Het exposoom en arbeidsgerelateerde gezondheid

Roel Vermeulen, PhD IRAS, Environmental Division Utrecht University, the Netherlands

Julius Center, Health Sciences and Primary Care University Medical Center Utrecht, The Netherlands

Imperial College London, School of , London, UK Opzet

• Hoe belangrijk zijn milieu-blootstellingen?

• Introductie van het Exposoom

• Aantal voorbeelden

• Uitdagingen en toekomst perspectief

Milieu: Alles dat niet genetisch is inclusief voeding, levensstijl, woon en werkomgeving, etc. Chronic diseases are primarily environmental in origin

PERCENT AVOIDABLE

Type 2 diabetes 91

Coronary heart disease 83

Stroke 72

Colon cancer 71

0 20 40 60 80 100

Willett, 2002, Science ObesityObesit y Trends*Trends* AmongAm ong U.S.U.S. AdultsAdult s BRFSS,BRFSS, 198512 90 8901 6912457803 (*BMI(*BMI ≥30,≥ 3 0 , oror ~ 303 0 lbs.lbs. overweightoverw eigh t forfor 5’5 ’ 4”4 ” person)person )

NoNoNo DataDaDa Dattaa t a < <10%< 1 1 0<0%%1 0 % 10%1 1 00 % % ––1–14%14%0%–14% 15%15%–19%–19% 20%≥ 2 020%%–24%–24% 25%≥ 2 5 % – 25%29% – 29% ≥ 30% ≥30%

Source: Behavioral Risk Factor Surveillance System, CDC. What do we know of these environmental risks?

1. Current risks underestimated • Measurement error • In appropriate risk models 2. Unknown risks • Nature of risks are different

Low Radon Drugs • Limitations Lowin iron investigative tools Occupational 0% Grafiektitel 0% vitamine A 0% chemicals High Lead 0% LowOzone zinc High 1% 1% cholesterol 3. Stochastic 0%0% sodium 4% 6% Alcohol 6%

High plasma glucose Unknown 7% 49% Rappaport et al., 2014 based on Active and passive smoking Lim et al., 2012 Airborne 13% particles 13% Why do we need new investigative tools? 1. Current risks underestimated • Measurement error • In appropriate risk models 2. Unknown risks • Nature of risks are different

• LimitationsLow in investigativeRadon toolsDrugs Low iron Occupational 0% Grafiektitel 0% vitamine A 0% chemicals High Lead 0% LowOzone zinc High 1% 1% cholesterol 3. Stochastic 0%0% sodium 4% 6% Alcohol 6%

High plasma glucose Unknown 7% 49% Rappaport et al., 2014 based on Active and passive smoking Lim et al., 2012 Airborne 13% particles 13% Historical and new environmental risk factors

Known risks New Risks Potency High Low Exposure levels High Low Co-exposures Few Many Occupational Hygiene and Health

• Occupational expidemiology has had a long history of studying the health effects of exposures experienced at the workplace

• Such studies have successfully identified a range of chemical and other agents that have been associated to a range of health outcomes

120

100

80

60 Total

Occupa onal 40

20

0 1970 - 1975 - 1980 - 1985 - 1990- 1995 - 2000 - 2005 - 2010 - 1974 1979 1984 1989 1994 1999 2004 2009 2014 Occupational Hygiene and Health

• However, due to declining occupational exposures its increasingly likely that health risks experienced by workers are due to a combination of wider range of workplace and non-workplace factors than was perhaps the case in the past where workers could be exposed to high levels to single or a limited number of substances.

• Furthermore, epidemiological studies of new technology and new infrastructure projects should not have to rely on studies of (irreversible) disease outcome in prospective cohort studies, but novel markers of exposure and health outcomes will need to be developed to manage risk during the development of new technology. The Exposome – a unifying concept for

Recognizing the disparity in current knowledge between genes and environmental exposures, Chris Wild defined the “exposome”

Representing all environmental exposures (including those from diet, lifestyle, and endogenous sources) from conception onwards, as a quantity of critical interest to disease etiology

Wild, C.P., Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology. Cancer Epidemiol Biomarkers Prev 14 (8), 1847-1850 (2005). Total Worker Health – NIOSH CDC

