Biological Monitoring of Exposure to Carcinogenic Substances

1
Biological Monitoring of Exposure to
Carcinogenic Substances
B I O M O N E C S

• Paul Aston, AB Biomonitoring, Cardiff, UK
• Paul Sessink, Exposure Control, Wijchen, The
  Netherlands
• Paul Scheepers, Radboud University, Nijmegen, The
  Netherlands
• CGC/NVvA Meeting, November 17th 2005
• (supported by EU contract QLK4-CT-2002-71801)

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Outline

• Generic protocol
• Documentation
• Background values
• Lab performance
• Pilot studies
• Pit falls

3
GBMP

• Generic biological monitoring protocol
• Public (scientific publication)
• Compilation of best practices covering study
  designs, communication protocols, ethical
  considerations, methods of data collection
• Background documentation for end-users

4
GBMP Best practices

• Study design
• Technical aspects
• Communication
• Ethical issues

5
GBMP Study design

• A number without a the story behind it has no
  value
• If no biological limit values are available, use
  internal or external background values
• Compare post-work exposure levels with the
  workers own baseline
• Always use a questionnaire

6
GBMP Technical aspects

• Ask the lab to send you suitable materials for
  sample collection
• Include a standard or test sample when sending
  samples across Europe
• Limit the volume of samples
• Use no additives without prior consultation of
  the lab
• Beware of freezing damage

7
GBMP Ethical aspects

• Use an informed consent procedure
• Use a code list and decide who will keep the key
• Arrange access to individual data
• Note
• If the biomonitoring study is part of normal
  routine
• health surveillance approval from an ethical
  committee is
• not needed (in Belgium or in The Netherlands)

8
GBMP Communication

• Talk and write to both employers and employees
• Be open about the reasons to initiate the study
• Anticipate on consequences of any possible
  outcome
• Report anonymous results on a group basis

9
BADS

• Biomonitoring Application Data Sheets
• Concise documentation on carcinogenic substances
  for which biomarkers are available
• Based on secondary literature resources (IARC
  Monographs, ACGIH BEI documentation, DFG, DECOS
  reports, IPCS)
• Public (internet)
• Reference values

10
BADS - Nickel
Nickel

i IARC (1990) Nickel and nickel compounds. IARC
Monograph no. 47. Lyon, France
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BADS - Nickel
Nickel



i IARC (1990) Nickel and nickel compounds. IARC
Monograph no. 47. Lyon, France
12
BADS - Nickel
Nickel

i IARC (1990) Nickel and nickel compounds. IARC
Monograph no. 47. Lyon, France
13
BADS - Nickel
Nickel



i IARC (1990) Nickel and nickel compounds. IARC
Monograph no. 47. Lyon, France
14
BADS - Nickel
Nickel

i IARC (1990) Nickel and nickel compounds. IARC
Monograph no. 47. Lyon, France
15
BADS - Nickel
Nickel



i IARC (1990) Nickel and nickel compounds. IARC
Monograph no. 47. Lyon, France
16
BADS - Nickel
Nickel




i IARC (1990) Nickel and nickel compounds. IARC
Monograph no. 47. Lyon, France
17
Background values

• Urine, blood, and exhaled air samples obtained
  from subjects from B, DE, DK, NL, S and UK (n
  64)
• Characterization of low non-occupational
  exposures
• Assessment of analytical performance by analysis
  of repeatability in a series of duplicate
  analyses against IUPAC criteria

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Background values (n 64)

• Substance Biomarker Median Range 0.95 perc.
• Arsenic Total arsenic (µg/g)a 9.4 3.4-54.2b
  23.0
• Benzene S-phenyl mercapturic acid 1.2
  lt0.02-4.5 3.1 (µmol/mol creatinine)
• Benzene t,t-muconic acid 0.07 0.02-0.35
  0.26
• (µmol/mol creatinine)
• PAH 1-Hydroxypyrene 0.03 0.01-0.21 0.09
• (µmol/mol creatinine)
• Cadmium Cadmium in urine (µg/g)
  0.17 lt0.02-0.52 0.39
• Chromium Chromium in urine (µg/g) lt0.10 lt0.05-13.2
  0.42
• Nickel Nickel (µg/g) 1.5 lt0.01-4.1 3.3
• Phthalatec DEHP-metabolites (µg/g)d 51.2 3.8-478.6
  195.4
• ______________________________________________
• atotal of inorganic and organic As bConsumption
  of sea food cdiethylhexylphthalate (DEHP)
• dtotal of metabolites of diethylhexylphthalate
  (MEHP, 5-hydroxy-MEHP, 5-oxo-MEHP)

