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Updated proposalLimit value of 1-hydroxypyrene in urine
for occupational PAH exposure
ISBM Manchester 2013
Frans Jongeneelen IndusTox Consult
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Take home message
1-Hydroxypyrene in urine (µmol/mol)
1,0 LOL-GEB = Lowest observed level without genotoxic effects in the body
0,0
0,5
1,5
Non-occupational background
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Updated proposal for BOEL of PAH
Reason for new proposal– New occupational exposure limit (OEL) in
Netherlands for PAH has been proposedOEL of PAH = 200 ng/m3 as benzo(a)pyrene
– Companies and employees have a positiveexperience and a positive attitude to biologicalmonitoring of PAH, however, a biological limit was not proposed
– Employers and Unions requested us to derivean equivalent biological occupational exposure limit (BOEL)
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Updated proposal for BOEL of PAH
Contents1. Introduction2. Biological indicators of PAH3. Biological occupational exposure limit (BOEL)
1. Overview existing proposals2. Updated proposal
4. Message
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Introduction
Biological monitoring of PAH
WorkerUptake of PAH by:
inhalationdermal absorptioningestion
Working environment Gaseous and particulate PAH
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IntroductionOccupational PAH-exposure
– PAH are present as complex mixtures – In gasphase and particulate matter– Dermal exposure may be significant– PAH-profile varies in between industries
and sometimes within industries– Carcinogenic potency of PAH varies: 4-6
ring components have highest potency– Benzo(a)pyrene = carcinogenic PAH with high potency– Pyrene = non-carcinogenic PAH
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IntroductionBiological indicator of PAH
PAH are metabolized in all tissues of the bodyEach PAH has different metabolite pattern withvarious toxic and non-toxic metabolitesHydroxylated-PAH metabolites are rapidlyexcreted in urine. Examples:
– 1- OH-pyrene– OH-phenantrenes– 3- OH-b(a)p
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Biological indicator of PAH Most experience: 1-hydroxypyrene in urine
In humans, pyrene is metabolizedto the main metabolite 1-hydroxypyrene, conjugated and excreted in urineFirst proposed as indicator-metabolite in 1985Broadly used in scientific studies and field testing of exposure
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Biological indicator of PAH Other hydroxylated PAH-metabolitesas biological indicator
OH-Phenantrenes– Indicator of volatile PAH– Example: Germany
Series of up to 10 hydroxylated metabolites– Not widely used– Example: US NHANES-study
3-OH-B(a)P– B(a)P is indicator of risk of PAH– Low concentrations in urine– Little experience, few labs
10Biological indicator of PAH Present status of monitoring of PAH-metabolites in urine
– 3-OH-B(a)P has potential as bioindicatorMetabolite of B(a)P, the PAH with high carcinogenicpotency, but:
– Few labs, limited experience– Excretion kinetics?– Rubustness analytical method?
– 1-Hydroxypyrene is sound bioindicator Many studies from various industries & countriesshows that it is a valuable tool for controlling exposureAnalytical method has proven to be solidElimination rate is known => end-of-workweek post shift urine sampling
– However, pyrene content varies, adjustment is needed forhealth risk assessment
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Biological occupational exposure limit of urinary 1-hydroxypyrene
Existing biological limits (1)HSE - UK 2004: Biological monitoring guidance value
Control-based biological monitoring guidance valueBased on 90th-percentile of urine levels of workers in ‘good hygiene practice’ industriesRecommendation BMGV: 4.0 μmol/mol creat
ACGIH - USA 2005: Biological exposure indexHealth-based biological exposure index of 1-hydroxypyrene in urine scientifically not justified, due to insufficient data: No BEI! However, measurement of 1-hydroxypyrene is valuable tool for controlling exposureRecommendation: control exposure towards the level in general population
Reference level as 99-percentile of general population = 1.0 μg/L = 0.5 μmol/mol creaat
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Biological occupational exposure limit of urinary 1-hydroxypyrene
Existing biological limits (2)
Organisation Country Type Limit level (μmol/mol)
HSE UK BMGV – not health based, but based on good hygiene practice
4.0
ACGIH USABEI Nq = nonquantitative
Level that warrants occupational exposure
0.5
In a table:
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How to derive the biological limit that is equal to health risk of exposure to 200 ng/m3 b(a)p?
