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Probability estimates for the unique childhood leukemia cluster in Fallon, Nevada, and risks near other U.S. military aviation facilities.



A unique cluster of childhood leukemia leukemia (lkē`mēə), cancerous disorder of the blood-forming tissues (bone marrow, lymphatics, liver, spleen) characterized by excessive production of immature or mature  has recently occurred around the city of Fallon in Churchill County, Nevada Churchill County is a county located in the southwestern U.S. state of Nevada. As of the 2000 census, the population was 23,982. Its population in 2006 was estimated to be 27,371. . From 1999 to 2001, 11 cases were diagnosed in this county of 23,982 people. Exposures related to a nearby naval air station A Naval Air Station is an airbase of the United States Navy. Such bases are used to house Naval Aviation squadrons and support commands. List of Functioning US Naval Air Stations
  • Atlanta, Georgia
  • Brunswick, Maine
  • Corpus Christi, Texas
 such as jet fuel or an infectious agent infectious agent Pathogen, see there  carried by naval aviators Well-known aviators
People largely known for their contributions to the history of aviation
While all of these people were pilots (and some still are), many are also noted for contributions in areas such as aircraft design and manufacturing, navigation or
 have been hypothesized as potential causes. The possibility that the cluster could be attributed to chance was also considered. We used data from the Surveillance, Epidemiology, and End Results Program (SEER) to examine the likelihood that chance could explain this cluster. We also used SEER and California Cancer Registry A cancer registry is a systematic collection of data about cancer and tumor diseases. The data is collected by Cancer Registrars. Cancer Registrars capture a complete summary of patient history, diagnosis, treatment, and status for every cancer patient in the United States, and  data to evaluate rates of childhood leukemia in other U.S. counties with military aviation facilities. The age-standardized rate ratio (RR) in Churchill County was 12.0 [95% confidence interval confidence interval,
n a statistical device used to determine the range within which an acceptable datum would fall. Confidence intervals are usually expressed in percentages, typically 95% or 99%.
 (CI), 6.0-21.4; p = 4.3 x [10.sup.-9]]. A cluster of this magnitude would be expected to occur in the United States United States, officially United States of America, republic (2005 est. pop. 295,734,000), 3,539,227 sq mi (9,166,598 sq km), North America. The United States is the world's third largest country in population and the fourth largest country in area.  by chance about once every 22,000 years. The age-standardized RR for the five cases diagnosed after the cluster was first reported was 11.2 (95% CI, 3.6-26.3). In contrast, the incidence rate was not increased in all other U.S. counties with military aviation bases (RR = 1.04; 95% CI, 0.97-1.12) or in the subset of rural counties with military aviation bases (RR = 0.72; 95% CI, 0.48-1.08). These findings suggest that the Churchill County cluster was unlikely due to chance, but no general increase in childhood leukemia was found in other U.S. counties with military aviation bases. Key words: ALL, childhood cancer, cluster, leukemia, military. Environ Health Perspect 112:766-771 (2004). doi:10.1289/ehp.6592 available via http://dx.doi.org/[Online 2 February 2004]

**********

Leukemia is the most common cancer diagnosed in children < 19 years of age (Ries et al. 2003). Several factors have been associated with increased rates of childhood leukemia, including ionizing radiation i·on·i·zing radiation
n.
High-energy radiation capable of producing ionization in substances through which it passes.


Ionizing radiation 
, Down syndrome Down syndrome, congenital disorder characterized by mild to severe mental retardation, slow physical development, and characteristic physical features. Down syndrome affects about 1 in every 730 live births and occurs in all populations equally. , and certain inherited and congenital conditions (Little 1999). However, known causes explain only a small fraction of all cases of leukemia.

This article was prompted by a recent cluster of leukemia cases occurring near the naval air station in Fallon (NAS (1) See network access server.

(2) (Network Attached Storage) A specialized file server that connects to the network. A NAS device contains a slimmed-down operating system and a file system and processes only I/O requests by supporting the popular
 Fallon), Churchill County, a sparsely populated pop·u·late  
tr.v. pop·u·lat·ed, pop·u·lat·ing, pop·u·lates
1. To supply with inhabitants, as by colonization; people.

2.
 area in western Nevada. From 1999 to 2001, 11 cases of childhood leukemia were diagnosed among children residing in Churchill County at the time of diagnosis. An additional five cases have been identified from 1997 to 2002 among children who were nor residents at the time of diagnosis but who lived in Churchill County at some point before diagnosis [Nevada State Health Division (NSHD NSHD Nevada State Health Division
NSHD Network Service Help Desk
) 2003]. In the preceding 20 years, only one case of childhood leukemia was reported to the Nevada Central Cancer Registry among Churchill County residents (Moore et al. 2002). This dramatic increase in the number of cases, the short time frame in which the cases were diagnosed, and the small population of the source area all highlight the unusual nature of this cancer cluster cancer cluster Epidemiology A cancer that occurs in a group of people living or working in a geographically defined region who may share one or more environmental factors–eg, DES, and a characteristic lesion–eg, vaginal adenoCA, in common. See Clusters. .

