Review of the Churchill County, NV ALL cluster, 1997–2004 Mark Walker a,⇑ , Chris Pritsos b , Ralph Seiler c a Department of Natural Resources and Environmental Sciences, University of Nevada, Reno, NV, USA b Department of Nutrition, University of Nevada, Reno, NV, USA c Environmental Sciences Graduate Program, University of Nevada, Reno, NV, USA article info Article history: Available online 30 April 2011 Keywords: Acute lymphocytic leukemia Leukemia cluster Childhood leukemia abstract Between 1997 and 2002, 16 cases of acute childhood leukemia were diagnosed in children who either lived in Churchill County, Nevada at the time of diagnosis or had lived in the county before their diagno- sis. The cases were characterized as a cluster of like illnesses and the probability of having such a cluster occur by chance was estimated to be very small (approximately one in 2.33 10 8 ). This suggested that the cluster could be linked to one or more physical, limnological, chemical, or biological agents. This review discusses the setting in which the cluster took place, the epidemiological investigations carried out by the Nevada Bureau of Health Protection Services, the National Center for Environmental Health Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry, and subsequent investigations supported by a special allocation of federal funds through the US Environ- mental Protection Agency’s Region IX office in San Francisco, CA. This review is meant as background for the papers in this special issue that report results from multi- and interdisciplinary research into environ- mental and biological factors potentially related to the Churchill County leukemia cluster. Ó 2011 Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction .......................................................................................................... 52 1.1. Churchill County and Lahontan Valley................................................................................ 53 1.1.1. Physical setting ........................................................................................... 53 1.1.2. Location and socio-economic characteristics ................................................................... 54 1.1.3. Drinking water ........................................................................................... 54 2. Hypotheses related to causes of the cluster ................................................................................. 55 2.1. Epidemiological investigations ...................................................................................... 56 2.1.1. Nevada Bureau of Health Protection Services oral survey of case and control families .................................. 56 2.1.2. National Center for Environmental Health (NCEH), Centers for Disease Control and Prevention .......................... 56 2.1.3. Agency for Toxic Substances and Disease Registry (ATSDR) air quality investigations .................................. 56 2.1.4. US Geological Survey groundwater investigations ............................................................... 57 2.2. Conclusions from epidemiological studies ............................................................................. 57 3. The research reported in this issue ........................................................................................ 57 Conflict of interest statement ............................................................................................ 58 References ........................................................................................................... 58 1. Introduction Between 1997 and 2002, 16 cases of acute childhood leukemia were diagnosed in children who either lived in Churchill County, Nevada at the time of diagnosis or had lived in the county for any period of time before their diagnosis [20,14]. The number of cases was considered to be unusually high, based on the number of residents in the county (approximately 24,000) and the short period in which the cases were diagnosed [20]. The cases were characterized as a cluster of like illnesses [21] and the probability of having such a cluster occur by chance was estimated to be very small (approximately one in 2.33 10 8 ) [20]. This suggested that 0009-2797/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.cbi.2011.04.001 ⇑ Corresponding author. Address: Department of Natural Resources and Envi- ronmental Science, University of Nevada/MS 370, 1664N. Virginia Street, Reno, NV 89557, USA. Tel.: +1 775 784 1938; fax: +1 775 784 4789. E-mail address: [email protected](M. Walker). Chemico-Biological Interactions 196 (2012) 52–58 Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint
Review of the Churchill County, NV ALL cluster, 1997–2004
Mark Walker a,⇑, Chris Pritsos b, Ralph Seiler c
a Department of Natural Resources and Environmental Sciences, University of Nevada, Reno, NV, USAb Department of Nutrition, University of Nevada, Reno, NV, USAc Environmental Sciences Graduate Program, University of Nevada, Reno, NV, USA
Between 1997 and 2002, 16 cases of acute childhood leukemia were diagnosed in children who eitherlived in Churchill County, Nevada at the time of diagnosis or had lived in the county before their diagno-sis. The cases were characterized as a cluster of like illnesses and the probability of having such a clusteroccur by chance was estimated to be very small (approximately one in 2.33 � 108). This suggested thatthe cluster could be linked to one or more physical, limnological, chemical, or biological agents. Thisreview discusses the setting in which the cluster took place, the epidemiological investigations carriedout by the Nevada Bureau of Health Protection Services, the National Center for Environmental HealthCenters for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry,and subsequent investigations supported by a special allocation of federal funds through the US Environ-mental Protection Agency’s Region IX office in San Francisco, CA. This review is meant as background forthe papers in this special issue that report results from multi- and interdisciplinary research into environ-mental and biological factors potentially related to the Churchill County leukemia cluster.
