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IARC Monographs’ evaluations on the carcinogenicity of benzene Kurt Straif, MD MPH PhD PSA, Stavanger, 5 November 2015

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Page 1: IARC Monographs’ evaluations on the - … 2015/benzen/6_IARC... · IARC Monographs’ evaluations on the carcinogenicity of benzene Kurt Straif, MD MPH PhD PSA, Stavanger, 5 November

IARC Monographs’ evaluations on the carcinogenicity of benzene

Kurt Straif, MD MPH PhD

PSA, Stavanger, 5 November 2015

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“The encyclopaedia of carcinogens”

The IARC Monographs evaluate

Chemicals Complex mixtures Occupational exposures Physical and biological agents Lifestyle factors

More than 950 agents have been evaluated

118 are carcinogenic to humans (Group 1) 75 are probably carcinogenic to humans (Group 2A) 288 are possibly carcinogenic to humans (Group 2B)

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

Lorenzo Tomatis 1929-2007

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Since 1971 over 1000 scientists from over 50 countries have contributed their expertise to the IARC Monographs

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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 TLO’s form — not WHO’s form — to TLO;

TLO summarizes this information alongside IARC’s summary

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Benzene Monographs, Vol 7, 1974Animal data

Benzene has been tested only in mice by subcutaneous

injection and skin application. The data reported do not

permit the conclusion that carcinogenic activity has been

demonstrated.

Human data

It is established that exposure to commercial benzene or

benzene-containing mixtures may result in damage to the

haematopoietic system.

A relationship between such exposure and the development

of leukaemia is suggested by many case reports, and this

suggestion is strengthened by a case-control study from

Japan.

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Benzene Monographs, Suppl 1, 1979• Benzene has shown no evidence of carcinogenicity when

tested in mice by skin application. Other animal

experiments were considered to be inadequate…

• Several case reports as well as an epidemiological case

control study suggest a relationship between benzene

exposure and leukaemia.

• 2 cohort studies showed an increased incidence of acute

non-lymphocytic leukaemia in workers exposed to

benzene. An additional report of a large number of

leukaemia cases among a group of workers exposed to

benzene.

• Group 1 based on sufficient evidence in humans and

inadequate evidence in experimental animals

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Benzene Monographs, Vol 29, 1982

• There is limited evidence that benzene is carcinogenic in

experimental animals.

• It is established that human exposure to commercial

benzene or benzene-containing mixtures can cause

damage to the haematopoietic system, including

pancytopenia.

• The relationship between benzene exposure and the

development of acute myelogenous leukaemia has been

established in epidemiological studies.

• Reports linking exposure to benzene with other

malignancies were considered to be inadequate for

evaluation.

• There is sufficient evidence that benzene is carcinogenic

to man.

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Benzene Monographs, Suppl 4, 1982

• Data on humans and on animals not re-evaluated

• Limited evidence for activity in short-term tests

Benzene Monographs, Suppl 7, 1987• Oral administration induced neoplasms at multiple sites in

males and females of both species,

• In mice, by inhalation increase of lymphoid neoplasms.

• Mouse-lung tumour bioassay by intraperitoneal injection,

increase of lung adenomas in males.

• Exposure of rats by inhalation increased the incidence of

neoplasms, mainly carcinomas, at various sites.

• Skin application or subcutaneous injection of benzene to

mice did not produce evidence of carcinogenicity, but most

of the experiments were inadequate for evaluation.

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Benzene Monographs, Vol 100F

• Sufficient evidence in humans for the carcinogenicity of benzene.

• Benzene causes acute myeloid leukaemia/acute non-lymphocytic

leukaemia.

• Positive association between exposure to benzene and acute

lymphocytic leukaemia, chronic lymphocytic leukaemia, multiple

myeloma, and NHL.

• Strong evidence that benzene metabolites, acting alone or in

concert, produce multiple genotoxic effects at the level of the

pluripotent haematopoietic stem cell resulting in chromosomal

changes in humans consistent with those seen in haematopoietic

cancer.

• In multiple studies in different occupational populations in many

countries over more than three decades a variety of genotoxic

changes, including chromosomal abnormalities, have been found

in the lymphocytes of workers exposed to benzene.

