MESOTHELIOMA The idea of preventive medicine is faintly

MESOTHELIOMA The idea of preventive medicine is faintly un-American it means, first, recognizing that the enemy is us” Chicago Tribune, 1975 Richard A. Lemen, Ph. D. MSPH Fellow Collegium Ramazzini

ASBESTOS CAUSES MESOTHELIOMA 2 Some never linked to asbestos because: (1) there is no known history of exposure to asbestos; (2) subjects die before an exposure history is obtained; (3) seeking a history from next of kin who may have no knowledge of asbestos exposure; (4) epidemiological studies assess occupational exposure, but not para - occupational or environmental exposures to asbestos. Source: Lemen, 2016 Demographics Dr. R. A. Lemen - Collegium Ramazzini 2016

3 Why question no asbestos link? Examples ☞ 81% reported no asbestos exposure; All had lung fiber counts >200, 000 [TEM]; Suggests unrecognized exposures to asbestos (Leigh et al, 2002) ☞ “Past exposure is not always recognized as such and this is more likely to be the case in females. ” (Leigh et al. , 2002) ☞ “If the deaths due to ‘take-home’ asbestos exposure were considered, the attributable risks may be around 90%. ” (Steenland et al. , 2003) ☞ “Failure to consider homogeneity within exposure patterns between Dr. R. A. Lemen - Collegium Ramazzini 2016 the sexes might account for reported differences in rates of Demographics mesothelioma. ” (Lemen, 2016)

REPORTING & INCIDENCE (U. S. DATA) ☞ < 10% occur in highest asbestos exposed (Kent filter workers = 18%) Similar to most environmental carcinogens ☞ Average latency ≅ 30 - 40 years. ☞ ICD-10 (C 45) first separate code for mesothelioma in 1990 s, 1. 05/100, 000 ♂ 1. 93/100, 00 ➢ Overall rates: ➢ Highest rates: White males = 2. 06/100, 000 Black males = 1. 05/100, 000 ➢ Highest rates in 75 ┼ years. vs ♁ 0. 41/100, 000 Sources: Tomatis et al. , 2007; Henley et al. , 2013; Lemen, 2011; 2016. Reporting & Incidence Dr. R. A. Lemen - Collegium Ramazzini 2016 4

REPORTING & INCIDENCE (DATA ESTIMATES) U. S. (2013) → 1. 3 x 106 Workers exposed to asbestos → 3, 200 diagnosed mesothelioma/year (≅ 2460 males vs. 707 females) → 12, 000 - 15, 000 ARD Deaths ➢ Anatomic site = ♂ 85% Pleural; ♁ 73% Pleural; 7% Peritoneal 18% Peritoneal Sources: Henley et al. , 2013; Lemen, 2011; 2016; Lunder, 2016; GBD, 2015; Reporting & Incidence Dr. R. A. Lemen - Collegium Ramazzini 2016 5

6 REPORTING & INCIDENCE (DATA ESTIMATES) World (2013) → 125 million workers exposed to asbestos. → 50, 400 mesothelioma deaths/year = 94. 7% ↑ since 1990. → 194, 000 deaths/year from all ARD. → ARD accounts for 2/3 rd of the burden of all occupational carcinogens. → 3. 4 million disability-adjusted life-years lost = 93. 4% ↑ since 1990. Sources: Lemen, 2016; http: //www. who. int/ipcs/assessment/publichealth/asbestos/en/. Reporting & Incidence Dr. R. A. Lemen - Collegium Ramazzini 2016

7 GENDER ➢ Men's & Women's risk similar from similar exposures ➢ Women’s risk frequently from non-occupational exposures: ☞ bystander, ☞ incidental, or ☞ take-home exposure. ➢ Pleural highest in men ➢ Peritoneal highest in women ➢ Incidence of pleural falls after 45 years latency but peritoneal did not. Source: Lemen, 2016; NCI, SEER Data Dr. R. A. Lemen - Collegium Ramazzini 2016 Gender

8 Gender Better survival associated: ✦ ✦ female; peritoneal; receipt of site-directed surgery; radiation. (Lemen, 2016) � mesothelioma similar in men and women � “…seems likely to be due to an increase in ambient asbestos exposure that coincided with the widespread occupational exposures of the 1960 s and 1970 s rather than to an increase in diagnostic awareness. ” (Peto et al. , 2009) Gender Dr. R. A. Lemen - Collegium Ramazzini 2016

