New Notation for Carcinogens with Threshold Michael Koller, MD, PhD Division of Occupational Medicine SUVA, Switzerland MEDICHEM 2016, Basel Seite 1
Program 1. Introduction 2. Thresholds in carcinogenesis 3. Swiss system of setting OELs 4. Notification of carcinogens with a threshold 5. Notified substances Seite 2
Introduction sciencephoto.com Seite 3
Some basics DNA damages are often: 1000s per cell per day DDR (DNA damage response) repair (mild damage) or apoptosis (severe damage) Overextension of repair and adaptation mechanisms permanent damage (= mutation) Mutation: gene or chromosome (structural: clastogenic numeric: aneugenic) Activation of proto-oncogenes or inactivation of tumour suppressor genes initiation of carcinogenesis Seite 4
Multistage Model: Initiation first step in multistage model of carcinogenesis genotoxic chemicals: physical interaction with DNA direct interaction: carcinogen interacts itself with DNA Alkylating substances indirect interaction: metabolite interacts with DNA PAH, Nitrosamines studyblue.com Seite 5
Benzo[a]pyren as an indirect genotoxin www.carcinogenesis.com Seite 6
Multistage Model: Initiation Initiation alone does not necessarily lead to cancer Promotion studyblue.com Seite 7
Promotion: Non-Genotoxic Carcinogens Non-DNA-reactive Non-genotoxic mechanisms Inflammation Immunosuppression ROS Receptor activation Epigenetics studyblue.com Seite 8
Multistage Model: Promotion Altered signal transduction and modified gene expression proliferation or apoptosis of initiated cell selective clonal expansion of initiated cell preneoplastic lesion studyblue.com Seite 9
Example: Benzo[a]pyren again Luch, Nature Reviews Cancer 2005 Seite 10
Multistage Model: Progression Further genetic changes (mainly on chromosomes) Genotoxic mechanisms (clastogenic or complete carcinogens) Conversion of benign to malignant tumor Autonomous, irreversible growth studyblue.com Seite 11
Thresholds in Carcinogenesis Koller et al (2013): Factsheet Suva Seite 12
Carcinogens without Threshold Genotoxic carcinogens Minimal concentrations may induce cancer minimize concentration! Dose-dependent tumorigenicity Carcinogens without enough data are treated as carcinogens without threshold Koller et al (2016): EKAS Mitteilungsblatt Seite 14
Carcinogens without Threshold Example: 2-Acetylaminofluorene 28 days feeding of female BALB/c mice dg-c8-af in hepatic nuclear DNA adenoma and carcinoma in liver incidence is linearly related to AAF concentration in diet Poirier et al (1991) Carcinogenesis 12;5:895-900 Seite 15
Initiation No Threshold Promotion With Threshold Carcinogens without and with threshold Seite 16
Carcinogens with Threshold Non-genotoxic carcinogens (promoter) Genotoxic carcinogens with effect at chromosomal level "Practical" threshold for weak genotoxic carcinogens Below threshold: no increased cancer risk 2-Acetylaminofluorene again dg-c8-af in bladder DNA after 28 days of AAF feeding bladder carcinoma with non-linear tumor response Poirier et al (1991) Carcinogenesis 12;5:895-900 Seite 17
Non-genotoxic substances with lower carcinogenesis at low dose (hormesis) Fukushima, Carcinogenesis, 2005, 26, 1835 scholarworks.umass.edu Seite 19
Carcinogens "without" Threshold Is there really no threshold? In reality: repair or adaptation mechanisms biological threshold Close to natural background Take into account when linear extrapolation from high-dose animal experiments to lowdose situation at working place Koller et al (2016): EKAS Mitteilungsblatt Seite 20
How are carcinogens with threshold notified? www.en.payzen.eu Seite 21
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Examples Group A: Genotoxic carcinogens without threshold Methyl bromide, dichlorodimethyl ether, epichlorhydrine, trichloropropane Group B: Genotoxic carcinogens where a threshold cannot be sufficiently supported Hydrazine, ethylene oxide, o-anisidine Group C: Genotoxic carcinogens with practical threshold Methylene chloride, cadmium, propylene oxide Group D: Non-genotoxic carcinogens with perfect threshold Amitrole, carbon tetrachloride, tetrachloroethylene Seite 24
Deutsche Forschungsgemeinschaft DFG Seite 25
Deutsche Forschungsgemeinschaft DFG Category Definition 1 Proven carcinogenicity for humans due to epidemiologic studies 2 Have to be taken as carcinogenic for humans due to results of animal studies 3 Cause for concern but not enough information to be classified definitely 4 Non-genotoxic carcinogenic substance and no increase of cancer risk when air concentration < OEL 5 Genotoxic carcinogenic substance and no considerable contribution to cancer risk when < OEL Seite 26
Classification of SCOEL and DFG SCOEL and DFG consider MoA (genotoxicity vs. non-genotoxicity) and potency/risk (in case of genotoxicity) Conventional cancer classification does not consider potency substances may be classified even though high doses are necessary to induce tumors [Hennes 2014] Seite 27
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Chapter 3.6.2.3.2. Additional considerations for classification existence of a threshold downgrade from C1 to C2 possible Seite 29
Notification of Carcinogens by Suva web-kuchi.ch Seite 30
Excursion to Swiss system of setting OELs Suva (Swiss National Accident Insurance Fund) issues legally binding limits 1) Occupational exposure limits Biological limit values Threshold values for physical impact Recommendations for maximum loads First published Swiss OEL list in 1968 New list is published every year in German and French 1) Regulation on the prevention of accidents and occupational diseases (Art. 50.2) Seite 31
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Procedure Suva experts Study publications and reports of OEL committees Attend meetings (DFG, SCOEL, ) and conferences Perform own investigations Suggestion of new OELs Meeting of Swiss OEL commission University State Industry Practitioners Suva Publication of new OEL list Seite 35
Classification of Carcinogens < 2015 > 2016 Risk of Cancer Signal word Hazard statement C 1 C1 A Known Danger H350 11 C 2 C1 B Presumed Danger H350 68 C 3 C2 Suspected Warning H351 61 Chemicals (incl. compounds) Seite 36
Notation for Carcinogens with Threshold No new class, but adding notation # No threshold With threshold C1 A C1 # A C1 B C1 # B Seite 37
Notation for Carcinogens with Threshold No new class, but adding notation # No threshold With threshold C1 A C1 A # C1 B C1 B # Minimization No minimization no hint to MoA (genotoxicity) or potency/risk but pragmatic solution allowing direct comparison of Swiss classification with GHS/CLP Seite 38
Notified Substances in Switzerland Substance Butylhydroxytoluene (BHT) Cadmium and compounds SUVA SCOEL DFG Cancer Critical effect C1 B # - C4 Liver Liver C1 B # C C1 Lung Lung, kidney Dichloromethane C1 # B C C5 Liver, lung Di-sec-octyl phthalate (DEHP) CNS C1 B # - C4 Liver Sertoli cells 1,2-Epoxypropane C1 B # C C4 Nose Nose irr Formaldehyde C1 B # (C) C4 Nose Eye irr In discussion: Hexachlorobutadien, Isopren, Trichlorethen, Seite 39
Suva Building in Luzern Thank you for your attention! www.radiopilatus.ch Seite 40