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Mogelijkheden en beperkingen van Biologische monitoring
Gezondheidskundig onderzoek of onderdeel
van het blootstellingsonderzoek?
Paul T.J. Scheepers, PhD, ERT, RAH, GAGS
Toxicoloog, arbeidshygiënist, gezondheidskundig adviseur gevaarlijke stoffen
Radboud Institute for Health Sciences
CGC-NVAB, Den Bosch, 14 juni 2018
Lancet Commission on pollution and health
Source: Landrigan P et al. (2018) The Lancet Commission on pollution and health. Lancet. 391(10119):462-512.
Beroepen met een risico voor kanker Beroepsgroep Blootstelling Classificatie a Weefsel met tumoren
Brandweerman Stoffen die vrijkomen bij het werken als brandweerman 2B (2010) -b
Dakdekker en wegenbouwer Bitumen en dampen die vrijkomen bij het leggen van asfalt
bitumen en asfalteren
2A (2013) Long
Drukker Emissies tijdens het drukproces 2B (1996) Blaas , long, nier, slokdarm
schoenmaker Leerstof, benzeen en andere oplosmiddelen en stoffen die
vrijkomen bij fabricage en reparatie van laarzen en schoenen
1 (2012) Bloed- en bloedvormende weefsels,
neus, en bijholten van de neus,
blaas
Kapper Kleurstoffen (aromatische amines, aminofenolen met
waterstofperoxide), oplosmiddelen, drijfgassen, aerosolen
2A (2010) Blaas, lymfesysteem, eierstokken
Lasser/metaalbewerkerc Lasdampen en UV (100-400 nm overeenkomend met UVA,
UVB, UVC)
1 (2017) Long, nier, oog
Metaalarbeider in coke
ovens/ijzer/staal/gieterijen;
Koolteerdampen, PAK, silica, metaaldampen, formaldehyde 1 (2012) Long, huid (inclusief scrotum),
blaas, nier
Glaswerker Fabricage van glas (lood, arseen, antimoonoxiden, silica,
asbest en andere metaaloxiden, PAK)
2A (1993) Long
Operator kolenvergassing en
olieraffinaderij
Koolteer, koolteerdampen, PAK 2A (1989) Huid (inclusief scrotum), blaas, long
Meubel- en kastenmaker en Houtstof 1 (2012) Neus en neusbijholten
Operator rubberindustrie Aromatische amines, oplosmiddelen 1 (2012) Blaas, long, maag, slokdarm, bloed-
en bloedvormende weefsels
Schilder Niet bekend 1 (2012) Long, blaas, leukemie (bij kinderen
van de schilder)
Schoorsteenveger Schoorsteenroet 1 (2012) Long, huid, blaas a 1 = humaan carcinogeen (groep 1), 2 = waarschijnlijk carcinogeen (groep 2A); 2B = mogelijk carcinogeen (groep 2B); b Bij het werk als brandweerman zijn stoffen en weefsels waarin tumoren zijn gevonden niet gespecificeerd; c De onderbouwende volledige rapportage is nog niet verschenen maar een voorpublicatie is beschikbaar (Guha et al., 2017).
Risk assessment and molecular epidemiology
Source: Budnik LT et al. J Occup Med Toxicol. 2018 Feb 5;13:6.
Early indicator of adaptive response According to the meet-in-the-middle principle (Paolo Vineis, Imperial College)
• Biomarker should reflect an ‘early’ non-adverse effect • Biomarker should be a confirmed and causal risk factor of disease • Derived from different routes of uptake (inhalation, dermal, oral)
Like a prognostic clinical biomarker?
Value of DNA adducts and repair products?
Value of urine metabolites vs. protein adducts?
How should these outcomes
be presented to the worker?
Biomarkers
Biomarker of exposure
Reflects (systemic) internal dose of a parent substances or product of metabolism e.g. Ethanol concentration in exhaled air or in blood Biomarker of susceptibility Reflects a person characteristic that interacts with the toxicokinetics and/or
toxicodynamics of the substance of interest e.g. Alcohol dehydrogenase activity
Biomarker of (physiological/biochemical) response Indicates physical change or physiological response to an exposure that is not necessarily adverse
e.g. Heart frequency, cognitive function level, reaction time, et cetera
Zielhuis and Henderson (1986) MOSHE 2015 Pagina 6
Analysis of biomarkers: for what purpose?
