Escola Nacional de Saùde Pùblica

As monografias publicadas pela Agéncia Internacional de pesquisa sobre o càncer (IARC/OMS) superestiman os “falsos positivos”?

B. TerraciniRio de Janeiro26 /03/2014

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.

“… “… in order to make sure for the project to be useful to in order to make sure for the project to be useful to those who are exposed to harmful chemicals and for the those who are exposed to harmful chemicals and for the Monographs to become an effective tool for their Monographs to become an effective tool for their protection, I had to get rid of …. the academic approach … protection, I had to get rid of …. the academic approach … (and) to …. dissent from the statements of the official (and) to …. dissent from the statements of the official academic establishment.academic establishment.

L Tomatis “Come nacque il progetto delle Monografie Iarc”,L Tomatis “Come nacque il progetto delle Monografie Iarc”, E&P 2008E&P 2008

““For most diseases, the identification of the causes has …captivated a For most diseases, the identification of the causes has …captivated a general consensus about the measures to be taken in order to prevent general consensus about the measures to be taken in order to prevent and cure them. and cure them.

In the case of cancer, on the contrary, the identification of a chemical 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. 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 The recognition of a chemical as a cause of cancer has invariably met with a strong opposition by those who dominate the financial power with a strong opposition by those who dominate the financial power and are also in the condition of molding the political decisions. 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 2008E&P 2008

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.

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).

•

The evaluations

The features of the IARC monographs The features of the IARC monographs programmeprogramme

Multidisciplinarity of both the composition of the Working Multidisciplinarity of both the composition of the Working Groups and the approach to evaluation.Groups and the approach to evaluation.

Transparency of the inferential reasoning.Transparency of the inferential reasoning.

Standardization of terms classifying the evidenceStandardization of terms classifying the evidence

Exclusive consideration of studies published in the Exclusive consideration of studies published in the international literature.international literature.

Consensus approach, occasional vote and expression of Consensus approach, occasional vote and expression of dissent dissent

IARC MonographsIARC Monographs

Separate evaluation of Separate evaluation of published published studies on: studies on:

Epidemiological evidenceEpidemiological evidenceResults of long-term experimental studiesResults of long-term experimental studiesOther relevant dataOther relevant data

IARC categories refer only to the strength of the evidence IARC categories refer only to the strength of the evidence that an agent is a carcinogen and not to its carcinogenic that an agent is a carcinogen and not to its carcinogenic potency. potency.

http://monographs.iarc.fr/ENG/Preamble/currentb6evalrationale0706.php (Jan 26, 2006)(Jan 26, 2006)

• 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

IARC evaluations volumes 1-109

Group Definition n (%)1 Carcinogenic to humans 113 (12%)

2 A Probable carcinogenic to humans

66 (7%)

2B Possible carcinogenic to humans

286 (29%

3 Not classifiable as for carcinogenicity

505 (52%)

4 Probably not carcinogenic 1 (<1%)

Total 971

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

Categorie di cancerogenesi e classificazione delle sostanze cancerogene,Categorie di cancerogenesi e classificazione delle sostanze cancerogene,come stabilite dalla direttiva 93/21/CEE (18° APT), recepita col D.M.come stabilite dalla direttiva 93/21/CEE (18° APT), recepita col D.M.

28 aprile 1997 (G.U. n. 192, del 19 agosto 1997). 28 aprile 1997 (G.U. n. 192, del 19 agosto 1997). 11

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 Esistono elementi sufficienti per ritenere verosimile che l’esposizione dell’uomo ad esse possa provocare lo sviluppo di tumori, in generale sulla base di: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

Valutazioni complessiveValutazioni complessiveIARC (anno piu IARC (anno piu recente revisione)recente revisione)

11th REPORT 11th REPORT ON ON

CARCINOGENS CARCINOGENS 20042004

UNIONE UNIONE EUROPEAEUROPEA

1,2-dicloroetano1,2-dicloroetano 2 B (1999)2 B (1999) ** 22Acrilonitrile Acrilonitrile 2 B 19992 B 1999 ** 22StireneStirene 2 B (2002)2 B (2002) 22

