Dermal, Inhalation, and Incidental IngestionExposure Results from the Models: How DidThey Handle the Data?Bruce Young, Jeffrey Driver, Valerie Zartarian, Jianping Xue,Luther Smith, Graham Glen, Jason Johnston,Christiaan Delmaar, Nicolle Tulve, and Jeff EvansOctober 13th, 2008 ISEA Conference, Pasadena CA2Affiliations• US EPA / OPP – Evans• US EPA / ORD – Zartarian, Xue, Tulve• Alion Science & Technology – Smith, Glen• Exponent – Johnston• National Institute for Public Health and theEnvironment (RIVM) – Delmaar• infoscientific.com, Inc. – Driver• Bayer CropScience – Young3Outline• IntroductionModels & Exposure Scenarios Evaluated• Scenario-Specific Exposure Pathway &Aggregate Absorbed Dose Comparison• Discussion & Conclusion4Models• EPA/OPPStandard Operating Procedures for Residential Exposure Assessment(1997 version)• EPA/ORDDraft Protocol for Measuring Children’s Non-Occupational Exposure toPesticides by all Relevant Pathways• EPA/ORDSHEDS (Stochastic Human Exposure and Dose Simulation Model)• CARES(Cumulative and Aggregate Risk Evaluation System)ILSI / Risk Sciences Institute• CalendexExponent• ConsExpoRIVM5Exposure ScenariosIndoor Total Release Fogger (6 oz. press. aerosol)• Dermal• Incidental Ingestion• 2 applications, 30 day time intervalIndoor Crack & Crevice Aerosol (hand-held, 16 oz.press. can)• Dermal• Incidental Ingestion• 5 applications, 14 day time intervalIndoor Flying Insect (FIK) Aerosol (hand-held, 16 oz.press. can)• Inhalation• 5 applications, 7 day time interval10% daily dissipation or 6.58 day half-lifePopulation of interest = Children, 2 to 5 yrs old6Comparing Model Outputs• EPA Residential SOPsExposure estimate based on default assumptions or provideddataUse single point deterministicequations based on a combinationof central tendency and high-end statistics•Draft ProtocolExposure estimate based on extant field dataUse single point deterministic equations• Probabilistic ModelsDay 0 exposure and/or maximum yearly exposure for eachindividual365 day time series for each individual (data not shown)7Transfer Coefficient (cm2/hr)Transfer Residue (mg/cm2) = Application Rate x Fract. Dislodged.Exposure Duration (hrs/day)Dermal Exposure = TR 

# ×TC 

# ×ED / BW8IngestionExposure = HR 

# ×HF 

# ×CF 

# ×ED 

# ×TE / BWHand Residue (mg/cm2)EPA SOP - AR 

# ×FD 

# ×SAModels - TR 

# ×TC 

# ×EDContact Frequency (events/hr)Exposure Duration (hr/day)Fraction Hand inMouth or SurfaceAreaTransfer Efficiency or Saliva Extraction9Air Concentration (mg/m3)Inhalation Rate (m3/hr)Based on basal metabolic rateAge and gender specificExposure Duration (hr/day)InhalationExposure = C 

# ×IR 

# ×ED / BW10Draft Protocol= 0.36 mg/kg/dEPA SOP= 0.73 mg/kg/d01020304050607080901000.1 1 10Dermal Exposure (mg/kg/d)

PercentileEPA SOPDraft ProtocolSHEDSCARESCalendexConsExpoPercentile SHEDS CARES Calendex ConsExpo100 1.04 2.37 2.70 0.5999.9 0.96 1.95 2.15 -99 0.74 1.50 1.47 0.5595 0.61 1.13 1.01 -90 0.53 0.95 0.81 0.4375 0.44 0.70 0.56 0.3850 0.35 0.50 0.36 0.3325 0.27 0.36 0.24 0.29Indoor Fogger (Day 0 or maximum)11EPA SOP= 4.75 mg/kg/dDraft Protocol= 2.37 mg/kg/d01020304050607080901000.1 1 10 100Dermal Exposure (mg/kg/d)

PercentileEPA SOPDraft ProtocolSHEDSCARESCalendexConsExpoPercentile SHEDS CARES Calendex ConsExpo100 6.36 22.05 27.58 3.9099.9 4.56 21.20 20.67 -99 3.57 16.52 12.82 3.3095 2.74 12.58 8.03 -90 2.39 10.59 6.14 2.8075 1.86 7.66 3.85 2.5050 1.39 5.44 2.14 2.2025 1.02 3.85 1.08 1.80Crack & Crevice(Day 0 or maximum)1210010-110-310-410-20102030405060708090100Incidental Ingestion Exposure (mg/kg/d)

