Cancer clusters – distinctive geographical groupings of cases – have always attracted
attention and none more so than those involving childhood leukaemia. The public, however,
has often found the approach of epidemiologists to these clusters disappointing. For
the frequent uncertainty about the genuineness of a cluster in reflecting a raised
underlying risk, and its treatment only as generating a hypothesis, with consequently
greater interest in possible future cases than in the (seemingly definite) recent
past, can all appear unhelpful. The fact remains that the choice of boundaries in
space and time greatly influences the magnitude of observed excesses; and tests of
significance are strictly inappropriate without a prior hypothesis, since a chance
would inevitably from time to time generate extreme fluctuations in disease occurrence,
which, in the absence of further information, cannot be distinguished from a genuinely
raised risk. The population mixing hypothesis of childhood leukaemia (Kinlen, 1988)
moved attention away from aggregations attracting notice and on to a possible cause;
if correct, it should reveal significant excesses even when these were previously
unsuspected.
If the long-standing suspicion of an infective origin in childhood leukaemia is correct,
it must (like all known infection-linked cancers) belong to that large group of illnesses
that are rare responses to the relevant infection, otherwise marked space–time clustering
would be more evident. This underlying infection, therefore, would, like polio virus
infection, be mainly immunizing and subclinical. The population mixing hypothesis
originated in the raised levels of childhood leukaemia near the nuclear sites at Sellafield
in north-west England and Dounreay in northern Scotland, which could not be explained
in terms of radiation exposure; for these remote and isolated rural areas had experienced
highly unusual population movements (Kinlen, 1988, 2000). From the well-established
premise that epidemics depend upon the presence of sufficient numbers of susceptible
individuals and that these are more prevalent in rural areas because of the reduced
opportunities for contacts with a wider infective pool, it was argued that a localised
epidemic of an underlying infection would be promoted by large-scale rural–urban population
mixing (i.e. by the increased level of contacts between susceptible and infected individuals)
(Kinlen, 1988). High doses of an infective agent are more likely to be received in
an epidemic than in sporadic infection and, by analogy to leukaemia in cats, these
may produce a heightened risk of leukaemia.
From this idea began a series of studies that eventually covered all known examples
of extreme rural–urban mixing in Britain in the past 60 years, each of which revealed
a significant temporary excess (Kinlen, 1995). They included rural new towns (Kinlen
et al, 1990), wartime evacuation of children to rural areas (Kinlen and John, 1994),
rural inflows of servicemen in the early days of national military service (Kinlen
and Hudson, 1991), areas near large rural (non-nuclear) construction sites (Kinlen
et al, 1995), rural Scottish communities where a large proportion of men worked away
from home in the North Sea oil industry (Kinlen et al, 1993) and wartime Orkney and
Shetland where large numbers of servicemen were stationed (Kinlen and Balkwill, 2001).
In the last four studies, the incomers were all adults, indicating that the infection
is not confined to children. Studies of unusual patterns of contact outside Britain
have confirmed their importance in relation to childhood leukaemia (Kinlen and Petridou,
1995; Petridou et al, 1996; Alexander et al, 1997, 1999; Koushik et al, 2001; Boutou
et al, 2002).
In the first US study of this subject, leukaemia incidence in SEER registry data was
recently examined in more rural counties that had experienced the largest population
influxes (Wartenberg et al, 2004). The use of whole counties as the basic geographic
unit of study would have reduced the likelihood of finding positive evidence: in Britain,
except for the extensive postwar construction of hydroelectric schemes in the Scottish
Highlands, these excesses are not apparent at the county level, but only in the (smaller)
local authority areas or parishes most exposed to the mixing. Despite this potential
obstacle, however, this US study found some evidence of population mixing effects
on childhood leukaemia.
The association with population mixing of a pronounced cluster of childhood leukemia
when noticed outside a formal study, when each is extreme in degree, must also be
relevant here. An example is the most well-known (until recently) US cluster, in Niles,
Illinois, involving eight cases in 1957–1960 centred on a crowded parish school, occurred
when the town received a massive influx of new residents, although its possible significance
was not recognised at the time; in the decade 1950–1960, its population increased
by 5.6-fold from 3587 to 20 393 with much of the influx in 1955–1960 into the relevant
parish (Heath and Hasterlick, 1963). Niles is suburban rather than rural, but the
variety of origins of incoming residents may have made for differences in proportions
of susceptibles within subgroups (as may have occurred in English towns with marked
increases in commuting levels, for these also experienced excesses (Kinlen et al,
1991)). The findings of their detailed study of the Niles cases (Heath and Hasterlick,
1963) led the Centre for Disease Control to create a special leukaemia section to
investigate clusters, but overall with disappointing results.
However, the magnitude of the excess in Niles is dwarfed by that in rural (largely
desert) Churchill County, Nevada where 10 cases of childhood leukaemia were diagnosed
in only 2 years (eight in 2000, two in 2001) compared to less than one expected; these
cases were mainly in the small town of Fallon (population 7536 in 2000) and they have
aroused widespread concern and interest. Indeed, no more striking childhood leukaemia
cluster in the world has been traced (Alexander, 1993) and its extreme nature even
at the county level (P=4.3 × 10−9) has recently been demonstrated (Steinmaus et al,
2004).
