MESOTHELIOMA “The idea of preventive medicine is faintly un-American - PowerPoint Presentation

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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 RamazziniSlide2

Asbestos Causes Mesothelioma

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.

Demographics

Source: Lemen, 2016

Dr. R.A. Lemen - Collegium Ramazzini 2016

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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 the sexes might account for reported differences in rates of mesothelioma.” (Lemen, 2016)

DemographicsSlide4

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 (C45) first separate code for mesothelioma in 1990s, ➢

Overall rates: 1.05/100,000

♂ 1.93/100,00 vs ♁

0.41/100,000

➢

Highest rates: White

males =

2.06/100,000 Black males = 1.05/100,000➢ Highest rates in 75 ┼ years. Sources: Tomatis et al., 2007; Henley et al., 2013; Lemen, 2011; 2016.

Reporting &

Incidence

Dr. R.A. Lemen - Collegium Ramazzini 2016

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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;

7%

Peritoneal

♁ 73

%

Pleural

;

18% Peritoneal Sources: Henley et al., 2013; Lemen, 2011; 2016; Lunder, 2016; GBD, 2015; Reporting & Incidence

Dr. R.A. Lemen - Collegium Ramazzini 2016

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Dr. R.A. Lemen - Collegium Ramazzini 2016

6World (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.

REPORTING & INCIDENCE

(DATA ESTIMATES)Sources: Lemen, 2016; http://www.who.int/ipcs/assessment/publichealth/asbestos/en/.Reporting & IncidenceSlide7

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 DataGenderDr. R.A. Lemen - Collegium Ramazzini 2016

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Dr. R.A. Lemen - Collegium Ramazzini 2016

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 1960s and

1970s rather

than to an increase in diagnostic awareness

.”

(Peto et al., 2009)GenderGender8Slide9

age

< 40 years of age > 40 years of age ☞

Rare = 1.7%

☞ Ratio = 51/49% male/female 78% / 22%✵ ☞ Less likely occupational ☞

49% between 35-40 years of age

☞ 84% white

92% white✵.

☞

47%/48% pleural/peritoneal 90% / 9% ☞ 34 months average survival 8 months ☞ 5-year survival = 38%

3%

✵ Statistically Significant

Sources

: Thomas et al., 2015; Lemen, 2016

Age

Dr. R.A. Lemen - Collegium Ramazzini 2016

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Genetic Role

(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.

Genetic Role

Sources:

Dragon et al., 2015: Lemen & Dodson, 2012; Lemen, 2016Dr. R.A. Lemen - Collegium Ramazzini 2016 10Slide11

Genetic Role

(undecided)➤

Germline

BAP1 mutations found in some mesothelioma-prone families having little history of heavy exposure to asbestos ⏤ other studies have not. ➤ Some consider BAP1 gene mutations as potential markers of susceptibility.

➤ It is thought specific non-invasive biomarkers will emerge.

➤

Recent consensus suggests :

☛

persons with

BAP1

germline mutations transmitted over the course of multiple generations are associated with very high incidence of MM upon exposure to asbestos.

☛ it is anticipated that carriers of germline BAP1 mutations may be more sensitive than the population at large to low amounts of asbestos and/or naturally occurring asbestos.

Genetic Role

Dr. R.A. Lemen - Collegium Ramazzini 2016

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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.Slide12

Plausible Fiber Action

in humans➤ Mechanical irritation

➤

Fibers interfere with mitotic process through disruption of the mitotic spindle, inducing chromosomal abnormalities and aneuploidy➤ 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).

Fiber Action

Source: Lemen, 2016

Dr. R.A. Lemen - Collegium Ramazzini 2016

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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, 2012Chrysotile vs. Amphibole

Chrysotile

Dr. R.A. Lemen - Collegium Ramazzini 2016

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Conclusions : Asbestos & mesothelioma

➣ 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 Source: Lemen, 2016ConclusionDr. R.A. Lemen - Collegium Ramazzini 2016 14Slide15

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

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