<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre> Childhood leukemia and
 environmental factors
             Health Council
             of the Netherlands
             Superior Health
             Council Belgium
             EuSANH
</pre>

====================================================================== Einde pagina 1 =================================================================

<br><br>====================================================================== Pagina 2 ======================================================================

<pre>Childhood leukemia and
environmental factors

=

Health Council
of the Netherlands

Superior Health
Council Belgium

EuSANH

Vy,
</pre>

====================================================================== Einde pagina 2 =================================================================

<br><br>====================================================================== Pagina 3 ======================================================================

<pre></pre>

====================================================================== Einde pagina 3 =================================================================

<br><br>====================================================================== Pagina 4 ======================================================================

<pre>the Minister of Social Affairs and Public Health of Belgium
Subject          : presentation of advisory report
                   Childhood leukaemia and environmental factors
Our reference : U 7469/EvR/bp/851-A / SHC 8548
Enclosure(s) : 1
Date             : December 6, 2012
Dear Ministers,
Although the treatment of childhood leukaemia has made progress in recent
decades, the occurrence of this serious disease tends to raise concerns about the
possibility of environmental causes. An extensive evaluation of the scientific
knowledge shows in general limited evidence for causal relations with specific
environmental factors. The disease occurs through a complex interplay of genetic
susceptibilities and different environmental factors that is hard to unravel.
This is the main conclusion of the advisory report that we are pleased to present
to you. It has been drafted by a joint Committee of the Belgian Superior Health
Council and the Health Council of the Netherlands, and has been reviewed by
experts connected to both councils as well as by experts from the European
Science Advisory Network for Health (EuSANH).
In the last decade of the 20th century the incidence of childhood leukaemia has
shown an increase, raising the question what role environmental exposures have
played in this. The trend now seems to have been stopped or even reversed, but
there are still approximately 80 new cases of childhood leukaemia per year in
Belgium and about 140 new cases in the Netherlands.
The possibilities to reduce these numbers are limited, since few environmental
factors could be identified as contributors. Most cases of childhood leukaemia
simply cannot be prevented. The report does, however, suggest a few protective
measures and health recommendations, given the available evidence and the
importance of a precautionary approach when much is still uncertain. The
application of precautionary measures is required more in the case of some
factors than in others, depending on, among other considerations, what is known.
                                               Health Council
                                               of the Netherlands
</pre>

====================================================================== Einde pagina 4 =================================================================

<br><br>====================================================================== Pagina 5 ======================================================================

<pre></pre>

====================================================================== Einde pagina 5 =================================================================

<br><br>====================================================================== Pagina 6 ======================================================================

<pre>Our reference : U 7469/EvR/bp/851-A / SHC 8548
Page             :2
Date             : December 6, 2012
In view of the relatively small numbers of cases of childhood leukaemia per
country, the councils recommend international cooperation in studying variations
in the incidence of childhood leukaemia and their possible relations to different
environmental exposures. Cooperation is also recommended in studying possible
interactions between different agents and genetic subtypes linked to the onset of
childhood leukaemia.
This is the first advisory report that is the result of a collaborative effort within
the framework of EuSANH. Both councils hope it will not prove to be unique.
The collaboration has resulted in an evaluation of the scientific evidence that is
fully agreed upon by the two health councils.
One of the goals of EuSANH is to provide science based policy advice that
transcends national boundaries, in order to prevent duplication of work and to
arrive at shared insights. This will not only have financial benefits, but also
provide a more solid basis for national and international policies. It is our hope
that this report will help to realise these aims.
Yours sincerely
Professor Jean Nève                            Professor Pim van Gool
Chair                                          President
Superior Health Council,                       Health Council
Belgium                                        of the Netherlands
                                                Health Council
                                                of the Netherlands
</pre>

====================================================================== Einde pagina 6 =================================================================

<br><br>====================================================================== Pagina 7 ======================================================================

<pre></pre>

====================================================================== Einde pagina 7 =================================================================

<br><br>====================================================================== Pagina 8 ======================================================================

<pre>Childhood leukaemia and
environmental factors
to:
the Minister of Health, Welfare and Sport of the Netherlands
the Minister of Social Affairs and Public Health of Belgium
</pre>

====================================================================== Einde pagina 8 =================================================================

<br><br>====================================================================== Pagina 9 ======================================================================

<pre>                      The Health Council of the Netherlands is an independent scientific
                      advisory body. It is our task to provide the government and Parliament
                      with advice in the field of public health and health/healthcare research.
                       The Superior Health Council of Belgium is a federal body that is part of
                       the Federal Public Service Health, Food Chain Safety and Environment.
                      The Health Council of the Netherlands and the Superior Health Council
                      of Belgium are members of the European Science Advisory Network for
                      Health (EuSANH), a network of science advisory bodies in Europe.
This report can be downloaded from:
www.healthcouncil.nl
www.css-hgr.be
www.eusanh.eu
all rights reserved
Preferred citation:
Health Council of the Netherlands. Childhood leukaemia and environmental
factors. The Hague: Health Council of the Netherlands, 2012; publication no.
2012/33. ISBN: 978-90-5549-926-7.
Superior Health Council. Childhood leukaemia and environmental factors.
Brussels Superior Health Council, 2012; Advisory report no. 8548. Legal deposit
no.: D/2012/7795/5. ISBN: 978-94-9054-230-6.
</pre>

====================================================================== Einde pagina 9 =================================================================

<br><br>====================================================================== Pagina 10 ======================================================================

<pre>   Contents
   Executive Summary 11
   Samenvatting 15
   Résumé 19
   Introduction 23
.1 Why this report? 23
.2 The Committee, its working procedures and objectives 25
.3 Content of this report 26
   Perspectives and review methods 27
.1 A precautionary perspective 27
.2 Sources of scientific evidence 27
.3 Classifying evidence and possible causality 30
.4 Presenting quantitative information on risks 31
.5 Presenting recommendations 32
   Incidence of childhood leukaemia 35
.1 Incidence in Belgium 35
.2 Incidence in the Netherlands 36
.3 Incidence in Europe 39
.4 Reported clusters and statistical clustering of incidence 40
.5 Conclusion 41
   Genetic factors 43
.1 Genetic subtypes 43
.2 Genetic susceptibility 44
.3 Conclusion 47
   Physical environmental factors 49
.1 Ionising radiation 49
.2 Extremely low-frequency (ELF) magnetic fields 65
.3 Radiofrequency radiation 67
.4 Diagnostic ultrasound scans during pregnancy 68
   Contents                                                     9
</pre>

====================================================================== Einde pagina 10 =================================================================

<br><br>====================================================================== Pagina 11 ======================================================================

<pre>    Chemical environmental factors 71
 .1 Pesticides 71
 .2 Benzene 77
 .3 Organic solvents other than benzene 78
 .4 Arsenic in drinking water 80
 .5 Parental tobacco smoking 81
 .6 Parental marijuana smoking 82
 .7 Parental alcohol consumption 83
 .8 Maternal cured meat intake 84
 .9 Other chemicals 85
    Biological and other factors 89
 .1 Infections and immune reactions 89
 .2 Maternal folate and vitamin supplementation 94
 .3 Birth weight 95
 .4 Socio-economic status 96
    Conclusion 99
 .1 Conclusions on possible associations 99
 .2 Recommended measures 100
 .3 Research needs 106
    References 111
    Annexes 125
A   The Committee 127
B   Consulted experts 129
C   ALL/AML: CCG Evidence Summary 131
D   Childhood leukaemia in general: Evidence Summary 139
E   Causality considerations and limitations 143
F   Classifications of evidence 149
 0  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 11 =================================================================

<br><br>====================================================================== Pagina 12 ======================================================================

<pre>Executive Summary
Childhood leukaemia is a cancer that affects the blood forming system in the
body. The disease is caused by a complex interplay of genetic, natural and man-
made environmental factors. In Belgium, the Netherlands and other
Northwestern European countries each year about 5 in 100,000 children are
confronted with this serious condition, which requires intensive treatment. In
recent years the average number of new cases per year was approximately 80 in
Belgium and 140 in the Netherlands.
    Most young patients have a lymphoid type of acute leukaemia, ALL. A
smaller percentage is affected by an acute myeloid manifestation of the disease,
AML. Due to the improvements in care and treatment in recent decades in
Western-European countries, about 85% of children with ALL and about 60% of
children with AML survive the first five years after they have been diagnosed.
    In the last decade of the 20th century the occurrence of childhood leukaemia
has shown a rise. The question arose whether this could be attributed to an
increased exposure to risk factors. Although this trend now seems to have been
stopped or even reversed, there is still every reason to get more clarity on the role
of environmental factors in the induction and development of childhood
leukaemia.
    It is the aim of this report, drawn up by a joint Committee of the Belgian
Superior Health Council and the Health Council of the Netherlands, to do just
that. The Committee has taken a precautionary perspective to guide its evaluation
of scientific knowledge and recommendations.
Evidence on the impact of environmental factors
The complex interplay of genetic abnormalities and natural and man-made
environmental exposures makes it hard to establish the role of separate factors.
Based on current knowledge, the most important conclusions are that the
majority of leukaemia cases cannot be explained and only a small fraction of
cases might be prevented. Those are addressed in this report.
    Only where ionising radiation is concerned, a causal relation with childhood
leukaemia has been established. Exposure to this type of radiation occurs
naturally, but also through medical applications such as X-rays and in particular
CT-scans.
    For exposure to benzene and tobacco smoking of fathers a causal relationship
with childhood leukaemia is deemed likely, given the available evidence. A
Executive Summary                                                                     11
</pre>

====================================================================== Einde pagina 12 =================================================================

<br><br>====================================================================== Pagina 13 ======================================================================

<pre>  relation with pesticides is labelled ‘possible to likely’. Two protective influences
  are also considered likely: breast feeding and day-care attendance or other
  contacts between young children.
      For the majority of physical, chemical and other environmental factors under
  study, the likelihood of a causal relation with the onset of childhood leukaemia
  could only be labelled as ‘possible’, ‘uncertain’ or ‘unknown’.
  Recommended measures
  In view of the findings in this report, the Committee advocates to complement
  the traditional anti-microbial hygiene with ‘physical-chemical hygiene’, aiming
  to limiting environmental exposures to possibly harmful agents as much as
  feasible.
      Given the tentative nature of much of the scientific knowledge and the
  limited possibilities to reduce the role of naturally occurring exposures, only a
  limited array of measures are (as yet) available to limit possibly harmful
  exposures or to utilise protective opportunities. In this, a balance needs to be
  struck between sufficient precaution and being overly careful.
      Some principles are, however, clear. The median age for the onset of
  childhood leukaemia is around five. To be effective, measures will therefore have
  to be primarily aimed at pre-school children, infants, pregnant women and
  women (and their partners) intending to conceive. The Committee recommends
  that women of childbearing age should be counselled, in order to create
  awareness of the risk of certain environmental and lifestyle factors previous to an
  intended conception. Furthermore, with this much still uncertain, it makes sense
  to suggest measures that are in accordance with policies and guidelines that have
  already been implemented to protect against other diseases or risks.
  Within these parameters, a number of recommendations can be given:
  • Priority should be given to reducing the exposure to ionising radiation for
      medical purposes in the case of pregnant women and young children. More
      risk awareness among professionals in choosing diagnostic methods can
      achieve this.
  • Although a causal relation with the currently used exposures to ultrasound
      scans that are routinely made during pregnancy is considered unlikely,
      ultrasound scans should not be offered without medical indication, to limit
      exposure.
  • An important measure is the reduction of exposure to pesticides, especially
      for pregnant women who may be exposed in the work place or at home, and
      for women who wish to conceive. They should refrain from working with
      pesticides, or use extra protective measures.
  • Since smoking (both of tobacco and marijuana) and alcohol use by parents
      are known to be able to contribute to several adverse health effects in
2 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 13 =================================================================

<br><br>====================================================================== Pagina 14 ======================================================================

<pre>    children, guidelines regarding these lifestyle factors are already in place.
    Although a causal relation with childhood leukaemia has not been
    established, the possibility of such a relation may give extra credence to the
    current advice to refrain from these activities, especially while trying to
    conceive and during pregnancy.
•   It is also advisable, given the possibility of a causal relation with childhood
    leukaemia, for pregnant women to avoid nitrite-cured meat, such as ham,
    bacon and sausages.
•   Finally, the existing recommendation to breast-feed up to the age of six
    months, whenever it is feasible to do so, is reinforced by the likelihood that
    breast feeding may also protect against childhood leukaemia.
A need for further knowledge
Although more knowledge has been emerging, many things about the
environmental causes of childhood leukaemia are as yet uncertain or only
tentatively understood. The findings in this report, however, clearly indicate
where further research is most needed.
    Since the numbers of patients per country are often too small to establish
relationships between causes and effects, international studies on the incidence
of childhood leukaemia and its relation to environmental factors are required. At
the same time, research into specific factors, particularly the adverse effects of
frequent ultrasounds and the use of pesticides, need to be carried out. In addition,
research is needed into the accumulation of risks due to combined exposures,
since this subject has so far hardly been explored.
Executive Summary                                                                    13
</pre>

====================================================================== Einde pagina 14 =================================================================

<br><br>====================================================================== Pagina 15 ======================================================================

<pre>4 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 15 =================================================================

<br><br>====================================================================== Pagina 16 ======================================================================

<pre>Samenvatting
Leukemie bij kinderen is een vorm van kanker in het bloedvormende systeem
van het lichaam. De ziekte wordt veroorzaakt door een complex samenspel van
genetische factoren en omgevingsinvloeden (zowel natuurlijke als door de mens
geproduceerde). In België, Nederland en andere landen in Noordwest Europa
worden elk jaar 5 op de 100.000 kinderen getroffen door deze ernstige
aandoening, die een zware behandeling vergt. Het gemiddelde aantal nieuwe
gevallen per jaar lag recent rond de 80 in België, en rond de 140 in Nederland.
    Het grootste deel van de jonge patiëntjes lijdt aan acute lymfatische leukemie
(ALL). Een kleiner percentage heeft acute myeloïde leukemie (AML). Dankzij
de verbeteringen in behandeling en zorg die de afgelopen decennia in West-
Europese landen zijn gerealiseerd, overleeft zo’n 85% van de kinderen met ALL
de eerste vijf jaar na de diagnose, en circa 60% van de kinderen met AML.
    In het laatste decennium van de 20e eeuw heeft de incidentie van
kinderleukemie een stijging laten zien. De vraag kwam daarbij op of dit kon
samenhangen met een verhoogde blootstelling aan schadelijke omgevings-
factoren. Hoewel de trend nu gestopt lijkt te zijn of zelfs gekeerd, is er nog steeds
alle reden om meer helderheid te krijgen over de mogelijke rol van omgevings-
factoren bij het ontstaan en de ontwikkeling van kinderleukemie.
    Dat is dan ook het doel van dit advies, dat is opgesteld door een gezamenlijke
commissie van de Belgische Hoge Gezondheidsraad en de Nederlandse
Gezondheidsraad. De commissie heeft zich bij haar evaluatie van de
wetenschappelijke kennis en bij het formuleren van aanbevelingen laten leiden
door het voorzorgprincipe.
Kennis over de invloed van omgevingsfactoren
Door het complexe samenspel tussen genetische afwijkingen en blootstelling aan
natuurlijke en kunstmatige omgevingsfactoren is het lastig een helder beeld te
krijgen van de rol die individuele factoren spelen. Op grond van de beschikbare
kennis is de belangrijkste conclusie dan ook dat het merendeel van de gevallen
van kinderleukemie niet verklaard kan worden, en dat slechts een klein deel te
voorkomen zal zijn. Dit advies gaat over de mogelijkheden om binnen dat kleine
deel een reductie te bewerkstelligen.
    Alleen voor ioniserende straling is een oorzakelijk verband met
kinderleukemie gevonden dat beschouwd kan worden als ‘aangetoond’.
Samenvatting                                                                          15
</pre>

====================================================================== Einde pagina 16 =================================================================

<br><br>====================================================================== Pagina 17 ======================================================================

<pre>  Blootstelling aan dit type straling komt van nature voor, maar ontstaat ook door
  medische toepassingen, zoals röntgenfoto’s en in het bijzonder CT-scans.
      Een verband tussen kinderleukemie en blootstelling aan benzeen is op basis
  van de huidige kennis beoordeeld als ‘waarschijnlijk’. Voor het roken door
  ouders en blootstelling aan bestrijdingsmiddelen is het bestaan van een verband
  beoordeeld als ‘mogelijk tot waarschijnlijk’. Verder zijn er twee beschermende
  invloeden die als ‘waarschijnlijk’ zijn gelabeld: het krijgen van borstvoeding en
  het bezoeken van een kinderdagverblijf of andere contacten tussen jonge
  kinderen.
      Voor het merendeel van de fysische, chemische en andere omgevings-
  invloeden die bestudeerd zijn kan het verband met kinderleukemie niet sterker
  worden aangeduid dan als ‘mogelijk’, ‘onzeker’ of ‘onbekend’.
  Aanbevolen maatregelen
  Op basis van deze bevindingen adviseert de commissie om naast de traditionele
  microbacteriële hygiëne ook ‘fysisch-chemische hygiëne’ toe te passen, om zo
  de blootstelling aan mogelijk schadelijke omgevingsinvloeden zoveel mogelijk
  te beperken.
      Vanwege het weinig robuuste wetenschappelijke bewijs en de beperkte
  mogelijkheden om de blootstelling aan natuurlijke invloeden te beperken, is er
  vooralsnog ook slechts een beperkte hoeveelheid maatregelen voorhanden om
  blootstellingen te reduceren of de mogelijkheden voor bescherming te benutten.
  Daarbij moet bovendien een evenwicht bewaard worden tussen voldoende
  voorzorg en te grote voorzichtigheid.
      Een aantal uitgangspunten is echter duidelijk. De gemiddelde leeftijd waarop
  kinderen leukemie krijgen ligt rond de vijf jaar. Om effect te hebben moeten
  maatregelen daarom primair gericht zijn op peuters, zuigelingen, zwangere
  vrouwen en vrouwen (en hun partners) die zwanger willen worden. De
  commissie adviseert om vrouwen die zwanger willen worden te voorzien van
  informatie, zodat zij weten welke omgevings- en leefstijlfactoren schadelijk
  kunnen zijn. Verder ligt het in de lijn, nu nog zoveel onzeker is, om met de
  aanbevelingen aan te sluiten bij bestaand beleid en bij de richtlijnen die al zijn
  geformuleerd met het oog op het voorkomen van andere ziektes of risico’s.
  Binnen deze contouren kunnen de volgende aanbevelingen worden gegeven:
  • Het is van belang om de blootstelling aan ioniserende straling voor medische
      doeleinden bij zwangere vrouwen en jonge kinderen te verminderen. Dit kan
      gerealiseerd worden wanneer medische professionals beter rekening houden
      met de risico’s bij de keuze voor diagnostische methoden.
  • Hoewel een oorzakelijk verband met de huidige blootstelling aan echo’s die
      routinematig tijdens de zwangerschap worden gemaakt onwaarschijnlijk
6 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 17 =================================================================

<br><br>====================================================================== Pagina 18 ======================================================================

<pre>    wordt geacht, zouden echo’s niet aangeboden moeten worden zonder
    medische indicatie, om zo de blootstelling aan ultrageluid te beperken.
•   Een belangrijke maatregel is ook om de blootstelling aan
    bestrijdingsmiddelen te beperken, in het bijzonder voor zwangere vrouwen
    op het werk en thuis, en voor vrouwen die zwanger willen worden. Beide
    groepen zouden niet met bestrijdingsmiddelen moeten werken, of extra
    beschermingsmaatregelen moeten nemen.
•   Aangezien roken (zowel van tabak als marihuana) en alcoholgebruik door
    ouders kunnen leiden tot diverse negatieve gezondheidseffecten bij kinderen,
    zijn op dat punt al richtlijnen geformuleerd. Een oorzakelijk verband van
    deze leefstijlfactoren met kinderleukemie is weliswaar niet aangetoond, maar
    de mogelijkheid van zo’n verband kan een extra reden zijn om van roken en
    alcoholgebruik af te zien, in het bijzonder in de periode voorafgaand aan de
    conceptie en tijdens de zwangerschap.
•   Het is ook aan te raden, gegeven de onzekerheid over een oorzakelijk
    verband met kinderleukemie, dat zwangere vrouwen geen vlees eten dat is
    behandeld met nitriet, zoals ham, spek en worst.
•   Tot slot bevestigen de bevindingen dat borstvoeding mogelijk beschermt
    tegen kinderleukemie het belang van de bestaande aanbeveling om, wanneer
    dat kan, borstvoeding te geven tot de leeftijd van zes maanden.
Noodzaak van meer kennis
Hoewel de wetenschappelijke kennis zich zeker ontwikkelt, is over het verband
tussen omgevingsinvloeden en kinderleukemie vooralsnog veel onduidelijk of
betrekkelijk onzeker. De bevindingen in dit advies laten duidelijk zien waar
verder onderzoek nodig is.
    Aangezien het aantal patiënten per land vaak te klein is om een verband
tussen oorzaken en gevolgen aan te kunnen tonen, is internationaal onderzoek
naar de incidentie van kinderleukemie en de relatie met omgevingsfactoren
noodzakelijk. Tegelijk is specifiek onderzoek nodig, met name naar de nadelige
effecten van het gebruik van bestrijdingsmiddelen en naar eventuele effecten van
frequent gebruik van echo’s. Ook moet onderzoek gedaan worden naar de
stapeling van risico’s als gevolg van meervoudige blootstelling; dat is een
onderwerp dat tot dusverre nog nauwelijks aandacht heeft gekregen.
Samenvatting                                                                     17
</pre>

====================================================================== Einde pagina 18 =================================================================

<br><br>====================================================================== Pagina 19 ======================================================================

<pre>8 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 19 =================================================================

<br><br>====================================================================== Pagina 20 ======================================================================

<pre>Résumé
La leucémie infantile est une forme de cancer affectant le système
hématopoïétique du corps humain. La maladie est provoquée par l’interaction
complexe de facteurs génétiques, naturels et environnementaux produits par
l’homme. En Belgique, aux Pays-Bas et dans d’autres pays d’Europe du nord-
ouest, 5 enfants sur 100.000 sont touchés chaque année par cette maladie grave,
nécessitant un traitement lourd. Au cours des dernières années, le nombre moyen
de nouveaux cas par an se situait autour de 80 en Belgique et de 140 aux Pays-
Bas.
     La plupart des jeunes patients souffrent de leucémie aiguë lymphoblastique
(LAL). Un pourcentage plus faible est atteint de leucémie aiguë myéloblastique
(LAM). Grâce aux améliorations apportées au traitement et aux soins dans les
pays d’Europe de l’Ouest au cours des dernières décennies, quelque 85% des
enfants atteints de LAL survivent durant cinq ans après le diagnostic et environ
60% des enfants atteints de LAM.
     Le nombre de cas de leucémie infantile a présenté une augmentation durant
la dernière décennie du 20ème siècle. La question qui se pose dès lors est de
savoir si cette augmentation peut être corrélée à une exposition accrue à des
facteurs de risque. Bien que cette tendance semble maintenant stoppée voire
inversée, il n’en reste pas moins nécessaire d’obtenir plus de précision au sujet
du rôle des facteurs environnementaux dans l’apparition et le développement de
la leucémie infantile.
     Le présent avis, élaboré conjointement par le Conseil Supérieur de la Santé
de Belgique et le Gezondheidsraad des Pays-Bas, a donc pour objectif d’y
parvenir. Cette commission mixte s’est basée sur le principe de précaution pour
évaluer les connaissances scientifiques et formuler des recommandations.
Preuves concernant l’impact des facteurs environnementaux
En raison de l’interaction complexe entre anomalies génétiques et expositions à
des facteurs environnementaux naturels et artificiels, il n’est pas facile de
déterminer clairement le rôle joué par les différents facteurs. Sur base des
connaissances disponibles, les principales conclusions sont donc que la plupart
des cas de leucémie infantile ne peuvent s’expliquer et que seule une petite partie
des cas pourra faire l’objet d’une prévention. Le présent avis traite des
possibilités de parvenir à une réduction au sein de cette petite fraction.
Résumé                                                                              19
</pre>

====================================================================== Einde pagina 20 =================================================================

<br><br>====================================================================== Pagina 21 ======================================================================

<pre>      Seules les radiations ionisantes présentent un lien causal considéré comme
  ‘démontré’ avec la leucémie infantile. L’exposition à ce type de rayonnements
  est présente dans la nature mais est également générée par des applications
  médicales telles que les radiographies et en particulier les CT-scans.
      En l’état actuel des connaissances, un lien entre la leucémie infantile et
  l’exposition au benzène est considéré comme ‘vraisemblable’. En ce qui
  concerne le tabagisme parental et l’exposition aux pesticides, l’existence d’un
  lien est jugée ‘possible à vraisemblable’. En outre, deux influences protectrices
  sont qualifiées de ‘vraisemblables’: l’allaitement maternel et la fréquentation
  d’une crèche ou tout autre contact entre jeunes enfants.
      Pour la majorité des facteurs environnementaux physiques, chimiques et
  autres étudiés jusqu’à présent, la vraisemblance du lien causal avec l’apparition
  d’une leucémie infantile ne peut être qualifiée que de ‘potentielle’, ‘incertaine’
  ou ‘inconnue’.
  Mesures recommandées
  Au vu des constatations reprises dans le présent rapport, la commission préconise
  d’appliquer, outre la traditionnelle hygiène antimicrobienne, également
  ‘l’hygiène physico-chimique’ afin de limiter autant que possible les expositions
  environnementales à des agents potentiellement nocifs.
      Vu le manque de consistance de la plupart des connaissances scientifiques et
  le peu d’opportunités de réduire le rôle des expositions naturelles, les mesures
  disponibles en vue de limiter les expositions potentiellement nocives ou de
  mettre à profit les possibilités de protection sont encore peu nombreuses. Dans ce
  contexte, il est nécessaire de trouver un équilibre entre précautions suffisantes et
  prudence excessive.
      Certains principes sont pourtant clairs. L’âge médian auquel apparaît la
  leucémie infantile est d’environ cinq ans. Pour être efficaces, les mesures
  devront dès lors viser principalement les enfants d’âge préscolaire, les
  nourrissons, les femmes enceintes et les femmes souhaitant être enceintes (et
  leurs partenaires). La commission recommande d’informer les femmes en âge de
  procréer afin qu’elles prennent conscience du risque que représentent certains
  facteurs environnementaux et comportementaux avant d’envisager toute
  conception. En outre, au vu des incertitudes qui subsistent, il est logique que les
  suggestions émises soient conformes à la politique et aux directives déjà
  implémentées dans le cadre de la protection contre d’autres maladies ou risques.
      Dans les limites fixées par ces paramètres, les recommandations suivantes
  peuvent être formulées:
  • Priorité doit être accordée à la réduction de l’exposition aux radiations
      ionisantes à des fins médicales chez les femmes enceintes et les jeunes
      enfants. Une meilleure prise en compte des risques par les professionnels lors
      du choix des méthodes diagnostiques permettrait d’y parvenir.
0 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 21 =================================================================

<br><br>====================================================================== Pagina 22 ======================================================================

<pre>•   Bien qu’un lien causal avec les doses d’exposition utilisées actuellement
    dans le cadre des échographies réalisées en routine durant la grossesse soit
    considéré comme invraisemblable, ces échographies ne devraient pas être
    proposées sans indication médicale afin de limiter l’exposition.
•   Une importante mesure consiste à réduire l’exposition aux pesticides, en
    particulier pour les femmes enceintes susceptibles d’être exposées au travail
    ou à domicile et pour les femmes souhaitant procréer. Elles devraient
    s’abstenir d’utiliser des pesticides dans le cadre du travail ou appliquer des
    mesures supplémentaires de protection.
•   Il est notoire que la consommation de tabac (et de marijuana) et d’alcool par
    les parents est susceptible d’engendrer divers effets néfastes sur la santé des
    enfants. Des directives existent donc déjà concernant ces facteurs
    comportementaux. Bien que le lien causal avec la leucémie infantile n’ait pas
    été établi, la possibilité d’un tel lien peut donner une crédibilité
    supplémentaire au présent avis qui encourage à s’abstenir de fumer et de
    boire, en particulier si l’on souhaite procréer et durant la grossesse.
•   Il est également conseillé, vu l’incertitude concernant le lien causal avec la
    leucémie infantile, que les femmes enceintes évitent de consommer de la
    viande traitée au nitrite comme le jambon, le bacon et les saucisses.
•   Enfin, la recommandation actuelle d’allaiter dans la mesure du possible
    jusqu’à l’âge de six mois se trouve renforcée par le fait que l’allaitement a
    probablement aussi un effet protecteur contre la leucémie infantile.
Nécessité de connaissances supplémentaires
Bien que les connaissances se soient développées, il subsiste beaucoup
d’incertitude ou d’incompréhension quant aux causes environnementales de la
leucémie infantile. Les conclusions du présent rapport montrent clairement les
domaines dans lesquels des études complémentaires sont les plus nécessaires.
    Le nombre de patients par pays étant souvent trop peu élevé pour établir un
lien de cause à effet, des études internationales sur l’incidence de la leucémie
infantile et son lien avec des facteurs environnementaux sont requises. Dans le
même temps, des études doivent être menées concernant des facteurs
spécifiques, en particulier les effets néfastes de l’utilisation de pesticides et tout
effet potentiel de l’utilisation fréquente des ultrasons. Des recherches doivent en
outre être réalisées quant aux risques cumulatifs dus à des expositions
simultanées, un sujet qui, jusqu’à présent, n’a guère été étudié.
Résumé                                                                                 21
</pre>

====================================================================== Einde pagina 22 =================================================================

<br><br>====================================================================== Pagina 23 ======================================================================

<pre>2 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 23 =================================================================

<br><br>====================================================================== Pagina 24 ======================================================================

<pre>1   Introduction
1.1 Why this report?
    What is the role of environmental factors in the onset of childhood leukaemia?
    This question has been the subject of a multitude of scientific studies. It has also
    been frequently discussed in the media and among concerned individuals. Given
    the increasing body of publications of different origin, it can be hard to keep
    track of the scientifically established knowledge about this important issue, and
    to consider measures based on sufficient evidence.
         It is the aim of this advisory report to address the question of environmental
    influences on the induction and development of childhood leukaemia, using the
    best available and most recent scientific insights. To do so, the Belgian Superior
    Health Council (SHC) and the Health Council of the Netherlands (HCN) have
    engaged in a joint advisory process, initiated by paediatric oncologists in
    Belgium, operating within the framework of the European Science Advisory
    Network for Health (EuSANH).
    Burden of disease and impact on society
    Leukaemias are cancers of the haematopoietic (blood forming) system. Although
    rare, they are the most common malignancies in early childhood. During the last
    two decades of the past century, the average annual incidence* of all childhood
    leukaemias in Europe was 4.4 per 100,000 per year.1
         Leukaemia occurs when immature white blood cells, produced in the bone
    marrow, keep multiplying. Different types of leukaemia originate from different
    cell types: lymphoid or myeloid cells. Therefore, leukaemia can be classified as
    lymphoid or myeloid, and as either acute or chronic. The majority
    (approximately 80%) of childhood leukaemias are acute lymphoblastic or
    lymphoid leukaemias (ALL). The remainder consists almost exclusively of acute
    myeloid leukaemia (AML). Chronic forms of childhood leukaemia are rare.2
         The median age of childhood leukaemia patients is low overall, but shows a
    difference where the two types are concerned, ALL patients being younger (4
    years, 9 months) than patients with AML (6 years, 1 month).3 As the latency
    period can be several years, possible causes of childhood leukaemia may be
    Incidence: the frequency of new cases within a certain period.
    Introduction                                                                         23
</pre>

====================================================================== Einde pagina 24 =================================================================

<br><br>====================================================================== Pagina 25 ======================================================================

<pre>  found very early in childhood, in pregnancy, or even before conception. The
  same applies to possibly protective environmental influences.
      Although improvements in treatment and care have led to a remarkable
  increase in survival rates in recent years, childhood leukaemias require
  burdensome and complication-prone treatments and remain lethal in a significant
  proportion of cases. In Western European countries the 5-year survival rate
  between 1988 and 1997 has been approximately 85% for ALL and less than 60%
  for AML.4 Because of the young age of children with leukaemia, the mean
  number of disability related life years or years lost is relatively high compared to
  other cancers.
  Trends in incidence and supposed role of the environment
  Between 1978 and 1997 the age-standardised incidence rates for leukaemia in
  about twenty European countries have shown a slow but continuous rise from 4.0
  to 4.5 per 100,000 children (age 0-14).1,4,5 This increase can only partly be
  explained by changes in diagnostic methods and registration artefacts.5 The
  patterns and magnitude of the increase therefore suggest that changes in lifestyle
  and in exposure to a variety of agents have contributed to the observed increase.5
      A vast body of scientific literature on environmental factors that may be
  associated with the induction and development of childhood leukaemia is
  available, ranging from ionising radiation, electromagnetic fields and chemicals
  such as pesticides to infectious agents and lifestyle factors. In recent years
  several publications have discussed the incidence of childhood leukaemia around
  nuclear facilities in Germany and the observed associations with living near
  overhead power lines or with pesticide exposures.6-9
      The specific dynamics of exposure in children can be expected to differ from
  that in adults. In addition to exposure during childhood, exposure of the mother
  during pregnancy and exposure of the parents before conception can also play a
  role. Furthermore, children are in general considered to be more sensitive to
  external influences, as a result of their developing physiology and behaviour.
  This sensitivity is especially high during the first weeks after conception, when
  parents might not even be aware of the pregnancy.
  Gene-environment interactions
  Exposure to environmental factors is, however, not the only cause. Gene
  mutations have been shown to play a central role in the aetiology of childhood
  leukaemia. Especially ALL, the most common type of cancer in children, is a
  heterogeneous disease in which different types of genetic abnormalities result in
  the development of multiple genetic subtypes (see 4.1). Genetic and
  environmental factors, and different types of environmental factors, may also be
  expected to interact. Different types of leukaemia may respond differently to
4 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 25 =================================================================

<br><br>====================================================================== Pagina 26 ======================================================================

<pre>    environmental factors. Moreover, some environmental influences may offer a
    measure of protection against childhood leukaemia. In exploring the role of
    environmental influences, these also need to be taken into account.
1.2 The Committee, its working procedures and objectives
    Committee
    The Chair of the SHC and the President of the HCN have established a
    multidisciplinary Committee to prepare an advisory report on the association
    between environmental factors and the incidence of childhood leukaemia. Its
    membership is listed in Annex A.
    Working procedures
    The Committee met eight times. During the review process several external
    experts were consulted (Annex B). Most of them were members of the HCN
    Standing Committees on Radiation and Health, on Health and the Environment,
    on Medicine and on Public Health, and members of the Reflection Groups
    Ionising Radiation and Non-Ionising Radiation and Chemical Agents of the
    SHC. A draft was also reviewed by members of EuSANH. The written
    comments have been discussed in a joint meeting with several reviewers. Finally
    the report has been validated by the Boards of the SHC and of the HCN.
    Objectives
    Given the rise in incidence and the possible association with environmental
    factors, the Committee’s aim is to review the evidence, consider possible causal
    relationships and draw up recommendations for measures that could reduce the
    incidence of childhood leukaemia. To reach this aim, the Committee formulated
    the following objectives:
    1 Collect epidemiological data from Belgium and the Netherlands on
        childhood leukaemia and discuss this in a European context.
    2 Consider the evidence on genetic risk factors of childhood leukaemia.
    3 Review the evidence on environmental factors regarding childhood
        leukaemia, discuss the relevance of indicators of environmental exposures
        and consider possible causal relationships with childhood leukaemia.
    4 Propose measures to reduce the impact of environmental risk factors on
        childhood leukaemia, propose risk communication strategies, and advise on
        further research.
    In dealing with the question of environmental factors, the Committee discusses
    physical, chemical and biological influences, excluding medication. Factors that
    Introduction                                                                     25
</pre>

====================================================================== Einde pagina 26 =================================================================

<br><br>====================================================================== Pagina 27 ======================================================================

