Evaluation of the Carcinogenicity of Red Meat & Processed ...

Evaluation of the Carcinogenicity of Red Meat & Processed ...

An overview of the IARC Monographs programme's evaluations of risk factors for childhood cancer and a perspective on ongoing research Kurt Straif MD PhD MPH The encyclopaedia of carcinogens The IARC Monographs evaluate Chemicals Complex mixtures Occupational exposures Physical and biological agents Personal habits Almost 1000 agents have been evaluated

119 are carcinogenic to humans (Group 1) 81 are probably carcinogenic to humans (Group 2A) 292 are possibly carcinogenic to humans (Group 2B) Lorenzo Tomatis 1929-2007 National and international health agencies use the Monographs As a source of scientific information on known or suspected carcinogens As scientific support for their actions to prevent exposure to known or suspected carcinogens Vol 100E, Parental smoking Increased risk of cancer in children born of parents who smoke preconception, during pregnancy and/or perinatally Hepatoblastoma 4 recent studies with significantly increased risk United Kingdom Childhood Cancer study Father only: 1.86 (0.5-7.6) Mother only: 2.01 (0.4-10.2) Both parents: 4.74 (1.68-13.4)

Sufficient evidence of carcinogenicity Leukaemia (in particular ALL) Meta-analysis of 11 studies Meta-RR for paternal smoking = 1.12 (1.04-1.21) Limited evidence of carcinogenicity Newborns of smoking mothers have increased frequencies of HPRT mutations, chromosomal translocations, and DNA strand breaks. Sperm of smokers has increased frequencies of aneuploidy, DNA adducts, strand breaks, and oxidative damage. Cigarette smoke also causes germ-cell mutations in mice Vol 100D, Ionizing radiation Radioiodines

Chernobyl accident: sharp increase in the risk of thyroid cancer associated with exposure to radioiodines, particularly iodine-131, during childhood and adolescence. This might be due to a higher milk intake per unit of body weight among children; a higher thyroid dose per unit of iodine-131 intake from milk; a higher susceptibility per unit of thyroid dose; or a combination of these. Sufficient evidence in humans for the carcinogenicity of exposure during childhood and adolescence to short-lived radioisotopes of iodine, including iodine-131. Short-lived radioisotopes of iodine, including iodine-131, cause thyroid cancer. X and gamma radiation There is sufficient evidence in humans for the carcinogenicity of in utero X and gamma radiation for childhood cancers. Vol 98, 100F, Occupational exposure as a painter Maternal exposure to paints and childhood leukemia Nine case-control studies (2 on acute leukemias, 5 on ALL, 3 on

AML) 5 studies with significant positive associations for maternal paint exposure either before or during pregnancy adjusted for age and/or sex, race, social class or other variables. 3 studies with borderline significant positive associations and non- significantly elevated ORs Significant exposure-response relationships, according to duration of maternal paint exposure, in 2 studies Evaluation Limited evidence of an association between maternal exposure to painting before and during pregnancy and an increased risk of childhood leukaemia in the offspring Vol 80 (2002), Non-ionizing radiation Extremely low-frequency (ELF) electric and magnetic fields Residential ELF magnetic fields and childhood leukaemia

Pooled analysis of nine well conducted studies (Ahlbom et al, 2000) RR=2.0(95%CI 1.3-3.1) for exposure > 0.4 T. Pooled analysis of 15 studies - less restrictive inclusion criteria (Greenland et al, 2000) RR=1.7 (95%CI 1.2-2.3) for exposure > 0.3 T Evaluation There is limited evidence in humans for ELF magnetic fields and childhood leukaemia and inadequate evidence for electric fields and childhood leukaemia Epstein-Barr virus & malaria, V100&104 In 1962, Denis Burkitt noted a strong geographical association between holoendemic malaria and the most frequent paediatric cancer in sub-Saharan Africa, later called endemic Burkitt lymphoma (eBL). Epstein-Barr virus (EBV), a ubiquitous oncogenic herpes virus, is a necessary agent for the pathogenesis of eBL. African children are infected by EBV early in life (<3 years of age), and the timing of EBV and Plasmodium

coinfection and the intensity of malarial infections at an individual level seem to influence EBV dysregulation, which may lead to eBL. Infection with P falciparum in holoendemic areas is probably carcinogenic to humans (Group 2A). Vol 100, Diethylstilbestrol Adenocarcinoma of the vagina is an extremely rare tumour, especially in young women. In 1971, however, Herbst et al. described 8 patients aged 15-22 years with this condition. The administration of diethylstilboestrol to women during pregnancy is associated with an increased risk of vaginal or cervical adenocarcinoma in their exposed female offspring (IARC Monographs Vol 6, 1974) Challenges in the causal inference for childhood cancer Occupational cohorts: important role in identification of environmental carcinogens (chimney sweeps, radon, benzene) with clearly defined study population, prospective exposure assessment, strong exposure contrast