Stirene 7,8 ossidoStirene 7,8 ossido 2 A (1994)2 A (1994) **

BenzeneBenzene 1 (2009)1 (2009) **** 11

PCBsPCBs 2 A (1987)2 A (1987) ****2,3,7,8-TCDD2,3,7,8-TCDD 1 (2009)1 (2009) ****

* Reasonably anticipated to be a human carcinogen* Reasonably anticipated to be a human carcinogen** Known to be a human carcinogen** Known to be a human carcinogen

• The target organs:• Monographs Volume 100

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

Hypothesis for the use of organ-specific Hypothesis for the use of organ-specific evaluation of group I agentsevaluation of group I agents

ConcernConcern

Identification of causal associations in order Identification of causal associations in order to unravel mechanisms of carcinogenesis (eg to unravel mechanisms of carcinogenesis (eg molecular targets, oncogenes etc) molecular targets, oncogenes etc)

To this praiseworthy aim, do we really To this praiseworthy aim, do we really need the complex and expensive exercise need the complex and expensive exercise underlying the preparation of vol 100 ?underlying the preparation of vol 100 ?

Primary preventionPrimary prevention Target organs of a carcinogen are irrelevantt Target organs of a carcinogen are irrelevantt to primary prevention. to primary prevention.

Screening for a specific cancer type in Screening for a specific cancer type in asymptomatic persons who have been asymptomatic persons who have been exposed to a carcinogenexposed to a carcinogen

The adoption of screening protocols relies The adoption of screening protocols relies on the demonstration of their ability to on the demonstration of their ability to improve the natural history of cancer. improve the natural history of cancer. Causal factors are irrelevant.. Causal factors are irrelevant..

Help justice to clarify court cases: Help justice to clarify court cases: knowledge on target organs can be of knowledge on target organs can be of practical interestpractical interest

Is this the audience for IARC evaluations? Is this the audience for IARC evaluations? How sill courts interpret the meaning of 2 A How sill courts interpret the meaning of 2 A and 2 B agents?and 2 B agents?

IARC MONOGRAPH VOLUME 100IARC MONOGRAPH VOLUME 100

Causal inference

Possible limitations of (observational) Possible limitations of (observational) epidemiological studiesepidemiological studies

sample sizesample size

non differential misclassification of outcome or exposure.non differential misclassification of outcome or exposure.

inadequate control of confounders.inadequate control of confounders.

multiple comparisons in exploratory studies.multiple comparisons in exploratory studies.

robustness of the underlying hypotheses.robustness of the underlying hypotheses. publication bias.publication bias.

Criteria for assessing the strength of the evidence of a Criteria for assessing the strength of the evidence of a causal relationship between a cause and a consequence , causal relationship between a cause and a consequence , suggested by Austin Bradford Hill (1897–1991) in 1965.suggested by Austin Bradford Hill (1897–1991) in 1965.

•ConsistencyConsistency•SpecificitySpecificity•Temporal relationship (temporality)Temporal relationship (temporality)•Biological gradient Biological gradient •PlausibilityPlausibility•CoherenceCoherence•Experiment Experiment •Analogy (consideration of alternate explanations)Analogy (consideration of alternate explanations)•Strength of associationStrength of association

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.

IARC Monographs: overall evaluations (2006 preamble)IARC Monographs: overall evaluations (2006 preamble)

Group I Group I EpiEpi sufficient sufficient Epi Epi less than sufficient + less than sufficient + expexpt sufficient + carcinogenesis related t sufficient + carcinogenesis related effectseffects in exposed humans (*) in exposed humans (*)

Group 2 AGroup 2 A Epi Epi limited limited + expt + expt sufficientsufficientEpi iEpi inadequate + nadequate + expt expt sufficientsufficient + mechanism + mechanism in animals occurs in animals occurs also in humansalso in humans..Epi Epi limited (*)limited (*)Agent belongs to group of substances with relevant Agent belongs to group of substances with relevant mechanism mechanism of of action, among which at least one 1 or 2 Aaction, among which at least one 1 or 2 A

Group 2 BGroup 2 B Epi Epi limited + limited + exptexpt sufficient sufficientEpiEpi inadequate + inadequate + exptexpt sufficient sufficientEpiEpi inadequate + inadequate + exptexpt limited or inadequate + limited or inadequate + mechanisticmechanistic considerations (*)considerations (*)MechanisticMechanistic considerations + other relevant considerations + other relevant informationinformation (*) (*)