Initially hypothesized causes of the Churchill County cluster included chemical exposures such as jet fuel or benzene benzene (bĕn`zēn, bĕnzēn`), colorless, flammable, toxic liquid with a pleasant aromatic odor. It boils at 80.1°C; and solidifies at 5.5°C;. Benzene is a hydrocarbon, with formula C6H6. , drinking water drinking water

supply of water available to animals for drinking supplied via nipples, in troughs, dams, ponds and larger natural water sources; an insufficient supply leads to dehydration; it can be the source of infection, e.g. leptospirosis, salmonellosis, or of poisoning, e.g.
 contamination by a radioactive isotope radioactive isotope or radioisotope, natural or artificially created isotope of a chemical element having an unstable nucleus that decays, emitting alpha, beta, or gamma rays until stability is reached.  or naturally occurring arsenic arsenic (är`sənĭk), a semimetallic chemical element; symbol As; at. no. 33; at. wt. 74.9216; m.p. 817°C; (at 28 atmospheres pressure); sublimation point 613°C;; sp. gr. (stable form) 5.73; valence −3, 0, +3, or +5. , population mixing, or a new infectious agent, potentially associated with the nearby naval air station (NSHD 2003). Jet fuel has been associated with immune system immune system

Cells, cell products, organs, and structures of the body involved in the detection and destruction of foreign invaders, such as bacteria, viruses, and cancer cells. Immunity is based on the system's ability to launch a defense against such invaders.
 effects in several studies (Harris et al. 1997a, 1997b, 2000, 2001; Jackman et al. 2002; Rhodes et al. 2003; Ullrich 1999), and benzene, a minor component of jet fuel, has been associated with increased rates of leukemia in occupationally exposed cohorts (Hayes et al. 2001; Savitz and Andrews 1997). The population-mixing theory holds that childhood leukemia can occur as a rare end result of some yet unknown infectious process, and large-scale mixing of urban and rural groups leads to increases in leukemia by allowing increased contact between potentially susceptible and infected individuals (Kinlen 1995). In fact, large-scale movements of people into rural areas have been associated with increased rates of childhood leukemia in many studies (Dickinson and Parker 1999; Kinlen 1988; Kinlen and Hudson 1991; Kinlen and John 1994; Kinlen et al. 1990, 1993).

Churchill County is highly rural, with a population of 23,982 people in an area of 5,023 square miles A square mil is a unit of area, equal to the area of a square with sides of length one mil. A mil is one thousandth of an international inch. This unit of area is usually used in specifying the area of the cross section of a wire or cable.  (U.S. Census Bureau Noun 1. Census Bureau - the bureau of the Commerce Department responsible for taking the census; provides demographic information and analyses about the population of the United States
Bureau of the Census
 2003a). NAS Fallon lies within this county and conducts several large military training operations. Annually, approximately 55,000 military personnel visit NAS Fallon for training, each staying an average of 14 days (U.S. Navy 2002a). This large and rapid movement of military aviators and other personnel in and out of Churchill County, many arriving from a wide range of international locations, provides opportunity for the introduction of a diverse array of new infective agents Noun 1. infective agent - an agent capable of producing infection
infectious agent

virus - (virology) ultramicroscopic infectious agent that replicates itself only within cells of living hosts; many are pathogenic; a piece of nucleic acid (DNA or RNA)
.

The Centers for Disease Control and Prevention Centers for Disease Control and Prevention (CDC), agency of the U.S. Public Health Service since 1973, with headquarters in Atlanta; it was established in 1946 as the Communicable Disease Center.  (CDC See Control Data, century date change and Back Orifice.

CDC - Control Data Corporation
) has recently completed the first portion of a large cross-sectional investigation of the Churchill County cluster (CDC 2003). More than 100 biologic measurements and more than 200 environmental measurements have been collected and analyzed. Despite this extensive testing, no obvious cause of the cluster has been identified. Further information on the CDC investigation and the cluster is available online through the Nevada State Health Division (NSHD 2003).

The goal of the present analysis was 2-fold. The first was to evaluate the possibility that the Churchill County cluster could be attributed to random chance. The second was to evaluate whether other areas with military aviation bases have experienced increased rates of childhood leukemia similar to those occurring in Churchill County. As discussed by several authors, routine tests of statistical significance may not be appropriate in the post hoc post hoc  
adv. & adj.
In or of the form of an argument in which one event is asserted to be the cause of a later event simply by virtue of having happened earlier:
 analysis of clusters, because the specific location and time frame being assessed are defined by the cluster and are not set a priori a priori

In epistemology, knowledge that is independent of all particular experiences, as opposed to a posteriori (or empirical) knowledge, which derives from experience.
 (Neutra 1990; Neutra et al. 1992; Rothman 1990; Waller 2000). However, an important feature of the Churchill County cluster was that many of the cases were diagnosed after the State of Nevada began its investigation in July 2000 (Todd 2001). Thus, the investigation of this cluster was not entirely post hoc Because of this, an a priori hypothesis regarding increased leukemia rates can be tested by confining con·fine  
v. con·fined, con·fin·ing, con·fines

v.tr.
1. To keep within bounds; restrict: Please confine your remarks to the issues at hand. See Synonyms at limit.
 the analyses to the time period after the state investigation had begun.

Materials and Methods

Age-standardized incidence rate ratios (RRs) for childhood leukemia in Churchill County were calculated separately for the cluster as a whole and for the time period that only included cases diagnosed after investigation of the cluster had begun in July 2000. In both analyses, cases were defined as children 0-19 years of age with leukemia confirmed by bone marrow biopsy Bone marrow biopsy
A procedure in which cellular material is removed from the pelvis or breastbone and examined under a microscope to look for the presence of abnormal blood cells characteristic of specific forms of leukemia and lymphoma.
 who lived in Churchill County at the time of diagnosis. For the cluster as a whole, an age-standardized incidence RR was estimated for the years 1999-2001. For the five cases diagnosed after the investigation had begun, an age-standardized incidence RR was calculated for the period beginning July 2000 and ending December 2001. In both analyses, RRs were estimated by comparing the observed number of cases with the expected number based on the most recent age-specific rates age-specific rate

a rate which specifies the age parameter for the rate.
 from the Surveillance, Epidemiology, and End Results Program (SEER). Population data in 5-year age groups for Churchill County were obtained from the 2000 U.S. Census (U.S. Census Bureau 2003a). Confidence intervals were calculated using the methods described by Breslow and Day (1987), and p-values were calculated using the Poisson probability distribution Probability distribution

A function that describes all the values a random variable can take and the probability associated with each. Also called a probability function.


probability distribution 
 model (Checkoway et al. 1989).

