TRAINING FOR THE HEALTH SECTOR [Date …Place …Event…Sponsor…Organizer]

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TRAINING FOR THE HEALTH SECTORTRAINING FOR THE HEALTH SECTOR [Date …Place …Event…Sponsor…Organizer] [Date …Place …Event…Sponsor…Organizer]

CHILDREN AND CANCER CHILDREN AND CANCER

Children's Health and the EnvironmentWHO Training Package for the Health Sector

World Health Organization

www.who.int/ceh

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Children and CancerChildren and Cancer

CHILDHOOD CANCERCHILDHOOD CANCER

OBJECTIVES

To discuss childhood cancer

To address the links between childhood environments and adult onset of cancer

To present current knowledge of causation and environmental risk factors

To discuss cancer clusters

To present educational and preventive measures

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OVERVIEWOVERVIEW

1. INCIDENCE AND TYPES OF CHILDHOOD CANCER

2. CAUSES, RISK FACTORS AND HYPOTHESES

3. BIOLOGICAL PROCESSES LEADING TO CANCER DEVELOPMENT

4. EXPOSURE ASSESSMENT AND ITS CHALLENGES

5. INVESTIGATING POTENTIAL CANCER CLUSTERS

6. QUESTIONS FROM PARENTS

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* Rates are per 100,000 population and age adjusted to the 2000 US standard population.

TEN LEADING CAUSES OF DEATHTEN LEADING CAUSES OF DEATH (Children aged under 15 years) U.S. 2006

CAUSE OF DEATH NO. OF DEATHS % OF TOTAL DEATHS DEATH RATE*

RANK ALL CAUSES 10780 100.0 19.0

1 Accidents (unintentional injuries) 3868 35.9 6.82 Cancer 1284 11.9 2.33 Congenital anomalies 859 8.0 1.54 Assault (homicide) 756 7.0 1.35 Heart diseases 414 3.8 0.76 Intentional self-harm (suicide) 219 2.0 0.47 Influenza & pneumonia 193 1.8 0.38 Septicemia 172 1.6 0.39 Chronic lower respiratory diseases 158 1.5 0.3

10 Cerebrovascular disease 149 1.4 0.3All other causes 2708 25.1 -

Based on US Mortality Data, 2006, National Center for Health Statistics, Centers for Disease Control and Prevention, 2009

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INCIDENCE CHILDHOOD CANCER INCIDENCE CHILDHOOD CANCER (Globally)(Globally)

Childhood14.9 per 100,000 < 15 years of age16.4 per 100,000 < 20 years of age

Adult470.1 per 100,000 Ries LAG, SEER U.S. 2000-2004

INCIDENCE CHILDHOOD CANCER INCIDENCE CHILDHOOD CANCER (U.S. 2006)(U.S. 2006)

Childhood160,000 new cases/year < 15 years of age 90,000 deaths/year < 15 years of age

Ferlay J, IARC Cancer Base N°5, 2004

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INCIDENCE CHILDHOOD CANCER INCIDENCE CHILDHOOD CANCER (Children aged under 15 years)

Year

Rat

e p

er 1

0000

0 p

erso

n-y

ears

Leukaemias

Brain & other nervous system

Non-Hodgkin's lymphomas

Hodgkin's disease

All non-epithelial skin

Based on Linet MS et al. J Natl Cancer Inst 1999;91(12):10520

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Incidence per million children (under 15 years old) in selected countries categorized by mean per capita gross national income

Incidence data are from the International Agency for Research on Cancer. Low-income country (LIC): the mean per capita annual income in 2005 is less than US $825;high-income country (HIC): the mean per capita annual income is more than $10,065.Annual per capita figures in US dollars. Gross national incomes were taken from the world development indicators database of the World Bank for 2005.Kaposi sarcoma accounted for 68.5 nonleukemia cancers per million per year in Uganda and 10.7 in Zimbabwe.

