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Exposure 		Modeling Public Meeting (EMPM) Information and Products

Minutes of the July 21, 2005 Exposure Modeling Public Meeting

Minutes of the July 21, 2005 Exposure Modeling Public Meeting

Office of Pesticide Programs (OPP) Conference Room 1126

1801 S. Bell St. - Crystal Mall 2

Arlington, VA  22202

On this Page

Attendees

Welcome and Introductions

Old Action Items

Brief Updates

Major Presentations

Wrap up

Attendees

Name	Association

Marietta Echeverria			OPP/EFED

Ron Parker	 			OPP/EFED

Betsy Behl				OPP/EFED

Mark Corbin				OPP/EFED

Dirk Young				OPP/EFED

Mohamed Ruhman			OPP/EFED

Nelson Thurman	 			OPP/EFED

James Hetrick				OPP/EFED

Lucy Shanaman				OPP/EFED

Bill Eckel				OPP/EFED

Greg Orrick				OPP/EFED

Norm Birchfield				OPP/EFED

Faruque Kahn				OPP/EFED

Cheryl Sutton				OPP/EFED

Keara Moore				OPP/EFED

Jonathan Angier				OPP/EFED

Kathy Carr				Monsanto

Mary Nett	 			WQC

Russell Jones	 			BayerCropScience

George Sabbagh				BayerCropScience

Nasser Assaff				Valent

Piyush Singh				Dupont

Paul Hendley	 			Syngenta

Scott Jackson	 			BASF

Uwe Wanner				Crompton

Wenlin Chen				Syngenta

Greg Leyes				ISKB

Marty Williams	 			Waterborne Environmental

Jenn Trask				Waterborne Environmental

Cathleen Hapeman			USDA/ARS

Garey Fox				University of Mississippi

Micah Reynolds				Toxcel

Carrie Graff				USDA ARS

Dean Hively				USDA ARS

Earl Hayter	 			EPA/ORD-NERL

Ian Kennedy	 PMRA

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Welcome and Introductions

The Exposure Modeling Work Group hosts quarterly meetings that are open to the public and provide a forum for cooperative exchange of facts and technical information on technical issues related to pesticide exposure modeling between EFED and stakeholders with similar technical expertise.  Marietta Echeverria (OPP/EFED) chaired the meeting in the capacity of co-chair of the EFED Water Quality Tech Team (WQTT).

This meeting includes presentations which focused on sediment and contaminant transport modeling, factors influencing erosion modeling, leaching modeling with the Root Zone Quality Model, and an evaluation of the effect of BMP on stream water phosphorus.  All FIFRA EMWG agendas, minutes and presentations can be found at:

http://www.epa.gov/oppefed1/models/water/emwg_top.htm

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Old Action Items

NAFTA Guidance for Conducting Terrestrial Field Dissipation Studies will be added to the EPA website when complete and approved.

Mark Corbin  reported that this document has been released as a final draft and posted on the web for comments at:

http://idocket.rptnc.epa.gov/edkreg/index.jsp

EFED will post a list of those developed specifically for the OP cumulative assessment.

Mark Corbin reported that the national/regional scenarios have been separated from those created specifically for the cumulative assessment of the organophosphate (OP) pesticides. Both groups are posted on the OPP/EFED website at

http://www.epa.gov/oppefed1/models/water/index.htm. The scenarios are included in a zipped file that will automatically extract into the two separate groups.

ORD will post revised PRZM 3.12.2 on the CEAM website.

Jim Hetrick reported that the final revised version of PRZM3.12.2 has been posted on the ORD/CEAM website at:

http://www.epa.gov/ceampubl/gwater/przm3/index.htm. This version is dated May 2005.

Information on PRZM 3.12.2 revised volatilization feature will be included in the description of model changes.

Jim Hetrick reported that a description of the changes to the volatilization routines in PRZM will be included in the EFED QA/QC write-up.