Between 1997 and 2002, 16 cases of acute childhood leukemiawere diagnosed in children who either lived in Churchill County,
d Ltd. All rights reserved.
Natural Resources and Envi-4N. Virginia Street, Reno, NV789.er).
Nevada at the time of diagnosis or had lived in the county forany period of time before their diagnosis [20,14]. The number ofcases was considered to be unusually high, based on the numberof residents in the county (approximately 24,000) and the shortperiod in which the cases were diagnosed [20]. The cases werecharacterized as a cluster of like illnesses [21] and the probabilityof having such a cluster occur by chance was estimated to be verysmall (approximately one in 2.33 � 108) [20]. This suggested that
Fig. 1. Location of Churchill County within Nevada and the United States.
M. Walker et al. / Chemico-Biological Interactions 196 (2012) 52–58 53
the cluster could be linked to exposures to one or more physical,chemical, or biological agents.
Leukemia accounted for 31% (approximately 3320 cases in theUnited States) of all cancers among children 14 years old or youn-ger in 2010 [1]. Leukemia is a cancer that begins in blood formingtissues, such as bone marrow, and leads to overproduction ofimmature lymphocytes (http://www.cancer.gov/cancertopics/types/leukemia, last accessed 2/2011). The most common formamong children is acute lymphocytic leukemia (ALL, also knownas acute lymphoblastic leukemia), which leads to overproductionof immature lymphocytes, including B and T cells. Within bonemarrow, the primary site of lymphocyte production, excessivenumbers of immature lymphocytes impair production of otherblood components, including red blood cells and platelets. Imma-ture lymphocytes may also accumulate in parts of the centralnervous system (spinal cord and brain) and the spleen and the li-ver, impairing function. Acute myeloid leukemia (AML) is reportedto be the second most common form of leukemia among children(http://childrenscancer.org/learning-center/understanding-child-hood-cancer/understanding-acute-myelogenous-leukemia.html,last accessed August 2010). AML is primarily a cancer of the bonemarrow that leads to drastic overproduction of immature cells thatdisrupt organ function and accumulate in the lymph system.
The causes of childhood ALL and AML are not well understood,though environmental, socioeconomic and genetic factors arethought to important factors, singly and in combination [5]. Asmall proportion of ALL cases are associated with genetic syn-dromes and exposure to ionizing radiation and drugs used forchemotherapies [11]. However, the majority of cases can neitherbe attributed to genetic predispositions or exposures to chemicalsand radiation in the environment [11]. Although benzene has beenidentified as a potential trigger of AML in adults, it is not clear thereis also an association with AML in children [12].
For the Churchill Country ALL cluster there was no singlehypothesis to guide investigations. Accordingly, investigationsconsidered several different potential exposures. Hypotheses weretested with sampling surveys that focused on airborne and water-borne contaminants, and on contaminants that could be uniquelyassociated with the occupations of parents of the ill children. Anexpert panel convened by the State of Nevada in 2001 [13] alsoconsidered a population mixing hypothesis, in part because ofthe large number of short-term visitors in the county associatedwith a military training facility [21]. Subsequently, several epide-miological surveys and environmental investigations examinedassociations between chemicals present in the environment (bothnaturally occurring and anthropogenic), radioactive isotopes inwater, chemicals used for agricultural production and withinhomes for pest control, and chemicals in air and airborne dust[3]. The epidemiological investigations conducted in the years fol-lowing the appearance of the first cases were characterized asbeing unprecedented in the level of detail considered, especiallywith respect to biological and environmental samples.