Childhood Cancer very rare disease -> Case-control studies, - often all childhood cancer cases combined, - questionnaire-based exposure information, Recall bias? (coffee drinking and childhood leukemia?) Conceptionally different exposure metrics are often highly correlated -> difficult to disentangle preconceptional, gestational by trimester, postnatal, maternal/paternal exposures Challenges in the causal inference for childhood cancer Long latency period of some cancers - sentinel events, asbestos and mesothelioma, DES and vaginal cancer -> critical exposure period in childhood (vs childhood cancer) Higher target exposure (eg RF-EMF to the brain) or increased susceptibility due to developing organ systems (DDT and breast cancer?) Obesity in childhood, adolescence, and young adulthood (25 years of age) linked with cancer in adult life, with the notable exception of postmenopausal

breast cancer. Childhood cancer registries, Vol 1, 1988 The study of geographical and ethnic variation in the risk of childhood cancer is of great value in formulating hypotheses concerning the relative contribution of genetic susceptibility and environmental exposure to etiology. This volume is the most extensive collection of data on the incidence of cancer in childhood that has ever been published. Lorenzo Tomatis, 1988 Childhood cancer registries, Vol 2, 1998 Cover the age range 0-14 years Classified by histology rather than by the site of the tumour. Number of specialized children's tumour registries, data from these are not published in

Cancer Incidence in Five Continents. The incidence is only about 1 % of that in adults, The most common adult cancers hardly ever occur in children. International Incidence of Childhood Cancer (IICC-3) 2001-2010 Incidence rate across all selected registries was 140/million at 0-14yrs Leading cancer types were leukaemias, followed by CNS tumours in most world regions. Highest leukaemia rates among US white Hispanics, Highest lymphoma rates in the Mediterranean (Northern Africa, Western Asia and Southern Europe Consortia of prospective cohort studies, I4C Agricultural pesticide exposures and risk of childhood cancers - Evaluate risk of childhood cancers in relation to residential proximity to

agriculture and associated pesticide use during pregnancy and early life - Evaluate the risk of childhood cancers associated with parental work in agriculture and pesticide related occupations - Evaluate combined effects of residential and occupational exposures to agriculture and pesticides Exposure Assessment Data Sources Agricultural records Pesticide use registries Land use records/ maps Remote Sensing

Exposure Measure Distance from residence to fields Density surrounding residence Crop land/total land By crop type General agriculture Corn, soybean, etc. E.g. Landsat satellite images Exposure Parental

occupational Harmonize different classification systems for occupational codes to ISCO-88 Exposure Modeling Residence with circular buffers overlaid on crop map Results from pesticide drift model, soybeans sprayed with 2,4-D with a south wind direction I4C Cohorts & Cancer Cases Cohort Total number live births Birth years

Total number of cancer cases Number of ALL ALSPAC (UK Avon area) 14 062 1991-1992 24 3 THIS (Australia) 10 628 1987-1995 31

3 JPS (Jerusalem Perinatal Study) 92 408 1964-1976 125 40 CPP (Collaborative Perinatal Project) 58 000 1960-1965 48

12 108 487 1999-2007 ? ~44 96840 1996-2002 200 41 228 102

MoBa (Norway nationwide) DNBC (Denmark nationwide) TOTAL 380 425 All 6 cohorts will be examined for parental occupational exposures ALSPAC, MoBa and DNBC will be examined for residential pesticide exposure Ways forward Established risk factors in adults for leukemia, - mother-child cohorts linked with drug prescription registries or biobanking data, Clearly (genetically) defined subsets of childhood cancer Systematic review of cancers in offsprings in cancer bioassays (e.g. nitrosamines) Use of mechanistic information to evaluate - placental transfer, - exposures reaching sperm cells or ovaries,