Issues Relevant to Advancing Worker Well-being Through Total Worker Health®

Control of Hazards and Exposures Compensation and Benefits Changing Workforce Demographics • Chemicals • Adequate Wages and Prevention of • Multigenerational and Diverse Workforce • Physical Agents Wage Theft • Aging Workforce and Older Workers • Biological Agents • Equitable Performance Appraisals • Vulnerable Worker Populations • Psychosocial Factors and Promotion • Workers with Disabilities • Human Factors • Work-Life Programs • Occupational Health Disparities • Risk Assessment and Risk Management • Paid Time Off (Sick, Vacation, Caregiving) • Increasing Number of Small Employers • Disability Insurance (Short- & Long-Term) • Global and Multinational Workforce theOrg anTWHization of Work approach• W orfocuseskers’ Compensation Benef itson how • Fatigue and Stress Prevention • Affordable, Comprehensive Healthcare Policy Issues environmental,• Work Intensification Prevention workplaceand Life Insurance factors• H eacanlth Informati onboth Privacy • Safe Staffing • Prevention of Cost Shifting between • Reasonable Accommodations • Overtime Management Payers (Workers’ Compensation, • Return-to-Work mitigate• Healthier Shift W orkand enhanceHealth Insura ncoveralle) worker• Equal Employ mhealthent Opportunity • Reduction of Risks from Long Work Hours • Retirement Planning and Benefits • Family and Medical Leave • Flexible Work Arrangements • Chronic Disease Prevention and • Elimination of Bullying, Violence, beyond• Adequate Mea l atraditionalnd Rest Breaks Disoccupationalease Management safetyHarassment, and D iscandrimination • • Prevention of Stressful Job Built Environment Supports Access to Confidential, Quality Healthcare Services Monitoring Practices • Healthy Air Quality health concerns • Career and Skills Development • Worker-Centered Organizational Policies • Access to Healthy, Affordable Food Options • Promoting Productive Aging • Safe and Clean Restroom Facilities Community Supports • Safe, Clean and Equipped Eating Facilities • Healthy Community Design New Employment Patterns • Safe Access to the Workplace • Safe, Healthy and Affordable Housing • Contracting and Subcontracting • Environments Designed to Accommodate Options • Precarious and Contingent Employment Worker Diversity • Safe and Clean Environment (Air and Water • Multi-Employer Worksites • Organizational Restructuring, Downsizing Leadership Quality, Noise Levels, Tobacco-Free Policies) • Access to Safe Green Spaces and Non- and Mergers • Shared Commitment to Safety, Health, Motorized Pathways • Financial and Job Security and Well-Being • Access to Affordable, Quality Healthcare • Supportive Managers, Supervisors, and Well-Being Resources and Executives • Responsible Business Decision-Making • Meaningful Work and Engagement • Worker Recognition and Respect

November 2015 Total Worker Health® is a registered trademark of the US Department of Health and Human Services The Exposome

• Study design - Lifecourse • Exposure is dynamic (repeated samples) • Critical exposure windows; conception to death

• Improved exposure assessment • Biomarkers (OMICS) • Sensor technologies • Geographical Information Systems • Portable computerized devices (momentary assessments) • Improved use of conventional measurements / questionnaires / databases

• Advances in statistical methods and bioinformatics • Large number of environmental exposures (correlated, protracting) • Weak associations • Low priors

New Investigative Technologies to Improve Occupational Exposure Assessment; Sensor Technology / Portable Communication Devices

• Tracking sensors • Chemical sensors • NO2 • CO • ….. Using Personal Sensors to Characterize our External Exposome Noise

UVB

Humidity

Temperature

BC

Sistolic

Dialostic

HRV

HRT

FEV1

Happiness

PA Improved Occupational Exposure Assessment; ExpomDiary - context-sensitive ecological momentary assessment (CS-EMA)

Data processing Data acquisition

Data repository Contextual Data acquisition Exposure / health Luuk van Wel et al., unpublished Using Big-Data to characterize the Exposome

• Develop method to analyze “Exposome” wrist bands and broaches New Investigative Technologies to Improve Occupational Exposure Assessment

Anderson, Oregon State University Use of Sensors if Occupational Health

• Combination of measurements sensors, geo-location (GPS, I-beacons), and CS-EMA allows for a more comprehensive assessment of external exposures. • Industrial hygiene / Exposure Science • Occupational Health Research • Individual (quantified-self)

• Could be combined with e-health applications

Improved identification of environmental exposures across the lifecourse Microbiome Epigenetics Epigenetics refers to the study of changes in the regulation of gene activity and expression that are not dependent on gene DNA sequence.

