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Human Biomonitoring Exposure Dr Peter J.
Boogaard, Shell Health, Shell International bv
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Environmental biomonitoring is widely applied
Dioxins/Furans
VOCs
Environmental Phenols
Metals
Fungicides
Perfluorinated compounds
Pyrethroid Pesticides
Organophosphate Pesticides
PBDEs
PCBs
Carbamate Insecticides
Halogenated Phenolic compounds
Phthalates
PAHs
Herbicides
Organochlorine Pesticides (12)
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Human Biomonitoring Whats new ?

• Different focus
• ? Shift from occupational to environmental
  exposures
• ? Shift to general health risk assessment
• ? No prescriptive legislation, no compliance
• Different levels of exposure
• ? Environmental ltlt occupational levels
• ? No analytical problem, but potentially
  methodological and interpretation problems

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Recent EU legislative initiatives

• REACh
• Registration, Evaluation Authorisation of
  Chemicals
• SCALE
• Science, Children, Awareness-raising, Legal
  implementation tools regular Evaluation

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Drivers for REACH

• Toxins Found in Body of E.U. Environment
  Commissioner
• Margot Wallström (Nov 2003)
• BRUSSELS, BelgiumThe European Union's
  environment chiefsaid Thursday her body contained
  28 potentially toxic chemicals as she gave a
  practical demonstration of the case for new
  safety rules that are opposed by the industry.
• A blood test on European Environment Commissioner
  Margot Wallstrom for human-made compounds
  commonly found in televisions, carpets,
  furniture, and food highlighted the presence of
  DDT, a pesticide the E.U. banned from farms in
  1983 after it was found to harm wildlife and
  attack the nervous system.

• She helped launch the proposed new chemicals
  safety law last week, which would mean that tens
  of thousands of chemicals developed before 1981,
  and exempt from checks under existing E.U. safety
  rules, would be reevaluated for safety.
• Toxicopathologist Vyvyan Howard, who presented
  Wallstrom's test results, said levels of
  chemicals in her blood were average but would
  have been two to three times higher before
  Wallstrom gave birth to her two sons. "If you
  breast feed a child for six months, it will get
  17 percent of its lifetime dose of chemicals,"
  Howard said.
• Chemicals that mimic the body's hormones could be
  especially damaging at small doses, he added.
• "In just a couple of generations we have
  accumulated thousands of chemicals that were not
  there in our grandfathers' and grandmothers'
  bodies," Wallstrom told a news conference.
• "There are many bad players that work at low
  dosages and affect development. There is a
  complete change in the way toxicologists are
  thinking about dose."

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REACH

• REACH is (partially) driven through human
  biomonitoring data (public opinion)
• REACH requires risk assessment for all exposure
  scenarios (industrial, consumer,
  man-via-the-environment)
• Human biomonitoring data may be extremely useful
  for risk assessments (man-via-the-environment)
• To do this it is essential to have good data and
  knowledge on their interpretation

CEFIC-LRI programme on human biomonitoring !
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SCALE

• Launched in 2004 (time path 2004-2010)
• Three technical working groups, focussing on
• 1. Priority diseases (childhood cancer, asthma,
  (neurological) developmental disorders)
• 2. Biomonitoring (dioxines PCBs, heavy
  metals, endocrine modulators)
• 3. Research Needs.
• HBM Action plan adopted 12/2004
• Now implementation phase ? some projects were
  set up (IG HBM, ESBIO under 6th and 7th Framework
  Programme) but currently stuck.

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Risk Assessment and the First Law of Toxicology

• Die Dritte Defension in Septem Defensiones

What is that is not poison ? All things are
posion, and nothing without poison, only the dose
makes that a thing is no poison
(Nothing is without toxicity if the the dose is
not considered) ?
Risk (hazard, dose)
Dose (exposure, time)
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Paradigm of Health Risk Assessment
Hazard assessment
Exposure assessment
Dose-response
Risk characterisation
In line with REACH In line with view of
chemical industry
Risk management
Adapted from EC, 2003
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What is human biomonitoring ?

• Biological monitoring
• biomarkers of exposure, internal dose, or body
  burden (e.g.1-HOPyr, PbB, S-PMA)

• Biochemical effect monitoring
• biomarkers of effective dose (e.g. protein-,
  DNA-adducts)

• Biological effect monitoring
• biomarkers of effect (e.g. ChE, SCE, µAlb, hprt)

• Clinical effect monitoring
• biomarkers of disease (e.g. Alb, AST, PSA)

• Genotyping and Phenotyping
• biomarkers of susceptibility (e.g. GSTs, P450s)

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Monitoring Methods
Biomarkers of susceptibility
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CEFIC-LRI and biomonitoring

• 1998 White paper STOTS Human Biomonitoring
• 2001 1st RfP - Trends Key developments in
  human biomonitoring
• 2004 ICCA/EPA/ILSI/CDC/ATDSR workshop on
  biomonitoring (RTP)
• 2nd RfP - Background values, inter-
  intra-individual variations
• 2005 ICCA workshop on biomonitoring (Paris)
• 2005 ECETOC Task Force on Biomonitoring
  Guidance for the Interpretation of
  Biomonitoring Data ? research issues
• 2006 ICCA workshop on biomonitoring Making
  sense of biomonitoring data (Minneapolis)
• 3rd RfP Interpretation biomonitoring
  guidance values
• 2007 ICCA/EPA workshop on biomonitoring Public
  Health Applications (Research Triangle Park)
• 2008 ICCA/EPA workshop on biomonitoring
  (Amsterdam)

