Fighting unknown chemicals: analytical strategies for risk ... · Fighting unknown chemicals:...
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Fighting unknown chemicals: analytical strategies for risk prioritization
Eelco Nicolaas Pieke
Research Group for Analytical Food ChemistryNational Food Institute of Denmark
Berlin, Germany30 November 2017
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
In this talk:
• Introduction to IAS & NIAS: the chemical headache in foodo Knowledge gapso The analytical “Pillars of Knowledge”o Difference between IAS and NIASo Risk-assessing IAS and NIAS
• Proposed methods for closing the knowledge gap (not detailed)o Quantification (how much?)o Identification (what?)o Hazard character (how bad?)o Preliminary risk (priority?)
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Knowledge gaps in Risk Assessment
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Intentionalor not?
Chemicalidentity
Knowledge on chemical intake
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Knowledge gaps in Risk Assessment
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Intentionalor not?
Chemicalidentity
Knowledge on chemical intake
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Introducing the Pillars
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[Identity & Potential] + [Quantity]
[Toxicity] + [Identity & Potential]
[Toxicity] + [Quantity]
= Exposure
= Hazard
= Effect level
Risk = Exposure + Hazard + Effect level
Identity &Potential
RISK
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
• Intentionally Added Substances (IAS):
– Limited number
– Pillars OK (well-defined data)
– Validated methods
– Substances are regulated
Existing tools & knowledge
Rarely problematic
A story of IAS and NIAS
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?
IAS
Che
mic
als
in foo
d
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
• Non-Intentionally Added Substances (NIAS):
– Virtually unlimited number
– Pillars NOT OK (missing data)
– No formalized methodology
– No effective regulation
Lack of tools & knowledge
Unknown & undefined risk!
A story of IAS and NIAS
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Unknown NIAS
Known NIAS + IAS
Che
mic
als
in foo
d
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Risk Assessment
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Suspect chemical
Exposure assessment
Hazard assessment
Risk Assessment
Existing tox. data Animal testing
Assay testing
Blood/urine tests
Consumption Surveys
Sample analysis
Structure assessment
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Risk Assessment for unknown NIAS
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Unknown NIAS
Exposure assessment
Hazard assessment
Risk assessment
Existing tox. data
Animal testing
Assay testing
Blood/urine tests
Consumption Surveys
Sample analysis
Structure assessment
No chemical structure
No availableexposure data
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Making informed decisions without tools?
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Because of inadequate tools, there is no choice
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
What is needed?
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• Methods to explore what is present & any effect on human health
• Decisions on unknowns should be information-based
• Data must be available fast & nonexhaustive:
» time is precious;
» information is expensive.
(standard matching, animal tests, identification studies, …)
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Chemicals in the tip of the iceberg
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IASKnown NIAS
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Chemicals in the bottom of the iceberg
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Lots of
Unknown NIAS
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
New tools to explore unknown chemicals
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Quantitative data
LC-QTOF-MSLC Liquid Chromatography QTOF Quadrupole x Time of Flight MS Mass Spectrometry
TCMTotal Migratable Content: The chemical portion of a sample that has potential to migrate to food.
Quantity
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Semi-quantitative tools
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0
20
40
60
80
100
120
140
1 2 3 4 5 6 7 8
[C] ± 3-fold error
Pieke et al., Anal Chim Acta. 2017 vol. 975, pp. 30-41.DOI: 10.1016/j.aca.2017.03.054.
Semi-quantify
Marker
Analyte Analyte
Quantity
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Semi-quantitative tools
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0
2
4
6
8
10
12
14
16
18
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1 51 101 151 201 251 301 351 401 451 501 551
Concentration (µmol/L) -> 1 sample (recycled cardboard)
-> 1 analytical run
-> No identification needed
-> 550+ semi-quantified compounds0
5
10
15
20 Max. Conc.
Min. Conc.
Features
Pieke et al., Anal Chim Acta. 2017 vol. 975, pp. 30-41.DOI: 10.1016/j.aca.2017.03.054.
Quantity
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Exploring the world of unknown chemicals
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Semi-quantitative data
0
20
40
60
80
100
120
140
1 2 3 4 5 6 7 8
Conc.
Quantity
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Exploring the world of unknown chemicals
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0
20
40
60
80
100
120
140
1 2 3 4 5 6 7 8
Conc.
Chemical structure data Semi-quantitative data
Identity Quantity
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Ambiguous structure assessment
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Controlled FragmentationSimilarity Correlations
?First moleculein DB1
Second molecule in DB1
Third molecule in DB3
Database #1
First molecule in DB2
Second molecule in DB2
Database #2?
Pieke et al. (in press), J. Mass Spectrom.
Outputs
Identity
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Ambiguous structure assessment
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• Result: best-matching similar compound from available databases:
Identity
Pieke et al. (in press), J. Mass Spectrom.
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
The Three Pillars: incomplete
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[Quantity] Semi-quantification
[Identity] Structure prediction
[Toxicity] ???
Identity &Potential
RISK
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Developmental Toxicity
The toxicity of tentative chemicals?
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Carcinogenicity
Mutagenicity
Cramer Classification
???Q SAR–
Computer-based toxicity predictions
Model evaluation
Toxicity
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
The Three Pillars: nonexact data
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Risk = Hazard * Exposure
Placeholders…
Identity &Potential
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
• We may not be able to calculate the true risk from approximated data, but …
• We can still get a nonconclusive perception of risk: preliminary risk assessment
Risk: starting from tentative data
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Estimated Hazard Exposure
Risk Likeliness
Toxicity (QSAR) +Identity (Pred.) =
Quantity (Semi-Q) +Identity (Pred.) =
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Risk: a classification method
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Rule-based decisions
Expertise decisions
Are exposure thresholds exceeded?”
Is the presence of this compound acceptable?
Classification
Identity &Potential
RISK
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Risk: the first things first
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Identification
QSAR alerts
Exposure
FACTORS
Decision
A: Substances of direct concern
B: Substances of lesser concern
C: Insufficient or incomplete data
CLASSIFICATION
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
The purpose of tentative data
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We needtentative data
… because the alternative isno data!
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
The purpose of tentative data
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The choice to do nothing should be deliberate
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Thank you for your attention
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Thanks to:
• Kit Granby• Jørn Smedsgaard
• Gilles Riviere• Bruno Teste
Eelco Nicolaas Pieke enpi(at)food.dtu.dk
• Elena Boriani
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DTU Food, Technical University of Denmark Berlin, Germany 30 November 2017
Wish-list for NIAS screening
• Better identification methods and tools – more knowledge on HRMS needed
• Greatly improved databases for possible IAS & NIAS – ideally from the source
• More comprehensive tools for hazard – QSAR is not mature and subject to discussion
• More work on sampling & semi-quantification – reduce the uncertainty in the assessment
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