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Progress Made on Tox21:
A Framework for the
Next Generation of Risk Science
Daniel Krewski, PhD, MHA
Professor and Director
McLaughlin Centre for
Population Heath Risk Assessment
&
Risk Sciences International
October 1, 2014
Outline
• NexGen: The next generation of risk science • TT21C: Toxicity testing in the 21st century (NRC, 2007)
• New Risk Assessment Methodologies (NRC, 2009)
• Population heath risk assessment (Krewski et al., 2007;
Chiu et al., 2011)
• Principles of risk management (Krewski et al., 2014)
• Case study prototypes (Krewski et al., 2014)
• Exposure assessment in the 21st Century (NRC,
2013)
• Future perspectives
McLaughlin Centre for Population Health Risk Assessment
McLaughlin Centre for Population Health Risk Assessment
Next generation risk assessment
McLaughlin Centre for Population Health Risk Assessment
Three Cornerstones
• New paradigm for toxicity
testing (TT21C), based on
perturbation of toxicity
pathways
• Advanced risk assessment
methodologies, including
those addressed in Science
and Decisions
• Population health approach:
multiple health determinants
and multiple interventions
McLaughlin Centre for Population Health Risk Assessment
Three Cornerstones
• New paradigm for toxicity
testing (TT21C), based on
perturbation of toxicity
pathways
• Advanced risk assessment
methodologies, including
those addressed in Science
and Decisions
• Population health approach:
multiple health determinants
and multiple interventions
Toxicity Testing in the 21st Century
www.nas.edu
Building the Scientific Toolbox
(Andersen & Krewski, 2009, Tox. Sci)
McLaughlin Centre for Population Health Risk Assessment
Human Toxicology Project Consortium
Hamburg, M. (2011), Science (Editorial). Vol. 335. p. 987
Collins, F.S., Gray, G.M. & Bucher, J.R. (2008),
Science (Policy Forum). Vol. 319. pp. 906 - 907
McLaughlin Centre for Population Health Risk Assessment
Reaction from Experts in Risk Assessment
8 +1 Invited Commentaries 2009-2010
6 Invited Commentaries 2009
Reaction from Experts in Toxicology
International Perspectives
Expert Panel on
the Integrated
Testing of
Pesticides
McLaughlin Centre for Population Health Risk Assessment
Canada-China collaboration
in toxicological risk assessment . . .
McLaughlin Centre for Population Health Risk Assessment Krewski et al. (2011), ARPH
Mapping Toxicity Pathways
McLaughlin Centre for Population Health Risk Assessment
Using Case Studies to implement NRC- TT21C report
1. Select a group of well-studied prototype compounds/pathways
2. Design & ‘validate’ human/rodent cell or tissue surrogate based
toxicity pathway assays
3. Examine results from the panel of assays to assess adversity
4. Refine quantitative risk assessment tools, i.e., computational systems biology pathway (CSBP) models and in vitro-in vivo extrapolation (IVIVE).
5. Integrate results into proposed health safety/risk assessments. Show the entire process in practice.
6. Take a look at results and modify steps to insure the process assist quantitative safety assessment
TT21C: Toxicity Pathway and Network Biology Program at The Hamner http://www.thehamner.org/institutes-centers/institute-for-chemical-safety-sciences/toxicity-testing-in-the-21st-century/
Specific TT21C Pathway Projects at Hamner
Receptor mediated pathways
PPARa – liver responses Estrogen Pathway – uterine and breast tissue responses Aryl-hydrocarbon receptor in liver
Stress Pathways involving chemical reactivity
DNA damage (p53-mdm2) – creating a computational model Oxidative stress (Nrf2-Keap1) Mitochondrial damage
See Mid-year report:
(http://www.thehamner.org/content/hamner_tt21c_midyear_report_2014.pdf)
Mapping the Human Toxome by Systems Toxicology
Hewitt et al., 2005. Science, 307:1572-1573
Endocrine disruption • Use “omics” to map PoT for endocrine disruption
• Develop software tools
• Identify PoT
• Develop a process for PoT annotation, validation
• Establish public database on PoT.
NIH Transformative Research Project
McLaughlin Centre for Population Health Risk Assessment
Three Cornerstones
• New paradigm for toxicity
testing (TT21C), based on
perturbation of toxicity
pathways
• Advanced risk assessment
methodologies, including
those addressed in Science
and Decisions
• Population health approach:
multiple health determinants
and multiple interventions
KEY MESSAGES
Enhanced framework
Formative focus
Four steps still core
Matching analysis to decisions
Clearer estimates of population risk
Advancing cumulative assessments
People and capacity building
Phase I Formulating and
Scoping Problem
For environmental
condition:
• What’s the
problem?