In 2003, the investigation of the leukemia cluster by the State ofNevada and the Centers for Disease Control and Prevention (CDC)and Agency for Toxic Substances and Disease Registry (ATSDR)concluded without identifying a cause for the cluster [14]. A com-munity group from Churchill County composed of members of thefamilies with children diagnosed with acute leukemia was con-cerned that this meant all research had ended. They petitionedSenator Harry Reid for support for further investigations. In 2007,following allocation of federal funds and a competitive grant appli-cation process, research proposals from the University of Nevada(Reno), University of California (San Francisco), and University ofArizona (Tucson) were selected to carry out research to comple-ment the epidemiological surveys. The researchers selected to car-ry out the individual projects included several multi-disciplinary
teams with diverse expertise in the etiology of childhood leukemia,epidemiology, groundwater contamination and geochemistry,magnetic field generation and measurement, toxicology, land useanalysis using geographic information systems, oncology, pulmon-ary diseases, and tree ring analysis.
The purpose of this introduction is to provide information aboutChurchill County, Nevada and review the community concerns andstudies that led to the research efforts reported in this specialissue.
1.1. Churchill County and Lahontan Valley
1.1.1. Physical settingChurchill County is in the central northwestern portion of Neva-
da and lies in the Great Basin region in the western United States(Fig. 1). The county boundaries enclose 5023 mile2 and the majorpopulation center is the town of Fallon. Churchill County is alsoknown as the Lahontan Valley, an informal name for the agricul-tural area. Fallon, the county seat, lies at 4500 feet above meansea level.
Much of the county is low relief basin (Fig. 2), with borderingmountain ranges to the west and south. The terminus of the CarsonRiver dissipates in two locations within the county – the CarsonSink and the Stillwater Marsh area, in the northeastern part ofthe valley and the Carson Lake area in the southern part of the val-ley. The mountain ranges are low relief and underlain largely bytertiary volcanic and sedimentary formations. The Carson Sink cov-ers the majority of the western area of the county and is underlainby deposits of Lake Lahontan, which inundated an estimated8500 mile2 of what is now northern Nevada and parts of Californiaand Oregon, approximately 13,000 years ago. Pre-tertiary
54 M. Walker et al. / Chemico-Biological Interactions 196 (2012) 52–58
formations are extensively exposed east of the Carson Sink in theStillwater Range, Clan Alpine Mountains and New Pass Mountains.Valleys in the eastern portion of the county are underlain by qua-ternary alluvial and lacustrine deposits left at approximately thesame time as western deposits of Lake Lahontan.
The climate is semi-arid with average annual maximum andminimum temperatures of 67.7 and 34.9 F. The amount of precip-itation received annually, 4.98 in., is far exceeded by evapotranspi-ration. The annual average pan evaporation rate is 37.11 in. peryear, based on observations from the Fallon Experiment Stationfrom 1903 to 2005 (www.wrcc.dri.edu/htmlfiles/westevap.final.html, last accessed 6/2010).
Soils in the county are largely the result of cycles of erosion anddeposition. The mountains and hills that border the basin portionof the county have terraces that are typical of waterlines from lakesthat recede and expand on a geologic time scale [6], which are anartifact of the historic Lake Lahontan. As a result, the surface andsubsurface soils include basin floor remnants, inset fans, streamterraces and other alluvial accumulations. Also, as Lake Lahontanperiodically receded, salts and other substances evapoconcentrat-ed, which has an important affect on groundwater quality. Becauseof the complex geological history of repeated expansion and reces-sion of Lake Lahontan and associated deposition and burial of sed-iments from inside and outside the Lahontan Valley, theenvironment is rich in arsenic, cobalt, tungsten, uranium, radon,and polonium-210 (210Po).
1.1.2. Location and socio-economic characteristicsThe county was established in 1861, approximately 3 years
prior to Nevada’s admission to the Union as a State [7]. Althoughsmall scale agriculture, mining and some commerce existed priorto the 1900s, the construction of the nation’s first federal reclama-tion project, the Newlands Irrigation District, substantially in-creased the amount of available water, which establishedagriculture as the dominant industry in the county for much ofthe 20th century.