<pre>    may be relevant as potential confounders* and effect modifiers**, such as genetic
    susceptibility, lifestyle factors and socio-economic status, are also taken into
    account. A review of diagnosis, treatment and survival rates of childhood
    leukaemia, however, is outside the scope of this advisory report.
1.3 Content of this report
    In Chapter 2 the review methods are described. Chapter 3 is concerned with the
    first objective of the Committee: collecting and discussing the incidence data on
    childhood leukaemia in Belgium and the Netherlands within a European context.
    Chapter 4 deals with the relevance of genetic susceptibility. In Chapter 5, 6 and 7
    the Committee reviews the evidence for causal relationships between the
    occurrence of childhood leukaemia and physical, chemical and other
    environmental exposures, thus addressing the third objective. Chapter 8 presents
    the overall conclusions of the Committee and the recommendations for risk
    management, risk communication and options for further research – the last
    objective of this advisory report.
    Confounder: known risk factor for a disease associated with the exposure under study, which is not
    functioning as an intermediary factor in the causal relationship between exposure and effect (e.g. life
    style factors of socioeconomic status).10
 *  Effect modifier: factor that modifies the measure of effect of a causal factor under study (e.g. genetic
    susceptibility or age of exposure).11
 6  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 27 =================================================================

<br><br>====================================================================== Pagina 28 ======================================================================

<pre>2   Perspectives and review methods
2.1 A precautionary perspective
    As will become clear from this report, knowledge about the impact of
    environmental and lifestyle factors on the occurrence of childhood leukaemia is,
    with a few exceptions, highly uncertain. In situations such as these, which are
    also characterised by complexity and ambiguity*, a precautionary perspective is
    recommended to guide the risk assessment and subsequent risk management.12
    Thus, the available scientific knowledge should be weighed with precaution in
    mind, sources of knowledge outside the area of science could be taken into
    account, and policy measures could be evaluated accordingly.
         Benefits and costs always have to be balanced, but this is especially
    important when gaps in knowledge exist and possibly detrimental influences can
    be serious. Taking a precautionary perspective, measures could then be
    recommended of which the effect on the occurrence of childhood leukaemia is
    uncertain or thought to be limited, but that at least also will have other benefits.
2.2 Sources of scientific evidence
    Scientific evidence for possible relationships between exposure to an
    environmental factor and childhood leukaemia is available from two sources:
    epidemiological and experimental data.
         On the one hand, relevant evidence can be obtained from observational
    studies: epidemiological research in which the association between exposure to
    an environmental factor and the disease is explored. The three most important
    types of epidemiological studies are cohort studies, case-control studies and
    ecological studies**.
         Epidemiological studies generally produce equivocal results, and for that
    reason the results are often insufficient to conclusively establish causal
    relationships.
    Ambiguity relates to different value judgements and conflicting interpretations of the scientific
    knowledge and controversies about the factors that may cause the risks.
 *  In a cohort study a large group of initially healthy subjects is followed for long periods of time,
    varying from years to decades. Exposure to the factor of interest and the occurrence of disease is
    monitored, and in due time associations can be determined. This is usually a prospective type of
    study, which allows adequate exposure assessment. In a case-control study a group of patients with
    the disease of interest is selected, and for each case one or more control subjects is sought who do not
    suffer from the disease. A comparison between case-control pairs is then made regarding exposure
    Perspectives and review methods                                                                          27
</pre>

====================================================================== Einde pagina 28 =================================================================

<br><br>====================================================================== Pagina 29 ======================================================================

<pre>       On the other hand, experimental data can be obtained in the laboratory by
  exposing human or animal cells (in vitro studies) or experimental animals (in
  vivo studies) to environmental factors. In some cases effects can be studied by
  exposing volunteers (human studies). In this way, knowledge can be gathered
  about mechanisms that might explain the associations observed in
  epidemiological studies or that indicate a possible role for a specific risk factor,
  even if relevant associations have not been observed or investigated.
       In this report, the Committee uses four approaches to obtaining evidence for
  possible environmental influences on the incidence of childhood leukaemia.
  Systematic reviews on childhood ALL and AML
  The first line of enquiry has been to commission The Cochrane Childhood
  Cancer Group (CCG) in Amsterdam to prepare a systematic review of the
  available epidemiological evidence on the aetiology of childhood leukaemia. The
  literature retrieval followed a strict protocol with specific inclusion criteria, and
  items for study quality assessment were a priori defined in the study protocol.
       Only publications evaluating ‘environmental factors’ were included that
  pertained to childhood leukaemia (i.e. that included subjects younger than 18
  years at the time of diagnosis) and that presented data on ALL and/or AML
  separately. Because of the very large number of publications retrieved by the
  initial search, inclusion was limited to systematic reviews and meta-analyses
  with a systematic literature search published between 1990 and March 2010.
       The year 1990 was chosen as a starting point since diagnostic methods to
  reliably differentiate between ALL and AML were not available before the
  1980s, and pooling the data is not appropriate, given the different aetiology of
  the two types of leukaemia. The first eligible publications could therefore be
  expected to have appeared from 1990 onwards. One review per aetiological
  factor was selected: either the most recent one or the one with the largest search
  period.
       The CCG has presented its findings in an ‘Evidence Summary’, which is
  published in conjunction with this report.225 Summary tables derived from the
  CCG Evidence Summary are included in this report in Annex C. Conclusions
  from a systematic review of systematic reviews, such as the CCG Evidence
  Summary, are always based on an analysis of the primary data by the authors of
  to the factor of interest. This allows for conclusions on whether exposure is higher in the cases, which
  might be an indication of causality. One of the main problems with this type of study is that exposure
  has to be determined retrospectively, and often on the basis of recollection by the subjects. In an
  ecological study the occurrence of disease at the population level is investigated in relation to
  exposure to the factor of interest. A limitation of this type of study is the usually poor level of insight
  into trends and patterns of exposure at the population level, and the retrospective assessment of
  exposure. Another main problem is that information on confounding factors is generally missing or is
  available only at an aggregated level.
8 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 29 =================================================================

<br><br>====================================================================== Pagina 30 ======================================================================

<pre>the original systematic reviews. However, if information on the primary data is
not available, specific aspects, such as the quality of the included studies, cannot
be discussed. Because of this limitation, and the wider scope of its objectives, the
Committee also studied other evidence.
Systematic reviews on childhood leukaemia in general
Given the focus on systematic reviews and the required separate analysis of ALL
and AML, the CCG Evidence Summary did not include several possibly
important aetiological factors. From a clinical point of view this selection was
warranted, but the Committee decided that additional information, specifically
relevant for identifying the environmental factors associated with the aetiology
of childhood leukaemia, should be weighed as well. It therefore systematically
evaluated the data on childhood leukaemia in general, which were identified in
the original CCG search for systematic reviews.
    Ten systematic reviews were thus identified in the CCG search, in each of
which 50% or more of the studies had been eliminated, as they only addressed
childhood leukaemia in general. The results of the evaluation of these studies are
presented in an ‘Evidence Summary on Childhood Leukaemia in General’,
which is published alongside this report.213 Summary tables derived from this
Evidence Summary are included in Annex D.
Other epidemiological evidence
The CCG search focussed on systematic reviews that were published between
1990 and March 2010. As a consequence, systematic reviews published before
1990 were not included, and neither were narrative reviews. Moreover,
dependent on their objectives, the systematic reviews did not review all earlier
studies. Because important information from relevant studies could have been
missed, the Committee identified key publications or reports from authoritative
national or international expert panels, including results published before 1990
and reviews published since March 2010.
Experimental evidence
In order to assess causality, information on the mechanisms of leukaemogenesis
also had to be taken into account. This means that in addition to epidemiological
data, results from experimental studies needed to be considered.
    The IARC*, an agency of the WHO, has evaluated several relevant risk
factors and classified them according to their carcinogenicity. The Committee
has taken into account the IARC Monographs in which these results are
IARC: the International Agency for Research on Cancer of the World Health Organization (WHO).
Perspectives and review methods                                                               29
</pre>

====================================================================== Einde pagina 30 =================================================================

<br><br>====================================================================== Pagina 31 ======================================================================

<pre>    presented. For some factors, such as ionising radiation, Committee members
    contributed additional experimental information.
         In weighing the information, the Committee has considered that not all
    agents that have been shown to cause cancer in experimental animals can also be
    expected to cause cancer in humans, although the animal studies may strengthen
    the biological plausibility of an association.13 Similarly, if an agent has been
    found to be carcinogenic in humans, this does not necessarily mean that it may
    cause (childhood) leukaemia.
2.3 Classifying evidence and possible causality
    In evaluating the evidence for an aetiological role of environmental factors in the
    initiation or development of childhood leukaemia, the Committee considered two
    questions:
    • What is the evidence for an association between the exposure to certain
         environmental factors and the incidence of childhood leukaemia?
    • What is known about possible mechanisms that would explain an observed or
         hypothesised association between the exposure to certain environmental
         factors and the incidence of childhood leukaemia?
    In answering the first question, the findings from epidemiological research play a
    central role. In answering the second question, evidence from experimental
    research is of primary importance.
         To evaluate the strength of evidence for a causal relationship between an
    environmental factor and childhood leukaemia, the Committee has taken into
    account the well-established considerations put forward by Bradford Hill to
    interpret epidemiological studies: temporality, biological gradient (or exposure-
    response), consistency, strength, specificity, plausibility, coherence, experiment,
    analogy (see also Annex E).14,15
    Evidence
    The Committee has classified the epidemiological evidence for an association
    between the exposure to an environmental factor and the incidence of childhood
    leukaemia, using a modified version of the classifications by IARC and Wigle
    (see Annex F). The conclusions are presented on a three point-scale: 16,17
    • Sufficient (based on results from high-quality systematic reviews or other
         overwhelming evidence, e.g. high-quality large scale observational studies).
    • Limited (based on results from low-quality systematic reviews or high-
         quality observational studies).
    • Inadequate (based on results from low-quality observational studies or expert
         opinions).
 0  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 31 =================================================================

<br><br>====================================================================== Pagina 32 ======================================================================

<pre>    Accordingly, the biological plausibility has been classified as high, moderate or
    low, as far as could be assessed from the available literature.
    Possible causality
    The Committee has classified its conclusions on a causal contribution of
    environmental exposures to the incidence of childhood leukaemia as:
    • Established
    • Likely
    • Possible
    • Uncertain
    • Unknown.
    These qualifications are based on the levels of epidemiological evidence and
    biological plausibility, as presented in the following table for the likelihood of
    causality:
     Levels of scientific evidence   Epidemiological evidence for an association
                                     Sufficient         Limited              Inadequate
     Biological            High      Established        Likely               Possible
     plausibility for a    Moderate  Likely             Possible             Uncertain
     causal relation       Low       Possible           Uncertain            Unknown
    In some classifications a fourth category of scientific evidence is added, to
    indicate whether there is sufficient evidence for the absence of (i.e. evidence
    against) an association or relation with a specific risk factor. In those situations a
    causal relation is classified as ‘unlikely’. However, where environmental risk
    factors of childhood leukaemia are concerned this appeared seldom to be the
    case.
2.4 Presenting quantitative information on risks
    When available, the Committee has presented quantitative information on the
    incidence of childhood leukaemia resulting from exposure to environmental
    factors in the form of the estimated fraction of childhood leukaemia cases that
    can be attributed to a given risk factor. This ‘population attributable fraction’ or
    PAF (sometimes called ‘population attributable risk’ or PAR) is expressed as a
    percentage.
    Two types of information are needed to estimate the PAF:18
    • The relative risk (RR): an estimate of the effect of exposure on the incidence
         of the disease.
    • The prevalence (P) of exposure in the population.
    Perspectives and review methods                                                        31
</pre>

====================================================================== Einde pagina 32 =================================================================

<br><br>====================================================================== Pagina 33 ======================================================================

<pre>    The formula to calculate the PAF is:
    PAF=[P*(RR-1)] / [1+P(RR-1)] * 100.
    However, in most cases the information on exposure distribution required to
    perform this estimation is not available. The Committee has therefore attempted
    to provide expert calculations whenever it was possible to do so, in some cases
    using the exposure distribution of control groups as an estimate for the
    population as a whole. When applicable, this is stated explicitly.
2.5 Presenting recommendations
    The Committee recommends measures that may contribute to the reduction of
    childhood leukaemia in the framework of precaution (see 2.1). The problem is
    complex and risk is created by a sequence of multifactorial elements. Causal
    evidence and plausibility range from ‘unknown’ to ‘established’, depending on
    the nature of contributing factors, while value judgements can differ.
    How has the Committee arrived at these recommendations?
    First, recommendations can be derived from available epidemiological evidence.
    Where this approach is applicable, the Committee has followed Wigle:17
    • Where relationships between adverse health effects in children and
        environmental exposures are supported by sufficient evidence of causal
        relationships, there is a need for (a) policies and programs to minimise
        population exposures and (b) population-based biomonitoring to track
        exposure levels, through ongoing or periodic surveys with measurements of
        contaminant levels in blood, urine and other samples.
    • For relationships supported by limited evidence, there is a need for targeted
        research and policy options ranging from ongoing evaluation of evidence to
        proactive actions.
    • There is a great need for population-based, multidisciplinary and
        collaborative research on the many relationships supported by inadequate
        evidence, as these represent major knowledge gaps.
    Which types of measures are appropriate depends on a large number of factors,
    including:
    • The nature of the risk.
    • The benefits of the activities associated with the risk.
    • The availability of feasible measures or alternatives.
    • The disadvantages (other risks and costs) of measures.
 2  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 33 =================================================================

<br><br>====================================================================== Pagina 34 ======================================================================

<pre>Finally, recommendations can be based on the quantitative contribution of a risk
factor to the occurrence of a disease, expressed as the population attributable
fraction (PAF) and defined as the proportional reduction that would occur if
exposure were to be reduced to zero. Where formulating policies is concerned,
this is the most important estimate.19 Mostly, however, it is not possible to
determine the PAF, due to a lack of data on the distribution of exposure in the
target population.
Perspectives and review methods                                                  33
</pre>

====================================================================== Einde pagina 34 =================================================================

<br><br>====================================================================== Pagina 35 ======================================================================

<pre>4 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 35 =================================================================

<br><br>====================================================================== Pagina 36 ======================================================================

<pre>3   Incidence of childhood leukaemia
    In this chapter, the Committee presents epidemiological data on childhood
    leukaemia from Belgium and the Netherlands. In Belgium, childhood leukaemia
    is defined as acute leukaemia diagnosed before the age of fifteen, in the
    Netherlands before the age of eighteen. To allow a comparison, data from the
    Netherlands are also provided for the 0-14 years age group. Subsequently, the
    results are discussed in a European context. The chapter concludes with a
    paragraph on reported clusters of incidence.
3.1 Incidence in Belgium
    In Belgium, the Belgian Cancer Registry (BCR) is responsible for data
    collecting. Data are available for all regions (Flanders, Wallonia and Brussels)
    from 2004 onwards.20 For Flanders, population-based data are available from
    1999. In Table 1 the childhood leukaemia incidence rates (WSR*) in Belgium are
    presented.
      Table 1. Leukaemia in children (0-14 years) in Belgium (2004-2008): absolute numbers over the
      5-year period and standardised incidence rates (WSR) by diagnosis.
      ICCCa category                  Absolute numbers         Incidence rate (number/ Percentage of total
                                      (total male and          100,000 person-years;
                                      female)                  total male and female)
      Ia Acute lymphoid                                  333                        3.95                79
         leukaemias
      Ib Acute myeloid leukaemias                         61                        0.71                15
      Ic Chronic myelopro-                                  6                       0.06                <1
         liferative diseases
      Id Myelodysplastic                                  18                        0.21                 4
         syndromes and other
         myeloproliferative
         diseases
      Ie Unspecified and                                    2                       0.02                <1
         other leukaemias
      Total                                              420                        4.94               100
    a
           International Classification of Childhood Cancer.21
    WSR (World Standardised incidence Rate): weighted average of the individual age-specific rates
    using the World Standard Population for standardisation, expressed as the number of new cases per
    100,000 person-years.
    Incidence of childhood leukaemia                                                                       35
</pre>

====================================================================== Einde pagina 36 =================================================================

<br><br>====================================================================== Pagina 37 ======================================================================

<pre>    Figure 1. Age-specific incidence rates of leukaemia in children (0-14 years) in Belgium (2004-2008).
    For the period 2004-2008, 23% of all childhood cancers were leukaemias. The
    average number of new cases per year was 67 for ALL and 12 for AML. The
    standardised incidence rate (WSR) was 3.95 per 100,000 person-years for ALL
    and 0.71 for AML. In Figure 1 the childhood leukaemia age-specific incidence
    rates in Belgium are presented.
    As complete data collection in all regions only started in 2004 and only small
    numbers of cases are involved, the data have a large variability. In Flanders,
    incidence rates of childhood leukaemia are available from 1999 onwards. The
    yearly incidence (WSR) for ALL and AML in Flanders between 1999 and 2008
    is presented in Figure 2.
    For the period 1999-2008 the estimated annual percentage of change (EAPC)
    showed a non-significant decrease: -2.57% for ALL (p=0.23) and -5.01% for
    AML (p= 0.44).
3.2 Incidence in the Netherlands
    In the Netherlands, the Dutch Childhood Oncology Group (DCOG) is
    responsible for collecting data on childhood cancers diagnosed up to 18 years of
    age. Data are available from all seven childhood oncology centres, starting in
    1972.20,22 Since 1984, data are available per type of leukaemia (ALL/AML).
 6  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 37 =================================================================

<br><br>====================================================================== Pagina 38 ======================================================================

<pre>Figure 2. Yearly incidence (WSR) of ALL and AML in children (0-14 years) in Flanders
(1999-2008).
In Table 2 the childhood leukaemia incidence (WSR) in the Netherlands is
presented.
  Table 2. Leukaemia in children (0-14 years) in the Netherlands (2004-2008): absolute numbers over
  the 5-year period and standardised incidence rates (WSR) by diagnosis.
  ICCCa category                         Absolute numbers     Incidence rate        Percentage of
                                         (total male and      (number / 100,000     total
                                         female)              person-years; total
                                                              male and female)
  Ia Acute lymphoid                                       537                  3.77                75
     leukaemias
  Ib Acute myeloid leukaemias                             115                  0.81                16
  Ic Chronic myelopro-                                     12                  0.07                 2
     liferative diseases
  Id Myelodysplastic                                       47                  0.35                 7
     syndromes and other
     myeloproliferative diseases
  Ie Unspecified and                                        4                  0.04                <1
     other leukaemias
  Total                                                   715                  5.04               100
a
      International Classification of Childhood Cancer.21
For 2004-2008 the average number of new cases per year was 108 for ALL and
23 for AML. The standardised incidence rate (WSR) per 100,000 person-years
was 3.77 for ALL and 0.81 for AML.
Incidence of childhood leukaemia                                                                      37
</pre>

====================================================================== Einde pagina 38 =================================================================

<br><br>====================================================================== Pagina 39 ======================================================================

<pre>  Figure 3. Age-specific incidence rates of leukaemia in children (0-14 years) in the Netherlands
  (2004-2008).
  In the case of ALL, 45% of the children is diagnosed at 1-4 years of age, 33% at
  5-9 years of age, 15% at 10-14 years of age (Figure 3).23 Another 7% are
  diagnosed at 15-17 years of age. The latter group is sampled ‘registry based’
  instead of ‘population based’, and is therefore not presented here. ‘Registry
  based’ means that children are only included in the DCOG registry if they are
  treated in a paediatric oncology centre. Children aged 15-17 are sometimes
  referred to a haematologist for adults.
  In Figure 4 the incidence (WSR) of ALL and AML in the Netherlands between
  1988 and 2010 is presented.
  Over the whole period, 1988-2010, the estimated annual percentage of change
  (EAPC) has not been statistically significant: 0.57% for ALL (p=0.10) and -
  0.45% for AML (p= 0.44). However, broken down per decade, the incidence of
  ALL shows a statistically significant increase of 2.5% (p=0.003) from 1990 to
  2000, and a non-significant decrease of -1.9% (p=0.07) from 2000 to 2010. The
  incidence of AML shows a non-significant decrease of -1.9% (p=0.17) from
  1990 to 2000, and a non-significant decrease of -1.5% (p=0.52) from 2000 to
  2010. According to the DCOG registry, the increase of ALL in the nineties
  cannot be explained by registration artefacts, since the registry has already
  started in the seventies and has not been changed since the eighties.23
8 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 39 =================================================================

<br><br>====================================================================== Pagina 40 ======================================================================

<pre>    Figure 4. Yearly incidence (WSR) of ALL and AML in children (0-14 years) in the Netherlands
    (1988-2010).
3.3 Incidence in Europe
    The standardised incidence rates (WSR) per 100,000 person-years for all
    childhood leukaemias combined over the period 2004-2008 are comparable for
    Belgium and the Netherlands (see Table 3). They are also approximately similar
    to the incidence rates in France over the period 2000-2004, to those in Sweden
    over the period 1990-1998 and to those in Europe as a whole over the period
    1993-1997. However, as this comparison is based on incidence rates over
    different time periods, caution in drawing conclusions is required.
     Table 3. Age-standardised incidence rates (WSR) per 100,000 person-years of childhood leukaemia
     in different countries.
                     Belgium        The Netherlands France             Sweden           Europe
                     2004-08        2004-08            2000-0424       1990-9825        1993-974
     ALL                      3.95                3.77            3.42             4.01          3.72
     AML                      0.71                0.81            0.72             0.49          0.65
     All types                4.94                5.04            4.59             5.10          4.45
    The incidence of childhood leukaemia in general (‘all types’) is statistically
    higher in Northern Europe (Scandinavia: 4.8 per 100,000 person-years, aged
    0-14) and statistically lower in eastern Europe (3.9 per 100,000 person-years,
    aged 0-14) than the incidence determined for Europe as a whole.1
    Incidence of childhood leukaemia                                                                  39
</pre>

====================================================================== Einde pagina 40 =================================================================

<br><br>====================================================================== Pagina 41 ======================================================================

<pre>    During the last two decades of the past century the incidence of childhood
    leukaemia in Europe has shown an increase. This particularly applies to ALL,
    where a rise of 0.8% per year was seen in children (age 0-14 years: p<0.0001),
    and a rise of 1.9% per year occurred among adolescents (age 15-19 years:
    p=0.008).4 This increase can only partly be explained by changes in diagnostic
    methods and registration artefacts.5
        It is currently unclear whether the increase in leukaemia incidence has
    continued in recent years. Data from the Netherlands and Belgium suggest no
    further increase since the year 2000. An update on the time trend of leukaemia
    incidence in Europe by the ACCIS* project, which is expected to be available by
    the end of 2012, may be able to confirm this.
3.4 Reported clusters and statistical clustering of incidence
    When dealing with the incidence of childhood leukaemia, one other topic needs
    to be addressed. There are many reports about ‘clusters’: unusually high numbers
    of cases in a given area, period or population.26 Statistically significant excess
    occurrences of leukaemia have been reported in a large variety of situations, for
    example: in a horticultural community in the Netherlands,27 near nuclear power
    plants in Germany and the UK,7,28 in areas around military encampments in
    England and Wales,29 in villages with wartime evacuation refugees in England
    and Wales,30 in rural areas with a high proportion of oil industrial workers in
    Scotland,31 near large rural construction sites (coal fired or hydropower stations
    and refineries) in Great Britain,32 in the neighbourhood of a navy base in the
    US,33 and near a coke by-products plant of a steel factory in Australia.34
        Some of these clusters will have occurred by chance: children with
    leukaemia who happen to live in close proximity. In other cases, however, a
    statistical variation should be considered very unlikely, since the difference
    between the number of observed and expected cases is too large to be attributed
    to chance alone. Different mechanisms have been proposed to explain these
    occurrences.
        The British Committee on Medical Aspects of Radiation in the Environment
    (COMARE) has studied the question as to whether or not childhood cancers have
    a ‘natural’ tendency to aggregate or ‘cluster’ closer in space or time than one
    would expect by chance alone.35 It appeared that the incidence of childhood
    leukaemia in Great Britain (1969-1993) occurred in a non-random pattern,
    varying more than would be expected if it were due to chance variations. These
    results are consistent with the hypothesis that a non-random distribution of
    leukaemia cases could be associated with the geographical distribution of
    environmental risk factors. In the British study, however, it could not be
    established what these factors were.
*   ACCIS: Automated Childhood Cancer Information System.
40  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 41 =================================================================

<br><br>====================================================================== Pagina 42 ======================================================================

<pre>        The modest evidence for time-space clustering is compatible with the
    ‘population-mixing’ hypothesis of Kinlen and the ‘delayed-infection’ hypothesis
    of Greaves.36 Both hypotheses posit that childhood leukaemia is a rare response
    to one or more common infections acquired by personal contact under particular
    ‘modern’ socio-demographic circumstances (see Chapter 7).
3.5 Conclusion
    The incidence of ALL in Europe has slowly but continuously increased during
    the last two decades of the 20th century. This increase can only partly be
    explained by improvements in diagnostic methods and registration.
        In the Netherlands, a statistically significant increase of ALL has been seen
    during the last decade of the past century. Since the year 2000, however, this
    increase seems to have come to a halt, and has possibly been reversed. The same
    seems to apply to Belgium. The incidence of AML has remained relatively
    stable.
        In the UK, it has been demonstrated that the geographical incidence of
    childhood leukaemia shows more clustering than would be expected if it were
    due to chance variations. This finding is consistent with the hypothesis that a
    non-random distribution of cases of leukaemia (i.e. clustering) could be due to
    the geographical distribution of environmental risk factors, including infectious
    agents.
    Incidence of childhood leukaemia                                                  41
</pre>

====================================================================== Einde pagina 42 =================================================================

<br><br>====================================================================== Pagina 43 ======================================================================

<pre>2 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 43 =================================================================

<br><br>====================================================================== Pagina 44 ======================================================================

<pre>4   Genetic factors
    Although the focus of this report is on environmental risk factors for the
    induction and development of childhood leukaemia, the Committee briefly
    considers the role of genetics, primarily to demonstrate the complexity of the
    issue. Given this limited objective, a systematic search of the literature has not
    been undertaken, and an extensive review of the scientific data is not provided.
    First, the different genetic subtypes of childhood leukaemias will be described.
    Then two types of genetic susceptibility will be discussed.
4.1 Genetic subtypes
    ALL and AML have distinct origins. They involve malignant transformation of
    lymphoid and myeloid progenitor cells*, respectively.2 Furthermore, for AML
    (~15% of cases) as well as for ALL of B-cell lineage (~70-75%) and T-cell
    lineage (~10-15%)**, many different subtypes can be distinguished, each
    characterised by specific genetic abnormalities.37 In Figure 5 the variation in
    age-specific incidence of different genetic subtypes of childhood leukaemia in
    the Netherlands is presented, starting in 1997.23
          In the cord blood of healthy newborns the prevalence of a TEL/AML
    translocation (a preleukaemic lesion in circa 1:4 of ALL patients) is circa 1 in
    100, while only 1 in 10,000 will later in life develop ALL with TEL/AML.38,39
    This forms an argument for a multistep pathogenesis: since at least 99% of the
    children with this ‘first hit’ will not develop leukaemia, there are more hits
    necessary to develop leukaemia. A recent international study revealed within
    families a high concordance of specific subtypes of childhood ALL, such as
    high-hyperdiploidy, indicating strong genetic or environmental risk factors for
    childhood ALL.40
    A progenitor cell is a cell that, like a stem cell, has a tendency to differentiate into a specific type of
    cell, but is already more specific than a stem cell and is pushed to differentiate into its ‘target’ cell.
    The most important difference between stem cells and progenitor cells is that stem cells can replicate
    indefinitely, whereas progenitor cells can only divide a limited number of times.
 *  B-cells are lymphocytes produced in the bone marrow. The precursors of T-cells are also produced in
    the bone marrow, but they leave the bone marrow and mature in the thymus.
    Genetic factors                                                                                             43
</pre>

====================================================================== Einde pagina 44 =================================================================

<br><br>====================================================================== Pagina 45 ======================================================================

<pre>      Figure 5. Age-specific incidence of childhood leukaemia by genetic and phenotypic subtype in the
      Netherlands (1997-2010). TEL/AML: B-cell Acute Lymphocytic Leukaemia (ALL) with TEL/AML
      fusion; HD: B-cell ALL with high hyperdiploidy (>50 chromosomes per cell); MLL: B-cell ALL
      with abnormalities including the mixed lineage leukaemia gene; T-ALL: T-cell ALL; ALLother: all
      other ALL; AML: Acute Myelocytic Leukaemia.
4.2   Genetic susceptibility
      Different genetic abnormalities are at the origin of the different types of
      leukaemia. Childhood ALL is a multifactorial malignancy with age-specific
      deletions, insertions and chromosomal translocations.41 Genetic factors might
      influence the risk induced by environmental factors.42
           The aetiology of acute leukaemia in children is characterised by immature
      blood cells acquiring different consecutive genetic abnormalities. A
      susceptibility to these abnormalities occurring can be inherited. However, most
      abnormalities are acquired gene mutations in the genetic material of somatic
      (blood precursor) cells.
4.2.1 Inherited genetic susceptibility
      Evidence
      Strong evidence for a genetic susceptibility to childhood leukaemia is provided
      by the increased risk associated with particular genetic disorders, such as Down’s
      syndrome (trisomy 21).43 However, even in the absence of these predisposing
      conditions, a genetic susceptibility may contribute to the origin of childhood
      leukaemia. This genetic susceptibility is related to so-called genetic
 4    Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 45 =================================================================

<br><br>====================================================================== Pagina 46 ======================================================================

<pre>  polymorphisms*.44
      Until recently, studies looking for polymorphisms related to the risk of
  leukaemia generally used a ‘candidate gene’** approach in a case-control design.
  These candidate gene studies were evaluated in a systematic review and meta-
  analysis.45 The authors identified significant associations between childhood
  ALL and eight polymorphisms.
      They mention, however, that numerous studies showed a defective
  methodological design and that their findings should be interpreted with caution,
  since the estimated ‘false-positive reporting probabilities’ for each association
  were considerable. Notably, none of the eight associations described in this meta-
  analysis were identified in the ‘genome wide association studies’ by
  Papaemmanuil et al.46 Although some methodological issues might explain this
  discrepancy, it more likely underscores the proneness of identifying false
  positive associations in previous studies. Also, the genes studied in the candidate
  gene studies were often selected for practical reasons, because data were
  available from other studies, such as the relation between polymorphism and the
  toxicity of chemotherapy.
      With the development of high throughput genotyping techniques, genome-
  wide association studies have become a feasible objective. In two landmark
  studies, using different genotyping platforms, strong susceptibility loci were
  identified.46,47 Genetic variation at these loci not only was associated with the
  development of ALL, but also with specific subtypes of ALL. The initially
  reported associations were verified in a replication study in precursor B-cell
  ALL, the most frequent type of ALL.48
      Although association studies might provide some mechanistic insights into
  the development of childhood leukaemia, the contribution of the described
  polymorphisms to leukaemic transformation remains unclear. Nonetheless, some
  studies convincingly have identified predisposing loci.49 However, modulation
  of the risk by environmental factors remains unexplored.
  Public health relevance
  Less than five per cent of childhood cancers reflect well-known hereditary
  cancer disposition syndromes.50 This means that more than 95% of children
  develop acute leukaemia in the absence of a predisposing syndrome.
  Polymorphisms: variations in genes.
* Candidate gene: gene with a biologically plausible function in the development of a specific disease.
  Genetic factors                                                                                       45
</pre>

====================================================================== Einde pagina 46 =================================================================

<br><br>====================================================================== Pagina 47 ======================================================================

<pre>4.2.2 Acquired genetic susceptibility
      Evidence
      In general, DNA abnormalities (gene mutations) play a major role in
      carcinogenesis.51 The vast majority of mutations in human tissues arise
      spontaneously and are due to endogenous factors. Only a small fraction of these
      acquired mutations, however, convert a normal cell into a cell that is initiated
      towards the development of cancer.52
          It is assumed that in most instances the initiation event is due to a mutation
      that may, for instance, cause inactivation or loss of a gene involved in the repair
      of damaged DNA. Another mechanism that may be involved in carcinogenesis is
      modification of gene expression by receptor binding or DNA methylation by
      specific chemicals. The regulation of gene expression by DNA methylation is a
      so-called epigenetic mechanism, for instance expressed as an enhanced
      proliferation of embryonal blood cells. The aetiology of leukaemia in children,
      especially ALL, is characterised by immature blood cells acquiring different
      consecutive genetic abnormalities, the first ones often occurring before birth.36,53
      However, only few children who are born with a chromosomal translocation will
      develop ALL, proving that these are preleukaemic changes and that
      leukaemogenesis is multifactorial and depending on multiple consecutive events.
      The ‘first hit’, most likely acquired during pregnancy, will give rise to
      preleukaemic cells and clones being more susceptible to additional oncogenic
      events, the ‘second hit’. Most children with ALL carry 6 up to ~20 different
      genetic abnormalities in their leukaemia cells; in AML the number of genetic
      abnormalities is lower.54,55 The genes involved often play a role in the
      differentiation or proliferation of blood cells.
          Although the causes of the oncogenic events remain largely unknown, the
      acquired genetic susceptibility is especially high during the first weeks of
      pregnancy, when parents might not even be aware of the pregnancy. This
      mechanism shows similarities with mechanisms in the development of
      congenital abnormalities, miscarriages, premature birth, intrauterine growth
      delay or other adverse pregnancy outcomes, since these are all related to cellular
      damage in the early development of the child. Depending on the phase of
      pregnancy in which the foetus is exposed to toxic agents, different outcomes may
      occur:
      • Death of the embryo during the pre-implantation phase (first week).
      • Malformations due to disturbed organ development (first trimester).
      • Mental retardation due to disturbed development of the brain (first and
          second trimester).
      • Increased risk of (childhood) cancer.
 6    Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 47 =================================================================

<br><br>====================================================================== Pagina 48 ======================================================================

<pre>    Public health relevance
    Genetic susceptibility factors, either separately or in conjunction with
    environmental factors, may be involved in the majority of childhood leukaemias
    that cannot be explained by identified specific genetic and environmental risk
    factors.56 In that respect, their relevance for public health is much greater than
    that of inherited genetic susceptibility.
4.3 Conclusion
    Genetic polymorphisms might result in an increased vulnerability and therefore
    in a higher risk of developing childhood leukaemia. Most cases of childhood
    leukaemia result from a combination of (prenatal) initiation through the
    occurrence of genetic abnormalities and postnatal acquisition of multiple genetic
    abnormalities in haematopoietic progenitor cells.
        Although the identification of genetic abnormalities has led to
    groundbreaking insights into the disrupted cellular pathways in leukaemic
    transformation, their origin is as yet unclear. However, insight into the genetic
    susceptibility of childhood leukaemia to risk factors is emerging, although the
    interaction with environmental factors is still largely unknown.
    Genetic factors                                                                    47
</pre>

====================================================================== Einde pagina 48 =================================================================

<br><br>====================================================================== Pagina 49 ======================================================================

<pre>8 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 49 =================================================================

<br><br>====================================================================== Pagina 50 ======================================================================

<pre>5     Physical environmental factors
      In this chapter the role of physical environmental influences on the induction and
      development of childhood leukaemia is discussed. The Committee evaluates the
      evidence on ionising radiation, extremely low-frequency magnetic fields,
      radiofrequency radiation and diagnostic ultrasound scans during pregnancy.
5.1   Ionising radiation
5.1.1 Introduction
      To evaluate the possible effect of ionising radiation on the incidence of childhood
      leukaemia, the Committee first discusses the evidence regarding ionising
      radiation in general. Since the exposure situations can show great variation, this
      is followed by a more specific evaluation, in which the Committee discusses five
      types of exposure, and assesses their possible contribution to the incidence of
      leukaemia in Belgium and the Netherlands:
      • Natural radiation exposures.
      • Medical radiation applications.
      • Parental occupational radiation exposure.
      • Residential proximity to nuclear facilities.
      • Radiation accidents.
      These exposure situations have been selected either because they are relevant in
      terms of their contribution to the exposure of the Belgian and Dutch population
      to ionising radiation, or because of their relevance in policy and societal
      debates.57,58
      Types of ionising radiation
      Ionising radiation is the scientific term for the phenomenon colloquially referred
      to as radioactive radiation or often, in short, as radiation. The term, however,
      covers various types of high-energy electromagnetic radiation and high-energy
      particles of subatomic dimensions. Examples of the former are X-rays generated
      by radiation machines and gamma rays emitted by radioactive substances.
      Examples of the latter are beta rays – electrons emitted by radioactive substances
      – and electron beams generated in so-called accelerators. Some radioactive
      substances emit positive electrons or positrons which also fall in the category of
      Physical environmental factors                                                      49
</pre>

