Radiation and Childhood
Leukaemia
From Sellafield to CT scans
A 30 + Year Odyssey
Alan Craft
1982
4 cases of leukaemia from the same housing estate in
Gateshead
Huge pylons and power cable going across the estate
3 cases lived within 100 m of same substation
Massive incinerator on top of hill overlooking estate
Microwave transmitter on ambulance station
Residential exposure to magnetic fields and acute
lymphoblastic leukaemia in children
Martha S Linet et al
NEJM;1997;1-7
The risk of ALL was not linked to summary time weighted average
residential magnetic field levels
Our results provide little evidence that living in homes characterised
by high measured time weighted average magnetic field levels or by
the highest wire code category increases the risk of ALL
Exposure to power frequency electric fields and the risk of
childhood cancer in the UK
British Journal of Cancer ; 2002;1257-1266
UKCCS Investigators
• No support for the hypothesis that residential exposure to electric
fields is associated with childhood cancer
• The study can exclude electric field exposure as a cause of a
substantial proportion of childhood leukaemia
November 1983. Yorkshire Television
“Windscale- The Nuclear Laundry”
Seascale Cluster
• Between 1968 and 1982 there were 4 cases of acute lymphhobastic leukaemia in
the village of Seascale close to the Sellafield nuclear power station and nuclear
fuel reprocessing plant
• The child population of Seascale was 411
• The overall incidence of ALL in childhood is around 1:2000
Craft AW, Openshaw S, Birch JM.
Apparent cluster of childhood lymphoid malignancy in Northern England.
Lancet 1984;ii:95-96
.
Black report ; 1984
• 1956-83 ; a tenfold excess incidence of leukaemia in the under 10 year old
population of Seascale
• 1968-78 ; a fourfold excess of leukaemia mortality in Millom Rural District
in those under 25
• 1968-78 ; Seascale had second highest leukaemia mortality rate out of 152
similar sized Districts in the UK
Conclusion
The Seascale incidence and the Millom mortality rates are unusual but not
unparalleled
There is no evidence that radiation released from Sellafield was responsible
for the increased incidence
Draper GJ, Stiller CA, Cartwright RA, Craft AW, Vincent TJ.
Cancer in Cumbria and in the vicinity of the Sellafield Nuclear Installation, 1963-90.
British Medical Journal 1993;306:89-94.
• The incidence of lymphoid malignancy in children and young people
in Seascale was higher than would be expected.
• Although this increased risk is unlikely to be due to chance, the
reasons for it are still unknown
What happened to the Seascale cluster?
Bunch KJ,Vincent TJ, Black RJ, Pearce, MS, McNally RJQ, McKinney PA, Parker L, Craft AW, Murphy
MFG
Updated investigations of cancer excesses in individuals born or resident in the vicinity of Sellafield
and Dounereay
British Journal of Cancer ; 2014
• No increased risks of cancer were found among children ,teenagers or
young adults living around Sellafield or Dounreay between 1991 and
2006
• Individuals born around these installations between 1950 to 1986
were not at an increased risk of cancer in their lifetime so far
Cumbrian birth cohort
• All children born in Cumbria between 1950 and 1989
• 267426 live births
• 10363 (3.9%) had a father who worked at Sellafield
Parker L, Craft AW, Smith J, Dickinson H, Wakeford R, Binks K, McElvenny D, Scott L, Slovak A.
Geographical distribution of preconceptional radiation doses to fathers employed at the
Sellafield nuclear installation, West Cumbria.
British Medical Journal 1993;307:966-971.