Group 3Group 3 EpiEpi inadequate + inadequate + expt expt inadequate or limitedinadequate or limited

(*) circumstance to be considered exceptionally(*) circumstance to be considered exceptionally

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

Cancer site Carcinogenic agents with sufficient evidence in humans

Carcinogenic agents with limited evidence in humans

Kidney Tobacco smoking

X_radiation, gamma radiation

Trichlorethylene

Arsenic and inorganic arsenic compoundsCadmium and cadmiunm compounts

Printting processes

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

Agent Sites for which there is sufficient evidence of carcinogenicity

Sites for which there is limited evidence of carcinogenicity

Asbestos Mesothelium (pleura and peritoneum)

Lung

Larynx

Ovary

Pharynx

Stomach

Colon and rectum

The “negative seesaw” betweenThe “negative seesaw” betweensignificance and irrelevance ofsignificance and irrelevance ofepidemiological and experimental epidemiological and experimental data on carcinogenesisdata on carcinogenesis

Extrapolation of animal experiments to man Extrapolation of animal experiments to man (WHO Techn Rep series 220, 1961)(WHO Techn Rep series 220, 1961)

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

A constant statement in the preamble of the IARC Monographs

In the absence of adequate data on humans, it is In the absence of adequate data on humans, it is biologically plausible and prudent to regard agents biologically plausible and prudent to regard agents and mixtures for which there is and mixtures for which there is sufficient evidence sufficient evidence of carcinogenicity in experimental animalsof carcinogenicity in experimental animals as if as if they presented a carcinogenic risk to humans.they presented a carcinogenic risk to humans.

The preamble of IARC Monographs, 1971 and 1977

The critical assessment of the validity of The critical assessment of the validity of the animal data should help national and/or the animal data should help national and/or international authorities to make decisions international authorities to make decisions concerning preventive measures or concerning preventive measures or legislation …..(1971)legislation …..(1971)

In the presence of appropriate positive In the presence of appropriate positive carcinogenicity animal data and in the carcinogenicity animal data and in the absence of adequate human data, it is absence of adequate human data, it is reasonable to regard such chemicals as if reasonable to regard such chemicals as if they were carcinogenic to humans (1977)they were carcinogenic to humans (1977)

TThe allegations typical of the iterative criticism to he allegations typical of the iterative criticism to (and neglect of ) long-term carcinogenicity tests(and neglect of ) long-term carcinogenicity tests

The doses given to animals are excessive The doses given to animals are excessive compared to those to which humans are exposed. compared to those to which humans are exposed. Routes of administration do not correspond to Routes of administration do not correspond to circumstances of human exposurecircumstances of human exposure Target organs in laboratory animals do not Target organs in laboratory animals do not correspond to those seen in humans.correspond to those seen in humans. Attempts to produce lung cancer through Attempts to produce lung cancer through exposure to tobacco smoke by inhalation have failed.exposure to tobacco smoke by inhalation have failed. Mice and rats are excessively sensitive to Mice and rats are excessively sensitive to carcinogens: any agent will produce cancer in these carcinogens: any agent will produce cancer in these specspecies. ies.

IARC Monographs: IARC Monographs: Mechanistic data Mechanistic data

The Working Group considers whether multiple mechanisms might The Working Group considers whether multiple mechanisms might contribute to tumour development, whether different mechanisms contribute to tumour development, whether different mechanisms might operate in different dose ranges, whether separate mechanisms might operate in different dose ranges, whether separate mechanisms might operate in humans and experimental animals and whether a might operate in humans and experimental animals and whether a unique mechanism might operate in a susceptible group. unique mechanism might operate in a susceptible group.

The possible contribution of alternative mechanisms must be The possible contribution of alternative mechanisms must be considered before concluding that tumours observed in experimental considered before concluding that tumours observed in experimental animals are not relevant to humans. animals are not relevant to humans.

An uneven level of experimental support for different mechanisms An uneven level of experimental support for different mechanisms may reflect that disproportionate resources have been focused on may reflect that disproportionate resources have been focused on investigating a favoured mechanism.investigating a favoured mechanism.

Huff J, 1999Huff J, 1999

Huff J, EHP, 1993Huff J, EHP, 1993

The conflicts of interest

In the spirit of transparency, Observers with relevant scientific In the spirit of transparency, Observers with relevant scientific credentials are welcome to attend credentials are welcome to attend IARC MonographsIARC Monographs meetings. meetings.