====================================================================== Einde pagina 50 =================================================================

<br><br>====================================================================== Pagina 51 ======================================================================

<pre>      ionising subatomic radiation; an important use of such substances is in positron
      emission tomography (PET scan). Other particle-type ionising radiations are
      alpha radiation – helium nuclei emitted by radioactive, heavy nuclei, e.g. radon –
      and neutrons released in nuclear fission or generated in particle accelerators.
           Ionising radiation is applied in medicine for diagnostic and therapeutic
      purposes, in industrial radiography, in various forms of scientific research and in
      the production of electricity through nuclear energy. The radiation can be a by-
      product, as with the release of radioactive substances into the environment by
      nuclear energy installations, but it also occurs naturally. As a result, all humans
      are exposed to cosmic radiation. When living at high altitudes and in aviation
      this type of exposure is increased. Furthermore, some radioactive substances are
      a natural part of the biosphere. Human exposure to these natural forms of
      radiation, however, depends on location and behaviour. Stony materials, for
      instance, have a much higher concentration of natural radioactivity than wood.
      The exposure to ionising radiation from natural radioactive substances is
      therefore quite variable.
5.1.2 Ionising radiation in general
      Radiation dose
      Ionising radiation manifests itself in a great variety of forms. Not all types of
      radiation and radiation energy have been studied in detail, neither
      epidemiologically nor in the laboratory, either in relation to cancer in general or
      leukaemia in particular. However, the general scientific view is that what holds
      for one type of radiation also holds for another, at least in a qualitative sense.59
           Central in this view is the absorption of radiation energy resulting in
      ionisation events that directly or indirectly affect biologically sensitive
      molecules, in particular DNA. Radiation exposure can be quantified in terms of
      an ‘equivalent dose’*, using sievert (Sv) as a unit. It is generally assumed that the
      risk of radiation exposure with DNA as a target is proportional to the absorbed
      energy, i.e. the equivalent dose. However, recent research has indicated that other
      mechanisms that do not directly affect DNA may cause harm as well.61 Whether
      these effects are proportional to the equivalent dose is as yet uncertain.
           In describing the exposures of populations, the quantity ‘effective dose’ is
      commonly used.** In the case of a (more or less) uniform exposure of the body,
      the effective dose is equal to the whole body equivalent dose. In the case of non-
      uniform exposure, for instance after ingesting radioactive substances, the
      Equivalent dose: the quantity of radiation energy absorbed at a certain point in the body per unit
      mass, adjusted for the biological effectiveness of that specific form of radiation.60 1 sievert (Sv)
      corresponds to 1 J⋅kg-1.
 *    Effective dose: a whole body equivalent dose corrected for differences in radiosensitivity related to
      cancer induction between the various organs and tissue.60
 0    Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 51 =================================================================

<br><br>====================================================================== Pagina 52 ======================================================================

<pre>effective dose is taken to represent a similar cancer risk as in the case of uniform
exposure.
    For leukaemia, the exposure of the lymphatic system, and in particular the
red bone marrow, is assumed to be especially relevant. The exposure quantity is
therefore usually established to be the equivalent dose to the red bone marrow.
For external exposures to ionising radiation, e.g. from cosmic rays or gamma
rays from natural radioactivity in soil and building materials, this quantity can be
equated to the exposure of the whole body. However, after the inhalation or
ingestion of radioactive substances the exposure of the body is not uniform. In
that case, the bone marrow equivalent dose has to be derived from complex
calculations, taking into account the distribution and fate of the radioactive
substances in the body.62-68 The available information on the relation between
exposure to ionising radiation and leukaemia includes the exposure of embryo
and foetus after the intake of radioactive substances by the pregnant mother, and
the doses from ingestion of radioactive substances with mothers’ milk. The
Committee, however, stresses that such data should not be used uncritically,
since the calculations are based on biokinetic models that might change as more
becomes known about the way substances are transported through the body, and
how they are transformed and retained in the various organs. An example is the
model used to calculate the exposures from noble gases. It uses irradiation of the
skin or of the whole body (depending on the radiations emitted), but does not
take into account inhalation and absorption in the lungs, nor the solubility in
body fat.
    Another reservation is in order. Even though the equivalent dose concept is
commonly used to estimate radiation risk and to derive standards for radiation
protection purposes, some doubt exists as to whether this concept is fully
applicable in the exposure regimes generally encountered in the environment, in
the work place and through medical diagnostic procedures. Given the present
insights in radiation disease mechanisms, however, it has so far not been possible
to propose a new or adjusted concept.
Epidemiological evidence
X-rays and radioactive substances were discovered at the end of the 19th century.
Not long afterwards, indications of negative health impacts became apparent.69
‘Radiation workers’ lost part of their hair and complained about burned skin and
vomiting.70 In the first decades of the 20th century, cases of cancer were observed
and related to the, often high, radiation exposure of radiation workers. A first
report of leukaemia after prolonged exposure to radiation is dated 1911.70
    In the course of the years, evidence has been gathered about the negative
health impacts of ionising radiation at much lower exposure levels. Pertinent
information about the health risks of ionising radiation exposure was obtained
from studies among the survivors of the atomic bomb explosions above the
Physical environmental factors                                                       51
</pre>

====================================================================== Einde pagina 52 =================================================================

<br><br>====================================================================== Pagina 53 ======================================================================

<pre>  Japanese cities of Hiroshima and Nagasaki at the end of World War II.71 Also,
  follow up studies of populations that were irradiated for medical purposes and of
  occupationally exposed populations have provided information about radiation
  risks. From these research data, and the evaluations by international and national
  scientific committees, evidence has emerged on the relationship between
  ionising radiation exposure and the incidence of childhood leukaemia. The
  Committee will use this information as a basis for its conclusions.
      It is not scientifically disputed that ionising radiation exposure may cause
  leukaemia. An exception is the occurrence of (adult) chronic lymphatic
  leukaemia where radiation does not appear to play a role.72 The Biological
  Effects of Ionising Radiation Committee (BEIR) of the US National Academy of
  Sciences has established relationships between radiation exposure and the
  incidence of leukaemia in the US population as a function of the age when
  exposure occurred and the time lapsed since the exposure, using the atomic bomb
  survivor data in Japan as a basis.73 The so-called latent period, between the time
  of exposure and the time of increased leukaemia risk, lasts a few years. After a
  further period of five years, the risk tends to decrease.
      The age at which exposure occurs appears to be relevant: the lower the age at
  the time of exposure, the higher the lifetime risk.74 Furthermore, after prenatal
  medical exposure through irradiation of the mother and medical exposure of
  young children, increased risks of childhood leukaemia have been
  observed.59,70,72,75,76
  Other evidence
  Experimental studies, i.e. laboratory research with cell lines and experimental
  animals, have provided insight in the mechanisms that operate on the pathway
  from exposure to disease. From the evidence gathered, it has become clear that
  exposure to ionising radiation has the potential to, directly or indirectly, affect the
  genetic information (DNA) in the nuclei of the cells in the body, which may lead
  – sometimes after many years – to cancer, including leukaemia.
      Damage to germ cells may lead to hereditary diseases, while in utero
  irradiation can cause congenital malformations and other damage.59 Whether
  direct or indirect processes at a cellular level, or both, affect the genetic
  properties of cells, is at present a matter of discussion.77,78 The foetus and the
  infant may be particularly vulnerable, given the relatively rapid division and
  multiplication of cells in the growing organism.
  An important issue is whether exposures to ionising radiation at the low levels
  and rates encountered normally in the environment and in the work place may
  also lead to an increased risk of cancer, hereditary effects or other disease.78,79
  Mainly based on experimental studies, international review committees have
  opted, in any case with respect to cancer induction, for the absence of an
2 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 53 =================================================================

<br><br>====================================================================== Pagina 54 ======================================================================

<pre>      exposure threshold below which the risk would be nil.60,78 The Committee feels
      that, with respect to radiological protection measures and policies, this
      interpretation of the available evidence is a prudent option. It will therefore
      follow this approach in its discussion of the relation between the risk of
      childhood leukaemia and exposure to ionising radiation.
            The precise nature of the relationship between low level exposures and health
      effects, in particular the risk that cancer will occur, is, however, not well
      known*.80 Based on insights in the processes leading to cancer, a linear
      relationship between radiation exposure quantities and cancer risk is widely
      assumed.60,79 However, there are indications that this relationship may in some
      situations underestimate the risk associated with radiation.81 Furthermore,
      research into the inter- and intracellular processes challenges the linear non-
      threshold model for cancer induction, and raises the possibility of protective
      responses at relatively low exposure (below 100 mSv).82
            However, the newer findings so far have only added complexity, suggesting
      both overestimation and underestimation of the risks at low doses, making it
      difficult to propose a better model.80
      Evaluation
      Following the UNSCEAR** and other international review committees, the
      Committee regards the findings from epidemiological research and research into the
      mechanisms of cancer inductions as evidence for the claim that exposure to
      ionising radiation of the foetus and of young children can cause childhood
      leukaemia. The Committee denotes the level of evidence for a causal relationship
      between exposure to ionising radiation and childhood leukaemia from both
      epidemiological research and laboratory research as established.59,72,75
5.1.3 Natural radiation exposures
      The exposure (average effective dose) to natural ionising radiation from cosmic
      origin, from radioactive substances in soil and building materials, and from
      natural radioactive substances in the body (not including the contribution from
      inhaled radon decay products) is about 1 millisievert (mSv) per person per year
      both in Belgium and in the Netherlands.58 This exposure is quite uniformly
      distributed over the body and therefore the bone marrow equivalent dose
      (relevant for leukaemia) is equal to the effective dose. In the Netherlands, people
      are rather uniformly exposed throughout the country. In Belgium, exposures in
      The data of the Japanese atomic bomb survivors suggest a linear-quadratic exposure-response
      relationship for leukaemia74. However, for the exposures commonly encountered in the present day
      environment or at work a linear relationship, extrapolated downwards from the epidemiological data,
      is also not inconsistent with the data.
 *    UNSCEAR: United Nations Scientific Committee on the Effects of Atomic Radiation.
      Physical environmental factors                                                                      53
</pre>

====================================================================== Einde pagina 54 =================================================================

<br><br>====================================================================== Pagina 55 ======================================================================

<pre>  the South are higher than in the North, due to higher concentrations of
  radioactivity in the soil.57 The maximum difference is about 0.6 mSv per person
  per year. A population group receiving relatively high exposures to cosmic
  radiation is aircraft personnel (see 5.1.5).
       Decay products of the noble gas radon are radioactive forms of polonium,
  bismuth and lead*. Radon is released by soil and stony building materials. The
  decay products get attached to airborne dust particles. When inhaled, they may
  be deposited in the lungs, and after absorption they may irradiate other organs.
  Due to radon accumulation in dwellings, exposure is considerably higher indoors
  than outdoors, and will depend on ventilation (replacement of indoor air by
  outdoor air), the degree to which radon from the basement or crawl space may
  diffuse into the living quarters and the choice of building materials.
       Radon concentrations in dwellings in the Netherlands amount on average to
  30 Bq⋅m-3 **, with building materials as the main contributor (about 70%).85 The
  variation from dwelling to dwelling is relatively small from an international
  perspective; concentrations above 100 Bq⋅m-3 are quite exceptional.
       In Belgium, the situation is different. The average concentration in dwellings
  is about 50 Bq⋅m-3, whereas in the South concentrations above 400 Bq⋅m-3 are
  found in a substantial fraction of the dwellings.57,86 The contribution from the
  soil below a dwelling is much more important in Belgium than in the
  Netherlands.
       However, the contribution of the inhalation of radon and radon decay
  products to bone marrow dose is quite uncertain. Estimates of bone marrow
  equivalent doses vary from 0.1 to 1 mSv per year at an exposure concentration of
  200 Bq⋅m-3.87 This means that for the average radon concentrations, the bone
  marrow equivalent dose may vary in the Netherlands from 0.015-0.15 mSv, and
  in Belgium from 0.025-0.25 mSv.
  Epidemiological evidence
  Except in the case of radon exposures, the Committee is not aware of research
  that has specifically investigated the relationship between natural background
  radiation and childhood leukaemia. Several studies did compare leukaemia
  incidence or mortality in areas with different natural radiation exposure due to
  differences in radioactivity in the soil.59 Even though some studies included quite
  large populations (several tens of thousand), generally no statistically significant
  differences were found between the ‘high’ and ‘low’ exposure regions. However,
  other genetic and environmental factors may have played a role that could not be
  accounted for.
  Two radioactive forms of radon exist that are denoted somewhat confusingly as ‘radon’ and ‘thoron’.
  In view of possible health effects – mainly lung cancer – ‘radon’ is of primary importance, although
  in the Netherlands recently the contribution of ‘thoron’ has also been investigated.83,84
* The unit of radioactivity is becquerel (Bq). 1 Bq equals one disintegration per second.
4 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 55 =================================================================

<br><br>====================================================================== Pagina 56 ======================================================================

<pre>    Regarding the exposure to radon decay products, a recent review has
summarised data from ecological and case-control studies on the association
with childhood leukaemia.88 By applying a meta-analysis, a statistically
significant increased risk for indoor radon exposure was noted for ALL and for
childhood leukaemia in general. However, the authors concluded that more
evidence is required to confirm this association.
Evaluation
The Committee concludes that the epidemiological evidence for an association
between environmental radon exposure and childhood leukaemia is limited. It is,
however, consistent with an assumed causal relationship with naturally occurring
ionising radiation exposure.
Public health relevance
For Great Britain, the contribution of natural radiation exposure to the incidence
of childhood leukaemia has been estimated at 15-20%.89-91 This estimate is based
on risk data derived from the studies on Japanese atomic bomb survivors, and
various models.72,73,92 It should, however, only be used as an indication.
Recently, a large case-control study in Great Britain supported the extrapolation
of high-dose rate risk models to protracted exposures at natural background
exposure levels.93 There appeared to be 12% excess relative risk of childhood
leukaemia per mSv of cumulative red bone marrow dose from gamma radiation,
insensitive to adjustment for socio-economic status.
    Given the similarity of exposure in Great Britain to that in Belgium and the
Netherlands, the Committee assumes that similar calculations for Belgium and
the Netherlands would lead to an estimate of the same magnitude.
Recommendations
In seeking policy measures to protect against natural radiation exposure with the
aim to reduce lung cancer, the focus has mainly been on building construction
(subsoil and crawl space ventilation) and the choice of building materials. In this
way, exposure to radon and its decay products originating from soil and building
materials may be reduced. Especially in dwellings in the south of Belgium, the
radon concentrations are relatively high. Knowing this, the Belgian authorities
have been providing information on measures that may help reduce this
exposure.86 In the north of Belgium and in the Netherlands, the possibilities for
exposure reduction are more limited, although some decrease may still be
possible by using building materials with low radium and thorium content, and
by providing adequate ventilation.94
Physical environmental factors                                                      55
</pre>

====================================================================== Einde pagina 56 =================================================================

<br><br>====================================================================== Pagina 57 ======================================================================

<pre>          Where radon is concerned, the main public health argument for taking
      measures is its impact on the occurrence of lung cancer. However, a reduction in
      exposure may also contribute to a decrease in the incidence of childhood
      leukaemia, but this would be expected to be limited.
5.1.4 Medical radiation applications
      Medical applications of ionising radiation encompass diagnostic investigation
      and therapeutic treatment. The main purpose of radiotherapy is to destroy tumour
      cells. This means that at the tumour location radiation exposures are quite high,
      amounting to equivalent doses of 10 Sv or more. Inevitably, other tissues,
      including bone marrow, are also exposed, albeit to a much lesser extent. As has
      been mentioned above, studies on therapeutic exposure have provided data about
      the relationship between ionising radiation exposure and childhood
      leukaemia.72,75
          The population exposure from diagnostic applications of imaging techniques
      has increased quite strongly.79,95,96 An important driver for the recent increase is
      the use of computed tomography (CT) scans, which, by providing three-
      dimensional images, has considerable medical advantages, but which has also
      led to an increase of exposure, in terms of the number of examinations as well as
      an in the exposure per examination as compared to classical radiography.97,98
      With new digital imaging opportunities presenting themselves (such total body
      CT, cone beam CT, hybrid technology), and given market trends, expanding use
      of CT could further increase medical exposure substantially.
          In 2009, the effective dose due to medical applications of ionising radiation
      (mainly diagnostics) was about 0.9 mSv per person per year, averaged over the
      whole population, in the Netherlands.99 As compared with 2005, the exposure
      has nearly doubled, mainly due to CT scans. In Belgium, medical radiation
      exposure was considerably higher than in the Netherlands. The corresponding
      population average effective dose was 1.7 mSv in 2003 and 1.9 mSv in 2007.100
          As radiographic exposures are not uniformly distributed over the body, the
      bone marrow equivalent dose will be different from the effective dose. However,
      the Committee considers that the numbers given above should be indicative of
      the bone marrow dose (per person per year, averaged over the whole population).
          Because of the high radiosensitivity of red bone marrow in childhood,
      prenatal exposure and postnatal exposure in the first years of life are especially
      relevant. However, exposure data, specifically for prenatal exposure, are almost
      not available.
          World-wide data collected by UNSCEAR for the period 1997-2007 resulted
      in an estimate of 3-10% of children in the age group of 0-15 years exposed to
      various radiographic examinations.101 From an analysis of Dutch insurance data,
      it may be concluded that the frequency of these examinations strongly increases
 6    Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 57 =================================================================

<br><br>====================================================================== Pagina 58 ======================================================================

<pre>with age.102 This implies that average exposures later in life are higher than those
at a younger age.
Epidemiological evidence
Epidemiological studies indicate that maternal exposure to X-rays during
pregnancy is associated with childhood leukaemia.75,76,103
    Recently, the authors of a retrospective cohort study concluded that the use of
CT scans in children and young adults (<22 years of age) may almost triple the
risk of leukaemia.104 Data on the leukaemia risk related to frequent X-ray
exposures during neonatal intensive care is lacking.
Evaluation
The Committee concludes that the epidemiological evidence on medical
radiation exposures lends support to the general conclusion that ionising
radiation may cause childhood leukaemia.
Public health relevance
Radiotherapeutic exposures of children may cause secondary cancers, including
leukaemia. As childhood cancer is relatively rare, the absolute number of cases will
be small as compared to the total number of childhood leukaemias in Belgium and
the Netherlands. From the scarce data on prenatal and postnatal (mainly diagnostic)
medical exposures, the Committee concludes that the contribution nonetheless is
relevant. However, any quantification of the risk is at present not possible.
Recommendations
Exposure to radiation for medical purposes needs to be justified, both
collectively (is the method as such justified?) and individually (is the patient’s
examination or treatment justified?). The individual justification is the primary
responsibility of the referring medical practitioner. Although clinical benefits
should outweigh the small absolute risks, radiation doses, specifically from CT
scans, ought to be kept as low as reasonably achievable (ALARA*), and
alternative procedures which do not involve ionising radiation should be
considered.104
    It is broadly accepted that medical diagnostic exposures can often be reduced
by increasing risk awareness among medical practitioners, and by applying
‘optimisation’ and diagnostic reference levels, without losing diagnostic
ALARA (As Low As Reasonably Achievable): a principle intended to guide action to reduce
exposure to harmful agents, such as ionising radiation.12
Physical environmental factors                                                          57
</pre>

====================================================================== Einde pagina 58 =================================================================

<br><br>====================================================================== Pagina 59 ======================================================================

<pre>      advantages.79,96,105-107 The Superior Health Council in Belgium suggested to
      improve risk awareness of medical staff in order to better manage the risk related
      to digital imaging.96 The Committee strongly supports this view and is of the
      opinion that it also needs to be applied with respect to prenatal and postnatal
      exposure, in view of the increased leukaemia risk*.
           First and foremost, the choice of an imaging technique is important,
      weighing the diagnostic benefits against potential harms. The use of techniques
      that do not involve ionising radiation (magnetic resonance imaging, ultrasound)
      should always be considered, especially where pregnant women, infants and
      young children are concerned. A susceptible subgroup that may require special
      attention are prematurely born children.109,110 As neonatal chest images are
      frequently required to investigate life-threatening lung diseases, optimisation in
      terms of X-ray exposure is necessary. Health care professionals may contribute
      to this cause by developing better techniques for radiology in children**.
      Furthermore, practitioners need to discuss the risks of radiation exposure with
      patients.
           To resolve gaps in knowledge, there is a need for more detailed and more
      precise data on the exposure of unborn children and infants, including subgroups
      such as prematurely born children, in order to apply dose reduction strategies for
      X-ray examinations in pregnant women and infants. In addition, research is
      needed on the biological effects of pre- and postnatal diagnostic X-ray exposure
      in general and exposures from CT scans in particular.
5.1.5 Parental occupational radiation exposure
      In various occupations workers are exposed to ionising radiation. In terms of
      average radiation exposure, the most important occupations are the nuclear
      industry (from mining to waste treatment), health care and industrial
      radiography.111 The average registered effective dose of monitored workers in
      the Netherlands in 2004 was 0.6 mSv per person.
           Although the average registered individual occupational exposure is
      generally low (an effective dose of 1 mSv or less), there are groups with much
      higher individual exposures. Examples are interventional cardiology personnel
      and groups of workers in nuclear power plants.111
           Aircraft crews have also been identified as being occupationally
      exposed.60,112-114 Depending on the nature of the flights, geographical location
      and the number of hours in the air, the increased exposure (effective dose) to
      The Committee draws attention to an initiative in a quality improvement program for CT scans in
      children, an on-line learning tool for radiologists: the ‘Image Gently’ Campaign of The Alliance for
      Radiation Safety in Pediatric Imaging.108 The Federal Agency of Nuclear Control in Belgium is a
      member of The Alliance.
 *    In 2012, the Dutch Health Inspectorate started a project on radiology in children. The aim is to
      enhance safer methods for radiological examinations in children.
 8    Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 59 =================================================================

<br><br>====================================================================== Pagina 60 ======================================================================

<pre>cosmic radiation may amount to several mSv per person per year*.115 The
average effective dose for aircraft crew members in the Netherlands in 2004 was
1.5 mSv. This is comparable to Belgium, where average values of 1.3-1.6 mSv
were established in the period from 2008 to 2010.116
     Given the established relation between exposures to ionising radiation and
childhood leukaemia and the fact that leukaemia can arise prenatally, exposure of
radiation workers was studied as a potential risk factor for the development of
childhood leukaemia in the offspring.
Epidemiological evidence
An epidemiological study on childhood leukaemia in the vicinity of the
Sellafield nuclear complex (UK) showed an association with preconceptional
occupational exposure of the fathers of children with the disease.117 The findings
were not confirmed, however, in further studies. The present consensus is that
this exposure pathway is unlikely to explain the original association between
childhood leukaemia in Sellafield and paternal preconceptional irradiation.90 In a
national record linkage case control study in the UK, excluding the Sellafield
cases, the significantly increased risk of leukaemia among children of male
radiation workers appeared not to be related to their preconception radiation
dose.118 Indeed, the association was greatest for the group with zero dose or
doses below the level of detection.
     The same study did not indicate that children of female radiation workers
have a significantly increased risk of developing leukaemia.118,119 The
Committee is not aware of other epidemiological data on childhood leukaemia in
relation to pre- and postconceptional occupational radiation exposure of women,
including aircraft crew.
Evaluation
The Committee concludes that the epidemiological evidence for an association
between parental occupational radiation exposure and childhood leukaemia is
inadequate.
Public health relevance
On a population level, the contribution of occupational exposure to the incidence
of childhood leukaemia will be quite small, because of the number of parents
involved in work where exposure occurs and due to the radiation protection
measures and the relatively low exposures.
E.g. for a return flight from Europe to Japan the effective dose is circa 0.1 mSv.
Physical environmental factors                                                     59
</pre>

====================================================================== Einde pagina 60 =================================================================

<br><br>====================================================================== Pagina 61 ======================================================================

<pre>      Recommendations
      Occupational radiation exposure of pregnant women needs to be restricted.
      According to European regulations, exposure of the foetus should be less than an
      equivalent dose of 1 mSv, and registered radiation workers are obliged to declare
      a pregnancy to their employer.112 Many employers then shift pregnant radiation
      workers to an alternate job, in which no exposure occurs.
           Because of the potential risks of radiation exposure during the first weeks of
      pregnancy, the Committee recommends radiation workers and aircraft personnel
      to also notify their employer of the intention to get pregnant. In any case,
      employers should adhere to the accepted approaches for reduction of radioactive
      exposures, such as ALARA, and employees should be aware of the relevance of
      preconceptional care.
5.1.6 Residential proximity to nuclear installations
      The possibly increased incidence of childhood leukaemia near nuclear
      installations is a recurrent social issue*.6,121 The most recent input were the
      findings in a French study that reported a possible excess risk of acute leukaemia
      in children in the close vicinity of French nuclear power plants.122
      Epidemiological evidence
      Many studies have been performed to gain clarity on the relationship between
      living near nuclear installations and childhood leukaemia. One of the reasons for
      such studies came from observing clusters of childhood leukaemia cases near
      these installations. The research hypothesis usually is concerned with
      radioactivity released into the local environment, exposure to which might lead
      to an increase in health risks in general, and to a higher cancer and leukaemia
      risk in particular.
           A recent report of the British Committee on Medical Aspects of Radiation in
      the Environment (COMARE)123 refers to two reviews124,125 that performed a
      meta-analysis by combining data from different studies. From the analysis of
      release data from nuclear power plants in the UK, France, Germany and
      Switzerland, COMARE concluded that equivalent doses related to radioactive
      releases are too low to explain a possible increase in leukaemia risk, given the
      present understanding of the biological impact of ionising radiation. It also
      rejected suggestions that the risk from exposure of the foetus to released tritium
      The issue was preceded by a debate on a fall-out related increased mortality of babies and young
      children due to the atmospheric atomic bomb tests.120 Such claims were refuted in the course of the
      years, but, with the expansion of nuclear electricity production, the discussion reignited and focused
      on childhood leukaemia.
 0    Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 61 =================================================================

<br><br>====================================================================== Pagina 62 ======================================================================

<pre>and radioactive carbon (as suggested by Fairlie126) could be much higher than
currently assumed.123
     Using the terminology the Committee has chosen in this report, COMARE
can be said to conclude that the evidence for an epidemiological association
between an increased leukaemia risk and a release of radioactivity in the local
environment is inadequate, and that the higher incidence cannot be explained by
airborne radioactive exposure. Therefore no evidence is known for a causal
relationship.
     The       German        Commission          on     Radiological      Protection
(Strahlenschutzkommission) has drawn a similar conclusion, based on the
German KiKK* study.127,128 A systematic review of French researchers was also
unable to draw a conclusion about a possible cause for the increased incidence of
childhood leukaemia sometimes observed in the vicinity of nuclear power
plants.129
     Recently, the results of an investigation into the incidence of childhood
leukaemia and thyroid cancer in Belgian communities near nuclear installations
became available.130 Results showed no increase in the incidence of acute
childhood leukaemia within a circle of 20 kilometers around five nuclear
installations, except for one. In the latter site the incidence was higher than the
national average, however based on a relatively small number of observed cases
(n=21). Dose-response analyses were hampered by the relatively large size of the
smallest administrative level at which cancer data are available in Belgium.
Therefore it was recommended to participate in international collaborative
initiatives to pool data on childhood leukaemia.
     A problem in all these investigations is that the exposure of members of the
population under study was not measured. Therefore, many studies used the
distance from a dwelling to the nuclear installation as an exposure proxy,
carrying out model calculations based on data of estimated releases of radioactivity
as declared by the operator of the installation. These usually resulted in very low
exposures. On this point, the Committee wishes to remark that the releases of noble
gases from nuclear installations may vary by more than a factor 100, and that
more or less instantaneous accidental releases of noble gases, often not registered,
may be of more importance than the average annual release reported by nuclear
installation operators. In addition, exposure quantities other than the usual
equivalent dose may be more relevant in studying an association between
childhood leukaemia and nuclear installations.
Evaluation
The Committee concludes that at present, the increased risk of childhood
leukaemia near some installations, observed in some studies, has not been
KiKK: Kinderkrebs in der Umgebung von Kernkraftwerken.
Physical environmental factors                                                       61
</pre>

====================================================================== Einde pagina 62 =================================================================

<br><br>====================================================================== Pagina 63 ======================================================================

<pre>      explained satisfactorily. Exposure to radioactive emissions seems an unlikely
      explanation, but uncertainties remain, especially with respect to the relevant
      exposure quantity and pattern.
      Public health relevance
      If there would indeed be an increased risk of childhood leukaemia when parents
      and young children live near a nuclear installation, the total number of cases in
      Belgium and the Netherlands will most likely be very small as compared to the
      total number of cases of childhood leukaemia in each country.
      Recommendations
      It is questionable whether the issue of a relationship between childhood
      leukaemia and living in the vicinity of a nuclear installation can be resolved by
      further epidemiological research, as long as meaningful exposure quantities (for
      radiation or other factors) have not been identified. Still, the Committee proposes
      to monitor the emissions of radioactive noble gases from nuclear installations,
      and to study locations that differ in the way emissions of radioactive noble gases
      are handled and locations with accidental releases of radioactive noble gases.
           It might also be helpful to pool epidemiological data on potential risk factors
      related to the vicinity of nuclear power plants at an international scale, as has
      recently been proposed on the basis of studies in France and Belgium.122,130,131 In
      any case, operators should adhere to the accepted approaches for reduction of
      radioactive emission, such as ALARA, using the best available techniques.
5.1.7 Radiation accidents
      A recent UNSCEAR report listed about 350 radiation accidents.132 The accidents
      are not limited to one sector, but occur with all applications of ionising radiation.
      Some are rather localised and involve overexposure of a few people, others may
      have impact on a much more extended scale, such as in the case of the Chernobyl
      accident in 1986.133 In addition, criminal use of radiation has been reported.
      According to UNSCEAR, medical radiation incidents and accidents might be
      underreported.
           Localised accidents leading to high radiation exposures may locally cause
      severe radiation sickness and death. In the case of accidents with a more
      extended release of radioactive substances into the environment, the exposures
      are much less, in any case at larger distances from the release point. In those
      situations, the question about a possible contribution to the incidence of
      childhood leukaemia arises. In Belgium and the Netherlands this was the case
      with respect to the Chernobyl accident.
 2    Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 63 =================================================================

<br><br>====================================================================== Pagina 64 ======================================================================

<pre>Epidemiological evidence
The consequences of the Chernobyl accident have been reviewed by UNSCEAR
several times, most recently in 2008.134 UNSCEAR concluded that
epidemiological studies among the population in the most severely contaminated
areas in the Ukraine, Belarus and Russia showed an increased incidence of
thyroid cancer, but not of other types of cancer. However, a more recent report
described an increase in childhood leukaemia cases (ALL and particularly AML)
in the most severely contaminated areas of the Ukraine.135,136 However, there is
uncertainty about the quality of the data and therefore about the magnitude of the
radiation risk.137
Evaluation
Based on an increase in childhood leukaemia cases in the most severely
contaminated areas of the Ukraine, the Committee concludes that the evidence
for an association between exposure from radiation accidents and childhood
leukaemia in general is limited.
Public health relevance
In Belgium and the Netherlands, the exposure to radioactive substances released
in the Chernobyl accident is not reflected in increased cancer risks observable
from cancer registers or dedicated epidemiological research. In low exposed
European countries such as Belgium and the Netherlands (average whole-body
dose <0.2 mSv) the attributable fraction of all leukaemia cases, including
childhood leukaemia cases, due to radiation exposure from the Chernobyl
accident has been estimated at about 0.01%.138 This is too low to be detected
epidemiologically. This study contradicts the conclusions of an earlier report that
Chernobyl fallout could well have caused a small, but significant excess of
childhood leukaemia cases in Europe, in view of the excess cases in the birth
cohort exposed in utero.139
    Looking at a population level, the Committee adheres to the view that the
impact of remote accidents where ionising radiation was released on an extended
scale, as was the case in Chernobyl, has been undetectable in Belgium and the
Netherlands. Local accidents, however, will always incur some risk, dependent
on the exposure situation.
Physical environmental factors                                                      63
</pre>

====================================================================== Einde pagina 64 =================================================================

<br><br>====================================================================== Pagina 65 ======================================================================

<pre>5.1.8 Overall conclusions and recommendations
      Conclusion
      On the basis of epidemiological and laboratory research as reviewed by
      international and national expert committees, the Committee concludes that
      prenatal and postnatal exposure to ionising radiation contribute to the incidence
      of childhood leukaemia. Because of this, the Committee considers a causal
      relation between exposures to ionising radiation and childhood leukaemia as
      established.
          In addition, the Committee supports the view expressed by several
      multidisciplinary Committees of scientists that this holds for all types of ionising
      radiation, and that there is no exposure threshold below which an increase in
      leukaemia risk is absent.59,60,73,78,79
          Of the specific exposure situations considered, the Committee believes that
      exposure to natural radiation may provide a non-negligible contribution to the
      incidence of childhood leukaemia. Exposure for medical reasons and the
      projected increase in this area, especially from CT scans for diagnostic purposes,
      is a specific matter of concern. Other widespread types of exposures, e.g. those
      of pregnant passengers and young children during flights, are thought to
      contribute only marginally to the risk of childhood leukaemia, both individually
      and on a population level.
      Recommendations
      Despite the overall risks being small, exposure reduction is warranted in the
      medical as well as in the environmental and occupational fields, not only to
      reduce childhood leukaemia, but also to reduce the occurrence of other adverse
      health effects.
          The possibilities for the reduction of exposure to ionising radiation will vary
      in different situations, and will also vary in Belgium and the Netherlands.
      Notwithstanding the large uncertainties, the contributions of natural and medical
      sources of ionising radiation exposure are the most relevant, and a reduction in
      the exposure to these sources may be expected to decrease the risks. Effective
      ways to achieve this may be: stricter justification standards and optimisation
      procedures for medical exposures, further reduction of emissions from nuclear
      installations and continuing or intensifying radon reduction programmes. The
      Committee emphasises that exposure reduction is not only important for
      leukaemia, but also for other forms of cancer and other diseases associated with
      exposure to ionising radiation.
 4    Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 65 =================================================================

<br><br>====================================================================== Pagina 66 ======================================================================

<pre>5.2 Extremely low-frequency (ELF) magnetic fields
    Exposure to ELF magnetic fields is highly dependent on location and time.
    Major indoor sources are the indoor electricity system and electrical appliances.
    Magnetic fields are only generated when current flows, and their strengths are
    therefore directly dependent on appliance use. The fields decrease in general
    with the square or the 3rd power of distance, so the magnetic field strength may
    vary considerably over short distances.
         The primary external source in Belgium and the Netherlands are overhead
    high voltage power lines. Their contribution to total exposure is relevant within a
    distance of up to approximately 150 m from the line, and also depends on the
    amount of current transported and the voltage on the line. Since the first report
    suggesting an association between living in the vicinity of power lines and
    childhood leukaemia was published in 1979, dozens of increasingly sophisticated
    studies have examined the possible association with exposure to ELF magnetic
    fields.140
    Evidence
    Based on consistent associations found in individual epidemiological studies and
    the results from two pooled analyses, in 2002 IARC classified ELF magnetic
    fields as ‘possibly carcinogenic to humans’ (group 2B: see Annex F).140 In 2007,
    a WHO expert task group concluded that consistent epidemiological evidence
    suggests that chronic exposure to low-intensity ELF magnetic fields (≥0.4 μT* as
    compared to <0.1 μT) is associated with an increased risk of childhood
    leukaemia.18 Both major reviews were taken into account in both Evidence
    Summaries of systematic reviews.213,225 A drawback of both reviews, however,
    is that the residential exposure to ELF magnetic fields was not defined uniformly.
    It varied from 24-hour or instantaneous measurements in one or more rooms,
    distance and relative load for power lines to exposure from different electrical
    appliances.18,140
         The results of a more recent pooled analysis by Kheifets et al. of seven
    studies published since 2000 are in line with the outcomes of previous pooled
    analyses, which showed an association between measured or calculated magnetic
    fields and childhood leukaemia in general.141 The association seems weaker in
    the most recently conducted studies, but these are small and lack the
    methodological improvements needed to clarify the apparent association.
         Although some experimental studies report effects of ELF on mutation
    frequency and gene expression, the WHO task group concluded that there is
    limited evidence for a causal relation.18
    The strength of magnetic fields is expressed in the magnetic flux density in microtesla (μT).
    Physical environmental factors                                                                65
</pre>