• Retrospective birth cohort study
• 10363 children born in Cumbria from 1950-1989 to fathers
employed at Sellafield
• Outcome measure- total and 6 month prior to conception dose
of radiation received by fathers and development of leukaemia
• 8% of children were born in Seascale
• Mean preconceptual doses of radiation were lower in Seascale
than rest of Cumbria
• The distribution of paternal preconceptual radiation dose is
incompatible with it providing a cause for the Seascale cluster
Quantifying the effect of population mixing on childhood leukaemia risk ; the Seascale
cluster
Dickinson HO and Parker L
British Journal of Cancer ; 1989 ; 144-151
• Model of risk of leukaemia and population mixing in 119539
children between 1969 and 1989 in Cumbria minus Seascale
• Predicition of number of cases expected for Seascale
• Incidence of ALL highest in areas of high population mixing
RR 11.7 (3.2-43)
Population mixing a significant risk factor for ALL , especially in
young children accounting for 50% of cases in Cumbria and most
of cases in Seascale
Bunch KJ,Vincent TJ, Black RJ, Pearce, MS, McNally RJQ, McKinney PA, Parker L, Craft AW, Murphy
MFG
Updated investigations of cancer excesses in individuals born or resident in the vicinity of Sellafield
and Dounereay
British Journal of Cancer ; 2014
• No increased risks of cancer were found among children ,teenagers or
young adults living around Sellafield or Dounreay between 1991 and
2006
• Individuals born around these installations between 1950 to 1986
were not at an increased risk of cancer in their lifetime so far
• We can get some idea about when population is well and truly
“mixed”
Initial evidence of radiation risks
1902
The first radiation-caused skin cancer identified
1911
The first radiation-caused leukaemia identified
Early evidence of radiation risks
Evidence from early radiologists
Skin cancers noted
Increased incidences of leukaemia
Early evidence of radiation risks
Luminous dial painters
• Anaemia, bone fractures
• Increased risk of bone cancer
• Particularly head, jaw and sinus
• Also X-rayed to assess the problems
• Increasing the risk further
Early evidence of radiation risks
Thorotrast imaging
•High alpha-radiation emission
•Increased incidence of various cancers,
predominantly of the liver, but also leukaemia, in
those receiving angiograms
with thorotrast
Atomic Bombs - August 1945
RERF Studies
•Includes over 120,000 individuals followed for over
60 years
•In 2007, 80% of those survivors aged 20 or less at the
time of the bombings were still alive
•Research includes dose estimation, as well as
assessing the health effects of the exposures
RERF Studies – Acute effects
Whole body
exposure
Acute Effects
>10 Gy
Almost certain death
3 Gy
Half of those exposed died within 60
days
1 Gy
10% experienced nausea & vomiting
0.5 Gy
Decreased blood lymphocyte counts
0.1 Gy
No more acute effects
RERF - Late effects
Radiation induced cataracts
Leukaemia and other cancers, but with different
latencies
Figure: Introduction to the Radiation Research Effects Foundation
RERF – Late effects
•Risk varies with age at exposure
•Highest lifetime risk of cancer in A-bomb survivors is in
those exposed at early ages
•Due in part to longer life expectancy
Age at time of
exposure
Estimated no. of deaths from
radiation-related cancers (per 100
survivors)
10 years
2.8
30 years
2.4
50 years
0.4
Prenatal X-rays
Childhood cancer type
RR
Leukaemia
1.5
Lymphoma
1.4
Wilms
1.6
Central Nervous System
1.4
Neuroblastoma
1.5
Bone
1.1
Other solid tumours
1.6
All leukaemia/lymphoma
1.5
All solid tumours
1.5
Bithell JF, Stewart AM. Br J Cancer 1975; 31:271-87
Prenatal X-rays
•The doses to the fetus in the Oxford survey had
‘appreciable’ uncertainties attached to them
•However, the findings were compatible with revised Abomb data
•A dose to the fetus of 10mSv gives an increased risk of
childhood cancer
Wakeford R, Little MP. Int J Radiat Biol 2003; 79: 293-309
Ankylosing spondylitis
•Vertebrae become fused together
•Many patients were irradiated with X-rays
•1955 MRC report
•Death rates from leukaemia in patients
treated with more than one x-ray course
