Escola Nacional de Saùde Pùblica

1. Escola Nacional de Saùde Pùblica As monografias publicadas pela Agéncia Internacional de pesquisa sobre o càncer (IARC/OMS) superestiman os “falsos positivos”? B. Terracini Rio de Janeiro 26 /03/2014

2. Structure of the presentation A little bit of history. The evaluations. Causal inference. The seesaw between experimental and epidemiological findings. The criticisms made to IARC. Some conclusions.

4. “… in ordertomakesurefor the project tobeusefultothosewho are exposedtoharmfulchemicals and for the Monographstobecomeaneffectivetoolfortheirprotection, I hadtogetridof …. the academicapproach … (and) to …. dissentfrom the statementsof the officialacademic establishment. L Tomatis “Come nacque il progetto delle Monografie Iarc”, E&P 2008

5. “Formostdiseases, the identificationof the causeshas…captivated a generalconsensusabout the measurestobetaken in ordertoprevent and cure them. In the case ofcancer, on the contrary, the identificationof a chemical or a mixtureas a cause hasusuallybeenreceivedwithhostility. The recognitionof a chemicalas a cause ofcancerhasinvariablymetwith a strong oppositionbythosewho dominate the financialpower and are also in the conditionofmolding the politicaldecisions. L Tomatis “Come nacque il progetto delle Monografie Iarc”, E&P 2008

7. The milestones in the history of IARC Monographs (I) • 1970 First Internal Report on the Evaluation of carcinogenic risks of chemicals to man (no epidemiologist among 30 external experts). • 1971 Monographs Volume 1 (1 “reluctant” epidemiologist among 12 external experts). • 1977Ad hoc Working Group to revise criteria for evaluation: preamble, bioassays, chemical carcinogenesis (8/23 epidemiologists). • 1979 Formal definition of categories of evidence. • 1987 Adaptation of previous evaluations to standard terms.

8. The milestones in the history of IARC Monographs (II) 1991 Inclusion of data on mechanisms of action in the evaluation of the evidence of carcinogenicity. 1994 Lorenzo Tomatis retires from IARC. 1998-2002 Tendency to “downgrade” previous evaluations. 2007 Ethical code of conduct for Working Groups members and observers. 2009 IARC Monograph Volume 100: target organs of agents recognized as carcinogens for humans. 2009 + Criticism raised by a part of the scientific milieu (and their limitations).

9. The evaluations

10. The featuresof the IARC monographsprogramme • Multidisciplinarityofboth the compositionof the WorkingGroups and the approachtoevaluation. • Transparencyof the inferentialreasoning. • Standardizationoftermsclassifying the evidence • Exclusiveconsiderationofstudiespublished in the internationalliterature. • Consensusapproach, occasional vote and expressionofdissent

11. IARC Monographs • Separate evaluationofpublishedstudies on: • Epidemiologicalevidence • Resultsoflong-termexperimentalstudies • Otherrelevant data • IARC categoriesreferonlyto the strengthof the evidencethatanagentis a carcinogen and nottoitscarcinogenicpotency. • http://monographs.iarc.fr/ENG/Preamble/currentb6evalrationale0706.php • (Jan 26, 2006)

12. IARC EVALUATES THE WEIGHT OF THE EVIDENCE SUGGESTING THAT AN AGENT IS ABLE TO INDUCE CANCER IN HUMANS- • IT DOES NOT ESTIMATE RISKS: RISK ASSESSMENT DEPENDS ON SPECIFIC CIRCUMSTANCES OF EXPOSURE. • EVALUATIONS ARE UPDATED, WHEN NECESSARY- • AGENTS EVALUATED BY IARC DO NOT REPRESENT ALL AGENTS PRESENT IN HUMAN ENVIRONMENT

13. IARC evaluations volumes 1-109

15. http://en.wikipedia.org/wiki/Carcinogen

16. Categorie di cancerogenesi e classificazione delle sostanze  cancerogene, come stabilite dalla direttiva 93/21/CEE (18° APT), recepita col D.M. 28 aprile 1997 (G.U. n. 192, del 19 agosto 1997). 1 Categoria 1. Sostanze note per gli effetti cancerogeni sull’uomo. Esistono prove sufficienti per stabilire un nesso causale tra l’esposizione dell’uomo ad esse e lo sviluppo di tumori. Categoria 2. Sostanze daconsiderare cancerogene per l’uomo. Esistono elementi sufficienti per ritenere verosimile che l’esposizione dell’uomo ad esse possa provocare lo sviluppo di tumori, in generale sulla base di:   -  adeguati studi a lungo termine su animali   -  altre informazioni specifiche  Categoria 3. Sostanze da considerare con sospetto per possibili effetti cancerogeni. Esistono prove ottenute da adeguati studi su animali che non bastano tuttavia per classificare la sostanza nella categoria 2. http://www.ispesl.it/cancerogeni/doc/DefCat.htm

17. Valutazioni complessive * Reasonablyanticipatedtobe a humancarcinogen ** Knowntobe a humancarcinogen

18. The target organs: • Monographs Volume 100

19. IARC Monographvol 100(parts 1 to 6) • Limited to agents shown to cause cancer in humans (group 1). • Evaluation of the strength of the evidence (sufficient, limited) regarding target organs

20. IARC MONOGRAPH VOLUME 100

21. Causal inference

22. Possiblelimitationsof (observational) epidemiologicalstudies • sample size • non differentialmisclassificationofoutcome or exposure. • inadequatecontrolofconfounders. • multiple comparisons in exploratorystudies. • robustnessofthe underlyinghypotheses. • publicationbias.