Agriculture is made possible by irrigation water delivered fromthe Carson and Truckee Rivers. Public Law 57–161 (1902, alsoknown as the Newlands Reclamation Act) authorized federalexpenditures to reserve and store water from the Truckee and Car-son rivers, to irrigate as much as 206,000 acres for agricultural pro-duction. The water is conveyed through canals that are for the
Fig. 2. Relief map of Churchill County, with the county seat, Fallon and two majorland transportation routes illustrated.
most part unlined [10]. Current agricultural production includesforage crops (especially alfalfa), dairy products and vegetables.
The county’s economic base includes the Fallon Naval Air Sta-tion. The Naval Air Station, fully commissioned in 1972 afterapproximately three decades of varying levels of activity, has astaff of approximately 2500 people, including approximately1000 active duty military personnel. The main base of the NavalAir Station is located 6 miles south and east of Fallon on 12.9 mile2.The Naval Air Station uses an additional 363.3 mile2 for gunneryand bombing ranges and other types of military training. In1999, the Naval Air Station consumed approximately 34 milliongallons of jet fuel and expended approximately 10.7 millionpounds of ordnance in training exercises (www.globalsecuri-ty.org/military/facility/fallon.htm, last accessed 6/2010). A subsur-face 6 in. pipeline managed by Kinder Morgan Energy Partnerstransports JP8 jet fuel to the Naval Air Station from a terminaland pumping station in Sparks, NV [21]. The Naval Air Station hostsmilitary personnel from throughout the world, with approximately40,000 participants in training per year taking part in short-term(approximately two weeks) sessions at the Naval Air Station.
Gold and silver production occasionally have been an importantpart of the county and state economy, with major, but short-lived,production followed by abandonment of mining facilities and asso-ciated settlements. Tungsten ore has also been mined [8], thoughmining ceased decades ago. Kennametal, Inc. (www.kennamet-al.com, last accessed 6/2010), an international corporation, hasmaintained facilities in Fallon to process and refine tungsten since1957. Kennametal’s facilities in Fallon include a refinery to processtungsten ore, 11 miles north of the Fallon city center and anadministrative and powder processing facility located within thecity. In addition, at the time of the childhood leukemia clusterChurchill County had a nickel plating facility, and a metal struc-tural fabrication facility with associated volatile organic chemicaluses, which were issued air quality permits by the Nevada Divisionof Environmental Protection [3].
One of 24 LORAN-C (LOng RAnge Navigation) sites in NorthAmerica was located 6 miles northwest of the center of Fallon(www.navcen.uscg.gov/loran/default.htm, last accessed 6/2010).The site was the master station for the west coast of the UnitedStates and was operated by the US Coast Guard until February,2010. The station broadcasted a low frequency (90–110 kHz), highpower (400 kW) signal for maritime navigation, using an antennathat extended 625 feet above the land surface.
Churchill County was the site of the Shoal Event, a nuclear test28 miles southeast of Fallon carried out in October 1963 with a12.5 kt weapon. The test was carried out 1205 feet below the landsurface as part of project Vela Uniform aimed at improved seismicdetection of underground nuclear tests (http://ndep.nv.gov/shoal/PSA.htm last accessed 6/2010).
In 2000, the median age of residents of Churchill County was35 years old, with 32% of the population <19 years old (Fig. 4;www.census.gov, last accessed 6/2010).
1.1.3. Drinking waterGroundwater resources include three primary aquifers used as
drinking-water sources: shallow saturated basin fill to approxi-mately 50 ft. below the land surface, intermediate depth basin fillextending from 50 to up to 1000 ft. below the surface, and a basaltaquifer northeast of the center of Fallon [9]. The distinction be-tween shallow and intermediate aquifers is based upon chemicalcharacteristics, rather than observed physical distinctions betweensaturated depths [9]. Recharge from irrigation water, includingseepage from fields and from unlined irrigation ditches, has in-creased groundwater levels to many feet above those observedprior to the completion of the Newlands Irrigation Project[15,10], most notably in the shallow aquifer. The public water
M. Walker et al. / Chemico-Biological Interactions 196 (2012) 52–58 55
supplies for Fallon, the Naval Air Station and the Paiute-Shoshonetribe obtain water from a fractured basalt aquifer.
