Mode of Action Analysis:

Organizing Questions, Tabular and 

Graphical Tools

Ted Simon, Ph.D. DABT

IRIS Bimonthly Meeting, Dec. 2013
Questions for Organizing MOA 

Consideration

• What is the MOA to be evaluated by the IPCS 

Human Relevance Framework and modified 

Bradford Hill considerations?

• Which events are truly causal or key events 

(KE)?

• Which events are associative events?

• What are the modulating factors?

• Is the proposed MOA relevant to humans?
Questions for Considering DoseResponse

• Are extant data sufficient for establishing dose 

response relationships for proposed KEs? 

• Are extant data sufficient for DR modeling of 

proposed KEs? Are there data gaps?

• Does the current understanding support a 

threshold or non-threshold DR and low dose 

extrapolation approach?

• On either theoretical or practical grounds, is 

there a dose or AUC level insufficient for KEs or 

the AO?

KE, key event; DR, dose response; AUC, area under the curve; AO, adverse outcome
Questions for Considering the AO or 

precursor KEs

• Does the weight-of-evidence suggest an 

appropriate model or approach for the doseresponse assessment?

• If so, what are the key data gaps? What data 

would have the highest value?
Three Proposed MOA Schemes

From Corton et al. 2013. Crit Rev Toxicol DOI: 10.3109/10408444.2013.835784

Dose Range Array

KE #1 KE #2 KE #3 AO
Correlation of KE with AO

Incidence of Tumors (Adenomas and Carcinomas)

Incidence x Severity for Hyperplasia
Comparison and Ordering of DoseResponse of KEs

100 1000 10000

0

20

40

60

80

0.0

0.2

0.4

0.6

0.8

1.0

EC50 not determined

 104 weeks

*

*

DEHP in diet (ppm)

Palmitoyl CoA Oxidation (PBOX)

(nmol NADH/min/mg protein)

Tumor Frequency

100 1000 10000

3

4

5

6

0.0

0.2

0.4

0.6

0.8

1.0

EC50 = 2994

104 weeks

*

*

DEHP in diet (ppm)

Liver-to-Body Weight Ratio

Tumor Frequency

100 1000 10000

0

10

20

30

40

0.0

0.2

0.4

0.6

0.8

1.0

EC50 = 21140

2 weeks

*

*

*

DEHP in diet (ppm)

Periportal DNA Synthesis

Tumor Frequency

100 1000 10000

0.0

0.2

0.4

0.6

0.8

1.0

EC50 = 15940

104 weeks

*

*

DEHP in diet (ppm)

Tumor Frequency

100 1000 10000

0

10

20

30

0.0

0.2

0.4

0.6

0.8

1.0

EC50 = 22985

2 weeks

*

*

*

DEHP in diet (ppm)

Centrilobular DNA Synthesis

Tumor Frequency

100 1000 10000

0

5

10

15

20

25

0.0

0.2

0.4

0.6

0.8

1.0

EC50 = 25640

2 weeks

*

*

*

DEHP in diet (ppm)

Total DNA Synthesis

Tumor Frequency

PPARa Induction

Hepatic changes

I ntercellular

Communication

D NA Synthesis

Neoplasms

100 1000 10000

0.00

0.05

0.10

0.0

0.2

0.4

0.6

0.8

1.0

EC50 = 2591

2 weeks

DEHP in diet (ppm)

Change in Dye Transfer Distance (mm)

Tumor Frequency

From Corton et al. 2013. Crit Rev Toxicol DOI: 10.3109/10408444.2013.835784
3D Graphs in Dose and Time

From Budinsky et al. 2013. Crit Rev Toxicol DOI: 10.3109/10408444.2013.835787
Summary

• Presenting MOA information in IRIS assessments 

in a credible fashion is important

• MOA is the central concept in the 2005 Cancer 

Guidelines

• Variety of ways to present data both in tables and 

in graphics

• The work of Edward Tufte may help conceiving 

effective data presentation methods

– The Visual Display of Quantitative Information

– Visual and Statistical Thinking: Displays of Evidence for 

Making Decisions