AB, Bassin JK, Gupta A.1999. Adaptation of cytochrome b5 reductase activity andmethemoglobinemia in areas with a high nitrate concen-tration in drinking-water. Bull WHO 77:749753.Hanukoglu A, Danon PN. 1996. Endogenous methemoglobine-mia associated with diarrheal disease in infancy. J PediatrGastroenterol Nutr 23:17.Haorah J, Zhou L, Wang X, Xu G, Mirvish SS. 2001. Determinationof total N-nitroso compounds and their precursors in frank-furters, fresh meat, dried salted fish, sauces, tobacco,and tobacco smoke particulates. J Agric Food Chem49:60686078.Hodgson RM, Wiessler M, Kleihues P. 1980. Preferential methy-lation of target organ DNA by the oesophageal carcinogenN-nitrosomethylbenzylamine. Carcinogenesis 1:861866.Hutson SS, Barber NL, Kenny JF, Linsey KS, Lumia DS, MaupinMA. 2004. Estimated Use of Water in the United States in2000. USGS Circular 1268. Denver, CO:U.S. GeologicalSurvey.Jedrychowski W, Maugeri U, Bianchi I. 1997. Environmentalpollution in central and eastern European countries: abasis for cancer epidemiology. Rev Environ Health 12:123.Kamiyama S, Ohshima H, Shimada A, Saito N, Bourgade MC,Ziegler P, et al. 1987. Urinary excretion of N-nitrosoaminoacids and nitrate by inhabitants in high- and low-risk areasfor stomach cancer in northern Japan. IARC Sci Publ84:479502.Kimura H, Hokari R, Miura S, Shigematsu T, Hirokawa M,Akiba Y, et al. 1998. Increased expression of an inducibleisoform of nitric oxide synthase and the formation of perox-ynitrite in colonic mucosa of patients with active ulcerativecolitis. Gut 42:180187.Knobeloch L, Salna B, Hogan A, Postle J, Anderson H. 2000.Blue babies and nitrate-contaminated well water. EnvironHealth Perspect 108:675678.Kostraba JN, Gay EC, Rewers M, Hamman RF. 1992. Nitrate lev-els in community drinking waters and risk of IDDM, anecologic analysis. Diabetes Care 15:15051508.Lambert KF, Driscoll C. 2003. Nitrogen Pollution: From theSources to the Sea. Hanover, NH:Hubbard Brook ResearchFoundation.Lashner BA, Hanauer SB, Silverstein MD. 1988. Optimal timingof colonoscopy to screen cancer in ulcerative colitis. AnnIntern Med 108:274278.Leaf CD, Wishnok JS, Tannenbaum SR. 1989. L-Arginine is aprecursor for nitrate biosynthesis in humans. BiochemBiophys Res Commun 8:10321037.Lees Murdock DJ, Barnett YA, Barnett CR. 2004. DNA damageand cytotoxicity in pancreatic beta-cells expressing humanCYP2E1. Biochem Pharmacol 68:523530.Le Marchand L, Donlon T, Seifried A, Wilkens LR. 2002. Red meatintake, CYP2E1 genetic polymorphisms, and colorectal can-cer risk. Cancer Epidemiol Biomarkers Prev 11:10191024.Levallois P, Ayotte P, Van Maanen JM, Desrosiers T, Gingras S,Dallinga JW, et al. 2000. Excretion of volatile nitrosaminesin a rural population in relation to food and drinking waterconsumption. Food Chem Toxicol 38:10131019.Levine JJ, Pettei MJ, Valderrama E, Gold DM, Kessler BH,Tractman H. 1998. Nitric oxide and inflammatory boweldisease: evidence for local intestinal production in chil-dren with active colonic disease. J Pediatr GastroenterolNutr 26:3438.Lhirondel J, Lhirondel J-L. 2002. Nitrate and man: toxic, harm-less, or beneficial? Wallingford, Oxfordshire, UK: CABIPublishing.Lijinsky W. 1986. The significance of N-nitroso compounds asenvironmental carcinogens. J Environ Sci Health C4:145.Longnecker MP, Daniels JL. 2001. Environmental contaminantsas etiologic factors for diabetes. Environ Health Perspect109:871876.Lu SH, Ohshima H, Fu HM, Tian Y, Li FM, Blettner M, et al. 1986.Urinary excretion of N-nitrosoamino acids and nitrate byinhabitants of high- and low-risk areas for esophageal can-cer in Northern China: endogenous formation of nitrosopro-line and its inhibition by vitamin C. Cancer Res 46:14851491.Lundberg JO, Herulf M, Olesen M, Bohr J, Tysk C, Wiklund NP,et al. 1997. Increased nitric oxide production in collage-nous and lymphocytic colitis. Eur J Clin Invest 27:869871.Mirvish SS, Grandjean AC, Moller H, Fike S, Maynard T, Jones L,et al. 1992. N-nitrosoproline excretion by rural Nebraskansdrinking water of varied nitrate content. Cancer EpidemiolBiomarkers Prev 1:455461.Mirvish SS, Haorah J, Zhou L, Hartman M, Morris CR, ClapperML. 2003. N-nitroso compounds in the gastrointestinal tractof rats and in the feces of mice with induced colitis or fedhot dogs or beef. Carcinogenesis 24:595603.Moller H, Landt J, Pedersen E, Jensen P, Autrup H, Jensen O.1989. Endogenous nitrosation in relation to nitrate exposurefrom drinking water and diet in a Danish rural population.Cancer Res 49:31173121.Morales-Suarez-Varela MM, Llopis-Gonzalez A, Tejerizo-PerezML. 1995. Impact of nitrates in drinking water on cancermortality in Valencia, Spain. Eur J Epidemiol 11:1521.Mueller BA, Newton K, Holly EA, Preston-Martin S. 2001.Residential water source and the risk of childhood braintumors. Environ Health Perspect 109:551556.National Academy of Sciences. 1981. The Health Effects ofNitrate, Nitrite, and N-Nitroso Compounds. Washington,DC:National Academy of Sciences.National Research Council. 1995. Nitrate and nitrite in drinkingwater. Washington DC:National Academy Press.Nolan BT, Hitt KJ, Ruddy BC. 2002. Probability of nitrate contami-nation of recently recharged groundwaters in the contermi-nous United States. Environ Sci Technol 36:21382145.Ohshima H, Bartsch H. 1994. Chronic infections and inflamma-tory processes as cancer risk factors: possible role of nitricoxide in carcinogenesis. Mutat Res 305:253264.Parslow RC, McKinney PA, Law GR, Staines A, Williams R,Bodansky HJ. 1997. Incidence of childhood diabetes melli-tus in Yorkshire, northern England, is associated withnitrate in drinking water: an ecologic analysis. Diabetologia40:550556.Pomeranz A, Korzets Z, Vanunu D, Krystal H. 2000. Elevated saltand nitrate levels in drinking water cause an increase ofblood pressure in schoolchildren. Kidney Blood Press Res23:400403.Roediger WE, Lawson MJ, Radclif