human health risk assessment: epa’s current challenges and the future stan barone jr., phd.,...

Human Health Risk Assessment: EPA’s Current Challenges and the Future

Stan Barone Jr., PhD.,National Center for Environmental Assessment

Office of Research and Development

United States Environmental Protection Agency

Presentation for the

National Capital Area Chapter - Society of Toxicology“Challenges and Opportunities in Putting High-Throughput Chemical Risk

Characterization Into Real-World Practice”April 19, 2011Washington, DC

Office of Research and DevelopmentNational Center for Environmental Assessment

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Human Health Risk Assessment

• Now and in the future, risk assessment remains fundamental to U.S. EPA’s approach to analysis of potential risk from exposure to environmental contaminants

• Essential for U.S. EPA regulatory decision-making

• Evolving in the face of new understandings about uncertainty, mode of action, metabolism, susceptibility, etc.

• Addressing emerging science and new science challenges

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Table 4-31. Noncancer effects in animals repeatedly exposed to chemical x by the oral route

Reference/species

Exposure (mg/kg-

day)

NOAEL LOAEL

Effect(mg/kg-day)

Burek et al., 1980F344 rat, M&F

0, 0.05, 0.2, 1, 5, or 2090 days in DW

0.21555

15202020

Degenerative nerve changes Degenerative nerve changesHindlimb foot splayDecreased body weight Atrophy of testes & skeletal muscle

Johnson et al., 1986F344 rat, M&F

0, 0.01, 0.1, 0.5, or 2.02 years in DW

0.520.50.52

2ND22ND

Degenerative nerve changes (LHindlimb foot splayDecreased body weight Early mortality after 24 weeksOther nonneoplastic lesions

Friedman et al., 1995F344 rat, M&F

0, 0.1, 0.5, or 2.0 (M)0, 1.0, or 3.0 (F)2 years in DW

0.5(M)1.0(F)2.0(M)3.0(F)

2.0(M)3.0(F)NDND

degenerative nerve changes (LDecreased body weight (8–9%)Early mortality after 60 weeksOther nonneoplastic lesions

• Large number of animals• Low throughput• Expensive• Time consuming• Pathology endpoints• Dose response extrapolations over a wide range• Application of uncertainty factors• Little focus on mode of action and biology• Few epidemiology studies

Current Approach

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Basic Principles of Risk Assessment at EPA

• The starting point for risk assessment is a critical analysis of available scientific information.

• Quantitative estimates of risk are, to the extent possible,

– Biologically-motivated,

– Data-driven.

• When there is insufficient data, default methods are used that

– Protect public health,

– Ensure scientific validity (i.e., scientifically plausible and extensively peer reviewed), and

– Create an orderly, transparent and predictable process.

• Implementation of these principles involves extensive independent peer review.


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Human Health Risk AssessmentTransforming to address emerging science

and new science challenges

• There are tens of thousands of chemicals that are untested and lack assessment of potential for human toxicity.

• Current toxicology testing methods are too expensive, too slow, and can cope with too few chemicals.

• Toxicology approaches are evolving away from reliance on in vivo testing of laboratory animals

• Current approaches to risk analysis need to be significantly modified to deal with more chemicals; innovative approaches

– Screening– Fingerprinting

• Risk assessment approaches must be developed that can use the new generation of data types and arrays; “omics”

• Thus, the environmental health community needs to develop next generation of risk assessment tools, approaches, and practices…NexGen risk assessment

– Toxicity pathways– Focused high-throughput assessments


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Human Health Assessment IssuesMechanistic Considerations in

Human Health Risk Assessment

• Increased need to characterize:

– A wider array of hazard traits

– More chemicals (no data on most chemicals in commerce)

• Human carcinogens increasingly emphasis on:

– Multiple toxicity pathways, mechanisms affected

– These mechanisms could inform new predictive approachesIn vitro assaysHuman biomarkers

• Dose-response curve:

– In an individual: can take multiple forms depending on genetic background, target tissue, internal dose

– In a population: variability in susceptibility in response are key determinants

Source: Guyton et al. Improving prediction of chemical carcinogenicity by considering multiple mechanisms and applying toxicogenomic approaches. Mutat Res. 681(2-3):230-40, 2009.

What Can Be Learned from Mechanistic Data and Analyses?