Arsenic concentrations in public water supplies were approxi-mately 10 times the current federal Maximum Contaminant Level(MCL) of 10 ppb until 2005, when treatment lowered concentra-tions to below the MCL. Arsenic is naturally present in concentra-tions that vary significantly and unpredictably throughoutLahontan Valley. Private water supplies, many of which are com-pleted in the shallow and intermediate depth aquifers, have extre-mely variable water quality, with individual wells that have veryhigh concentrations of arsenic, tungsten and radionuclides[18,22,24,17]. Although treatments such as reverse osmosis can re-duce concentrations of arsenic in water supplies, a survey of drink-ing water quality indicated that many types of small scaletreatment commonly applied in households served by domesticwells in Churchill County failed to reduce concentrations to below10 ppb [23].
2. Hypotheses related to causes of the cluster
Hypotheses about the causes of the cluster were expressed for-mally and informally during hearings and reports generated by ahearing held in Fallon in 2002 by the US Senate Committee onEnvironment and Public Works [21], during a hearing held by theNevada State Assembly’s Committee on Natural Resources, Agricul-ture and Mining (Assembly 2001) [2] and by an expert panel con-vened by the Nevada Division of Health [13]. These hypothesesbecame the foundations for data collection through questionnaires
Fig. 3. Number of diagnosed cases of leukemia in Churchill County from 1997 to 2002(NBHPS), the US Senate Environment and Public Works (EPW) field hearings in Fallon NV– Centers for Disease Control and Prevention (NCEH-CDC) and Agency for Toxic Substan
and environmental surveys conducted as the number of cases diag-nosed increased (Fig. 3). Surveys included comprehensive inter-views of case families by the State Epidemiologist for Nevada, anenvironmental and indoor survey of air quality conducted by ATS-DR and surveys of water, dust and biological samples, directed bythe CDC with participation from the US Environmental ProtectionAgency, the Nevada Department of Environmental Protection theNevada Division of Health Protection Services, and the US Geolog-ical Survey [14].
Several proposed hypotheses were beyond the scope of whatcould be tested with the epidemiological approaches used by fed-eral and state agencies that assisted with the investigations. As anexample, testimony given by Dr. Stephen Prescott, of the Hunts-man Cancer Institute at the University of Idaho (http://www.huntsmancancer.org/, last accessed 6/2010) during the USSenate’s Committee on Environment and Public Works field hear-ing in Fallon, NV in 2001 expressed the opinion (p. 14) that geneticmakeup of the affected children could be an important factor,though techniques that could be used to investigate this werepoorly understood and difficult to apply credibly [21]. Dr. Prescottalso suggested that linking cases of ALL to environmental expo-sures would be difficult given the poor understanding of leukemo-genesis in children and past failures to identify likely causes ofother clusters, even when exposure to carcinogens were identifi-able and present. Nevada State Assembly hearings suggested arange of environmental insults that could be important to consider,including chemicals used for agricultural and domestic pest con-trol, the chemical quality of water quality in public and privatesupplies, fuel jettisoned by jets during military maneuvers,
, with timeline of responses from the Nevada Bureau of Health Protection Servicesand Nevada Assembly special sessions, the National Center for Environmental Healthces and Disease Registry (ATSDR).
Fig. 4. Proportions of Churchill County’s population by age group, in 2000(www.census.gov, last accessed 6/2010).
56 M. Walker et al. / Chemico-Biological Interactions 196 (2012) 52–58
ventilation and possible leakage from the jet fuel pipeline, electro-magnetic emissions from the LORAN-C station, chaff from militaryexercises in the air and on the soil surface, historical nuclear test-ing, industrial emissions, naturally occurring and anthropogenicradionuclides (including historical nuclear testing) and floodingin 1997 (Assembly 2001).
In 2001 the Nevada State Health Division convened an expertpanel to consider hypotheses and recommend appropriate nextsteps [13]. The panel considered the following three hypotheses:
� The cluster, with the twelve reported cases as of 2001, was ran-dom, without a root cause,� Exposure to one or more chemical contaminants led to the ele-
vated number of cases, and� Population mixing caused by a highly transient population
associated with the Naval Air Station, leading to introductionof an infectious agent that caused the cases of ALL.