were more than 12 times that expected
Nuclear worker studies - NRRW
•National Registry for Radiation Workers (NRRW)
•175,000 past and present workers
•Third analysis published in 2009
http://www.hpa.org.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1259152489100
•Healthy worker effect (independent of SES)
•Except for pleural cancer mortality (asbestos)
•Cancer mortality and incidence increased with increasing
dose
Nuclear worker studies- 15 countries
•407,391 workers in 15 countries
Excess RR for all cancers other than leukaemia was 0.97
per Sv (95% CI 0.14 to 1.97)
Not likely to be explained by smoking confounding
ERR for leukaemia was 1.93 per Sv
Suggests 1-2% of cancers in the cohort may be
attributable to radiation
CT scans
The Lancet, published online, June 7th 2012
The Lancet 2012, Volume 380, Issue 9840, Pages 499 - 505
The team
• Newcastle University, UK
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Mark Pearce
Jane Salotti
Sir Alan Craft
Nicola Howe
Richard Hardy
Wenhua Metcalf
Richard Harbron
• NCI
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Amy Berrington de González
Choonsik Lee
Mark Little
Jay Lubin
Preetha Rajamaran
Elaine Ron
Cecile Ronckers
 Dalhousie University, Canada
• Louise Parker
 Great Ormond Street Hospital, London
• Kieran McHugh
 Kyung-Hee University, Korea
• Kwang Pyo Kim
The UK CT Scan Study
• Long-term sequelae of radiation exposure
due to computed tomography in childhood
and early adulthood
• Funders:
• US National Cancer Institute
• UK Department of Health
• The European Union
CT scans
 A very useful tool
 11% of all medical imaging examinations in the
UK
 68% of total collective dose to UK population from
medical x-ray examinations
Justification
Specific to CT:
•Mostly risk projection studies extrapolating
‘expected’ doses and ‘expected’ cancer risks
•i.e. no empirical data
•Projections often limited to certain scans,
mortality outcomes only and made assumptions
regarding modern protocol adjustments that
may not have been possible historically
Why study young people?
• With their smaller mass, children tend to receive
higher doses to specific organs
• Great variability of doses, as procedures are not always
adapted for young patients
• Paediatric parameters are dependent on age and weight
• Historically these parameters were often ignored
• Children have a longer remaining life span
Why in the UK?
• National Health Service (NHS)
• Free access to healthcare for all
• CT scans performed primarily in public hospitals
• NHS Central Register
• National and regional cancer registries
• Ability to obtain ‘umbrella consent’
Any drawbacks to doing it in the UK?
• Not many
• Expensive matching processes compared to Scandinavian
countries
• But a much bigger country/patient group
• Lower usage of CT compared to countries such as the USA and
Japan
• But more difficult to do the data linkage in these countries
The Study
• Primary Objective
• To assess the risk of subsequent cancers in individuals
exposed via CT scanning during childhood or as young
adults
Study protocol – phase 1
Cohort study
• Patients having one or more CT scans between 1985-2002
• First scanned aged <22 years
• Free from cancer at first CT
• Radiology departments with available electronic RIS data of sufficient
quality
• Film / paper records from small number of Trusts
Cohort study dosimetry
• Date and type of scan, age and sex available from
electronic RIS records
• Typical CT machine settings for young people taken from
2 UK-wide surveys (1989 and 2001)
• These data combined with those from hybrid
computational phantoms and Monte Carlo radiation
transport techniques to give estimated absorbed organ
doses (e.g. red bone marrow)
• Cumulative doses where more than one CT scan
Outcome data
• RIS data linked with the NHSCR (1985-2008)
• Cancer incidence
• Mortality
• Loss-to-follow-up (e.g. notified emigrations)
• Excluded patients with existing cancer and those
diagnosed with leukaemia within 2 years of first CT scan
and brain tumours within 5 years
Statistical Methods
• Used Poisson relative risk models fitted by
maximum likelihood methods.