====================================================================== Einde pagina 66 =================================================================

<br><br>====================================================================== Pagina 67 ======================================================================

<pre>  Evaluation
  Many epidemiological studies have focussed on the association between
  residential exposure to ELF magnetic fields from power lines or electric
  appliances and childhood leukaemia. Most of these have considered childhood
  leukaemia in general; consequently separate information on ALL and AML is
  very limited. Since more than 80% of childhood leukaemia is ALL, the
  Committee considers the association to be applicable to this most common form,
  although it cannot be ruled out that the association could be due to a combination
  of selection bias and confounding.14,142 Therefore, the Committee considers the
  epidemiological evidence for an association between exposure to ELF magnetic
  fields and ALL (and childhood leukaemia in general) sufficient, whereas for
  AML it is characterised as inadequate.
      The epidemiological findings are insufficiently supported by results from
  experimental studies and by mechanistic insights into causality, which means
  that the plausibility of there being a biological mechanism should be considered
  low.
      Based on the available evidence from these two types of research, the
  Committee considers a causal relation between exposure to ELF magnetic fields
  and ALL or childhood leukaemia in general as possible, whereas the existence of
  a causal relation between ELF magnetic fields and AML is unknown.
  Public health relevance
  The number of children exposed to ELF magnetic field levels above which an
  increased risk of childhood leukaemia is observed in epidemiological studies
  (exceeding 0.4 µT) is small. A survey in Belgium indicated that the prevalence of
  children exposed to at least 0.4 µT is approximately 1.4% for modelled exposure
  from overhead power lines and 4% for measured exposures from power lines and
  other sources.143
      No such data are available for the Netherlands. For the Netherlands it was
  calculated in 2003 that approximately 11,100 children live in areas near overhead
  high power lines where the magnetic field strengths exceed 0.4 µT.144 Assuming
  a total number of children up to age 15 of approximately 3 million, the exposure
  prevalence in the Netherlands is approximately 0.4%.144,145 Ahlbom et al.
  calculated a relative risk for exposure levels of at least 0.4 µT, compared to levels
  of less than 0.4 µT, of 2.00 (95% confidence limits 1.27-3.13).146
      Combining these data into the formula given in section 2.3 of this report
  results in a population attributable fraction (PAF, expressed as a percentage) for
  Belgium of 1.38 (0.38-2.90)% for modelled and 3.85 (1.10-7.85)% for measured
  exposures and for the Netherlands a PAF of 0.40 (0.11-0.84)% for modelled
  exposures (measured exposures not available). The maximum additional
6 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 67 =================================================================

<br><br>====================================================================== Pagina 68 ======================================================================

<pre>    individual risk to develop leukaemia for children in the Netherlands was found to
    be 3x10-5 per year.144,145
         Considering that an incidence of 3.8 per 100,000 was used, these data pertain
    to ALL only. This means that, if a causal relation exists, and given a total of
    approximately 110 new ALL cases each year, the number of extra cases of ALL
    attributed to magnetic exposures from high voltage power lines in the
    Netherlands is estimated at 0.4-0.5 per year.144
    Recommendations
    If the relation between exposure to ELF magnetic fields and childhood
    leukaemia would be causal, its impact is likely to be small at the level of the
    general population. However, in situations where children are long-term exposed
    to magnetic fields exceeding approximately 0.4 µT it might be relevant. This
    warrants taking precautionary measures for these high-risk groups to reduce
    exposures.8
5.3 Radiofrequency radiation
    In the past decades, exposure of the population to radiofrequency
    electromagnetic fields (RF EMF) has been ubiquitous. Radio- and television
    transmitters have increased in number and become more powerful. The rise of
    mobile telephony has added another layer of RF EMF to society. Several studies
    have investigated a possibly increased incidence of childhood leukaemia near
    sources of RF EMF.
    Evidence
    No systematic reviews on the association between radiofrequency radiation and
    childhood leukaemia have been identified. Individual studies are all hampered by
    difficulties in assessing the exposure. This is especially problematic since
    exposure is highly variable, depending on frequencies and types of signals.147
         In its 2005 Electromagnetic Fields Annual Update, the HCN discussed the
    available epidemiological studies on cancer incidence near radio and television
    transmitters.148 Several included childhood leukaemia. The HCN concluded that
    the overall picture emerging from these studies shows that there is insufficient
    evidence to establish an association between living in the immediate vicinity of a
    radio or television transmitter and increased risk of leukaemia or any other form
    of cancer.148
         A more recent case-control study found no association between childhood
    leukaemias (and other early childhood cancers) and the estimated RF exposure
    from mobile telephone base stations of the mothers during pregnancy.149
    Physical environmental factors                                                     67
</pre>

====================================================================== Einde pagina 68 =================================================================

<br><br>====================================================================== Pagina 69 ======================================================================

<pre>        Recent reviews of experimental studies indicate a low plausibility for a
    causal relation.150,151
        Based on indications for an increased risk for glioma, a malignant type of
    brain cancer, associated with mobile phone use, in 2011 IARC has classified RF
    EMF as ‘possibly carcinogenic to humans’ (group 2B).152 Data on childhood
    leukaemia were not provided.
    Evaluation
    There is inadequate epidemiological evidence that pre- or postnatal exposure to
    RF EMF does increase the risk of childhood leukaemia, and the plausibility of a
    causal biological mechanism is low. The Committee therefore considers the
    existence of a causal relation between exposure to RF EMF and childhood
    leukaemia to be unknown.
    Recommendations
    Since the general trend is likely one of increasing exposures, more insight in
    actual exposures is recommended. Further research on the potential association
    between RF EMF and childhood leukaemia is not considered to be a high
    priority.
5.4 Diagnostic ultrasound scans during pregnancy
    Ultrasound is a commonly used imaging modality during pregnancy, and is
    generally regarded as safe to the foetus.153 Current ultrasound technology,
    however, has a significantly higher output potential than the older machines used
    in most clinical studies, and the safety profile of the increasingly frequent use of
    Doppler, 3-dimensional (D) and 4-D ultrasound with modern machines is
    unknown. Since ultrasound is a form of energy, it has the potential to produce
    biological effects that may constitute a risk for health.154 Prenatal diagnostic
    ultrasound scans are increasingly used during pregnancy.153 In the Netherlands, a
    routine ultrasound scan is offered to all pregnant women in the first and the
    second trimester of the pregnancy, the latter having been added in 2006.155 In
    Belgium, three standard ultrasound scans are offered per pregnancy. Ultrasound
    exposure of the mother has also been investigated as a possible causal factor for
    childhood leukaemia.
    Evidence
    Information on the possible effects of ultrasound exposure in utero on the
    incidence of ALL or AML is not available, and the systematic analysis identified
    only three studies on childhood leukaemia in general.156 Neither higher or lower
 8  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 69 =================================================================

<br><br>====================================================================== Pagina 70 ======================================================================

<pre>risks were observed. A more recent systematic review carried out by the WHO
concluded that ultrasound in pregnancy was not associated with childhood
leukaemia nor with other adverse health effects.154 In a recent case-control study,
logistic regression models which adjusted for maternal age and child's birth
weight also showed no evidence of increased risk of childhood cancer due to in
utero exposure to ultrasound scans.157
    Experimental evidence has shown that ultrasound is capable of inducing
double strand breaks in DNA, but this only occurs only at higher energy levels
than the ones used in diagnostics.158
Evaluation
Considering the available diagnostic imaging techniques, ultrasound offers the
best possibilities to reduce exposure to medical ionising radiation. According to
the epidemiological evidence, exposure to diagnostic ultrasound during
pregnancy appears to be safe. However, new experimental data indicates that
DNA can be mechanically damaged, albeit at higher levels than used in
diagnostic ultrasounds.
    The available epidemiological data does not support a potential causal
relation between the current diagnostic ultrasound exposure and the risk of
childhood leukaemia, neither does the scarce experimental data (only available at
higher energy levels than used in diagnostics). Therefore, the Committee
considers a causal relation between the limited exposures to routine diagnostic
ultrasounds and childhood leukaemia unlikely. Ultrasound exposure can be
assumed to rise, both in frequency and in level. Whether a causal relation may
exist between more frequent and higher level exposures and childhood
leukaemia is unknown.
Recommendations
Since ultrasound scans are offered to all pregnant women in the first and second
trimester of pregnancy, exposure is very common. Since technical developments
may be expected to result in higher exposure levels, possible adverse effects of
more intensive or frequent ultrasound scans, e.g. following in vitro fertilisation
(IVF), warrant further research, and the recommendation that ultrasound scans
should not be offered without medical indication.
Physical environmental factors                                                      69
</pre>

====================================================================== Einde pagina 70 =================================================================

<br><br>====================================================================== Pagina 71 ======================================================================

<pre>0 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 71 =================================================================

<br><br>====================================================================== Pagina 72 ======================================================================

<pre>6   Chemical environmental factors
    In this chapter the role of chemical risk factors on the induction and development
    of childhood leukaemia is evaluated. These include pesticides, benzene, organic
    solvents other than benzene, arsenic in drinking water, parental tobacco smoking,
    parental marijuana smoking, parental alcohol consumption, maternal intake of
    cured meat, and other chemicals.
6.1 Pesticides
    ‘Pesticides’ is a generic term used for a great number of chemical preparations.
    Over the last decades, several hundreds of pesticides have been marketed for
    agricultural or domestic use. They consist of biologically active ingredients
    commonly used to control unwanted organisms in agricultural and residential
    (indoor or outdoor) environments, and are grouped or classified according to the
    pests they control (i.e. insecticides, herbicides, fungicides, rodenticides), their
    application (plant protection products or biocides), their chemical structure
    (organic or inorganic), how/when they work (i.e. contact, systemic, residual, etc.)
    or their mode/site of action (i.e. inhibitors of acetyl CoA carboxylase, inhibitors
    of acetyl cholinesterase, etc.).
        Pesticides are widely used: they protect agricultural crops against disease and
    infestation, they remove weeds from pavements, and they combat vermin in and
    around homes. They may, however, also be harmful to other than the target
    organisms. And they may have unwanted effects on human health. Some
    pesticides can cause short-term (acute) as well as long-term (chronic) adverse
    effects, including cancer. There are three main routes of exposure to pesticides:
    oral, dermal, and inhalation.
    Pesticide exposure
    Given their widespread use, pesticides are ubiquitously present in our
    environment and humans are inevitably exposed: the general population (adults
    and children) come into contact with the residues of pesticides in air, water and
    food, and occupational groups may be exposed at all stages of pesticide
    formulation, manufacturing, application or re-entry. The level, however, varies
    according to the patterns of exposure. Individuals who personally apply
    pesticides in agricultural, occupational or residential settings are likely to
    experience the highest levels, whereas indirect exposure to residues of pesticides
    Chemical environmental factors                                                      71
</pre>

====================================================================== Einde pagina 72 =================================================================

<br><br>====================================================================== Pagina 73 ======================================================================

<pre>  through drinking water, air, dust and food is likely to result in low-level
  exposures.159
       Exposure scenarios vary greatly among groups and across the world. Low
  amounts of pesticides (residues) can remain in or on a crop after harvesting or
  storage and make their ways into the food chain. That is why they are only
  allowed onto the market after an extensive safety assessment.160 In many
  countries, Belgium and the Netherlands included, accepted levels of residues in
  food are controlled by regulatory bodies.
       A recent study, based on the 2008 surveillance data of the Belgian Federal
  Agency for the Safety of the Food Chain, has demonstrated that for most of the
  pesticide residues in fruits and vegetables, the chronic exposure of the adult
  population is 100 times lower than the ‘acceptable daily intake’ (ADI)*. With
  regard to children, however, there are indications that for some pesticides** the
  ADI can be exceeded.161
       Children can be exposed to pesticides from various sources: indirectly via
  parental (occupational) exposure, but also directly via residential exposure, e.g.
  from indoor use (biocides in homes, schools or other buildings), from outdoor
  use (garden, playing areas/public lands, agricultural application drift, overspray
  or off-gassing), through residues in food and drinking water, by handling pets
  treated or contaminated with biocides or other pesticides, or by other routes (e.g.
  through the use of insecticidal shampoos for lice infestation).162 Three critical
  time windows of exposure are relevant to the effects of pesticides in children:
  exposure of the parents prior to conception, exposure of the mother during
  pregnancy, and exposure of the child after birth.
       Pesticides have been particularly scrutinised as potential aetiological factors
  in childhood leukaemia.9,163-165 Discrepancies among epidemiological studies
  have made it especially important to conduct systematic reviews and meta-
  analyses.166-170 In the following sections the Committee provides a brief
  overview of these reviews.
  Epidemiological evidence on parental occupational exposure
  Indirect exposure of children through occupational exposure to pesticides by
  adults in the reproductive age may substantially exceed the exposures from other
  sources.166
       Systematic reviews, one included in the CCG Evidence Summary166 and one
  published later168, indicate increased risks for ALL, AML and childhood
  leukaemia in general following prenatal maternal occupational exposure to
  pesticides, although not reaching statistical significance for ALL in one
  review.168 The associations with paternal occupational exposure to pesticides
  ADI: measure of the amount of a specific substance in food or drinking water that can be ingested on
  a daily basis over a lifetime without an appreciable health risk.
* For genotoxic carcinogens no ADI can be derived.
2 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 73 =================================================================

<br><br>====================================================================== Pagina 74 ======================================================================

<pre>before conception were weaker, and no significantly increased risks were
observed for ALL, AML or childhood leukaemia in general.
     A third more recent meta-analysis observed different results, as paternal
exposure was associated with a significantly increased risk of childhood
leukaemia.170 However, these results have to be viewed with caution, since
several overlapping datasets were included. Therefore, the results cannot be
reasonably compared with those of the other meta-analyses*.
Epidemiological evidence on residential exposure
Residential pesticide use, defined as indoor or outdoor domestic use of
pesticides, is associated with elevated exposure of children.167 Systematic
reviews, one included in the CCG Evidence Summary and one published later,
investigated residential pesticide exposure during the three critical time
windows: preconception, pregnancy and childhood.167,169 Studies on the
proximity to agricultural activities were not included in these meta-analyses.
     Significantly increased risks associated with exposure during pregnancy
were observed for ALL in both reviews, and for AML in one review.169 During
childhood no significantly increased risks for ALL and AML were found.
However, both reviews did report statistically significant associations between
childhood leukaemia in general and exposure during pregnancy, as well as during
childhood.167,169
     A third more recent meta-analysis reported significantly increased risks for
childhood leukaemia in general connected with parents’ use of pesticides in the
home or garden.170 This is in agreement with the results of the two earlier
systematic reviews.
     As in the previous section, however, the Committee considers that these
results need to be viewed with caution, since several overlapping datasets were
included and the results therefore cannot be reasonably compared with those of
the other meta-analyses.
     One more systematic review investigated whether professional pesticide
treatments (i.c. pest control) in or around the home before birth or during
childhood increased the risk of childhood ALL.171 An increased risk of
borderline statistical significance was observed when pesticide treatment was
applied during pregnancy. The results for treatments carried out between birth
and diagnosis were similar, and slightly lower.
Some methodological aspects of this meta-analysis are of questionable value: the authors have
extracted several risk estimators (and variances) from each individual study, rather than one estimator
per study, to compute the summary effects in the meta-analyses.163 This renders it impossible to
rigorously compare the results with those of the other meta-analyses.
Chemical environmental factors                                                                          73
</pre>

====================================================================== Einde pagina 74 =================================================================

<br><br>====================================================================== Pagina 75 ======================================================================

<pre>  Other evidence
  In 1991, IARC evaluated the carcinogenic risk to humans posed by occupational
  exposure during the spraying and application of insecticides, on the basis of the
  epidemiological and experimental studies.172 The volume also features separate
  monographs evaluating the carcinogenicity of 17 individual pesticides, including
  several that have been banned by industrialised countries, but that are still in use
  in the developing world. Although some of these pesticides have been applied for
  more than four decades, evaluations of carcinogenicity were hindered by the
  scarcity of well-designed epidemiological studies.
       The first and most extensive monograph was dedicated to an evaluation of
  data from various epidemiological studies suggesting an increased risk of cancer,
  most notably lung cancer, multiple myeloma and other tumours of B-cell origin
  in workers exposed to insecticides during their application. On the basis of this,
  IARC concluded that the spraying and application of non-arsenical insecticides
  entail exposures that are ‘probably carcinogenic to humans’.
       In the remaining monographs an evaluation was carried out of the
  carcinogenicity of aldicarb, atrazine, captafol, chlordane, DDT, deltamethrin,
  dichlorvos, fenvalerate, heptachlor, monuron, pentachlorophenol, permethrin,
  picloram, simazine, thiram, trifluralin, and ziram*. Of these, captafol, a fungicide
  used on plants for seed treatment and as a wood preservative, was classified as
  ‘probably carcinogenic to humans’. Atrazine, chlordane, DDT, dichlorvos,
  heptachlor and pentachlorophenol were classified as ‘possibly carcinogenic to
  humans’ (see Annex F). The remaining pesticides could not be classified on the
  basis of available data. Among these are deltamethrin, picloram, thiram and
  ziram, which are still approved in EU countries.
       More recently, several pesticides appeared to be able to change gene
  expression through a broad array of gene regulatory mechanisms, including
  regulation of gene translocation, DNA methylation or DNA repair.173
  Causality considerations
  As there is a lot of controversy and debate with regard to the role of pesticide
  exposure in childhood leukaemia, and the available information appeared to be
  not unequivocal, the Committee followed explicitly the well-established
  Bradford Hill considerations to evaluate, as objectively as possible, the available
  scientific evidence that pesticide exposure may cause childhood leukaemia (see
  also Annex E).14,15
       Strength. Inherent to most environmental factors, the observed associations
  between pesticide exposure through parental occupational exposure or
  Of these, aldicarb, atrazine, captafol, chlordane, DDT, dichlorvos, fenvalerate, heptachlor, monuron,
  pentachlorofenol, permethrin, simazine and trifluralin are no longer approved in EU countries.
4 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 75 =================================================================

<br><br>====================================================================== Pagina 76 ======================================================================

<pre>residential exposure and childhood leukaemia were mostly weak and only barely
significant.
    Consistency. Although all meta-analyses showed a tendency toward
increased risk (except in the case of paternal occupational exposure and AML),
discrepancies were observed in statistical significance. This might argue against
a causal relationship. For childhood leukaemia in general, the statistically
significant associations with pesticide exposure during pregnancy (via maternal
occupational or residential exposure) observed in the different meta-analyses
tends to support a causal relationship. It has to be stressed, however, that the
individual studies included in the different meta-analyses are largely the same
ones, and the consistency in the results is therefore not surprising.
    Specificity. The ability to associate specific pesticide exposures with specific
childhood cancers is limited by both the low prevalence of childhood cancer and
the imprecise exposure assessment. The aetiology of childhood leukaemia is
likely multifactorial, resulting from the effect of either genetic or environmental
factors, and, probably, from their interaction. Conversely, pesticide exposure is
not uniquely associated with childhood leukaemia.
    Temporality. While it is obvious that, given a causal relationship, an exposure
to a risk factor should occur before childhood leukaemia develops, it is not clear
in which time window it would exert its causative action: prior to conception,
during early, mid or late pregnancy or during childhood. However, maternal
exposure to pesticides during pregnancy appears to be more consistently
associated with childhood leukaemia than exposures during childhood.
    Biological gradients. Many of the epidemiological studies did not attempt to
assess cancer risks in response to increasing frequency or intensity of pesticide
exposures. However, some authors tried to establish an exposure-response-like
relationship between residential exposure to pesticides and childhood leukaemia
in general.169 Although they showed that, in most cases, the risk of leukaemia is
increased with frequency of use, these observations provide only weak additional
support to the suspicion of a positive exposure-response relationship between
pesticide exposure and childhood leukaemia.
    Plausibility. Pesticides are biologically active molecules that may play some
role in cancer aetiology. The US Environmental Protection Agency (EPA) and
other national and international bodies have identified about 165 active
ingredients of pesticides as known, probable or possible human carcinogens,
many of which have been banned or restricted.174
Evaluation
Due to limitations in the available research, including questions regarding
exposure assessment and exposure-response, the epidemiological evidence that
parental occupational and residential exposure to pesticides is associated with an
Chemical environmental factors                                                       75
</pre>

====================================================================== Einde pagina 76 =================================================================

<br><br>====================================================================== Pagina 77 ======================================================================

<pre>   increased risk of childhood leukaemia in general is classified as limited. The
   most consistent evidence is for maternal exposures during pregnancy.
        In spite of the scarcity of specific data on ALL, the Committee still considers
   the evidence for this type of leukaemia to be limited, as it is by far the most
   common type of leukaemia in children and data for leukaemia in general are
   heavily weighted towards ALL. It would therefore be unrealistic to conclude
   differently for leukaemia in general and for ALL.
        The evidence regarding AML, on the other hand, is inadequate. The
   available studies are scarce, and some are of insufficient quality to allow for a
   robust conclusion on causality. In addition, the epidemiological evidence is
   based on data from case-control studies with, in most cases, poor characterisation
   of exposure. Chance, bias or confounding cannot be ruled out with reasonable
   confidence. Since several pesticides have been classified as known, possible or
   probable* human carcinogens**, causal relations with (past) exposures to
   (mixtures of) pesticides are moderately to highly plausible.
        Based on the available evidence, which is scarcer for ALL and AML than for
   childhood leukaemia in general, the Committee considers a causal relation
   between exposure to pesticides and childhood leukaemia in general and ALL
   possible to likely, and a causal relation between exposure to pesticides and AML
   uncertain to possible. The Committee does not rule out that past exposure to
   specific (classes of) pesticides might play a greater role in the development of
   childhood leukaemia than others.
   Public health relevance
   Population attributable fractions (PAF) have been calculated for maternal
   occupational exposures during pregnancy***, ranging from 1% (for all types) to
   4% (for ALL) and 5% (for AML). Residential exposures have been calculated to
   account for 17% (in the case of ALL), 25% (for all types), and 26% (for AML).
   This indicates that especially residential exposures are relevant, provided the
   relation with childhood leukaemia can be considered causal.
   Recommendations
   The Committee recommends reducing parental, and particularly maternal,
   occupational exposure to pesticides. Also, it recommends the monitoring of
   pesticide exposures among occupationally exposed women, at least of
   Probable carcinogen (US EPA classification) or ‘presumed’ carcinogen (EU classification).
*  ‘Known’ and ‘presumed’ carcinogenic pesticides will no longer be approved in EU countries.
** Personal communication Van Maele-Fabry 2011: For occupational exposure, the data from the
   systematic review of Wigle et al. were used for ALL and AML (based on 1213 cases and 674
   controls); for all types of leukaemia and for residential exposure, the data from the systematic review
   of Van Maele-Fabry et al. were used (based on 3386 controls).166,168,169
6  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 77 =================================================================

<br><br>====================================================================== Pagina 78 ======================================================================

<pre>    reproductive age, incorporating biomarkers of exposure whenever feasible. In
    general the Committee advocates preventive actions, including education and
    counselling, focused specifically on women of childbearing age, resulting in
    more risk awareness previous to intended conception. Furthermore, limiting the
    use of pesticides or biocides for residential purposes is recommended, in order to
    keep the exposure of pregnant women and young children as low as possible.
        The possibility of simultaneous exposure to several pesticides with a
    common mechanism of toxicity and of simultaneous exposure to the same
    compounds from various sources, including food, merits systematic attention in
    the risk assessment of individual pesticides.160 Finally, the Committee
    recommends to include young children in risk assessments.
6.2 Benzene
    Benzene is a frequently used organic solvent and a component of gasoline,
    ubiquitously present in the environment, although in general in relatively low
    concentrations. In epidemiological studies occupational exposure to benzene has
    been associated with adult AML.175 To a lesser extent associations have been
    found between environmental exposure situations and childhood leukaemia.
    Evidence
    Evidence for an association between benzene exposure and childhood leukaemia
    is accumulating. Multiple epidemiological studies have shown an increase in
    childhood ALL, and particularly in AML, nearby air pollution sources emitting
    benzene, such as gas stations and traffic.176,177 However, the available reviews
    present different conclusions regarding environmental exposures.
        IARC classifies benzene as ‘carcinogenic to humans’.178 This classification
    has been primarily based on the relation with adult AML found in occupational
    epidemiological studies. Although leukaemia in children (predominantly ALL)
    undoubtedly has some biological characteristics that differ from leukaemia
    occurring at a later age (predominantly AML), the pattern of ‘microdeletions’ of
    relevant genes in adult and adolescent leukaemia sufficiently resembles that in
    childhood leukaemia to suggest that, genetically speaking, adult, adolescent and
    childhood cases may be more similar than previously thought.179
        Benzene may be leukaemogenic through genotoxic, epigenetic and other
    gene-regulatory mechanisms. It induces chromosomal abnormalities, epigenetic
    modifications, including changes in DNA methylation of genes related to
    carcinogenesis, which lead to changes in gene expression. Moreover, benzene
    has been observed to cause haematotoxic effects and to activate cell-cycle-
    regulating genes, resulting in compensatory formation of white blood cells.180
    These haematotoxic properties of benzene are also suggestive of leukaemogenic
    effects.175,180
    Chemical environmental factors                                                     77
</pre>

====================================================================== Einde pagina 78 =================================================================

<br><br>====================================================================== Pagina 79 ======================================================================

<pre>        More recently gained mechanistic insights lend support to the potential
    associations between benzene exposure and childhood leukaemia.176
    Evaluation
    The few available data from epidemiological studies on the relation between
    exposure to benzene and childhood leukaemia are not consistent, in part due to
    insufficient exposure data. However, the data on adult leukaemia do show
    consistent associations between occupational exposure to benzene and
    leukaemia, especially AML. Recently supporting mechanistic evidence has also
    become available.
        Overall, the Committee considers the epidemiological evidence for an
    association of exposure to benzene and childhood leukaemia to be limited, and
    the biological plausibility of causality to be high. The Committee therefore
    considers a causal relation between exposure to benzene and childhood
    leukaemia to be likely.
    Recommendations
    In order to obtain more solid evidence on the possible causal relation between
    exposure to benzene and childhood leukaemia, targeted monitoring studies
    should be performed in situations where exposure may occur. In the meantime,
    the available evidence warrants taking measures to limit or prevent exposure of
    children and pregnant women to benzene. In particular counseling previous to
    intended conception may improve risk awareness of traffic exposures and other
    sources of benzene exposure of pregnant women and children.
6.3 Organic solvents other than benzene
    Organic solvents are commonly used, for instance in gasoline or indoors as a
    paint thinner or in chipped wood (i.c. formaldehyde). This is a very broad
    category. For most solvents no information on possible effects on childhood
    leukaemia is available, therefore only some examples can be discussed.
    Evidence
    For a number of specific solvents epidemiological evidence is available that they
    might contribute to the risk of childhood leukaemia.181-183 In a study among
    children with ALL, 15.2% showed specific genetic mutations that were related to
    maternal exposure to solvents.184 However, a more recent review concluded that
    there is no consistent support for the claim that parental exposure to solvents and
    petroleum-based hydrocarbons is a causative factor in the development of
    childhood ALL or AML.177
 8  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 79 =================================================================

<br><br>====================================================================== Pagina 80 ======================================================================

<pre>    For several other substances (including styrene and formaldehyde), only
associations have been reported between adult exposures and adult
leukaemia.185-188
    In 1989, IARC classified diesel engine exhaust as ‘probably carcinogenic to
humans’ and gasoline engine exhaust as ‘possibly carcinogenic to humans’.178
Petroleum solvents were considered as ‘not classifiable as to their
carcinogenicity to humans’. Occupational exposure as a painter was classified as
‘carcinogenic to humans’. However, occupational exposure in paint manufacture
was considered as ‘not classifiable as to its carcinogenicity to humans’.
    Formaldehyde is an established human carcinogen178, known to induce
chromosomal abnormalities in blood cells.189 Styrene is classified by IARC as a
‘possibly carcinogenic to humans’178 and is associated in many epidemiological
studies with cancers of the blood-forming organs and the lymphoid system in
adults.190 These substances might therefore potentially contribute to an increased
risk of childhood leukaemia.
Evaluation
The Committee considers the available evidence from epidemiological studies
inadequate as a basis for any conclusion on a relation between exposure to
organic solvents other than benzene and childhood leukaemia. Without
experimental data, it therefore considers a causal relation between most organic
solvents and childhood leukaemia as unknown.
    Since specific organic solvents such as styrene and formaldehyde have been
classified respectively as ‘possibly and established carcinogenic’, the Committee
considers the plausibility of a causal relation with childhood leukaemia for these
solvents respectively as moderate and high. Therefore, the Committee considers
a causal relation with exposure to specific organic solvents such as styrene and
formaldehyde respectively as uncertain and possible.
    Based on IARC evaluations, the Committee considers a relation with
exposure to engine exhausts as moderately to highly plausible and occupational
exposure to paints as highly plausible. Therefore she considers a causal relation
with childhood leukaemia for engine exhausts uncertain to possible and for
occupational exposure to paints as possible.
Recommendations
The application of volatile organic compounds with carcinogenic properties,
such as styrene and formaldehyde, in materials commonly encountered in the
living environment should be avoided. Reducing exposures to solvents, for
instance during painting indoors, might also be beneficial for the prevention of
other adverse health effects. In view of the scarcity of adequate information,
there is a need for both epidemiological and experimental studies into the
Chemical environmental factors                                                     79
</pre>

====================================================================== Einde pagina 80 =================================================================

<br><br>====================================================================== Pagina 81 ======================================================================

<pre>    relation between commonly encountered organic solvents and childhood
    leukaemia.
6.4 Arsenic in drinking water
    Arsenic is widely occurring both naturally and as a result of human activity. Food
    is the main source of exposure for the general population in Europe.191 Inorganic
    arsenic is produced primarily as a by-product from metal smelting processes.192
    Up to 70% of global arsenic production is used in the industrial preservation of
    wood, as chromated copper arsenate (CCA).
         Arsenic combines with oxygen, chlorine, and sulphur to form inorganic
    arsenic compounds, which are more toxic. Inorganic arsenic compounds have
    been found as contaminants of drinking water worldwide. They enter drinking
    water supplies from natural deposits in the earth or from agricultural and
    industrial practices. Arsenic has been found to cross the placenta, and can cause
    foetal toxicity.193
         The Joint FAO/WHO Food Standards Programme Codex Committee on
    contaminants in food has noted that drinking water is a major contributor to total
    inorganic arsenic dietary exposures and, depending on the concentration, can
    also be an important source of arsenic in food, through food preparation and
    possibly irrigation of crops.194 For certain regions in the world, where
    concentrations of inorganic arsenic in drinking water are above the WHO
    guideline value of 10 μg/l, the FAO/WHO Committee has remarked that there is
    a possibility that adverse effects could occur. The provisional guideline value for
    a ‘safe limit’ for arsenic in drinking water has been adopted as a national
    standard worldwide, including the European Union.
         Arsenic has been shown to cause cancer in human beings (e.g. lung, skin,
    bladder), but few studies have been conducted to assess whether arsenic
    exposure is also a risk factor for childhood cancers.195
    Evidence
    In two reviews, including one identified in the CCG Evidence Summary, no
    statistically significant increased risks for childhood ALL were observed in
    relation to high levels of arsenic in drinking water.195,196
         IARC classifies arsenic and inorganic arsenic compounds as ‘carcinogenic to
    humans’.178
    Evaluation
    The Committee concludes that there is inadequate epidemiological evidence that
    exposure to inorganic arsenic compounds in drinking water is associated with an
    increased risk of childhood leukaemia. Since arsenic and inorganic arsenic
 0  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 81 =================================================================

<br><br>====================================================================== Pagina 82 ======================================================================

<pre>    compounds have been classified as carcinogenic, the biological plausibility for
    causality is considered high, however. As a consequence, the Committee
    considers a causal relation between exposure to inorganic arsenic compounds in
    drinking water and childhood leukaemia possible.
    Public health relevance
    In view of the ubiquitous potential of exposure to inorganic arsenic compounds
    by ingestion of drinking water, the relevance to public health is obvious. Even
    when the concentrations remain below the levels recommended by WHO, the
    resulting health problems are not negligible.197 However, due to a lack of data the
    effect on childhood leukaemia cannot be estimated.
    Recommendations
    The Panel on Contaminants in the Food Chain (CONTAM Panel) has
    recommended that exposure to inorganic arsenic should be reduced.191 The
    Committee endorses this recommendation. If this general recommendation is
    followed, there is no need for further studies on a possible relation between
    exposure to arsenic and childhood leukaemia.
6.5 Parental tobacco smoking
    Another chemical factor that may enhance the risk of childhood leukaemia is
    parental tobacco smoking. The effects of passive smoke on cancers other than
    lung cancer are, however, still a matter of discussion.198
    Evidence
    A meta-analysis identified in the CCG Evidence Summary studying the
    association between the amount of parental tobacco smoking and childhood
    cancers showed inconsistent results with respect to risks for ALL and AML.198 A
    more recent meta-analysis observed an increased cancer risk for any paternal
    smoking around the time of the child’s conception and for smoking more than 20
    cigarettes per day around that time.199 As most studies of maternal smoking
    during pregnancy have reported no increased risks for the occurrence of
    childhood cancers, a meta-analysis for maternal smoking was not conducted.
        IARC has classified (second-hand) tobacco smoke as ‘carcinogenic to
    humans’.178
    Chemical environmental factors                                                      81
</pre>

====================================================================== Einde pagina 82 =================================================================

<br><br>====================================================================== Pagina 83 ======================================================================

<pre>    Evaluation
    The Committee concludes that there is limited evidence that paternal smoking
    increases the risk of childhood leukaemia. Since there is ample evidence that
    tobacco smoke is carcinogenic, the Committee considers the biological
    plausibility high and a causal relation between paternal tobacco smoking and
    childhood leukaemia likely. For maternal smoking the epidemiological evidence
    is inadequate, so a causal relation in that case is possible. Causal relations with
    ALL and AML separately are uncertain.
    Recommendations
    Since parental smoking increases the risk of many disorders in embryos, foetuses
    and children (abortion, preterm birth, intra uterine growth retardation, congenital
    malformations, sudden infant death, asthma, allergy)200, parents should be
    urgently advised to stop or avoid smoking before conceiving a child. It is
    advisable to do so at least three months before intended conception, and maintain
    this during and after pregnancy.
6.6 Parental marijuana smoking
    Marijuana smoke contains several of the same carcinogens and co-carcinogens
    as the tar from tobacco, raising concerns that smoking marijuana may be a risk
    factor for tobacco-related cancers and, possibly, for childhood leukaemia.201
    Evidence
    In a review included in the CCG Evidence Summary, the association between the
    frequency, duration, amount, mode and period of marijuana use (ever,
    preconceptionally, during pregnancy or current) and cancer risk was looked into.
    In one study maternal use of marijuana during pregnancy or in the year before
    pregnancy was found to be associated with an increased risk for AML.201
    However, no other studies corroborated this finding.
    Evaluation
    The available epidemiological data provide inadequate evidence that parental
    use of marijuana during or in the year preceding pregnancy increases the risk of
    childhood AML. In view of the known toxic properties of cannabinol
    derivatives, however, the Committee considers a causal mechanism moderately
    plausible. Overall, the Committee considers the existence of a causal relation
    between parental marijuana smoking and AML uncertain, and a causal relation
    between parental marijuana smoking and ALL unknown.
 2  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 83 =================================================================

<br><br>====================================================================== Pagina 84 ======================================================================