The panel considered the first hypothesis to be unlikely, be-cause of the estimates of very low probability of the number ofcases occurring within a small population. The panel also felt thatthe second hypothesis offered an unlikely explanation becausethere was only one case of acute myeloid leukemia, which is mostassociated with exposure to toxic chemicals. The panel felt that themost credible hypothesis among the three was population mixingand recommended evaluating population movements into Fallonthroughout the 1990s. The panel recommended investigation ofpotential excess environmental exposures unique to the commu-nity with a focus on specific contaminants and evaluation of re-leases into the environment, especially with respect toassessment of completed exposure pathways for the case families[13].
2.1. Epidemiological investigations
Four efforts investigated potential causes of the cluster with thegoal of seeking evidence of differential and unique exposures offamilies with diagnosed cases of ALL compared with families serv-ing as controls. These were led by the State Epidemiologist withthe Nevada Division of Health Protection Services, the NationalCenter for Environmental Health of the Centers for Disease Control
and Prevention and the Agency for Toxic Substances and DiseaseRegistry, and the US Geological Survey. Each study is describedbriefly below, with their conclusions.
2.1.1. Nevada Bureau of Health Protection Services oral survey of caseand control families
As a first response to the increasing number of cases of ALL in2000, the State Epidemiologist for Nevada (Dr. Randall Todd) de-signed and administered a survey of case families regarding resi-dential history prior to conception, pregnancy history, watersupply choices and use, chemical use inside the home, occupationhistory of the parents, sources of radiation and exposure to electro-magnetic emissions, child activities and play areas, and smoking inthe home [4]. The study also collected information about popula-tion trends in Churchill County in the 1990s related to schoolenrollment, military base population, and the numbers of peoplein various age cohorts
2.1.2. National Center for Environmental Health (NCEH), Centers forDisease Control and Prevention
In 2001, the National Center for Environmental Health (NCEH)of the Centers for Disease Control and Prevention led an exposureassessment that sought significant associations between chemicalsin the environment, biological sampling results and ALL cases. Thepopulation sampled included 14 families in which there was a casediagnosed of ALL and 55 families, randomly chosen, in which therewere no cases of ALL [14]. The study explored the potential associ-ation between gene polymorphisms and exposure to tungsten, ar-senic and dichlorodiphenyldichloroethylene (DDE – formed bydegradation of DDT) [19].
Environmental field sampling examined residences for 11/14case and 55 control families (including current and previous resi-dences). The sampling effort engaged the Nevada Division of Envi-ronmental Protection, the US Geological Survey, the USEnvironmental Protection Agency (Region 9) and the Nevada Divi-sion of Agriculture. Media sampled included tap water, indoor air,play yard soil, and household dust within each household. Thestudy also examined tungsten in tap water, floor dust, yard soiland urine from participating subjects in Churchill County and inthree nearby communities that had histories of tungsten mining[14]. Environmental samples (air, tapwater, soil and dust) fromnearly 80 homes of case and control families were analyzed forapproximately 200 chemicals. Blood and urine samples were ana-lyzed for 139 chemicals and eight viral markers in blood and urinesamples and included genetic analysis from whole blood from 205people from 14 of the 15 eligible case families and 55 families se-lected for comparison. Investigators also administered question-naires and interviewed family members.
2.1.3. Agency for Toxic Substances and Disease Registry (ATSDR) airquality investigations
ATSDR investigated potential differences in exposures betweencase and control families in chemicals and particulates in indoor airsamples [3]. ATSDR also evaluated results of other air sampling ef-forts, and reviewed air emissions permits in Churchill County andresults of national-level air modeling conducted by the US Environ-mental Protection Agency. Indoor air sampling focused on a vola-tile organic chemical (benzene) and radon concentrations infrequently used rooms within the homes of 14 case families and55 control families. Air samples were collected as an instantaneous6 l volume of air and 48–96 h sampling for radon gas, using radonkits. Permits reviewed included Kennametal’s metals powderblending facility, a nickel plating facility, a metal structural fabrica-tion facility with associated volatile organic chemical uses andemissions, prescribed burns in irrigation canals and associated re-leases of herbicide residues in smoke.