- exposures classified as reproductive hazards - periods of susceptibility by period of organ development Ways forward Mendelian randomization (eg coffee drinking and childhood leukemia) Biomarkers of exposure, intermediate effects or genetic susceptibility to complement questionnaires, however these could be affected by disease status (cord blood) Meta-analysis of methylation data identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood (Joubert et al, 2016) Large and growing number of childhood cancer survivors; compared with the general population, childhood cancer survivors have an increased risk of second malignancies Annual update from the Monographs

Acknowledgements The IARC Monographs and Handbooks are supported by grants from U.S. National Cancer Institute (since 1982) European Commission, DG Employment, Social Affairs and Inclusion (since 1986) U.S. National Institute of Environmental Health Sciences (since 1992) Thank you! Global burden and control of cancer Rising burden of cancer: estimates by 2025 19.3 million new cases/a compared to 14.1 million in 2012 Majority of the increase in cancer burden expected in low- and middle-income countries (LMIC)

Prevention probably the single most effective response to these challenges, particularly in LMIC where health services are least able to meet the impending challenge. The first step in cancer prevention is to identify the causes of human cancer http://monographs.iarc.fr/ and what works in cancer prevention http://handbooks.iarc.fr/ The IARC Monographs, a worldwide endeavour that since 1971 has involved over 1000 scientists from over 50 countries Advisory Group, Priorities 2015-2019

Bisphenol A Disinfected water Iron, dietary Mat & coffee drinking Nicotine Opium H Cytomegalie Virus Beta-carotene Dimethylformamide Carbon nanotubes

Sedentory work Tin compounds Pesticides Shift work Styrene Welding Coal dust How are Evaluations Conducted? ?? Published guidelines for participant selection, conflict of interest & stakeholder involvement Criteria for data eligibility Guidelines for review of human, animal and mechanistic evidence

Decision process for overall evaluations http://monographs.iarc.fr/ENG/Preamble/index.php WHO Declaration of Interests To ensure public confidence that interested parties do not have links to the WG, IARC strives to identify and avoid real or apparent conflicts of interests Before official invitation WG have to declare employment, research, and financial interests At the opening of the meeting they are asked to update their Declaration Pertinent interests are disclosed To meeting participants To the public ((http://monographs.iarc.fr/) In the published volume of Monographs They are asked also to complete the conflict-of-interest form required by The Lancet Oncology IARC sends TLOs form not WHOs form to TLO;

TLO summarizes this information alongside IARCs summary Subgroup work Cancer in humans Sufficient evidence Limited evidence Inadequate evidence Evidence suggesting lack of carcinogenicity Cancer in experimental animals

Sufficient evidence Limited evidence Inadequate evidence Evidence suggesting lack of carcinogenicity Mechanistic and other relevant data Mechanistic data weak, moderate, or strong? Mechanism likely to be operative in humans? Overall evaluation Group 1 Carcinogenic to humans Group 2A

Probably carcinogenic to humans Group 2B Possibly carcinogenic to humans Group 3 Not classifiable as to its carcinogenicity to humans Group 4 Probably not carcinogenic to humans Evaluating human data (Subgroup 2) Cancer in humans Cancer in experimental animals

Mechanistic and other relevant data Preamble Part B, Section 6(a) Sufficient evidence Causal relationship has been established Chance, bias, and confounding could be ruled out with reasonable confidence Limited evidence Causal interpretation is credible Chance, bias, or confounding could not be ruled out Inadequate evidence Studies permit no conclusion about a causal

association Several adequate studies covering the full range of exposure levels are mutually consistent in not Evidence suggesting showing a positive association at any observed lack of level of exposure carcinogenicity Conclusion is limited to cancer sites and conditions studied Evaluating experimental animal data (Subgroup 3) Cancer in humans Cancer in experimental animals Mechanistic and other relevant data

Preamble Part B, Section 6(b) Causal relationship has been established through either: - Multiple positive results (2 species, studies, sexes Sufficient evidence of GLP) - Single unusual result (incidence, site/type, age, Data suggest a carcinogenic effect but: (e.g.) single multi-site) Limited evidence study, benign tumours only, promoting activity only

Inadequate Studies permit no conclusion about a carcinogenic evidence effect Adequate studies in at least two species show that the agent is not carcinogenic Evidence suggesting lack of Conclusion is limited to the species, tumour sites, carcinogenicity age at exposure, and conditions and levels of exposure studied Evaluating mechanistic and other data (Subgroup 4) Cancer in humans Cancer in experimental animals

