UC RASS 2 - Dourson Risk Assessment Seminar Series 12/18/2015 2 ... Impact of CYP2C9 Polymorphism on...
Transcript of UC RASS 2 - Dourson Risk Assessment Seminar Series 12/18/2015 2 ... Impact of CYP2C9 Polymorphism on...
UC-DEH Risk Assessment Seminar Series
12/18/2015
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Hazard & Dose Response Assessment:Roadmaps & Methods
for Using 21st Century Data
Michael L. DoursonToxicology Excellence for Risk Assessment Center
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Seminar Overview
• What is harmonization in risk assessment?
• The risk paradigm with a quiz
• The Future– Epigenetics– Toxicology 21– Collaboration
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What is Harmonization in Risk Assessment?
• Understanding each others judgments and methods, with a future move to resolve differences
• Sharing information among groups, with contemplation of developing a unified source where all can contribute
• Creating problem formulation frameworks to sort through the confusing landscape of different safe doses, safe concentrations, or adverse effect probabilities
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Health Based OELs• Regulatory, Authoritative
•Traditional(TLVs, MAKs, WEELs, PELs, MACs,
RELs)
Working Provisional OELs(internal company, trade association,
vendor limits)
Hazard Banding Strategies• Pharmaceutical banding• Occupational exposure bands
More toxicological and epidemiological data allow one to move up the hierarchy of OELs, but one needs to work on the problem formulated by the risk manager.
Prescriptive Process Based OELs(REACH DNELs/DMELs)
Most Extensive Data Requirements(human epidemiology studies)
> quality, > certainty
Moderate Data Requirements(in vitro and animal studies and anecdotal
reports of human health effects)> quality, > certainty
Least Data Requirements
(in vitro and animal studies)
Hierarchy of OELs
Control Banding = Hazard Bands + Exposure Risk Assessment + Exposure Management
Quantitative Health Based
OELs
Task force: M. Guillemin, D. Heidel, M. Jayjock, C. Laszcz‐ Davis, P. Logan, A. Maier, J. Mulhausen, K. Niven, D. O’Malley, J. Perkins, S. Ripple
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The Risk Paradigm (in part)Step 1. Evaluate Toxicology data to derive a “safe dose”
Dose Response Measure (NOAEL)
Safe Dose (OEL) =
Uncertainty Factors (UA x UH x UD)
Step 2. Characterize risk:
Exposure (UCL)
Hazard Quotient (HQ) =
Safe Dose (LCL)
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DoseUF
Response
5/10%
0%
Extrapolation Observed
x
x
x
OEL
• No Observed Adverse Effect Level (NOAEL)• Lowest Observed Adverse Effect Level (LOAEL) • Benchmark dose (BMD) • Benchmark dose lower limit (BMDL) • UF = Uncertainty Factor
Confidence LimitConfidence Limit
BMDL
x
x
xNOAEL
LOAEL
BMD
Human Exposure
HQ
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Risk Paradigm Quiz?
• If we had a array of effects that were all linked into one syndrome of toxicity, what would be the point of departure for a dose response assessment?
• If we had only 8 fingers, what would be the uncertainty factor covering experimental animal to human and within-human variation?
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Risk Paradigm: Critical Effect
• Risk assessment is… preventive medicine. Thus, toxicologists, epidemiologists, and clinicians are needed in judgment of critical effect– conduct hazard identifications collaboratively– Focus on effects of medical significance
• Critical effect is… the first adverse effect, or its known precursor, that occurs as dose rate increases (EPA, 2013).
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NAS, 2005. Health implications of perchlorate ingestion
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Risk Paradigm: Uncertainty Factors
• Uncertainty factors for within human variability, experimental animal to human extrapolation, LOAEL to NOAEL, subchronic to chronic, and lack of certain data.
• Misconceptions:– Studies with small “n” are not useful.– The variability of the human population is large; an
uncertainty factor of 10-fold with human data is often not enough.