Rates of childhood leukemia in counties with military aviation bases (base counties) were compared with rates in counties without military bases (nonbase counties) using all counties covered by SEER and the California Cancer Registry (CCR 1. CCR - condition code register.
2. CCR - (Database) concurrency control and recovery.
). These registries were chosen because they are the largest cancer registries in the United States and both provide readily accessible yearly cancer incidence data on a county level [California Cancer Registry 2000; National Cancer Institute (NCI See Liberate. ) 2001]. SEER provides cancer incidence data for five states and four metropolitan areas, representing approximately 9% of the U.S. population, for 1973-1999. The CCR provides cancer incidence data for approximately 97% of the population in California for 1992-1998.

The goal in selecting base counties was to choose areas with military facilities similar to NAS Fallon. All active naval air stations and Air Force bases in U.S. counties covered by SEER and CCR were identified using publicly available data provided by the U.S. Navy and Air Force (U.S. Air Force 2003; U.S. Navy 2003). Counties with facilities where the type of aircraft, or volume of air traffic, were substantially different than NAS Fallon were excluded from the analysis. These included Air National Guard bases, Air Force Reserve bases, Marine Corp air stations, outlying out·ly·ing  
adj.
Relatively distant or remote from a center or middle: outlying regions.


outlying
Adjective

far away from the main area

Adj. 1.
 fields, Army air fields, and Navy air landing facilities. Air Force bases where the primary mission was space or missile technology were also excluded. All other Air Force bases and naval air stations in the selected counties were included in the analysis.

Rates of childhood leukemia in base counties were compared with those in nonbase counties. Analyses were performed for all types of childhood leukemia combined and separately for acute lymphocytic leukemia acute lymphocytic leukemia
n.
See acute lymphoblastic leukemia.


acute lymphocytic leukemia Acute lymphoblastic leukemia, ALL A malignant lymphoproliferative process that commonly affects children and young adults
 (ALL). In the first analysis, incidence RR estimates were calculated for four individual age groups (04, 5-9, 10-14, and 15-19 years). Leukemia rates were estimated for all base counties combined by dividing the sum of all the cases diagnosed in the base counties by the sum of the age-specific populations of these counties. Yearly population estimates provided by SEER and CCR were used for these calculations. Similar calculations were performed to produce rate estimates in nonbase counties, and incidence RRs were generated by dividing the rate in all base counties combined by the rate in all nonbase counties combined. Poison regression was used to calculate age-adjusted RR estimates for all ages combined.

In the second analysis, incidence RR estimates were calculated for individual counties. This was done by dividing the rate in each base county by the rate in all nonbase counties. Incidence RRs were calculated by individual calendar year and for all years combined using the Poisson model.

In the third analysis, we attempted to evaluate whether the location of a military base in an urban versus a rural area may affect leukemia risks. This was done by grouping counties on population density, defined as the total population of the county divided by the area of the county in square miles using data from the year 2000 U.S. Census. Rural counties were defined as those with a population density of less than 200 people per square mile.

Several bases included in this report had closed or realigned during the years covered by the SEER and CCR registries (DefenseLink 1998). In our initial set of analyses, counties with closed bases were treated as base counties for the years the base was open but were excluded as either base or nonbase counties for the years the bases were closed. Although adverse health effects due to base-related exposures may have occurred after a base had closed, we felt this method was the most conservative became the latency of any potential effects was unknown. In addition, substantial changes in population could occur soon after a base is closed. This may involve not only military families but also on-site civilian employees and others who may be economically linked to the military base. If large numbers of people move out of an area where a base has recently closed, this could potentially bias our results. Regardless, we evaluated the impact of excluding closed bases by performing separate analyses where counties with closed bases were treated as base counties, regardless of the date of closure. Most bases had closed within 4 years of the final year covered by the CCR and SEER registries.

Results

The age-standardized incidence RR of childhood leukemia for Churchill County for 1999-2001 was 12.0 [95% confidence interval (CI), 6.0-21.4; 11 cases observed, 0.92 cases expected] compared with age-specific rates from SEER counties. The p-value based on the Poisson probability model was 4.3 x [10.sup.-9]. The age-adjusted incidence RR using SEER rates for comparison for the time period after the State of Nevada began its investigation was 11.2 (95% CI, 3.6-26.3; 5 cases observed, 0.44 expected; Poisson p = 0.0001). One of the children in the Churchill County cluster was diagnosed with acute myeloid leukemia myeloid leukemia
n.
See myelogenous leukemia.
 (AML AML - A Manufacturing Language ), and 10 were diagnosed with ALL. In the analysis confined con·fine  
v. con·fined, con·fin·ing, con·fines

v.tr.
1. To keep within bounds; restrict: Please confine your remarks to the issues at hand. See Synonyms at limit.
 to ALL, the age-standardized incidence RR for Churchill County for 1999-2001 was 14.3 (95% CI, 6.9-26.3; 10 cases observed, 0.70 cases expected) using age-specific ALL rates from SEER counties for comparison. Table 1 presents a comparison of the Churchill County cluster with other well-known clusters of childhood leukemia.

