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OCCUPATIONAL CARCINOGENS THEIR CLASSIFICATION AND OCCURRENCE

IN CANADIAN WORKPLACES

MICHEL GÉRIN

Département de santé environnementale et santé au travail

École de santé publiqueUNIVERSITÉ DE MONTRÉAL

Documents available• Power point (in English)

• Power point (en français)

• Table of IARC 1 and 2A carcinogens

• Texte sur le CIRC (M. Gérin, en français, incluant Tableau des cancérogènes 1 et 2A)

• http://monographs.iarc.fr/

• http://www.carexcanada.ca/

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Why classify carcinogens? Hazard identification = first step in risk assessment

In Canada: designated substances

• British Columbia: ACGIH, IARC classifications

• Quebec: own classification inspired from ACGIH

Direct impact in risk management:

• elimination / substitution

• ALARA (levels As Low As Reasonably Achievable)

• worker information: labeling and MSDS

• formulation restrictions (e.g. < 0.1 %)

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http://www.iarc.fr

http://monographs.iarc.fr

• CANCER IN HUMANS – HIGH WEIGHT

– LITTLE DATA

• CANCER IN ANIMALS – LOWER WEIGHT

– MORE DATA

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General principles in carcinogenic hazardassessment

• Epidemiology is the only source of direct evidence allowing to affirm that an agent iscarcinogenic to humans

• In the absence of adequate data in humans, it is biologically plausible and prudent to regard proven animal carcinogens as if they presented a carcinogenic risk to humans

IARC evidence of carcinogenicity

Tiered process

• Epidemiological data

• Animal data

• Mechanistic and other relevant data

• Based on peer-reviewed literature

• Judgment of working group

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Working groups

• Three meetings per year since 1972• 20 to 30 scientists + other participants• A dozen substances (agents) per group• 4 subgroups:

– Chemistry and exposure– Epidemiology– Cancer in animals– Other data (toxicology, mecanisms)

Participants

• Members (no conflict of interest)• Invited specialists (experts, conflicts of

interest)• Representatives of agencies• Observers (industry, unions….)• Secretariat (IARC scientists)

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Carcinogenicity in humansSufficient evidence: causal relationship (chance,

bias and confounding ruled out)

Limited evidence: causal relationship credible but methodological limitations

Inadequate evidence: studies of insufficient qualityor absence of study

Evidence suggesting lack of carcinogenicity: several adequate non positive studies

Carcinogenicity in animals

Sufficient evidence: causal relationship (2 speciesor studies)

Limited evidence: effect suggested but single study or methodological limitations

Inadequate evidence: studies of insufficient qualityor absence of study

Evidence suggesting lack of carcinogenicity:adequate non positive studies involving 2 species

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Overall evaluation (1) • Group 1: the agent is carcinogenic to humans

(asbestos, formaldehyde, trichloroethylene…)- sufficient evidence in humans

• Group 2 A: the agent is probably carcinogenic tohumans (tetrachloroethylene, shift work…)

- limited evidence in humans and sufficientevidence in animals

Overall evaluation (2)

• Group 2 B: the agent is possiblycarcinogenic to humans (dichloromethane, ELF magnetic fields, welding fumes…)– Either: inadequate evidence in humans

and sufficient evidence in animals– Or: limited evidence in humans and less

than sufficient evidence in animals

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Overall evaluation (3)• Group 3: the agent is not classifiable as to its

carcinogenicity to humans (chromium III compounds, mineral oils highly refined, coaldust…)– evidence inadequate in humans and

inadequate or limited evidence in animals(neither group1, nor 2A, nor 2B, nor 4)

• Group 4: the agent is probably not carcinogenicto humans (= caprolactame):– evidence suggesting lack of carcinogenicity in

humans and in animals

MECHANISTIC AND OTHERRELEVANT DATAMETABOLISMGENOTOXICITYEPIGENETICSDIFFERENCES HUMANS-ANIMALSCOMPOSITION…

UPGRADE FROM 2A TO 1: ETHYLENE OXIDE, DIOXIN (TCDD), BENZO(A)PYRENE…

UPGRADE FROM 2B TO 2A: ACRYLAMIDE, SEVERAL PAHs, VINYL BROMIDE…

UPGRADE FROM 3 TO 2B: 1,2-EPOXYBUTANE, GASOLINE…DOWNGRADE FROM 2B TO 3: D-LIMONENE, ATRAZINE,

MELAMINE, SACCHARIN…

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D-LIMONENE

d-Limonene – example of downgradeRole of mechanism

• Kidney cancer in male rats (NTP 1990)• Should be group 2B • Protein droplet nephropathy, male rat

specific mecanism, not applicable to humans

• Classified as group 3 IARC (1994)• Very good substitution solvent

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Ethylene oxide – example of upgradeRole of mechanism

• Limited epidemiological evidence in workers (chemical, sterilisation): lymphatic + hematopoeitic cancer (confoundingpossible)

• Animal carcinogen (lung, lymphoma, leukemia, brain…)• Should be group 2A, but:

Powerful mutagenExposed workers: chromosomal aberrations, SCE in peripheral lymphocytes, micronuclei in bone marrow cells, haemoglobin adducts in cells, dose-response

• Classified as group 1 (since 1994)

Summary IARC monographs program• TYPES OF AGENTS EVALUATED

substances and mixtures (work, environment, food, consumer products) physical agentsbiological agents, pharmaceuticals and treatmentslifestyle factorsoccupations-industries