AGE 9 < 40 years of age > 40 years of age ☞ Rare = 1. 7% ☞ Ratio = 51/49% male/female ☞ Less likely occupational ☞ 49% between 35 -40 years of age ☞ 84% white 92% white✵. ☞ 47%/48% pleural/peritoneal 90% ☞ 34 months average survival ☞ 5 -year survival = 38% 78% / 22%✵ / 9% 8 months 3% Dr. R. A. Lemen - Collegium Ramazzini 2016 Age ✵ Statistically Significant Sources: Thomas et al. , 2015; Lemen, 2016

GENETIC ROLE 10 (SUSPECTED) → Family clusters in Italy & erionite exposed families in Turkey suggest genetic role. → Precise genetic role in family susceptibility unknown. → Low incidence in heavily exposed suggest possible genetic role. → Autosomal dominant inheritance found in family clusters in Turkey. → More genome-wide expression in pleural mesothelioma cells vs peritoneal cells. → Consistent with finding higher exposures to asbestos in peritoneal cases. Sources: Dragon et al. , 2015: Lemen & Dodson, 2012; Lemen, 2016 Genetic Role Dr. R. A. Lemen - Collegium Ramazzini 2016

GENETIC ROLE 11 (UNDECIDED) ➤ Germline BAP 1 mutations found in some mesothelioma-prone families having little history of heavy exposure to asbestos �other studies have not. ➤ Some consider BAP 1 gene mutations as potential markers of susceptibility. ➤ It is thought specific non-invasive biomarkers will emerge. ➤ Recent consensus suggests : persons with BAP 1 germline mutations transmitted over the course of multiple generations are associated with very high incidence of MM upon exposure to asbestos. ☛ ☛ and/or it is anticipated that carriers of germline BAP 1 mutations may be more sensitive than the population at large to low amounts of asbestos naturally occurring asbestos. Sources: (Testa et al. 2011; Sneddon et al. , 2015; Betti et al. , 2015; Rusch et al. , 2015; Panou et al. , 2015; Carbone et al. , 2016. Genetic Role Dr. R. A. Lemen - Collegium Ramazzini 2016

PLAUSIBLE FIBER ACTION IN HUMANS ➤ 12 Mechanical irritation ➤ Fibers interfere with mitotic process through disruption of the mitotic inducing chromosomal abnormalities and aneuploidy spindle, ➤ Highly reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated by asbestos fibers causing DNA damage and strand breaks. ➤ Asbestos fibers induce cytokines and growth factors, i. e. : ☞ ☞ ☞ transforming growth factor-β (TGF-β); platelet-derived growth factor (PDGF); transcription factors including nuclear factor kappa B (NF-ĸB) and activator protein-1 (AP-1). Source: Lemen, 2016 Dr. R. A. Lemen - Collegium Ramazzini 2016 Fiber Action

Chrysotile vs. Amphibole 13 Meta-analyses of studies having good exposure assessment show less differences in potency between chrysotile and amphiboles Chrysotile's fibers breakdown into smaller fibrils readily leaving the lung for areas outside the lung demonstrating the fallacy of lung burden analysis seeking their presence Mesothelial (pleural) tissues show chrysotile fibers 30. 3 times more common than amphiboles. ATEM not SEM most appropriate for quantification of both chrysotile & short fibers Sources: Suzuki et al. , 2002; Lenters et al. , 2011; Lemen & Dodson, 2012 Chrysotile Dr. R. A. Lemen - Collegium Ramazzini 2016

CONCLUSIONS : ASBESTOS & MESOTHELIOMA 14 ➣ No safe concentration (CR, WHO; IPCS; NIOSH; EPA etc. ) ☞ ☞ ☞ Likely involves unknown factors in genetic susceptibility; Multiple processes taking place to produce mesothelioma; No way to pinpoint which exposure caused disease. ➣ Asbestos is a complete carcinogen, both initiates & promotes cancer. ➢ Both early and late exposures relevant (CR Statement). ➢ Sentinel tumor, most often associated with asbestos exposure. ➢ Like all ARDs is both risk and dose/intensity dependent to some degree as cumulative exposures rise. As proposed by NIOSH in 1976 - only a BAN can assure prevention Conclusion Dr. R. A. Lemen - Collegium Ramazzini 2016 Source: Lemen, 2016

15 EPILOGUE MESOTHELIOMA RISK FROM OTHER RESPIRABLE ELONGATED MINERAL PARTICLES (REMP) Many of same factors associated with asbestos induced mesothelioma may be relevant → mineral type, → physical features of inhalation, → surface chemical composition. Source: Aust, Cook, Dodson, 2011 Dr. R. A. Lemen - Collegium Ramazzini 2016 Epilogue