9.1 Jongeneelen


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9.1 Jongeneelen

  1. 1. 1 Updated proposal Limit value of 1-hydroxypyrene in urine for occupational PAH exposure Frans Jongeneelen IndusTox Consult ISBM Manchester 2013
  2. 2. 2 Take home message 1,5 1,0 1-Hydroxypyrene in urine (µmol/mol) LOL-GEB = Lowest observed level without genotoxic effects in the body 0,5 Non-occupational background 0,0
  3. 3. 3 Updated proposal for BOEL of PAH Reason for new proposal – New occupational exposure limit (OEL) in Netherlands for PAH has been proposed OEL of PAH = 200 ng/m3 as benzo(a)pyrene – Companies and employees have a positive experience and a positive attitude to biological monitoring of PAH, however, a biological limit was not proposed – Employers and Unions requested us to derive an equivalent biological occupational exposure limit (BOEL)
  4. 4. 4 Updated proposal for BOEL of PAH Contents 1. Introduction 2. Biological indicators of PAH 3. Biological occupational exposure limit (BOEL) 1. 2. Overview existing proposals Updated proposal 4. Message
  5. 5. 5 Introduction Biological monitoring of PAH Working environment Gaseous and particulate PAH Worker Uptake of PAH by: inhalation dermal absorption ingestion
  6. 6. 6 Introduction Occupational 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
  7. 7. 7 Introduction Biological indicator of PAH PAH are metabolized in all tissues of the body Each PAH has different metabolite pattern with various toxic and non-toxic metabolites Hydroxylated-PAH metabolites are rapidly excreted in urine. Examples: – – – 1- OH-pyrene OH-phenantrenes 3- OH-b(a)p
  8. 8. 8 Biological indicator of PAH Most experience: 1-hydroxypyrene in urine In humans, pyrene is metabolized to the main metabolite 1hydroxypyrene, conjugated and excreted in urine First proposed as indicatormetabolite in 1985 Broadly used in scientific studies and field testing of exposure
  9. 9. 9 Biological indicator of PAH Other hydroxylated PAH-metabolites as 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
  10. 10. Biological indicator of PAH Present status of monitoring of PAH-metabolites in urine – 3-OH-B(a)P has potential as bioindicator Metabolite of B(a)P, the PAH with high carcinogenic potency, but: – Few labs, limited experience – Excretion kinetics? – Rubustness analytical method? – 1-Hydroxypyrene is sound bioindicator Many studies from various industries & countries shows that it is a valuable tool for controlling exposure Analytical method has proven to be solid Elimination rate is known => end-of-workweek post shift urine sampling – However, pyrene content varies, adjustment is needed for health risk assessment 10
  11. 11. 11 Biological occupational exposure limit of urinary 1-hydroxypyrene Existing biological limits (1) HSE - UK 2004: Biological monitoring guidance value Control-based biological monitoring guidance value Based on 90th-percentile of urine levels of workers in ‘good hygiene practice’ industries Recommendation BMGV: 4.0 μmol/mol creat ACGIH - USA 2005: Biological exposure index Health-based biological exposure index of 1hydroxypyrene in urine scientifically not justified, due to insufficient data: No BEI! However, measurement of 1-hydroxypyrene is valuable tool for controlling exposure Recommendation: 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
  12. 12. 12 Biological occupational exposure limit of urinary 1-hydroxypyrene Existing biological limits (2) In a table: Organisation Country HSE UK Type BMGV – not health based, but based on good hygiene practice BEI ACGIH Limit level (μmol/mol) 4.0 Nq = nonquantitative USA Level that warrants occupational exposure 0.5
  13. 13. 13 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 airborne exposure 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 early effect studies
  14. 14. Updated biological exposure limit of PAH 14 Procedure for derivation of level of 1hydroxypyrene 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 1hydroxypyrene in urine at which no genotoxic effect was observed. 3. Select study with lowest effect level as key-study. This key-study holds: ‘Lowest observed level without genotoxic effect`in the body (= LOL-GEB)’
  15. 15. 15 Updated biological exposure limit of PAH Search for relevant studies Various bibliographic databases were consulted Studies from 1990 – 2012 Cross-sectional studies of PAH-exposed workers – 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
  16. 16. 16 Updated biological exposure limit of PAH Markers of genotoxic effects in studies of PAH-exposed workers Endpoint Name of test In short Chromosomal disorders Chromosomal aberrations in structure or number CA Breaks in and exchanges of DNAstrands Sister chromatid exchange frequency SCE High frequency sister chromatid exchange frequency HFC-SCE Chromosomal disorders Micronucleus-test during replication Cytokinesis Block Micronucleus-test MN CBMN NucleoPlasmic bridges Nuclear Buds DNA-damage (strand breaks) NPB NBUD Single Cell Gel Electrophoresis assay Comet
  17. 17. 17 Updated biological exposure limit of PAH Characteristics of studies of PAH-exposed workers with 1-OH-pyrene and genotoxic effects Nr Study subjects Genotoxic endpoints 1 Belgian coke ovenworkers + graphite anode plant workers Dutch primary aluminum workers SCE HFC-SCE MN DNA-adducts German coke oven workers Swedish potroom workers 5 Dutch coke oven workers 6 Polish coke ovenworkers. 7 Polish non-smoking coke oven workers Chinese coke oven workers Chinese coke oven workers 2 3 4 8 9 Level of 1Pyrene/hydroxypyrene in b(a)p ratio urine without genotoxic effects (μmol/mol) 1.3 1.5 – 4.5 Controlled for smoking (Y/N) Reference Y Buchet et al, 1995; 3.8 2 - 30 Y van Schooten et al, 1995. SCE Comet-assay DNA-adducts 1.9 2.2 Y 4.3 2.8 Y Popp et al, 1997 Carstensen et al, 1999 SCE HFC-SCE MN SCE HFC-SCE MN Comet-assay MN DNA-adducts MN, NPB’s and NBUDs CBMN 1.1 ? Y Van Delft et al, 2001 1.0 ? Not needed Siwinska et al, 2004 3.1 ? 1.3 ? 2.4 ? Only nonsmokers Not needed, no effect No Pavanello et al, 2008 Duan et al, 2009 Guan et al, 2010 (abstract)
  18. 18. 18 Updated biological exposure limit of 1-hydroxypyrene Key study: Siwinska et al (2004) Probability of increased SCE is < 5% at < 1.0 μmol/mol
  19. 19. 19 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 nonoccupational exposure) 1-hydroxypyreen in urine End of shift at end of workweek 0.5 μmol/mol creatinine Biological limit (as lowest observed level without genotoxic effects in the body) 1.0 μmol/mol creatinine
  20. 20. 20 Updated 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 1.5 2.5 (default) 5 10 limit 1-hydroxypyrene (μmol/mol cr) 0,7 1.0 1.8 3.3 Type Adjusted Basis Adjusted Adjusted
  21. 21. 21 Updated biological exposure limit for 1-hydroxypyrene Discussion Is 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 limits OEL of 200 ng/m3 B(a)P is based on annual cancer risk between 1: 10.000/year and 1:1.000.000/year Cancer 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 & unions Expected result – No legal status, supplemental industry-adopted limit
  22. 22. 22 Take home message Proposal for occupational exposure limit of 1hydroxypyrene in urine: 1,5 1,0 1-Hydroxypyrene in urine (µmol/mol) LOL-GEB = Lowest observed level without genotoxic effects in the body 0,5 Non-occupational background 0,0
  23. 23. 23 Biological monitoring of PAH More info? E-mail: frans.jongeneelen@industox.nl Voice: +31.24.3528842 Internet: www.industox.nl Thank you!