PercentileEPA SOPDraft ProtocolSHEDSCARES Mass BalanceCARES EPA SOPCalendexConsExpoPercentile SHEDSCARESMass Bal.CARESEPA SOP Calendex ConsExpo100 0.0231 0.0073 0.0175 0.014 0.05999.9 0.0183 0.0065 0.0168 0.011 -99 0.014 0.005 0.0143 0.007 0.05595 0.0099 0.0036 0.0102 0.005 -90 0.0082 0.0029 0.0085 0.004 0.04375 0.0058 0.0019 0.0063 0.002 0.03850 0.0036 0.0013 0.0042 0.001 0.03325 0.0022 0.0008 0.0028 0.001 0.029EPA SOP= 0.023 mg/kg/dDraft Protocol= 0.0008 mg/kg/dIndoor Fogger (Day 0 or maximum)13EPA SOP= 0.155 mg/kg/dDraft Protocol= 0.0053 mg/kg/d10-110010-210-410-30102030405060708090100Incidental IngestionExposure (mg/kg/d)

PercentileEPA SOPDraft ProtocolSHEDSCARES Mass BalanceCARES EPA SOPCalendexConsExpoPercentile SHEDSCARESMass Bal.CARESEPA SOP Calendex ConsExpo100 0.028 0.091 0.261 0.133 0.39099.9 0.022 0.084 0.239 0.098 -99 0.015 0.060 0.173 0.061 0.33095 0.011 0.041 0.111 0.036 -90 0.009 0.033 0.091 0.026 0.28075 0.006 0.022 0.065 0.015 0.25050 0.004 0.014 0.045 0.007 0.22025 0.002 0.010 0.030 0.003 0.180Crack & Crevice (Day 0 or maximum)1410-210-310-410-510-60102030405060708090100Inhalation Exposure (mg/kg/d)

PercentileEPA SOPDraft ProtocolSHEDSCARESCalendexConsExpoPercentile SHEDS CARES Calendex ConsExpo100 6.00E-05 4.19E-05 1.33E-04 1.00E-0399.9 5.14E-05 3.49E-05 1.14E-04 -99 4.37E-05 3.32E-05 8.70E-05 9.90E-0495 3.69E-05 2.90E-05 6.65E-05 -90 3.32E-05 2.62E-05 5.73E-05 9.30E-0475 2.68E-05 2.29E-05 4.38E-05 7.50E-0450 2.03E-05 1.94E-05 3.18E-05 6.00E-0425 1.50E-05 1.67E-05 2.29E-05 4.30E-04Draft Protocol= 3.92E-05 mg/kg/dEPA SOP= 6.09E-05 mg/kg/dFlying Insect Killer (Day 0 or maximum)15Total, Multi-Route Absorbed Dose• Incorporate dermal & oral absorption to estimatethe aggregate absorbed dose for a scenario: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 daily365 day time series• Contribution analysis at 99.9thpercentile1610010-110-210-310-410-510-610-710-80102030405060708090100Total, Multi-Route Absorbed Dose (mg/kg/d)

PercentileSHEDSCARESCalendexConsExpoPercentile SHEDS CARES Calendex ConsExpo100 0.012 0.049 0.036 0.07199.9 0.005 0.019 0.022 0.06699 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 0.035Indoor Fogger (daily 365 day time series)17Indoor Crack & Crevice (daily 365 day time series)10010-110-210-310-410-510-610-710-80102030405060708090100Total, Multi-Route Absorbed Dose (mg/kg/d)