Tables 2 and 3 show the facilities included and excluded from the analysis of military aviation bases. Twenty counties, incorporating 22 military aviation facilities, were included as base counties. Table 4 shows the incidence RR estimates for childhood leukemia for counties with military aviation bases compared with counties without bases for all years combined for each registry. No increases in childhood leukemia were identified in any of the four individual age groups, or for all ages combined, in either the SEER or CCR areas. RR estimates for each individual county with a military aviation base are shown in Table 5. An elevated RR was identified for Bernalillo County (RR = 1.22; 95% CI, 1.04-1.41) using all nonbase CCR counties for comparison. In the analysis confined to base counties with low population densities, an increase was identified for ages 10-14 years in the CCR base counties compared with CCR nonbase counties (RR = 1.36; 95% CI, 1.02-1.83; Table 6). All other RR estimates had 95% CIs that included 1.0.

Similar results were found in analyses confined to ALL. Incidence RRs for ALL were elevated for Bernalillo County (RR = 1.25; 95% CI, 1.04-1.50) and for ages 10-14 years for base counties in the CCR (RR = 1.39; 95% CI, 0.98-1.98) compared with CCR nonbase counties. In all other analyses of ALL, 95% CIs included the null A character that is all 0 bits. Also written as "NUL," it is the first character in the ASCII and EBCDIC data codes. In hex, it displays and prints as 00; in decimal, it may appear as a single zero in a chart of codes, but displays and prints as a blank space. .

As shown in Table 2, nine bases included in this analysis had closed or were realigned an average of 3.25 yeas before 1998, the last year of CCR data. Incorporating these years had little impact on the results. For example, the relative risk estimate for 1988-1998 for ages 0-19 years in the CCR base counties compared with CCR nonbase counties remained at 1.01 (95% CI, 0.94-1.10) when the years after base closure were included in base county rate calculations. None of the eligible bases in the SEER areas had closed during the years covered in this analysis.

In the analysis of yearly RRs for each individual base county compared with all nonbase counties, the large majority of RRs were near 1.0 (data not shown). Several base counties had yearly incidence ratios greater than 3.0, but all of these involved three or fewer cases and all occurred in counties that also had yearly RR estimates at " 0.5 in other years. For example, in 1997, Curry County Curry County is the name of several counties in the United States:
  • Curry County, New Mexico
  • Curry County, Oregon
 had a 4.8 higher incidence of childhood leukemia compared with nonbase counties. However, this was based on only three cases, and one year later, no cases were diagnosed in this county.

Discussion

The recent cluster of childhood leukemia cases in Churchill County represents a 12-fold increase above leukemia rates in SEER registries. The probability that this cluster would occur by chance is 4.3 x [10.sup.-9], or about 1 in 232 million. Given that the U.S. population 0 to 19 years of age is 10,662 times larger than that of Churchill County (U.S. Census Bureau 2003a), we would expect a cluster of this size to occur in the United States by chance alone about once every 22,000 years. In contrast, the p-value for the cluster in Woburn, Massachusetts Woburn (/'wu.bə(r)n/) is a city in Middlesex County, Massachusetts, USA. The population was 37,258 at the 2000 census. Woburn is the birthplace of Anglo-American scientist Benjamin Thompson, a.k.a. , the basis of the novel A Civil Action (Harr 1995), was 0.0084 (Table 1), or about 1 in 120 (Lagakos et al. 1986).

Importantly, the rate of childhood leukemia seen in Churchill County remained markedly elevated after the State of Nevada began its investigation. Thus, the elevated rates identified in this report are not based solely on post hoc hypothesis testing hypothesis testing

In statistics, a method for testing how accurately a mathematical model based on one set of data predicts the nature of other data sets generated by the same process.
. Given these findings, it appears very unlikely that the Churchill County cluster was attributed only to chance.

No new cases have been diagnosed among Churchill County residents since 2001, although one former resident was diagnosed with leukemia in 2002. Thus, it appears that the cluster among Churchill County residents has spanned a period of 3 years. Table 1 shows a comparison of the Churchill County cluster with other well-known childhood leukemia clusters. By virtue of its large magnitude and short time span, the Churchill County cases seem to represent one of the most unique clusters of childhood cancer ever reported.

One of the goals of this investigation was to evaluate whether the large increases in childhood leukemia risks near NAS Fallon might have occurred near other military aviation facilities. In this analysis, no clear association was found between residence in a county containing a military aviation base and risk of childhood leukemia. Elevated RRs were identified in a few subgroup sub·group  
n.
1. A distinct group within a group; a subdivision of a group.

2. A subordinate group.

3. Mathematics A group that is a subset of a group.

tr.v.
 analyses. However, given the large number of analyses performed and the lack of consistent findings across subgroups, these elevations could be due to chance.

One strength of this investigation was the use of cancer registry data from SEER and CCR. Both registries provide a readily accessible source of incident cancer data for a wide geographic area and for a relatively broad number of years. Because of the lack of a nationwide cancer registry and current unavailability of county-specific data after 1999, we were unable to assess all military aviation facilities and unable to assess more recent effects. Despite this, the use of SEER and CCR data provided a relatively quick and simple, albeit limited, method of evaluating whether the elevated rates of childhood leukemia in Churchill County might be more widespread.

A cause of the Churchill County cases has not been identified. The CDC has recently completed the first portion of a large cross-sectional investigation of the cluster area (CDC 2003). Biologic samples collected from cases and controls, and the families of both groups, were analyzed for 16 metals, 31 nonpersistent non·per·sis·tent
adj.
Having a short life or existence under natural conditions.
 pesticides and metabolites Metabolites
Substances produced by metabolism or by a metabolic process.

