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 order to make sure for the project to be useful to those who are exposed to harmful chemicals and for the Monographs to become an effective tool for their protection, I had to get rid of …. the academic approach … (and) to …. dissent from the statements of the official academic establishment. L Tomatis “Come nacque il progetto delle Monografie Iarc”, L Tomatis “Come nacque il progetto delle Monografie Iarc”, E&P 2008 E&P 2008

5. “For most diseases, the identification of the causes has …captivated a general consensus about the measures to be taken in order to prevent and cure them. In the case of cancer, on the contrary, the identification of a chemical or a mixture as a cause has usually been received with hostility. The recognition of a chemical as a cause of cancer has invariably met with a strong opposition by those who dominate the financial power and are also in the condition of molding the political decisions. L Tomatis “Come nacque il progetto delle Monografie Iarc”, L Tomatis “Come nacque il progetto delle Monografie Iarc”, E&P 2008 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). 1977 Ad 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 features of the IARC monographs programme  Multidisciplinarity of both the composition of the Working Groups and the approach to evaluation.  Transparency of the inferential reasoning.  Standardization of terms classifying the evidence  Exclusive consideration of studies published in the international literature.  Consensus approach, occasional vote and expression of dissent

11. IARC Monographs Separate evaluation of published studies on:  Epidemiological evidence  Results of long-term experimental studies  Other relevant data IARC categories refer only to the strength of the evidence that an agent is a carcinogen and not to its carcinogenic potency. 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 GroupDefinition n (%) 1Carcinogenic to humans113 (12%) 2 AProbable carcinogenic to humans 66 (7%) 2BPossible carcinogenic to humans 286 (29% 3Not classifiable as for carcinogenicity 505 (52%) 4 Probably not carcinogenic1 (<1%) Total971

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

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 da considerare 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 - adeguati studi a lungo termine su animali - altre informazioni specifiche - 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 IARC (anno piu recente revisione) 11th REPORT ON CARCINOGENS 2004 UNIONE EUROPEA 1,2-dicloroetano 2 B (1999) *2 Acrilonitrile 2 B 1999 *2 Stirene 2 B (2002) 2 Stirene 7,8 ossido 2 A (1994) * Benzene 1 (2009) **1 PCBs 2 A (1987) ** 2,3,7,8-TCDD 1 (2009) ** * Reasonably anticipated to be a human carcinogen ** Known to be a human carcinogen

18. The target organs: Monographs Volume 100

19. IARC Monograph vol 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. Hypothesis for the use of organ-specific evaluation of group I agents Concern Identification of causal associations in order to unravel mechanisms of carcinogenesis (eg molecular targets, oncogenes etc) To this praiseworthy aim, do we really need the complex and expensive exercise underlying the preparation of vol 100 ? Primary prevention Target organs of a carcinogen are irrelevantt to primary prevention. Screening for a specific cancer type in asymptomatic persons who have been exposed to a carcinogen The adoption of screening protocols relies on the demonstration of their ability to improve the natural history of cancer. Causal factors are irrelevant.. Help justice to clarify court cases: knowledge on target organs can be of practical interest Is this the audience for IARC evaluations? How sill courts interpret the meaning of 2 A and 2 B agents? Is this the audience for IARC evaluations? How sill courts interpret the meaning of 2 A and 2 B agents? IARC MONOGRAPH VOLUME 100

21. Causal inference

22. Possible limitations of (observational) epidemiological studies  sample size  non differential misclassification of outcome or exposure.  inadequate control of confounders.  multiple comparisons in exploratory studies.  robustness of the underlying hypotheses.  publication bias.

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. 1.Consistency 2.Specificity 3.Temporal relationship (temporality) 4.Biological gradient 5.Plausibility 6.Coherence 7.Experiment 8.Analogy (consideration of alternate explanations) 9.Strength of association

24. IARC’s development of 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: overall evaluations (2006 preamble) IARC Monographs: overall evaluations (2006 preamble) Group I Epi sufficient Epi less than sufficient + expt sufficient + carcinogenesis related effects in exposed humans (*) Group 2 A Epi limited + expt sufficient Epi inadequate + expt sufficient + mechanism in animals occurs also in humans. Epi limited (*) Agent belongs to group of substances with relevant mechanism of action, among which at least one 1 or 2 A Group 2 B Epi limited + expt sufficient Epi inadequate + expt sufficient Epi inadequate + expt limited or inadequate + mechanistic considerations (*) Mechanistic considerations + other relevant information (*) Group 3 Epi inadequate + expt inadequate or limited (*) circumstance to be considered exceptionally

26. List of Classifications by cancer sites with sufficient or limited evidence in humans, Volumes 1 to 109 ( Cancer siteCarcinogenic agents with sufficient evidence in humans Carcinogenic agents with limited evidence in humans KidneyTobacco smoking X_radiation, gamma radiation Trichlorethylene Arsenic and inorganic arsenic compounds Cadmium and cadmiunm compounts Printting processes