Based on Scott CH, Cancer, 2007

INCIDENCE CHILDHOOD CANCERINCIDENCE CHILDHOOD CANCER

CountryCancer

incidenceLeukemia incidence

Nonleukemia incidence

Gross National income* Country

Cancer incidence

Leukemia incidence

Nonleukemia incidence

Gross National income*

Low-income countries (n = 9)

102 16 85 491 High-income countries (n=9)

130 41 89 32872

Malawi 100.0 1.1 98.9 160 Finland 148.6 47.3 101.3 37460 Uganda 183.5 10.3 173.2 280 United Kingdom 118.2 38.6 79.6 37600 Zimbabwe 111.2 22.8 88.4 340 Japan 107.6 35.5 72.1 38980 Mali 77.4 4.0 73.4 380 Sweden 149.4 45.6 103.8 41060 Nigeria 71.2 8.6 62.6 560 USA 137.9 43.1 94.8 43740 Vietnam 108.4 33.4 75.0 620 Iceland 109.0 37.2 71.8 46320 Papua New Guinea 100.0 8.1 91.9 660 Denmark 149.3 47.2 102.1 47390 Pakistan 100.0 40.5 59.5 690 Switzerland 139.5 43.8 95.7 54930 India 64.4 19.2 45.2 730 Norway 143.2 44.0 99.2 59590

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CAUSES OF CHILDHOOD CANCERSCAUSES OF CHILDHOOD CANCERS

1. Identified familial and genetic factors (5-15%)

2. Known Environmental exposures & exogenous factors (<5-10%)

3.3. UNKNOWNUNKNOWN 75-90%75-90%

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MULTI-CAUSAL! - MULTI-GENERATIONAL?MULTI-CAUSAL! - MULTI-GENERATIONAL?

Based on Anderson LM, Environ Health Perspect, 2000, 108(suppl 3):573-594

Maternal

Paternal

Environmental exposuresGene pool

eg. Retinoblastomaeg. Leukaemia

(trisomy)

eg. Vaginal adenocarcino

ma (DES)

eg. Leukaemia (X-ray)

eg. Hepatocellular

carcinoma (hepatitis B virus)

Parental grandmothers

Parental preconceptional

Gestational Postnatal

Parental gametesDirectTransplacental

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Raphael, National Gallery of Art, Washington, DC

CHILDREN ARE NOT LITTLE ADULTSCHILDREN ARE NOT LITTLE ADULTS

1. Different and unique exposures

2. Dynamic developmental physiology

3. Longer life expectancy

4. Politically powerless

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OVERVIEWOVERVIEW







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RISK FACTORSRISK FACTORS

Definition : Specific agent statistically associated with a disease either positively or negatively

Increasing levels of exposure

or incidence of disease

causation more likely

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1. EXTERNAL AGENTS:

Physical carcinogens:

ionizing radiation (X-ray)

non-ionizing radiation (electromagnetic fields, UV)

Biological carcinogens: infections from viruses (Epstein Barr virus: Burkitt's lymphoma

and Hodgkin's disease;

Hepatitis B: liver carcinoma;

and HHV8 and HIV: Kaposi's sarcoma)


Carcinogenic Agents identified as Risk Factors

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Chemical carcinogens:

tobacco: mothers who smoke during pregnancy

pesticides, asbestos: parental occupation

aflatoxin, arsenic: food and drinking water contaminants

drugs and medication: pregnant women treatment (diethylstilboestrol: cell

adenocarcinoma of the vagina or cervix )

Dietary constituents

2. INTERNAL AGENTS:

Inherited factors

predisposition to particular familial diseases

genetically determined features

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Weight of evidence may be

1) Known2) Suggestive3) Limited

according to extent to which evidence of causality supports a relationship between

a risk factor and a disease


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Associated with each type of Childhood Cancer1) Known