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Background values

• Substance Biomarker N Median Range 0.95 perc.
• Aniline Aniline in urine 60 9.30 2.79-140
  29.1
• (µmol/mol creatinine)
• Benzene Benzene 12 0.06 lt0.01-0.14 -
• (pmol/L in alveolar air)
• Chloroform Chloroform 12 0.70 lt0.1-4.5
  -
• (pmol/L in alveolar air)
• o-Toluidine o-Toluidine in urine 60
  0.29 0.11-0.75 0.66
• (µmol/mol creatinine)
• Trichloroethylene Trichloroethylene 12
  lt0.1 lt0.1-0.70 -
• (pmol/L in alveolar air)
• Tetrachloroethylene Tetrachloroethylene 12 0.05 0.
  04-32.8 -
• (pmol/L in alveolar air)
• _____________________________________________

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Analytical performance
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Analytical performance
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Perfor-manceRepea-tability
Carcinogenic Biomarker RSD () RSD
() Substances BIOMONECS IUPAC ________
__________________________________________________
___ Acrylamide Hb-adducts in blood
9.9 11.3 Arsenic (As) As in urine
19.1 22.6 Benzene ttMA in urine .
- SPMA in urine 15.4 16.0 BTXa BTX
in alveolar air . - Beryllium
(Be) Be in urine ndd
- Cadmium Cd in urine
18.4 32.0 Chromium (Cr) Cr VI in blood
nd - tot Cr in plasma nd
- tot Cr in urine 24.0 32.0 Cyclophos-
nd - phamide (CP) CP in
urine Phthalate (DEHP)e MEHP in urinec
5.5 10.4 11.3-16.0 Ethylene oxide Hb-adducts
in blood . . Nickel Nickel in
urine 12.4 22.6 PAH 1-OH-pyrene in
urine 15.5 45.0 Platinum (Pt) Pt in
urine 15.9 22.6 PERd PER in
alveolar air . . Propylene
oxide Hb-adduct . .
__________________________________________________
___________ aBTX benzene, toluene, xylene
bDEHP diethylhexylphthalate cMEHP
mono(2-ethylhexyl)phthalate, 5-carbo-MEHP,
5-hydroxy- MEHP, 6-hydroxy-MEHP, and 5-oxo-MEHP
dPER tetrachlororoethylene dnd below the
limit of quantification
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Pilot studies
Carcinogenic Biomarker Industry (Country) No.
of Substances subjects _______________________
______________________________________ Arsenic
(As) As in urine Semiconductor (NL) 9 As in
urine Copper smelter (B) 26 Benzene SPMA, ttMA
in urine Petrochemical (DK) 2 SPMA in U Oil
company (F) 5 BTXa BTX in alveolar air Paint
industry (NL) 20 Beryllium (Be) Be in
urine Hard metals (NL) 5 Cadmium Cd in
urine Copper smelter (B) 43 Chromium (Cr) Cr VI
in blood Fine chemical (NL) 60 tot Cr in
plasma Welding (NL) 64 Cr VI in
erythrocytes Galvanization (NL) 10 Cyclophos- CP
in urine Hospital (NL) 10 phamide (CP) CP in
urine Hospital (P) 12 Phthalate (DEHP)e MEHP in
urinec Rubber (S) 60 Ethylene oxide Hb-adducts
in blood Pharmaceutical (FI) 23 PAH 1-OH-pyrene
in urine Hospital (NL) 18 Platinum (Pt) Pt in
urine Hospital (NL) 10 PERd PER in alveolar
air Galvanization (NL) 3 Propylene
oxide Hb-adduct Pharmaceutical
(FI) 23 __________________________________________
___________________ aBTX benzene, toluene,
xylene bDEHP diethylhexylphthalate cMEHP
mono(2-ethylhexyl)phthalate, 5-carbo-MEHP,
5-hydroxy- MEHP, 6-hydroxy-MEHP, and 5-oxo-MEHP
dPER tetrachlororoethylene
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User interface

Service provider
SME-lab
study plan
User
Occupational hygienist, occupational
physician, or safety engineer
quotation
study plan
Private company, governmental authority
End-user
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Pit falls

• The end-user may be reluctant to share data with
  third parties
• Decide on a protocol for informing workers who
  have a positive sample for a carcinogen
• Do not use dry ice if you only want to cool your
  sample
• Samples may be kept at customs for 6 weeks
• Do not store breath samples in refrigerators also
  used for storage of organic solvents

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Conclusions

• 22 Biomarkers of 20 carcinogenic substances are
  ready to be used
• Routine labs perform well in analytical
  performance evaluations (repeatability and
  reproducibility)
• A generic study protocol (GBMSP) was prepared
• Concise documentation (BADS) is available
• Indicative background values are available for
  biomarkers derived from ubiquitous substances

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Recommendations

• Occupational hygienist can act as user between
  service provide and end-user
• End-users need guidance with things like study
  design, communication, technical aspects and
  ethical aspects (GBMP)
• Use concise information (BADS)
• Beware of pitfalls

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Where to find BIOMONECS?

• Website www.biomonecs.com
• Services
• Results from the project
• New biomarker developments
• (Downloadable documentation)
• (Final report)