• Identify mechanism-based sources of human variability/ susceptibility (e.g., background diseases and processes, genetic polymorphisms, age, co-exposures)

• Address mechanism-based likelihood of other outcomes

• Improve prediction of interactions across environmental and endogenous exposures

• Identify mechanistic drivers of response at low-doses

An individual’s dose response

BackgroundExposure:

Endogenous& Xenobiotic

Heterogeneity in BackgroundExposure and Susceptibility

Population dose response

Environmental Chemical Dose

Environmental Chemical Dose

Probability ofEffect from

EnvironmentalExposure

Fraction ofPopulation

Responding toEnvironmental

Chemical

EnvironmentalChemical Stressor

Adverse endpoint

BiologicalSusceptibility:

Health and DiseaseStatus, Genetics,

Age, Gender

Source: National Academy of Sciences Report “Science and Decisions: Advancing Risk Assessment” Adapted from Figure 5-3a (December 2008)

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• Increases appreciation of individual and population heterogeneity of disease mechanisms

• Improves prediction of interactions across environmental exposures

• Addresses mechanism-based likelihood of other outcomes

• Identifies mechanism-based sources of human variability/susceptibility (e.g., background diseases and processes, genetic polymorphisms, age, co-exposures)

• Uses Systems biology level tools and data

• Advances high throughput methodologies (microarray, proteomics)

• The use of mechanistic data will play a key role in the future of risk assessment to:– Aid in identification of sources of human variability/susceptibility (e.g., background diseases and

processes, co-exposures, etc) and early stage disease biomarkers.

– Address likelihood of other outcomes

– Improve prediction of interactions across environmental and endogenous exposures

– Indentify mechanistic drivers of response at low doses.

Focus on Mechanisms of Human Disease


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Human Relevance/ Cost/Complexity

Throughput/ Simplicity

High-Throughput Screening Assays(EPA’s National Center for Computational Toxicology,

Office of Research and Development)

10s-100s/yr

10s-100s/day

1000s/day

10,000s-100,000s/day

LTS HTSMTS uHTS

batch testing of chemicals for pharmacological/toxicological endpoints using automated liquid handling, detectors, and data acquisition

Gene-expression


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Future of Toxicity Testing

Bioinformatics/Machine Learning

in silico analysis

Cancer

ReproTox

DevTox

NeuroTox

PulmonaryTox

ImmunoTox

HTS -omics

in vitro testing

$Thousands


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Toxicity Pathways

Receptors / Enzymes / etc.Direct Molecular Interaction

Pathway Regulation / Genomics

Cellular Processes

Tissue / Organ / Organism Tox Endpoint

Chemical

ToxCast in vitro HTS assays

• Cell lines– HepG2 human hepatoblastoma– A549 human lung carcinoma– HEK 293 human embryonic kidney

• Primary cells– Human endothelial cells– Human monocytes– Human keratinocytes– Human fibroblasts– Human proximal tubule kidney cells– Human small airway epithelial cells

• Biotransformation competent cells– Primary rat hepatocytes– Primary human hepatocytes

• Assay formats– Cytotoxicity– Reporter gene – Gene expression– Biomarker production– High-content imaging for cellular phenotype

• Protein families– GPCR– NR– Kinase– Phosphatase– Protease– Other enzyme– Ion channel– Transporter

• Assay formats– Radioligand binding– Enzyme activity– Co-activator recruitment

Cellular Assays

Biochemical Assays

Assays(n = 467)

Chem

icals

(n

= 3

20)

http://www.epa.gov/ncct/toxcast/Judson et al EHP (2010)

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Signature Derivation for Rat Liver Carcinogens

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Virtual Tissues, Organs and Systems: Linking Exposure, Dosimetry and Response

LiverInjury

Tissue Morphology changes

Cell Fate Transitionsdeath /division

Molecular Network Structure & Dynamics

Molecular interactions & fluxes

Intra/inter- cellular signaling/ fluxes

Cell spatial interactions

Lobular / vascular damage


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Challenges and Opportunities

Extrapolation from in vitro to in vivo

Recapitulation and modeling of complex cell-cell and tissue interactions.

Development of virtual models to describe systems biology

Recapitulation of complex behaviors


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• A pilot implementation of a new approach for risk based decision-making, including characterization of risk management needs, policy relevant questions and implications for NexGen risk assessments;

• An operational scale knowledge mining, creation and management system to support risk assessment work and interface with gene environment data bases.

• Develop approaches using HT/HC data for toxicity pathways to predict/estimate points of departure for assessment purposes.

• Prototype examples of increasingly complex assessments responsive to the risk context and refined through discussions with scientists, risk managers, and stakeholders.

