1. Carcinogens August 2010

2. Carcinogens 0. Introduction 1. Definitions 2. Mechanism 3. Toxicology 4. Carcinogens 5. Preventive measures 6. What needs to be documented

3. 0. Introduction 1.Examples of cancers? 2.Examples of products causing cancer? 3.Only cancer at workplace? 4.What do e.g. asbest and cigarette smoke have in common?

4. 0. Introduction 1.Examples of cancers? Breast cancer, lung cancer, colon cancer, skin cancer,... 2.Examples of products causing cancer? Benzene, asbest, cigarette smoke, food, ethylene oxide, chromium VI, toluene, … 3.Only cancer at workplace? No! 4.What do e.g. asbest and cigarette smoke have in common? In beginning, these were ‘promoted’ to use It took years before link between exposure to asbest or cigarette smoke and cancer was known Exposure limits are very often lowered in progress of time

5. 1. Definitions Carcinogen: Substance that can cause cancer by inhalation, ingestion or skin contact Mutagen: Substance that can damage the hereditary material (DNA) Mutagen may cause cancer, but not always

6. 6 Repro-toxic substance: Substance that can be toxic to the development of the unborn child (= teratogen) or can cause impairment of fertility in male and/or and female subjects Can be a chemical substance, a virus, ionizing radiation Most countries: same requirements applicable for carcinogens, mutagens and repro-toxic substances = CMR legislation 1. Definitions

7. 2. Mechanism Cancer = unrestrained cellular proliferation For this different steps are necessary: 1. Initiation 2. Promotion 3. Progression

8. !Important! Cancer development is a multistep process: -For the growth of a cancer several factors must work together -Several influencing factors play an additional large role if a cancer will develop: food, age, hormones, … 2. Mechanism

9. The begin of cancer generally needs many years Different carcinogens have different working mechanism 2. Mechanism

10. 3. Toxicology Basic Toxicological Terms Cancer = Chronic effect –Occur some time after exposure –Usually from repeated lower doses over many months / years –Usually irreversible Stochastic - describes likelihood of an event taking place – synonymous with random –e.g. malignant disease such as cancer for which the probability of an effect occurring is a function of dose without threshold –Paracelsus: not 100 % applicable here (see next slide) –Once it occurs consequence is independent of initiating dose –Stochastic effects do not have a threshold dose

11. Any chemical may be toxic if the dose is high enough ‘All substances are poisons, there is none which is not a poison. The right dose differentiates a poison and a remedy.’ Paracelsus (1493-1541 ) ResponseDose 3. Toxicology Paracelsus?

12. The effect may not occur at time of exposure –By the time it occurs the person may not be working with the substance (latency time) People vary in susceptibility (react differently) –Variations may be due to age, gender, health status,... Complications of combined effects –Exposure to different substances –Exposure to alcohol, tobacco or prescribed drugs (e.g. synergistic effects asbestos and tobacco) Impact of life style Detailed toxicological information is often not available for many substances 3. Toxicology Problems linking cause and effect

13. Conclusion: Association between certain cancers and a profession difficult Important that we can demonstrate that we fulfilled our duty to prevent exposure to carcinogens at work! 3. Toxicology Problems linking cause and effect

14. 14 Different exposure routes: inhalation ingestion skin contact Different end points: respiratory system digestive system skin bones blood … 3. Toxicology Exposure routes - end points

15. Estimation of % of cancer deaths due to several factors (Doll en Peto, 1981) Tabacco: 30% (range 25-40) Food : 35% (range 10-70) Infections:10% (range 1-7) Alcohol: 3% (range 2-4) Sexual behaviour: 7% (range1-13) Profession: 4% (range 2-8) Geographical factors: 3% (range 2-4) Out door air pollution: 2% (range 1-5) Medicine: 1% (range 0,5 -3) 3. Toxicology Causes of cancer Learns us that most of the cancers are avoidable when people have a healthy lifestyle

