Use of “Omic” Technology to Inform 

the Risk Assessment

Nancy McCarroll

Health Effects Division/ Office of Pesticide 

Programs, U.S. Environmental Protection 

Agency

&

Stephen Nesnow, Ph.D.

National Health and Environmental Effects 

Research Laboratory, Office of Research 

and Development, U.S. Environmental 

Protection Agency

May 24, 2011
Introduction

• Goal: To set the stage for the 

toxicogenomic investigations conducted 

by NHEERL, ORD

• General background information:

• Toxicogenomics

• MOA/AOP

• Case Study

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IATA Strategy: Use of Computational and 

Molecular Tools: Toxicogenomics

• Scientific field that examines apical endpoints from 

classical toxicology studies and combines them with 

information about gene, protein, and/or endogenous 

metabolite levels within particular cells, tissues, or 

organisms in response to a toxic substance.

• “Omics” is the general term that is applied to other 

molecular profiling data generated from:

• Genomics - global analysis of gene expression

• Proteomics - global analysis of proteins (i.e., gene product)

• Metabolomics - global analysis of endogenous metabolites

• Bioinformatics – Collection, interpretation & storage 

of data from the above areas of “omics” 

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IATA Strategy: Use of Computational and 

Molecular Tools: Toxicogenomics

• Ideally suited for MOA/AOP analysis (NAS, 2007)

• Allows a more comprehensive understanding of the 

progression of an adverse effect starting with a 

molecular initiating event (initial point of chemicalbiological interaction with the organism that initiates 

the AOP). 

• More mechanistic approach

• Other events that occur along the pathway that lead 

to the adverse outcome are termed intermediate key 

events.

• MOA analysis not limited to cancer risk assessment; 

can also be applied to non-cancer endpoints.

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Mode of Action Framework

• Hypothesis Based Weight of Evidence Approach

International Framework

 Introduced by USEPA & IPCS (1999, 2001)

 ILSI and IPCS expands work (2003, 2006, 

2008)

 IPCS continues works to update (ongoing)

•Based on Bradford Hill Considerations for Causality 

(e.g., temporal & dose response concordance, biological 

plausibility, etc)

•Distinguishes MoA vs Mechanism

•Describes Human Relevance (Concordance) Analysis 5
MOA Framework: 

Plausible Hypothesis Detailed Molecular 

Description 

Mode vs. Mechanism

Key event: 

• Critical 

• Measurable 

MoA: Not every step in the process, but the key events that are 

likely to “drive” the process. 

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IATA Strategy: Use of Computational and 

Molecular Tools: MOA Framework

• Begins with a brief description of the 

postulated MOA

• Provides data to support the key events

• Explains the sequence of key events 

that lead to the tumor response with 

respect to: 

• Dose-response &

• Temporal relationships

• Analyzes alternative MOAs & human 

relevance

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Case Study: Propiconazole

• Reasons for Selection of Propiconazole as 

the Model Compound:

• Exceptionally rich database

• Some information on a MoA, based on 

apical endpoint data

• Belongs to a class of chemical (conazoles) 

for which OPP has voluminous data.

• The regulatory status of this chemical in not 

the focus of this effort. 

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Case Study: Propiconazole

• Conazole, antifungal pesticide

• Mechanism of antifungal activity: 

inhibition of CYP51 protein, ergosterol. 

Steroid necessary for the fungal cell 

wall

• Inhibits CYP isoforms

• Induces liver tumors in male mice

• Not mutagenic in conventional Genetic 

Toxicology test battery

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Apical based MOA for Propiconazole

Increase Liver Tumors

Increased Liver/body 

weight

Induce Cyp2b 

protein and 

increased PROD 

activity

Increase cell 

proliferation

Hypertrophy

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Bradford Hill Considerations for Causal Relationships: 

Propiconazole Mouse Oral Ingestion Studies

Key Event/ppm 1 day 4 day 14 day 4 wk 13 wk 100 wk

Increased cell proliferation 

850 X X

2500 X X

Increased PROD activity

850 X

2500 X

Increased liver hypertrophy

850 X

2500 X

Increased liver weight

2500 X

Adenomas & carcinomas

2500 X

DOSE RESPONSE 

TEMPORAL ASSOCIATIONS

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