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Preamble, 2006

• A Monograph may undertake to estimate dose–response

relationships within the range of the available epidemiological

data .... A subsequent publication may be prepared by a

separate WG with expertise in quantitative dose–response

assessment.

AG Quantitative Risk Characterization, 2013• Recommendation to summarize exposure–response

relationships seen in epidemiological studies

• Additional resources will be needed to pursue QRC

AG on Priorities, 2014• AG supported recommendations by the AG on QRC to

progressively include exposure–response associations in the

Monographs, particularly from epidemiological studies.

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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)

Institut National du Cancer (INCa), France

U.S. Center for Disease Control (CDC)

Acknowledgements

Mange takk !

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Occupational exposure as a

Painter (Vol 98)Cancer in humans

There is sufficient evidence in humans for the

carcinogenicity of occupational exposure as a painter.

• Occupational exposure as a painter causes cancers of

the lung and urinary bladder.

• There is limited evidence in humans, based primarily on

studies of maternal exposure, that painting is associated

with childhood leukaemia.

Overall evaluation

Occupational exposure as a painter is carcinogenic to

humans (Group 1).

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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.

• First step in cancer prevention is to identify

what causes and what prevents cancer

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Impact of Monographs & HandbooksCollaboration of Monographs scientists with

• WHO and UN Interagency Committees

- Global Collaboration in Chemical Risk Assessment

- Conference of the Parties, WHO FCTC

- Interagency Working Group WHO, ILO, UNEP, UNITAR,

Rotterdam Convention and Basel Convention

• Global Burden of Disease 2010/2013

• National Agencies, e.g. NTP Report on Carcinogens, ANSES

Directly used by other agencies or companies

• California Proposition 65, IARC Group 2B

• Denmark List of Occupational Diseases, shift-work

• Lawsuits, Tobacco Institute Australia v. Federation of Australian Consumer Societies

• Modifications of production processes (4-methylimidazole)

• Implementation of national screening programs

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Meeting participants

Working Group Members

Write the critical reviews and develop the evaluations

Serve as individual scientists, not representatives of any organization

Invited Specialists assist in the WG

Have similar knowledge, but also a conflicting interest

Do not serve as chair, draft text that describes or interprets cancer data, or participate in the evaluations

Representatives of national and international health agencies

Observers

Here to observe the meeting, not to influence its outcome

All participants agree to respect the Guidelines for Observers

IARC Secretariat

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Subgroup work

Cancer inhumans

Sufficient evidence

Limited evidence

Inadequate evidence

Evidence suggesting lack of carcinogenicity

Cancer inexperimental animals

Sufficient evidence

Limited evidence

Inadequate evidence

Evidence suggesting lack of carcinogenicity

Mechanistic andother 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

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From Recommended Priority to Publication of Monograph

IARC ad hoc Advisory Group Meeting

~ every 5 years, last in 2014

Human exposure; suspicion of carcinogenicity

Selection of topic(s) by IMO

~ 1 year before meeting; availability of key studies?

Overall management considerations

Preparation of meeting

Draft outline, selection of experts, writing

assignments, conference calls, pre-meeting peer-

review, working drafts

8-day Meeting at IARC

to reach consensus and make final evaluations

Lancet Oncology summary report

published shortly after the closing of the meeting

Publication of full-text Monograph, on-line (for free

download) and in print; ~ 1 year after meeting

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Dissemination of information

http://monographs.pubcan.org

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Evaluating human data(Subgroup 2)

Cancer inhumans

— Preamble Part B, Section 6(a)

Evidence suggesting lack of carcinogenicity

Sufficient evidence

Limited evidence

Inadequate evidence

Causal relationship has been established

Chance, bias, and confounding could be ruled out with reasonable confidence

Causal interpretation is credible

Chance, bias, or confounding could not be ruled out

Studies permit no conclusion about a causal association

Several adequate studies covering the full range of exposure levels are mutually consistent in not showing a positive association at any observed level of exposure

Conclusion is limited to cancer sites and conditions studied

Cancer inexperimental animals

Mechanistic andother relevant data

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Evaluating experimental animal data (Subgroup 3)

Cancer inexperimental animals

— Preamble Part B, Section 6(b)