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Uncertainties to Consider in NoncancerDose Response Assessment
Population Cumulative Response
Concentration (mg/m3)
0.1 UFH
UFS
UFL
UFD
UFA
Human
AnimalSub-chronic
Reproductive
PBPK
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NOAELs or BMDs
LOAELs
H‐human variabilityA‐animal to humanL‐LOAEL to NOAELS‐subchronic to chronicD‐data gap
OEL 11
Dourson, M.L., G. Charnley and R. Scheuplein, 2002
Factor of 10 Enough?
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Factor of 10 Enough?
Human NOAEL or BMDa
Animal NOAEL or BMD
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5b.
Factor of 10 Enough?
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Susceptibility Factors
Internal Dose Factors• Age • Sex • Genetic factors• Preexisting disease
External Exposure Factors• Exposure variability• Individual concurrent exposures
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The Future: Addressing Human Variability:Chemical Specific Adjustment Factor (CSAF)
International Programme on Chemical Safety (IPCS, 2005)
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Intent of the CSAF HKAF• Using the CSAF
– MOA known
– Data in range of exposures
– Data in representative population
– Statistical test (CV)
http://whqlibdoc.who.int/publications/2005/9241546786_eng.pdf17
Gentry, P.R., C.E. Hack, L. Haber, A. Maier and H.J. Clewell, 3rd. 2002. Toxicol Sci. 70(1):120‐39.
Liver
Gas Exchange
RapidlyPerfused
Fat
SlowlyPerfused
Metabolism
QFCA
QRCA
QSCA
QLCA
QP
QC
QFCF/PF
QRCR/PR
QSCS/PS
QL
CL/PL
Cinh Cexh
VMax KM KF
QCCV
Impact of CYP2C9 Polymorphism on Warfarin Dose
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The Future: Epigenetics• Epigenetics – heritable change in gene
expression NOT caused by DNA code
• Epigenetics >> Genetics in variability?
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Frameworks for Consideration
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Kramer et al. CriteriaKramer et al. (2006) developed the following criteria for considering genetic (and epigenetic) information in risk assessment and development of OELs:
• The gene product must be relevant to the pathophysiology of a clearly defined and consistent phenotype (again toxic MOA needed).
• Gene function must be associated with exposure to a regulated-pollutant or, at the very least, to a disease-progression process known to be associated with exposure to the chosen regulated pollutant.
• The mutation (or expression change) must be functionally relevant.• The magnitude or frequency of occurrence in the population must be
measured, and variation across populations (e.g., geography, race) must be considered.
• There must be a high magnitude of association (i.e., preferably a relative risk >1.5) between the phenotype of interest and an adverse health effect.”
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Toxicology 21: Systems Biology-based Toxicology Testing?
• >84,000 chemicals on the Toxic Substances Control Act inventory
• >100,000 chemicals registered in REACH • ~1000 new industrial chemicals and pesticides introduced
to the market annually• Only a fraction of new chemicals are evaluated more than
superficially for human risk…
…because current testing paradigm is slow, expensive, requires large numbers of animals, and involves considerable scientific understanding to develop credible extrapolations.
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The Future: Toxicology 21---Systems Biology-based Toxicology Testing?