16. Lung membrane cancer (mesothelioom) –Asbestos Cancer nose –Tropical hardwood Leukaemia –Benzene, ionizing radiation Bladder cancer –Aniline industry – dyes Mostly avoidable causes 3. Toxicology Work related cancers

17. Legislation China takes IARC (see further) as a basis Other sources to look at: - J&J guidance list: carcinogens following agencies like IARC, ACGIH, EU - MSDS: Risk (R)-sentences (GHS: H-sentences) see heading 15 of the MSDS Reach-legislation (MSDS needs to be more extended on how exactly to handle compounds in a safe way in different applications) 4. Carcinogens - where to find information

18. 18 Important R-sentences (between brackets: H-sentence GHS): R 40 : Carcinogenetic impact have not been excluded (insufficient proof or insufficiently examined) (H351) R 45: Can cause cancer (H 350) R 46: Can cause hereditary genetic damage (H340) R 49: Can cause cancer due to inhalation (H350i) R 60: May impair fertility (H360F) R 61: May cause harm to the unborn child (H360D) R 62: Possible risk of impaired fertility (H361f) R 63: Possible risk of harm to the unborn child (H361d) R 64: May cause harm to breastfed babies (H362) 4. Carcinogens GHS: pictogram will be used for e.g. carcinogens - mutagens – repro-toxic substances

19. IARC Since 1971 900 substances examined Extensive work: complete range of studies necessary e.g.: - bacterial mutagenese e.g. Ames test - study at molecular level (DNA) - animal tests etc.. 4. Carcinogens IARC - International Agency for Research on Cancer

20. 20 1Carcinogenic to humansSufficient evidence 2AProbably carcinogenic tot humansLimited indication 2BPossibly carcinogenic to humans Insufficient indication in lab situations 3 Not classifiable as to carcinogenicity to humans Limited indication in animal surveys 4Probably not carcinogenic to humansIndication for absence of carcinogenicity 4. Carcinogens IARC - International Agency for Research on Cancer - http://www.iarc.fr/

21. Own toxicological department Estimation is reflected in monograph (notation ‘carc’) Difficulty: not all compounds are tested even extensively (e.g. intermediates) 4. Carcinogens J&J products - see monograph

22. Show list of carcinogens in use on your site 4. Carcinogens

23. 5. Preventive measures Basic principles: 1. Risk evaluation 2. Measures in certain hierarchical order 3. Medical surveillance Objective: Protect workers against risks specifically arising or likely to arise from exposure to carcinogens at work

24. 24 SUBSTITUTION by less hazardous compound Risk assessment of activities with carcinogens = general RA with RBEAP-approach = for class 1 carcinogens: additional detailed RA (with e.g. what-if technique) - see example attached: Limit quantity of carcinogens handled Limit # of persons to zone where carcinogens are handled 5. Preventive measures

25. 25 Good design of work processes and engineering controls to avoid or minimize the release of carcinogens (work as closed as possible - avoid open handling) Removal of the carcinogens at the source - appropriate local and general ventilation as needed Collective protection measures and/or, where exposure cannot be avoided by other means, individual protection measures Good hygiene practices! (in particular regular cleaning of floors, walls and other surfaces) All people need to be well informed and trained specifically to work with carcinogens 5. Preventive measures

26. 26 Clearly trace / indicate zone where carcinogens are handled Make up emergency plan how to deal with emergencies likely to result in abnormally high exposure of carcinogens Means for safe storage (e.g. keep carcinogens separated from flammables), handling and transportation, using sealed and clearly and visibly labeled containers Means for safe collection, storage and disposal of waste, including use of sealed, clearly and visibly labeled containers People who work with carcinogens need to receive appropriate medical checks (goal: early detection) 5. Preventive measures

27. 27 What persons handled what quantity of what carcinogen on what day during what kind of activity (logbook) Activities and/or industrial processes carried out, including the motivation why carcinogens are used Quantities of substances or preparations manufactured or used which contain carcinogens Number of workers exposed Preventive measures taken Type of protective equipment used Nature and degree of exposure Cases of substitution 6. What needs to be documented