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Brief Updates

PRZM3.12.2 Evaluation

Jim Hetrick reported on finalizing the EFED QA/QC of the new version of PRZM 3.12.2 which is now on the ORD CEAM website. The QA/QC is largely complete and the final report mostly written. Completing the report as soon as possible is a high priority for EFED.

EXPRESS

Ron Parker reported on QA/QC of the EXPRESS PRZM/EXAMS shell. The Office of Research and Development (ORD) Center for Exposure Assessment Modeling (CEAM) is conducting an extensive review and QA/QC of the shell. EFED is conducting a similar review of all of the surface water modeling scenarios which will be included in EXPRESS.

EFED's Modeling Scenarios

Mark Corbin reported on EFED's effort to respond to public comments on PRZM surface water runoff modeling scenarios. The only comments were received from CLA. EFED sent a general response to the public docket in September 2004 and is now working on scenario-specific issues. This includes both the regional/national scenarios and the scenarios which were designed for use in the cumulative OP assessment only.

Corrected scenarios have been received back from the contractor and will now be reviewed in EFED before posting on the website. EFED is planning the release of the scenarios before the end of the year.

Spray Drift Update

Norm Birchfield reported that there is a new version of RegDisp which is linked to a new version of PE4, but that version has not been evaluated due to other work priorities. Work is also ongoing for the ground-spray model which would also be included in RegDisp. A version of RegDISP should go into QA/QC by the end of 2005 with approval following shortly after that.

Drift Reducing Technologies Project. An OPP/ORD group has been awarded about $300,000 to evaluate spray drift reducing technologies. This will allow evaluation of 2 - 4 different technical options. If some options are shown to reduce the amount of drift, it is possible that growers using these technologies would be allowed reduced buffers or other modifications would be made to pesticide labels to reflect reduced exposures.

Carbamate Cumulative Assessment

Nelson Thurman reported that the minutes and report of the February 15-18 Science Advisory Panel (SAP) meeting discussing the N-Methyl Carbamate Cumulative Assessment can be found at:

http://www.epa.gov/scipoly/sap/2005/february/minutes.pdf.

The second SAP meeting on this subject will be held August 23-26 in Washington. Times and locations for this meeting are available on the SAP website.

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Major Presentations

All of the following presentations will be posted on the EMWG website.

Coupled Watershed - Instream Sediment and Contaminant Transport and Fate Modeling System (Earl Hayter, USEPA-ORD/NERL)

Earl Hayter, of the USEPA Office of Research and Development, National Exposure Research Laboratory presented a coupled modeling system for simulating watershed and instream sediment and contaminant transport. The externally coupled modeling system consists of a watershed loading model and an instream hydrodynamic, sediment and toxicant fate and transport model.  The watershed loading model, the Hydrologic Simulation Program - FORTRAN (HSPF), simulates watershed hydrology and water quality for both conventional and organic pollutants.  The instream sediment fate and transport model, the Environmental Fluid Dynamics Code (EFDC), is a 3D model that simulates the transport of suspended sediment and contaminants.  Multiple size classes of sediments and associated depositions and resuspension processes and bed geomechanics are also simulated with EFDC.  The coupled modeling system has been applied to a 282 mi2 watershed and stream network that contains both point and non-point sources of an organic pollutant of concern.  The data requirements for the coupled modeling system are extensive and include hydrological, meteorological, land use and soil data; hydraulic and geomorphic data; flow and spatially varying sediment data; settling and resuspension velocities; and chemical properties of the toxicant(s) being modeled.

Factors Influencing Erosion in PRZM Modeling (Mark Corbin, EPA/OPP-EFED)

Mark Corbin, Senior Scientist of Environmental Fate and Effects Division of the Environmental Protection Agency presented the effects of some key parameters of PRZM and crop scenarios, which can potentially influence the estimated environmental concentrations (EECs). The objective of his presentation was to share the information with stakeholders regarding the Agency's ongoing internal investigation of the PRZM model and crop scenarios. The results of these investigations are critical in developing Agency's risk assessment and characterization approaches transparent, clear, consistent and reasonable (TCCR). The presentation consisted of

the evaluation of relative importance of erosion and runoff in contributing 	sediment mass as a function of Koc,

the evaluation using discrete C factors versus using an average value 	throughout the year on resulting EECs,

an illustration of the importance of compartment thickness on pesticide flux 	in erosion and the non-equilibrium condition between runoff and erosion, and

preliminary investigation on the effect on the resulting EECs using 	irrigation routine of selected scenarios for compounds with high and low Koc.

