Occupational Cancer -Ionizing Radiation-

1. Occupational Cancer-Ionizing Radiation- Oren Zack MD MOccH

2. Introduction • Twenty-nine occupational agents, as well as 18 exposure circumstances are carcinogenic to humans • It has been known for over 200 years that exposures encountered at the workplace are a cause of cancer • Initially detected by clinicians: Percival Pott - scrotal cancer, chimney sweeps (soot) (1771), Creech and Johnson’s – liver angiosarcoma, vinyl chloride workers (1974) • The period of formal epidemiological assessment of the occurrence of cancer in relation to workplace exposures started after World War II. Knowledge of the occupational and other environmental causes of cancer grew rapidly in the 1950s and 1960s. • Estimates of the burden of occupational cancer in high-resource countries are in the order of 2–5%.

3. Group 1: World Cancer Report, 2008

4. Group 2A: World Cancer Report, 2008

5. Introduction (cont.) • The distinction between occupational and environmental carcinogens is not always straightforward • Exposure levels tend to be higher at the workplace • There are agents that have been evaluated in IARC groups 1 or 2A, for which exposure is not primarily occupational, but which often encountered in the occupational environment • Nursing staff - cyclophosphamide, cyclosporine • Food processors – aflatoxins • Medical personnel – HBV, HCV, HIV • Agriculture, fishing, outdoor occupants – solar radiation • Public settings, bars – secondhand tobacco smoke

6. Introduction (cont.) • Polycyclic aromatic hydrocarbons (PAHs) represent a specific problem in the identification of occupational carcinogens • Includes several potent experimental carcinogens, such as benzo[a]pyrene, benz[a]anthracene and dibenz[a,h]anthracene. • However, humans are always exposed to mixtures of PAHs and an assessment of the carcinogenicity of individual PAHs in humans is difficult • Current understanding of the relationship between occupational exposures and cancer is far from complete; in fact, for many experimental carcinogens no definitive evidence is available from exposed workers. • In some cases, there is considerable evidence of increased risks associated with particular industries and occupations, although no specific agents can be identified as etiological factors • Fifteen occupations and industries are listed in IARC Group 1 and four in Group 2A

7. World Cancer Report, 2008

8. Difficulties in Establishing Causality • Constructing and interpreting lists of chemical or physical carcinogenic agents and associating them with specific occupations and industries is complicated by a number of factors: • Information on industrial processes and exposures is frequently poor, not allowing a complete evaluation of the importance of specific carcinogenic exposures in different occupations or industries • Exposures to well-known carcinogenic exposures, such as vinyl chloride and benzene, occur at different intensities in different occupational situations • Changes in exposure occur over time in a given occupational situation, either because identified carcinogenic agents are substituted by other agents or (more frequently) because new industrial processes or materials are introduced • Any list of occupational exposures can only refer to the relatively small number of chemical exposures that have been investigated with respect to the presence of a carcinogenic risk • A single figure on the proportion of cancers due to occupations might be misleading as exposure concentrates on subgroups of the population, namely male blue-collar workers, among whom the burden can be substantial.

9. Other Factors • The increasing employment of women in jobs outside the home has probably contributed to changes in reproductive habits, which may entail an increased risk of hormone-related cancers • Shiftwork that involves circadian disruption has been classified as a probable human carcinogen by the IARC Monographs Program, on the basis of limited evidence of an increased risk of breast cancer • Occupational cancer is likely to be a more important problem in medium- and low-resource countries than in high-resource countries: • Importance of the informal sector • Lack of stringent implementation of existing regulations • Low level of attention paid by management and the workforce to industrial hygiene • Presence of child labor

10. Frequent Tumor Sites: Occupational • Lung • Urinary bladder • Nasal cavity • Liver (angiosarcoma) • Mesothelioma • Leukemia • Non-melanocytic skin cancer

11. Carcinogenesis • Cancer is a multi-step process during which cells undergo profound metabolic and behavioral changes, leading them to proliferate in an excessive and untimely way, to escape surveillance by the immune system, and ultimately to invade distant tissues to form metastases

12. Initiators and Promoters • Examples: • PAH • Tobacco smoke • Diethyl-nitrosamine • Methylnitrosurea • 2-naphthylamine • 2-Acetylaminofluorene • Examples: • Croton oil • Tobacco smoke • DDT, PCBs • Saccharin • D, L Tryptophan • Phenobarbital

13. Oncogenes and TSGs

14. International Agency for Research on Cancer (IARC)

15. Monograph Program • The International Agency for Research on Cancer was established in May, 1965 • Monograph program is functioning since 1971 • More than 900 agents have been evaluated, of which more than 400 have been identified as carcinogenic, probably carcinogenic, or possibly carcinogenic to humans • Objective: identifying environmental factors that can increase the risk of human cancer

16. Agents Classified by the IARC Monographs, Volumes 1-108

17. IARC Classification • Evaluations of the epidemiological and experimental evidence of the carcinogenicity are performed for chemicals, complex mixtures, occupational exposures, physical and biological agents, and lifestyle factors. • Agents are selected by the IARC to be evaluated if there is evidence that exposure occurs in humans, and also if there is suspicion that the agent could cause cancer. • The evidence used in the IARC monographs is based on • Exposure data • Epidemiological studies • Studies in experimental animals • Data on mechanisms of action (e.g. kinetics, mutagenicity)

18. IARC Classification (cont.) • The IARC does not categorize the carcinogens evaluated as for the source of exposure and therefore does not indicate which should be considered as occupational. • To identify which carcinogens could be classified as occupational, it is necessary to review the text of the monographs and then apply ad hoc criteria. • The identification and listing of exposures that could be defined as occupational can be complex. Many occupational exposures also occur in the general environment and, vice versa, many predominantly environmental exposures occur in the occupational environment.