a) Genetic/congenital disordersb) Age peakc) Ethnicsd) Gendere) Environmental

2) Suggestivea) Family historyb) Reproductive factorsc) Environmental

3) Limiteda) Family History b) Environmental


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Familial

neoplastic

syndromes

SYNDROME GENE CHILDHOOD CANCER

Familial retinoblastoma RB1 Retinoblastoma, osteosarcoma

Familial Wilms' tumour FWT1/2 Wilms' tumour

Li-Traumeni syndrome TP53/CHK2/SNF5 Adrenocortical carcinoma/

Soft-tissue sarcoma/

Osteosarcoma, CNS tumor

Hereditary nonpolyposis colon cancer MSH2/MLH1/PMS2 Glioma

Familial adenomatous polyposis APC Medulloblastoma, hepatoblastoma

Inherited

immunodeficiency

and bone marrow

failure syndromes


Ataxia telangiectasia ATM Lymphoma, leukaemia

Wiskott-Aldrich syndrome WAS Non Hodgkin's Lymphoma

Blood syndrome BLM Non Hodgkin's Lymphoma, Wilms' tumour, osteosarcoma

IgA deficiency IGAD1 Lymphoma

Fanconi anaemia FANCA Acute myeloid leukaemia, hepatoma

Based on Stiller CA. Oncogene, 2004, 23:6429–6444

a) Genetic risks factors associated with childhood cancer

1) Known

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Xeroderma pigmentosum ERCC2 Skin carcinoma, melanoma

Beckwith-Wiedemann syndrome Complex Wilms' tumour, hepatoblastoma, neuroblastoma, pancreatoblastoma

Tuberous sclerosis TSC1/2 Subependymal giant cell astrocytoma

Numerical

chromosome

abnormalities

associated with

childhood cancers

Miscellaneous genetic syndromes associated with childhood cancers

SYNDROME CHILDHOOD CANCER

Down syndrome (Trisomy 21) Leukaemia, germ-cell tumours

Trisomy 18 Wilms' tumour

Turner syndrome (45,X; other rare forms) Neuroblastoma, Wilms' tumour

Klinefelter syndrome (47,XXY; other rare forms) Germ-cell tumours

Based on Stiller CA. Oncogene, 2004, 23:6429–6444

1) Known

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b) Age peak


Age at onset:

Age-related exposures Some prenatal exposures (see: e) Environmental exposures) Hormonal influences of adolescence

Age peak: infancy: sympathetic nervous system tumors,

rhabdomyosarcoma, Wilm’s tumor adolescent: malignant bone tumors, soft tissue sarcomas,

renal cell carcinoma

1) Known

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Based on Ries LAG et al. Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Am. Indian = American Indian/Native American

API = Asian/Pacific IslanderHispanic = Hispanic of any race and overlaps other categories

Ave

rag

e an

nu

al r

ate

per

mill

ion

Ethnical differences:

incidence in Blacks: sympathetic nervous

system cancers, Ewing sarcoma, ALL

incidence in Asians: renal tumors

incidence in Arabs: bilateral retinoblastoma


c) Ethnics

1) Known

White Black Am. Indian HispanicAPI

Ethnicity

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Gender:

Exposures differing by gender

Effects of hormonal influences

Gender related genetic differences

Male / female ratio:

males: Hodgkin’s and Non-Hodgkin’s lymphomas, ALL, ependymomas, primitive neuroectodermal tumours

females: thyroid carcinoma, malignant melanoma

WHO

1) Known

d) Gender

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Ionizing radiation:

Diagnostic x-ray in utero acute lymphoblastic leukaemia Chernobyl radiation fallout thyroid cancer Radiation therapy malignant bone tumours, leukaemia

Immunosuppressive therapy: Non-Hodgkin’s lymphoma

Treatment with diethylstilboestrol: adenocarcinoma of vagina

Infections:

HIV/AIDS Kaposi’s sarcoma Malaria and Epstein Barr virus Burkitt’s lymphoma


e) Environmental exposures

1) Known

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b) Maternal reproductive factors

Fetal loss, first born and age > 35 years: acute lymphoblastic leukaemia

Diet (cured meats): brain tumours

Preterm birth: germ cell tumours

Alcohol, tobacco: sympathetic nervous system tumours

2) Suggestive

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c) Environmental exposures

Parental smoking: neuroblastoma, acute lymphoblastic leukaemia,

acute myeloid leukaemia

Residential pesticides:

Prenatal maternal & paternal exposures brain, bone, kidney tumours, acute

myeloid leukaemia, Hodgkin’s disease

Postnatal exposures brain, bone, kidney tumours, acute myeloid leukaemia, Hodgkin’s disease

WHO

2) Suggestive

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Parental occupational exposures:

Agriculture brain, CNS, renal tumours

Paint, solvents germ cell tumours, hepatic tumours, brain and CNS tumours, acute lymphoblastic leukaemia

Welder renal tumours, retinoblastoma

Petroleum acute lymphoblastic leukaemia, brain and CNS tumours, hepatic tumours

Paper or pulp mill brain tumours

High fluoride exposure osteosarcoma


WHO

2) Suggestive

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1) Known

Example: Acute Lymphoblastic Leukaemia


Genetic/congenital disorders: ataxia telangiectasia, Fanconi

syndrome, Bloom syndrome, neurofibromatosis Age peak: 2-4 years Age-adjusted incidence: 26.3 per million Race: W:B = 2.0 Gender: M:F = 1.3 Environmental: Ionizing Radiation

(diagnostic-in utero, therapeutic-postnatal)

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2) Suggestive

Reproductive factors: maternal fetal loss, mother older than 35 years at pregnancy, first born

Example: Acute Lymphoblastic Leukaemia


3) Limited

Environmental: Paternal smoking before conception Parental occupational exposures (hydrocarbons,

paints, motor vehicle exhaust)60-Hz magnetic fields >0.4ųT

Postnatal chloramphenicol use Other: Decreased risk associated with

breastfeeding

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3) Limited: Infection (hypothesis)

1. Areas of rapid population growth

2. Areas of increased population commuting

3. Influences of population war, disasters, tourism

4. Maternal infection in pregnancy

5. Immunization or risks

6. Exposure to infection in infancy or early childhood - child care, spacing of siblings


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OVERVIEWOVERVIEW







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BIOLOGIC PROCESS: CARCINOGENESISBIOLOGIC PROCESS: CARCINOGENESIS

PROGRESSIONPROMOTIONINITIATION

Cytotoxic/mutagenic DNA damage induction in some

cells

DNA repair or cell death mechanisms (eliminate damaged

cells)

Clonal expansion leads to cancer

Mutated cell transforms

DNA damage is fixed as a mutation

Based on James MA and Travis LB. Nature Reviews Cancer, 2005, 5:943-955

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BIOLOGIC PROCESS: DNA DAMAGEBIOLOGIC PROCESS: DNA DAMAGE

(mutation: change coding sequence)

(double stranded DNA

breaks)

ChemicalsViruses

Radiation

Heredity

Based on National Cancer Institute pictures

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CANCER GENESCANCER GENES

when activated:

transforms normal to cancer cells

when inactivated:

disregulation of normal cellsBased on National Cancer Institute pictures

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BIOMARKERS AND OTHER MARKERSBIOMARKERS AND OTHER MARKERS Biomarkers: indicators that measure a physiological, biochemical, or pharmacological event.

Diagnostic (screening) biomarker: for diagnosis and classification

i.e. Bence–Jones protein in urine indicator of multiple myeloma

Prognostic biomarker: for refining staging

Stratification (predictive) biomarker: for predicting or monitoring response

to treatment

Circulating tumour markers for cancer testing and noninvasive prenatal diagnosis:

nucleic acids : detection of gene mutations, chromosomal rearrangements,

microsatellite alterations, viral sequences, gene promoter hypermethylation and

changes in microarray-generated profiles (genetic signatures)

hormones, enzymes, glycoproteins, oncofoetal antigens and receptors

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Proteomics: promising for the analysis of biological fluids and biomarker identification.

Fetal-derived epigenetic markers in maternal plasma: differences between the maternal and the fetal DNA.