Mentioned in: Interactions
, 11 persistent pesticides, 36 polychorinated biphenyls (PCBs), 12 volatile organic compounds volatile organic compound Environment Any toxic cabon-based (organic) substance that easily become vapors or gases–eg, solvents–paint thinners, lacquer thinner, degreasers, dry cleaning fluids , and six viruses. Elevated levels of tungsten tungsten (tŭng`stən) [Swed.,=heavy stone], metallic chemical element; symbol W; at. no. 74; at. wt. 183.85; m.p. about 3,410°C;; b.p. 5,660°C;; sp. gr. 19.3 at 20°C;; valence +2, +3, +4, +5, or +6. , arsenic, two chlorophenol pesticides, and 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (DDE (Dynamic Data Exchange) A message protocol in Windows that allows application programs to request and exchange data between them automatically.

DDE - Dynamic Data Exchange
) were found community-wide, but none were elevated in cases compared with controls. No association was found with Epstein-Barr Virus Epstein-Barr virus (EBV), herpesvirus that is the major cause of infectious mononucleosis and is associated with a number of cancers, particularly lymphomas in immunosuppressed persons, including persons with AIDS. , human T-lymphotropic virus Human T-lymphotropic virus (HTLV) is a human, single-stranded RNA retrovirus that causes T-cell leukemia and T-cell lymphoma in adults and may also be involved in certain demyelinating diseases, including tropical spastic paraparesis.  type-1, or other retroviruses. Levels of naturally occurring arsenic in the public water supplies of Fallon are about twice the current U.S. standard (Focazio et al. 2000). However, these levels have been relatively unchanged over many decades and no clear link has been established between ingested in·gest  
tr.v. in·gest·ed, in·gest·ing, in·gests
1. To take into the body by the mouth for digestion or absorption. See Synonyms at eat.

2.
 arsenic and elevated rates of leukemia [Focazio et al. 2000; Moore et al. 2002; National Research Council (NRC NRC
abbr.
1. National Research Council

2. Nuclear Regulatory Commission

Noun 1. NRC - an independent federal agency created in 1974 to license and regulate nuclear power plants
) 1999].

Population mixing has been hypothesized as a possible cause of the Churchill County cluster. In several studies, increased rates of childhood leukemia were found in areas experiencing large-scale population influxes. These areas include rural new towns, towns with large increases in commuting, areas with large numbers of military personnel or wartime evacuees Resident or transient persons who have been ordered or authorized to move by competent authorities, and whose movement and accommodation are planned, organized and controlled by such authorities. , and areas with large numbers of migrant construction workers (Alexander et al. 1997; Kinlen 1995; Kinlen and Petridou 1995; Li et al. 1998; Stiller and Boyle 1996). For example, in a study of 14 British rural towns newly developed in the period 1946-1950, Kinlen et al. (1990) reported relative risks of childhood leukemia of 2.75 (p < 0.01) for ages 0-4 years and 1.58 (p < 0.05) for ages 0-14 years. The large numbers of military personnel who come in and out of NAS Fallon each year would seem to provide ample opportunity for the introduction of new infectious agents. Approximately 55,000 personnel attend training operations at NAS Fallon annually, each staying an average of 14 days. In most studies of population mixing, the large influxes occurred just before periods when leukemia risks were elevated (Kinlen 1995). At NAS Fallon, large movements of personnel have occurred for at least the past 10 years (U.S. Navy 2002a). The arrival of the Navy Fighter Weapons School Fighter Weapons School can mean the following:
  • United States Navy Fighter Weapons School
  • United States Air Force Fighter Weapons School now the United States Air Force Warfare Center
 (nicknamed "Topgun") and the Carrier Airborne Early Warning The detection of enemy air or surface units by radar or other equipment carried in an airborne vehicle, and the transmitting of a warning to friendly units. Also called AEW.  Weapons School at NAS Fallon in 1996 resulted in only moderate increases in the numbers of personnel.

In most studies of population mixing, relative risks have been near 2.0. In both post hoc and a priori analyses, the relative risk we identified for the Churchill County cluster is substantially higher than this. As discussed by several authors, one may find higher relative risks depending on the boundaries of time and space used to analyze a cluster. This can be especially true in post hoc analyses of known clusters because the specific region and time frame being assessed is typically defined by the cluster (Doll 1999; Neutra 1990; Neutra et al. 1992; Rothman 1990; Waller 2000). For example, in an analysis of all parishes within a 10-km radius of a power station in Drax, North Yorkshire North Yorkshire, county (1991 pop. 698,800), 3,209 sq mi (8,313 sq km), N England. The county comprises the districts of Craven, Hambleton, Harrogate, Richmondshire, Ryedale, Scarborough, Selby, and York. , United Kingdom, Kinlen et al. (1995) reported a relative risk of 1.5 based on 22 observed cases. However, in a post hoc analysis that focused on one particular parish with five cases, a relative risk of 7.9 was reported.

Another hypothesis that was proposed as a cause of the Churchill County cluster was exposure to JP-8 jet fuel, or benzene, a minor component of JP-8 (Carlton and Smith 2000; U.S. Navy 2002b). Several studies have shown that JP-8 can affect immune system cells and may be genotoxic genotoxic /ge·no·tox·ic/ (je´no-tok?sik) damaging to DNA: pertaining to agents known to damage DNA, thereby causing mutations, which can result in cancer.

ge·no·tox·ic
adj.
, although no clear link has been established with leukemia in humans or animals (Grant et al. 2001; Harris et al. 1997a, 1997b, 2000, 2001; Jackman et al. 2002; Rhodes et at. 2003; Ullrich 1999). Benzene has been associated with AML and possibly ALL in occupationally exposed cohorts (Hayes et al. 2001; Savitz and Andrews 1997). One of the Churchill County leukemia cases is AML; however, the remaining 10 are ALL, and the five cases among former residents are all cases of ALL (NSHD 2003). Environmental exposures to benzene are typically well below those associated with leukemia risks in occupational settings (Duarte-Davidson et al. 2001), and to date, no evidence of significant benzene or JP-8 exposure has been linked to the Churchill County cases (CDC 2003). In addition, the high relative risks we have identified for Churchill County, combined with the lack of increased risks in other base counties with similar military related exposures, provides further evidence that a routine exposure specifically related to military aviation was not the cause of the Churchill County cluster.

