APPLICATION OF THE ICCR PRINCIPLEStt21c.org/wp-content/uploads/2019/02/TATT-M-Dent2.pdf · ICCR...
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APPLICATION OF THE ICCR PRINCIPLES MATT DENT, UNILEVER SAFETY AND ENVIRONMENTAL ASSURANCE CENTRE
Transcript of APPLICATION OF THE ICCR PRINCIPLEStt21c.org/wp-content/uploads/2019/02/TATT-M-Dent2.pdf · ICCR...
APPLICATION OF THE ICCRPRINCIPLESMATT DENT, UNILEVER SAFETY AND ENVIRONMENTAL ASSURANCE CENTRE
ICCR NINE PRINCIPLES OF NGRA
Main overriding principles: The overall goal is a human safety risk assessment The assessment is exposure led The assessment is hypothesis drivenThe assessment is designed to prevent harm
Principles describe how a NGRA should be conducted: Following an appropriate appraisal of existing informationUsing a tiered and iterative approachUsing robust and relevant methods and strategies
Principles for documenting NGRA: Sources of uncertainty should be characterized and documentedThe logic of the approach should be transparently and documented
APPLICATION OF PRINCIPLES VIA A TIERED FRAMEWORK
Calculate Exposure
“The assessment is exposure-led”
Literature search
“Using all available information”
Next generation risk
assessment
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Can a decision be made? If so
STOP
“Using a tiered and iterative approach”
“Exposure-led, human-relevant, hypothesis driven, designed to prevent harm”
ONE EXAMPLE NGRA WORKFLOW
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Continue through tiers
until sufficient information to
make a decision:
assessment may be
complete at any tier
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In chemico assays
Human studies
Pathways modelling
3D culture systems
Organ-on-chip
Zebrafish larva assays*
Metabolism and metabolite identification
Physiologically-based kinetic modelling
Reporter gene assays
‘Omics
In vitro pharmacological profiling
In silico tools
ONE EXAMPLE NGRA WORKFLOW
Read across
Exposure-based waiving
* ‘non-animal’ in a regulatory context
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In chemico assays
Human studies
Pathways modelling
3D culture systems
Organ-on-chip
Zebrafish larva assays*
Metabolism and metabolite identification
Physiologically-based kinetic modelling
Reporter gene assays
‘Omics
In vitro pharmacological profiling
Read across
Exposure-based waiving
In silico tools
ONE EXAMPLE NGRA WORKFLOW
* ‘non-animal’ in a regulatory context
EXAMPLE – ANDROGEN RECEPTOR ANTAGONISM (SIMPLIFIED EXAMPLE)
Problem formulation: Can Bakuchiol be safely used at 0.5% in a body lotion or a shampoo?
• Calculate exposure –above TTC for both exposure scenarios
• Perform literature search – no ‘definitive’ toxicology data but indications of hormonal activity
• In-silico screen – suggestive of AR interaction
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HYPOTHESIS: Exposure to bakuchiol present at 0.5% in a body lotion or shampoo would not cause adverse effects in consumers due to perturbed
androgen signalling
From Dent et al., (2018) Toxicological Sciences https://doi.org/10.1093/toxsci/kfy245
PHYSIOLOGICALLY-BASED KINETIC MODELLING
Low-tier assessment based on predicted/scaled values
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Predicted concentration in plasma for females (dotted line) and males (solid line) following daily use of a body lotion containing Bakuchiol at 0.5%
“Exposure-led”
From Dent et al., (2018) Toxicological Sciences https://doi.org/10.1093/toxsci/kfy245
BAKUCHIOL DOSE-RESPONSE DATA
Dose-response data generated in a human-relevant system
(AR-CALUX® assay)
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“Human relevant”
“Robust and relevant methods and approaches”
From Dent et al., (2018) Toxicological Sciences https://doi.org/10.1093/toxsci/kfy245
BAKUCHIOL DOSE-RESPONSE DATA
Dose-response data generated in a human-relevant system
(AR-CALUX® assay)
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Risk assessment = comparison of exposure and effect concentrations. Exposure concentration = IC50 or PC50
From Dent et al., (2018) Toxicological Sciences https://doi.org/10.1093/toxsci/kfy245
“Human relevant”
“Robust and relevant methods and approaches”
COMPARING EXPOSURE AND EFFECT CONCENTRATIONS
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Triangles show plasma or serum levels, circles show IC50 values for bakuchiol and several anti-androgens
What is an appropriate ‘Margin of Exposure’?