The efforts of the Nevada State Health Department to address earlier recommendations
have recently been reviewed in a long-awaited final report by a specialist panel (Expert
Panel on Childhood Leukemia in Churchill County, Nevada, 2004; Sinks and Smith, 2004).
No evidence was found to suggest that the cluster was due to any environmental contaminant,
including arsenic levels in water and jet fuel emissions from planes of the nearby
naval air station.
The only putative cause which the panel could not exclude was the effect of the recent
large increase in the numbers of military personnel temporarily assigned to the Fallon
Naval Air Station for training, reaching the extraordinary level of 55 000 in 2000
from 20 000 per year in the early 1990s (U.S. Navy, 2002; GlobalSecurity.org, 2003).
However, the panel could not decide whether the temporariness of the trainees' residence
made them relevant to this hypothesis. This is surprising since infective transmissions,
or even epidemics, are not usually regarded as requiring more than a short period
of exposure. In fact, except for rural new towns, much of the support for the hypothesis
has come from situations, like that near this naval air base, with no major increase
in the permanent population, but which involved large temporary influxes and much
‘changing of places’. Thus, excesses of childhood leukaemia were found near rural
military camps when the numbers of national servicemen increased in the early 1950s
(Kinlen and Hudson, 1991). Such excesses also occurred near large rural construction
projects in Britain (Kinlen et al, 1993, 1995) where the large-scale coming and going
of men carrying out different jobs is typical. Thus, the building of the THORP plant
at Sellafield in the years 1984–1993 involved a workforce of 50 000, although the
maximum working at any one time was 7800.
Further, the expert panel assumed that the relevant infection would have been introduced
into the community when trainees were for the first time stationed in the area, producing
an epidemic occurring among local children in that earlier period. This is too simple
a model of the probable history of the infection. The dynamics of epidemics are complex
with much evidence of threshold effects and they do not usually begin with the first
opportunity for transmission of an infection, but only when a complex set of circumstances
has occurred (Topley 1942; Anderson and May, 1991). Previous excesses of childhood
leukaemia associated with population mixing have not begun with first exposure to
incomers but only when their numbers reached fairly high levels. Thus, the excess
linked to the construction of the Sullom Voe oil terminal in Shetland began not in
the mid-1970s when its construction was started but in 1979 when the work force and
its turnover on the site reached unusually high levels (Kinlen et al, 1993). It would
therefore not be predicted, nor is it found, that excesses would occur near military
bases in general (Kinlen and Hudson, 1991; Steinmaus et al, 2004), but only near that
minority with marked increases of personnel.
At Fallon, any epidemic would initially be among the trainees coming from various
parts of the US, whose previous experience of infective agents can hardly have been
uniform. An epidemic would have been promoted among these personnel as numbers, population
density and contacts (both direct and indirect) increased on the base in the late
1990s. The variety of origins of servicemen and their relatively crowded conditions
combine to promote infective transmission and on occasions epidemics, and it is hardly
surprising that military camps and bases both in the US and other countries have figured
prominently in the history of infectious disease epidemiology since at least the First
World War (Love and Davenport, 1919). The spread of an epidemic of the underlying
infection to local residents would then occur secondarily with consequent increases
of its complication, childhood leukaemia, as also noted for paralytic poliomyelitis
near military camps when personnel numbers greatly increased (Kinlen and Hudson, 1991).
There is no shortage of routes (including schools and civilian workers at the bases)
for epidemics to affect more permanent residents of local areas. Fallon residents
may reasonably be assumed to include a relatively high proportion of ‘susceptibles’:
for its desert location would tend to prevent or delay some of its residents from
acquiring the same experience of infective agents as some trainees, drawn as they
were from all parts of the country. Fallon's earlier indirect exposure to lower numbers
of trainees on the air base, which the panel stressed, would not prevent an epidemic
in the late 1990s when the annual trainee numbers became massive, if some ‘contact
threshold level’ was exceeded. It is also notable that some children with leukaemia
were not even present in that earlier period and for them, exposure to (the exceptional
levels of) trainees in the late 1990s could only have been recent (no less than four
of them had been resident for less than 3 years before diagnosis; no details were
provided for the other six). The occurrence of the last case in December 2001 would
be in keeping with a decline in the numbers of susceptible residents to below some
threshold level for the relevant underlying infection.
The indirect exposure of Fallon in only a few years to around 100 000 people from
outside the area represents a more extreme example of rural–urban population mixing
than any of those traced and studied in Britain. That the world's most sharply defined
cluster of childhood leukaemia should occur in association with the most extreme example
of rural–urban population mixing so far recorded could not be more arresting. Given
the support that has accumulated from earlier tests of the hypothesis, strong reasons
would be required for rejecting a link.
Among its recommendations, the panel urged that new hypotheses about the causation
of childhood leukaemia be proposed and that opportunities then be found for testing
them. However, this already implies a turning away from the Fallon cluster and from
population mixing, which they had noted as being of possible relevance. It would be
unfortunate if interest was abandoned in population mixing in relation to this cluster
before its relevance had been thoroughly considered. Indeed, details were not tabulated
in the report for all the cases on such elementary aspects as age at diagnosis (and
calender year), length of residence in the area before diagnosis and parental occupation.
It may be hoped that further work will include a detailed search for the underlying
agent in the blood samples that have been collected and stored from the affected young
people.