• Accrual of person-time began 2 years after the
initial CT scan
• Lag time of 2 years also included
Results - descriptive
• Initial cohort, including cancer patients: 245,000
• Excluding those with cancer and those that could
not be linked by NHSCR left around 180,000
patients in the leukaemia and brain analyses
• These patients had nearly 300,000 CT scans, over
60% of which were of the head
Leukaemia dose-response
ERR/mGy= 0.036 (95%CI: 0.005 - 0.120)
p-trend=0.010
Brain dose-response
ERR/mGy = 0.023 (95% CI: 0.010 - 0.049)
p-trend<0.0001
Main findings of the UK study
• Significant associations between the estimated radiation doses and
subsequent incidence of leukaemia and brain tumours
• Assuming typical doses:
• 5-10 head CTs (≈50mGy to RBM) give an estimated tripling of risk of
leukaemia
• 2-3 head CTs (≈60mGy to the brain) give an estimated tripling of risk of brain
tumour
Critical appraisal
• Dosimetry was improved on previous estimates
• Provided organ doses
• Uncertainties still exist
• Not expected to bias the findings
• Unable to obtain individual-level parameter data for such a large and
historical cohort
Sensitivity analyses
• Excluding all scans in the 10 years prior to a brain tumour diagnosis
gave a higher dose-response than in the original analysis
• i.e. the opposite to that expected if bias from CT related to diagnosis was
driving the findings
• Little evidence of non-linearity of the dose-response for either
leukaemia or brain tumours
Interpretation
•Our results so far suggest that the risk of leukaemia is tripled
with 5-10 head CTs in children aged under 15 years (based on
50mGy exposure)
•For every 10,000 head CTs in under 10s, expect one excess
case of leukaemia in the 1st decade after 1st CT
What next for the UK Study?
• Extension as part of the EPI-CT consortium
• Obtaining pathology reports and trying to get indication data for
cases
• Assessment of dose response if underlying conditions excluded
• Potential for interactions with radiation sensitive underlying conditions
• Nested case-control studies to improve dose estimation
Conclusion so far
• The immediate benefits outweigh the (small) risks in most
settings when CT is used appropriately
• Of utmost importance is that, where CT is used, it should
only be used where fully justified from a clinical perspective
The Lancet, published online, June 7th 2012
The Lancet 2012, Volume 380, Issue 9840, Pages 499 - 505
Eligible
Study Population
of 180,000
Comparison
with ERR/mGy
from A-bomb Data
Life Span Study
•Single acute exposure (γ rays & small neutron dose)
•Restricted to 0-21yrs at exposure & follow-up <15 yrs
71
Mathews JD et al
BMJ 2013 ; 346-
Cancer risk in 680,000 people exposed to computed tomography scans
in childhood or adolescence; data linkage study of 11 million Australians
Aaron Sodickson , Boston
Editorial- BMJ 2013 ;7.
• The Life span study of Japanese atomic bomb survivors
• The landmark UK CT study
• The Australian CT study
All three studies show good concordance within CI that cohort size
permits
They are consistent with the linear – no threshold- dose response
model
Double the dose doubles the cancer risk
The Lancet, published online, June 7th 2012
The Lancet 2012, Volume 380, Issue 9840, Pages 499 - 505
640 citations in 3 years
Is nuclear power safe?
Chernobyl and Fukushima
Chernobyl
26th April 1986
Cancer consequences of the Chernobyl accident ;20 years on.
Cardis et al
J Radiol Protection;2006;127-40
A dramatic increase in the incidence of thyroid cancer particularly for
those exposed when young. Virtually all can be successfully treated
No other convincing evidence of increased incidence of any cancer
There were deaths amongst the “liquidators”
Magnanti BL , Dorak MT , Parker L , Craft AW , James PW ,
McNally RJQ ,
Geographical analysis of thyroid cancer in young people
from northern England : Evidence for a sustained excess
in females in Cumbria
European Journal of Cancer :2009 : 1624-1629
Magnanti BL , Dorak MT , Parker L , Craft AW , James PW ,
McNally RJQ ,
Geographical analysis of thyroid cancer in young people
from northern England : Evidence for a sustained excess
in females in Cumbria
European Journal of Cancer :2009 : 1624-1629
Comparison of the Chernobyl and Fukushima nuclear accidents
Steinhauser et al
Science of the Total Environment;2014;800-817
• Amount of radiation released was 4x greater at Chernobyl
• No fatalities related to acute radiation effects at Fukushima
A non-radiation consequence of Chernobyl
•Fear can be a greater risk than radiation itself
•A higher number of legal abortions was noted in
Sweden and Denmark after the accident
•Relatively low levels of radiation exposures
•Reduced birth rates in some Scandinavian countries
July 6 1988