50 g
From Dent et al., (2018) Toxicological Sciences https://doi.org/10.1093/toxsci/kfy245
USING DIETARY COMPARATOR RATIOS TO BENCHMARK RISK
Calculation of Exposure:Activity Ratios (After Becker et al 2015 Regul. Toxicol. Pharmacol. 71(3), 398–408):
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EAR (unitless) =Exposure (plasma exposure in µM)
Activity (IC50 µM)
DCR =EAR (test substance)
EAR (dietary comparator)
If DCR<1 the activity of the test substance exposure would be lower than the activity of the dietary comparator exposure which has a history of safe use
DIETARY COMPARATOR RATIOS
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Range indicates variability in exposure for both dietary comparator and test substances
From Dent et al., (2018) Toxicological Sciences https://doi.org/10.1093/toxsci/kfy245
DIETARY COMPARATOR RATIOS
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Outcome: Enough precision to make a decision for shampoo, more refinement needed for body lotion
From Dent et al., (2018) Toxicological Sciences https://doi.org/10.1093/toxsci/kfy245
UNCERTAINTIES?
• Predicted skin penetration for Bakuchiol
• Lack of metabolic activation in AR-CALUX® assay
• Reliance on Cmax as the measure of exposure – may not be appropriate where comparator is cleared much faster than test substance
• Total vs. free concentration
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“Identifying and characterizing sources of uncertainty”
Major areas for refinement
HIGHER TIER APPROACHES TO REFINE RISK ASSESSMENT
Where anti-androgenic activity is suspected we need to determine whether this will result in an adverse health effect
ACTIVITY ≠ ADVERSITY
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“The assessment is designed to prevent harm”
Human studies
Pathways modelling
3D culture systems
Organ-on-chip
Zebrafish larva assays*
* ‘non-animal’ in a regulatory context
HIGHER TIER APPROACHES TO REFINE RISK ASSESSMENT
Where anti-androgenic activity is suspected we need to determine whether this will result in an adverse health effect
ACTIVITY ≠ ADVERSITY
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“The assessment is designed to prevent harm”
Human studies
Pathways modelling
3D culture systems
Organ-on-chip
HIGHER TIER APPROACHES TO REFINE RISK ASSESSMENT
Where anti-androgenic activity is suspected we need to determine whether this will result in an adverse health effect
ACTIVITY ≠ ADVERSITY
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“The assessment is designed to prevent harm”
Pathways modelling
3D culture systems
3D PROSTATE CULTURES
19Epithelial cells stained for CK5/6
Over time spheroids show secretion of PSA
“The assessment is designed to prevent harm”
“Human relevant”
ROLE OF COMPUTATIONAL MODELS
Barton and Andersen Toxicological Sciences 45, 174-187 (1998)
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Computational model describing androgen
homeostasis – can help determine the effects that perturbing one part of the axis will have across the
whole system
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Metabolism and metabolite identification
Physiologically-based kinetic modelling
Reporter gene assays
Read across XExposure-based waiving XIn silico tools
CASE STUDY SUMMARY
Applying ICCR principles and a tiered framework means a risk
assessment for shampoo can be completed with these data. Also
likely ot be possible for body lotion with further exposure/metabolism
refinement
CONCLUSIONS
The 9 ICCR Principles underpin the use of novel data in Next Generation Risk Assessment
The Principles can be applied to improve safety decision making
Use of tiered approaches means that gaps in some of the higher tier tools does not prevent risk assessments from being completed
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ACKNOWLEDGEMENTS
Dr Hajime Kojima and the ICCR Joint Working Group on Integrated Strategies
Prof. Paul Carmichael, Dr. Hequn Li and the team at Unilever
Prof. Kim Boekelheide and the team at Brown University
Prof. Frank Martin at the University of Central Lancashire
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