Mechanistic and other relevant data Preamble Part B, Section 6(c) Have the mechanistic events been established? Are there consistent results in different experimental Are the mechanistic systems? Is the overall database coherent? data weak, Has each mechanism been challenged moderate, or experimentally? Do studies demonstrate that strong? suppression of key mechanistic processes leads to suppression of tumour development? Are there alternative explanations? Could different mechanisms operate in different dose ranges, in Is the mechanism humans and experimental animals, or in a likely to be susceptible group?

operative in Note: an uneven level of support for different humans? mechanisms may reflect only the resources focused on each one The plenary sessions will combine the human and experimental evaluations EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Sufficient Limited EVIDENCE IN HUMANS Inadequat e ESLC Limited

Inadequate ESLC Group 1 (carcinogenic to humans) Group 2A (probably carcinogenic) Group 2B (possibly carcinogenic) Group 2B (possibly carcinogenic) (exceptionally, Group 2A) Group 3 (not classifiable) Group 4 Mechanistic data can be pivotal when the human data are not conclusive

EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Sufficient Inadequate ESLC Group 1 1 strong evidence 2A belongs to a mechanistic class where other members Limited in exposed humans Group 2A 1 strong

evidence EVIDENCE IN HUMANS Inadequat e in exposed humans 2A strong evidence mechanism also operates in humans Group 2B 3 strong evidence ESLC mechanism does not operate

in humans are classified in Groups 1 or 2A Group 2B (exceptionally, Group 2A) 2A belongs to a mechanistic class 2B with supporting evidence from mechanistic and other relevant data Group 3 Group 3 2A belongs to a mechanistic class 2B with strong

evidence from mechanistic and other relevant data Group 3 Group 3 4 consistently and strongly supported by a broad range of mechanistic and other relevant data Group 4 IARC Monographs, Volume 100 A Review of Human Carcinogens Scope of volume 100 Update the critical review for each carcinogen in Group 1

Identify tumour sites and plausible mechanisms Compile information for subsequent scientific publications The volume was developed over the course of 6 meetings A. B. C. D. E. F. Pharmaceuticals (23 agents, Oct 2008) Biological agents (11 agents, Feb 2009) Metals, particles and fibres (14 agents, Mar 2009) Radiation (14 agents, June 2009) Lifestyle factors (11 agents, Sept 2009) Chemicals and related occupations (34 agents, Oct 2009) The IARC Monographs, Volume 100 Update the critical review for each Group-1 carcinogen

Identify tumour sites and plausible mechanisms Vol. 100 will also provide data for subsequent scientific publications Tumour Site Concordance between Humans and Animals Increase understanding of the correspondence across species Identify human cancer sites without good animal models Mechanisms Involved in Human Carcinogenesis Organized by mechanism to facilitate joint consideration of agents that act through similar mechanisms

Identify biomarkers that could be influential in future studies Identify susceptible populations and developmental Known and suspected causes of cancer History of IARC Cancer Prevention IARC Sc Pub #139 PrinciplesHandbooks of Chemoprevention (Nov 1995) Preventive Agents Vol 1 NSAIDs Vol 2 Carotenoids Vol 3 Vitamin A Vol 4 Retinoids Vol 5 Sunscreens Vol 6 Weight Control & Physical Activity Vol 8 Fruit and Vegetables Vol 9 Cruciferous Vegetables,Isothiocyanates and Indoles Screening Vol 7 Breast Cancer Screening (Working procedures) Vol 10 Cervix Cancer Screening Vol 15 Breast Cancer Screening

Tobacco Control Vol 11 Reversal of Risk after Quitting Smoking Vol 12 Methods for Evaluating Tobacco Control Policies Vol 13 Evaluating the Effectiveness of Smoke-free Policies Vol 14 Effectiveness of Price and Tax Policies for Control of Tobacco particular challenges in the causal inference for childhood cancer Childhood Cancer methodologically very rare disease In the year 2000, malignant neoplasms comprised about 8% of deaths among l~ year olds, 15% among 5-9 year olds, 12% among 10--14 year olds, and 6% among 15-19 year olds, with ranking as the third, second, second, and fourth leading causes of death, respectively (Accidents are the leading cause of d~ in children and comprise between 40%-50% of mortality) Childhood cancer registries ACS Cancer Atlas, high-quality Eva Poster Eva Investigators Lead investigators:

Mary Ward (NCI) Ann Olsson (IARC) Leslie Stayner (UIC) Joachim Schz (IARC) Benjamin Booth (UIC) Kurt Straif (IARC) Co-investigators Martine Vrijheid (CREAL) Gabriella Tikellis (MCRI) Martha Linet (NCI) Mike Dellarco (NICHD/NCS) Exposure Approaches in Childhood Cancer Research Study design: Pesticide purchase/use records exposure level Reynolds et al. (2002) Reynolds et al. (2005)

Rull et al. (2009) Land use records Carozza et al. (2008) Walker et al. (2008) Thompson et al. (2008) Aerial imagery Carozza et al. (2009) Ecologic: block group Case-control: mile (804.7 m) buffer Ecologic: county Case-control: 1,000 m buffer Application to I4C Geocode addresses at birth

Utilize land use maps and cropspecific pesticide use data Circular buffer around birth address to derive exposure Sensitivity analysis to explore most appropriate buffer 750 m & 1000 m buffers have been used in previous studies Study Design Case-cohort study, 10 controls per case Cohorts with birth addresses for geocoding - DNBC, MoBa, ALSPAC Land cover maps and crop-specific pesticide use data - Obtained from each country for birth year - Changes in pesticide regulation by country & time Adjust for exposures from agricultural

and pesticide related occupations Occupational Exposure Assessment Harmonize the different classification systems to ISCO-88. Evaluate the risk of childhood cancer (primarily leukaemia, lymphomas and brain cancer) associated with parental occupation in different types of farming; Estimate the relative risk of childhood cancer associated with duration and low and high levels of parental occupational exposure to pesticides (insecticides & herbicides); . Strengths & Limitations Strengths First to evaluate crop density and childhood cancer in

a cohort study Ability to compare results across countries Ability to pool data across studies for additional power Limitations May be underpowered to detect associations in specific cancer types Crop rotation can lead to complications in exposure measure where pesticide use information is not available Rare crop/pesticide Occupational Exposure

Assessment Apply the ALOHA+ job exposure matrix made available from IRAS at Utrecht University to estimate no, low and high exposure to herbicides, insecticides and fungicides, based on ISCO-88. This project will also prepare the ground for studying other parental occupational exposures in relation to childhood cancer by harmonizing all occupational histories of the individual studies to ISCO-88, eg . from ALOHA+ mineral dust, solvents, and metals Booth, biological dust See abstract, parental exposures (AGRICOH?) Maternal occupational exposure to organic dust was associated with increased risk of any cancer (HR=1.33, 95% CI=1.04-1.70) and non-leukemia cancers (HR=1.38, 95% CI=1.02-1.86), but not with leukemia

Discussion after presentation Possibility to take into account moving of parents (MoBa) for sensitivity analysis Availability of covariates as advantage of cohort studies Future analyses by combination of pesticides by mechanism of action, 2nd step after first results DNBC, use of biospecimen for validation of exposure assessment, as a 2nd step Data from Israel cohort post 1973 (?) could be included Environmental Group Detailed descriptive analyses of childhood cancers and trends by subtypes & country Environm. and occupational pesticides: private application, dietary intake (FFQ), seasonal spraying (Dengue); validation of exposure assessment in biospecimen (blood, breast milk, fat tissue); by mechanism o

fpesticides Occupational coding available for other cohorts for application of JEMs Air pollution and childhood leukemia: benzene, distance from roads, gas filling stations also potential links with ~omics proposal Environmental Group Natural radiation, indoor radon and childhood leukemia: need to explore possibilities of exposure assessment Arsenic in drinking water, exposure assessment? Endocrine disruptors incl estrogene in drinking water EMF/ELF, medical (diagnostic) radiation: currently studied in dedicated cohorts Testicular cancer, as of now: Outcome too old for childhood cancer cohorts, too young (in terms of exposures) for adult cohorts Environmental Group, plenary

Air pollution, outdoor What can be learned beyond ESCAPE? Cohorts beyond Europe, developing countries (China) Air pollution, indoor Norway has data on wood burning, gas cooking, use of candles Japan has data on VOC, aldehydes, pm2.5, NOx, SOx, ozone Radon would an ecologic exposure assessment be accurate enough?? Diagnostic radiation, perhaps some interesting perspectives for I4C, check with Ausra Kesimiene/IARC

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