In this analysis, we found no evidence that large widespread increases in the risks of childhood leukemia have occurred in U.S. counties with military aviation facilities. However, this investigation was limited in its ability to identify small isolated increases. One potential limiting factor A factor or condition that, either temporarily or permanently, impedes mission accomplishment. Illustrative examples are transportation network deficiencies, lack of in-place facilities, malpositioned forces or materiel, extreme climatic conditions, distance, transit or overflight rights,  was that the unit of exposure was restricted to the county level. If significant exposures were occurring near bases, it could be that only those children living in close proximity to the base, or those with a parent actually working on the base, were truly exposed. If so, any increase in leukemia associated with the base might be diluted by the cancer experience of the rest of the county. None of the counties with bases included in this analysis had a population or population density as low as that of Churchill County. However, many of the base counties we assessed were small enough that, on average, fewer than three cases of leukemia were diagnosed each year. In these counties, a substantial increase in cases, such as the eight new cases diagnosed in Churchill County in the year 2000, could have been detected by the methods used here. Three of the base counties we analyzed had individual yearly RR estimates above 3.0. However, all of these were based on few cases, and all occurred in counties that also had some yearly relative risk estimates [less than or equal to] 0.5 in other years. None of the base counties had RR estimates that approached those seen in Churchill County.

In this analysis, exposure was based on county of residence at the time of diagnosis. Migration of families in and our of the study area may have also limited our ability to detect erects, although in the United States, the rate of migration of families with children is low. According to according to
prep.
1. As stated or indicated by; on the authority of: according to historians.

2. In keeping with: according to instructions.

3.
 data from the U.S. Census, only 6% of children 1-19 years of age move across counties each year (U.S. Census Bureau 2003b). Military families likely move more often. However, in Churchill County, only three of the 16 total cases were from military families (NSHD 2003).

We could not obtain detailed data on specific base activities or specific chemical exposures. Many of the exposures that occur near military aviation bases may occur at other facilities such as municipal airports, heavily industrialized in·dus·tri·al·ize  
v. in·dus·tri·al·ized, in·dus·tri·al·iz·ing, in·dus·tri·al·iz·es

v.tr.
1. To develop industry in (a country or society, for example).

2.
 areas, or nonaviation military bases. Including counties with these facilities among our nonbase counties may have biased RR estimates toward the null. We also did not have access to specific data on yearly troop movements at each military base. Although most military aviation bases have influxes of personnel from diverse locations, few appear to have the consistently high troop movements seen at NAS Fallon (GlobalSecurity.org 2003). Including bases with low rates of migration would have biased any effects related to population mixing towards the null and thus limited our ability to evaluate this hypothesis.

In summary, the cluster of childhood leukemia cases in Churchill County appears to be one of the most unusual childhood cancer clusters It may never be fully completed or, depending on its its nature, it may be that it can never be completed. However, new and revised entries in the list are always welcome.

This is a list of cancer clusters.
 ever reported and may warrant further investigation. Our study of risks near other military aviation bases was limited to an evaluation of exposure based on county of residence, so specific exposures such as jet fuel and population mixing could not be precisely evaluated. However, we found no evidence of consistent associations between the risk of childhood leukemia and residence near other military aviation facilities and no evidence that the childhood cancer experience near NAS Fallon was much more widespread. Given the results of previous studies of population mixing, the large troop movements at many military facilities, and the far-ranging and diverse locations traveled by military aviators and other personnel, a more comprehensive study of population mixing in areas near military facilities may be warranted. In addition, several studies have shown that certain specific genetic changes play an important role in the development of leukemia (Greaves greaves

cracklings, an edible raw fat from the meat trade. The skimmings from the preparation of this fat are also called greaves. They represent a low grade of meat meal.
 1999). Given the unusual clustering of the Churchill County cases, further in-depth analyses of tumor tumor: see neoplasm.  and nontumor genetics might provide evidence of a common link between these cases and insight into the cause of this cluster and the causes of childhood leukemia in general.
Table 1. Comparison of the Churchill County cluster with other
selected childhood leukemia clusters.

Location                RR        No.   Age (years)   Time frame

Churchill County, NV   12.0 (b)   11       0-19       1999-2001
Niles, IL (c)           4.3        8       0-14       1956-1960
Dounreay, UK (d)        9.75       5       0-24       1979-1984
Woburn, MA (e)          2.26      12       0-19       1969-1979
Sellafield, UK (f)     11.07       6       0-14       1963-1990

Location               No. of years      p-Value (a)

Churchill County, NV         3        4.3 x [10.sup.-9]
Niles, IL (c)                5        4.3 x [10.sup.-4]
Dounreay, UK (d)             6        1.9 x [10.sup.-4]
Woburn, MA (e)              11        8.3 x [10.sup.-3]
Sellafield, UK (f)          28        2.2 x [10.sup.-5]

(a) p-Values based on the Poisson probability distribution model.

(b) Age-standardized incidence RR using SEER registry data for
years 1996-2000 as the referent group.

(c) Heath and Hasterlik 1963.

(d) Heasman et al. 1986.

(e) Lagakos et al. 1986.

(f) Draper et al. 1993.

Table 2. U.S. military aviation facilities included in the analysis,
based on SEER and CCR data.

