Risk-Based Decision Making in Public and Population Health

Office of Research and Development National Center for Computational Toxicology

EXPOSURE ASSESSMENT AND FUTURE DIRECTIONS IN EXPOSURE SCIENCE

Risk-Based Decision Making in Public and Population Health

Office of Research and Development

E L A I N E C O H E N H U B A L U S E P A , N A T I O N A L C E N T E R F O R C O M P U T A T I O N A L T O X I C O L O G Y

Disclaimer. Although this work was reviewed by EPA and approved for

presentation, it may not necessarily reflect official Agency policy.

May 30, 2012


Exposure Assessment


Purpose of Exposure Assessment

2

SOURCE / STRESSOR

FORMATION

TRANSPORT/

TRANSFORMATION

ENVIRONMENTAL

CHARACTERIZATION

EXPOSURE

DOSE

•Individual

•Community

•Population

ADVERSE

OUTCOME EXPOSURE

MODELS

PBPK

MODELS

TRANSPORT, TRANSFORMATION,

and FATE PROCESS MODELS

ACTIVITY

PATTERN


Exposure in Risk Assessment and Management

3

www.isesweb.org

http://www.isesweb.org/


Exposure Assessment

• Exposure is the contact between a stressor and a human or ecological

receptor.

• Risk analysis step in which receptor interaction with the exposure

stressor of concern is evaluated.

• To assess exposure to a particular stressor we need to know

– Properties of the stressor

– Sources, pathways, routes

– Pattern of exposure (magnitude, frequency, duration, location)

– Characteristics of receptor

• Sometimes we can measure exposure directly

• Often we need to estimate exposure

4


Problem Formulation

• Scope of assessment

– Scale (national, site specific, far-field, near-field)

– Receptor (vulnerable life stages and groups)

• Conceptual model

– Guide for collection of exposure data and other required information

– Traditionally, follow source-to-effects paradigm

– Shift to target-oriented view

5


Exposure Assessment Approaches

• Questionnaire based metrics (epidemiology)

• Surrogate exposure metrics (ambient measures)

• Exposure measurement (direct or point-of-contact)

• Biomonitoring (dose reconstruction)

• Modeled estimates (indirect or scenario evaluation)

• Often used to conduct risk assessments required to make regulatory

decisions.

6


Exposure Data and Models

• Exposure measurement data

• Exposure media concentrations

• Exposure factor data

– Contact rates of target with

exposure media

– Contaminant transfer efficiency

– Contaminant uptake rates

through portal of entry

– Human activities

7

• Aggregate models

• Dietary models

• Waste Site models

• Consumer product models

• Air models

• Occupational models


Source •indoor residential

•outdoor

residential

•consumer

products

•industrial

•agricultural

•occupational

Outdoor •air

•water

•soil

•plants

•surfaces

•consumer

products

Indoor •air

•water

•house dust

•food

•surfaces

•consumer

products

Exposure

Media

Release

&

Transfer

Respiratory

Tract

Inhalation

Exposure

Rate

Skin Surface

Dermal

Exposure

Rate

G.I. Tract

Ingestion

Exposure

Rate

Target

Absorbed

Dose

Activity

Patterns

Contact

Activities

Mouthing

Activities

Diet

Ingestion

Rate

Uptake

Rate

Inhalation

Rate

Inhalation

Mass

Transfer

Rate

Mouthing

Activities

Ingestion

Rate

Ingestion

Rate

Uptake

Rate

Uptake

Rate

Dermal Contact

Nondietary

Ingestion

Dietary Ingestion

Exposure

R.T. Uptake

Dermal Uptake

G.I. Uptake

Cohen Hubal et al. 2000 JEAEE

Children’s Residential Exposure to Pesticides


Receptor

Individual, Community,

Population

Sourcei

Exposurei Dosei

Environmenti

Source2

Exposure2 Dose2

Environment2

Source1

Exposure1

Dose1

Environment1

OutcomeA

OutcomeZ

Early Effecta

Altered

Structure

Functiona

Early Effectb

Early Effectz

Altered

Structure

Functionb

Altered

Structure

Functionz

Developmental

Stage

Genetic

Susceptibility

Health

Status

OutcomeB

Adapted from Ryan et al. EHP

Receptor Oriented Model


Future Directions in Exposure Science


Future Challenges for Exposure Science

• Sustainability: Improve the health of individuals and communities

today without compromising the health and welfare of future

generations

• Risk analysis: Incorporate exposure science more effectively and

efficiently into decisions

• Prevention: Shift from treatment to prevention of diseases through

improved understanding of the role of environmental factors in

etiology of disease

Hubal et al., JESEE 21:119, 2011

11

Office of Research and Development National Center for Computational Toxicology 12 12