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CEFIC LRI Human Biomonitoring phase 1

• 2001 LRI members survey ? need for industry to
  seriously examine research requirements in the
  area of biomarkers (both effects and exposure) in
  terms of its scientific importance and business
  relevance
• RfP on Trends and Key Developments in Human
  Biomonitoring (August 2001)
• Slow start.
• A large number of proposals was received and two
  were awarded CTL, Syngenta (Macclesfield, UK)
  NOFER Inst Occ Medicine (Lodz, Poland) (July 2002)

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LRI Human biomonitoring phase 1 publications
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CEFIC LRI Human Biomonitoring phase 2

• Background values ? What is normal ?
• What about inter- and intra-individual variation
  ?
• Three new RfPs (2004)
• Three new projects
• Biomarker backgrounds Institute of
  Environmental Health, Cranfield Univ (UK)
  finished Sept 2008
• Inter-individual variation in key biomarkers
  within the general population VITO (B),
  Institute of Public Health, Univ Copen-hagen
  (DK), Center for Statistics, Univ Hasselt (B)
  finished July 2008
• Analysis of inter- and intra-individual variation
  in key biomarkers of chemical exposure within the
  general population HSL (UK), TNO (NL) extended
  until Dec 2008

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LRI Human biomonitoring phase 2 publications (1)
Final study report available Number of
publication in peer-reviewed scientific press
expected in 2009
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Background variations
BIOMARKERS from normality, to dysfunction, to
disease
Clearly outside normal variation indicative for
potential health effects ?
Variation outside normal background
Normal variation in background
Background
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LRI Human biomonitoring phase 2 publications (2)
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LRI Human biomonitoring phase 2 publications (3)

• Den Hond, E., Govarts,E., Bruckers, L.,
  Schoeters,G. Determinants of polychlorinated
  aromatic hydrocarbons in serum in three age
  classes methodological implications for
  biomonitoring Env Research (submitted)
• Determinants of serum PCBs in adolescents and
  adults linear regression analysis and regression
  tree analysis (paper in preparation)

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LRI Human biomonitoring phase 2 publications (4)
Morton, J., Smith, B., Leese, L., Cotton, R.,
Warren, N., Cocker, J. Trends in Blood Lead
Levels at the Health Safety Laboratory
1996-2007 (BOHS, 2008)
Project extended until Dec 2008
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CEFIC LRI Human Biomonitoring phase 3

• Interpretation Biomonitoring guidance values
  three RfPs
• The role of biomonitoring guidance values in the
  interpretation of HBM data
• Computational tools for the derivation of
  biomonitoring guidance values
• Structured data acquisition via in vitro
  metabolism screens to enhance computational tools
• Four projects
• A framework for the development and application
  of environmental biological monitoring guidance
  values Inst Environ Health, Univ Cranfield
  (UK) Health Protection Agency (UK) Institut für
  Arbeits-, Sozial- und Umwelt-medizin, Univ
  Erlangen-Nürnberg (D) Health Safety Lab (UK)
  VITO (B)

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Perspectives biomonitoring equivalents (BEs)
MAK
BAT
TLV
BEI
TDI
BE
RfC
BE
MRL
BE
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Multiple Ways to obtain a BE
With knowledge of pharmacokinetics in animals,
the same endpoint can be derived ..
Safe Human Dose TDI, RfC
Animal Dose NOAEL/LOAEL
Human Biomarker Level
Animal Biomarker Level
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Perspectives
This approach works well with data-rich
substances, but how to go about the majority of
chemicals without kinetic data ?
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CEFIC LRI Human Biomonitoring phase 3

• 2. Development of a computer program with a
  multi-level modelling tool for the estimation of
  biomonitoring equivalent guidance values for
  chemical agents related to health-based exposure
  limits for inhalation, oral intake and/or skin
  exposure. Industox (NL)
• 3. Development of a Tiered Set of Modelling Tools
  for Derivation of Biomonitoring Guidance Values -
  Computational tools for the derivation of
  biomonitoring guidance values. Dow Chemicals, MI
  (USA), Health Safety Lab (UK)
• Taking it one step further with REACh in mind
• 4. Data on in vitro metabolism and mechanisms of
  action in combination with kinetic modelling
  integrating in risk assessment. IRAS, Univ
  Utrecht (NL), Hamner Institutes for Health
  Sciences, NC (USA)

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Conclusions

• The CEFIC-LRI programme on biomonitoring is and
  has always been in close contact with the
  scientific regulatory communities
• RfPs are developed in response to and aligned
  with inter-disciplinary international workshops
  organised by ICCA
• Always high response rates to the RfPs
• Projects are successful resulting in
• Multiple publications
• Tools for risk-based management of exposure to
  environmental chemicals
• Tools to comply with REACh regulations

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Thank you for your attention !
Any questions ?
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