UC RASS 2 - Dourson Risk Assessment Seminar Series 12/18/2015 2 ... Impact of CYP2C9 Polymorphism on Warfarin Dose 18. UC-DEH Risk Assessment Seminar …

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

1

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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Human NOAEL or BMDa

Animal NOAEL or BMD

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5b.


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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

NAS, 2007 24


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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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Documents

UC RASS 2 - Dourson Risk Assessment Seminar Series 12/18/2015 2 ... Impact of CYP2C9 Polymorphism on Warfarin Dose 18. UC-DEH Risk Assessment Seminar …