Human Relevance/

Cost/Complexity

Throughput/

Simplicity

High-Throughput Screening Assays

10s-100s/yr

10s-100s/day

1000s/day

10,000s-

100,000s/day

LTS HTS MTS uHTS

batch testing of chemicals for pharmacological/toxicological

endpoints using automated liquid handling, detectors, and data

acquisition

Gene-expression

Office of Research and Development National Center for Computational Toxicology 13

Toxicity Testing in the Twenty-first Century:

A Vision and a Strategy

• Key aspect of the NRC vision is that new tools are available to examine

toxicity pathways in a depth and breadth that has not been possible

• An explosion of high-throughput-screening (HTS) data for in vitro toxicity

assays will become available over the next few years ---- Data are

available now!

How will this new toxicity

information be integrated

with exposure information

to assess potential for real-

world human health risk?

NAS, June 2007.


Stressor

Biological

Receptor Outcome Perturbation Perturbation

Population

Individual

Tissue

Cell

Biological

Molecules

Environmental

Source Ambient

Exposure Environmental

Source Personal

Exposure

Internal Exposure

(Tissue Dose)

Dose to Cell

Dose of Stressor

Molecules

Disease

Incidence/Prevalence

Disease State (Changes to Health Status)

Dynamic Tissue Changes (Tissue Injury)

Dynamic Cell Changes (Alteration in Cell Division,

Cell Death)

Dynamic Changes in

Intracellular Processes

Cohen Hubal, JESEE, 2008

Comp Tox: Exposure at All Levels of Biological Organization


Susceptibility

(Genetic Variants / Epigentic Modifications)

Improved Measures of Individual Etiological

Processes and Individual Exposures

Key Perturbations

Key Targets

Personal Risk Profile

Extrapolation for

Risk Assessment

Biomarkers

Indicators Metrics

Public Health Policy

Prevention

Education

Personal Risk

Management

Information

Biological Insight

(Toxicity Pathways) Environmental Factors

(Exposure)

Cohen Hubal, et al. JTEH, 2010

Exposure for Decision Making


ExpoCastTM: Exposure Science for

Prioritization and Toxicity Testing

• Recognizes critical need for exposure information to inform

– Chemical design and evaluation

– Health risk management

• Goal

– Advance characterization of exposure required to translate findings in

computational toxicology to support exposure and risk assessment

– Together with ToxCast™ help EPA determine priority chemicals

• Approach

– Mine and apply scientific advances and tools in a broad range of fields

– Develop novel approaches for evaluating chemicals based on potential for

biologically-relevant human exposure


August 26, 2010

Select doses for

toxicity testing

Relate real-world exposures with

toxicity pathway perturbations Translate in vitro results

for risk assessment

Exposure

Human Environment

Biomonitoring

Population

N

N N

NH NH

Cl

Products

Sources

Chemicals

Host

Susceptibility

Biotransformation

Rapid

Prioritization

Exposome Informatics

Approaches

Network

Models

Knowledge

Systems

Mechanistic

Models

Data

Repositories

N

N N

NH NH

Cl

Toxicity

endpoints

In vivo

bioassays

HTS assays

Distribution/Fate

Office of Research and Development National Center for Computational Toxicology 18 18 18

H E H E H E

H E H E

H E

H E H E

H E H E H E

H E

Low exposure potential High exposure potential

H E H E

H E

ToxCast Hazard Prediction

Intelligent, Targeted Testing

Prioritization:

Using Hazard and Exposure Information

Human Biomonitoring

ToxCast Low

Hazard

Prediction Low Priority for

Bioactivity Profiling

ToxCast targets

Lower Priority for

Testing and Monitoring

High Priority

Low Priority


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)



for Dose

that Activates

Biological Pathway

BPADL

Pharmacodynamics Pharmacokinetics

Judson et al, CRT (2011)

High-Throughput

Risk Assessment


Biological Pathway Altering Dose (BPAD)

Conazole / CAR/PXR results

20

LEL, NEL

BPAD Range

Exposure estimate

NEL/100

Judson et al, CRT (2011)


