MoE Approach: An Alternate Approach 

to Evaluate Bioactivity and Exposure

S. Marty (S. Chaudhuri, M. Bartels) 

mmarty@dow.com

The Dow Chemical Company

December 3, 2014

FIFRA SAP Meeting: “Integrated Bioactivity and Exposure Ranking: A 

Computational Approach for the Prioritization and Screening of 

Chemicals in the Endocrine Disruptor Screening Program” 
Margin of Exposure Approach to ToxCast Data

• Conceptually similar, but approach differs from US EPA IBER 

scoring

– AUC approach not available

– ExpoCast data not used

• Alternate approach: Uses exposure to interpret ToxCast data

• Takes advantage of existing data on exposures for pesticides

– Focus on General Public

• Use IVIVE extrapolations to determine human internal 

dosimetry

• If sufficient MoE between the lowest AC50 concentration in 

ToxCast and internal dosimetry based on estimated human 

exposures, then compound is of ‘Low Concern”

• Results agree with the EPA’s conclusions with IBER approach

DOW RESTRICTED
Approach for MoE Calculations

• Downloaded “active results” from ToxCast (September 2014)

• Separated data: endocrine-related and non-endocrine assays

• Used lowest AC50 values (AUC approach not available)

• Future determinations could use AC5, point of departure, etc.

• Cell cytotoxicity was considered in paired assays

• EPA risk assessment values used to estimate exposures

• Use IVIVE extrapolations (TK) utilizing measured external exposure 

to predict human blood concentrations (internal dose)

• MoE was based on the highest exposed group

• TK parameters were adjusted for age-related physiology

• MoE: Compared the lowest AC50 concentration in ToxCast assays 

with internal blood concentrations estimated from human 

exposures

3
IBER Estimations

3. Refined TK

1. Ag Chem

Exposure Data

2. Lowest AC50 Value

Margin of 

Exposure 
Test

Chemical

ExpoCast Estimated 

Exposure – mg/kg/day 

Highest Dietary

Exposure (Chronic) –

mg/kg/day

Source of Data

Benfluralin 8.44E-8

to 9.35E-6

(Total 95%ile: 6.386E-6)

1.4E-5

(20-50+ yr olds)

7.0E-6

(1-2 yr olds)

Chronic Dietary 

Risk Assessment, 

RED, EPA, 2004

1. Ag Chemical Exposure Data: Dietary 

Exposures

Ag Chemical Exposures are: 

• Well characterized; acquired as part of registration process

- ExpoCast data may span orders of magnitude

• Evaluated by age-group 

- Can focus on age group with highest predicted exposure
2. Lowest AC50 Values – Endocrine and Nonendocrine

• AC50 values from ToxCast Phase 2

– AC50 has greater stability 

– AC5 or POD could be used for future calculations

Test

Chemical

ToxCast AUC ToxCast Phase 2 Lowest AC50 Values

ER Agonist Endocrine Non-endocrine

Benfluralin 0.0413 9 μM 

(OT_ERa_EREGFP_0120)

11.7 μM 

(ATG_NRF2_ARE_CIS)
3. EPA: Toxicokinetics to Estimate External Dose

• HTTK based on Wetmore et al., 2010:

1) Whole body is at the same concentration

2) Environmental exposure is constant and uniform

3) Assumes 100% absorption

4) Plasma concentration is at steady state (Css)

5) Includes elimination due to liver metabolism

• Substrate depletion by primary hepatocytes

6) Includes elimination via passive glomerular filtration

• Unbound chemical determined by rapid equilibrium dialysis

• Adjusted for plasma protein binding 

7) Css predicted for steady state dose of 1 mg/kg BW/day

• Linear dose adjustment based on Css value using a PK model

• Monte Carlo analysis to simulate human variability in TK in adults
GastroPlus (v. 8.5): Oral absorption model attached to PBPK Model

Refined predictions: plasma concentrations and fraction absorbed from GI 

1) Highest exposure (mg/kg/day) was split into 3 daily exposures

– Mimic 3 meals per day

– Administered for a period of 28 days

2) Integrated metabolic clearance, plasma protein binding, and renal 

clearance (Wetmore et al., 2010)

3) Used variables in generic PBPK model of fed humans

– Age-appropriate physiology

4) Metabolic clearance rate at 1 or 10 μM were used depending on AC50

(> 5 μM used 10 μM rate)

5) PBPK model run under fed conditions

6) Permeability was based on physiologically relevant QSAR predictions of GI 

permeation in human

7) Oral absorption uses the Advanced Compartmental Absorption and 

Transit (ACAT) model to predict passive absorption across the gut, 

account for soluble and insoluble portions of administered dose

– Benfluralin absorption = 31.5%

3. Alternative Approach: Toxicokinetics to Estimate 

Internal Dose (μM)
Test 

Compound

IBER 

Scores

Age 

Ranges

MOE by 

Wetmore 

Approach

MOE by 

adjusting for 

fraction

absorbed 

(Wetmore 

Approach)

MOE by Gastro 

Plus PBPK (Using 

Wetmore in vitro

assays)

Benfluralin

79,231 

(ER)

20-50+ 

yrs old

52,957 (E) 168,386 (E) 24,938,182 (E)

68,845 (NE) 218,902 (NE) 32,419,636 (NE)

1,000,000 

(AR)

1-2 yrs 

old

105,915 (E) 336,772 (E) 2,414,016,000 (E)

137,689 (NE) 437,803 (NE) 3,138,220,800 

(NE)

MOE Values for Benfluralin

Options to Consider for Bioactivity/Exposure 

Profiling

• Use the most refined exposure data

• For TK, use PBPK models that account for: 

– Percent absorption 

– Absorption rate

– Age-related physiology

• Determine suitable MoE to differentiate chemicals that 

require additional follow-up work

• Alternate approach yielded the same conclusion as the 

EPA’s IBER approach – Low Priority for ER and AR 

screening.
Thank You!