19. Carcinogenicity in Humans • Sufficient evidence of carcinogenicity • A causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence • Limited evidence of carcinogenicity • A positive association has been observed, but chance, bias or confounding could not be ruled out with reasonable confidence • Inadequate evidence of carcinogenicity • Available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association between exposure and cancer, or no data on cancer in humans are available • Evidence suggesting lack of carcinogenicity • Several adequate studies covering the full range of levels of exposure that humans are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent and any studied cancer at any observed level of exposure

20. Carcinogenicity in Experimental Animals • Sufficient evidence of carcinogenicity • A causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols • An increased incidence of tumors in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence • A single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumor or age at onset, or when there are strong findings of tumors at multiple sites • Limited evidence of carcinogenicity • (a) the evidence of carcinogenicity is restricted to a single experiment; • (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; • (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or • (d) the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs

21. Carcinogenicity in Experimental Animals • Inadequate evidence of carcinogenicity • Evidence suggesting lack of carcinogenicity • Studies involving at least two species are available which show that, within the limits of the tests used, the agent is not carcinogenic • A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites, age at exposure, and conditions and levels of exposure studied

22. Mechanistic and Other Relevant Data • Data on preneoplastic lesions, tumor pathology, genetic and related effects, structure-activity relationships, metabolism and toxicokinetics, physicochemical parameters and analogous biological agents • Strength of evidence: weak, moderate or strong • Working Group assesses whether the particular mechanism is likely to be operative in humans • Data may be considered to be especially relevant if they show that the agent in question has caused changes in exposed humans that are on the causal pathway to carcinogenesis • The conclusion that a mechanism operates in experimental animals is strengthened by findings of consistent results in different experimental systems, by the demonstration of biological plausibility and by coherence of the overall database • Multiple mechanisms might contribute to tumor development • Different mechanisms might operate in different dose ranges • Separate mechanisms might operate in humans and experimental animals • A unique mechanism might operate in a susceptible group

24. Group 1 Agents, Volumes 1-108

25. Group 1 Agents, Volumes 1-108

26. Group 1 Agents, Volumes 1-108

27. Group 1 Agents, Volumes 1-108

28. Group 1 Agents, Volumes 1-108

29. Group 1 Agents, Volumes 1-108

30. Group 1 Agents, Volumes 1-108

31. Group 1 Agents, Volumes 1-108

32. Group 1 Agents, Volumes 1-108

33. Selected Group 2 & 3 Agents • Group 2A • Acrylamide • Hairdresser as a barber • Lead - inorganic • Shiftwork that involves circadian disruption • Group 2B • Aloe vera, whole leaf extract • Coffee (urinary bladder) • DDT • Dry cleaning • Fire fighter • ELF – magnetic fields • RF – electromagnetic fields • Pickled vegetables (traditional in Asia) • Group 3 • Polystyrene • Caffeine • Chromium (III) • ELF – electric fields • Lead – organic • Polyethylene • PVC • …

47. Common Exposures, EU Data: CAREX, 2010, http://www.ttl.fi/en/chemical_safety/carex/countries/pages/default.aspx

48. Diagnosis Considerations • Occupation accounts for all or part of the tumor process in 5 per cent of cancers • Long latency-induction times for cancer • As a general rule, cancers that are of occupational origin are not distinguishable from non-occupational cancers whether in clinical features, natural history, pathological findings or other special investigations • Occupational cancer may present earlier than the non-occupational varieties • Movement of workers between jobs, work areas or industries • Rare tumors may be an indicator • Multiple exposures • Diversity of chemical nomenclature • Confounding risk factors

49. Ionizing Radiation & Cancer

50. Stochastic Effects • Carcinogenesis • The cancers induced by radiation, with or without the contributions of other agents, are indistinguishable from those occurring ‘spontaneously’ or from other causes • Studies on Hiroshima and Nagasaki, radium exposed employees in luminizing industry, miners exposed to radon, Chernobyl survivors • The cancer risks derived from such exposed groups are influenced largely by exposures to high doses, which were delivered over a short period of time. In practice, most people are exposed occupationally to low doses of radiation received over relatively long periods • The risk factor or lifetime fatality probability coefficient from ICRP for a reference population of both sexes and of working age is 4.1 × 10−2/Sv for the sum of all fatal malignancies, i.e. A dose of 1Sv in a working lifetime results in a 4 per cent chance of a fatal cancer occurring