Prioritization: Recent ExpoCast Activities

• Data Access

– Incorporating and Linking Exposure

Information into ACToR

– ExpoCastDB

• Mining

– Integrated Chemical Prioritization Scheme

– Partnering to Develop Exposure Indices for

Rapid Prioritization of Chemicals in

Consumer Products

– Intake Production Ratio

• Modeling

– Prioritization Model Challenge

– High Throughput Exposure Estimates

– Rapid modeling of SVOC exposure in

indoor environment

Chemical

properties

Pathways

In vitro

assays

Exposure

Tabular

Data,

Links to

Web

Resources

Chemical ID,

Structure Chemical

Internet

Searches

ACToR API

ToxRefDB ToxMiner ExpoCastDB

In Vivo

Study Data

ToxCast Data

– Exposure

Data –

ACToR Core


22

ACToR: Aggregated Computational Toxicology

Resource

Tabular Data,

Links to Web

Resources

Chemical

ID,

Structure

Chemical

Internet

Searches

ACToR API

ToxRefDB

http://actor.epa.gov/

ToxMiner ExpoCastDB

In Vivo Study

Data - OPP

ToxCast Data –

NCCT, ORD,

Collaborators

(Currently

Internal)

Exposure Data –

NERL, NCCT

(Just Released)

ACToR Core

http://actor.epa.gov/


Generic_chemical

table in ACToR 1

Measure

(Chemical)

Laboratory method

N

1

Sample

N N

N

1

N N

Subject

N

N

Exposure

Taxonomy

(Assay_

category_

CV table

in ACToR)

N

N

Location

Location_CV

(cont vocab.)

Study Sources

N

N

N

N

N

N

N

N

N

1

N

1

N

N

N

1

N N

N

N

N

N

Study_CV

cont. vocab

1

ExpoCastDB

v0.5

N

N

N

N

Sumit Gangwal, et al. NCCT

Medium

(serum, air, soil, etc.)

Technique /

sampling method


Rationale for an integrated chemical

prioritization scheme

A numerical index that can be used for ranking (instead of absolute

thresholds) is more flexible for different prioritization tasks.

Can better accommodate new data, new chemicals, data adjustments, etc.

ToxPi (Toxicological Priority Index) • Integration over multiple domains

of information

• Extensibility to incorporate

additional types of data

• Transparency in score derivation

and visualization

• Flexibility to customize

components for diverse

prioritization tasks

Chemical

properties

Pathways

In vitro assays

Exposure

Reif et al., 2010, Environ. Health Perspect.

Putative endocrine profiles


Incorporating Exposure Information: ToxPi Endocrine Scores

Previous top 15 prioritized chemicals by

overall ToxPi score

AR

TR

Log P

ER Other NR

Other XME/ADME

CaCO-2

KEGG path Ingenuity

path Disease classes

BCF/BAF

Persistence

New top 15 prioritized chemicals with

exposure domain

#16 #27 #29 #23 #17

AR

TR

Log P

ER Other NR

Other XME/ADME

CaCO-2

KEGG path

Ingenuity path

Disease classes

BCF/BAF

Persistence

Slide 25



Comp Tox: Recent ExpoCast Activities

• Inform Design of Toxicity Testing

– Selecting Doses for ToxCast In Vitro Testing –

Nanomaterials

– Application of Biogeographical Methods to

Chemical Co-Occurrence Data to Identify

Priorities for Mixture Research

• Translate in vitro Results for Risk Assessment

– Combining ToxCast, Dosimetry and Exposure

– ExpoDat2012: Exposure determinants for high

throughput risk assessment (HTRA)

• Relate Real-World Exposures with Tox

Pathway Perturbations

– ExO: An Exposure Ontology

27

Diseases

Genes

(Stressor) Chemicals

chemical-disease

relationships

chemical-gene

interactions

gene-disease

relationships

Receptor

Exposure (Time,

Location)

La

cto

fen

Dit

hio

py

rA

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azin

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hlo

rpro

ph

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zin

on

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los

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bin

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ab

en

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rop

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Ox

ad

iazo

nC

ou

ma

ph

os

Te

tra

co

na

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be

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arb

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me

tsu

lam

Pro

py

za

mid

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tyl

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tha

late

Me

so

su

lfu

ron

-me

thy

lA

me

try

nC

yc

loa

teF

en

itro

thio

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ex

yth

iazo

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riti

co

na

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eth

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yfe

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luro

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uty

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Pe

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ulf

uro

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rox

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cil

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zin

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thio

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0.00001

0.0001

0.001

0.01

0.1

1

10

100

1000

10000

100000

Compound

Ora

l E

qu

ivale

nt

Do

se o

r E

sti

mate

d E

xp

osu

re

(mg

/kg

/day)

Wetmore et al, 2011, Tox Sci


Comp Tox: Selecting Doses for ToxCast Nano Pilot

28

Gangwal et al. 2011, Environ Health Perspect


Exposure Ontology, ExO: Definitions of Central Concepts

• Exposure Stressor - An agent, stimulus, activity, or event that causes

stress or tension on an organism and interacts with an exposure receptor

during an exposure event.