23. Criteria for assessing the strength of the evidence of a causal relationship between a cause and a consequence , suggested by Austin Bradford Hill (1897–1991) in 1965. • Consistency • Specificity • Temporal relationship (temporality) • Biological gradient • Plausibility • Coherence • Experiment • Analogy (consideration of alternate explanations) • Strength of association

24. IARC’s developmentof Bradford Hill’s criteria • Sufficient evidence: confounding, bias and chance can be ruled out. • Limited evidence: confounding, bias and chance are unlikely but cannot be ruled out with certainty. • Unclassifiable: confounding, bias and chance cannot be ruled out.

25. IARC Monographs: overallevaluations (2006 preamble) (*) circumstance to be considered exceptionally

26. List of Classifications by cancer sites with sufficient or limited evidence in humans, Volumes 1 to 109 (<www.monographs.iarc.fr>

27. List of Classifications by cancer sites with sufficient or limited evidence in humans, Volumes 1 to 109 (<www.monographs.iarc.fr>

28. The “negative seesaw” between significance and irrelevanceof epidemiological and experimental data on carcinogenesis

29. Extrapolation of animal experiments to man (WHO Techn Rep series 220, 1961) …. It is conceivable that dose levels (of a carcinogen) exist that would not induce cancer. However, carcinogenesis is a complex process and this may vitiate such predictions … The uncertainty of the extrapolation of the safe dose to man, and the lack of knowledge of the possible summating or potentiating effects of different carcinogens in the total human environment, preclude the establishment of a safe dose … on grounds of prudence.

30. A constant statement in the preambleof the IARC Monographs In the absence of adequate data on humans, it is biologically plausible and prudent to regard agents and mixtures for which there is sufficient evidence of carcinogenicity in experimental animalsas if they presented a carcinogenic risk to humans.

31. The preamble of IARC Monographs, 1971 and 1977 • The critical assessment of the validity of the animal data should help national and/or international authorities to make decisions concerning preventive measures or legislation …..(1971) • In the presence of appropriate positive carcinogenicity animal data and in the absence of adequate human data, it is reasonable to regard such chemicals as if they were carcinogenic to humans (1977)

32. The allegationstypicalof the iterative criticismto (and neglectof ) long-termcarcinogenicitytests • The dosesgiventoanimals are excessivecomparedtothosetowhichhumans are exposed. • Routesofadministration do notcorrespondtocircumstancesofhumanexposure • Target organs in laboratoryanimals do notcorrespondtothoseseen in humans. • Attemptsto produce lungcancerthroughexposuretotobaccosmokebyinhalationhavefailed. • Mice and rats are excessively sensitive tocarcinogens: anyagentwill produce cancer in thesespecies.

33. IARC Monographs: Mechanistic data The Working Group considerswhether multiple mechanismsmightcontributetotumourdevelopment, whetherdifferentmechanismsmight operate in different dose ranges, whether separate mechanismsmight operate in humans and experimentalanimals and whether a uniquemechanismmight operate in a susceptiblegroup. The possiblecontributionof alternative mechanismsmustbeconsideredbeforeconcludingthattumoursobserved in experimentalanimals are notrelevanttohumans. An unevenlevelofexperimentalsupportfordifferentmechanismsmayreflectthatdisproportionateresourceshavebeenfocused on investigating a favouredmechanism.

35. Huff J, 1999

36. Huff J, EHP, 1993

37. The conflicts of interest

38. Guidelines for Observersat IARC Monograph Meetings I

39. Guidelines for Observersat IARC Monograph Meetings II

40. The criticisms

41. Criticisms made to IARC monographs programme (frequently reported in publications sponsored by the industry • To the abilityofepidemologytodemonstratecausalassociations. • To the weightgivento the resultsofexperimentalbioassays. • To the vestedinterestsofmembersof the workinggroup. • To the compositionof the workinggroup • Tospecificevaluations.

43. The allusion fo scientists’ vested interests I JK McLaughlin, C La Vecchia, RE Tarone, L Lippworth, W Blot and P Boffetta (*) have suggested that IARC evaluations are influenced by working groups members’ “careerism” and vested interests. (*) JNCI 2010;102:134-135, IJE 2010;39:679-680

44. IARC’s reply on the Working Groups Members’ alleged vested interests (IJE 2011:40:253) • The multidisplinarity of Working Groups recitifies the (rare) instances in which scientists place undue emphasis in their own research. • Allusion to “careerism “ driven by conflicts of interests diverts attention from the problem of “experts” being funded by (often undisclosed) indusrrial sources. • The allusion made by McLaughlin et al implies and implausible overall lack of objectivity of 1200 scientists from more than 50 countries participating to the Monographs programme since 1970.

45. Does the category “possible carcinogen” have the right to exist??? What is its purpose for public health? How should it be used in research?

46. Given the generalpaucityofepidemiological data and the low probabilitythatagentslisted in group 2B …. are attractivesubjectsforepidemiologicalstudies, indiscriminate downgradingof the resultsoftests in experimentalanimalswouldresult in eliminationof the onlyindicationofpotentialhazardforhumansfor a considerablenumberofenvironmentalchemicals and chemicalmixtures Tomatis L AnnIst Super Sanità 2006;42:113-117

48. … omissis …