• What are the
options for altering?
• What assessments
are needed to
evaluate options?
Phase III Risk Management
• Relative benefits of
proposed options?
• How are other factors
(e.g., costs) affected by
options?
• Which option is chosen?
What’s the uncertainty
and justification?
• How to communicate it?
• Should decision
effectiveness be
evaluated? If so, how?
Phase II Planning and
Risk Assessing
Stage 1: Planning for:
• Options Assessment
• Uncertainty and
Variability Analysis
Stage 2: Assessing
Stage 3: Confirming
Utility of Assessment
No
t O
K
OK
Stakeholder involvement at each phase
“Risk-Based Decision-Making” Framework
Methodological Issues
• Adversity
• Variability
• Susceptible populations
• Dose and species extrapolation
• Mixtures and multiple stressors
• Uncertainty analysis
McLaughlin Centre for Population Health Risk Assessment
Issue Current Approach NexGen Approach
Adverse outcomes
Apical outcomes in mammalian systems, or precursors to these outcomes, serve as the basis for risk assessment.
In vitro assays identify critical toxicity pathway perturbations, which serve as the basis for risk assessment, even in the absence of a direct link with an apical outcome.
Methodological Issues: (1) Adversity
.
McLaughlin Centre for Population Health Risk Assessment
Issue Current Approach NexGen Approach
Dose-response
assessment
Empirical or biologically-based models describe apical endpoints, and determine an appropriate point of departure (such as the benchmark dose) for establishing a reference dose.
Computational systems biology pathway models describe dose-response relationships for pathway perturbations, reflecting dose-dependent transitions throughout the dose range of interest.
Methodological Issues: (2) Dose-response
McLaughlin Centre for Population Health Risk Assessment
A WHO/PAHO Collaborating Centre
Signal-to-Noise Crossover Dose (SNCD) Sand, Portier & Krewski (2011), EHP
Issue Current Approach NexGen Approach
Inter-individual variability
Adjustment factors used in establishing reference doses account for inter-individual variability in PK and PD. Variability in exposure is also taken into account.
Variability in biological response is characterized through the use of a diverse range of human cell lines. Dosimetry models link variation in human exposure with corresponding in vitro doses.
Methodological Issues: (3) Variability
From Zeise et al. (2012): “Assessing Human Variability in the
Next Generation Health Assessments of Environmental Chemicals”
Issue Current Approach NexGen Approach
Susceptible populations
Life-stage, genetics, and socioeconomic and lifestyle factors determine susceptible population groups.
Molecular and genetic epidemiology defines susceptible populations in terms of critical pathway perturbations.
Methodological Issues: (4) Susceptibility
How susceptibility arises from variability (from Zeise et al., 2012)
Issue Current Approach NexGen Approach
Dose and
species extrapolation
Dose and species extrapolation translate animal test results to humans.
Cellular assays provide direct measures of toxicity pathway perturbations in humans. IVIVE techniques and pathway modeling calibrate in vitro and in vivo exposures. Sensitive in vitro tests are used to evaluate risk directly at environmental exposure levels.
Methodological Issues: (5) Extrapolation
McLaughlin Centre for Population Health Risk Assessment
Rotroff DM, Wetmore BA, Dix DJ, Ferguson SS, Clewell HJ, Houck KA, Lecluyse EL, Andersen ME, Judson RS, Smith CM, Sochaski MA, Kavlock RJ, Boellmann F, Martin MT, Reif DM, Wambaugh JF, Thomas RS (2010) Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. Toxicol Sci 117: 348-358
Issue Current Approach NexGen Approach
Mixtures and
multiple stressors
Common experimental protocols include testing of mixtures and factorial experiments with joint exposures. However, there are only a limited number of such studies because of cost and complexity of experimental design.
Cost-effective high throughput technologies permit expanded testing of mixtures and multiple stressors.
Methodological Issues: (6) Mixtures
Issue Current Approach NexGen Approach
Uncertainty analysis
Uncertainty considerations include species differences in susceptibility, low-dose and route-to-route extrapolation, and exposure ascertainment.
Probabilistic risk assessments characterize overall uncertainty, and identify the most important sources of uncertainty that guide value-of-information decisions.