Causal relationship has been established through either:

- Multiple positive results (2 species, studies, sexes of GLP)

- Single unusual result (incidence, site/type, age, multi-site)

Data suggest a carcinogenic effect but: (e.g.) single study, benign tumours only, promoting activity only

Studies permit no conclusion about a carcinogenic effect

Adequate studies in at least two species show that the agent is not carcinogenic

Conclusion is limited to the species, tumour sites, age at exposure, and conditions and levels of exposure studied

Cancer inhumans

Mechanistic andother relevant data

Evidence suggesting lack of carcinogenicity

Sufficient evidence

Limited evidence

Inadequate evidence

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Forthcoming meetings snip from w3

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Evaluating mechanistic and other data (Subgroup 4)

• Is the mechanism likely to be operative in humans?

• Are the mechanistic data “weak,” “moderate,” or “strong”?

Have the mechanistic events been established? Are there consistent results in different experimental systems? Is the overall database coherent?

Has each mechanism been challenged experimentally? Do studies demonstrate that suppression of key mechanistic processes leads to suppression of tumour development?

Are there alternative explanations? Could different mechanisms operate in different dose ranges, in humans and experimental animals, or in a susceptible group?

Note: an uneven level of support for different mechanisms may reflect only the resources focused on each one

Mechanistic andother relevant data

— Preamble Part B, Section 6(c)

Cancer inhumans

Cancer inexperimental animals

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The plenary sessions will combine the human and experimental evaluations

Sufficient Limited Inadequate ESLC

EVIDENCE IN EXPERIMENTAL ANIMALS

Group 1 (carcinogenic to humans)

EVIDENCE

IN HUMANS

Group 4

Group 2A

(probably

carcinogenic)

Group 3 (not classifiable)

Group 2B (possibly carcinogenic)

(exceptionally, Group 2A)

Group 2B

(possibly

carcinogenic)

ESLC

Sufficient

Limited

Inadequate

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Overall carcinogenicity evaluation

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Mechanisms Involved in Human Carcinogenesis

Use of mechanistic data to identify carcinogens is accelerating

Types of mechanistic upgrades

Ethylene oxide: Dose-related increase in the frequency of SCE, CA, and

MN in lymphocytes of exposed workers.

Benzo[a]pyrene: Genotoxic mechanism involves its metabolism to highly

reactive species that form covalent adducts to DNA that induce mutations

in K-Ras and the TP53 genes in both human and mouse lung tumours. K-

RAS mutations have been found in nonsmokers exposed to coal smoke

Benzidine-based dyes: Metabolism results in the release of free

benzidine in humans and in all experimental

animal species studied.

Total new Group 1

Mechanistic up-

grades to Group 1

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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. Pharmaceuticals (23 agents, Oct 2008)

B. Biological agents (11 agents, Feb 2009)

C. Metals, particles and fibres (14 agents, Mar 2009)

D. Radiation (14 agents, June 2009)

E. Lifestyle factors (11 agents, Sept 2009)

F. Chemicals and related occupations (34 agents, Oct 2009)

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Known and suspected causes of cancer

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IARC Workshop: Defining ‘Shift Work’ for

epidemiological Studies of Cancer

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Joint IARC, NIOSH-NORA, ACS, n

US NIEHS and NCI Workshop

AcetaldehydeAtrazineCarbon black Chloroform Cobalt metal with

tungsten carbideDichloromethane Diesel engine exhaustDi-2-ethylhexyl phthalate

FormaldehydeIndium phosphideLead and lead compoundsPolychlorinated biphenyls (PCB)Propylene oxideRefractory ceramic fibersShiftwork that involves nightworkStyreneTetrachloroethyleneTitanium dioxideTrichloroethyleneWelding fumes

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Advisory Group, Priorities 2015-2019

• Beta-carotene

• Bisphenol A

• Disinfected water

• Dimethylformamide

• HCMV

• Indium-tin oxide

• Iron, dietary

• Coal mining

• MTBE, ETBE

• Nicotine

• Obesity , Physical inactivity

• Opium

• Phenyl and octyl tin compounds

• Pesticides

• Shift work

• Styrene

• Welding