<pre>    Recommendations
    Targeted epidemiological studies would be helpful in obtaining more
    information. Considering the toxic properties of cannabinol and the parallels
    with tobacco smoking, parents should be urgently advised to stop or avoid using
    cannabis at least three months before intending to conceive a child, to be
    continued during pregnancy and childhood.
6.7 Parental alcohol consumption
    Given that the metabolites of alcohol are carcinogenic and that leukaemia can
    arise prenatally, parental alcohol consumption was studied as a potential risk
    factor for the development of childhood leukaemia in the offspring.
    Evidence
    A review identified in the CCG Evidence Summary studied the effect of amount,
    type and period of parental alcohol consumption on the incidence of childhood
    ALL and AML.202 Maternal alcohol consumption one year before pregnancy
    showed a non-significantly higher risk for ALL in one individual study. For
    maternal alcohol consumption one month prior to pregnancy a significant higher
    risk for AML was found in one study, while for paternal alcohol consumption in
    several studies non-significantly higher risks for both ALL and AML were
    found.
        On the basis of available in vitro studies, animal experiments and studies in
    non-pregnant women the possibility cannot be ruled out that exposure to even
    very low amounts of ethanol may increase the risk of cancer.20
        IARC classifies the consumption of alcoholic beverages as ‘carcinogenic to
    humans’.178
    Evaluation
    Although there are indications that parental alcohol use preceding conception
    and maternal alcohol use during pregnancy may increase the risk of a child
    developing leukaemia, the Committee concludes that there is inadequate
    epidemiological evidence for an association of this kind. Since IARC has
    classified the consumption of alcoholic beverages as ‘carcinogenic to humans’,
    the Committee considers the biological plausibility as high. Overall, the
    Committee considers a causal relation between parental alcohol consumption
    and childhood leukaemia possible.
    Chemical environmental factors                                                    83
</pre>

====================================================================== Einde pagina 84 =================================================================

<br><br>====================================================================== Pagina 85 ======================================================================

<pre>    Recommendations
    Since alcohol consumption is considered ‘carcinogenic to humans’, and parental
    (mainly maternal) alcohol use prior to conception and during pregnancy
    increases the risk of other disorders in embryos, foetuses and children (reduced
    fertility, miscarriage, foetal death, intra-uterine death, premature birth, congenital
    malformations or adverse effects on the child’s psychomotor development), the
    Committee recommends that parents-to-be abstain from alcohol consumption
    prior to intended conception, and mothers also during pregnancy.203,204
6.8 Maternal cured meat intake
    Since transplacental exposure to N-nitroso compounds have been shown to
    produce tumors in laboratory animals and these compounds are sometimes found
    in cured meat or may be formed endogenously, consumption of cured meat
    during pregnancy was studied as a potential risk factor for the development of
    cancers in the offspring.205
    Evidence
    Three of the epidemiological studies identified in a systematic review of
    childhood leukaemia in general, have studied the association between the intake
    of individual cured meats, such as luncheon meat, ham, bacon, sausages or hot
    dogs and childhood leukaemias.205 Both higher and lower risks were found, but
    they were either non-significant or without the significance level mentioned.
        Experimental investigations have shown that transplacental exposure to N-
    nitroso compounds, which are sometimes found in (nitrite-) cured meats, can
    produce tumors in laboratory animals.205 IARC classifies the consumption of
    nitrite under conditions that result in endogenous nitrosation (high acidity
    environment of the stomach) as ‘probably carcinogenic to humans’.178
    Evaluation
    There is inadequate evidence that consumption of cured meat is a potential cause
    of childhood leukaemia.205 The experimental evidence indicates a moderate
    plausibility of causality. Overall, the Committee considers a causal relation
    between consumption of cured meat during pregnancy and childhood leukaemia
    to be uncertain.
    Recommendations
    Since IARC classifies the consumption of nitrite as ‘probably carcinogenic to
    humans’, and nitrite is used in the curing of some types of meat, the Committee
 4  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 85 =================================================================

<br><br>====================================================================== Pagina 86 ======================================================================

<pre>    recommends targeted studies into a relation between cured meat ingestion during
    pregnancy and childhood leukaemia. The Committee also recommends limiting
    the intake of nitrite-cured meat (e.g. ham, bacon and sausages) by pregnant
    women.
6.9 Other chemicals
    There are many chemicals for which limited or no information on health risks is
    available. Some of these may contribute to the risk of childhood leukaemia, such
    as persistent organic pollutants (POPs).206 The 4th WHO-coordinated survey of
    human milk for POPs has indicated that most organochlorinated pesticides
    banned 25-30 years ago were below or around detection limits in Belgian human
    milk samples, although DDE was still found at low levels in all samples.207 Over
    the last five years the levels of marker PCBs* and PCDD/Fs** in Belgian human
    milk decreased by 58% and 39% respectively.
    Evidence
    Parental occupational exposure to different chemicals and industrial dusts or
    fumes was assessed in three German case-control studies that were conducted
    from 1992-1997. Maternal exposure to paints or lacquers before conception and
    during the pregnancy was shown to be related to an increased risk of childhood
    ALL.183
        In a large case-control study in the US an association between self-reported
    paternal exposure to plastic materials during the preconception period and ALL
    was found.182 Also maternal exposure to plastic materials during the postnatal
    period were related to an increased risk of childhood ALL. An earlier case-
    control study in the US investigated occupational exposures of parents of 204
    children (younger than 18 years) with acute non-lymphoid leukaemia. The most
    consistent finding was an association with pesticide exposure (see 6.1).181 Other
    occupational exposures were also reported significantly more often: paternal
    exposure to solvents, petroleum products, plastics or lead, and maternal exposure
    to paints and pigments, metal dusts and sawdust.
        In a nationwide case-control study in the Netherlands mothers of children
    with ALL reported a greater occupational exposure to chemicals (paint,
    petroleum products and unspecified chemicals) during pregnancy than mothers
    of controls.208
        Among 837 children with ALL studied by the Childrens Cancer Study Group
    in the United States, 15.2% showed ras mutations.184 Specific ras mutations in
    the leukaemic cells were found to be associated with parental exposure to certain
    PCBs: polychlorinated biphenyls.
 *  PCDD: polychlorinated dibenzo-p-dioxin; PCDF: polychlorinated dibenzofuran.
    Chemical environmental factors                                                    85
</pre>

====================================================================== Einde pagina 86 =================================================================

<br><br>====================================================================== Pagina 87 ======================================================================

<pre>  medications, solvents, plastic materials, oil, coal products and other
  hydrocarbons. However, the risk of childhood leukaemia is modified by genetic
  characteristics affecting the metabolic activation or inactivation of exogenous
  chemicals. The risk for ALL increased threefold when three susceptibility
  genotypes occurred in the same children.209 This may suggest a causal relation
  between environmental exposures, specific ras mutations and ALL.
      PCBs, which were classified as ‘probable human carcinogens’ by IARC in
  1987178 and which cause perturbations of the immune system, may represent a
  previously unrecognised risk factor for childhood leukaemia.210 In a case-control
  study in the USA, the highest levels of PCBs in carpet dust were associated with
  a three times higher risk of ALL.
      Other substances that could potentially contribute to an increased risk of
  childhood leukaemia include specific phthalates (plasticisers); di(2-
  ethylhexyl)phthalate is classified by IARC as a ‘possible human carcinogen.178
  Evaluation
  Epidemiological and biological data provide, respectively, limited and moderate
  to high evidence that specific (classes of) reactive (mutagenic or receptor-
  binding) chemical agents found in the environment might, either alone or in
  combination with other factors, be contributing to childhood leukaemia. The
  Committee considers a causal relation for PCBs likely, for plasticisers possible
  and for other chemicals unknown.
  Public health relevance
  Children that carry genetic polymorphisms which result in a comparative
  inability to process chemicals to which they are environmentally exposed, show
  a higher incidence of leukaemia.207 This indicates that these chemicals play an
  important role in the causation of leukaemia and that a segment of the population
  is at increased risk of leukaemia from these chemicals. This might explain a
  sizeable fraction of childhood leukaemia.211 However, specific information is not
  available.
  Recommendations
  Many chemicals may, either alone or in combination with other factors,
  contribute to the induction or development of childhood leukaemia. This requires
  an integrated approach. Since many different mutagenic or receptor-binding
  agents may be involved in the development of leukaemia, it seems desirable and
  reasonable to complement the traditional anti-microbial hygiene with ‘physical-
  chemical hygiene’, limiting environmental exposures to possibly harmful agents
  as much as feasible.
6 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 87 =================================================================

<br><br>====================================================================== Pagina 88 ======================================================================

<pre>    Furthermore, targeted epidemiological studies should be performed on agents
associated with an increase in chromosomal abnormalities or DNA abnormalities
(gene mutations) in human blood cells, as these agents have access to and are
active in human haematopoietic tissues. These studies should not only target
pesticides and organic solvents, but also other potentially reactive or genotoxic
chemicals, such as polychlorinated biphenyls (PCBs) and phthalates
(plasticisers).
Chemical environmental factors                                                    87
</pre>

====================================================================== Einde pagina 88 =================================================================

<br><br>====================================================================== Pagina 89 ======================================================================

<pre>8 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 89 =================================================================

<br><br>====================================================================== Pagina 90 ======================================================================

<pre>7     Biological and other factors
      This chapter explores the available evidence on the role of a number of other
      environmental factors on the occurrence of childhood leukaemia: infectious
      agents and immune reactions, maternal folate and vitamin supplementation, birth
      weight and socio-economic status. Some of these may have a protective effect.
7.1   Infections and immune reactions
      The relationships between various forms of immunological stimulation and the
      occurrence of childhood cancer are diverse and complex. In some cases a
      protective effect may be involved. In the following sections the Committee
      discusses the available scientific evidence regarding four groups of indicators for
      infections and immune reactions which have been identified as possible
      influences on childhood leukaemia: infectious exposures, early social contacts,
      allergies and breast-feeding.
          These possible associations may also shed light on an underlying mechanism.
      In this regard, Greaves has proposed a general ‘delayed-infection’ hypothesis for
      childhood leukaemia36, in which the absence or diminution of infections early in
      life is stated to predispose the immune system to abnormal responses
      (‘inadequate priming’) when exposure to common infectious agents occurs at a
      later stage in life. A deregulated immune response to infection could then result
      in a potent inflammatory response.
          Postnatal malignant progression of prenatally initiated preleukaemic clones
      may also play a role in the risk of ALL, particularly common B-cell precursor
      ALL (cALL), the most common type of ALL. In other words, children who face
      a narrower range of antigens in early childhood may be, according to Greaves,
      more susceptible to leukaemogenesis in their maturing B-cell compartment.
7.1.1 Infectious exposures
      There are two hypotheses concerning the role of infections in the aetiology of
      childhood leukaemia, each relating to a specific time of exposure:212
      • Absence or diminution of infections early in life, later followed by exposure
          to common infections (Greaves‘ hypothesis).
      • Unusual infectious exposures, due to unusual ‘population mixing’ (Kinlen’s
          hypothesis).
      Biological and other factors                                                        89
</pre>

====================================================================== Einde pagina 90 =================================================================

<br><br>====================================================================== Pagina 91 ======================================================================

<pre>  Evidence
  In a review identified in the CCG Evidence Summary, different infectious
  exposures were shown to be associated with, on the one hand, direct indicators of
  exposure to infectious agents, and to be associated with, on the other hand,
  indirect (‘proxy’) indicators, such as vaccinations, breast-feeding, early day-care
  attendance and unusual ‘population mixing’.212 Where maternal infections
  during pregnancy are concerned, several studies have shown significantly or
  non-significantly higher risks for ALL. In the case of childhood infections,
  vaccinations and ‘individual social mixing’ (birth order), inconsistent results (i.e.
  both significantly higher and lower risks in identical settings and groups) were
  found. One study identified a statistically significant association between
  paternal occupational contact levels (i.e. the number of social contacts with the
  father whilst at work) and a higher risk for ALL.
      For childhood leukaemia in general two individual studies showed
  inconsistent results with respect to a relation between paternal occupational
  contact levels and childhood leukaemia.213 Also for maternal infections,
  childhood infections, different vaccinations and birth order, inconsistent results
  were found.
      According to the ‘population mixing’ hypothesis of Kinlen, large increases or
  shifts in population enhance the opportunity to infect members of the resident
  population with infectious agents for which the community’s children have
  developed limited immunity.214 Kinlen has suggested that an epidemic of an
  underlying infection, to which childhood leukaemia may be a rare response, is
  promoted by marked population mixing in rural areas, where the prevalence of
  susceptible individuals is higher than average.
      Although the working mechanisms still need to be determined, a possible
  aetiological mechanism may be found in an abnormal immune response to
  common infections.36 This idea is supported by several discoveries: the
  retrovirus human T-cell lymphotropic virus 1 (HTLV1) is a causative factor for
  adult T-cell leukaemia and lymphoma; leukaemia in domestic cattle, cats and
  chickens is viral in origin; and Epstein-Barr virus is the causative agent in some
  lymphomas. Evidence from the mechanisms in other haematological cancers also
  supports this view.
  Evaluation
  The epidemiological evidence shows inconsistent results, and does not
  sufficiently support the hypotheses of Greaves and Kinlen to draw any
  conclusions as to their accuracy. The Committee therefore concludes that there is
  inadequate evidence that (responses to) different infectious exposures are
  associated with an increased risk of childhood leukaemia. One of the reasons for
  these complex findings may be that the patterns of exposure, the timing of
0 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 91 =================================================================

<br><br>====================================================================== Pagina 92 ======================================================================

<pre>      infections and the immunological response are associated with multifactorial
      determinants.36 In addition, the Committee does not rule out that other than
      infectious environmental factors may play a role in explaining the observed
      association with population mixing. Large increases in a population (i.e. forming
      of ‘new towns’) might, for instance, also be associated with exposures to
      solvents in new buildings.
          Because of the delayed-infection hypothesis of Greaves, the Committee
      considers the biological plausibility as moderate. The Committee therefore
      considers a causal relation between different infectious exposures and the
      incidence of ALL and childhood leukaemia in general uncertain, and considers
      the existence of a relation between infectious exposures and AML unknown. It
      may be possible that childhood exposures to common infections offer some
      protection against childhood leukaemia, specifically against ALL. Parental or
      childhood exposures to specific infectious agents (e.g. Epstein-Barr virus) may,
      however, increase the risk.
      Recommendations
      Since there is a lack of adequate data on a possible relation between infectious
      exposures and childhood leukaemia, more research in this area is warranted. It
      would be especially useful if, in addition to infectious agents, other
      environmental determinants of population mixing would be investigated.
7.1.2 Early social contacts
      A rare response to common infections acquired by personal contact with infected
      individuals may be another relevant environmental factor in developing
      childhood leukaemia.215 This has been studied by looking into a possible
      association between day-care attendance and other early social contacts and the
      risk of childhood ALL, with specific attention paid to early-life exposure to
      infections and any protection this may provide against ALL.
      Evidence
      In a review in the CCG Evidence Summary, the association between duration and
      timing of day-care attendance early in life (less than two years of age) and
      childhood ALL was investigated.215 This exposure measure served as an
      indicator for the increased likelihood of early exposure to infections. A pooled
      analysis of the identified data showed a significantly lower risk for common-
      ALL*.
      Most frequent type of ALL: common B-cell precursor ALL (cALL).
      Biological and other factors                                                      91
</pre>

====================================================================== Einde pagina 92 =================================================================

<br><br>====================================================================== Pagina 93 ======================================================================

<pre>      Evaluation
      The epidemiological data provide sufficient evidence to suggest a protective
      association between early social contacts and the risk of ALL.215 Because of the
      ‘delayed-infection’ hypothesis of Greaves, the Committee considers the
      biological plausibility as moderate. A protective effect of early social contacts in
      the case of ALL is therefore considered likely. In the case of AML it is unknown
      whether such an effect occurs.
      Public health relevance
      No information is available on population attributable fractions. However, in
      view of the widespread nature of early social contacts, the Committee considers
      their potential protective effect to be very important.
      Recommendations
      The Committee considers further research into the possible protective effects of
      early social contacts not of high priority. The Committee does however
      recommend to stimulate early social contacts between young children. This will
      also be beneficial for reasons other than reducing the risk of childhood
      leukaemia.
7.1.3 Allergies
      Higher incidences of both childhood leukaemia and allergic diseases are found in
      western industrialised countries, as compared to developing countries.216
      Worldwide incidence data indicate a significant correspondence between rates of
      childhood allergies and ALL, suggesting there may well be shared infectious or
      immunological risk factors.36 A decline in exposure to infections in early
      childhood might play a role in the aetiology and increase of both.
      Evidence
      In a systematic review identified in the CCG Evidence Summary, pooled
      analyses showed a significantly lower risk for ALL in persons with hay fever,
      eczema and overall allergy.216
      Evaluation
      In spite of the above mentioned correspondence between childhood allergies and
      ALL in ‘ecological’ studies, from case-control studies, there is sufficient
      evidence to suggest an inverse association between allergy and the risk of
 2    Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 93 =================================================================

<br><br>====================================================================== Pagina 94 ======================================================================

<pre>      ALL.216 However, the Committee considers the biological plausibility of a causal
      relation between allergy and childhood leukaemia as low. The Committee
      therefore considers a protective effect of allergy (i.c. an allergic constitution) for
      ALL possible and for AML unknown.
      Public health relevance
      Despite the frequent occurrence of allergies in the population*, there is no
      information available to derive population attributable fractions.
      Recommendations
      The Committee sees no reason to give priority to further studies in this area.
7.1.4 Breast-feeding
      It has been suggested that breast milk may play a role in the prevention of certain
      childhood cancers.217
      Evidence
      In the systematic review retrieved in the CCG Evidence Summary, breast-
      feeding was associated with a significantly lower risk for ALL and AML.217
           Given the multiple immunological effects of breast-feeding in offspring,
      Greaves has considered this relation to be biologically plausible.218
      Evaluation
      There is sufficient evidence that breast-feeding is inversely associated with the
      development of childhood leukaemia. The Committee considers this to be
      moderately biologically plausible.218 The Committee therefore considers an
      inverse causal relation between breast-feeding and AML and ALL likely.
      Recommendations
      Since the Committee has concluded that a protective effect of breast-feeding is
      likely, and bearing in mind that breast-feeding has many other benefits, the
      Committee supports the recommendation made by the Netherlands Nutrition
      Centre, which is in turn based on the recommendations by the WHO, that,
      whenever feasible, infants should be exclusively breast-fed up to the age of
      approximately six months.219,220
      In the Netherlands, at least one in four children (12-14 years) reported allergic disorders.200
      Biological and other factors                                                                    93
</pre>

====================================================================== Einde pagina 94 =================================================================

<br><br>====================================================================== Pagina 95 ======================================================================

<pre>7.1.5 Overall conclusion and recommendations
      Whether other forms of immunological stimulation have the same protective
      effect as early social contacts, allergies and breast-feeding is not clear.215 The
      observed complexity certainly reflects the complexity of the stimulating and
      inhibiting influences of different immunological stimuli on the proliferation of
      the various cell types in haematological and immunological tissues. Because of
      the unknown interactions of infectious diseases, allergies and social contacts, the
      Committee concludes that there is limited evidence that infections and immune
      reactions are associated with the risk of childhood leukaemia.
          The Committee therefore considers a protective effect of exposure to
      common childhood infections and immune reactions regarding childhood
      leukaemia, and specifically regarding ALL, to be possible. Parental or childhood
      exposures to specific infectious agents (e.g. Epstein-Barr virus) may, however,
      increase the risk of childhood leukaemia.
      The Committee concludes that not enough knowledge currently exists to
      recommend measures to prevent or stimulate exposure to infections or other
      immune reactions. An exception is made in the case of breast-feeding, since a
      recommendation in this regard is in line with existing advice to mothers. To
      further understand the role of infections or other immune reactions, more
      research would be necessary, for instance to explain space-time clustering of the
      incidence of childhood leukaemia in different populations.
7.2   Maternal folate and vitamin supplementation
      Given the hypothesis that deficiencies in vitamins and some other micronutrients
      might increase the risk of cancer, and that leukaemia can arise prenatally,
      maternal folate and vitamin supplementation were studied as potential protective
      factors in the development of childhood leukaemia in the offspring.221
      Evidence
      A review discussed in the CCG Evidence Summary studied the association
      between maternal use (and dose) of folic acid and other vitamin supplements
      before and during pregnancy, and the risk of ALL.221 In one study, a non-
      significantly higher risk for ALL was observed in relation to folate
      supplementation before pregnancy. Pooled analyses showed non-significant
      results in the case of vitamin supplementation before pregnancy. For vitamin
      supplementation during pregnancy, however, a significantly lower risk for ALL
      was observed. Combinations of vitamins and folate did not reveal any
      associations.
 4    Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 95 =================================================================

<br><br>====================================================================== Pagina 96 ======================================================================

<pre>        A protective effect of maternal folate supplementation during pregnancy
    against the occurrence of childhood leukaemia is biologically plausible, given its
    dual roles in methylation and the synthesis and repair of DNA.221
    Evaluation
    There is limited evidence that extra vitamin supplementation during pregnancy
    protects against ALL.221 However, the Committee found no evidence to consider
    this plausible and therefore considers a causal relation between vitamin
    supplementation during pregnancy and a decrease in ALL uncertain. Although
    the Committee considers a causal relation with folate intake as moderately
    plausible, there is inadequate evidence from epidemiological studies that the
    intake of folate before or during pregnancy has a protective effect. So, whether a
    protective relation with folate supplementation exists is also uncertain. Based on
    the CCG Evidence Summary a causal relation with AML is unknown.
    Recommendations
    More research is required to obtain insight in the possible protective effect of
    vitamin supplementation during pregnancy on the risk of childhood leukaemia,
    in particular ALL. For other reasons than reducing the risk of childhood
    leukaemia, and since it is relatively easy to accomplish, folate supplementation
    should be promoted from four weeks before intended conception until eight
    weeks after conception.
7.3 Birth weight
    A growing body of evidence suggests that childhood leukaemia may be initiated
    in utero when lymphoid and myeloid cells are not fully differentiated and are
    particularly susceptible to malignant transformation.222 Likewise, stem cells that
    give rise to the myeloid cell line may also be susceptible to circulating growth
    factors and hormones. These then act to increase the size of the stem cell pool,
    which in turn increases the total number of replicating cells now at risk for
    conversion into tumour cells. This subsequently may increase the risk of
    leukaemia. Since one factor related to the size of the stem cell pool is birth
    weight, this has been postulated as a risk factor for childhood leukaemia.
    However, birth weight has also been associated with other factors, some of which
    have been discussed before, e.g. smoking
    Evidence
    In the relevant review identified in the CCG Evidence Summary, a high birth
    weight was associated with a higher risk of ALL and AML, and a low birth
    Biological and other factors                                                       95
</pre>

====================================================================== Einde pagina 96 =================================================================

<br><br>====================================================================== Pagina 97 ======================================================================

<pre>    weight with a higher risk of AML.222 Furthermore, for each kilogram increase in
    birth weight a higher risk for ALL was found.
    Evaluation
    There is limited evidence that birth weight, affecting many physiological
    parameters, is associated with the risk of ALL (higher birth weight) and AML
    (higher and lower birth weight).222 The Committee considers the biological
    plausibility of a relation between a high birth weight and childhood leukaemia to
    be moderate. The plausibility that a relation with low birth weight exists is
    considered low. The Committee therefore considers a causal relation between a
    high birth weight and ALL or AML possible, and one between a low birth
    weight and AML uncertain and for ALL unknown.
    Recommendations
    In view of the benefits for many other aspects of health, a normal birth weight
    should be aimed for during pregnancy.
7.4 Socio-economic status
    A long-held view links higher socio-economic status (SES) to higher rates of
    childhood leukaemia.223 Some recent studies, however, showed associations in
    the opposite direction.
    Evidence
    In a review identified in the CCG Evidence Summary, associations were studied
    between childhood ALL and AML and socio-economic circumstances.223 Family
    income and mother’s education showed inconsistent associations with ALL, with
    significantly higher AML rates, however, being found when family income was
    lower. In the case of paternal education, (non-)significantly higher ALL rates
    were associated with higher SES, while (non-)significantly higher AML rates
    once again showed an association with lower SES. One study, however, found
    significantly higher ALL rates to be related to ‘ecological’ SES measures at an
    aggregated or population level, i.c. higher education and occupational class. For
    childhood leukaemia in general, inconsistent associations were found for family
    income, parental education, father’s occupational class and household density.223
        The authors of the original review concluded that case-control studies
    conducted in North America since 1980 have consistently reported inverse
    (negative) associations of childhood leukaemia with individual measures of
    family income, mother's education and father's education.223 In contrast, the
 6  Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 97 =================================================================

<br><br>====================================================================== Pagina 98 ======================================================================

<pre>incidence of childhood leukaemia has consistently shown to be lower when
father's occupational class is identified as low.
Evaluation
The systematic analyses provide inconsistent evidence, showing both positive
and negative associations of childhood leukaemia with indicators of SES.
However, SES might only be a proxy for other factors that might explain the
(indirect) relations. Based on these results, the Committee considers there to be
inadequate epidemiological evidence for such associations. The Committee also
considers the biological plausibility that a causal relation exists to be low.
According to the Committee, the existence of a causal relation between SES and
childhood leukaemia is therefore unknown.
Biological and other factors                                                      97
</pre>

====================================================================== Einde pagina 98 =================================================================

<br><br>====================================================================== Pagina 99 ======================================================================

<pre>8 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 99 =================================================================

<br><br>====================================================================== Pagina 100 ======================================================================

<pre>8   Conclusion
    The main objective in this report has been to evaluate the existing scientific
    evidence on possible relations between environmental factors and the occurrence
    of childhood leukaemia, and to recommend balanced measures to reduce risks
    when sufficient knowledge is available or uncertainties exist. In this final
    chapter, the Committee gives an overview of its conclusions and
    recommendations.
8.1 Conclusions on possible associations
    Given that leukaemia is the most common malignancy in children, and observing
    the increase that has occurred in the last decade of the 20th century, there is every
    reason to look for ways to reduce environmental risks, although this trend now
    seems to have stopped and has maybe even been reversed. It needs to be noted,
    however, that a certain level of incidence of childhood leukaemia is inevitable,
    since genetic susceptibilities, naturally occurring exposures and man-made
    factors all play a role. Separating these influences to arrive at a baseline or
    ‘natural’ occurrence of childhood leukaemia is impossible, since the
    development of leukaemia is a multifactorial process, depending on multiple
    consecutive events, and with simultaneous exposure to multiple factors.
    Complicated interplay of factors
    The most important conclusions therefore are that (a) the majority of leukaemia
    cases cannot be explained; (b) only a small fraction of leukaemia cases might be
    prevented. Consequently, suggesting a full range of measures aiming at a
    baseline incidence is not possible. Where sufficient evidence is available for
    associations with individual factors and uncertainties exist regarding the
    complex interplay of risk factors, the precautionary principle can be used as a
    guideline. The uncertainties are due to our rudimentary knowledge about the
    multistep process that leads to the disease and about the way environmental
    factors, such as exposure to pesticides or other chemicals, affects this process.
    Knowledge about the role of concurrent or subsequent exposures and about
    critical pre- and postnatal periods of susceptibility is lacking or in varying
    degrees deficient.
    Conclusion                                                                            99
</pre>

====================================================================== Einde pagina 100 =================================================================

<br><br>====================================================================== Pagina 101 ======================================================================

<pre>    Likelihood of causality per factor
    Arriving at conclusions on the role of separate causal relations has not proved to
    be easy. Most possible relations under consideration in this report could not be
    sufficiently established, given the available epidemiological and experimental
    evidence.
        In the following two tables the Committee summarises the findings,
    indicating for each factor to which extent the available evidence supports the
    likelihood of an association with childhood leukaemia and what measures and
    research are proposed. Table 6 contains the conclusions on possible risk factors,
    whereas Table 7 summarises the findings on factors with a possibly protective
    influence. Whenever a distinction could be made between ALL and AML this is
    indicated. In all other cases the Committee refers to ‘childhood leukaemia’.
        For most risk factors it has not been possible to calculate which percentage of
    leukaemias they cause. In a few cases, the Committee was able to provide rough
    estimates of ‘population attributable risks’ (PAFs), ranging from less than 1% for
    exposure to magnetic fields from overhead power lines up to 15-20% for
    exposure to naturally occurring ionising radiation. Since these numbers are very
    uncertain, they are not provided in the table.
8.2 Recommended measures
    Which measures could be taken to reduce the impact of environmental factors on
    childhood leukaemia, or to utilise protective influences? Since many different
    mutagenic or receptor-binding agents may be involved in the development of
    leukaemia, it seems desirable and reasonable to complement the traditional anti-
    microbial hygiene with ‘physical-chemical hygiene’, limiting environmental
    exposures to potential reactive agents as much as feasible.
    Limited array of measures
    In theory, the expected contribution to the number of cases of childhood
    leukaemia would be an important consideration in selecting the most promising
    measures. It was shown in the previous chapters, however, that for most factors
    no reliable estimate could be made. Moreover, in most cases not even the
    relationship itself has been scientifically proven.
        Only where ionising radiation is concerned a causal relationship has been
    established. For benzene and paternal tobacco smoking such a relation is deemed
    to be likely, for pesticides it is considered possible to likely, while early social
    contacts and breast-feeding are likely protective factors. In all other cases, less
    certainty exists on the possible relation between an environmental influence and
 00 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 101 =================================================================

<br><br>====================================================================== Pagina 102 ======================================================================

<pre>Table 6. The likelihood of involvement of environmental risk factors in the causation of childhood leukaemia.
Environmental         Potential exposure    Type of              Likelihood of      Proposed             Proposed
factor                                      leukaemia            causality          measures             research
                                            (when
                                            differentiated)
Ionising radiation    Ionising radiation    Childhood            Established        Exposure             Assessment of
                                            leukaemia                               reduction            exposure of
                                                                                    (ALARA)              unborn children
                                                                                                         and infants.
                                                                                                         Biological effects
                                                                                                         of pre- and
                                                                                                         postnatal
                                                                                                         diagnostic X-rays
                                                                                                         (esp. CT scans)
Electromagnetic       Extremely Low         Childhood            Possible           Exposure
fields                Frequency magnetic    leukaemia                               reduction
                      fields                ALL                  Possible           Exposure
                                                                                    reduction
                                            AML                  Unknown
                      Radiofrequency        Childhood            Unknown                                 Monitoring actual
                      radiation             leukaemia                                                    exposures
Ultrasound            Diagnostic            Childhood                               Optimisation and     Effects of more
                      ultrasound scans      leukaemia                               standardisation      intensive or
                      - routine/limited                          Unlikely                                frequent
                                                                                                         ultrasound scans
                      - frequent/intensive                       Unknown
Chemicals             Pesticides            Childhood            Possible to        Preconceptional      Monitoring
                                            leukaemia            likely             counselling to       exposures among
                                                                                    reduce exposure      occupationally
                                                                                                         exposed women
                                            ALL                  Possible to        Preconceptional      Monitoring
                                                                 likely             counselling to       exposures among
                                                                                    reduce exposure      occupationally
                                                                                                         exposed women
                                            AML                  Uncertain to       Preconceptional      Monitoring
                                                                 possible           counselling to       exposures among
                                                                                    reduce exposure      occupationally
                                                                                                         exposed women
                      Benzene               Childhood            Likely             Preconceptional      Monitoring
                                            leukaemia                               counselling to       exposures in
                                                                                    reduce exposure      specific situations
                      Formaldehyde          Childhood            Possible           Exposure
                                            leukaemia                               reduction
                      Styrene               Childhood            Uncertain          Exposure
                                            leukaemia                               reduction
                      Other organic         Childhood            Unknown            Exposure             Epidemiological
                      solvents              leukaemia                               reduction            and experimental
                                                                                                         studies for
                                                                                                         commonly
                                                                                                         encountered
                                                                                                         organic solvents
            Conclusion                                                                                                   101
</pre>

====================================================================== Einde pagina 102 =================================================================

<br><br>====================================================================== Pagina 103 ======================================================================

<pre> Environmental      Potential exposure   Type of         Likelihood of Proposed        Proposed
 factor                                  leukaemia       causality     measures        research
                                         (when
                                         differentiated)
                    Inorganic arsenic in Childhood       Possible      Exposure
                    drinking water       leukaemia                     reduction
                    Paternal tobacco     Childhood       Likely        Refrain from
                    smoking              leukaemia                     tobacco smoking
                    Maternal tobacco     Childhood       Possible      Refrain from
                    smoking              leukaemia                     tobacco smoking
                    Parental marijuana   AML             Uncertain     Refrain from    Epidemiological
                    smoking                                            marijuana       studies
                                                                       smoking
                                         ALL             Unknown       Refrain from    Epidemiological
                                                                       marijuana       studies
                                                                       smoking
                    Parental alcohol     Childhood       Possible      Refrain from
                    consumption          leukaemia                     alcohol
                                                                       consumption
                    Maternal cured       Childhood       Uncertain     Exposure        Effects of cured
                    meat intake          leukaemia                     reduction       meat ingestion
                                                                                       during pregnancy
                    PCBs                 Childhood       Likely        Preconceptional Epidemiological
                                         leukaemia                     counselling to  studies
                                                                       reduce exposure
                    Plasticisers         Childhood       Possible      Preconceptional Epidemiological
                                         leukaemia                     counselling to  studies
                                                                       reduce exposure
                    Other chemicals      Childhood       Unknown       Exposure        Epidemiological
                                         leukaemia                     reduction       studies on agents
                                                                                       associated with
                                                                                       DNA damage
 Biological and     Infectious           Childhood       Uncertain                     More research in
 other factors      exposures            leukaemia                                     this area
                                         ALL             Uncertain
                                         AML             Uncertain
                    High birth weight    ALL             Possible
                                         AML             Possible
                    Low birth weight     ALL             Unknown
                                         AML             Uncertain
                    Socio-economic       Childhood       Unknown
                    status               leukaemia
102          Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 103 =================================================================

<br><br>====================================================================== Pagina 104 ======================================================================

<pre>Table 7. The likelihood of a protective influence of environmental factors in the occurrence of childhood leukaemia.
Environmental         Potential exposure       Type of             Likelihood of     Proposed              Proposed research
factor                                         leukaemia           causality         measures
                                               (when
                                               differentiated)
Biological and        Early social contacts    ALL                 Likely            Encourage
other factors
                                               AML                 Unknown           Encourage
                      Allergies                ALL                 Possible
                                               AML                 Unknown
                      Breast-feeding           ALL                 Likely            Encourage
                                               AML                 Likely            Encourage
                      Maternal vitamin         ALL                 Uncertain                               More research on
                      supplementation                                                                      protective effect
                      during pregnancy                                                                     of vitamin
                                               AML                 Unknown                                 supplementation
                                                                                                           during pregnancy
                      Maternal folate          ALL                 Uncertain         Encourage
                      supplementation
                                               AML                 Unknown           Encourage
            childhood leukaemia, ranging from ‘possible’ in a number of cases to ‘uncertain’
            or ‘unknown’ in others.
                Another problem is that not every environmental factor can be influenced by
            policy measures. Cosmic radiation, for instance, is not something for which
            measures are practically available, except in the case of flying personnel during
            pregnancy.
                Still, several options present themselves when aiming for a reduction in the
            occurrence of childhood leukaemia. If avoiding exposures that are suspected to
            contribute to childhood leukaemia is a reasonable option, this should be
            contemplated, especially if measures to this effect could also protect against
            other adverse health effects.
                The situation with childhood leukaemia is characterised by uncertainty,
            complexity and ambiguity. Therefore it is warranted to take, as the Committee
            has done, a precautionary perspective to guide the risk assessment and
            subsequent risk management.
                The Committee suggests preventive measures when (a) plausible and
            relevant environmental risk factors of childhood leukaemia have been identified
            or (b) behavioural risk factors have been identified that are in line with existing
            recommendations given for other reasons, e.g. smoking and alcohol consumption
            during pregnancy.
                Three measures stand out because of their possible contribution to decreasing
            the number of cases of childhood leukaemia: reducing exposure of parents and
            children to ionising radiation, especially through medical applications; reducing
            Conclusion                                                                                                    103
</pre>

====================================================================== Einde pagina 104 =================================================================

<br><br>====================================================================== Pagina 105 ======================================================================