Two indirect approaches are possible:
1. Estimate urine level in workers equal to airborneexposure at 200 ng/m3 b(a)p from meta-analysis of cross-sectional exposure studies
2. Derive urine level in workers without early genotoxic effects from meta-analysis of cross-sectional earlyeffect studies
14Updated biological exposure limit of PAH
Procedure for derivation of level of 1-hydroxypyrene in urine without genotoxic effects
1. Search in scientific literature for cross-sectional studies of PAH-exposed workers with:
One or more genotoxic effect markers (in lymphocytes)Determination of 1-hydroxypyrene in urine as exposure indicator
2. Analyse each study and estimate the level of 1-hydroxypyrene in urine at which no genotoxic effect was observed.
3. Select study with lowest effect level as key-study. Thiskey-study holds: ‘Lowest observed level without genotoxic effect`in the body (= LOL-GEB)’
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Updated biological exposure limit of PAH
Search for relevant studies
Various bibliographic databases were consultedStudies from 1990 – 2012Cross-sectional studies of PAH-exposedworkers
– with genotoxic effects in lymphocytes– with 1-hydroxypyrene in urine – threshold of genotoxic effect(s) can be derived
9 Studies were found, that met the criteria
16Updated biological exposure limit of PAH
Markers of genotoxic effects in studies of PAH-exposed workers
Endpoint Name of test In short Chromosomal disorders in structure or number
Chromosomal aberrations CA
Breaks in and exchanges of DNA-strands
Sister chromatid exchange frequency
High frequency sister chromatid exchange frequency
SCE
HFC-SCE
Chromosomal disorders during replication
Micronucleus-test
Cytokinesis Block Micronucleus-test
NucleoPlasmic bridges
Nuclear Buds
MN
CBMN
NPB
NBUD
DNA-damage (strand breaks)
Single Cell Gel Electrophoresis assay Comet
17Updated biological exposure limit of PAH Characteristics of studies of PAH-exposed workers with 1-OH-pyrene and genotoxic effects
Nr Study subjects Genotoxic endpoints
Level of 1-hydroxypyrene in urine without genotoxic effects (μmol/mol)
Pyrene/-b(a)p ratio
Controlled for smoking(Y/N)
Reference
1 Belgian coke oven-workers + graphite anode plant workers
SCEHFC-SCEMN
1.3 1.5 – 4.5 Y Buchet et al, 1995;
2 Dutch primary aluminum workers
DNA-adducts 3.8 2 - 30 Y van Schootenet al, 1995.
3 German coke oven workers
SCEComet-assay
1.9 2.2 Y Popp et al, 1997
4 Swedish potroom workers
DNA-adducts 4.3 2.8 Y Carstensen et al, 1999
5 Dutch coke oven workers
SCEHFC-SCEMN
1.1 ? Y Van Delft et al, 2001
6 Polish coke oven-workers.
SCEHFC-SCEMNComet-assay
1.0 ? Not needed Siwinska et al, 2004
7 Polish non-smoking coke oven workers
MNDNA-adducts
3.1 ? Only non-smokers
Pavanello et al, 2008
8 Chinese coke oven workers
MN, NPB’s and NBUDs
1.3 ? Not needed, no effect
Duan et al, 2009
9 Chinese coke oven workers
CBMN 2.4 ? No Guan et al, 2010 (abstract)
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Updated biological exposure limit of 1-hydroxypyrene
Key study: Siwinska et al (2004)
Probability of increased SCE is < 5% at < 1.0 μmol/mol
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Updated biological exposure limit of PAH
Proposed biological occupational exposure limit (as 1-hydroxypyrene in urine)
Biological parameter
Valid as Reference value (as upper bound of non-occupational exposure)
Biological limit (as lowest observed level without genotoxic effects in the body)
1-hydroxy-pyreen in urine
End of shift at end of workweek
0.5 μmol/mol creatinine 1.0 μmol/mol creatinine
20Updated biological exposure limit of PAH
PAH-profile adjustment of biological occupational exposure limit
Biological occupational exposure limit is valid at coke oven type exposure with a pyrene/-benzo(a)pyrene ratio of 2.5
Adjust limit for deviating pyrene/benzo(a)pyrene ratios. Linear adjustment results in:pyrene/benz(a)pyrene
ratio limit 1-hydroxypyrene
(μmol/mol cr) Type
1.5 0,7 Adjusted 2.5 (default) 1.0 Basis
5 1.8 Adjusted 10 3.3 Adjusted
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Updated biological exposure limit for 1-hydroxypyrene
DiscussionIs risk level of OEL of 200 ng/m3 [as B(a)P] equal to risk level of updated BOEL?
Nowadays carcinogens often have risk-based limitsOEL of 200 ng/m3 B(a)P is based on annual cancerrisk between 1: 10.000/year and 1:1.000.000/yearCancer risk of BOEL of 1.0 μmol/mol is ??????
Interference of smoking?BOEL derived form group of non-smoking workers
Legal status of proposal?Proposal will be discussed in advisory counsel SER of Netherlands
– Representatives of employers & unionsExpected result
– No legal status, supplemental industry-adopted limit
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Take home message
Proposal for occupational exposure limit of 1-hydroxypyrene in urine:
1-Hydroxypyrene in urine (µmol/mol)
1,0 LOL-GEB = Lowest observed level without genotoxic effects in the body
0,0
0,5
1,5
Non-occupational background
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Biological monitoring of PAHMore info?
E-mail: [email protected]: +31.24.3528842Internet: www.industox.nl
Thank you!