Ideal factors for a serological tumour biomarker: Produced by the tumour cells and can also enter the circulation

Present at low levels in the serum of healthy individuals and those with benign

disease but increases substantially in cancer (preferably in one cancer type only)

Easily quantifiable with an inexpensive assay

Present in detectable (or higher than normal) quantities at early or preclinical stages

Quantitative levels of the tumour marker reflect the tumour burden

High diagnostic sensitivity (few false negatives) and specificity (few false positives)

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Cancer biomarkers that are

currently in clinical use

D, diagnosis; P, prognosis.FISH, fluorescence in situ hybridization; Q-RT-PCR, quantitative RT-PCR;

RISH, RNA in situ hybridization.

Selected candidate biomarkers identified

by DNA microarray analysis

TUMOUR BIOMARKER CANCER TYPE

Alfa-fetoprotein Germ-cell hepatoma

CalcitonIn Medullary thyroid carcinoma

CA 125 Ovarian

CA 15-3 Breast

CA 19-9 Pancreatic

Carcinoembryonic antigen Colon

ER and PgR Breast

HER2 Breast

Human chorionic gonadotropin-beta Testicular

Lactate dehydrogenase Germ cell

Prostate-specific antigen Prostate

Thyroglobulin Thyroid

GENE CANCER USE ASSAY

AMACR Prostate D IHC

AURKA (STK15) Medulloblastoma P IHC

AZGP1 Prostate P IHC

BCL6 DLBCL P Q-RT-PCR

CK17; CK5/6 Breast P IHC

DOG1 GI stromal tumour D RISH, IHC

EZH2 Prostate P IHC

HOXB13:IL17BR Breast P Q-RT-PCR

HPN Prostate P IHC

MN1 AML P Q-RT-PCR

MUC1 Prostate P IHC

NBS1 Uveal melanoma P IHC

PLA2G2A Gastric P Q-RT-PCR

S100P Bladder D IHC

SPP1 (OPN) Colon P IHC

TLE1 Synovial sarcoma D IHC

TMPRSS2-ERG Prostate D, P FISH, Q-RT-PCR

ZAP70 CLL (IgVH mutation) P Flow cytometry

Based on Kulasingam V. Nature Clinical Practice Oncology, 2008,5:588-599

Based on Pollack JR. Am J Pathol, 2007, 171:375–385

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Human biological fluids: a

source for biomarker discovery

ENVIRONMENTAL EXPOSURES:

chemicals

radiations

viruses

DISEASE OUTCOMES

Cancer (Leukaemia)

Biomarkers help link environmental

exposures to disease outcomes:

BIOMARKERS

exposure

early effects

mechanisms

Based on Kulasingam V. Nature Clinical Practice Oncology, 2008,5:588-599

TUMOUR BIOMARKER CANCER TYPE

Plasma Broad spectrum of diseases

Serum Broad spectrum of diseases

Cerebrospinal fluid Brain

Nipple aspirate fluid Breast

Breast cyst fluid Breast

Ductal lavage Breast

Cervicovaginal fluid Cervical and endometrial

Stool Colorectal

Pleural effusion Lung

Bronchoalveolar lavage Lung

Saliva Oral

Ascites fluid Ovarian

Pancreatic juice Pancreatic

Seminal plasma Prostate and testicular

Urine Urological

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OVERVIEWOVERVIEW







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EXPOSURE ASSESSMENTEXPOSURE ASSESSMENT

a) Environmental

b) Occupational

c) Biological

Objective:

obtaining measurements quantifying effects

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Questionnaire data

Laboratory measurement

Environmental

Biological

Molecular genetic evidence


Approaches

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Relevant past exposures

Recall variation in affected vs. healthy

Varying levels of exposures

Relation with growth, development, behaviour

Challenges

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OVERVIEWOVERVIEW







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CHILDHOOD CANCER CLUSTERSCHILDHOOD CANCER CLUSTERS

Cluster definition: notable aggregations of cases in

Geographic proximity

Similar temporal onset

seemingly statistically higher

incidence than expected

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Residential/school proximity

Manufacturing facilities/waste sites

Underground storage tanks

Environmental/industrial accidents


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Define the minimum number of cases (rare disease small number of cases)

Type of cluster:

Transient: occurring in given period and disappearing Prolonged: persisting, new cases developing