<pre>   occupational and residential exposure to pesticides and to benzene; and reducing
   parental tobacco smoking, also to reduce the risk of several other adverse health
   effects. Although considerable uncertainty still exists, the Committee considers it
   very likely that the contribution of these factors to the incidence of childhood
   leukaemia in high-risk groups might be substantial.
   Reducing exposure to radiation
   Medical radiation. Limiting the exposure to ionising radiation for medical
   purposes is important for both women in their (early) pregnancy and for children.
   In applying medical radiation, the risks always have to be justified and weighed
   against the advantages, but this is especially important where these two groups
   are concerned. The Committee feels that risk awareness in physicians can be
   improved.
       Applying optimisation and diagnostic reference levels is the way to achieve
   exposure reduction. Whenever possible, diagnostic techniques that do not
   involve ionising radiation should be used, such as ultrasound. However, this
   technique should also be used prudently: although a causal relation with limited
   exposures to routine ultrasound scans is considered unlikely, ultrasound scans
   should not be offered without medical indication. The Committee therefore sees
   a need for stricter justification standards and optimisation procedures for
   ultrasounds as well.
   Other radiation sources. Where other radiation sources are concerned, the focus
   should also be on the reduction of exposure to as low as reasonably achievable
   (ALARA). This applies, for instance, to the emission of radioactive noble gases
   from nuclear facilities. These emissions should be monitored.
   Reducing exposure to chemicals
   Pesticides. Although uncertainty exists about the risks of occupational and
   residential use of pesticides, a reduction in the use of pesticides should be
   considered a priority. When using pesticides at home (i.c. biocides for pest
   control), risks and benefits should be carefully weighed. Especially women who
   want to become pregnant or who are already expecting should refrain from using
   pesticides, or should make sure they use extra protection measures.
   Other chemicals. The available evidence warrants taking measures to limit or
   prevent exposure of children and pregnant women to benzene and specific
   classes of other chemicals, such as PCBs.
04 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 105 =================================================================

<br><br>====================================================================== Pagina 106 ======================================================================

<pre>Reducing other environmental risks
Reducing environmental exposure to ELF magnetic fields, radon and chemicals.
Precautionary measures are most obviously required for environmental factors
that may possibly contribute to childhood leukaemia. Examples are limiting
exposures to ELF magnetic fields from high-voltage power lines and, mainly for
reasons other than childhood leukaemia, striving for a further reduction in
exposures to radon from soil and building materials, as well as to specific
chemicals such as formaldehyde, inorganic arsenic and plasticisers.
Avoiding parental smoking and consumption of alcohol and cured meat. For
several parental lifestyle factors that have been linked with other diseases,
considerable uncertainty exists where a causal relationship with childhood
leukaemia is concerned. This applies to tobacco and marijuana smoking as well
as to alcohol use. In these cases, a possible risk of leukaemia for the unborn child
could provide an extra incentive to refrain from smoking and alcohol
consumption when the conception of a child is intended. Although uncertainty
exists about the evidence for a causal relation between parental intake of cured
meat and childhood leukaemia, the Committee nevertheless recommends
limiting the intake of nitrite-cured meat (e.g. ham, bacon and sausages) by
pregnant women.
Enhancing protective influences
Encouraging folic acid supplementation and breast-feeding. Some of the factors
the Committee has studied may protect against childhood leukaemia, although
once again considerable uncertainty exists. Folate supplementation before the
intended conception and during early pregnancy is already recommended
because of other beneficial effects, but may also reduce the risk of childhood
leukaemia. The Committee therefore strongly supports this recommendation.
The Committee also recommends to breastfeed children up to the age of
approximately six months, whenever feasible, in line with the general
recommendation.
The importance of risk communication and public participation
Risk communication is the exchange of information and opinions between the
authorities, the public and other parties involved, about the nature and extent of a
risk.224 The message should be tailored to the needs of the receiver and must
include clear information on what is known about the plausibility of potential
health risks and the certain and uncertain effects of preventive measures.
Different value judgements should be taken into account, and the risk
communication should contribute to a balanced risk awareness. This can help
Conclusion                                                                           105
</pre>

====================================================================== Einde pagina 106 =================================================================

<br><br>====================================================================== Pagina 107 ======================================================================

<pre>    people make informed choices. Any risk communication should also clarify that
    at a population level many factors may be shown to have an impact and that there
    is a complex interplay of causes; it will therefore never be possible to explain
    individual cases of leukaemia.
        As an important part of risk communication, the Committee recommends that
    women of childbearing age should be counselled, in order to create awareness of
    the risk of certain potentially harmful environmental and lifestyle factors
    previous to an intended conception.
        Risk communication targeted at the general public or professionals can only
    be part of the approach. For medical radiation, risk awareness created by a risk
    communication programme can be a driving force in adopting new protocols and
    increasing the willingness to reduce exposure. Besides, implementation of
    measures is necessary, not only to reduce exposure to medical radiation, but also
    to radon, ELF magnetic fields and pesticides.
        In conclusion, a number of factors discussed in this report have been shown
    to contribute to the risk of childhood leukaemia, or are likely to do so. Other
    factors carry only a small risk, or may turn out to be not involved at all. Despite
    this, people may worry, particularly in relation to locally observed clusters of
    childhood leukaemia, for instance around high voltage power lines. When
    concerns are raised, proper risk communication can help ensure that those
    involved are able to arrive at an informed opinion about risks that may be posed
    by local environmental factors. The involvement of residents at an early stage of
    risk assessment and risk management is a precondition for an effective policy to
    address local environmental health concerns or concerns of specific groups.
    Openness and transparency are key principles in this process.
8.3 Research needs
    In identifying research needs, the expected contribution of a factor to the number
    of cases of childhood leukaemia should be the most important consideration,
    with exposure at the population level as the guiding principle. This means that
    studies need to focus on factors to which a large number of people are exposed or
    factors which greatly impact a smaller group. However, other considerations can
    play a role as well.
    On the incidence of childhood leukaemia
    Because of the relatively small numbers of childhood leukaemia cases per
    country, there is a need for international collaboration in studying variations in
    incidence in relation to variations in environmental exposures.
        There is also a need for further research into why the peak in incidence
    occurs early in life. This might be associated with exposures during critical
    periods of differentiation.
 06 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 107 =================================================================

<br><br>====================================================================== Pagina 108 ======================================================================

<pre>On genetic factors
Although insight into the genetic susceptibility of childhood leukaemia to risk
factors is emerging, the interaction with environmental factors remains to be
explored. A research question closely associated with that in the previous section
concerns the causes that may explain the peak in incidence occurring early in life
for genetic subtypes of ALL.
On environmental risk factors
In epidemiological research designs, the Committee recommends to pay more
attention to the quality of exposure assessment and to specific leukaemia
diagnoses (ALL/AML). In the analyses, specific attention needs to be paid to the
most relevant exposure periods: before and during pregnancy, and in early
childhood. Because of the differences in potential damage, it is important to
differentiate, in research regarding the critical time windows of exposure during
pregnancy, in ‘early’ (first 3-6 weeks), ‘mid’ and ‘late’ (last trimester).
On combined exposures
Children and their parents are exposed to mixtures of different agents. However,
hardly any study has looked into interactions, for instance between prenatal
parental and postnatal environmental exposures. Therefore, the Committee
recommends that, in epidemiological studies, more attention should be paid to
the accumulation of risks of combined exposures.
On ionising radiation
A lot is known about the mechanism underlying the relation between leukaemia
in children and the exposure to ionising radiation, but more research is still
needed concerning the role of a number of specific exposure situations. Life has
evolved under continuous exposure to natural ionising radiation, but due to the
concentration of radioactive substances in building materials and high-altitude
flights, and especially due to medical radiation, exposures have increased. More
research into these types of exposures is therefore needed.
Medical radiation. More detailed and precise data should be acquired on the
exposure of unborn children and infants, including subgroups such as
prematurely born children, in order to better apply justification of exposure and
to apply dose reduction strategies for X-ray examinations. In addition, research is
needed into the biological effects of pre- and postnatal diagnostic X-ray exposure
in general and exposures from CT scans in particular.
Conclusion                                                                          107
</pre>

====================================================================== Einde pagina 108 =================================================================

<br><br>====================================================================== Pagina 109 ======================================================================

<pre>   Residential proximity to nuclear installations. The Committee recommends to
   monitor the emissions of radioactive noble gases from nuclear installations, and
   to study locations that differ in the way emissions of radioactive noble gases are
   handled and locations in which accidental releases of radioactive noble gases
   have occurred. Also, it may be helpful to pool epidemiological data on all potential
   risk factors (i.e. not only those concerning ionising radiation) related to the vicinity
   of nuclear power plants on an international scale.
   Nuclear accidents. More research is also needed on the health effects, including
   non-cancer effects, of chronic internal exposures of children resulting from
   environmental contamination by radionuclides released during a nuclear
   accident.
   On ultrasound scans
   Ultrasound scans are offered to all pregnant women in the first and second
   trimester of pregnancy and are generally regarded as safe to the foetus. Current
   ultrasound technology, however, has a significantly higher output potential than
   the older machines used in most clinical studies. Ultrasound investigations
   during pregnancy are also commercially provided for non-medical purposes.
   More knowledge about the possible adverse effects of intensive and/or frequent
   ultrasound scans (e.g. following in vitro fertilisation, IVF) on leukaemia and
   other diseases is therefore needed.
   On electromagnetic fields
   More experimental research into possible carcinogenic mechanisms of extremely
   low frequency and radiofrequency electromagnetic fields is recommended.
   On pesticides and other chemicals
   The uncertainty about the leukaemic potential of different chemical
   environmental factors is large. So it is important to gain more insight into the
   possible contribution of separate factors to the occurrence of childhood
   leukaemia.
   Pesticides. The Committee recommends the monitoring of pesticide exposures
   among occupationally exposed women, at least of reproductive age, and to
   incorporate biomarkers of exposure in these studies, whenever feasible.
   Benzene. In order to obtain more solid evidence on the causal relation between
   exposure to benzene and childhood leukaemia, targeted exposure monitoring
   studies should be performed.
08 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 109 =================================================================

<br><br>====================================================================== Pagina 110 ======================================================================

<pre>Other organic solvents. There is a need for both epidemiological and
experimental studies into the relation between commonly encountered organic
solvents and childhood leukaemia.
Cured meat. Nitrite is used in the curing of some types of meat. Because IARC
classifies the consumption of nitrite as ‘probably carcinogenic to humans’, the
Committee recommends targeted studies into a possible relation between cured
meat ingestion during pregnancy and childhood leukaemia.
Other chemicals. Many other chemicals might, either separately or in
combination with other factors, contribute to childhood leukaemia. Therefore
targeted epidemiological studies should be performed on agents associated with
an increase in chromosomal abnormalities or DNA abnormalities (gene
mutations) in human blood cells, as these agents have access to and are active in
human haematopoietic tissues. These studies should not only target pesticides
and organic solvents, but also other potentially reactive or genotoxic chemicals,
such as polychlorinated biphenyls (PCBs) and phthalates.
On other risk factors
Since there is a lack of adequate data on a possible relation between infectious
exposures and childhood leukaemia, research in this area is warranted, for
instance into the space-time clustering of childhood leukaemia incidence in
different populations. Finally, more research is required to obtain insight in the
possible protective effect of vitamin supplementation during pregnancy on the
risk for childhood leukaemia, in particular ALL.
Conclusion                                                                         109
</pre>

====================================================================== Einde pagina 110 =================================================================

<br><br>====================================================================== Pagina 111 ======================================================================

<pre>10 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 111 =================================================================

<br><br>====================================================================== Pagina 112 ======================================================================

<pre>  References
  Kaatsch P and Mergenthaler A. Incidence, time trends and regional variation of childhood leukaemia
  in Germany and Europe. Radiat Prot Dosimetry, 2008; 132(2): 107-113.
  Smith MA, Ries LA, Gurney JG, et al. Leukemia. In: Cancer Incidence and Survival among Children
  and Adolescents: United States SEER Program 1975-1995, Smith MA, Ries LA, Gurney JG, et al.,
  Eds. Publication no 99-4649. Bethesda, MD: National Cancer Institute, 1999.
  Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev, 2010; 36(4): 277-285.
  Coebergh JW, Reedijk AM, de Vries E, et al. Leukaemia incidence and survival in children and
  adolescents in Europe during 1978-1997. Report from the Automated Childhood Cancer Information
  System project. Eur J Cancer, 2006; 42(13): 2019-2036.
  Kaatsch P, Steliarova-Foucher E, Crocetti E, et al. Time trends of cancer incidence in European
  children (1978-1997): report from the Automated Childhood Cancer Information System project. Eur
  J Cancer, 2006; 42(13): 1961-1971.
  Kaatsch P, Spix C, Schmiedel S, et al. Epidemiologische Studie zu Kinderkrebs in der Umgebung von
  Kernkraftwerken (KiKK-Studie). Berlin: Bundesamt für Strahlenschutz, 2007.
  Hoffmann W, Terschueren C, and Richardson DB. Childhood leukemia in the vicinity of the
  Geesthacht nuclear establishments near Hamburg, Germany. Environ Health Perspect, 2007; 115(6):
  947-952.
  World Health Organization. Extremely low frequency fields. Geneva: WHO, 2007; Environmental
  Health Criteria 238.
  Infante-Rivard C and Weichenthal S. Pesticides and childhood cancer: an update of Zahm and Ward's
  1998 review. J Toxicol Environ Health B Crit Rev, 2007; 10(1-2): 81-99.
0 Rothman KJ, Greenland S, and Lash TL. Modern epidemiology. 3rd edition. Philidelphia: Lippincott,
  Williams & Wilkins, 2008.
1 Porta M, Greenland S, and Last JM. A dictionary of epidemiology (fifth edition). Oxford: University
  Press, 2008.
2 HCN - Health Council of the Netherlands. Prudent precaution. The Hague: Health Council of the
  Netherlands, 2008; publication no. 2008/18E.
3 World Health Organization and International Agency for Research on Cancer. IARC Monographs on
  the evaluation of carcinogenic risks to humans. Lyon, France, 2006.
4 Maslanyj M, Lightfoot T, Schuz J, et al. A precautionary public health protection strategy for the
  possible risk of childhood leukaemia from exposure to power frequency magnetic fields. BMC Public
  Health, 2010; 10: 673.
5 Bradford Hill A. The environment and disease: association or causation? Proc R Soc Med, 1965; 58:
  295-300.
6 IARC - International Agency for Research on Cancer. IARC Monographs on the Evaluation of
  Carcinogenic Risks to Humans. Preamble. Internet: http://monographs.iarc.fr/ENG/Preamble/
  CurrentPreamble.pdf. Access date 13-7-2011.
  References                                                                                          111
</pre>

====================================================================== Einde pagina 112 =================================================================

<br><br>====================================================================== Pagina 113 ======================================================================

<pre>7  Wigle DT, Arbuckle TE, Turner MC, et al. Epidemiologic evidence of relationships between
   reproductive and child health outcomes and environmental chemical contaminants. J Toxicol Environ
   Health B Crit Rev, 2008; 11(5-6): 373-517.
8  World Health Organization. Extremely low frequency fields. Geneva: WHO, 2007; Environmental
   Health Criteria 238.
9  Greenland S and Kheifets L. Leukemia attributable to residential magnetic fields: results from
   analyses allowing for study biases. Risk Anal, 2006; 26(2): 471-482.
0  Belgian Cancer Registry. Leukemia in children; epidemiologic data 2004-2008. Belgian Cancer
   Registry, 2010.
1  Steliarova-Foucher E, Stiller C, Lacour B, et al. International Classification of Childhood Cancer,
   third edition. Cancer, 2005; 103(7): 1457-1467.
2  SKION. Jaarverslag 2009. SKION, 2010.
3  Pieters R. Personal communication, 2010.
4  Sommelet D, Clavel J, and Lacour B. Epidémiologie des cancers chez l'enfant. Springer Verlag
   France, 2009.
5  Dreifaldt AC, Carlberg M, and Hardell L. Increasing incidence rates of childhood malignant diseases
   in Sweden during the period 1960-1998. Eur J Cancer, 2004; 40(9): 1351-1360.
6  HCN - Health Council of the Netherlands. Local environmental health concerns - risk
   communication, exposure assessment and cluster investigation. The Hague: Health Council of the
   Netherlands, 2001; publication no. 2001/10.
7  Mulder YM, Drijver M, and Kreis IA. Case-control study on the association between a cluster of
   childhood haematopoietic malignancies and local environmental factors in Aalsmeer, The
   Netherlands. J Epidemiol Community Health, 1994; 48(2): 161-165.
8  Draper GJ. An overview of reports and current research concerning childhood leukaemia and cancer
   around nuclear installations in the UK. Sci Total Environ, 1992; 127(1-2): 9-12.
9  Kinlen LJ and Hudson C. Childhood leukaemia and poliomyelitis in relation to military
   encampments in England and Wales in the period of national military service, 1950-63. BMJ, 1991;
   303(6814): 1357-1362.
0  Kinlen LJ and John SM. Wartime evacuation and mortality from childhood leukaemia in England and
   Wales in 1945-9. BMJ, 1994; 309(6963): 1197-1202.
1  Kinlen LJ, O'Brien F, Clarke K, et al. Rural population mixing and childhood leukaemia: effects of
   the North Sea oil industry in Scotland, including the area near Dounreay nuclear site. BMJ, 1993;
   306(6880): 743-748.
2  Kinlen LJ, Dickson M, and Stiller CA. Childhood leukaemia and non-Hodgkin's lymphoma near
   large rural construction sites, with a comparison with Sellafield nuclear site. BMJ, 1995; 310(6982):
   763-768.
3  Expert panel on childhood leukemia in Churchill County Nevada. Final report and recommendations
   to the Nevada State Health Division. 2004.
4  Westley-Wise VJ, Stewart BW, Kreis I, et al. Investigation of a cluster of leukaemia in the Illawarra
   region of New South Wales, 1989-1996. Med J Aust, 1999; 171(4): 178-183.
5  COMARE - Committee on Medical Aspects of Radiation in the Environment. COMARE 11th
   Report: The distribution of childhood leukaemia and other childhood cancer in Great Britain 1969-
   1993. COMARE, 2006.
12 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 113 =================================================================

<br><br>====================================================================== Pagina 114 ======================================================================

<pre>6 Greaves M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer,
  2006; 6(3): 193-203.
7 Meijerink JP, den Boer ML, and Pieters R. New genetic abnormalities and treatment response in
  acute lymphoblastic leukemia. Semin Hematol, 2009; 46(1): 16-23.
8 Mori H, Colman SM, Xiao Z, et al. Chromosome translocations and covert leukemic clones are
  generated during normal fetal development. Proc Natl Acad Sci USA, 2002; 99(12): 8242-8247.
9 Lausten-Thomsen U, Madsen HO, Vestergaard TR, et al. Prevalence of t(12;21)[ETV6-RUNX1]-
  positive cells in healthy neonates. Blood, 2011; 117(1): 186-189.
0 Schmiegelow K, Lausten TU, Baruchel A, et al. High concordance of subtypes of childhood acute
  lymphoblastic leukemia within families: lessons from sibships with multiple cases of leukemia.
  Leukemia, 2012; 26(4): 675-681.
1 Finette BA. Analysis of mutagenic V(D)J recombinase mediated mutations at the HPRT locus as an
  in vivo model for studying rearrangements with leukemogenic potential in children. DNA Repair
  (Amst), 2006; 5(9-10): 1049-1064.
2 Clavel J. [Epidemiology of childhood cancers]. Rev Prat, 2007; 57(10): 1061-1069.
3 Bruwier A and Chantrain CF. Hematological disorders and leukemia in children with Down
  syndrome. Eur J Pediatr, 2011.
4 Sherborne AL, Hemminki K, Kumar R, et al. Rationale for an international consortium to study
  inherited genetic susceptibility to childhood acute lymphoblastic leukemia. Haematologica, 2011;
  96(7): 1049-1054.
5 Vijayakrishnan J and Houlston RS. Candidate gene association studies and risk of childhood acute
  lymphoblastic leukemia: a systematic review and meta-analysis. Haematologica, 2010; 95(8): 1405-
  1414.
6 Papaemmanuil E, Hosking FJ, Vijayakrishnan J, et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are
  associated with risk of childhood acute lymphoblastic leukemia. Nat Genet, 2009; 41(9): 1006-1010.
7 Trevino LR, Yang W, French D, et al. Germline genomic variants associated with childhood acute
  lymphoblastic leukemia. Nat Genet, 2009; 41(9): 1001-1005.
8 Prasad RB, Hosking FJ, Vijayakrishnan J, et al. Verification of the susceptibility loci on 7p12.2,
  10q21.2, and 14q11.2 in precursor B-cell acute lymphoblastic leukemia of childhood. Blood, 2010;
  115(9): 1765-1767.
9 Ulusoy G, Adali O, Tumer TB, et al. Significance of genetic polymorphisms at multiple loci of
  CYP2E1 in the risk of development of childhood acute lymphoblastic leukemia. Oncology, 2007;
  72(1-2): 125-131.
0 Schmiegelow K. [Cancer in childhood and inheritance]. Ugeskr Laeger, 2006; 168(24): 2373-2376.
1 De Bont R and van Larebeke N. Endogenous DNA damage in humans: a review of quantitative data.
  Mutagenesis, 2004; 19(3): 169-185.
2 Deman J and van Larebeke N. Carcinogenesis: mutations and mutagens. Tumour Biol, 2001; 22(3):
  191-202.
3 Greaves M. Darwin and evolutionary tales in leukemia. The Ham-Wasserman Lecture. Hematology
  Am Soc Hematol Educ Program, 2009; 3-12.
4 Mullighan CG and Downing JR. Global genomic characterization of acute lymphoblastic leukemia.
  Semin Hematol, 2009; 46(1): 3-15.
  References                                                                                         113
</pre>

====================================================================== Einde pagina 114 =================================================================

<br><br>====================================================================== Pagina 115 ======================================================================

<pre>5  Mullighan CG, Zhang J, Harvey RC, et al. JAK mutations in high-risk childhood acute lymphoblastic
   leukemia. Proc Natl Acad Sci USA, 2009; 106(23): 9414-9418.
6  Chokkalingam AP and Buffler PA. Genetic susceptibility to childhood leukaemia. Radiat Prot
   Dosimetry, 2008; 132(2): 119-129.
7  Blootstelling aan ioniserende straling in België. SCK.CEN. Internet: http://www.sckcen.be/nl/
   content/download/4931/60130/file/2_Blootstelling_aan_ioniserende_straling_in_Belgie_2007.pdf.
   Access date 25-7-2011.
8  Eleveld H. Ionising radiation exposure in the Netherlands. Bilthoven: Rijksinstituut voor
   Volksgezondheid en Milieu, 2003; RIVM Rapport 861020002.
9  UNSCEAR - United Nations Scientific Committee on the Effects of Atomic Radiation. Annex G.
   Biological effects at low radiation doses. In: Sources and effects of ionizing radiation. UNSCEAR
   2000 Report to the General Assembly, with scientific annexes. New York: United Nations, 2000.
0  ICRP - International Commission on Radiological Protection. The 2007 Recommendations of the
   International Commission on Radiological Protection. ICRP publication 103. Ann ICRP, 2007; 37(2-
   4): 1-332.
1  Hamada N, Maeda M, Otsuka K, et al. Signaling pathways underpinning the manifestations of
   ionizing radiation-induced bystander effects. Curr Mol Pharmacol, 2011; 4(2): 79-95.
2  ICRP - International Commission on Radiological Protection. Age-dependent doses to members of
   the public from intake of radionuclides: Part 1. ICRP publication 56. Ann ICRP, 1989; 20(2): 1-122.
3  ICRP - International Commission on Radiological Protection. Age-dependent doses to members of
   the public from intake of radionuclides: Part 2. Ingestion dose coefficients. ICRP publication 67. Ann
   ICRP, 1993; 23(3-4): 1-167.
4  ICRP - International Commission on Radiological Protection. Age-dependent doses to members of
   the public from intake of radionuclides: Part 3. Ingestion dose coefficients. ICRP publication 69. Ann
   ICRP, 1995; 25(1): 1-74.
5  ICRP - International Commission on Radiological Protection. Age-dependent doses to members of
   the public from intake of radionuclides: Part 4. Inhalation dose coefficients. ICRP publication 71.
   Ann ICRP, 1995; 25(3-4): 1-405.
6  ICRP - International Commission on Radiological Protection. Age-dependent doses to members of
   the public from intake of radionuclides: Part 5. Compilation of ingestion and inhalation dose
   coefficients. ICRP publication 72. Ann ICRP, 1996; 26(1): 1-91.
7  ICRP - International Commission on Radiological Protection. Doses to the embryo and fetus from
   intakes of radionuclides by the mother. ICRP publication 88. Ann ICRP, 2001; 31(1-3): 19-515.
8  ICRP - International Commission on Radiological Protection. Doses to infants from ingestion of
   radionuclides in mothers' milk. ICRP publication 95. Ann ICRP, 2004; 34(3-4).
9  Clarke R and Valentin J. A history of the international commission on radiological protection. Health
   Phys, 2005; 88(5): 407-422.
0  Doll R. Hazards of ionising radiation: 100 years of observations on man. Br J Cancer, 1995; 72(6):
   1339-1349.
1  Wakeford R. The cancer epidemiology of radiation. Oncogene, 2004; 23(38): 6404-6428.
2  UNSCEAR - United Nations Scientific Committee on the Effects of Atomic Radiation. Annex A:
   Epidemiological studies of radiation and cancer. In: Effects of ionizing radiation. UNSCEAR 2006
   Report to the General Assembly, with scientific annexes. New York: United Nations, 2006.
14 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 115 =================================================================

<br><br>====================================================================== Pagina 116 ======================================================================

<pre>3 BEIR - Committee on the Biological Effects of Ionizing Radiation. Health risks from exposure to low
  levels of ionizing radiation (BEIR VII Phase 2). Washington, DC: National Academy Press, 2005.
4 Richardson D, Sugiyama H, Nishi N, et al. Ionizing radiation and leukemia mortality among
  Japanese Atomic Bomb Survivors, 1950-2000. Radiat Res, 2009; 172(3): 368-382.
5 ICRP - International Commission on Radiological Protection. Biological effects after prenatal
  irradiation (embryo and fetus). ICRP publication 90. Ann ICRP, 2003; 33(1-2): 5-206.
6 Wakeford R. Childhood leukaemia following medical diagnostic exposure to ionizing radiation in
  utero or after birth. Radiat Prot Dosimetry, 2008; 132(2): 166-174.
7 Baverstock K and Karotki AV. Towards a unifying theory of late stochastic effects of ionizing
  radiation. Mutat Res, 2011; 718(1-2): 1-9.
8 UNSCEAR - United Nations Scientific Committee on the Effects of Atomic Radiation. Report of the
  United Nations Scientific Committee on the Effects of Atomic Radiation 2010. Fifty-seventh session,
  includes scientific report: Summary of low-dose radiation effects on health. New York: United
  Nations, 2011.
9 HCN - Health Council of the Netherlands. Risks of exposure to ionising radiation. The Hague: Health
  Council of the Netherlands, 2007; publication no. 2007/03.
0 Feinendegen LE, Brooks AL, and Morgan WF. Biological consequences and health risks of low-level
  exposure to ionizing radiation: commentary on the workshop. Health Phys, 2011; 100(3): 247-259.
1 Beels L, Bacher K, De WD, et al. Gamma-H2AX foci as a biomarker for patient X-ray exposure in
  pediatric cardiac catheterization: are we underestimating radiation risks? Circulation, 2009; 120(19):
  1903-1909.
2 Averbeck D. Non-targeted effects as a paradigm breaking evidence. Mutat Res, 2010; 687(1-2): 7-12.
3 Blaauboer RO, Dekkers SAJ, Slaper H, et al. Stralingsbelasting in nieuwbouwwoningen - voorlopige
  resultaten. VERA-survey 2006. Bilthoven: RIVM, 2008; RIVM briefrapport 610790004.
4 de With G and de Jong P. Modellering van de thoron- en thorondochterconcentraties in het
  binnenmilieu. Petten: NRG, 2009; NRG-912089/09.93696.
5 Stoop P, Glastra P, Hiemstra Y, et al. Results of the second Dutch national survey on radon in
  dwellings. Bilthoven: Rijksinstituut voor Volksgezondheid en Milieu, 1998; RIVM-rapport
  610058006.
6 FANC - Federaal Agentschap voor de Nucleaire Controle. Radon. Internet: http://www.fanc.fgov.be/
  nl/page/hebt-u-een-vraag-in-verband-met-radon-het-fanc-geeft-u-het-antwoord-meer-weten/
  650.aspx. Access date 25-7-2011.
7 Harley NH and Robbins ES. Radon and leukemia in the Danish study: another source of dose. Health
  Phys, 2009; 97(4): 343-347.
8 Tong J, Qin L, Cao Y, et al. Environmental radon exposure and childhood leukemia. J Toxicol
  Environ Health B Crit Rev, 2012; 15(5): 332-347.
9 Wakeford R, Kendall GM, and Little MP. The proportion of childhood leukaemia incidence in Great
  Britain that may be caused by natural background ionizing radiation. Leukemia, 2009; 23(4): 770-
  776.
0 Wakeford R, Little MP, and Kendall GM. Risk of childhood leukemia after low-level exposure to
  ionizing radiation. Expert Rev Hematol, 2010; 3(3): 251-254.
  References                                                                                             115
</pre>

====================================================================== Einde pagina 116 =================================================================

<br><br>====================================================================== Pagina 117 ======================================================================

<pre>1  Little MP, Wakeford R, and Kendall GM. Updated estimates of the proportion of childhood
   leukaemia incidence in Great Britain that may be caused by natural background ionising radiation. J
   Radiol Prot, 2009; 29(4): 467-482.
2  UNSCEAR - United Nations Scientific Committee on the Effects of Atomic Radiation. Effects of
   ionizing radiation. UNSCEAR 2006 Report to the General Assembly, with scientific annexes. New
   York: United Nations, 2006.
3  Kendall GM, Little MP, Wakeford R, et al. A record-based case-control study of natural background
   radiation and the incidence of childhood leukaemia and other cancers in Great Britain during 1980-
   2006. Leukemia, 2012.
4  de Jong P. Exposure to natural radioactivity in the Netherlands: the impact of building materials (PhD
   thesis). Groningen: Rijksuniversiteit Groningen, 2010.
5  Brenner DJ and Hall EJ. Computed tomography--an increasing source of radiation exposure. N Engl
   J Med, 2007; 357(22): 2277-2284.
6  HGR - Hoge Gezondheidsraad. Evaluatie van de stijgende stralingsblootstelling van patiënten door
   Computed Tomography (CT) en optimalisatie van de stralingsbescherming. Brussel: Hoge
   Gezondheidsraad, 2006; Publicatie No 8080.
7  Stoker J, Kipp JB, Geleijns K, et al. Stralingsbelasting door computertomografie in Nederland.
   Afweging tussen voordelen en risico's [Radiation exposure in computed tomography in the
   Netherlands: risk-benefit analysis]. Ned Tijdschr Geneeskd, 2009; 153(8): 348-352.
8  Smith-Bindman R, Miglioretti DL, Johnson E, et al. Use of diagnostic imaging studies and associated
   radiation exposure for patients enrolled in large integrated health care systems, 1996-2010. JAMA,
   2012; 307(22): 2400-2409.
9  Bijdrage diagnostische verrichtingen aan de gemiddelde effectieve dosis. Rijksinstituut voor
   Volksgezondheid en Milieu. Internet: http://www.rivm.nl/ims/object_document/o1n1414.html.
   Access date 25-7-2011.
00 Medische blootstelling aan ioniserende straling. Internet: http://www.milieurapport.be/nl/
   feitencijfers/MIRA-T/milieuthemas/ioniserende-straling/blootstelling-aan-ioniserende-straling/
   medische-blootstelling-aan-ioniserende-straling/. Access date 25-7-2011.
01 UNSCEAR - United Nations Scientific Committee on the Effects of Atomic Radiation. Annex A:
   Medical radiation exposure. In: Sources and effects of ionizing radiation. UNSCEAR 2008 Report to
   the General Assembly, with scientific annexes. Vienna: United Nations, 2010.
02 Meeuwsen EJ and Brugmans MJP. Gegevens over medische stralingstoepassingen: van
   ziekenhuisenquetes tot zorgverzekeraars. Bilthoven: Rijksinstituut voor Volksgezondheid en Milieu,
   2002; RIVM rapport 610059009/2002.
03 Linet MS, Kim KP, and Rajaraman P. Children's exposure to diagnostic medical radiation and cancer
   risk: epidemiologic and dosimetric considerations. Pediatr Radiol, 2009; 39 Suppl 1: S4-26.
04 Pearce MS, Salotti JA, Little MP, et al. Radiation exposure from CT scans in childhood and
   subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet, 2012.
05 ICRP - International Commission on Radiological Protection. Radiation and your patient: a guide for
   medical practitioners. Ann ICRP, 2001; 31(4): 5-31.
06 ICRP - International Commission on Radiological Protection. Managing patient dose in digital
   radiology. ICRP publication 93. Ann ICRP, 2004; 34(1): 1-73.
16 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 117 =================================================================

<br><br>====================================================================== Pagina 118 ======================================================================

<pre>07 Eggermont, G and Hugé, J. New perspectives for radiation protection concepts in the frame of
   sustainability. Presentation at the meeting of the Nordic Society for Radiation Protection (NSFS),
   Reykjavik, 22-25 August 2011. Internet: http://nsfs.org/NSFS-2011/. Access date 21-2-2012.
08 The Alliance for Radiation Safety in Pediatric Imaging. A practice quality improvement program for
   radiologists. Internet: http://spr.affiniscape.com/associations/5364/ig/index.cfm?page=518. Access
   date 12-7-2012.
09 Smans K. The development of dose optimisation strategies for X-ray examinations of newborns (PhD
   thesis). Leuven: Katholieke Universiteit Leuven, 2009.
10 Smans K, Struelens L, Smet M, et al. Cu filtration for dose reduction in neonatal chest imaging.
   Radiat Prot Dosimetry, 2010; 139(1-3): 281-286.
11 UNSCEAR - United Nations Scientific Committee on the Effects of Atomic Radiation. Annex E.
   Occupational radiation exposures. In: Sources and effects of ionizing radiation. UNSCEAR 2000
   Report to the General Assembly, with scientific annexes. New York: United Nations, 2000.
12 Richtlijn 96/29/Euratom van de Raad van 13 mei 1996 tot vaststelling van de basisnormen voor de
   bescherming van de gezondheid der bevolking en der werkers tegen de aan ioniserende straling
   verbonden gevaren. Publikatieblad, 1996; L159(29/06/1996): 1-114.
13 ICRP - International Commission on Radiological Protection. 1990 recommendations of the
   International Commission on Radiological Protection. ICRP publication 60. Ann ICRP, 1991; 21(1-
   3).
14 ICRP - International Commission on Radiological Protection. General principles for the radiation
   protection of workers. ICRP publication 75. Ann ICRP, 1997; 27(1): 1-60.
15 UNSCEAR - United Nations Scientific Committee on the Effects of Atomic Radiation. Annex B.
   Exposure from natural radiation sources. In: Sources and effects of ionizing radiation. UNSCEAR
   2000 Report to the General Assembly, with scientific annexes. New York: United Nations, 2000.
16 FANC - Federaal Agentschap voor de Nucleaire Controle. Kosmische straling. Internet: http://
   www.fanc.fgov.be/nl/page/kosmische-straling/1191.aspx. Access date 12-7-2012.
17 Gardner MJ, Snee MP, Hall AJ, et al. Results of case-control study of leukaemia and lymphoma
   among young people near Sellafield nuclear plant in West Cumbria. BMJ, 1990; 300(6722): 423-429.
18 Draper GJ, Little MP, Sorahan T, et al. Cancer in the offspring of radiation workers: a record linkage
   study. BMJ, 1997; 315(7117): 1181-1188.
19 Bunch KJ, Muirhead CR, Draper GJ, et al. Cancer in the offspring of female radiation workers: a
   record linkage study. Br J Cancer, 2009; 100(1): 213-218.
20 Boffey PM. Ernest J. Sternglass: controversial prophet of doom. Science, 1969; 166(3902): 195-200.
21 Atomkraft: Risiken schon im Normalbetrieb. Berlin: IPPNW, 2011; IPPPNW Factsheet.
22 Sermage-Faure C, Laurier D, Goujon-Bellec S, et al. Childhood leukemia around French nuclear
   power plants--the Geocap study, 2002-2007. Int J Cancer, 2012; 131(5): E769-E780.
23 COMARE - Committee on Medical Aspects of Radiation in the Environment. Further consideration
   of the incidence of childhood leukaemia around nuclear power plants in Great Britain. Chilton, Dicot,
   UK: Health Protection Agency, 2011; Fourteenth Report.
24 Baker PJ and Hoel DG. Meta-analysis of standardized incidence and mortality rates of childhood
   leukaemia in proximity to nuclear facilities. Eur J Cancer Care (Engl), 2007; 16(4): 355-363.
25 Greiser E. Leukämie-Erkrankungen bei Kindern und Jugendlichen in der Umgebung von
   Kernkraftwerken in fünf Ländern. Meta-Analyse und Analyse (Leukaemia in children and young
   References                                                                                             117
</pre>