The Vision • Cheaper• High throughput• Predictive analyses• Minimize animal testing• Focus on relevant dose levels• More informative and efficient• Characterize human variability• Improve scientific basis of risk assessment• Human cells – minimal interspecies extrapolation
Driving impetus (US) ‐ Toxicity Testing 21st Century: ‐‐ A Vision and a Strategy ‐ (NAS, 2007)
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Biologicinputs
“Normal” BiologicalFunction
AdverseOutcomes
(e.g., mortality, ReproductiveImpairment)
Cell injury,
Inability to
regulate
AdaptiveResponses
Early cellularchanges
Exposure
Uptake-Delivery to Target Tissues
Perturbation
Cellular response pathway
Molecularinitiating event
Perturbed cellular response pathway
Adverse outcomerelevant to
risk assessment
Toxicity Pathway
Adverse Outcome Pathway
Tox 21: Outcome Pathways of NAS
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Some Risk Assessment Uses of Systems Biology
• Hazard characterization:– Hypothesis generation for AOPs/MOAs (maturing)– Hypothesis testing of AOPs/MOAs (developing)– Endpoint identification (immature/developing)
• Dose-response assessment:– Characterize dose-response on biomarker data (developing)– Decreased need for low dose extrapolation (developing)– Reduced extrapolation across species (developing/immature)
• Exposure assessment– Use biomarkers of effect to combine exposures (immature)– High-throughput exposure assessments (EPA’s ExpoCast
program); RAIDAR and USETOX models – immature
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Group Genes by Cellular Function
Fit Each Gene with Statistical
ModelProliferation
Apoptosis
Thomas et al. Tox. Sci. 98:240, 2007Yang et al. BMC Genomics 8:387, 2007
Calculate Dose at which response
significantly deviates from
control (i.e., BMD)
BMR
BMDBMDL
LOAEL
NOAEL
Pa
thw
ay
Tra
ns
cri
pti
on
al
Re
sp
on
se
Dose
Estimate Dose at Which Cellular
Function is Perturbed
Mean +1 SD-1 SD
34.1%34.1%
13.6% 13.6%
+2 SD-2 SD +3 SD-3 SD
Stepwise Process for Estimating Genomic BMD Values
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Thomas et al. (2012 ‐Mutation Research 746:135– 143) found a strong correlation between transcriptional BMDs for specific pathways and traditional BMDs 27
Risk Assessment Needs
• Phenotypic anchoring for clinical, critical, or adverse effects
• Markers for common critical effects, such as decreased body weight & models for specific “icities” – e.g., neurotoxicity
• Address communication among tissues; endocrine effects, in vitro to in vivo extrapolation
• Incorporate metabolism, differences in individuals and durations
• Test volatile chemicals
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Susceptibility Factors?
Internal Dose Factors• Age • Sex • Genetic factors• Preexisting disease
“External” Exposure Factors• Exposure variability• Individual concurrent exposures
– Employment, diet, medications, psychosocial
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Exposure Variability
• Often variability in exposure is large and scenario-based:– Time– Location– Source of contamination– Equipment (e.g., PPE)– Worker and source mobility– Environmental conditions
• Typically estimate:– Mean, Median and UCL – Representative and reasonable worst case
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The Future – Individualized Data• Historically, sparse exposure data - 13% of
epidemiologic studies used quantitative exposure
• Amount and quality of exposure data has been increasing new technology, regulations, and concepts (e.g. biomarkers and the exposome), may promote “putting the E into “G x E” interaction studies”
•• Simple inexpensive direct reading exposure
measurement techniques should allow for a broader and more comprehensive exposure assessment
References [Rappaport and Kupper 2008; Smith and Rappaport 2009]
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The EXPOSOME
“… the measure of all the exposures of an individual in a lifetime and how those exposures relate to disease.”
http://www.cdc.gov/niosh/topics/exposome/
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Trend: Cumulative Risk
• EPA working hard on guidance on multiple exposure routes and stressors– www.epa.gov/ncer/cra/multim
edia/webinars/2013/
• NIOSH Initiatives focus on total exposure– Total Worker HealthTM– Exposome– http://www.cdc.gov/niosh/twh/– http://www.cdc.gov/niosh/topi
cs/exposome/
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Meek et al., 201134
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Contemporary: PBPK
• It is now routine to ask folks whether or not a PBPK model is available for the chemical of interest.
• Numerous PBPK papers; some have been given top awards (RASS of SOT papers of the year):– Sweeney, L. et al. (2001). Proposed occupational
exposure limits for select glycol ethers using PBPK models and Monte Carlo simulation. Toxicol. Sci. 62(1):124-139.
– Kirman, C.R., et al. (2004). Addressing nonlinearity in the exposure-response relationship for a genotoxic carcinogen: cancer potency estimates for ethylene oxide. Risk Anal. 24:1165-1183.
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Contemporary: BMD
• Clear advantages and disadvantages exist in the use of a benchmark dose (BMD)– Uses responses near the range of observation.
– Includes a measure of variability in the response.
– Determines a consistent measure of response.
