Dermal, Inhalation, and Incidental Inge

Exposure Results from the Models: HoThey Handle the Data?

Bruce Young, Jeffrey Driver, Valerie Zartarian, Jianpin

Luther Smith, Graham Glen, Jason Johnston, 

Christiaan Delmaar, Nicolle Tulve, and Jeff Evan

October 13th, 2008 ISEA Conference, Pasadena CA 
Affiliations

• US EPA / OPP – Evans• US EPA / ORD – Zartarian, Xue, Tulve• Alion Science & Technology – Smith, Gle• Exponent – Johnston• National Institute for Public Health and th

Environment (RIVM) – Delmaar

• infoscientific.com, Inc. – Driver• Bayer CropScience – Young
Outline

• Introduction

 Models & Exposure Scenarios Evaluated

• Scenario-Specific Exposure Pathway & 

Aggregate Absorbed Dose Comparison

• Discussion & Conclusion
Models

• EPA/OPP

 Standard Operating Procedures for Residential Exposure As

(1997 version)

• EPA/ORD

 Draft Protocol for Measuring Children’s Non-Occupational E

Pesticides by all Relevant Pathways

• EPA/ORD

 SHEDS (Stochastic Human Exposure and Dose Simulation 

• CARES (Cumulative and Aggregate Risk Evaluation S

 ILSI / Risk Sciences Institute 

• Calendex

 Exponent

• ConsExpo

 RIVM
Exposure Scenarios

 Indoor Total Release Fogger (6 oz. press. ae

• Dermal• Incidental Ingestion• 2 applications, 30 day time interval

 Indoor Crack & Crevice Aerosol (hand-held, 1

press. can)

• Dermal• Incidental Ingestion• 5 applications, 14 day time interval

 Indoor Flying Insect (FIK) Aerosol (hand-held

press. can) 

• Inhalation• 5 applications, 7 day time interval

 10% daily dissipation or 6.58 day half-life Population of interest = Children, 2 to 5 yrs ol
Comparing Model Outputs

• EPA Residential SOPs

 Exposure estimate based on default assumptions or p

data

 Use single point deterministic equations based on a co

of central tendency and high-end statistics

• Draft Protocol

 Exposure estimate based on extant field data Use single point deterministic equations

• Probabilistic Models 

 Day 0 exposure and/or maximum yearly exposure for 

individual

 365 day time series for each individual (data not show
Transfer Coefficient (cm2/hr)

Transfer Residue (mg/cm2) = Application Rate x Fract. Dislod

Exposure Duration (hrs/d

Dermal Exposure = TR × TC × ED / BW
Ingestion Exposure = HR × HF × CF × ED × TE / 

Hand Residue (mg/cm2) 

EPA SOP - AR × FD × SAModels - TR × TC × ED

Contact Frequency (events/hr)

Exposure Dur

Fraction Hand in Mouth or Surface Area

Transfer Efficiency or Saliva Extraction
Air Concentration (mg/m3)

Inhalation Rate (m3/hr)

Based on basal metabolic rate

Age and gender specific 

Exposure Duration 

InhalationExposure = C × IR × ED / BW
Draft Protocol

= 0.36 mg/kg/d

EPA SOP 

= 0.73 mg/kg/d

0

102030405060708090

100

0.1 1 

Dermal Exposure (mg/kg/d)

Percentile

EPA SOPDraft ProtocolSHEDSCARESCalendexConsExpo

Percentile SHEDS CARES Cale

100 1.04 2.37 

99.9 0.96 1.95 

99 0.74 1.50 95 0.61 1.13 90 0.53 0.95 75 0.44 0.70 50 0.35 0.50 25 0.27 0.36 

Indoor Fogger (Day 0 or maximum)
EPA SOP 

= 4.75 mg/kg/d

Draft Protocol

= 2.37 mg/kg/d

0

102030405060708090

100

0.1 1 10 

Dermal Exposure (mg/kg/d)

Percentile

EPA SOPDraft ProtocolSHEDSCARESCalendexConsExpo

Percentile SHEDS CARES Calen

100 6.36 22.05 2

99.9 4.56 21.20 2

99 3.57 16.52 195 2.74 12.58 90 2.39 10.59 75 1.86 7.66 50 1.39 5.44 25 1.02 3.85 

Crack & Crevice (Day 0 or maximum
10-1 10-3 10-4 10-2

0

102030405060708090

100

Incidental Ingestion Exposure (mg/kg/d)

Percentile

EPA SOPDraft ProtoSHEDSCARES MCARES ECalendexConsExpo

Percentile SHEDS

CARES

Mass Bal.