1. Detection of aggregated exposure
2. Response to worker’s concerns
3. Testing of a well controlled setting
4. Worker’s performance indicator
Detection of aggregate exposure
The total of all contributions to exposure of a single substance from all sources
- Derived from different routes of uptake (inhalation, dermal, oral) - Exposures at work as well as off-work exposures - Products used at work well as consumer products and dietary contributions - Reflecting recent exposure as well as historic exposure
Biomonitoring as ‘safety net’
Result is often positive for ubitiquous substances
Very specific strategies are required to disentangle
worker’s exposures from ‘background’
Aggregate exposures: contribution of arsenic from diet
Plaice
Reference Salmon
Smart study designs
• Determine a baseline for each individual
• Compare pre-shift and post-shift (or pre-work week and end-of-week) • Compare groups of workers • Make a comparison before and after an intervention • Long-term monitoring to identify workers/situations/trends
tetrachloroethylene
Response to worker’s concerns
Treating the individual outcome as a reflection of uptake to satisfy: • Uncertainty concerning complex procedures or involvement in spill • May satisfy questions related to personal behaviour/hygiene issues • What is the real worker’s incentive? (in need of reassurance?)
Biomonitoring to satisfy concerns?
A low value or non-detect may be reassuring
A high value may lead to questions difficult to answer.
What value to be used as biological guidance value?
What is the health relevance of the lab result?
Worker’s performance indicator
Commissioned by the employer e.g. • Alcohol and drugs testing in demanding tasks • As part of an ALARA strategy • Keep a registry of exposure to CMR substances
Biomonitoring as in a ‘doping test’
What is the worker’s participation incentive?
Are individual results kept confidential from the employer?
How about ethics issues (voluntary participation)?
Testing of good practices
Field test to evaluate the efficacy of an intervention • Gloves to reduce skin absorption (reduce or enhance exposure) • Respiratory protection (technical specs vs. field performance) • Personal hygiene issues
Biomonitoring as tool for evaluation
How does a protective technology perform in practice?
Is the extra effort of wearing PPE worthwhile?
Skin protection in dermatology nurses
Comparison of excretion of 1-hydroxypyrene (1-OHP, total and increase from baseline). Based on
collection of urine during 24 h after application of CTO.
Subgroup 1-Hydroxypryrene in urine
(1-OHP) 2004 2007
Median Range Median Range
Paired
observations
(N = 6)
Total (nmol) 1.6 0.84-5.0 0.69* 0.45-3.4
Increase (μmol/mol creat) 0.05 -0.01-0.18 0.03 0.01-0.17
Unpaired
observations
(N = 10 –12)
Total (nmol) 1.5 0.74-5.0 0.64* 0.15-2.8
Increase (μmol/mol creat) 0.04 -0.09-0.18 0.02 -0.01-0.05
2004
2007
* p < 0.05 Scheepers et al. Scand J Work Environ Health 2009; 35:212-221
Recent developments in the field
Phthalates in medical devices
Tri-2-hexylethyl-trimellitate (TOTM) and tri-(2-ethylhexyl) trimellitate (TEHTM) as
an alternative for DEHP (Eckert, University of Erlangen-Nürnberg)
Chromium VI
New Occupational Exposure Level (NL) of 1 µg/m3
Specific analysis of Cr VI in exhaled breath condensate (Liz Leese, HSE)
Exposure to diesel exhaust particles New (proposed) occupational exposure level (NL): 1.03 µg/m3
Detection of soot particles in urine (Tim Nawrot, University of Hasselt)
PMO Periodiek ‘Convenience sample’ Gezondheidseindpunt Trends op groepsbasis Individuele feed back ??
HBM Periodiek ‘Smart design’ ‘Intermediaire marker’ Trends op groepsbasis Individuele feed back Rond interventies
PMO en HBM ‘go alone-together’
PMO
HBM1 HBM2
PMO-Y1 PMO-Y2 PMO-Y3 MPO-Y4
RI&E + PvA
RI&E + PvA
Training opportunities
• HBM4EU Training School: www.hbm4eu.eu/training
12-16 November 2018
• PIGOR Chemical Incidents: www.raboudumc.nl
• November 2019 (to be announced)
• PET Occupational toxicology: www.toxcourses.nl
May-June 2020
Biomonitoring application datasheets (BADS)
• Acrolein
• Acrylonitrile • Arsenic • Benzene
• Cadmium • Chromium • Cyanides
• Dioxin (TCDD) • Ethylene oxide • Fluorides
• Hydrogen sulfilde • Mehyl bromide • Polycyclic Aromatic Hydrocarbons (PAH) • Styrene • Toluene • Xylenes
215 biomarkers for 160 substances
Take home
• PMO en HBM kunnen in elkaars verlengde liggen
• Trajecten kunnen samen lopen en worden afgestemd
• Goed voor effectiviteit en biedt mogelijk synergie