Transcript Diapositiva 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
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
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”,
E&P 2008
“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”,
E&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
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
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)
• 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%)
2A
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/Carcinogen
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
- 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 complessive
1,2-dicloroetano
Acrilonitrile
IARC (anno piu
recente revisione)
11th REPORT ON
CARCINOGENS
2004
UNIONE
EUROPEA
2 B (1999)
*
2
2 B 1999
*
2
Stirene
2 B (2002)
Stirene 7,8 ossido
2 A (1994)
*
1 (2009)
**
2 A (1987)
**
1 (2009)
**
Benzene
PCBs
2,3,7,8-TCDD
2
* Reasonably anticipated to be a human carcinogen
** Known to be a human carcinogen
1
• 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
IARC MONOGRAPH VOLUME 100
Hypothesis for the use of organ-specific
evaluation of group I agents
Concern
Identification of causal associations in order To this praiseworthy aim, do we really
to unravel mechanisms of carcinogenesis (eg need the complex and expensive exercise
molecular targets, oncogenes etc)
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 Is this the audience for IARC evaluations?
on target organs can be of practical interest How sill courts interpret the meaning of 2 A
and 2 B agents?
Causal inference
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.
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
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.
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
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
Arsenic and inorganic
arsenic compounds
Cadmium and
cadmiunm compounts
Trichlorethylene
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)
Pharynx
Stomach
Lung
Colon and rectum
Larynx
Ovary
The “negative seesaw” between
significance and irrelevance of
epidemiological and experimental
data on carcinogenesis
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.
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.
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)
The 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
species.
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.
An uneven level of experimental support for different mechanisms
may reflect that disproportionate resources have been focused on
investigating a favoured mechanism.
Huff J, 1999
Huff J, EHP, 1993
The conflicts of interest
Guidelines for Observers
at IARC Monograph Meetings I
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.
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 II
-
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
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
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.
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
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
… omissis …
(…omissis…)
Conclusions
The watershed between the pressure on
epidemiologists to
Either
force the interpretation of results in order to protect
people’s health
or
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
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
Austin Bradford Hill 1965
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.