Methodological Issues: (7) Uncertainty
Adverse Effect
Toxicity Pathway
Key Events
MOA
HTS Assays
Intrinsic
Clearance
Plasma Protein
Binding
PopulationsPK Model
Biological Pathway Activating
Concentration (BPAC)
Probability Distribution
Dose-to-Concentration
Scaling Function (Css/DR)
Probability Distribution
Probability Distribution
for Dose
that Activates
Biological Pathway
BPADL
Pharmacodynamics Pharmacokinetics
Reverse Toxicokinetics (rTK):
in vitro concentration to in vivo dose
McLaughlin Centre for Population Health Risk Assessment
Three Cornerstones
• New paradigm for toxicity
testing (TT21C), based on
perturbation of toxicity
pathways
• Advanced risk assessment
methodologies, including
those addressed in Science
and Decisions
• Population health approach:
multiple health determinants
and multiple interventions
Health Risk Science Determinants and Interactions
Health Risk Policy Analysis Evidence Based Policy
Biology
and
Genetics
Social
and
Behavioural
Biology-social interactions
Environment
and
Occupation
Biology-environment
interactions
Population Health
Environment-social
interactions
Multiple Interventions
Advisory
Regulatory
Economic
Community
Technological
Chiu, W.A., et al., Approaches to advancing quantitative human health risk assessment of environmental chemicals
in the post-genomic era, Toxicol. Appl. Pharmacol. (2010), doi:10.1016/j.taap.2010.03.019
McLaughlin Centre for Population Health Risk Assessment
Social-Environment Interaction
Darby et al. (2005), Radon in homes and risk of lung cancer: collaborative analysis
of individual data from 13 European case-control studies. BMJ 330: 223-226
McLaughlin Centre for Population Health Risk Assessment
Social-Genetic Interaction
McLaughlin Centre for Population Health Risk Assessment
Risk
Management
Risk Management Principles (1/2)
• Beneficence and non-maleficence (do more
good than harm)
• Natural justice (a fair process of decision
making)
• Equity (ensure an equitable distribution of risk)
• Utility (seek optimal use of limited risk
management resources)
• Honesty (be clear on what can and cannot be
done to reduce risk)
McLaughlin Centre for Population Health Risk Assessment
Risk Management Principles (2/2)
• Acceptability of risk (do not impose risks that
are unacceptable to society)
• Precaution (be cautious in the face of
uncertainty)
• Autonomy (foster informed risk decision-making
for all stakeholders)
• Flexibility (continually adapt to new knowledge
and understanding)
• Practicality (the complete elimination of risk is
not possible)
McLaughlin Centre for Population Health Risk Assessment
McLaughlin Centre for Population Health Risk Assessment
Case
Study
Prototypes
NexGen Tiered Approach to Risk Assessment www.epa.gov/risk/nexgen/docs/NexGen-Program-Synopsis.pdf
Tier 1: Screening and Ranking
Judson et al. (2010), EST
Tier 2: Limited Scope Assessment
Traditional versus Toxicogenomics Determination of BMD
Thomas et al. (2012), Mutation Research
Thomas et al. (2012) found a strong correlation between
transcriptional BMDs for specific pathways and traditional BMDs
McLaughlin Centre for Population Health Risk Assessment
• To identify toxicity pathways using
‘omics’ data
• To determine accuracy of
predicting in vivo responses from
in vitro toxicity pathway induction
from toxicants
• To develop a biologically-based
dose-response (BBDR) based on
the integration of diverse data sets
Lung Injury and Ozone
Tier 3: Major Assessment
0.5
1
1.5
2
2.5
3
-4 0 4 8 12 16 20 24
IL8
Fo
ld-C
han
ge
Time (hrs)
IL8 RNA Expression Time Course Relative to Mean Air Value
1 ppm O3
0.75 ppm O3
0.5 ppm O3
0.25 ppm O3
Air
Response time course of IL8 RNA expression, relative to mean air
value. Peak response occurs 3 hours post exposure cessation.
McLaughlin Centre for Population Health Risk Assessment
Lung Injury and Ozone
Conclusion
NF-κB signaling is seen early
during ozone exposure,
and there is a clear dose-response
with the cytokine IL-8.