This strategy focuses on development of:

Screening/Ranking

Tier 110,000s of chemicals

Limited decision-making Regulatory decision-making

Increasing Weight of Evidence

NexGen Types of DataNexGen Types of Data

High Throughput

Molecular Mechanisms of Action

• In vitro only bioassay batteries (~73-500 assays)

Network/disease pattern recognition

Metabolism or surrogates

QSAR• Anchored to in vivo data• Bioinformatic data integration

+High Content/Med Throughput

Adds Tissue/Organism Level Integration

• Short-term in vivo exposures with in vitro assaysMammalian speciesAlternative species

• Primary tissue culture• In silico virtual tissues• In vivo or anchored to in

vivo data• Bioinformatic data &

knowledge integration

+High Content, Med/Low Throughput

Adds Most Realistic Scenarios

• Molecular epidemiology & clinical Studies

• Molecular biology + traditional animal bioassay

• Environmental exposures • Upstream & phenotypic outcomes

• Mechanism of action for multiple stressors

• Knowledge integration

Tier 21000s of chemicals

Tier 3100s of chemicals

Goals1. Rank/ group chemicals2. Assessment of high

priority chemicals

Are there existing assessments (hazard id & dose response), based on in vivo data, that can be utilized?

Are there in vivo data toinform qualitative hazard?

Decision Framework for Incorporating High Throughput Data

YES

YES

NO

Are there non-in vivo data to inform qualitative hazard?

Overall WOE for hazard

NO

YES

Assemble WOE by:•Proximity to in vivo condition: tissue explants>cells in culture > cell-free assays>in silico•Traditional WOE criteria e.g. multiple studies/laboratories, multiple dose-response.

NO

Use (Q)SAR and read-across to predict estimates of risk based on surrogate(s)

and/or

Relative potencies and/or dose-response

YES

NO

Identify thechemicals of interest, exposure sources and pathways.

What tissues/cell types/toxicitypathways are affected by thechemical in question?

Conduct literature search to determine if new data will significantly alter existing assessment; update if needed.

Use existing assessments to anchor in vitro /in silicoanalyses, if appropriate.

• ToxCast/ToxPi and reverse dosimetry

• Predictive Phenotyping • Traditional DR modeling

(w optional test data)

Is data sufficient to determine relative potencies or dose-response?

Assess dose-response:• Conduct high throughput

testing with a battery of assays

• Conduct alternative species &/or targeted in vivo testing (optional)

Conduct high throughput testing with a battery of assays, alternative species

• ToxCast/ToxPi and reverse dosimetry

• Predictive Phenotyping • Traditional DR modeling

(w optional test data)how

how

Incorporating CSS/Next Generation of Risk Assessment (3-5 yrs)Three Assessment Tiers—

Informed by Molecular & System Biology - Responsive to Risk Context

Flagged for

Additional Analysis

Tier 1 Assessments• Screening &

prioritization• Unknown hazard

but exposures• Thousands of

chemicals• High-throughput &

QSAR-driven• Minimize false

negatives

Decision-making

Testing NTP, REACH, TSCA,

etc.

Input to Decision-making

Testing, Research, Assessment Loop

Tier 2 Assessments• Narrow scope decision-

making• Limited hazard &/or

exposures• Many chemicals

(hundreds of chemicals)• High-and medium

throughput assays & some systems level integration

• Science-based defaults & upper confidence limit risk estimates

Tier 3 Assessments• Broad scope, major

regulatory decision-making

• Highest national hazard & exposures

• Few chemicals (dozens)

• All feasible, policy-relevant emerging & traditional data

• Best estimates of risk & uncertainty analyses

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Research by NCCT, ORD labs, & partners

Predictive

Systems Models

PPRTV’s & IRISSuperfund tech center & PPRTV’s

IRIS, ISA’s & Multi-Pollutant Assessments


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Toxicity Pathways in Prioritization

Toxicity Pathways inRisk Assessment

Institutional Transition

The Path to 21st Century Toxicology

0

10

20

30

40

50

60

70

2010 2015 2020 2025

Screening/Prioritization

Toxicity Pathways in RiskAssessment

Institutional Transition

The Future of Risk AssessmentSummary

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• The landscape of risk assessment is changing to an extent that significant modernization of risk assessment is necessary.

• These changes are driven largely by advances in understanding the gene environment; the important input and advice from expert science panels; and volumes of new test data from Europe.

• These events prompt us to look anew at risk assessment and develop this strategy to thoughtfully position environmental health scientists and assessors for the future and contribute to meaningful change within the larger risk assessment/risk management community.

• The goal of this strategy is to map a course forward, focusing on creating 1st approximation NexGen risk assessments, learning from these efforts and, then, refining the next versions based on this new knowledge.

• It may take a decade before risk assessment can rely primarily on new advances in science

• It is necessary, however, to begin now to address needed changes.

Figure by Jane Ades, Courtesy National Human Genome Research Institute

Thank you

human health risk assessment: epa’s current challenges and the future stan barone jr., phd.,...

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