• Exposure Receptor - An entity (e.g., a human, human population, or a

human organ) that interacts with an exposure stressor during an

exposure event.

• Exposure Event - An interaction between an exposure stressor and an

exposure receptor.

• Exposure Outcome - Entity that results from the interaction between an

exposure receptor and an exposure stressor during an exposure event.

29

Mattingly et al, EST, 2012


Exposure Event

Exposure Outcome

Exposure Stressor

Exposure Receptor

Biolog. Agent

Chem. Agent

Biomech. Agent

Phys. Agent

Psychosoc. Agent

Public Policy

Inter- vention

Biolog. Response

Anthro- sphere

Disease

Symptom

Molecular Response

•Location •Temporal Pattern •Intensity •Route •Assay

•Medium •Method •Location

Human Pop.

•Location •Genetic Background •Lifestage •Health Status •Socioeconomic Status •Occupation

•Source •Location •Process

•Transport Path

Individual

Relational View of Selected ExO Domains

Mattingly et al, 2012, EST


Exposure Outcome

Phenotype

(e.g., OMIM, MeSH)

Chemical

(e.g., MeSH)

Biological System

(e.g., Functional model of

anatomy)

Assessed by

Pathways, Networks Reactions

(e.g., KEGG, Reactome)

Occur within

Genes Gene

Products

Biological Process Molecular Function Cellular Component (e.g., Gene Ontology

Interact via

Encode

Annotated with

Exposure Stressor

(e.g., ExO)

Exposure Receptor

(e.g., ExO)

Is a

Interacts with

Exposure Event

(e.g., ExO,

ExpoCastDB)

Via an

Results in an

Interacts with

(e.g., CTD)

Interacts with

(e.g., CTD)

Is a

Mattingly et al, EST, 2012

High-level schematic of Exposure Ontology (ExO) integration

within a broader biological context.


Customized Dashboards for Programs

EPA Data

Warehouse

Public Domain

Repositories

Biomedical

Literature

Decision

Analysis Tools

Predictive

Modeling

Tools

Web-services

Knowledge-base

(KB)

Ontology

Decision

Support

Dashboards

Analysis

Workbench

Analysis

Workflows

Web-based Visual Analytics

Knowledge Management and Decision Support Tools

For EPA Chemical Safety for Sustainability Research


Knowledge Management and Decision Support Tools for CSS

• Data Management Warehouse (e.g., ACToR)

– federate raw data generated by CSS/EPA and available in the public domain on:

chemical structure, production, environmental fate, human use, ecological and

health effects, exposure, etc.

• Ontologies for Interoperability

– publicly available ontologies will be used to specify the semantics to integrate

experimental data from multiple sources, as well as the inputs and outputs of

diverse predictive tools (e.g. empirical models, pathway analysis, systemsmodels,

etc.).

• Knowledge-based management system (KB):

– Develop KB systems that use the above ontologies to acquire, organize, store and

share the complex information flows across diverse CSS activities on chemical

inherency, production, exposure, hazard, pathways and sustainability metrics.


EXPOSURE ASSESSMENT: KEY MESSAGES

• Exposure is the contact between a stressor and a human or ecological receptor.

• Exposure Science is the bridge between the sources of chemical, physical and biological agents and human health

• Exposure Science provides crucial information to estimate real-life risks to health and to identify the most effective ways to prevent and reduce these risks.

www.isesweb.org

http://www.isesweb.org/


FUTURE DIRECTIONS IN EXPOSURE SCIENCE: KEY MESSAGES

• Sustainability: Improve the health of individuals and communities today without compromising the health and welfare of future generations

• Risk analysis: Incorporate exposure science more effectively and efficiently into decisions

• Prevention: Shift from treatment to prevention of diseases through improved understanding of the role of environmental factors in etiology of disease

Hubal et al., JESEE 21:119, 2011

Documents

Risk-Based Decision Making in Public and Population Health