Observers can play a valuable role in ensuring that all published Observers can play a valuable role in ensuring that all published information and scientific perspectives are considered.information and scientific perspectives are considered.

The chair may grant observers an opportunity to speak, generally The chair may grant observers an opportunity to speak, generally after they have observed a discussion. Observers do not ... draft any after they have observed a discussion. Observers do not ... draft any part of a Monograph, or participate in the evaluations.part of a Monograph, or participate in the evaluations.

Implicit in the term "Observer" is the responsibility to Implicit in the term "Observer" is the responsibility to observeobserve the the meeting and not to attempt to influence its outcome. This includes - meeting and not to attempt to influence its outcome. This includes - before and during the meeting before and during the meeting ––

Guidelines for ObserversGuidelines for Observersat at IARC MonographIARC Monograph Meetings I Meetings I

- - Not to contact participants before the meeting or to lobby them at any time.Not to contact participants before the meeting or to lobby them at any time.- Not to send written materials to meeting participants. - Not to send written materials to meeting participants. - Not to offer meals, drinks ... social invitations to meeting participants. - Not to offer meals, drinks ... social invitations to meeting participants. - Participants are asked to report any contact or attempt to influence ...- Participants are asked to report any contact or attempt to influence ...

- - Observers may not make a written transcript, audio or video recording, or Observers may not make a written transcript, audio or video recording, or audio or video transmission .....audio or video transmission .....

-Observers must complete the WHO Declaration of Interests, which covers Observers must complete the WHO Declaration of Interests, which covers financial interests, employment and consulting, and .... research support financial interests, employment and consulting, and .... research support related to the subject of the meeting. related to the subject of the meeting.

-Pertinent interests will be disclosed to the meeting participants and in the Pertinent interests will be disclosed to the meeting participants and in the published volume of published volume of IARC MonographsIARC Monographs..

..... Lack of cooperation with these Guidelines may result in an Observer ..... Lack of cooperation with these Guidelines may result in an Observer being asked to leave the meeting and the reason disclosed to the meeting being asked to leave the meeting and the reason disclosed to the meeting participants.participants.

April 2006April 2006

Guidelines for ObserversGuidelines for Observersat at IARC MonographIARC Monograph Meetings II Meetings II

The criticisms

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.

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

IARC’s reply on the Working Groups IARC’s reply on the Working Groups Members’ alleged vested interestsMembers’ alleged vested interests(IJE 2011:40:253)(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.

Does the category “possible carcinogen” have the right to exist???

What is its purpose for public health?

How should it be used in research?

Given the general paucity of epidemiological Given the general paucity of epidemiological data and the low probability that agents data and the low probability that agents listed in group 2B …. are attractive subjects listed in group 2B …. are attractive subjects for epidemiological studies, indiscriminate for epidemiological studies, indiscriminate downgrading of the results of tests in downgrading of the results of tests in experimental animals would result in experimental animals would result in elimination of the only indication of potential elimination of the only indication of potential hazard for humans for a considerable hazard for humans for a considerable number of environmental chemicals and number of environmental chemicals and chemical mixtureschemical mixtures

Tomatis L Ann Ist Super Tomatis L Ann Ist Super

Sanità 2006;42:113-117Sanità 2006;42:113-117

… … omissis …omissis …

(…omissis…)

Conclusions

The watershed between the pressure on The watershed between the pressure on epidemiologists toepidemiologists to

EitherEither

force the interpretation of results in order to protect force the interpretation of results in order to protect people’s healthpeople’s health

oror

preserve the scientific credibility of the discipline by strict preserve the scientific credibility of the discipline by strict adherence to rules of causal inferenceadherence to rules of causal inference

Epidemiology on the side of the angels …or the people?Epidemiology on the side of the angels …or the people?

Siemiatycki J Int J Epidemiol 2002;31:1027-1028Siemiatycki J Int J Epidemiol 2002;31:1027-1028Hurtig AK, San Sebastian M Int J Epidemiol 2003;32:658-59Hurtig AK, San Sebastian M Int J Epidemiol 2003;32:658-59

The tension between scientific rigour and the application of The tension between scientific rigour and the application of the precautionary principle: two contrasting attitudes. 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 2011Saracci & Vineis Environmental Health 2011

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