– Applies to fewer, more robust, toxicity data sets.
– Accounts for more dose response of critical effect
Casarett and Doull (Sixth Edition) page 94
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Contemporary: Categorical Regression
RfD Definition Regression model
"without appreciable risk" r < 10‐2
"is likely to be" P(*) > 0.95"deleterious effect" severity = moderate or frank
New RfD Definition
P ( r < 10‐2 at dose<RfD ) > 0.95 where r = P (severity >1)
Hertzberg R.C. and M.L. Dourson, 1993
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Contemporary: Categorical Regression
• Advantages:– provides a consistent basis for calculating risk above
the RfD– all useful data can be categorized– accounts for severity of toxic effect
• Limitations:– animal to human extrapolation is still needed– data are transformed into categories which loses
informationHaber et al. 2001. Patty’s Toxicology, Volume 1 (Fifth Edition) pages 209‐213
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Expedite the Future: Open Collaborative R&D
• Occupational Alliance for Risk Science (OARS)
• Alliance for Risk Assessment (ARA) – Risk Information Exchange (RiskIE) – International Toxicity Estimates for Risk (ITER)
• Beyond Science and Decisions: From Problem Formulation to Dose Response
• Mixtures and Combined Exposures • Peer Review
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Alliance for Risk Assessment (ARA)(www.allianceforrisk.org)
States, Fed. Agencies,
Public Interests, Industry
Initiation ofRisk Issue
Document Draft
PeerReviews
Release toPublic
Risk DocumentDevelopment
Peer Review &Consult
Risk ResearchAnd Tools
Training andCertification
Non-profitCollaborators
ARA ProcessStakeholder Process
RiskCommunication
SteeringCommittee
Risk Information Exchange (RiskIE)
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“Beyond Science and Decisions: From Problem Formulation to Dose Response” 37 case studies
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BackgroundRange
Increasing Dose
BeneficialEffect
A Variety of Possibilities Essentially (– –), Hormesis (–), Toxicity (---)
Nonmontonic (red)
AdverseEffect
Wherein lies endocrine disruption?
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Summary
• Defend traditional risk methods; practice contemporary methods; harmonize at every opportunity
• Develop individual & cumulative exposures, measures of susceptibility, & data for genomics and 21st century toxicology so as to improve the biological basis of OELs and lead to more credible management decisions.
• Expedite the future thru collaboration
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EXTRA SLIDES
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http://www.who.int/ipcs/methods/harmonization/en/
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Inflammatory Cell Proliferation(Macrophages, PMN, etc.)
TiO2 Lung Burden
Change in Alveolar Air:Blood Barrier /Loss of Integrity
(Proteins in BALF)
Cell Proliferation(BrdU labeling)
Fibrosis (Incidence)
Tumor(Incidence)
TiO2 Tumor Progression
Biologically-Informed D-R Modeling
Allen et al., in preparation
What we used to do!
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Key Limitations in TK• How to assess the relative contribution of
different enzyme systems,• Reconciling differences between in vitro and in
vivo data– Role of other rate-limiting factors– Impacts of epigenetics
• The lack of toxicokinetic data for many allelic variants, and
• The effect of co-exposures which could lead to either induction or inhibition.
