Risks Factors for Childhood Leukemia

Scope of the Workshop

Childhood leukemia is a heterogeneous disease and the most common malignancy in children accounting for around one third of all childhood cancer cases below the age of 15 years. The causes of most leukemias are still unknown, but both genetic and environmental factors have been implicated in the aetiology of the disease.

Ionizing radiation is regarded as an established environmental risk factor, found in epidemiological studies and confirmed by experimental data. At the same time data on an increased incidence of childhood leukemia near nuclear facilities are puzzling experts, because the exposures in relation to the case numbers are too low to be considered causal.

Non-ionizing radiation has been studied as a possible risk factor since more than 30 years. No carcinogenic potential of low-level fields (levels below ICNIRP recommendations) has been revealed in experimental studies. However, a consistent pattern of a two-fold increase in childhood leukemia is observed in epidemiological studies associated with average exposure to residential low-frequency magnetic fields above 0,3-0,4 µT. The epidemiological evidence is weakened by methodological limitations and no accepted or even plausible biophysical mechanism challenging the crucial question of causal relationship are currently available.

The apparent inconsistencies between empirical findings and the lack of supportive experimental data have to be considered in the light of other possible risk factors and of new data on the complex origin of childhood leukemia. A number of studies supports the hypothesis that initiation of the disease arises prenatally and that exposures before birth or early in life and/or an abnormal immune response play an important role in its further manifestation.

The international workshop brought together experts from different disciplines and backgrounds in order to summarize the current knowledge on all known risk factors and the recent hypothesis on the aetiology of childhood leukemia. The workshop was intended to help the organizers and other experts in radiation protection to assess the statistical associations observed frequently or consistently at low dose/low level areas in epidemiological studies.

Summary

Leukemia contributes about 1/3 of all cancers in children below the age of fifteen. This heterogeneous, multi-factorial disease of the hematopoietic system accounts for the largest proportion of all cancers in this age group, with acute lymphatic leukemia (ALL) being the most common subtype. Incidence rates show a slight increase with time.

There is increasing evidence that a first damaging event to the hematopoietic stem cells (1st hit) occurs during the prenatal phase and one or more postnatal hits are needed to transform the pre-leukemic clones into leukemia cells. In parallel to the body of research investigating the different indicators of molecular damage, therapeutic procedures have been continually developed and improved. Today individually optimized therapeutic plans for childhood ALL patients are available which result in a survival rate of more than 80%.

The aim of the international workshop, jointly organized by ICNIRP, WHO and BfS was to bring together experts from different disciplines to summarize the current knowledge about the role of genetic and environmental risk factors for childhood leukemia. It became clear that, in spite of the many available epidemiological studies, knowledge about the causes of leukemia is still rather incomplete.

Genetic risk factors
Studies on monozygotic twins and the fact that most ALLs occur in the age between 2 and 5 years, suggested an increased inherited susceptibility to damage by environmental exposures in ALL patients. For example, the chromosomal rearrangement TEL-AML1 (t12;21) is commonly associated with ALL, but is also found in approximately 1% of children who do not develop leukemia. Studies currently in progress are focusing on candidate pathways involved in protection against various external threats. These include folic acid metabolism, immune function, xenobiotic metabolism, DNA repair and oxidative stress. The research into genetic predisposition is challenged by the fact that the expected effect sizes for common, low-penetrance markers are small requiring large sample sizes.

Environmental risk factors
1. Ionizing radiation
Two forms of ionizing radiation exposure were discussed: singular relatively high exposures and chronic low dose exposures. These included:
- X-ray examinations during pregnancy, i.e. prenatal exposures of the mother through diagnostic x-ray procedures. The Oxford survey of childhood cancers revealed a clear exposure-risk relationship, whereas data on postnatal X-ray exposures were inconclusive.
- Knowledge from studies of the Japanese atomic bomb survivors.
- Proximity to nuclear power plants: the current German study (KiKK-Study) compared with British and other European studies. The results of the KiKK-Study lead to reanalyzes of the national data in the UK, but these could not support the German results. There is no obvious explanation for the differences. Only with regard to site location was it obvious that almost all UK nuclear power plants are in coastal locations, which is not the case in Germany.
- Indoor radon exposure. Studies so far show only inconsistent results. Many studies were poor, because the radon exposure was not measured individually. In a current study from Denmark, a model was developed and validated to calculate the radon levels in residences of children. In this study the cumulative radon exposure (intensity x time) was associated with increased risk for ALL.

2. Non-ionizing radiation
Epidemiological studies on non-ionizing radiation in the low frequency range (50/60 Hz) have consistently shown an increased leukemia risk from magnetic field strengths above 0.3 -0.4 µT. There is no biological explanation or support from animal studies for such findings. Recent powerful epidemiological studies involving high frequency electromagnetic fields caused e.g. by high power radio and TV transmitter, do not indicate a causal relationship.