M. Walker et al. / Chemico-Biological Interactions 196 (2012) 52–58 57
2.1.4. US Geological Survey groundwater investigationsIn 2001, USGS sampled 92 domestic wells providing water to
rural areas and outlying suburbs of Fallon, and all eight public-supply wells providing municipal water to the residents of Fallon,the Naval Air Station, and the Fallon Paiute-Shoshone Tribe [16].USGS investigated differences in well-water quality from 14domestic wells used at past and current residences of case familiesand well-water quality from 78 domestic wells used by theremainder of the community [16]. USGS resampled 29 wells thathad been sampled in 1989 to determine if there had been asignificant change in water quality that could be correlated withthe leukemia cluster.
2.2. Conclusions from epidemiological studies
Results of tapwater and air sampling, with urine and blood sam-ples, did not produce statistically significant differences betweencases and controls. Steinberg et al. [19] found a statistically signif-icant association between the frequency of polymorphic genesencoding for sulfite oxidase in case and comparison samples. Basedon their results, they recommended that the association betweendisease status and this gene locus be investigated further, espe-cially when populations are exposed to high concentrations oftungsten and arsenic. Results of urine sampling indicated thatthe geometric mean concentration of tungsten among those sam-pled was more than 10 times the geometric mean reported inthe 1999 National Health and Nutrition Examination Survey(NHANES) (Fig. 5). However, tungsten concentrations in urine inthree nearby Nevada communities included as controls were alsoelevated [14], though there were no reported cases of childhoodleukemia. Similarly, although arsenic concentrations in urine werehigh, they were not significantly different in case and control chil-dren sampled. Among 12 volatile organic compounds tested inblood samples from case and control children, only ethylbenzeneappeared to have a significant association with a restricted defini-tion of leukemia cases, with an odds ratio of 6.13 (95% confidenceinterval 1.29–29.00) when compared with controls. The restricteddefinition identified a sub-sample of nine cases, selected based onage of children at the time of diagnosis (66 years old), residencetime in the county prior to diagnosis (P6 months) and type ofleukemia diagnosed (based on cell type (B-cell), and excludingALL T-cell cases and a case of acute myelocytic leukemia).
Fig. 5. Distributions of tungsten concentrations in urine samples from participantsin the National Health and Nutrition Examination Survey (NHANES, 1999–2000)and participants in the sampling survey in the Lahontan Valley, conducted by theNational Center for Environmental Health, Centers for Disease Control in 2001(http://sodapop.pop.psu.edu/data-collections/nhanes/nhanes99/nhanes99_lab/index_html, last accessed 7/2010), with data provided to the US Geological Surveyby the Centers for Disease Control and Prevention in 2004.
However, when all of the cases were considered, the associationwas not significant. Although some levels of persistent and nonper-sistent pesticides were detectable in blood samples, none had asignificant association with cases [14]. Other factors with no signif-icant association included maternal exposure to X-rays, age of par-ents, birth weight, prior diagnosis of allergies, and duration ofbreast feeding. ATSDR’s air sampling also found no significant asso-ciations. The studies determined that levels of arsenic, benzene andmercury in air exceeded health-based comparison values, thoughnot at concentrations considered to be a health hazard.
Results of groundwater analyses indicated drinking-water stan-dards for gross alpha radioactivity, arsenic, radon, and uraniumwere commonly and sometimes greatly exceeded but concentra-tions at past and current case-family residences did not statisti-cally differ from the remainder of the community [16]. Isotopicanalyses indicated that uranium in water had a natural sourceand did not originate from nuclear testing in Nevada. In manywells gross alpha radioactivity was much higher than could be ex-plained by the amount of uranium present. This suggested polo-nium-210 was present in the water [16] and this was confirmedin subsequent investigations [17]. Volatile organic compoundswere seldom detected in well water and those with MCLs wereconsistently found at levels below drinking-water standards. Acomparison of water quality from 29 wells sampled in both 1989and 2001 indicated water-quality in the valley had not changedsignificantly over that period [16,17].
