Combined Exposures to Dangerous Substances in the Workplace; An - PowerPoint PPT Presentation

Combined Exposures to Dangerous Substances in the Workplace; An epidemiological perspective Roel Vermeulen, PhD Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Institute for Risk Assessment Sciences University of Utrecht

Institute for Risk Assessment Sciences An interfacultary research institute within the faculties Veterinary Medicine, Medicine, Pharmaceutical Sciences and Biology of Utrecht University The mission of IRAS is to provide education and research on the human health risks of exposure to potentially harmful agents in the environment, at the workplace and through the food chain

Dr. Roel Vermeulen • Background: – Environmental Health – Toxicology – Epidemiology • Focus area IRAS – Cancer Epidemiology • Hemato- Lymphopoietic disorders • Lung – Molecular epidemiology

Focus Area Environmental Cancer • Hemato- Lymphopoietic disorders – Benzene – Dioxin – Electromagnetic fields – Formaldehyde – Trichloroethylene – Selected pesticides • Lung – Asbestos – Diesel exhaust – Indoor air pollution – Metals – Polycyclic Hydrocarbons

Exposures in the Workplace are by Definition Complex • Combined exposures to multiple chemicals – Multiple exposures / complex mixtures • Combined exposures to chemicals and psychosocial risk factors – Occupational exposures and stress • Combined exposures and lifestyle factors – Occupational exposures and nutritional status

Synergistic or Antagonistic? • Antagonistic – Saturation of metabolic systems • Synergistic – Inflamation + genotoxicity

Epidemiological Evidence? Lung cancer risk associated with working in A) cotton textile industry and B) agricultural industry. B A B u r m e is te r ( 1 9 8 1 ) L e v in ( 1 9 8 8 ) H e n d e r s o n ( 1 9 7 3 ) W ilk u n d ( 1 9 8 8 ) M e r c h a n t ( 1 9 8 1 ) S ta r k ( 1 9 9 0 ) L e v i n ( 1 9 8 7 ) G u n n a r d o ttir ( 1 9 9 1 ) A lb e r g h in i ( 1 9 9 1 ) K o s k e l a ( 1 9 9 0 ) R o n c o ( 1 9 9 2 ) H o d g s o n ( 1 9 9 0 ) F a u s tin i ( 1 9 9 3 ) W ik lu n d ( 1 9 9 4 ) W u - W i l l i a m s ( 1 9 9 3 ) M a s tr a n g e lo ( 1 9 9 6 ) S z e s z e n i a - D a b r o w s k a ( 1 9 9 9 ) P u k k a la ( 1 9 9 7 ) F r i t s c h i ( 2 0 0 4 ) S p e r a ti ( 1 9 9 9 ) J a h n ( 1 9 9 9 ) K u z m i c k i e n e ( 2 0 0 7 ) W a n g ( 2 0 0 2 ) A s t r a k i a n a k i s ( 2 0 0 7 ) A la v a n ja ( 2 0 0 5 ) M a s tr a n g e lo ( 2 0 0 5 ) M a s t r a n g e l o ( 2 0 0 8 ) L e e ( 2 0 0 6 ) L a a k k o n e n ( 2 0 0 8 ) O v e r a ll ( I- s q u a r e d = 9 7 .8 % , p = 0 .0 0 0 ) . 1 6 8 1 1 5 . 9 7 .2 0 7 1 1 4 .8 4 R R R R Lenters et al., submitted

Combined Exposures to Multiple Chemicals • Rubber industry – Cross-sectional survey on genotoxic exposures in the rubber industry • RAPTES – to characterize the physical, chemical and oxidant properties of inhaled particulate matter and establish which of these characteristics are critical determinates of adverse systemic and respiratory effects • Synergy – Synergistic effects of multiple exposures to lung carcinogens

The Rubber I ndustry • The rubber industry has been associated with increased cancer risks: lung, bladder, larynx and leukemia 1 • Exposure to a complex mixture of compounds  Aromatic amines  PAHs  Carbon black  Nitrosamines  Solvents • Both inhalation and dermal exposure 2  Current genotoxic risks largely unknown 1. IARC Monographs “The rubber industry” (1982) 2. Vermeulen et al. Occup Environ Med (2003)