PercentileSHEDSCARESCalendexConsExpoPercentile SHEDS CARES Calendex ConsExpo100 0.015 0.508 0.445 0.46899.9 0.006 0.219 0.257 0.39699 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 0.21618Dermal88%Oral12%CARESDermal31%Oral69%SHEDSDermal90%Oral10%CalendexDermal87%Oral13%CARESDermal53%Oral47%SHEDSDermal93%Oral7%CalendexINDOOR TOTAL RELEASE FOGGERINDOOR CRACK & CREVICE AEROSOLContribution to Total Absorbed Dose By Exposure Route atthe 99.9thPercentile19Summary of Results• For these scenarios/inputs, model-to-model pathway comparisonswere consistent, given independently developed models• FoggerDermal• Models within factor 1.5 at50%ile; within 2.2 at 99%ileIncidental Ingestion (i.e., Hand-to-Mouth)• 4/5 Models within factor 3.2at 50%ile; within 2.8 at 99%ile• Crack & CreviceDermal• Models within factor 3.9 at 50%ile; within4.6 at 99%ile (excluding the CARESEPA SOP)Incidental Ingestion (i.e., Hand-to-Mouth)• 4/5 Models within factor 3.5at 50%ile; within 4.5 at 99%ile• FIKInhalation• 3/4 Models within factor 1.6 at50%ile; within 4.5 at 99.9%ile• More variability across models for aggregate dose estimates (but 2out of 4 close) and dominant pathway (but 2 out of 3 close)Model evaluation vs. measurements data needed20Discussion• Dermal ExposureFogger results more consistent than C&C; contactprobability with treated surface and body-part-specificcontact rate assumptions are important• CARES, Calendex and ConsExpo conservatively assumedindividual spends all the time near treated area• SHEDS assumed contact probability in treated room 25% fortreated surface and 75% for untreated surface (C&C); 100%for fogger (50% prob. being in treated room).• SHEDS dermal (hand) loadingreflects sequential loadingand removal processes21Discussion• Incidental Ingestion (Hand-to-Mouth) ExposureDifferences influenced by dermal exposure (TC), activity data (contactassumptions), and mouthing assumptions (replenishment)• ConsExpo currently assumes oral exposure is 10% of dermal• SHEDS splits TC hands and TC bodyon input; CARES uses single TC butsplits hand and body exposurewithin model calculations• SHEDS has max dermal loading, resulting in similar ingestion exposure fortwo scenarios.• Fogger vs. Crack & Crevice contact probabilities• Total, Multi-Route (Aggregate)Absorbed Dose & Other IssuesModels do not address absorption, distribution, metabolism orelimination kinetics/dynamicsModels do not address within day temporal aspects due to productuse/time activity data limitations, e.g., on the day of application, whenreentry into a treated area occurs relative to when the product was usedon that dayContribution analysis requires further comparison• e.g., SHEDS hand-to-mouth > dermal contribution because of different TCassumption (50% of total dermal onhand vs. 14% on hand used in othermodels)22Discussion• Inhalation ExposureInhalation exposures influenced by activity data, e.g.,• SHEDS uses activity-specific inhalation rates; others usedaily average• Time spent in each location varies in SHEDS by CHADdiaries• SHEDS exposes simulated people to different concentrationsin treated and untreated rooms; CARES assumes zeroexposure in untreated rooms• CARES does not correlate air concentration and exposureduration• ConsExpo spray model simulates air concentrations after theuse of an aerosol spray. Directly after spraying, the airconcentration is assumed to bewell-mixed. Removal is byventilation and gravitational sedimentation23CONCLUSIONS3⁄46 models (2 deterministic, 4 probabilistic) compared with 3 scenarios and 3pathways3⁄4For these scenarios/inputs, model-to-model pathway comparisons wereconsistent, given independently developed modelsMajority of models within a factor of 5 or less at 50thand 99.9thpercentilesDifferences partially explained by activity assumptions, inputdistributions, exposure algorithms3⁄4Dermal exposure was a key pathway for fogger and c&cMore consistent among models forfogger than the other applicationtypesContact w/ treated surfaces and body-part-specific contact rateassumptions are important3⁄4Incidental ingestion (hand-to-mouth)exposure can also be key pathway forfogger and c&cInfluenced by dermal exposure, assumptions related to transfer, andactivity data24CONCLUSIONS (cont’d)3⁄4Inhalation exposures similar, influenced by activity data andinhalation rate assumptions3⁄4More variability in dose estimates suggest that further modelevaluation, comparison to biomonitoring data, and morerefined kinetic and dynamic dose algorithms are needed3⁄4Model comparisons to biological monitoring in this case studywere similar for foggers andprovide more confidence inexposure algorithms (data not shown)3⁄4Model comparisons to biological monitoring in this case studysuggest that c&c algorithms need closer examination; EPA iscurrently revising the c&c SOPs25RECOMMENDATIONS3⁄4Conduct sensitivity and uncertainty analyses to identifykey inputs, data gaps, uncertaintiesExplore similarities/differences across models toprioritize data needs3⁄4Conduct model evaluations with real-world data (e.g.,comparisons to biological samples)3⁄4Explore impact of underlying time/location assumptions,e.g.,SHEDS uses CHAD diariesCARES and the EPA SOPs use the Exposure FactorsHandbooksDraft Protocoluses participant-specific diaries3⁄4Explore how models/algorithms could be refined (e.g.,PBPK modeling, hand-to-mouth, dynamic dermalprocesses, crack and crevice algorithms)3⁄4Explore how key model inputs could be refined