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Childhood cancer research in oxford III: The work of CCRG on ionising radiation

British Journal of Cancervolume 119pages771778 (2018) | Download Citation



High doses of ionising radiation are a known cause of childhood cancer and great public and professional interest attaches to possible links between childhood cancer and lower doses, particularly of man-made radiation. This paper describes work done by the Childhood Cancer Research Group (CCRG) on this topic


Most UK investigations have made use of the National Registry of Childhood Tumours and associated controls. Epidemiological investigations have included national incidence and mortality analyses, geographical investigations, record linkage and case-control studies. Dosimetric studies use biokinetic and dosimetric modelling.


This paper reviews the work of the CCRG on the association between exposure to ionising radiation and childhood cancer, 1975–2014.


The work of CCRG has been influential in developing understanding of the causes of 'clusters' of childhood cancer and the risks arising from exposure to ionising radiation both natural and man-made. Some clusters around nuclear installations have certainly been observed, but ionising radiation does not seem to be a plausible cause. The group’s work has also been instrumental in discounting the hypothesis that paternal preconception irradiation was a cause of childhood cancers and has demonstrated an increased leukaemia risk for children exposed to higher levels of natural gamma-ray radiation.

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The work of the Childhood Cancer Research Group has involved collaboration with many colleagues in the UK and abroad. There are far too many to list individually, but we would like to record our thanks to them all.

Author contributions

All authors contributed to the planning, writing and/or revision of this paper.

Author information


  1. Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Oxford, OX3 7LF, UK

    • Gerald M. Kendall
  2. Department of Statistics, University of Oxford, 24-29 St Giles’, Oxford, OX1 3LB, UK

    • John F. Bithell
    •  & Gerald J. Draper
  3. National Perinatal Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Oxford, OX3 7LF, UK

    • Kathryn J. Bunch
    •  & Mary E. Kroll
  4. Formerly of Childhood Cancer Research Group, University of Oxford, Oxford, UK

    • Tim J. Vincent
  5. Nuffield Department of Women’s and Reproductive Health John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK

    • Michael F. G. Murphy
  6. National Cancer Registration and Analysis Service, Public Health England, Chancellor Court, Oxford Business Park South, Oxford, OX4 2GX, UK

    • Charles A. Stiller


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Competing interests

The authors declare no competing interests.


The work of the CCRG was supported by the Department of Health for England and Wales and the Scottish Government. Funding also came from CHILDREN with CANCER (UK), Cancer Research UK, the Leukaemia Research Fund, The Kay Kendall Leukaemia Research Fund, The Health and Safety Executive and the National Cancer Institute (USA).


This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Corresponding author

Correspondence to Gerald M. Kendall.



Infective mechanisms and clusters of childhood leukaemia

Two main hypotheses concerning infectious mechanisms in the aetiology of childhood leukaemia have been advanced: Greaves’s Delayed Infection hypothesis75 and Kinlen’s Population Mixing Hypothesis76. The Population Mixing Hypothesis has been extended by other researchers. In addition it has been suggested by workers from CCRG that under-diagnosis of childhood leukaemia, varying both with calendar period and with SES might play a role.

The steady increase in support for these infection-based hypotheses and the dwindling of support for alternatives has left them as widely regarded as the most plausible explanations for clustering and as responsible for many features of childhood leukaemia. However, the available evidence does not allow a clear choice between them. McNally and Eden reviewed the evidence77 and concluded 'It is very important to realize that the Greaves (1988) and Kinlen population mixing hypotheses are not mutually exclusive. Elements of both may be involved in individual cases.'

For more recent reviews of clustering see ref.2,78.

Greaves’s delayed infection hypothesis

Greaves suggested that precursor B-cell Acute Lymphoblastic Leukaemia might require two independent mutations75,79. Infection was postulated to have a crucial role in promoting, through the immune response, the crucial second or postnatal genetic error. Greaves pointed out that absence or diminution of infections early in life is a feature of more affluent ‘hygienic’ societies. This has produced substantial benefits in terms of reduced infant mortality. However, such infectious insulation might predispose the immune system to aberrant or pathological responses following subsequent or ‘delayed’ exposure.

Greaves and Alexander80 published a comprehensive review of theories of an infectious aetiology for childhood leukaemia. The Greaves hypothesis receives support from, for example, an investigation from the UKCCS into day care in infancy and the risk of ALL81 which showed that increasing levels of social activity were associated with consistent reductions in risk of ALL.

Kinlen’s population mixing hypothesis

A possible explanation for clusters of childhood leukaemia around nuclear sites (and elsewhere) has been suggested by Kinlen76,82 who proposed a population mixing hypothesis under which

  • Some childhood leukaemia is a rare response to an as yet unidentified infection;

  • Individuals in isolated or rural areas would be less likely to have been exposed to this agent in early life and would be susceptible to infection by it later;

  • Marked influxes of people into rural areas would lead to mini-epidemics of subclinical infections by this agent; such infections are mainly immunizing but in rare cases lead to childhood leukaemia.

This hypothesis does not involve ionising radiation but it is frequently discussed in the context of clusters. Several studies have been published that support this idea82 and it has been gaining acceptance83. The NRCT has provided data to test it84.

Extended population mixing hypothesis

Some studies have considered population mixing in a broader sense than that defined by Kinlen82. In Kinlen’s sense, population mixing requires striking increases of population in rural areas. These other studies examine childhood leukaemia rates in the context of variables such as immigration rates in areas where there is no such dramatic influx into an isolated rural community.

Thus Stiller and co-workers85,86 using NRCT data found increased levels of childhood leukaemia in areas with greater levels of population influx both for CDs and for Census wards. Dickinson and co-workers, using data partly from the NRCT, found elevated levels of childhood ALL in electoral wards with the highest levels of population mixing87. They applied these ideas to studies of cancers (particularly LNHL) in the children of Cumbrian nuclear workers where measures of population mixing were again associated with childhood cancer. CCRG staff were again involved in some of this work88.

Pre-emptive infection

Another way in which infection might affect childhood cancer rates, possibly including the Sellafield cluster, is that ‘pre-emptive infection’ might be a mechanism explaining increasing time trends in recorded childhood acute lymphoblastic leukaemia incidence, and relatively low rates in children from more deprived communities89,90,91,92. Under this hypothesis, acute leukaemia in children pre-disposes to fatal infection, and does not always have obvious clinical symptoms. Some children might die of such infections without leukaemia ever being diagnosed. In Britain, this would probably have been more frequent in the 1970s and 80s and in more deprived communities. Clinical evidence from the 1980s and 90s supports this suggestion in the context of the socioeconomic gradient93. Greater awareness of the possibility of cancer around nuclear installations might have resulted in a smaller chance of leukaemias being missed than in other areas and under-diagnosis is likely to have been greater in the 1960s. However, it is highly implausible that such an effect could be large enough to explain the Sellafield cluster fully.

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