RNA Interference

Gene Expression

Histone DNA Modifications Methylation

Dichotomised smoking status – p-values evolution according to t

sites CpG

Time since quitting smoking (years)  Evolution of the strength of association between methylation level and dichotomised smoking status across t . 751 CpG sites significant at least once across t  2 groups identifiable in both cohorts

. Those loosing statistical significance after a certain t within the 3 first decade after smoking cessation23 . Those remaining differentially methylated more than 35 years after smoking cessation Metabolomics / High Resolution LC-MSMS

Trichloroethylene

• 80 workers exposed to TCE enrolled from 6 factories with metal cleaning operations

• 96 healthy age- and sex-matched unexposed controls from 2 clothes and 1 food factory

• Plasma was prepared and analyzed daily in batches of 20 by HRM with

C18 liquid chromatography

Subjects Controls Exposed Controls (n= 95) Total (n= 80) ≤ 12 p.p.m (n= 39) > 12 p.p.m (n= 41) Demographic characteristics Age, mean (SD) 27 (7) 25 (7) 24 (5) 27 (8) BMI, mean (SD) 22 (3) 21 (3) 21 (2) 22 (3) Sex, n (%) Female 23 (24%) 23(29%) 15 (38%) 8 (20%) Male 72 (76%) 57 (71%) 24 (62%) 33 (80%) TCE exposure TCE air level < 0.03 22.19 (35.9) 5.19 (3.5) 38.36 (44.6) (p.p.m), mean (SD) Metabolomic Analysis of Plasma Samples from Workers Exposed to TCE

Walker et al., submitted 4A 4AB 4B

Urinary TCE exposure markers Urinary TCE exposure markers

Renal biomarkers Renal biomarkers

Immunological markers Immunological markers Unidentifiable halogenated m/z, by isotopic pair Unidentifiable halogenated m/z, by isotopic pair Identified metabolite MetabolomeId entified m etassociationabolite network with molecular Unidentifiable m/z; pos mass defect Unidentifiable m/z; pos mass defect Unidentifiable m/z; neg mass defect Unidentimarkersfiable m/z; neg mass defect of TCE exposure Correlation coefficient Correlation coefficient

-0.7 0 0.6 -0.7 0 0.6

4C Urinary TCE exposure markers 44NephrotoxicityDC markers 4D 4A Renal biomarkers 4ExB posure markers Immunological markers Immunological markers Unidentifiable halogenated m/z, by isotopic pair Identified metabolite Unidentifiable m/z; pos mass defect Unidentifiable m/z; neg mass defect

Correlation coefficient

-0.7 0 0.6

Urinary TCE exposure markers

Renal biomarkers

Immunological markers Unidentifiable halogenated m/z, by isotopic pair Identified metabolite Unidentifiable m/z; pos mass defect Unidentifiable m/z; neg mass defect

Correlation coefficient

-0.7 0 0.6

4C 4D

Walker et al., submitted Improved assessment of the Exposome Using OMICS

• New biotechnological advancements allow for a more comprehensive evaluation of (historical) exposures and associated biological responses at the individual level

• Improved exposure assessment • Improved health impact assessment

• Monitoring • Screening Het exposoom en arbeidsgerelateerde gezondheid

• Beroepsmatige blootstellingen maken een belangrijk deel uit van de blootstellings-levenslijn (TWH)

• Technologieën die ontwikkeld worden binnen Exposoom- onderzoek kunnen worden ingezet in het beter kwantificeren van beroepsmatige blootstellingen

• Het op een meer individueel niveau kwantificeren van de blootstelling en biologische-effecten geeft de mogelijkheid tot precisie-risico assessment

• Geeft mogelijkheden voor de quantified-self

Acknowledgements

Exposure Science Group

Gerard Anke Marc Lutzen Jelle Max Hoek Huss Chadeau-Hyam Portengen Vlaanderen Leenders

Nahid Virissa Erik Marije Mostafavi Lenters van Nunen Reedijk THANKS

[email protected]