27. L ist of Classifications by cancer sites with sufficient or limited evidence in humans, Volumes 1 to 109 ( AgentSites for which there is sufficient evidence of carcinogenicity Sites for which there is limited evidence of carcinogenicity AsbestosMesothelium (pleura and peritoneum) Lung Larynx Ovary Pharynx Stomach Colon and rectum

28. The “negative seesaw” between significance and irrelevance of 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 preamble of 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 animals as 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. T he allegations typical of the iterative criticism to (and neglect of ) long-term carcinogenicity tests  The doses given to animals are excessive compared to those to which humans are exposed.  Routes of administration do not correspond to circumstances of human exposure  Target organs in laboratory animals do not correspond to those seen in humans.  Attempts to produce lung cancer through exposure to tobacco smoke by inhalation have failed.  Mice and rats are excessively sensitive to carcinogens: any agent will produce cancer in these spec ies.

33. IARC Monographs: Mechanistic data The Working Group considers whether multiple mechanisms might contribute to tumour development, whether different mechanisms might operate in different dose ranges, whether separate mechanisms might operate in humans and experimental animals and whether a unique mechanism might operate in a susceptible group. The possible contribution of alternative mechanisms must be considered before concluding that tumours observed in experimental animals are not relevant to humans. The possible contribution of alternative mechanisms must be considered before concluding that tumours observed in experimental animals are not relevant to humans. An uneven level of experimental support for different mechanisms may reflect that disproportionate resources have been focused on investigating a favoured mechanism.

35. Huff J, 1999

36. Huff J, EHP, 1993

37. The conflicts of interest

38. In the spirit of transparency, Observers with relevant scientific credentials are welcome to attend IARC Monographs meetings. Observers can play a valuable role in ensuring that all published information and scientific perspectives are considered. The chair may grant observers an opportunity to speak, generally after they have observed a discussion. Observers do not... draft any part of a Monograph, or participate in the evaluations. The chair may grant observers an opportunity to speak, generally after they have observed a discussion. Observers do not... draft any part of a Monograph, or participate in the evaluations. Implicit in the term "Observer" is the responsibility to observe the meeting and not to attempt to influence its outcome. This includes - before and during the meeting – Guidelines for Observers at IARC Monograph Meetings I

39. - Not to contact participants before the meeting or to lobby them at any time. - Not to send written materials to meeting participants. - Not to offer meals, drinks... social invitations to meeting participants. - Participants are asked to report any contact or attempt to influence... - Observers may not make a written transcript, audio or video recording, or audio or video transmission..... -Observers must complete the WHO Declaration of Interests, which covers financial interests, employment and consulting, and.... research support related to the subject of the meeting. -Pertinent interests will be disclosed to the meeting participants and in the published volume of IARC Monographs...... Lack of cooperation with these Guidelines may result in an Observer being asked to leave the meeting and the reason disclosed to the meeting participants. April 2006 Guidelines for Observers at IARC Monograph Meetings II

40. The criticisms

41. Criticisms made to IARC monographs programme (frequently reported in publications sponsored by the industry To the ability of epidemology to demonstrate causal associations. To the weight given to the results of experimental bioassays. To the vested interests of members of the working group. To the composition of the working group To specific evaluations.

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 general paucity of epidemiological data and the low probability that agents listed in group 2B …. are attractive subjects for epidemiological studies, indiscriminate downgrading of the results of tests in experimental animals would result in elimination of the only indication of potential hazard for humans for a considerable number of environmental chemicals and chemical mixtures Tomatis L Ann Ist Super Sanità 2006;42:113-117 Sanità 2006;42:113-117

48. … omissis …

51. (…omissis…)

52. Conclusions

53. The watershed between the pressure on epidemiologists to Either force the interpretation of results in order to protect people’s health or or preserve the scientific credibility of the discipline by strict adherence to rules of causal inference preserve the scientific credibility of the discipline by strict adherence to rules of causal inference Epidemiology on the side of the angels …or the people? Siemiatycki J Int J Epidemiol 2002;31:1027-1028 Hurtig AK, San Sebastian M Int J Epidemiol 2003;32:658-59

54. The tension between scientific rigour and the application of the precautionary principle: two contrasting attitudes. Scientists only trusting “hard “ science and reluctant to accept evidence that fall short of a rigorous experimental demonstration (eg. those who in the 50s considered the early epidemiological studies on tobacco smoking to provide “only statistical”, and not experimental evidence). Scientists for whom epidemiological findings of doubtful interpretation should be considered as evidence of potential hazard and require precautionary action Saracci & Vineis Environmental Health 2011

55. ALL SCIENTIFIC WORK IS INCOMPLETE – WHETHER IT BE OBSERVATIONAL OR EXPERIMENTAL. ALL SCIENTIFIC WORK IS LIABLE TO BE UPSET OR MODIFIED BY ADVANCING KNOWLEDGE. THIS DOES NOT CONFER UPON US A FREEDOM TO IGNORE THE KNOWLEDGE WE ALREADY HAVE, OR TO POSTPONE THE ACTION THAT IT APPEARS TO DEMAND AT A GIVEN TIME. Austin Bradford Hill 1965