McLaughlin Centre for Population Health Risk Assessment
Three Cornerstones
• New paradigm for toxicity
testing (TT21C), based on
perturbation of toxicity
pathways
• Advanced risk assessment
methodologies, including
those addressed in Science
and Decisions
• Population health approach:
multiple health determinants
and multiple interventions
Exposure Assessment
McLaughlin Centre for Population Health Risk Assessment
Hubal et al., 2010, JTEH 13:299
Exposomics
McLaughlin Centre for Population Health Risk Assessment
``The exposome represents
the combined exposures
from all sources that reach
the internal chemical
environment. Toxicologically
important classes of
exposome chemicals are
shown. Signatures and
biomarkers can detect these
agents in blood or serum.``
Two Approaches to Exposomics
Rappaport et al., 2011 J.Exp. Sc. & Envir. Epi. 21:5
McLaughlin Centre for Population Health Risk Assessment
Biomarkers of Exposure
McLaughlin Centre for Population
Health Risk Assessment
NRC Report
McLaughlin Centre for Population Health Risk Assessment
National Health and Nutrition Examination Survey
Human Biomonitoring Programs
NHANES
Canadian Health Measures
Survey (CHMS)
Toxicity Pathways at Multiple Levels of Biological Organization
Mapping toxicity pathways
is key to identifying biomarkers
Balshaw, NIH
Biomonitoring Equivalents
McLaughlin Centre for Population Health Risk Assessment
McLaughlin Centre for Population Health Risk Assessment
Establishing Biomonitoring Equivalents
Hayes et al., 2008
Biomonitoring Equivalents (BEs)
Biomonitoring Equivalents (BEs) are defined as the concentration of a chemical (or
metabolite) in a biological medium (blood, urine, human milk, etc.) consistent with
defined exposure guidance values or toxicity criteria including reference doses and
reference concentrations (RfD and RfCs), minimal risk levels (MRLs), or tolerable
daily intakes (TDIs) [Hays, 2007. Regul. Toxicol. Pharmacol. 47(1), 96–109].
McLaughlin Centre for Population Health Risk Assessment
http://www.biomonitoringequivalents.net/html/chemical_specific_bes.html
• 2,4-D
• Acrylamide
• Cadmium
• Cyfluthrin
• Di(2-ethylhexyl)phthalate
• Phthalate Esters: Diethyl phthalate Di-n-butyl phthalate Benzylbutyl phthalate
• Polychlorinated dibenzo-p-dioxins and dibenzofurans
• Toluene
• Trihalomethanes: Chloroform Dibromochloromethane Bromodichloromethane Bromoform
Reverse Toxicokinetics (rTK)
McLaughlin Centre for Population Health Risk Assessment
Rotroff DM, Wetmore BA, Dix DJ, Ferguson SS, Clewell HJ, Houck KA, Lecluyse EL, Andersen ME, Judson RS, Smith CM, Sochaski MA, Kavlock RJ, Boellmann F, Martin MT, Reif DM, Wambaugh JF, Thomas RS (2010) Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. Toxicol Sci 117: 348-358
Incorporating Human Dosimetry and Exposure
Into High-Throughput In Vitro Toxicity Screening
Adverse Effect
Toxicity Pathway
Key Events
MOA
HTS Assays
Intrinsic
Clearance
Plasma Protein
Binding
PopulationsPK Model
Biological Pathway Activating
Concentration (BPAC)
Probability Distribution
Dose-to-Concentration
Scaling Function (Css/DR)
Probability Distribution
Probability Distribution
for Dose
that Activates
Biological Pathway
BPADL
Pharmacodynamics Pharmacokinetics
Reverse Toxicokinetics (rTK):
in vitro concentration to in vivo dose (Dix, 2011)
Example: Bisphenol A
Estrogenicity In Vitro
vs.
In Vivo Reproductive Toxicity
• Rat reproduction tests resulted in a NOEL of 50 mg/kg/day,
with a corresponding RfD of 0.5 mg/kg/day
• HTRA lower limit BPADL99 is 0.16 mg/kg/day, derived from six
ToxCast estrogen receptor assays
• Actual human exposure is estimated to be 0.00008 mg/kg/day
McLaughlin Centre for Population Health Risk Assessment
McLaughlin Centre for Population Health Risk Assessment
Rotroff DM, Wetmore BA, Dix DJ, Ferguson SS, Clewell HJ, Houck KA, Lecluyse EL, Andersen ME, Judson RS, Smith CM, Sochaski MA, Kavlock RJ, Boellmann F, Martin MT, Reif DM, Wambaugh JF, Thomas RS (2010) Incorporating human dosimetry and exposure into high-throughput in vitro toxicity screening. Toxicol Sci 117: 348-358
Exposure Science in the 21st
Century
“An NRC committee will develop a long-range vision for exposure science . . . . It will include development of a unifying conceptual framework for advancement of exposure science to study and assess human and ecological contact with chemical, biological, and physical stressors in their environments. concern.”
http://www.nap.edu/openbook.php?record_id=13507
Conclusions and Future Directions
• TT21C (NRC, 2007) has received widespread support, both in the
United States and internationally: progress towards the implementation
of TT21C ahead of projected timetable
• NexGen (EPA, 2014) integrates three cornerstones of the future of risk
science: TT21C, new assessment methodologies, and a population
health perspective
• High-throughput exposomics: assess toxicity pathway perturbations
measured directly in humans
• RS21C: a coordinated international approach needed to chart the future
of risk science, building on the powerful new tools, technologies, and
methodologies now available to the scientific community
McLaughlin Centre for Population Health Risk Assessment
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