====================================================================== Einde pagina 118 =================================================================

<br><br>====================================================================== Pagina 119 ======================================================================

<pre>   people in the vicinity of nuclear power stations in five countries. Meta-analyses and analyses).
   Musweiler, Deutschland: Epi.Consult GmbH, 2009.
26 Fairlie I. Childhood cancer near German nuclear power stations. J Environ Sci Health C Environ
   Carcinog Ecotoxicol Rev, 2010; 28(1): 1-21.
27 Strahlenschutzkommission. Bewertung der Epidemiologischen Studie zu Kinderkrebs in der
   Umgebung von Kernkraftwerken (KiKK-Studie). Stellungnahme der Strahlenschutzkommission.
   Berlin: H Hoffmann, 2008; Berichte der Strahlenschutzkommission (SSK) des Bundesministeriums
   für Umwelt, Naturschutz und Reaktorsicherheit - Heft 57.
28 Strahlenschutzkommission. Bewertung der Epidemiologischen Studie zu Kinderkrebs in der
   Umgebung von Kernkraftwerken (KiKK-Studie). Wissenschaftliche Begründung zur Stellungnahme
   der Strahlenschutzkommission. Berlin: H Hoffmann, 2009; Berichte der Strahlenschutzkommission
   (SSK) des Bundesministeriums für Umwelt, Naturschutz und Reaktorsicherheit - Heft 58.
29 Bernier MO, Gregoire E, Jacob S, et al. Les études épidémiologiques des leucémies autour des
   installations nucléaires chez l'enfant et le jeune adulte: revue critique. Institut de Radioprotection et
   de Sûreté Nucléaire, 2008; Rapport DRPH/SRBE - no 2008-001.
30 Bollaerts K, Fierens S, Simons K, et al. Possible health effects of living in the vicinity of nuclear sites
   in Belgium. Brussels: ISP-WIV, 2012; Report 2012/001.
31 Sermage-Faure C, Laurier D, Goujon-Bellec S, et al. Childhood leukemia around French nuclear
   power plants - the Geocap study, 2002-2007. Int J Cancer, 2012.
32 UNSCEAR - United Nations Scientific Committee on the Effects of Atomic Radiation. Annex C:
   Radiation exposure in accidentes. In: Sources and effects of ionizing radiation. UNSCEAR 2008
   Report to the General Assembly with scientific annexes. New York: United Nations, 2011.
33 Chernobyl disaster. WikipediA, The Free Encyclopedia. Internet: http://en.wikipedia.org/wiki/
   Chernobyl_disaster. Access date 27-7-2011.
34 UNSCEAR - United Nations Scientific Committee on the Effects of Atomic Radiation. Annex D:
   Health effects due to radiation from the Chernobyl accident. In: Effects of ionizing radiation.
   UNSCEAR 2006 Report to the General Assembly, with scientific annexes. New York: United
   Nations, 2006.
35 Noshchenko AG, Bondar OY, and Drozdova VD. Radiation-induced leukemia among children aged
   0-5 years at the time of the Chernobyl accident. Int J Cancer, 2010; 127(2): 412-426.
36 Davis S, Day RW, Kopecky KJ, et al. Childhood leukaemia in Belarus, Russia, and Ukraine
   following the Chernobyl power station accident: results from an international collaborative
   population-based case-control study. Int J Epidemiol, 2006; 35(2): 386-396.
37 Working party on research implications on health and safety standards of the Article 31 Group of
   Experts. Recent scientific findings and publications on the health effects of Chernobyl. Luxembourg:
   European Commission, 2011; Radiation Protection 170.
38 Cardis E, Krewski D, Boniol M, et al. Estimates of the cancer burden in Europe from radioactive
   fallout from the Chernobyl accident. Int J Cancer, 2006; 119(6): 1224-1235.
39 Hoffmann W. Has fallout from the Chernobyl accident caused childhood leukaemia in Europe? A
   commentary on the epidemiologic evidence. Eur J Public Health, 2002; 12(1): 72-76.
40 IARC - International Agency for Research on Cancer. Non-ionizing radiation, part 1: static and
   extremely low-frequency (ELF) electric and magnetic fields. Lyon: IARC, 2002; IARC Monographs
   on the evaluation of carcinogenic risks to humans; Volume 80.
18 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 119 =================================================================

<br><br>====================================================================== Pagina 120 ======================================================================

<pre>41 Kheifets L, Ahlbom A, Crespi CM, et al. Pooled analysis of recent studies on magnetic fields and
   childhood leukaemia. Br J Cancer, 2010; 103(7): 1128-1135.
42 Schuz J. Exposure to extremely low-frequency magnetic fields and the risk of childhood cancer:
   update of the epidemiological evidence. Prog Biophys Mol Biol, 2011; 107(3): 339-342.
43 Decat G, Van Den Heuvel I, and Mulpas L. Final report of the BBEMG research contract (July 2001 -
   June 2005). Monitoring survey of the 50 Hz magnetic field for the estimation of the proportion of
   Belgian children exposed to the epidemiological cut-off points of 0.2, 0.3, and 0.4 microtesla. Mol:
   Vito, 2005.
44 Pruppers MJM. 'Blootstelling aan extreem laag frequente elektromagnetische velden van
   hoogspanningslijnen' - Herberekening naar aanleiding van het KEMA/RIVM-onderzoek naar de
   kosten en baten van maatregelen ter beperking van magnetische velen bij hoogspanningslijnen.
   Bilthoven: Rijksinstituut voor Volksgezondheid en Milieu, 2003; RIVM briefrapport 032/2003.
45 van der Plas M, Houthuijs DJM, Dusseldorp A, et al. Magnetische velden van hoogspanningslijnen
   en leukemie bij kinderen. Bilthoven: Rijksinstituut voor Volksgezondheid en Milieu, 2001; RIVM
   rapport 610050007.
46 Ahlbom A, Day N, Feychting M, et al. A pooled analysis of magnetic fields and childhood
   leukaemia. Br J Cancer, 2000; 83(5): 692-698.
47 Kheifets L and Oksuzyan S. Exposure assessment and other challenges in non-ionizing radiation
   studies of childhood leukaemia. Radiat Prot Dosimetry, 2008; 132(2): 139-147.
48 HCN - Health Council of the Netherlands: Electromagnetic Fields Committee. Electromagnetic
   Fields: Annual Update 2005. The Hague: Health Council of the Netherlands, 2005; publication no.
   2005/14.
49 Elliott P, Toledano MB, Bennett J, et al. Mobile phone base stations and early childhood cancers:
   case-control study. BMJ, 2010; 340: c3077.
50 AFFSET - French Agency for Environmental and Occupational Health Safety. Mise à jour de
   l’expertise relative aux radiofréquences. Internet: http://www.anses.fr/ET/DocumentsET/
   Rapport_RF_final_25_091109_web.pdf. Access date 22-2-2012.
51 Verschaeve L, Juutilainen J, Lagroye I, et al. In vitro and in vivo genotoxicity of radiofrequency
   fields. Mutat Res, 2010; 705(3): 252-268.
52 Baan R, Grosse Y, Lauby-Secretan B, et al. Carcinogenicity of radiofrequency electromagnetic fields.
   Lancet Oncol, 2011; 12(7): 624-626.
53 Houston LE, Odibo AO, and Macones GA. The safety of obstetrical ultrasound: a review. Prenat
   Diagn, 2009; 29(13): 1204-1212.
54 Torloni MR, Vedmedovska N, Merialdi M, et al. Safety of ultrasonography in pregnancy: WHO
   systematic review of the literature and meta-analysis. Ultrasound Obstet Gynecol, 2009; 33(5): 599-
   608.
55 HCN - Health Council of the Netherlands. Population Screening Act: Prenatal screening for Down’s
   syndrome and neural tube defects. The Hague: Health Council of the Netherlands, 2007; publication
   no. 2007/05WBO.
56 Salvesen KA and Eik-Nes SH. Ultrasound during pregnancy and birthweight, childhood
   malignancies and neurological development. Ultrasound Med Biol, 1999; 25(7): 1025-1031.
57 Rajaraman P, Simpson J, Neta G, et al. Early life exposure to diagnostic radiation and ultrasound
   scans and risk of childhood cancer: case-control study. BMJ, 2011; 342: d472.
   References                                                                                           119
</pre>

====================================================================== Einde pagina 120 =================================================================

<br><br>====================================================================== Pagina 121 ======================================================================

<pre>58 Furusawa Y, Fujiwara Y, Campbell P, et al. DNA double-strand breaks induced by cavitational
   mechanical effects of ultrasound in cancer cell lines. PLoS One, 2012; 7(1): e29012.
59 Alavanja MC, Hoppin JA, and Kamel F. Health effects of chronic pesticide exposure: cancer and
   neurotoxicity. Annu Rev Public Health, 2004; 25: 155-197.
60 HCN - Health Council of the Netherlands. Pesticides in food: assessing the risk to children. The
   Hague: Health Council of the Netherlands, 2004; publication no. 2004/11E.
61 Claeys WL, Schmit J-F, Bragard C, et al. Exposure of several Belgian consumer groups to pesticide
   residues through fresh fruit and vegetable consumption. Food Control, 2011; 22: 508-516.
62 Zahm SH and Ward MH. Pesticides and childhood cancer. Environ Health Perspect, 1998; 106 Suppl
   3: 893-908.
63 Metayer C and Buffler PA. Residential exposures to pesticides and childhood leukaemia. Radiat Prot
   Dosimetry, 2008; 132(2): 212-219.
64 Nasterlack M. Do pesticides cause childhood cancer? Int Arch Occup Environ Health, 2006; 79(7):
   536-544.
65 Nasterlack M. Pesticides and childhood cancer: an update. Int J Hyg Environ Health, 2007; 210(5):
   645-657.
66 Wigle DT, Turner MC, and Krewski D. A systematic review and meta-analysis of childhood
   leukemia and parental occupational pesticide exposure. Environ Health Perspect, 2009; 117(10):
   1505-1513.
67 Turner MC, Wigle DT, and Krewski D. Residential pesticides and childhood leukemia: a systematic
   review and meta-analysis. Environ Health Perspect, 2010; 118(1): 33-41.
68 Van Maele-Fabry G, Lantin AC, Hoet P, et al. Childhood leukaemia and parental occupational
   exposure to pesticides: a systematic review and meta-analysis. Cancer Causes Control, 2010; 21(6):
   787-809.
69 Van Maele-Fabry G, Lantin AC, Hoet P, et al. Residential exposure to pesticides and childhood
   leukaemia: a systematic review and meta-analysis. Environ Int, 2011; 37(1): 280-291.
70 Vinson F, Merhi M, Baldi I, et al. Exposure to pesticides and risk of childhood cancer: a meta-
   analysis of recent epidemiological studies. Occup Environ Med, 2011; 68(9): 694-702.
71 Bailey HD, Armstrong BK, de Klerk NH, et al. Exposure to professional pest control treatments and
   the risk of childhood acute lymphoblastic leukemia. Int J Cancer, 2011; 129(7): 1678-1688.
72 IARC - International Agency for Research on Cancer. Occupational exposures in insecticide
   application, and some pesticides. Lyon: IARC, 1991.
73 Edwards TM and Myers JP. Environmental exposures and gene regulation in disease etiology.
   Environ Health Perspect, 2007; 115(9): 1264-1270.
74 Goldman LR. Chemicals and children's environment: what we don't know about risks. Environ
   Health Perspect, 1998; 106 Suppl 3: 875-880.
75 Smith MT, Zhang L, McHale CM, et al. Benzene, the exposome and future investigations of
   leukemia etiology. Chem Biol Interact, 2011; 192(1-2): 155-159.
76 Smith MT. Advances in understanding benzene health effects and susceptibility. Annu Rev Public
   Health, 2010; 31: 133-148.
77 Pyatt D and Hays S. A review of the potential association between childhood leukemia and benzene.
   Chem Biol Interact, 2010; 184(1-2): 151-164.
20 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 121 =================================================================

<br><br>====================================================================== Pagina 122 ======================================================================

<pre>78 IARC - International Agency for Research on Cancer. Agents classified by the IARC Monographs,
   Volumes 1-103. IARC. Internet: http://monographs.iarc.fr/ENG/Classification/index.php. Access
   date 24-2-2012.
79 Paulsson K, Cazier JB, Macdougall F, et al. Microdeletions are a general feature of adult and
   adolescent acute lymphoblastic leukemia: Unexpected similarities with pediatric disease. Proc Natl
   Acad Sci U S A, 2008; 105(18): 6708-6713.
80 Hirabayashi Y, Yoon BI, Li GX, et al. Mechanism of benzene-induced hematotoxicity and
   leukemogenicity: current review with implication of microarray analyses. Toxicol Pathol, 2004; 32
   Suppl 2: 12-16.
81 Buckley JD, Robison LL, Swotinsky R, et al. Occupational exposures of parents of children with
   acute nonlymphocytic leukemia: a report from the Childrens Cancer Study Group. Cancer Res, 1989;
   49(14): 4030-4037.
82 Shu XO, Stewart P, Wen WQ, et al. Parental occupational exposure to hydrocarbons and risk of acute
   lymphocytic leukemia in offspring. Cancer Epidemiol Biomarkers Prev, 1999; 8(9): 783-791.
83 Schüz J, Kaletsch U, Meinert R, et al. Risk of childhood leukemia and parental self-reported
   occupational exposure to chemicals, dusts, and fumes: results from pooled analyses of German
   population-based case-control studies. Cancer Epidemiol Biomarkers Prev, 2000; 9(8): 835-838.
84 Shu XO, Perentesis JP, Wen W, et al. Parental exposure to medications and hydrocarbons and ras
   mutations in children with acute lymphoblastic leukemia: a report from the Children's Oncology
   Group. Cancer Epidemiol Biomarkers Prev, 2004; 13(7): 1230-1235.
85 Kolstad HA, Lynge E, Olsen J, et al. Incidence of lymphohematopoietic malignancies among styrene-
   exposed workers of the reinforced plastics industry. Scand J Work Environ Health, 1994; 20(4): 272-
   278.
86 Kolstad HA, Pedersen B, Olsen J, et al. Clonal chromosome aberrations in myeloid leukemia after
   styrene exposure. Scand J Work Environ Health, 1996; 22(1): 58-61.
87 Sathiakumar N, Graff J, Macaluso M, et al. An updated study of mortality among North American
   synthetic rubber industry workers. Occup Environ Med, 2005; 62(12): 822-829.
88 Delzell E, Sathiakumar N, Graff J, et al. An updated study of mortality among North American
   synthetic rubber industry workers. Res Rep Health Eff Inst, 2006; (132): 1-63.
89 NTP - National Toxicology Program. Report on carcinogens; Background document for
   formaldehyde. US Departerment of Health and Human Services, Public Health Service, National
   Toxicology Program. Internet: http://ntp.niehs.nih.gov/ntp/roc/twelfth/2009/november/
   formaldehyde_bd_final.pdf. Access date 3-10-2012.
90 NTP - National Toxicology Program. Final report on carcinogens. Background document for styrene.
   Rep Carcinog Backgr Doc, 2008; 8-5978: i-398.
91 EFSA Panel on Contaminants in the Food Chain (CONTAM). Scientific opinion on arsenic in food.
   Parma: European Food Safety Authority, 2009; EFSA Journal.
92 Pritchard JD. Inorganic arsenic. In: HPA Compendium of chemical hazards. London: Health
   Protection Agency, 2011.
93 Red RT, Richards SM, Torres C, et al. Environmental toxicant exposure during pregnancy. Obstet
   Gynecol Surv, 2011; 66(3): 159-169.
94 Codex Alimentarius Commission. Joint FAO/WHO Food Standards Programme. Rome: FAO/WHO,
   2011.
   References                                                                                          121
</pre>

====================================================================== Einde pagina 122 =================================================================

<br><br>====================================================================== Pagina 123 ======================================================================

<pre>95 Engel A and Lamm SH. Arsenic exposure and childhood cancer--a systematic review of the
   literature. J Environ Health, 2008; 71(3): 12-16.
96 Smith AH and Steinmaus CM. Health effects of arsenic and chromium in drinking water: recent
   human findings. Annu Rev Public Health, 2009; 30: 107-122.
97 Bakker SA, van Halem D, van Dijk H, et al. Arseen in drinkwater: niet alleen een probleem voor
   Bangladesh. H twee O : tijdschrift voor watervoorziening en afvalwaterbehandeling, 2008; 41(16):
   18-21.
98 Boffetta P, Tredaniel J, and Greco A. Risk of childhood cancer and adult lung cancer after childhood
   exposure to passive smoke: A meta-analysis. Environ Health Perspect, 2000; 108(1): 73-82.
99 Milne E, Greenop KR, Scott RJ, et al. Parental prenatal smoking and risk of childhood acute
   lymphoblastic leukemia. Am J Epidemiol, 2012; 175(1): 43-53.
00 HCN - Health Council of the Netherlands. Asthma, allergy and environmental factors. The Hague:
   Health Council of the Netherlands, 2007; publication no. 2007/15E.
01 Hashibe M, Straif K, Tashkin DP, et al. Epidemiologic review of marijuana use and cancer risk.
   Alcohol, 2005; 35(3): 265-275.
02 Infante-Rivard C and El-Zein M. Parental alcohol consumption and childhood cancers: a review. J
   Toxicol Environ Health B Crit Rev, 2007; 10(1-2): 101-129.
03 HCN - Health Council of the Netherlands. Risks of alcohol consumption related to conception,
   pregnancy and breastfeeding. The Hague: Health Council of the Netherlands, 2005; publication no.
   2004/22.
04 HCN - Health Council of the Netherlands. Preconception care: a good beginning. Den Haag: Health
   Council of the Netherlands, 2007; publication no. 2007/19E.
05 Blot WJ, Henderson BE, and Boice JD, Jr. Childhood cancer in relation to cured meat intake: review
   of the epidemiological evidence. Nutr Cancer, 1999; 34(1): 111-118.
06 IARC - International Agency for Research on Cancer. Third International Childhood Cancer Cohort
   Consortium Workshop. Lyon: IARC, 2010.
07 Colles A, Koppen G, Hanot V, et al. Fourth WHO-coordinated survey of human milk for persistent
   organic pollutants (POPs): Belgian results. Chemosphere, 2008; 73(6): 907-914.
08 van Steensel-Moll HA, Valkenburg HA, and van Zanen GE. Childhood leukemia and parental
   occupation. A register-based case-control study. Am J Epidemiol, 1985; 121(2): 216-224.
09 Sinnett D, Krajinovic M, and Labuda D. Genetic susceptibility to childhood acute lymphoblastic
   leukemia. Leuk Lymphoma, 2000; 38(5-6): 447-462.
10 Ward MH, Colt JS, Metayer C, et al. Residential exposure to polychlorinated biphenyls and
   organochlorine pesticides and risk of childhood leukemia. Environ Health Perspect, 2009; 117(6):
   1007-1013.
11 Van Larebeke NA, Birnbaum LS, Boogaerts MA, et al. Unrecognized or potential risk factors for
   childhood cancer. Int J Occup Environ Health, 2005; 11(2): 199-201.
12 McNally RJ and Eden TO. An infectious aetiology for childhood acute leukaemia: a review of the
   evidence. Br J Haematol, 2004; 127(3): 243-263.
13 Kreis IA, van Rongen E, and Kremer L. Aetiology of childhood leukaemia: summary of reviews that
   did not separate acute lymphoblastic and myeloid leukaemia. The Hague: Health Council of the
   Netherlands, 2011.
22 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 123 =================================================================

<br><br>====================================================================== Pagina 124 ======================================================================

<pre>14 Kinlen L. Childhood leukaemia, nuclear sites, and population mixing. Br J Cancer, 2011; 104(1):
   12-18.
15 Urayama KY, Buffler PA, Gallagher ER, et al. A meta-analysis of the association between day-care
   attendance and childhood acute lymphoblastic leukaemia. Int J Epidemiol, 2010; 39(3): 718-732.
16 Dahl S, Schmidt LS, Vestergaard T, et al. Allergy and the risk of childhood leukemia: a meta-
   analysis. Leukemia, 2009; 23(12): 2300-2304.
17 Martin RM, Gunnell D, Owen CG, et al. Breast-feeding and childhood cancer: A systematic review
   with metaanalysis. Int J Cancer, 2005; 117(6): 1020-1031.
18 Greaves MF. Aetiology of acute leukaemia. Lancet, 1997; 349(9048): 344-349.
19 WHO - World Health Organization. Global strategy for infant and young child feeding. Geneva:
   World Health Organization, 2003.
20 Voedingscentrum. Voeding van zuigelingen en peuters; uitgangspunten voor de voedingsadvisering
   voor kinderen van 0-4 jaar. Den Haag: Voedingscentrum, 2007.
21 Milne E, Royle JA, Miller M, et al. Maternal folate and other vitamin supplementation during
   pregnancy and risk of acute lymphoblastic leukemia in the offspring. Int J Cancer, 2010; 126(11):
   2690-2699.
22 Caughey RW and Michels KB. Birth weight and childhood leukemia: a meta-analysis and review of
   the current evidence. Int J Cancer, 2009; 124(11): 2658-2670.
23 Poole C, Greenland S, Luetters C, et al. Socioeconomic status and childhood leukaemia: a review. Int
   J Epidemiol, 2006; 35(2): 370-384.
24 HCN - Health Council of the Netherlands. Local environmental health concerns - risk
   communication, exposure assessment and cluster investigation. The Hague: Health Council of the
   Netherlands, 2001; publication no. 2001/10E.
25 van Dalen E, Kreis I, van Rongen E, et al. Aetiology of childhood acute lymphoblastic and myeloid
   leukaemia: an overview of reviews (evidence summary). Amsterdam: Cochrane Childhood Cancer
   Group, 2010.
26 Schulze-Rath R, Hammer GP, and Blettner M. Are pre- or postnatal diagnostic X-rays a risk factor
   for childhood cancer? A systematic review. Radiat Environ Biophys, 2008; 47(3): 301-312.
27 Laurier D, Jacob S, Bernier MO, et al. Epidemiological studies of leukaemia in children and young
   adults around nuclear facilities: a critical review. Radiat Prot Dosimetry, 2008; 132(2): 182-190.
28 Waller LA, Turnbull BW, Gustafsson G, et al. Detection and assessment of clusters of disease: an
   application to nuclear power plant facilities and childhood leukaemia in Sweden. Stat Med, 1995;
   14(1): 3-16.
29 Vlaanderen J, Vermeulen R, Heederik D, et al. Guidelines to evaluate human observational studies
   for quantitative risk assessment. Environ Health Perspect, 2008; 116(12): 1700-1705.
30 Calvente I, Fernandez MF, Villalba J, et al. Exposure to electromagnetic fields (non-ionizing
   radiation) and its relationship with childhood leukemia: a systematic review. Sci Total Environ, 2010;
   408(16): 3062-3069.
31 Elwood JM. Critical appraisal of epidemiological studies and clinical trials. 3rd edition. Oxford:
   Oxford University Press, 2007.
32 Freudenheim JL and Marshall JR. The problem of profound mismeasurement and the power of
   epidemiological studies of diet and cancer. Nutr Cancer, 1988; 11(4): 243-250.
   References                                                                                             123
</pre>

====================================================================== Einde pagina 124 =================================================================

<br><br>====================================================================== Pagina 125 ======================================================================

<pre>33 Armstrong BG. Effect of measurement error on epidemiological studies of environmental and
   occupational exposures. Occup Environ Med, 1998; 55(10): 651-656.
24 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 125 =================================================================

<br><br>====================================================================== Pagina 126 ======================================================================

<pre>  Annexes
A The Committee
B Consulted Experts / Reviewers
C ALL/AML CCG: Evidence Summary
D Childhood leukaemia in general: Evidence Summary
E Causality considerations and limitations
F Classifications of evidence
  Annexes                                          125
</pre>

====================================================================== Einde pagina 126 =================================================================

<br><br>====================================================================== Pagina 127 ======================================================================

<pre>26 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 127 =================================================================

<br><br>====================================================================== Pagina 128 ======================================================================

<pre>A The Committee
  •  M. van Eijkeren, Professor of Radiation Oncology, University of Ghent,
     Belgium, chairman
  •  F. Woudenberg, Psychologist, Public Health Service Amsterdam,
     The Netherlands, vice-chairman
  •  G. Eggermont, Visiting professor of Radiation Protection, Vrije Universiteit
     Brussel, Belgium
  •  J. Francart, Epidemiologist, Research Manager Belgian Cancer Registry,
     Brussels, Belgium, (since July 2012)
  •  S. van Gool, Professor of Paediatric Oncology, KU Leuven, Belgium
  •  W.A. Kamps, Emeritus Professor of Paediatric Oncology, University of
     Groningen, The Netherlands
  •  A. Keverling Buisman, Expert in Ionising Radiation, The Netherlands
  •  M. Kirsch-Volders, Professor of Genotoxicity, Vrije Universiteit Brussel,
     Belgium
  •  L.C.M. Kremer, Paediatrician, Academic Medical Centre Amsterdam, The
     Netherlands, and Head, International Cochrane Childhood Cancer Group
  •  N. van Larebeke, Professor of Carcinogenesis and Cancer Prevention,
     University of Ghent, Belgium
  •  G. van Maele-Fabry, Professor of Systematic Review and Meta-analysis,
     Université catholique de Louvain, Belgium
  •  W.F. Passchier, Emeritus Professor of Risk Analysis, Maastricht University,
     The Netherlands
  •  R. Pieters, Professor of Paediatric Oncology, Erasmus Medical Centre
     Rotterdam, The Netherlands
  •  B. Poppe, Geneticist, University of Ghent, Belgium
  •  F. Renard, Epidemiologist, Belgian Cancer Registry, Brussels, Belgium,
     (until March 2011)
  •  H. de Schutter, Physician Researcher, Belgian Cancer Registry, Brussels,
     Belgium, (since November 2011; since July 2012 as advisor)
  •  P. Smeesters, Expert in Ionising Radiation, Federal Agency for Nuclear
     Control, Brussels, Belgium
  •  L. Verschaeve, Professor of Genetic Toxicology, University of Antwerp &
     Scientific Public Health Institute Brussels, Belgium
  •  I. Kreis, Environmental Epidemiologist, Health Council of the Netherlands,
     The Hague, The Netherlands and Honorary Professor, University of
     Wollongong, Australia, advisor
  The Committee                                                                   127
</pre>

====================================================================== Einde pagina 128 =================================================================

<br><br>====================================================================== Pagina 129 ======================================================================

<pre>   •   K. Cauwerts, Veterinary Microbiologist, Superior Health Council, Brussels,
       Belgium, scientific secretary (until April 2012)
   •   M. Drijver, Medical Public Health Specialist in Environmental Health,
       Epidemiologist, Toxicologist, Health Council of the Netherlands, The Hague,
       The Netherlands, scientific secretary
   •   L. Peeters, Pharmaceutical Biotechnologist, Superior Health Council,
       Brussels, Belgium, scientific secretary (since April 2012)
   •   E. van Rongen, Radiobiologist, Health Council of the Netherlands, The
       Hague, The Netherlands, scientific secretary
   During the third meeting D. Heederik, Professor of Health Risk Assessment,
   Institute for Risk Assessment Sciences, University Utrecht, The Netherlands,
   was invited to give his views on quantitative risk assessment in human
   observational studies.
28 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 129 =================================================================

<br><br>====================================================================== Pagina 130 ======================================================================

<pre>B Consulted experts
  A draft version of this report has been reviewed by members of several Standing
  Committees of the Health Council of the Netherlands, by members of the
  Council and expert groups of the Superior Health Council, by (co)authors of
  meta-analyses on pesticides in relation to childhood leukaemia and by members
  of the EuSANH network. The following experts have contributed to this process:
  • P. Ambrósio, Lab. de Doenças Hematológicas Malignas, Unidade de
      Citogenética, Departamento de Genética, Instituto Nacional de Saúde Dr.
      Ricardo Jorge, Lisboa, Portugal
  • A.C. Ansink, Gynaecologist-oncologist, Chief medical officer curative
      medicine, Health Inspectorate, Ministry of Health, Utrecht, The Netherlands
  • I. de Beaufort, Professor of Medical Ethics, University Medical Center,
      Rotterdam, The Netherlands
  • Y. Benoit, Professor of Paediatric Hemato-oncology, Ghent University
      Hospital, Ghent, Belgium
  • H.F. Boersma, Radiation Protection Unit, University of Groningen, The
      Netherlands
  • H.R. Büller, Professor of Vascular Medicine, Academic Medical Center,
      Amsterdam, The Netherlands
  • M. Duverger van Bogaert, PH-toxicology section, WIV-ISP, Brussels,
      Belgium
  • L. Gamet-Payrastre, UMR 1089 Xénobiotiques, INRA, Toulouse, France
  • P. Groenewegen, Professor of Sociology, NIVEL, The Netherlands
  • T.H.J.J. van der Hagen, Professor of Reactor Physics, Faculty of Applied
      Sciences, Technical University, Delft, The Netherlands
  • J.J. Heimans, Professor of Neurology, VU Medical Center, Amsterdam, The
      Netherlands
  • L. Hens, Professor of Human Ecology, College HGR, Belgium
  • M. Hunink, Professor of Clinical Epidemiology and Radiology, University
      Medical Center, Rotterdam, The Netherlands
  • C. Infante-Rivard, Professor of Epidemiology, Faculty of Medicine, McGill
      University, Montréal, Canada
  • J.C. de Jongste, Professor of Paediatric Respiratory medicine, University
      Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands
  • G. Kok, Professor of Applied Psychology, Maastricht University, Maastricht,
      The Netherlands
  Consulted experts                                                               129
</pre>

====================================================================== Einde pagina 130 =================================================================

<br><br>====================================================================== Pagina 131 ======================================================================

<pre>   •  A. Knottnerus, Professor of General Practice, Scientific Council for
      Government Policy, The Hague, The Netherlands
   •  J. Leer, Professor of Radiotherapy, University Nijmegen Medical Center,
      Nijmegen, The Netherlands
   •  J. Mackenbach, Professor of Public Health, University Medical Center,
      Rotterdam, The Netherlands
   •  R. Marcos-Gragera, Unitat d’Epidemiologia i Registre de Càncer de
      Girona, Institut d’Investigació Biomèdica de Girona, Spain
   •  P. Martens, Professor of Sustainable Development, International Center for
      Integrated Assessment & Sustainable Development (ICIS), Maastricht
      University, Maastricht, The Netherlands
   •  J. van der Meer, Professor of Medicine, Nijmegen Institute for Infection,
      Inflammation and Immunity, University Nijmegen Medical Center,
      Nijmegen, The Netherlands
   •  G. Mulder, Emeritus Professor of Toxicology, Oegstgeest, The Netherlands
   •  J.G. Nijhuis, Professor of Gynaecology-perinatology, Maastricht University
      Medical Center, Maastricht, The Netherlands
   •  D. van Norren, Emeritus Professor of Ophthalmic Physics, Leusden, The
      Netherlands
   •  M. de Ridder, Occupational and Environmental Health, Public health
      department, Ghent University, Belgium
   •  S. de Sanjosé, Unit of Infections and Cancer, Cancer Epidemiology Research
      Programme, Institut Català d’Oncologia, Spain
   •  M.C. Turner, McLaughlin Centre for Population Health Risk Assessment,
      University of Ottawa, Ottawa, Canada
   •  J. Vanderstraeten, Research Center on Environmental Health and Work
      Health, School of Public Health, Université Libre de Bruxelles, Belgium
   •  A.L.M. Verbeek, Professor of Clinical Epidemiology, Department of
      Epidemiology, Biostatistics and HTA, University Nijmegen Medical Center,
      Nijmegen, The Netherlands
   •  S.P. Verloove-Vanhorick, Emeritus Professor of Paediatrics, Oegstgeest, The
      Netherlands
   •  M. Verweij, Public Health Ethics, Ethics Institute, Department of Philosophy,
      Utrecht University, Utrecht, The Netherlands
   •  C. Vleminckx, Unit Toxicology, Public Health and Surveillance, Brussels,
      Belgium
   •  D.T. Wigle, McLaughlin Centre for Population Health Risk Assessment,
      University of Ottawa, Ottawa, Canada
30 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 131 =================================================================

<br><br>====================================================================== Pagina 132 ======================================================================

<pre>C             ALL/AML: CCG Evidence Summary
              This annex contains summary tables of the evidence summary of the systematic
              review of reviews, performed by the Cochrane Childhood Cancer Group (CCG),
              in which ALL and AML were considered separately. 225
C.1           Physical risk factors
              Ionising radiation
                                                                                                      a 226
 Table C1. Short summary of the selected systematic review on pre- and postnatal diagnostic X-rays .
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.225)
 Pre- / postnatal          Type of leukaemia        Number of                  Results                 Quality of systematic
                                                                                             b                                c
 diagnostic X-rays                                  pooled or individual       OR (95% CI)             review/meta-analysis
                                                    studies
 Prenatal                  ALL                      1 individual               0.95 (0.73-1.23)        6/9 (67%)
                           AML                      1 individual               2.35 (0.79-7.00)
 Postnatal                 ALL                      1 individual               1.63 (1.43-1.85)
    The specific purpose of this review was to study the hypothesis that the association between prenatal and postnatal radiation
    exposure and childhood leukaemia would have become less strong, given technological improvements and the shift to non-
    ionising imaging technologies (ultrasound). The authors concluded that their results might be interpreted as a confirmation
    of this hypothesis, underlining, however, that the results do not contradict previous evidence accumulated since 1956,
    indicating risk increases associated with prenatal X-ray exposure.
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
              ALL/AML: CCG Evidence Summary                                                                                 131
</pre>

====================================================================== Einde pagina 132 =================================================================

<br><br>====================================================================== Pagina 133 ======================================================================

<pre> Table C2. Short summary of selected systematic review on residential proximity to nuclear facilities.227
  (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.225)
 Endpoint                  Type of leukaemia         Number of pooled or        Results                    Quality of systematic
                                                                                                                                 a
                                                     individual studies                                    review/meta-analysis
 Living closer to          ALL                       1 individual               Higher risk b              1/9 (11%)
 nuclear facility                                                               (significance level not
                                                                                stated)
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
    The conclusions in the ‘CCG Evidence Summary are based on one Swedish study, selected from the French review, as this
    was the only study that explicitly mentioned the type of leukaemia (ALL).228 There is a problem with this study as the
    conclusion of the reviewers in the original French research report (’Risque de leucémies pas plus élevé à proximité des sites
    qu’ailleurs’)129 differs from that published in an international journal in a special issue with the proceedings of a childhood
    leukaemia workshop (’Risk of leukaemia higher close to NPP than elsewhere’). It appears that the conclusion in the French
    research report is the correct one.
Extremely low-frequency (ELF) magnetic fields
 Table C3. Short summary of selected systematic reviews on ELF magnetic fields.18,140
                                                                                                             225
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Extremely low-frequency (ELF)            Type of         Number of pooled or        Results                   Quality of
                                                                                                        a
 magnetic fields                          leukaemia       individual studies         OR/RR (95% CI)            systematic review/
                                                                                                                              b
                                                                                                               meta-analysis
 Residential magnetic fields:140          ALL             > 2 individual             (Non-) significant        1/10 (10%)
 different definitions and                                                           higher risks
              c
 subgroups
 ≥ 0.4 μT                                 ALL             Pooled (unclear nr)        2.1 (1.3–3.3)
 Electric blankets:                       ALL             1 individual               1.6 (1.1-2.3)
 prenatal use
 postnatal use                            ALL                                        2.8 (1.5-5.0)
 Exposed to magnetic fields ≥0.4          ALL             1 individual               4.73 (1.14-19.7)          1/9 (11%)
 μT (as compared to <0.1 μT)18            AML             1 individual               Risk not increased
                                                                                     (no further
                                                                                     information
                                                                                     available)
    OR: odds ratio, RR: risk ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
    24-hour or spot measurements in one or more rooms, wire-codes, distance and relative load for power lines, exposure from
    different electrical appliances, etc.
 32            Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 133 =================================================================