Rubber Industry; Complex Mixture of Compounds

Particulate exposure; Mass and Mutagenicity Geometric mean particulate Geometric mean mutagenicity TSM exposure (rev/m3) for each exposure (mg/m3) for each production function in each plant production function in each plant 6 1200 5 1000 4 800 Rev/m3 mg/m3 600 3 7 7 6 6 5 Company 400 2 5 Company 4 4 200 3 1 3 2 0 2 0 mix pre 1 mix mod pre cur mod 1 fin cur ship fin lab ship es lab Production function Production function

Potency Measures of Combined Exposures • Relevance of potency measures? – Mutagenicity – Oxidant properties – Metabonomics • Legislation? Holmes et al., 2008

Pooled Analysis of European Case-control Studies on the Interaction of Occupational Carcinogens in the Development of Lung Cancer Included case-control studies: HDA Germany AUT Germany LUCAS Sweden TURI N-ROME I taly EAGLE I taly I NCO-Copernicus Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, UK LUCA France PARI S France I CARE France EPI C The Netherlands Montreal Canada Overall alm ost 3 0 ,0 0 0 cases and controls

Targeted Exposures – Lung Carcinogens Asbestos chrysotile (white asbestos); amphibole; other type chromium VI; Chrom ium total chromium Nickel soluble nickel compounds; insoluble nickel compounds; total nickel PAHs benzo(a)pyrene; naphthalene respirable quartz; Respirable Crystalline Silica respirable cristobalite; respirable tridymite; respirable crystalline silica 14

Challenges in Detecting Interactions The power to detect interactions in epidemiological studies is low: •Increase in study size •Improved exposure assessment methods

Joint Exposure Prevalences pah cr ni as mmmf rcs dme asb 4722 3008 1467 396 1714 933 1748 (33%) (21%) (10%) (3%) (12%) (7%) (12%) pah 3502 2196 2873( 1641 3744 4656 (24%) (15%) 20%) (12%) (26%) (32%) cr 2217 296 1607 912 81 (16%) (2%) (11%) (6%) (1%) 281 248 80 62 ni (2%) (2%) (1%) 81 (1%) 2389 2346 as (17%) (16%) 723 17 mmmf (5%) rcs 2902 (20%)

Joint Exposure Prevalences - High pah cr ni as mmmf rcs dme 567 7 6 0 0 10 0 asb (4%) 7 7 0 18 686 525 pah (5%) (4%) 7 0 0 0 0 Cr 0 0 0 0 Ni 0 0 0 As mmmf 0 0 rcs 438 (3%)

Highest Joint Exposure Prevalences • Highest joint prevalences found for: – Asbestos and PAH (33%; 4% high) – PAH and diesel (32%; 4% high) – PAH and silica (26%; 5% high) – Silica and diesel (20%; 3% high) Relatively low joint prevalences

Challenges in Detecting Interactions The power to detect interactions in epidemiological studies is low: •Increase in study size •Improved exposure assessment methods

I m proved Exposure Assessm ent Required data: Personal measurement data is preferred above stationary Individual data points needed to build multivariate models Auxiliary data, such as: • Purpose/ strategy of measurement • Sampling devices • Analytical procedures 20

Data collection – So far Data being entered at moment Data already in ExpoSYN (n ~28,000) 20000 18000 16000 14000 12000 10000 8000 6000 4000 2000 0 ** Russia ** ** NL ** ** UK ** Denmark Finland ** Hungary ** ** Italy ** Norway ** Poland ** ** Czech Rep. ** ** France ** ** Germany ** Iceland ** Slovakia ** ** Romania ** ** Canada ** ** Sweden ** 21

Research Actions • Integration of functional test systems into epidemiological research • Improved exposure assessment tools – Better utilization of existing data? • Large epidemiological studies on occupational risk factors

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