CARES

EPA SOP 

100 0.0231 0.0073 0.0175 

99.9 0.0183 0.0065 0.0168 

99 0.014 0.005 0.0143 95 0.0099 0.0036 0.0102 90 0.0082 0.0029 0.0085 75 0.0058 0.0019 0.0063 50 0.0036 0.0013 0.0042 25 0.0022 0.0008 0.0028 

EPA SOP 

= 0.023 mg/kg/d Draft Protocol = 0.0008 mg/kg/d

Indoor Fogger (Day 0 or maximum)
EPA SOP 

= 0.155 mg

Draft Protocol

= 0.0053 mg/kg/d

10-1 

10-2 10-4 10-3

0

102030405060708090

100

Incidental Ingestion Exposure (mg/kg/d)

Percentile

EPA SOPDraft ProtocolSHEDSCARES Mass BalanceCARES EPA SOPCalendexConsExpo

Percentile SHEDS

CARES

Mass Bal.

CARES

EPA SOP 

100 0.028 0.091 0.261 

99.9 0.022 0.084 0.239 

99 0.015 0.060 0.173 95 0.011 0.041 0.111 90 0.009 0.033 0.091 75 0.006 0.022 0.065 50 0.004 0.014 0.045 25 0.002 0.010 0.030 

Crack & Crevice (Day 0 or maximum)
10-3 10-4 10-5 10-6

0

102030405060708090

100

Inhalation Exposure (mg/kg/d)

Percentile

EPA SOPDraft ProtocolSHEDSCARESCalendexConsExpo

Percentile SHEDS CARES Cale

100 6.00E-05 4.19E-05 1.3

99.9 5.14E-05 3.49E-05 1.1

99 4.37E-05 3.32E-05 8.795 3.69E-05 2.90E-05 6.690 3.32E-05 2.62E-05 5.775 2.68E-05 2.29E-05 4.350 2.03E-05 1.94E-05 3.125 1.50E-05 1.67E-05 2.2

Draft Protocol

= 3.92E-05 mg/kg/d

EPA SOP 

= 6.09E-05 mg/kg/d

Flying Insect Killer (Day 0 or maximum
Total, Multi-Route Absorbed Dose

• Incorporate dermal & oral absorption to e

the aggregate absorbed dose for a scena

 Fogger (dermal + incidental ingestion) C&C (dermal + incidental ingestion)

• Dermal absorption fraction:

 triangular (0.0048, 0.0195, 0.0322)

• Oral absorption fraction:

 uniform (1)

• Generate percentile distribution based on 

365 day time series

• Contribution analysis at 99.9th percentile
10-

10-2 10-3 10-4 10-5 10-6 10-7 10-8

0

102030405060708090

100

Total, Multi-Route Absorbed Dose (mg/kg/d)

Percentile

SHEDS

CARES

Calendex

Con

Percentile SHEDS CARES Calendex ConsExpo

100 0.012 0.049 0.036 0.071

99.9 0.005 0.019 0.022 0.066

99 0.003 0.009 0.010 0.05295 0.001 0.003 0.003 0.04790 0.001 0.001 0.001 0.04675 0.000 0.000 0.000 0.04050 0.000 0.000 0.000 0.03625 0.000 0.000 0.000 0.035

Indoor Fogger (daily 365 day time ser
Indoor Crack & Crevice (daily 365 day time 

10

10-2 10-3 10-4 10-5 10-6 10-7 10-8

0

102030405060708090

100

Total, Multi-Route Absorbed Dose (mg/kg/d)

Percentile

SHEDS

CARES

Calendex

Co

Percentile SHEDS CARES Calendex ConsExpo

100 0.015 0.508 0.445 0.468

99.9 0.006 0.219 0.257 0.396

99 0.004 0.108 0.124 0.33695 0.002 0.047 0.055 0.31290 0.002 0.026 0.031 0.30075 0.001 0.006 0.002 0.26450 0.000 0.000 0.000 0.22825 0.000 0.000 0.000 0.216
Dermal

88%

Oral

12%

CARES

Dermal

31%

Oral

69%

SHEDS

Derm

90%

Oral

10%

Calendex

Dermal

87%

Oral

13%

CARES

Dermal

Oral 53%47%

SHEDS

Derm

93%

Oral

7%

Calendex

INDOOR TOTAL RELEASE FOGGER

INDOOR CRACK & CREVICE AEROSOL

Contribution to Total Absorbed Dose By Exposure the 99.9th Percentile
Summary of Results

• For these scenarios/inputs, model-to-model pathway com

were consistent, given independently developed models

• Fogger

 Dermal

• Models within factor 1.5 at 50%ile; within 2.2 at 99%ile

 Incidental Ingestion (i.e., Hand-to-Mouth)