• EVALUATIONS: 968 AGENTS (monographs 1-108)111 GROUP 166 GROUP 2A285 GROUP 2B505 GROUP 31 GROUP 4

• http://monographs.iarc.fr/

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Regular re-evaluation processe.g. formaldehyde: 1987, 1994, 2004, 2009

• Formaldehyde (1987, 1994): Group 2A – Limited evidence in humans: nasopharynx, sufficient

evidence in animals• Formaldehyde (2004): Group 1

– Sufficient evidence in humans (nasopharynx), leukemia: strong but not sufficient evidence, sufficient evidence in animals

• Formaldehyde (2009): Group 1 – Sufficient evidence in humans (nasopharynx, leukemia),

sufficient evidence in animals

Special re-evaluationMonograph vol 100 (2009)

• Re-evaluation of all group 1 carcinogens(approximately 100)

• Six working groups• Monograph 100 C: arsenic, metals, dusts and

fibers• Monograph 100D: radiation• Monograph 100F: chemical agents and related

occupations• Emphasis on tumour sites and mechanisms

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Recent and upcoming monographs• Radiofreq. electromagn. fields - group 2B• Oxidized bitumens (roofing) – group 2A• Diesel engine exhausts – group 1• Trichloroethylene – group 1• Tetrachloroethylene – group 2A• PCBs – group 1• Planned upcoming evaluations: ambiant air pollution,

dichloromethane…• Priorities advisory group (2008): nano and ultrafine

particles, crystalline fibers, iron and welding fumes, sedentary work, stress…

Examples of occupational agents in IARC 1 + 2A groups

• Metals and metalloids: As, CrVI, Ni, Be, Cd, Pb

• Other inorganic compounds: asbestos (all fibers), silica, strong inorganic acid mists

• Polycyclic aromatic hydrocarbons (PAHs) and relatedexposures: coal tar, oxidised bitumens, unrefined mineraloils, soot, creosotes, shale oils, diesel engine exhausts, benzo[a]pyrene…

• Epoxides: ethylene oxide, epichlorohydrin…

• Unsat. and halogen. aliphatic hydrocarbons: vinyl chloride, 1,3-butadiene, tetrachloroethylene, trichloroethylene…

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Examples of occupational agents in IARC 1 + 2A groups (continuing)

• Aromatic hydrocarbons + amino + chlorinated derivatives: benzene, dioxin (TCDD), furan (PCDF), PCBs, variousaromatic amines…

• Radiation: ionising radiation (all: X, gamma, radon, neutrons…), solar radiation, UV

• Other: formaldehyde, wood dust, leather dust, environmentaltobacco smoke…

• Occupations, industries, circumstances: aluminium production, painters, coal tar paving/roofing, hairdressers, rubber-manufacturing, shift work with circadian disruption…

• http://monographs.iarc.fr/ENG/Classification/index.php

Main cancer sites and occupational agents• Lungs: asbestos, silica, chromium VI, nickel, arsenic,

cadmium, coal tar, soot, ionizing radiations, aluminium production, second hand tobacco…

• Pleura: asbestos• Bladder: various aromatic amines, aluminium production…• Leukemia, lymphoma: benzene, ethylene oxide,

formaldehyde, butadiene, ionizing radiations…• Skin: coal tar, mineral oil, arsenic, solar radiation…• Liver: vinyl chloride• Nose, nasopharynx: wood, leather, nickel, formald…• Larynx: acid mists, asbestos… • Ovaries: asbestos• http://monographs.iarc.fr/ENG/Classification/Table4.pdf

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Summary: IARC Monographs Website

• Preamble (the rules)

• Availability of text or summary sections

complete pdf since 1987

summaries (section 5) before 1987 most recent: Lancet Oncology

• Classification by CAS nb, alphab. order, group

• Table on cancer sites (suff. or limited)

• Priorities from advisory group

Other classification systems• ACGIH: A1 to A5, close to IARC 1, 2A, 2B, 3 and 4,

TLV booklet and documentation

• National Toxicology Program (US):

– group 1: known to be…, group 2 : reasonably anticipatedto be (a human carcinogen)

– 12th report on carcinogens, 2011

http://ntp.niehs.nih.gov/ntp/roc/twelfth/roc12.pdf

• Globally Harmonized System (GHS): categories 1A, 1B, 2: known, presumed, suspected humancarcinogen

http://esis.jrc.ec.europa.eu/

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CAREX Canada (1)

• National carcinogen surveillance program (Canadian partnership against cancer)

• Based on similar experience in Europe

• Which carcinogens exist in the Canadian environment?

• Who is exposed to them?

• http://www.carexcanada.ca/

CAREX Canada (2)

Profiles and estimates for 85 carcinogens:

• Carcinogenic evidence

• Main uses

• Regulatory information

• Occupational and environmental exposure estimates(e.g. number workers exposed, by industry, occupation, province, levels, data sources)

• http://www.carexcanada.ca/en/profiles_and_estimates/

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Formaldehyde Carex (1)

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Formaldehyde Carex (2)

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Quebec study (Labrèche et al.: IRSST report R-732, 2012; AJIM 56: 1040-50, 2013)

Presentation main points

• IARC expert working groups (credibility)

• IARC tiered process: epi, animal, other data

• IARC accessibility of evaluations (including cancer sites)

• Examples of main 1 and 2A agents

• Other classification systems

• Focus on most recent data, read summaries

• Occurrence in Canada: Carex, Labrèche et al. study

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Credits

• Paul Demers (Carex)

• France Labrèche (IRSST)