3. The research reported in this issue
Testimony provided to the US Senate’s Environment and PublicWorks Committee suggested that epidemiological approaches todetermining a cause for the ALL cluster were unlikely to produceconclusive results [21] for several reasons. Leukemogenesis ispoorly understood and past investigations of associations betweenALL and other forms of leukemia and anthropogenic and naturallyoccurring chemicals in the environment have usually been incon-clusive. In addition, epidemiological investigations were limitedto post-facto sampling surveys, with environmental sampling con-ducted after the number of cases of ALL in Churchill County wasrecognized as unusual. Sampling after the cluster appeared wouldnot be useful in detecting exposures that were short term andtransient.
In 2006, after release of the NCEH-CDC findings and 4 yearsafter the last diagnosed case of ALL in Churchill County, the USEnvironmental Protection Agency’s Region nine offices (San Fran-cisco) awarded a grant to the Families in Search of Truth fromChurchill County. The group, formed by members of case familiesin Churchill County, appealed to the US government for fundingto explore hypotheses related to the leukemia cluster. Fundingwas authorized and awarded through sec. 1442(1) of the SafeDrinking Water Act. The University of Nevada (Reno, NV) adminis-tered the grant on behalf of the families, seeking proposals toinvestigate aspects of the cluster that could not be considered aspart of the epidemiological investigations. This included develop-ing a request for proposals, a peer-review process for selectionand award and a process to ensure that results were extended peri-odically to the families throughout the life of the funded researchprojects. The total award was $677,000, to be used for research be-tween 2006 and 2009.
Three research consortia were selected for funding. Theseincluded:
� A group led by the University of California (San Francisco), com-prised of researchers from the University of California (SanFrancisco) Department of Epidemiology and Biostatistics, the
58 M. Walker et al. / Chemico-Biological Interactions 196 (2012) 52–58
University of Nevada’s Division of Health Sciences, University ofCalifornia at Berkeley and several private sector researcherswith expertise in geographic information system application,electromagnetic fields and data analysis,� A group led by the University of Arizona Medical School’s
Department of Pediatrics, comprised of researchers from theUniversity of Arizona’s Laboratory of Tree-Ring Research andMcGill University’s Sir Mortimer B. Davis Jewish General Hospi-tal, and� A group led by the University of Nevada (Reno, NV), comprised
of researchers from the University of Nevada’s Department ofNutrition and Department of Microbiology and Immunology(School of Medicine) and the US Geological Survey’s NevadaWater Science Center in Carson City, NV.
Research goals of the funded efforts included:
� Exploring leukemogenesis, including viral and chemical signa-tures of leukemia cells,� Examining the potential role of electromagnetic fields, includ-
ing changes in signal strength related to periodic flooding,� Evaluating the correlation between the cluster and morbidity
and mortality reports using Nevada-based disease registries,� Assessing the spatial distribution of potential causative factors,
within Churchill County and in demographically similar townsin Nevada,� Examining the correlation between the number of cases of ALL
and concentrations of tungsten in environments associatedwith the cases,� Examining the potential for enhanced tumorigenicity as a result
of co-exposure to tungsten and arsenic,� Considering the role that age of fathers and pre- and post-natal
exposure to tungsten or tungsten/cobalt might have in leuke-mogenesis, using mouse models for experimentation,� Confirming the hypothesis that exposure to complex mixtures
of arsenic, uranium, tungsten, and polonium-210 in naturalgroundwater affects hematopoiesis and oxidative stress,� Determining the occurrence, distribution, and temporal stabil-
ity of 210Po in Lahontan Valley groundwater, and� Examining the sources of trace-element and radioactive carcin-
ogens in Lahontan Valley sediments and groundwater.
The papers included in this special issue report the results of re-search carried out to test the hypotheses presented above. The re-sults represent a truly multi-disciplinary approach to a verychallenging topic – developing credible hypotheses associatedwith leukemogenesis and environmental and biological factorsthat could be significant with respect to the occurrence of theChurchill County ALL cluster. In doing so, the research consideredhypotheses that were well beyond the scope of the epidemiologicalinvestigations carried out in response to the unique cluster ofchildhood leukemia cases that occurred in Lahontan Valley.
Conflict of interest statement
The authors declared no competing interests related to thispaper.
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