The preventable burden of work-related ill-health

1. The preventable burden of work-related ill-health Pierluigi Cocco Professor of Occupational Medicine Department of Medical Sciences and Public Health. University of Cagliari

2. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Tomasetti & Vagelstein ,Science 347: 78–81. Isthis science?

3. Nature 2016;529:43-7 Abstract. (156 words) Recent research has highlighted a strong correlation between tissue-specific cancer risk and the lifetime number of tissue-specific stem-cell divisions. Whether such correlation implies a high unavoidable intrinsic cancer risk has become a key public health debate, with the dissemination of the “bad luck hypothesis”. Here we provide evidence that intrinsic risk factors contribute only modestly (less than around 10-30% of lifetime risk) to cancer development. First we demonstrate that the correlation between stem-cell division and cancer risk does not distinguish between the effects of intrinsic and extrinsic risk factors.. We then show that intrinsic risk is better estimated by the lower bound risk by controlling for total ste-cell divisions. Finally, we show that the rates of endogenous mutation accumulation by intrinsic processes are not sufficient to account for the observed cancer risks. Collectively, we conclude that cancer risk is heavily influenced by extrinsic factors. These results are important for strategizing cancer prevention, research and public health.

4. Smoking and lung cancer mortality in the U.S. 1982 1991 http://www.cdc.gov, personal analysis

5. Pro-capita consumption of asbestos in 1915-1992 and mortality from pleural mesothelioma in Italy, observed in 1970-1999 and forecasted in 2000-2030. Marinaccio A, Int J Cancer, 2005

6. Attributable risk to occupational risk factors by cancer site (adapted from Doll & Peto, 1981)

7. UK deaths and registrations for cancer in 2004-2005 attributable to occupational risk factors Rushton L, Br J Cancer, 2012

8. Despite a substantialliterature on riskofcardiovasculardiseasesoverall, ischaemicheartdisease, acute myocardalinfarction, hypertension, and exposuretoparticulatematter, lead, noise, shiftwork, and psychosocialstress, far fewerstudieshaveexplored the burdenofoccupationalexposures on cardiovasculardiseases • Causes: • Difficulty in assessing the share ofoccupationalillhealthInadequate information on exposures, lackofexposuremeasurements, and numberofexposedindividuals; • Lackofregistrationofoccupational information in routinelycollectedhealth data, including family doctorrecords, hospital records, and diseaseregistries Rushton L, Curr Environ Health Rep, 2017

9. Metanalysisof long workinghours and riskofcoronaryarterydisease Kivimaki M, Lancet, 2015

10. Disability Adjusted Life Years lost attributed to risk factors in 2013 for both genders combined. The Global Burden of Disease project Lancet, 2015;386:2287-2323

11. Numbersof global occupationallyrelateddeaths in 2015 by WHO region and major diseasegroups Rushton L, Curr Environ Health Rep, 2017

12. Bernardino Ramazzini “De morbis artificum diatriba” “Medicine, as Law,should contribute to workers wellbeing so that they could, as much as possible, practice their job free of danger. As far as I am concerned, I did what I could and I never thought it was inconvenient to enter the dirtiest shops and to study the secrets of the mechanical arts. “When the physician questions…a patient…. he should add one question to those Hippocrates recommended: what is your job?”

13. Aims of this presentation: to compare the attributable fraction of occupational factors with that of heritability, as calculated from GWAS studies, so to understand to what extent occupational medicine can contribute to reduce the human burden of ill health.

14. Procedure for the calculation of the fraction of a given disease attributable to multiple occupational exposures 1. calculation of the attributable fraction (AFe) for each specific occupational exposure, based on the published risk estimates (RR): AFe = (RR-1)/RR 2. calculation of the attributable fraction at the population level (AFp) for each occupational factor, using their estimated prevalence among the general population (CF): AFp = AFe x CF 3. calculation of the burden of disease attributable to occupation as a whole by combining the individual AFp values, as suggested by Steenland and Armstrong: AFoverall = [1-Pk (1-AFk)]

15. Occupational risk factors for CLL so far identified • Contact with meat • Ethylene oxide • Benzene • Trichloroethylene • Organophosphate pesticides • Herbicides Occupational risk factors currently being investigated • Shift work • Organic dust • Ionizing radiation • Non ionizing radiation

16. Attributable fraction of CLL due to known or probable occupational risk factors and to heritable polygenic polymorphisms

17. Aetiological factors of Chronic Lymphocytic Leukaemia • About 12% of chronic lymphocytic leukaemias are attributable to occupational exposures. • The proportion is higher for polygenic heritable polymorphisms (about 16%) • About 70% of CLL cases are attributable to other factors, such as viral agents, environmental factors (such as dioxin and PCBs) and other yet unknown factors.

18. Evidence from prospective cohort studies: work stress and elevated risks of depression • Demand-controlmodel: 12 of 14 studies: OR varyingfrom 1.2 to 3.4 • Effort-rewardimbalancemodel: 10 studies: OR varyingfrom 1.5 to 4.6 • Organisational injusticemodel: 11 studies: OR varyingfrom 1.2 to 2.4 Population-attributablefraction: 10%-20% Siegrist J, Global Health, 2012

19. Attributable fraction of major depressive disorder due to known or probable occupational risk factors and to heritable polygenic polymorphisms

20. Risk of high work stress of symptomatic and asymptomatic LQTS mutation carriers compared to young Finns control subjects Hintsa T, JOEM, 2013

21. Shiftwork and LQTS Meloni M, Am J Ind Med, 2013

22. Attributablefractionof LQTS due toknown or probableoccupationalriskfactors and toheritablepolygenicpolymorphisms

23. Limitations Possible causes of underestimation of true attributable fractions • only a handful of occupational risk factors for the selected diseases are documented properly enough to contribute to our analysis, compared to the extensive GWAS coverage; • in case of true associations, the inter-individual variability of occupational exposure, and the uncertainty in defining it at toxicologically relevant levels in retrospective studies, result in underestimating the strength of the association. Possible causes of overestimation of true attributable fractions • psychosocial risk factors would likely occur jointly, so that the attributable fraction for the combined effects would be overestimated • the smaller size of occupational studies results in lesser precision of the risk estimates compared to GWAS risk estimates

24. Conclusions • The Educational system and the Academy need to reverse the current trend of lesser consideration towards education and research in occupational health in respect to other medical disciplines. • Acknowledgment of the relevance of occupational health research and education would translate into a longer and more productive life for the working population.