Base         SEER/CCR     County, state      Density         Open
                                             (a)
Alameda
  NAS          Both     Alameda, CA           1,957      Closed 1997
Castle AFB     CCR      Merced, CA              109      Closed 1995
Edwards
  AFB          CCR      Kern, CA                 81          Yes
El Centro
  NAF          CCR      Imperial, CA             34          Yes
George AFB     CCR      San Bernardino, CA       85      Closed 1992
Lemoore
  NAS          CCR      Kings, CA                93          Yes
March AFB      CCR      Riverside, CA           214    Realignment 1996
Mather AFB     CCR      Sacramento, CA        1,267      Closed 1993
McClellan
  AFB          CCR      Sacramento, CA        1,267      Closed 2001
Miramar
  NAS          CCR      San Diego, CA           670    Realignment 1997
Moffet
  Field
  NAS          CCR      Santa Clara, CA       1,303      Closed 1994
North
  Island
  NAS          CCR      San Diego, CA           670          Yes
Norton AFB     CCR      San Bernardino, CA       85      Closed 1994
Point Mugu
  NAS          CCR      Ventura, CA             408          Yes
Travis AFB     CCR      Solana, CA              475          Yes
Atlanta
  NAS          SEER     Cobb, GA              1,786          Yes
Cannon AFB     SEER     Curry, NM                32          Yes
Hill AFB       SEER     Davis, Weber, UT        494          Yes
Holloman
  AFB          SEER     Otero, NM                 9          Yes
Kirtland
  AFB          SEER     Bernalillo, NM          477          Yes
McChord
  AFB          SEER     Pierce, WA              417          Yes
Whidbey
  Island
  NAS          SEER     Island, WA              343          Yes

Abbreviations: AFB, Air Force base; NAF, naval airfield.

(a) Population density of the county (people per square mile)
from the 2000 U.S. Census (U.S. Census Bureau 2003a).

Table 3. U.S. military aviation facilities in CCR and SEER
areas excluded from the analysis.

Aviation
facility         SEER/CCR     County, state            Exclusion

Camp Pend-
  leton, USMC      CCR      San Diego, CA             Rotary wing
El Toro Marine
  Corp Air
  Station,
  USMC             CCR      Orange, CA                Rotary wing
Fresno Air
  Terminal
  AGS, USAF        CCR      Fresno, CA                    ANG
Los Alamitos
  AFRC, USAF       CCR      Orange, CA                 AAF, AFRC
Los Angeles
  AFB, USAF        CCR      Los Angeles, CA      Space/missile research
North High-
  lands AGS,
  USAF             CCR      Sacramento, CA                ANG
Onizuka AFB,
  USAF             CCR      Santa Clara, CA      Space/missile research
Ontario IAP
  AGS, USAF        CCR      San Bernardino, CA            ANG
Tustin Marine
  Corps Air
  Station,
  USMC             CCR      Orange, CA                Rotary wing
Van Nuys Air-
  port AGS,
  USAF             CCR      Los Angeles, CA               ANG
Vandenburg
  AFB, USAF        CCR      Santa Barbara, CA    Space/missile research
Bradley IAP
  AGS, USAF        SEER     Hartford, CT                  ANG
Des Moines IAP
  AGS, USAF        SEER     Polk, IA                      ANG
Dobbins ARB,
  USAF             SEER     Cobb, GA                      ARB
McCollum AGS,
  USAF             SEER     Cobb, GA                      ANG
Orange AGS,
  USAF             SEER     New Haven, CT                 ANG
Salt Lake City
  IAP AGS,
  USAF             SEER     Salt Lake, UT                 ANG
Selfridge AFB,
  USAF             SEER     Macomb, MI                    ANG
Sioux City MAP
  AGS, USAF        SEER     Woodbury, IA                  ANG

Abbreviations: AAF, Army airfield; AFB, Air Force base; AFRC,
Armed Forces Reserve Center; AGS, Air Guard station; ANG,
Air National Guard; ARB, Air Force Reserve base; IAP,
international airport; MAP, municipal airport; USAF, U.S. Air
Force; USMC, U.S. Marine Corp.

Table 4. Age-adjusted RRs of childhood leukemia in counties
with military aviation bases, based on SEER and CCR data.

                     Counties with        Counties without
                       air bases             air bases

                            Person-               Person-
Age (years)         No.      years       No.       years

SEER
  0-4                451    6,386,081   2,136    32,053,769
  5-9                225    6,095,212   1,122    31,923,232
  10-14              140    6,067,279     787    33,041,840
  15-19              139    6,282,183     787    34,168,595
  All (0-19)         955   24,830,756   4,832   131,187,436
CCR
  0-4                705    9,667,251     446     5,575,697
  5-9                395    8,713,971     214     5,400,364
  10-14              228    7,738,112     134     5,009,599
  15-19              216    7,473,471     152     4,822,352
  All (0-19)       1,544   33,592,804     946    20,808,012
Churchill County
  All (0-19) (b)      11       22,644

Age (years)        RR (a) (95% CI)

SEER
  0-4              1.06 (0.96-1.17)
  5-9              1.05 (0.91-1.21)
  10-14            0.97 (0.81-1.16)
  15-19            0.96 (0.80-1.15)
  All (0-19)       1.04 (0.97-1.12)
CCR
  0-4              0.91 (0.81-1.03)
  5-9              1.14 (0.97-1.35)
  10-14            1.10 (0.89-1.36)
  15-19            0.92 (0.75-1.13)
  All (0-19)       1.01 (0.93-1.10)
Churchill County
  All (0-19) (b)   12.0 (6.0-21.4)

(a) Age-standardized incidence RR far counties with military
aviation bases using rates in all SEER (1973-1999) and CCR
(1992-1998) counties without bases as the respective referent
group.

(b) Age-standardized incidence RR for Churchill County,
1999-2001, using SEER registry data for years 1998-2000 as
the referent group.