Define:

Homogeneous/heterogeneous types of cancer Designate temporal and geographic boundaries

(latency periods may be long)


Analysis of clusters

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1. Logical time sequence (i.e. cause preceded effect)

2. Specificity of effect (i.e. same type of cancer)

3. Dose-response relationship

4. Biologic plausibility

5. Consistency with other observations

6. Exclusion of concomitant variables

7. Disappearance of effect when cause removed


Reporting cancer clusters

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Chernobyl childhood thyroid cluster

April 26, 1986 - nuclear reactor 4 releases1311


Year Num. cases

1986 2

1987 4

1988 5

1989 6

1990 29

1991 30

1992 50

Incidence thyroid cancer in Belarus (0-15 yrs age)

Total numbers reported

Mainly papillary thyroid cancer (aggressive)

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OVERVIEWOVERVIEW







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PREVENTIONPREVENTION

1. Avoid smoking/SHTS, chewing tobacco

2. Sun protection

3. Diet

fibre fat salt / smoke, cured food carotenoids aflatoxins

4. Test for radon, asbestos (mitigate risks)

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EARLY CHILDHOOD EXPOSURESEARLY CHILDHOOD EXPOSURES

1. Ionising radiation breast cancer, ALL, thyroid cancer

2. Radiotherapy for Hodgkin’s disease osteosarcoma, leukaemia, skin cancer, breast cancer, soft tissue sarcoma

3. UV sunlight melanoma, basal and squamous cell carcinomas

4. Tobacco

5. Asbestos

6. Diet - fats and aflatoxins cancer colon, breast, and Liver

Predisposing to adult cancer

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We hold our future in our handsWe hold our future in our handsand it is our children.and it is our children.

Poster Contest by HRIDAY with support from WHO SEAROPoster Contest by HRIDAY with support from WHO SEARO

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First draft prepared by Irena Buka, MD, Canada

With the advice of the Working Group Members on Training Package for the Health Sector: Cristina Alonzo, MD (Uruguay); Yona Amitai, MD, MPH (Israel); Stephan Boese-O’Reilly, MD, MPH (Germany); Stephania Borgo, MD (ISDE, Italy); Irena Buka, MD (Canada); Lilian Corra, MD (Argentina); Ligia Fruchtengarten, MD (Brazil); Amalia Laborde, MD (Uruguay); Leda Nemer, TO (WHO/EURO); R. Romizzi, MD (ISDE, Italy); Katherine M. Shea, MD, MPH (USA).

Reviewer: Carolina Espina, PhD (Spain)

WHO CEH Training Project Coordination: Jenny Pronczuk, MDMedical Consultant: Ruth A. Etzel, MD, PhD Technical Assistance: Marie-Noël Bruné, MSc

Latest update: December 2009

WHO is grateful to the US EPA Office of Children’s Health Protection for the financial WHO is grateful to the US EPA Office of Children’s Health Protection for the financial support that made this project possible and for some of the data, graphics and text used in support that made this project possible and for some of the data, graphics and text used in

preparing these materials.preparing these materials.

ACKNOWLEDGEMENTSACKNOWLEDGEMENTS

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DISCLAIMERDISCLAIMER The designations employed and the presentation of the material in this publication do not imply the expression of

any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

The opinions and conclusions expressed do not necessarily represent the official position of the World Health Organization.

This publication is being distributed without warranty of any kind, either express or implied. In no event shall the World Health Organization be liable for damages, including any general, special, incidental, or consequential damages, arising out of the use of this publication

The contents of this training module are based upon references available in the published literature as of its last update. Users are encouraged to search standard medical databases for updates in the science for issues of particular interest or sensitivity in their regions and areas of specific concern.

If users of this training module should find it necessary to make any modifications (abridgement, addition or deletion) to the presentation, the adaptor shall be responsible for all modifications made. The World Health Organization disclaims all responsibility for adaptations made by others. All modifications shall be clearly distinguished from the original WHO material.

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TRAINING FOR THE HEALTH SECTOR [Date …Place …Event…Sponsor…Organizer]