• 4/5 Models within factor 3.2 at 50%ile; within 2.8 at 99%ile

• Crack & Crevice

 Dermal

• Models within factor 3.9 at 50%ile; within 4.6 at 99%ile (excludi

EPA SOP)

 Incidental Ingestion (i.e., Hand-to-Mouth)

• 4/5 Models within factor 3.5 at 50%ile; within 4.5 at 99%ile

• FIK

 Inhalation

• 3/4 Models within factor 1.6 at 50%ile; within 4.5 at 99.9%ile

• More variability across models for aggregate dose estimat

out of 4 close) and dominant pathway (but 2 out of 3 close

 Model evaluation vs. measurements data needed
Discussion

• Dermal Exposure

 Fogger results more consistent than C&C; co

probability with treated surface and body-partcontact rate assumptions are important

• CARES, Calendex and ConsExpo conservatively a

individual spends all the time near treated area

• SHEDS assumed contact probability in treated roo

treated surface and 75% for untreated surface (C&for fogger (50% prob. being in treated room).

• SHEDS dermal (hand) loading reflects sequential l

and removal processes
Discussion

• Incidental Ingestion (Hand-to-Mouth) Exposure

 Differences influenced by dermal exposure (TC), activity dat

assumptions), and mouthing assumptions (replenishment)

• ConsExpo currently assumes oral exposure is 10% of dermal• SHEDS splits TC hands and TC body on input; CARES uses si

splits hand and body exposure within model calculations

• SHEDS has max dermal loading, resulting in similar ingestion e

two scenarios.

• Fogger vs. Crack & Crevice contact probabilities

• Total, Multi-Route (Aggregate) Absorbed Dose & Other Is

 Models do not address absorption, distribution, metabolism o

elimination kinetics/dynamics

 Models do not address within day temporal aspects due to p

use/time activity data limitations, e.g., on the day of applicatireentry into a treated area occurs relative to when the produon that day

 Contribution analysis requires further comparison

• e.g., SHEDS hand-to-mouth > dermal contribution because of d

assumption (50% of total dermal on hand vs. 14% on hand usemodels)
Discussion

• Inhalation Exposure

 Inhalation exposures influenced by activity da

• SHEDS uses activity-specific inhalation rates; othe

daily average

• Time spent in each location varies in SHEDS by C

diaries

• SHEDS exposes simulated people to different conc

in treated and untreated rooms; CARES assumes exposure in untreated rooms

• CARES does not correlate air concentration and ex

duration

• ConsExpo spray model simulates air concentration

use of an aerosol spray. Directly after spraying, the concentration is assumed to be well-mixed. Removventilation and gravitational sedimentation
CONCLUSIONS

3⁄4 6 models (2 deterministic, 4 probabilistic) compared with 3 sce

pathways

3⁄4 For these scenarios/inputs, model-to-model pathway comparis

consistent, given independently developed models

 Majority of models within a factor of 5 or less at 50th and 9

percentiles

 Differences partially explained by activity assumptions, inp

distributions, exposure algorithms

3⁄4 Dermal exposure was a key pathway for fogger and c&c

 More consistent among models for fogger than the other a

types

 Contact w/ treated surfaces and body-part-specific contact 

assumptions are important

3⁄4 Incidental ingestion (hand-to-mouth) exposure can also be ke

fogger and c&c

 Influenced by dermal exposure, assumptions related to tra

activity data
CONCLUSIONS (cont’d)

3⁄4 Inhalation exposures similar, influenced by activity d

inhalation rate assumptions

3⁄4 More variability in dose estimates suggest that furth

evaluation, comparison to biomonitoring data, and mrefined kinetic and dynamic dose algorithms are ne

3⁄4 Model comparisons to biological monitoring in this c

were similar for foggers and provide more confidencexposure algorithms (data not shown)

3⁄4 Model comparisons to biological monitoring in this c

suggest that c&c algorithms need closer examinatiocurrently revising the c&c SOPs
RECOMMENDATIONS

3⁄4 Conduct sensitivity and uncertainty analyses to i

key inputs, data gaps, uncertainties

 Explore similarities/differences across models 

prioritize data needs

3⁄4 Conduct model evaluations with real-world data 

comparisons to biological samples)

3⁄4 Explore impact of underlying time/location assum

e.g.,

 SHEDS uses CHAD diaries CARES and the EPA SOPs use the Exposure 

Handbooks

 Draft Protocol uses participant-specific diaries

3⁄4 Explore how models/algorithms could be refined 

PBPK modeling, hand-to-mouth, dynamic dermaprocesses, crack and crevice algorithms)

3⁄4 Explore how key model inputs could be refined