Table 5. Age-adjusted RRs of childhood leukemia in individual
counties with military aviation bases, based on SEER and CCR data.

                               Person-
County                  No.     years     RR (a) (95%, CI)

SEER
  Alameda, CA           310   8,409,581   1.00 (0.89-1.12)
  Bernalillo, NM        172   3,843,281   1.22 (1.04-1.41)
  Cobb, GA              105   2,952,786   0.97 (0.80-1.17)
  Curry, NM              10     424,363   0.64 (0.34-1.19)
  Davis and Weber, UT   136   3,615,670   1.02 (0.86-1.21)
  Island, WA             13     408,770   0.86 (0.50-1.49)
  Otero, NM              14     475,246   0.80 (0 47-1.35)
  Pierce, WA            173   4,508,106   1.04 (0.90-1.211
CCR
  Alameda, CA           191   4,030,004   1.04 (0.89-1.22)
  Imperial, CA           29     515,879   1.24 (0.85-1.79)
  Kern, CA              105   2,250,151   1.03 (0.84-1.26)
  Kings, CA              41     951,207   0.95 (0.69-1.30)
  Merced, CA             45     787,174   1.26 (0.93-1.70)
  Riverside, CA         195   4,537,685   0.95 (0.81-1.10)
  Sacramento, CA        154   3,603,639   0.94 (0.79-1.11)
  San Bernardino, CA    277   5,883,799   1.04 (0.91-1.18)
  San Diego, CA         377   8,354,212   0.99 (0.88-1.12)
  Santa Clara, CA       227   4,784,558   1.04 (0.90-1.21)
  Solano, CA             61   1,261,367   1.06 (0.82-1.38)
  Ventura, CA           110   2,347,259   1.03 (0.85-1.26)
Churchill County (b)     11      22,644   12.0 (6.0-21.4)

(a) Age-standardized incidence RR for individual counties with military
aviation bases using rates in all SEER (1973-1999) and CCR (1992-1998)
counties without bases as the respective referent group.

(b) Age-standardized incidence RR for Churchil County, 1999-2001, using
SEER registry data for years 1996-2000 as the referent group.

Table 6. Age-adjusted RRs of childhood leukemia in counties
with military aviation bases and low population density, based
on SEER and CCR data.

                Counties with       Counties with
                  air bases           air bases

                      Person-              Person-
Age (years)    No.     years      No.       years      RR (a) (95% CI)

SEER
  0-4            8     237,653   2,136    32,053,769   0.51 (0.25-1.01)
  5-9            4     222,714   1,122    31,923,232   0.51 (0.19-1.36)
  10-14          5     218,046     787    33,041,840   0.96 (0.40-2.32)
  15-19          7     221,208     787    34,168,595   1.37 (0.65-2.89)
  All (0-19)    24     899,621   4,832   131,187,436   0.72 (0.48-1.08)
CCR
  0-4          157   2,249,046     446     5,575,697   0.87 (0.73-1.05)
  5-9           97   2,052,710     214     5,400,364   1.19 (0.94-1.52)
  10-14         68   1,862,587     134     5,009,599   1.36 (1.02-1.83)
  15-19         48   1,688,677     152     4,822,352   0.90 (0.65-1.25)
  All (0-19)   370   7,853,019     946    20,808,012   1.04 (0.92-1.17)

(a) Age-standardized incidence RR for counties with military
aviation bases and low population density using rates in all
SEER (1973-1999) and CCR (1992-1998) counties without bases
as the respective referent group.


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Craig Steinmaus, (1,2) Meng Lu, (1) Randall L. Todd, (3) and Allan H. Smith (1)

(1) Arsenic Health Effects Research Group, School of Public Health, University of California, Berkeley The University of California, Berkeley is a public research university located in Berkeley, California, United States. Commonly referred to as UC Berkeley, Berkeley and Cal , California, USA; (2) Division of Occupational and Environmental Medicine, University of California, San Francisco Coordinates:  , California, USA; (3) Nevada State Health Division, Carson City, Nevada The Consolidated Municipality of Carson City is the capital of the State of Nevada. A 2006 population estimate places its population at 57,701[1]. Carson City is now an independent city and is its own Metropolitan Statistical Area. , USA

Address correspondence to C. Steinmaus, School of Public Health, 140 Warren Hall, University of California, Berkeley, CA 94760-7360 USA. Telephone: (510) 504-5395. Fax: (510) 843-5539. E-mail: craigs@uclink.berkeley.edu

Work reported here was supported in part by grant 1 K23 ESO ESO European Southern Observatory
ESO Educación Secundaria Obligatoria (Spain: compulsory secondary education)
ESO European Organisation for Astronomical Research in the Southern Hemisphere
ESO Edmonton Symphony Orchestra
11133-01 from the National Institute of Environmental Health Sciences The National Institute of Environmental Health Sciences (NIEHS) is one of 27 Institutes and Centers of the National Institutes of Health (NIH),which is a component of the Department of Health and Human Services (DHHS). The Director of the NIEHS is Dr. David A. Schwartz.  (NIEHS NIEHS National Institute of Environmental Health Sciences (NIH, DHHS) ) and the University of California The University of California has a combined student body of more than 191,000 students, over 1,340,000 living alumni, and a combined systemwide and campus endowment of just over $7.3 billion (8th largest in the United States).  Center for Occupational and Environmental Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIEHS.

The authors declare they have no competing financial interests.

Received 14 July 2003; accepted 2 February 2004.
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No portion of this article can be reproduced without the express written permission from the copyright holder.
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Title Annotation:Children's Health
Author:Smith, Allan H.
Publication:Environmental Health Perspectives
Date:May 1, 2004
Words:7412
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