3. Chemicals
Pesticides and other chemicals have been investigated as risk factors for several decades, with relatively small observed risk factors (OR <2). However, exposure assessment has been rare, and recent validation studies have shown that previous exposure assessments based on self reports were in part heavily over-estimated. Thus, misclassification (false positive) has to be taken into account and, so far, only solvents have been confirmed as a risk factor.

4. Life style
The data showing a relation between elevated risk and elevated birth weight are relatively consistent. The basic hypothesis is that an excess of growth factors may result in an amplification of proliferative processes in the hematopoietic system. In this connection, the role of folic acid, diet and the age of the mother has been investigated without definite results to date. The influence of the social status was included in some studies, but the results were inconsistent.

5. Immune system
Current complex evidence supports the hypothesis that the second (or last) postnatal damaging event, that leads to manifestation of leukemia, may be related to a deregulation of the immune system. The clear incidence peak of the disease in children aged 2-5 years in industrialized countries can be related to the common ALL (aberrant B-lymphocyte precursor cells). It is assumed that insufficient or delayed activation of the immune system (isolation, too little social contact, too much hygiene) might be a risk factor. A current meta-analysis concerning day care studies supports this hypothesis. The results show a consistent and in part considerable reduction in risk for children participating in day care programs. Participation in day care is used as an indicator for first social contacts and the associated activation of the immune system.

Conclusions and suggestions for future work
Leukemia in children is a multi-factorial disease and none of the environmental risk factors mentioned above prove to have major explanatory power. The observed risk factors were small, in general less than 2. In all areas similar problems and uncertainties were discussed: Essential, but difficult to provide retrospectively, is an improved exposure assessment to prevent misclassification. Confounders seem to have little influence on the results. It became evident that new research paths are needed as there is no simple explanation for the etiology of childhood leukemia. Genetic studies on associations between a specific gene and childhood leukemia need sufficient power to detect small effect sizes. Individual studies might not be able to overcome the foreseen challenges. The need for larger sample sizes and for pooling genetic, environmental and behavioral data has led to the initiation of the Childhood Leukemia International Consortium. It was stated at the workshop that concerted efforts must be made to increase our knowledge in the genetic basis of hematopoietic cancers, the role of the immune system and the interactions between genes and environmental factors.

The workshop proceedings are published in Radiation Protection Dosimetry 132 (2); December 2008.

Program

5 May 2008 Session 1 – Childhood Leukemia

P Kaatsch
Incidence, time trends and regional variations of childhood leukemia

C Rössig
Aetiology of acute childhood leukaemias

A Chokkalingam
Genetic susceptibility to childhood leukemia

M Schrappe
Risk-adapted stratification and treatment of childhood acute lymphoblastic leukemia

Session 2 – Uncertainties and Challenges

C Muirhead
Exposure assessment - implications for epidemiological studies of ionizing radiation

L Kheifets
Exposure assessment and other challenges in non-ionizing radiation studies

B Ritz
Pesticides exposure assessment issues in childhood leukemia studies

P Schlattmann
Cluster investigation using disease mapping methods

Session 3 - Environmental Risk Factors - Ionizing Radiation
Epidemiological Studies - High (Single) Dose

M Little
Childhood Leukemia in the Japanese atomic bomb survivors and in radiotherapeutically exposed groups

R Wakeford
Childhood leukaemia following antenatal or postnatal exposure to X-rays for diagnostic purposes

Epidemiological Studies - Chronic Exposure at Low Doses

O Raaschou-Nielsen
Indoor radon and childhood leukemia

6 May 2008

D Laurier
Childhood leukemia near nuclear installations

J Bithell
Childhood leukemia near British nuclear installations: methodological issues and recent results

B Grosche
The recent KIKK study: results put into perspective

Session 4 - Environmental Risk Factors - Non-Ionizing Radiation

A Ahlbom
Epidemiological studies: low frequency fields

J Schüz
Epidemiological studies: high frequency fields

Session 5 - Environmental Risk Factors - Pesticides and Other Chemicals

C Metayer
Insecticides, herbicides, fungicides and childhood leukemia

C Infante-Ricard
Chemical risk factors and childhood leukemia

J Juutilainen
Do EMFs enhance effects of environmental carcinogens?

Session 6 - Prenatal Parental Exposures

G Draper
Maternal occupational exposures and childhood leukemia and lymphoma

C Kühni
Childhood leukemia and socio-economic status

N de Klerk
Childhood leukemia, intrauterine growth and diet

7 May 2008

Session 7 - Hypotheses on Dysregulated Immune Response to Common Infections

J Clavel
Childhood leukemia and infection: current hypotheses under studies and gene-environment interaction

K Urayama
A meta-analytic evaluation of day-care attendance and risk of childhood acute lymphoblastic leukemia

G Law
Host, family and community proxies for infections associated with leukemia

Session 8

C Portier
Round up, discussions and recommendations