<br><br>====================================================================== Pagina 134 ======================================================================

<pre>C.2           Chemical risk factors
Parental occupational exposure to pesticides
                                                                                                     166
 Table C4. Short summary of selected systematic review on parental occupational pesticide exposure.
                                                                                                 225
 (A detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Parental occupational      Type of               Number of           Results                 Quality of systematic review/
 pesticide exposure         leukaemia             combined or         OR (95% CI) a           meta-analysis b
                                                  individual studies
 Paternal                   ALL                   8                   1.30 (0.86-1.95)        5/10 (50%)
 (preconceptual)
                            AML                   4                   1.13 (0.59-2.14)
 Maternal                   ALL                   6                   2.64 (1.40-5.0)
 (prenatal)
                            AML                   4                   2.64 (1.47-4.74)
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
Residential exposure to pesticides
                                                                                          167
 Table C5. Short summary of selected systematic review on residential pesticide exposure.
 (A detailed summary is presented in the original CCG Evidence summary of systematic reviews.225)
 Residential pesticide     Type of             Number of combined or         Results               Quality of systematic
                                                                                           a                             b
 exposure                  leukaemia           individual studies            OR (95% CI)           review/meta-analysis
 During pregnancy          ALL                 5                             2.04 (1.54-2.68)      6/10 (60%)
                           AML                 3                             1.44 (0.81-2.59)
 During childhood          ALL                 4                             1.40 (0.90-2.16)
                           AML                 2                             1.71 (0.77-3.80)
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
Arsenic exposure in drinking water
                                                                                               195
 Table C6. Short summary of selected systematic review on arsenic exposure in drinking water.
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.225)
 Arsenic exposure in      Type of            Number of combined or       Results                Quality of systematic
                                                                                                                      a
 drinking water           leukaemia          individual studies                                 review/meta-analysis
 Prenatal                 ALL                1 individual                Non-significantly      0/9 (0%)
                                                                         lower risk
 Postnatal                ALL                1 individual                Non-significantly
                                                                         higher risk
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
              ALL/AML: CCG Evidence Summary                                                                              133
</pre>

====================================================================== Einde pagina 134 =================================================================

<br><br>====================================================================== Pagina 135 ======================================================================

<pre>Parental tobacco smoking
 Table C7. Short summary of selected systematic review on parental tobacco smoking.198
                                                                                                     225
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews )
 Exposure to passive             Type of            Number of pooled or      Results              Quality of systematic
                                                                                               a                        b
 smoking from parents            leukaemia          individual studies       OR/RR (95% CI)       review/meta-analysis
 From mother during              ALL                6 individual             Inconsistent         2/11 (18%)
 pregnancy; several                                                          results
            c
 subgroups                       AML                2 individual             Inconsistent
                                                                             results
 From mother before              ALL                1 individual             2.1 (1.0-4.3)
 pregnancy
 From father; several            ALL                4 pooled                 1.17 (0.96-1.42)
 subgroups                       AML                3 individual             Inconsistent
                                                                             results
    OR: odds ratio, RR: risk ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
    Number of cigarettes per day or any smoking.
Parental marijuana smoking
 Table C8. Short summary of selected systematic review on parental marijuana smoking.201
                                                                                                      225
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Marijuana (cannabis)           Type of            Number of pooled or     Results                 Quality of systematic
                                                                                           a                              b
 smoking by parents             leukaemia          individual studies      OR (95% CI)             review/meta-analysis
 Maternal use during or in      AML                1 individual            11.0 (1.42-85.20)       1/9 (11%)
 the year before pregnancy
 Paternal use                   AML                1 individual            1.47 (CI: not
                                                                           provided; p=0.32)
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
Parental alcohol consumption
                                                                                           202
 Table C9. Short summary of selected systematic review on parental alcohol consumption.
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.225)
 Parental alcohol             Type of            Number of pooled or    Results                   Quality of systematic
                                                                                       a                                b
 consumption                  leukaemia          individual studies     OR (95% CI)               review/meta-analysis
 Maternal alcohol consumption
 Year before pregnancy        ALL                1 individual           1.2 (0.9-1.5)             1/10 (10%)
 Month prior to pregnancy     ALL                2 individual           Inconsistent results
                              AML                1 individual           1.8 (1-3.3)
 During pregnancy;            ALL                > 2 individual         Inconsistent results
 several subgroups c
                              AML                > 2 individual         Inconsistent results
 34           Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 135 =================================================================

<br><br>====================================================================== Pagina 136 ======================================================================

<pre> During breast-feeding          ALL                 2 individual            Inconsistent results
                                AML                 1 individual            0.8 (0.3-1.9)
 Paternal alcohol consumption
 Month prior to                 ALL                 > 2 individual          Inconsistent results
 conception; several            AML                 > 2 individual          Inconsistent results
 subgroups
 Exposure period not            ALL                 1 individual            1.2 (0.8-1.9)
 stated
 One year prior to              AML                 1 individual            1.5 (0.6-3.5)
 conception
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
    Prior to conception, first, second or third trimester, number of glasses, type of drinks.
C.3           Infectious agents and other factors
Different infectious exposures
 Table C10. Short summary of selected systematic review on different infectious exposures.212
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.225)
 Different infectious              Type of             Number of pooled or       Results              Quality of systematic
                                                                                               a                            b
 exposures                         leukaemia           individual studies        OR (95% CI)          review/meta-analysis
 Different maternal                ALL                 > 2 individual            (Non-)               0/9 (0%)
 infections                                                                      significantly
                                                                                 higher risk
 Different childhood               ALL                 > 2 individual            Inconsistent results
 infections
 Different vaccinations            ALL                 > 2 individual            Inconsistent results
 Birth order; several              ALL                 > 2 individual            Inconsistent results
 subgroups                         AML                 1 individual              1.59 (1-2.53)
 Paternal occupational             ALL                 1 individual              1.5 (1.1-2.1)
 social contact levels
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
              ALL/AML: CCG Evidence Summary                                                                               135
</pre>

====================================================================== Einde pagina 136 =================================================================

<br><br>====================================================================== Pagina 137 ======================================================================

<pre>Early social contacts
 Table C11. Short summary of selected systematic review on early social contacts.215
                                                                                                      225
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Day-care attendance and other        Type of          Number of pooled or     Results              Quality of systematic
                                                                                             a                              b
 early social contacts                leukaemia        individual studies      OR (95% CI)          review/meta-analysis
 Day-care attendance or social        ALL              > 2 individual          (Non-)               4/11 (36%)
 contacts; different definitions                                               significantly
                 c
 and subgroups                                                                 lower risks
                                      common-          7 pooled                0.83 (0.70-0.98)
                                      ALL d
                                                       > 2 individual          (Non-)
                                                                               significantly
                                                                               lower risks
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
    Day-care attendance, preschool playgroup, regular contact with children from outside home or social activities at different
    age or in different intensity.
    Most frequent type of ALL: common B-cell precursor ALL (cALL).
Allergies
                                                                        216
 Table C12. Short summary of selected systematic review on allergies.
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.225)
 Different types of           Type of           Number of pooled or         Results               Quality of systematic
                                                                                           a                              b
 allergy                      leukaemia         individual studies          OR (95% CI)           review/meta-analysis
 Overall allergy              ALL               8 pooled                    0.67 (0.54-0.82)      5/11 (45%)
                              AML               3 individual                Non-significantly
                                                                            lower risk
 Asthma                       ALL               6 pooled                    0.82 (0.63-1.10)
 Hay fever                    ALL               5 pooled                    0.53 (0.43-0.65)
 Eczema                       ALL               5 pooled                    0.68 (0.56-0.83)
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
 36           Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 137 =================================================================

<br><br>====================================================================== Pagina 138 ======================================================================

<pre>Breast-feeding
 Table C13. Short summary of selected systematic review on breast-feeding.217
                                                                                                      225
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Breast-feeding                     Type of          Number of pooled or     Results                 Quality of systematic
                                                                                            a                               b
                                    leukaemia        individual studies      OR (95% CI)             review/meta-analysis
 Breast-feeding                     ALL              17 pooled               0.91 (0.84-0.98)        6/11 (55%)
                                    AML                9 pooled              0.88 (0.76-1.02)
 Duration of breast-feeding         ALL              12 pooled               0.93 (0.86-1.00)
 < 6 months                         AML                8 pooled              0.97 (0.81-1.17)
 Duration of breast-feeding         ALL              13 pooled               0.81 (0.72-0.91)
 > 6 months                         AML                9 pooled              0.72 ( 0.57-0.91)
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
Maternal folate and vitamin supplementation
                                                                                                          221
 Table C14. Short summary of selected systematic review on maternal folate and vitamin supplementation.
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.225)
 Maternal folate and vitamin           Type of      Number of pooled or        Results              Quality of systematic
                                                                                              a                           b
 supplementation                       leukaemia    individual studies         OR (95% CI )         review/meta-analysis
 Vitamins with folate versus no        ALL          2 pooled                   1.06 (0.77-1.46)     1/11 (9%)
 folate during pregnancy
 Vitamins with folate versus no        ALL          2 pooled                   1.02 (0.86-1.21)
 vitamins during pregnancy
 Vitamins before pregnancy             ALL          2 pooled                   0.95 (0.95-1.18)
 Vitamins only before pregnancy        ALL          2 pooled                   1.05 (0.55-2.01)
 Vitamins during pregnancy             ALL          5 pooled                   0.83 (0.73-0.94)
 Folate before pregnancy               ALL          1 individual               1.63 (0.55-4.82)
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
              ALL/AML: CCG Evidence Summary                                                                             137
</pre>

====================================================================== Einde pagina 138 =================================================================

<br><br>====================================================================== Pagina 139 ======================================================================

<pre>Birth weight
                                                                           222
 Table C15. Short summary of selected systematic review on birth weight.
                                                                                                        225
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Birth weight              Type of leukaemia      Number of pooled or       Results                Quality of systematic
                                                  individual studies        OR (95% CI) a          review/meta-analysis b
 High birth weight         ALL                    23 pooled                 1.24 (1.18-1.33)       2/11 (18%)
 compared to normal        AML                      9 pooled                1.24 (1.16-1.32)
 birth weight
 Low birth weight          ALL                    10 pooled                 0.97 (0.81-1.16)
                           AML                      9 pooled                1.50 (1.05-2.13)
 Per kilogram increase     ALL                    16 pooled                 1.18 (1.12-1.23)
 in birth weight
     OR: odds ratio, CI: confidence interval.
     Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
     criteria.
Socio-economic status
 Table C16. Short summary of selected systematic review on socio-economic status.223
                                                                                                        225
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Socioeconomic status            Type of      Number of             Results                            Quality of systematic
                                 leukaemia    pooled or                                                review/meta-analysis a
                                              individual studies
 Family income                   ALL          4 individual          Inconsistent results               2/9 (22%)
                                 AML          1 individual          Higher AML rates
                                                                    significantly associated with a
                                                                    lower socioeconomic status
 Mother’s education              ALL          6 individual          Inconsistent results
                                 AML          1 individual          Higher AML rates non-
                                                                    significantly associated with a
                                                                    lower socioeconomic status
 Father’s education              ALL          4 individual          Higher ALL rates (non-)
                                                                    significantly associated with a
                                                                    higher socioeconomic status
                                 AML          2 individual          Higher AML rates (non-)
                                                                    significantly associated with a
                                                                    lower socioeconomic status
 Father’s occupational class     ALL          2 individual          Higher ALL rates non-
                                                                    significantly associated with a
                                                                    higher socioeconomic status
 Household density               ALL          1 individual          Higher ALL rates non-
                                                                    significantly associated with a
                                                                    higher socioeconomic status
 Derived measure (i.e.           ALL          1 individual          Higher ALL rates non-
 combining father’s                                                 significantly associated with a
 education and occupation)                                          lower socioeconomic status
 Ecological measures             ALL          1 individual          Higher ALL rates
 (i.e. both education and                                           significantly associated with
 occupational class)                                                a higher socioeconomic
                                                                    status
     Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
     criteria.
 38            Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 139 =================================================================

<br><br>====================================================================== Pagina 140 ======================================================================

<pre>D             Childhood leukaemia in general:
              Evidence Summary
              This annex contains summary tables of the evidence summary of the systematic
              review of reviews in which childhood leukaemia in general was considered.213
D.1           Physical risk factors
              Ionising radiation
                                                                                                      a 226
 Table D1. Short summary of the selected systematic review on pre- and postnatal diagnostic X-rays .
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.213)
 Pre- / postnatal                  Number of                        Results                          Quality of systematic
                                                                                               b                           c
 diagnostic X-rays                 pooled or individual studies     OR / SIR / SMR (95% CI)          review/meta-analysis
 Prenatal                          9 pooled                         0.99 (0.87-1.13)                 8/10 (80%)
 Postnatal                         1 individual                     1.29 (1.04-1.60)
                                   3 individual                     Non-significant results
    The purpose of this review was to study the hypothesis that the association between prenatal and postnatal radiation
    exposure and childhood leukaemia would have become less strong, given technological improvements and the shift to non-
    ionising imaging technologies (ultrasound). The authors concluded that their results might be interpreted as a confirmation
    of this hypothesis, underlining, however, that the results do not contradict previous evidence accumulated since 1956,
    indicating risk increases associated with prenatal X-ray exposure.
    OR: odds ratio, SIR: standardized incidence ratio, SMR: standardized mortality ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
                                                                                                       227
 Table D2. Short summary of selected systematic review on residential proximity to nuclear facilities.
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.213)
 Endpoint                   Number of pooled or           Results                           Quality of systematic
                                                                                                                  a
                            individual studies                                              review/meta-analysis
 Living closer to           25 individual                 No significance levels given      2/10 (20%)
 nuclear facility
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
              Childhood leukaemia in general: Evidence Summary                                                             139
</pre>

====================================================================== Einde pagina 140 =================================================================

<br><br>====================================================================== Pagina 141 ======================================================================

<pre>Extremely low-frequency (ELF) magnetic fields
                                                                                       18,140
 Table D3. Short summary of selected systematic reviews on ELF magnetic fields.
                                                                                                             213
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Extremely low-frequency (ELF)               Number of pooled or            Results                      Quality of systematic
                                                                                               a                               b
 magnetic fields                             individual studies             OR/RR (95% CI)               review/meta-analysis
 Residential magnetic fields:140             22 individual                  (Non-)significant            2/10 (20%)
    different types of studies, different                                   higher risks
                                 c
    definitions and subgroups
    ≥0.4 μT                                  9 pooled                       2.0 (1.3-3.1)
 Electric blankets, pre- and                 3 individual                   Inconsistent results
 postnatal use
 Hair dryer                                  1 individual                   2.8 (1.4-6.3)
 Distance to transmission lines <49 m        1 individual                   1.67                         1/10 (10%)
                             18
 (as compared to > 600 m)
 Exposure to magnetic fields ≥0.4 μT         1 individual                   2.63 (0.77-8.96)
 (as compared to <0.1 μT)
    OR: odds ratio, RR: risk ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
    Prior to conception, first, second or third trimester, number of glasses, type of drinks.
Diagnostic ultrasound scans
                                                                                              156
 Table D4. Short summary of selected systematic reviews on diagnostic ultrasound scans.
                                                                                                             213
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Diagnostic ultrasound       Number of pooled or             Results                             Quality of systematic review/
       156                                                                                                      a
 scans                       individual studies                                                  meta-analysis
 Ultrasound exposure         3 individual                    Neither higher or lower risk        3/10 (30%)
 in utero
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
D.2           Chemical risk factors
Parental occupational exposure to pesticides
 Table D5. Short summary of selected systematic review on parental occupational pesticide exposure.166
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.213)
 Parental occupational      Number of combined or           Results                            Quality of systematic review/
                                                                          a                                   b
 pesticide exposure         individual studies              OR (95% CI)                        meta-analysis
 Paternal                                                                                      7/11 (64%)
 (preconceptional)
    - any pesticides        30 pooled                       1.09 (0.88-1.34)
    - insecticides            3 pooled                      1.43 (1.06-1.92)
    - herbicides              5 pooled                      1.25 (0.94-1.66)
 40           Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 141 =================================================================

<br><br>====================================================================== Pagina 142 ======================================================================

<pre>    - fungicides             4 pooled                   1.66 (0.87-3.17)
 Maternal (prenatal)
    - any pesticides       16 pooled                    2.09 (1.51-2.88)
    - insecticides          6 pooled                    2.72 (1.47-5.04)
    - herbicides            2 pooled                    3.62 (1.28-10.3)
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
Residential exposure to pesticides
                                                                                          167
 Table D6. Short summary of selected systematic review on residential pesticide exposure.
                                                                                                     213
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Residential pesticide     Number of combined or        Results                         Quality of systematic review/
 exposure                  individual studies           OR (95% CI) a                   meta-analysis b
 During pregnancy                                                                       8/11 (73%)
    - unspecified          11 pooled                    1.54 (1.13-2.11)
    - insecticides           8 pooled                   2.05 (1.80-2.32)
    - herbicides             5 pooled                   1.61 (1.20-2.16)
 During childhood
    - unspecified            9 pooled                   1.38 (1.12-1.70)
    - insecticides           7 pooled                   1.61 (1.33-1.95)
    - herbicides             4 pooled                   0.96 (0.59-1.58)
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
Maternal cured meat intake
                                                                                      205
 Table D7. Short summary of selected systematic review on maternal cured meat intake.
                                                                                                     213
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Maternal cured meat       Number of pooled or          Results                         Quality of systematic review/
                                                                      a                                b
 intake                    individual studies           OR (95% CI)                     meta-analysis
 Intake level              3 individual                 Non-significantly higher risk   4/10 (40%)
 Meat type:                1 individual                 (no significance level given)
 hotdogs                                                0.9
 bacon & sausages                                       1.5
 lunch meat                                             1.0
 Ham                                                    1.5
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
              Childhood leukaemia in general: Evidence Summary                                                         141
</pre>

====================================================================== Einde pagina 142 =================================================================

<br><br>====================================================================== Pagina 143 ======================================================================

<pre>D.3           Infectious agents and other factors
Different infectious exposures
 Table D8. Short summary of selected systematic review on different infectious exposures.212
                                                                                                      213
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews. )
 Different infectious        Number of pooled or         Results                                    Quality of systematic
 exposures                   individual studies          OR (95% CI) a                              review/meta-analysis b
 Different maternal          > 2 individual              (Non-) significantly higher risks
 infections
 Different childhood         > 2 individual              Inconsistent (non) significant results
 infections
 Different vaccinations      > 2 individual              Non-significant results, except for
                                                         significant lower risk for
                                                         ‘immunisations’
 Birth order; several        > 2 individual              Conflicting results
 subgroups
 Paternal occupational       > 2 individual              Inconsistent results
 social contact levels
    OR: odds ratio, CI: confidence interval.
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
Socio-economic status
 Table D9. Short summary of selected systematic review on socio-economic status.223
 (A more detailed summary is presented in the original CCG Evidence summary of systematic reviews.213)
 Socioeconomic status                 Number of pooled or      Results                            Quality of systematic
                                                                                                                        a
                                      individual studies                                          review/meta-analysis
 Family income                        1 individual             Non-significant higher risk        3/10 (30%)
                                      4 individual             Significant lower risks
                                      3 individual             Non-significant lower risks
 Mother’s education                   2 individual             Significant higher risks
                                      4 individual             Non-significant higher risks
                                      5 individual             Significant lower risks
                                      2 individual             Non-significant lower risks
 Father’s education                   2 individual             Non-significant higher risks
                                      4 individual             Significant lower risks
                                      3 individual             Non-significant lower risks
 Father’s occupational class          3 individual             Significant higher risks
                                      5 individual             Non-significant higher risks
                                      1 individual             Significant lower risk
                                      2 individual             Non-significant lower risks
 Household density                    1 individual             Significant higher risk
                                      1 individual             Non-significant higher risk
                                      1 individual             Non-significant lower risk
 Derived measure (i.e. combining      1 individual             Non-significant lower risk
 father’s education and
 occupation)
 Highest parental education           3 individual             Inconsistent results
    Methodological quality of systematic review/meta-analysis, i.e. total number of criteria scored as yes out of applicable
    criteria.
 42           Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 143 =================================================================

<br><br>====================================================================== Pagina 144 ======================================================================

<pre>E   Causality considerations and
    limitations
    The Committee has focussed in this report on epidemiological studies. In such
    observational studies the quality of exposure assessment is crucial, especially in
    deriving dose response relations.229 Moreover, the reduction of bias and the
    adjustment for confounding factors are important in assessing the evidence for
    causality of associations. The data presented in chapters 4-6 show that some
    associations have been found, but these cannot be taken as proof of causality.
    One standard tool in assessing evidence for causality are Bradford Hill’s
    considerations: strength, consistency, specificity, temporality, biological gradient
    (or exposure-response), plausibility, coherence, experiment, analogy.14,15
E.1 The Bradford Hill considerations
    Bradford Hill emphasised that none of the following nine considerations can
    bring indisputable evidence for or against the cause-and-effect hypothesis and
    none can be required as a sine qua non. So, absence does not disprove causality,
    only presence is considered a contributing argument that causality exists.
    Strength
    A relative risk or odds ratio higher than 2 would usually be considered a
    relatively strong association. However, few environmental risk factors of disease
    reach such values. Also as there is often substantial misclassification of
    exposure, this mostly leads to underestimation of the real risk, thus decreasing
    the strength. In this report most of the relative risks and odds ratios are too low
    (< 2-3) to be considered as contributing to the strength argument.
    Consistency
    Consistency of results from different studies strengthens the causality argument.
    However, different exposure situations are often not identical, which makes it
    very hard for environmental causes to fulfil this criterion. In this report most of
    the evidence for individual exposures comes from a limited number of studies.
    As in the previous consideration, the absence of consistency does not disprove
    causality, the argument is just not strengthened.
    Causality considerations and limitations                                             143
</pre>

====================================================================== Einde pagina 144 =================================================================

<br><br>====================================================================== Pagina 145 ======================================================================

<pre>   Specificity
   Specificity of outcome means that the exposure is not associated with different
   adverse outcomes. The literature evaluated in this report is often focussed on
   childhood leukaemia and other diseases/outcomes are usually not considered.
   This does not mean that other outcomes do not occur, the information on that is
   simply not available. However, in general specificity is one of the weakest
   considerations, as it very rarely the case that only one carcinogen causes disease.
   Temporality
   Risk factors for childhood leukaemia can mostly only be investigated in case-
   control studies. This means that exposure is measured retrospectively, so
   temporality can never truly be addressed like in prospective cohort studies. This
   is a considerable problem, as temporality is a crucial consideration. A potential
   cause cannot be an actual cause if the exposure occurred after the disease
   developed. It should be noted that various biases in case-control studies, such as
   responder and recall bias, might influence the recall of timing of exposure.
   Ultimately only prospective cohort studies can solve this, but these are rare in the
   collection of investigations reviewed in this report.
   Biological gradient or exposure-response
   Exposure-response relationships can only be assessed if exposure can be
   measured adequately and with sufficient precision.229 However, since often only
   the use of questionnaires or at best spot-sampling are available methods,
   exposure assessment is difficult and often also done poorly.
       A complicating factor with childhood leukaemia is that exposure can occur at
   different phases in the development of a child: before, during and after
   pregnancy. Exposure of the parent to environmental factors before conception or
   during the pregnancy may both related to genetic or epigenetic damage, the latter
   for instance by enhanced proliferation of cells.230 Effects of exposure at an early
   stage of pregnancy may differ from exposure at a later stage and from postnatal
   exposure.
       Another problem is that in practice children and their parents are exposed to
   mixtures of different agents, but there is hardly any study performed on
   interactions, not only of agents, but also between prenatal and postnatal
   exposures.
   Plausibility
   This refers to the understanding of the biological model behind the causality of
   the exposures in questions. If there is information available, the argument for
44 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 145 =================================================================

<br><br>====================================================================== Pagina 146 ======================================================================

<pre>    causality is strengthened, but for many suspected carcinogens the quantitative
    details of biological model are unknown.
    Coherence
    This argument means that the cause and effect interpretation should not seriously
    conflict with the generally known facts of the natural history and biology of the
    disease. However, as in reality little is known about the natural history of
    childhood leukaemias besides their clinical features, it is not a useful
    consideration in the framework of this report.
    Experiment
    Data from experimental studies, showing evidence for effects, may strengthen
    the biological plausibility of an association. Of course for childhood leukaemia
    only animal experiments are acceptable. However, the question is whether the
    animals used (mostly rodents) are an adequate model for humans and how the
    doses given to the animals are comparable to doses in humans. For exposure
    around pregnancy the timing of the exposure may well be different also.
    Analogy
    According to Bradford Hill, it would in some circumstances be fair to judge by
    analogy. This means that if it is known that the effect of one type of exposure can
    lead to childhood leukaemia, a similar effect from another type of exposure
    might also. However, the variety of types of exposure addressed in this report is
    so wide and so little is known about these exposures, that analogy is not a very
    useful consideration in practice.
E.2 Chance, bias and confounding
    In addition to the Bradford Hill considerations and the strength of evidence,
    alternative explanations for epidemiological associations other than causality
    should be considered: chance, bias (specifically exposure misclassification) and
    confounding. If these are unlikely, a causal relation is more likely. In particular in
    situations of sparse epidemiological evidence and a lack of information on these
    factors, judgements about the causal nature of reported associations between
    exposures and childhood leukaemia have to be made with caution.
    Causality considerations and limitations                                               145
</pre>

====================================================================== Einde pagina 146 =================================================================

<br><br>====================================================================== Pagina 147 ======================================================================

<pre>   Chance
   If associations are observed in epidemiological studies, it needs to be determined
   whether they can be explained by either chance or a particular cause. By
   definition there is a five-percent likelihood that a ‘statistically significant’
   association will be found that can be attributed to chance (a ‘false positive’). If
   several statistical tests (multiple comparisons) are made, a ‘statistically
   significant’ association will be attributable to coincidence in one in twenty tests.
   On the other hand, not finding an association can also be a chance finding (a
   ‘false negative’).
   Bias
   Effect measured in epidemiological studies can be biased in three ways: through
                                                       10
   selection bias, information bias or confounding. They differ for different types
   of studies, such as cohort and case-control studies.
   Selection bias. Selection bias may occur as a result of the way the study
   population is selected. In case-control studies, participants enter the study based
   on being ill (cases) or explicitly not having the disease of interest (controls). The
   selection that occurs at the start of the study can already bias the results. In some
   studies the selection of both cases and controls is conducted within one or several
   hospitals. However, the patterns of hospital admission can be different for
   different diseases. For instance, if the hospital is the only possible treatment
   facility for cancer in the region but there are many smaller hospitals for e.g.
   emergencies, the hospital treating cancer will cater for different populations for
   the cancer patients than for its emergency ward patients. If the controls are
   recruited from the latter groups, the cases and controls are drawn from different
   populations that might not be comparable. Population-based case-control studies
   suffer less from this selection bias, but in these studies it needs to be clear that the
                                                                                        231
   controls are truly representative for the same community as the cases.
   Response rates in case-control studies need to be high enough for the study
   population to be representative of the population it stems from, ideally at least
   70%, and they also need to be sufficiently similar between cases and controls.
   Information bias. Information bias can occur through misclassification of health
   effects as well as through misclassification of the exposure.
   Misclassification of effect. Misclassification of effects may, for example, occur
   as the result of differences in reporting, diagnostics, registration, coding,
   admission and treatment policy, or availability and accessibility of health care.
46 Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 147 =================================================================

<br><br>====================================================================== Pagina 148 ======================================================================

<pre>Misclassification of exposure. Quantification of exposure is almost always very
crude and this lack of precision leads to a flattening of the exposure-response
       232
curve.     Misclassification can also occur if the exposure occurred many years
before the health effects, making it difficult to measure the exposure in question.
If the misclassification of the exposure occurs proportionally in the case and
                                                                     233
control population, the result generally underestimating the risk.
Reduction of information bias: blinding. In case-control studies it is impossible
to blind the cases for the diagnosis. Once diagnosed, patients will search for
explanations of their illness. They are likely to report their past exposure for any
potential cause differently from controls who do not have this incentive. As
patients are often clearly ill, it is also virtually impossible to blind interviewers
for the disease status, thus allowing for suggestive interviewing in either
direction. Blinding the observers through the use of mailed-in or web-based
questionnaires is the only way to control this. Even telephone interviews are
often not blinded, as patients are likely to reveal their disease status.231
Confounding
Health status depends on many factors, including age, sex, level of urbanisation,
socio-economic status, ethnicity, smoking habits and other lifestyle factors.
Availability of health services can also affect the health status. The effect of these
factors may differ considerably from one situation to another, which increases
the risk of confounding the study on the relationship between environmental
exposure and disease, especially if associations are weak.
    A confounding factor is described as a known risk factor that is associated
with the exposure being studied, but that is not an intermediary factor in the
                                                      10
causal relationship between exposure and effect. If there are sufficient data on
relevant risk factors, it is possible to adjust for confounding. They need to be
controlled for and thus measured. Age, sex, social-economic status and education
are common confounders, but other factors are also possible. Matching of cases
and controls can be a way to control confounding, but in some cases can
                                                                      231
introduce confounding also, so over-matching should be avoided.
Causality considerations and limitations                                               147
</pre>

====================================================================== Einde pagina 148 =================================================================

<br><br>====================================================================== Pagina 149 ======================================================================

<pre>48 Childhood leukaemia and environmental factors</pre>

====================================================================== Einde pagina 149 =================================================================

<br><br>====================================================================== Pagina 150 ======================================================================

<pre>F Classifications of evidence
  IARC-classification of scientific evidence
  To characterise the strength of evidence for a causal relation between exposure to
  environmental factors and cancer IARC16 developed a classification based on:
  • Epidemiological evidence
  • Animal experimental evidence and
  • Mechanistic and other evidence.
  The evidence from studies in humans and experimental animals is classified into
  one of the following categories:
  • Sufficient evidence of carcinogenity
  • Limited evidence of carcinogenity
  • Inadequate evidence of carcinogenity
  • Evidence suggesting lack of carcinogenity.
  Together with the available mechanistic and other evidence the body of evidence
  is considered as a whole, in order to reach an overall evaluation of the
  carcinogenity of the agent to humans. The following categories are
  distuinguished:
  • Group 1: the agent is carcinogenic to humans
  • Group 2A: the agent is probably carcinogenic to humans
  • Group 2B: the agent is possibly carcinogenic to humans
  • Group 3: the agent is not classifiable as to its carcinogenicity to humans
  • Group 4: the agent is probably not carcinogenic to humans.
  This classification cannot as such be used in the present report, since
  experimental and mechanistic evidence is not considered in detail.
  Wigle-classification of epidemiological evidence
  Wigle expressed the IARC-classification of epidemiological evidence for causal
  relationships between child health outcomes and environmental chemical
  contaminants as three ‘levels of evidence’: sufficient, limited or inadequate,
  according to predefined criteria of the U.S. National Academy of Sciences (Table
       17
  F1).
  Classifications of evidence                                                        149
</pre>

====================================================================== Einde pagina 150 =================================================================

<br><br>====================================================================== Pagina 151 ======================================================================

<pre>Table F1. Wigle’s classification of epidemiological evidence.
Level of         Definition
evidence
Sufficient       At least one expert group has reviewed the available evidence and published a peer-reviewed report
                 indicating a consensus view that there is a causal relationship.
Limited          Limited evidence is suggestive of an association between the agent and the outcome but is limited (and
                 may or may not represent a causal relationship) because chance, bias and confounding cannot be ruled out
                 with confidence, e.g. at least one high quality study shows a positive association but the results of other
                 studies are inconsistent.
Inadequate       Available studies are of insufficient quality (e.g. available studies have failed to adequately control for
                 confounding or have inadequate exposure assessment), consistency or statistical power to permit a
                 conclusion regarding the presence or absence of an association or no studies exist that examine the
                 relationship.
50         Childhood leukaemia and environmental factors
</pre>

====================================================================== Einde pagina 151 =================================================================

<br><br>====================================================================== Pagina 152 ======================================================================

<pre>About the Superior Health Council
of Belgium and the Health Council of
the Netherlands
                                     153
</pre>

====================================================================== Einde pagina 152 =================================================================

<br><br>====================================================================== Pagina 153 ======================================================================

<pre>   The Superior Health Council
   The Superior Health Council (SHC) is a federal body that is part of the Federal
   Public Service Health, Food Chain Safety and Environment. It was founded in
   1849 and provides scientific advisory reports on public health issues to the
   Ministers of Public Health and the Environment, their administration, and a few
   agencies. These advisory reports are drawn up on request or on the SHC’s own
   initiative. The SHC takes no decisions on the policies to follow, nor does it
   implement them. It does, however, aim at giving guidance to political decision-
   makers on public health matters. It does this on the basis of the most recent
   scientific knowledge
   Apart from its 25-member internal secretariat, the Council draws upon a vast
   network of over 500 experts (university professors, members of scientific
   institutions), 200 of whom are appointed experts of the Council. These experts
   meet in multidisciplinary working groups in order to write the advisory reports.
   As an official body, the Superior Health Council takes the view that it is of key
   importance to guarantee that the scientific advisory reports it issues are neutral
   and impartial. In order to do so, it has provided itself with a structure, rules and
   procedures with which these requirements can be met efficiently at each stage of
   the coming into being of the advisory reports. The key stages in the latter process
   are: 1) the preliminary analysis of the request, 2) the appointing of the experts
   within the working groups, 3) the implementation of the procedures for
   managing potential conflicts of interest (based on the declaration of interest, the
   analysis of possible conflicts of interest, and a referring committee) and 4) the
   final endorsement of the advisory reports by the Board (ultimate decision-
   making body). This coherent set of procedures aims at allowing the SHC to issue
   advisory reports based on the highest level of scientific expertise available whilst
   maintaining all possible impartiality.
   The advisory reports drawn up by the working groups are submitted to the
   Board. Once they have been endorsed, they are sent to those who requested them
   as well as to the Minister of Public Health and are subsequently published on the
   SHC website (www.css-hgr.be), except as regards confidential advisory reports.
   Some of them are also communicated to the press and to target groups among
   healthcare professionals.
   The SHC is also an active partner in developing the EuSANH network
   (European Science Advisory Network for Health), which aims at drawing up
   advisory reports at the European level.
   In order to receive notification about the activities and publications of the SHC,
   you can send a mail to info.hgr-css@health.belgium.be.
54
</pre>

====================================================================== Einde pagina 153 =================================================================

<br><br>====================================================================== Pagina 154 ======================================================================

<pre>The Health Council of the Netherlands
The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, and Education, Culture & Science. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to
government policy.
Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
Members of Health Council Committees are appointed in a personal capacity
because of their special expertise in the matters to be addressed. Nonetheless, it
is precisely because of this expertise that they may also have interests. This in
itself does not necessarily present an obstacle for membership of a Health
Council Committee. Transparency regarding possible conflicts of interest is
nonetheless important, both for the chairperson and members of a Committee
and for the President of the Health Council. On being invited to join a
Committee, members are asked to submit a form detailing the functions they
hold and any other material and immaterial interests which could be relevant for
the Committee’s work. It is the responsibility of the President of the Health
Council to assess whether the interests indicated constitute grounds for non-
appointment. An advisorship will then sometimes make it possible to exploit the
expertise of the specialist involved. During the inaugural meeting the
declarations issued are discussed, so that all members of the Committee are
aware of each other’s possible interests.
                          The EuSANH-ISA project is supported by funding under the Seventh
                          Framework Programme of the European Conmmunity under grant
                          agreement number 229716.
                                                                                           155
</pre>

====================================================================== Einde pagina 154 =================================================================

<br><br>====================================================================== Pagina 155 ======================================================================

<pre>56</pre>

====================================================================== Einde pagina 155 =================================================================

<br><br>====================================================================== Pagina 156 ======================================================================

<pre>														
														
</pre>

====================================================================== Einde pagina 156 =================================================================

<br><br>