Haber et al. (2002)
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The Future: Subpopulations
• Increasing focus on aging workforce
• Increasing focus on Children’s risk– EPA FQPA Factor– California Children’s
Risk Guidance
• Plus – a host of other susceptibility factors (background disease, etc.) http://www.epa.gov/risk/guidance.htm
http://www.cdc.gov/niosh/updates/upd-12-01-09.html
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Reference Results
Renwick (1998)
Child kinetic within factor < 3.16 in 19/22 chemicals, < 5 for 22/22
Naumann and Faria
Child kinetic within factor of 3.16 for 3/3
Rane (1992)10-14 chemicals, newborn poorer at clearance; tk factor of 3.16 covers 71%
Skowronski and Abdel-Rahman (2001)
5/6 chemical, kinetic factor <3.16
Calabrese (1986)
Animal adult; young LD50 ratios, 86% of chemicals covered by total factor of 10
0.1 1.0 10.0
Alfentanil
Aztreonam
Busulfan
Ceftibuten
Chlorpheniramine
Ciprofloxacin
Digoxin
Ganciclovir
Methotrexate
Theophylline
Trichloroethanol Glucuronide
Che
mic
al
Ratio of Child to Adult Value (1 Indicates Unity)
Dourson, M.L., G. Charnley and R. Scheuplein, 2002
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(Epi)Genetics for Risk
• Growing but limited data (e.g. GWAS)• Mode of action and adverse outcome pathways• Assessing gene-environment interaction is the
foundation • Design studies to maximize information on both
genetic and epigenetic variation • Use of genetic and epigenetic data requires
attention to ethical, legal, societal, and political implications. Schulte et al. 2014
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Adapted from Schulte (1989); Farland et al. 2000
ExposureInternal
DoseEffective
Dose
EarlyBiological
Effect
AlteredFunction:Critical Effect
ClinicalDisease
Exposure Effect
Susceptibility
Water Perchlorate
Blood Perchlorate
Perchlorate uptake in thyroid
Altered T3, T4, TSH
Thyroid Histopathology
TumorsCNS
Tox 21: The Black Box Revealed
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Statistically significant
Tox 2: Biomarkers of Effect
The authors think this argues against a hormone MOA, but does it?
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Mixture RfD/RfC;
Slope Factor
Interaction-BasedHazard Index,
Interaction Profiles,Weight of Evidence,
PBPK Models
RelativePotencyFactors
HazardIndex
ResponseAddition
Whole Mixture Data Available
SufficientlySimilarMixture
WholeMixture
of Concern
ComponentData Available
ToxicologicallySimilar
Components
ToxicologicallyIndependentComponents
Epidemiological Evaluations,
Toxicity Profiles
Dose Addition
Mix of Toxicologically
Similar & IndependentComponents
IntegratedAdditivityMethods
Health Evaluations
HazardQuotient;
Risk Estimate
Index Chemical-Based Risk Estimate;
Hazard Quotient
Risk Estimate
Available Interactions
Data
Whole Mixture Exposure Assessment Component Exposure Assessment
Flow Charts for Evaluating Chemical Mixtures
EPA, various references54
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RiskIERisk Information Exchangewww.allianceforrisk.org/RiskIE.htm
• An interactive Database to Communicate In-Progress Risk & Toxicity Assessments
• Includes over 7800 projects being conducted by more than 30 organizations representing 15 countries
• Available at the Alliance for Risk Assessment (ARA) website
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• Provides chronic human health risk values and cancer classifications from organizations around the world for over 650 chemicals, including values from journal publications after quality assurance
• Includes synopsis on the underlying basis and rationale for each risk value and differences in risk values
• Links to each organization’s website or source document
• - A forum through which independent parties can share - their peer reviewed risk values after peer review
www.tera.org/ITERhttp://toxnet.nlm.nih.gov
ITERInternational Toxicity Estimates for Risk
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Advancing Risk Assessment: Integrating Committee Recommendations• Problem formulation should be linked to risk management;
doing so does not “pollute” the risk assessment science• The “safe” dose concept has evolved; CSAFs should be
used• Mode Of Action (MOA) is the assessment’s organizing
principle, but integrate key events in dose-effect continuum• Key dose-dependent transitions are the norm;
understanding MOA is essential for dose response• Cumulative risk and mixtures assessment is iterative and
should focus on the lowest tier needed to understand risk• Biomonitoring is now interpretable; communication essential
Dourson, Becker, Haber, Pottenger, Bredfeldt, and Fenner‐Crisp (Crit Rev Toxicol, 2013; 43(6): 467–492)
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Risk Assessment Peer Review
• Cornerstone principles– Scientific robustness – Selection of
appropriate panel expertise & chair
– Transparency– Independence
• Distinguish conflict-of-interest from bias – Avoid COI – Balance biases
• Rule of thirds; ~1/3 of the panel should be – Experience risk
assessors– Chemical or related-
chemical experts– Effect experts
• Balanced affiliations
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