 The Agency will continue to probe the above key areas. He emphasized that no changes have been made or implemented in the Agency's current risk assessment and characterization processes. If changes occur, they will be communicated with the stakeholders by posting them on the OPP website.

Issues Associated with Estimating Slope Length Factor for GIS-based Sediment Erosion Modeling (Scott Jackson, BASF and Paul Hendley, Syngenta)

Scott Jackson and Paul Hendley presented analyses done for the Pyrethroids Working Group (PWG) to parameterize the Universal Soil Loss Equation, in particular the LS (slope length - slope gradient factor).    (Part 1) They discussed a method used by the Bureau of Land Management, devised by Moore and Wilson, and available on the BLM website under Terrain and Geomorphic Modeling.  The results were compared to historical (1920-1970 Purdue University) data sets from run-off plots of fixed length (670 feet) in Iowa and New York.  For the NY plot, correlation (R2) between measured and predicted results increased from 0.2 to 0.67 as plot length decreased from 90-m to 10-m.  The DEM-based method was also compared to National Resource Inventory data for Wilson County, NC (site of the NC cotton PRZM scenario), which uses a 30-m LS factor.  Total soil loss predicted was similar: 2.25 to 3 tons/year for NRI and 2-2.5 tons/year for DEM.  Paired point erosion (by mapping unit ID) was not consistently greater or lesser for either approach.  In comparison to STATSGO data, the gridded approach has finer resolution.  (Part 2)  The NRI method for erosion was examined.  It supplies a population of LS measurements, split by crop and slope class.  There is a close relationship between slope length and slope steepness (R2 = 0.91), and the slope length distribution is approximately log-normal.  The PWG concluded that the DEM method, while technically more attractive (the underlying SSURGO data better attach a particular soil ID to a crop with a county), was computationally too intense, and that the NRI approach was adequate for a coarse-level assessment.

Uncalibrated Modeling of Conservative Tracer and Pesticide Leaching to Ground Water using the Root Zone Water Quality Model (RZWQM) (Garey Fox, University of Mississippi)

Garey Fox of the University of Mississippi presented an evaluation of RZWQM, a leaching model using the Green-Ampt equation for infiltration and the Richards equation for redistribution.  Some advantages include its capacity to consider macropore flow and sub-daily precipitation and to modify half-life and sorption with depth.  A North Carolina soybean scenario and a Georgia peanut scenario were modeled "cold" and based on site-specific data.  PRZM modeling of the same data had been performed previously and the results were compared using the normalized objective function (NOF), a statistic assessing the difference between predicted and observed concentrations.  In the North Carolina scenario, RZWQM had better pore water NOFs than PRZM for most cases and for soil concentrations, the two models were generally equivalent at shallow depths but RZWQM improved over PRZM deeper in the soil profile.  In Georgia, PRZM had slightly better results for pore water herbicide concentrations.  The two models' results for soil concentrations were generally equivalent for bromide and a nematicide, but RZWQM was slightly better for the herbicide.  General trends showed that both models tended to overpredict leaching and that soil concentrations were more accurately predicted than pore water concentrations.

Modeling Sediment and Nutrient Transport at Field and Watershed Scales (Carrie Graff, USDA/ARS-Environmental Quality Lab, Beltsville, MD)

Carrie Graff, of the USDA/ARS Environmental Quality Laboratory (EQL), presented and compared four models that can be used to estimate sediment and nutrient loads transported from agricultural fields.  These are:

HSPF (Hydrologic Analysis Software Support Program);

SWAT (Soil, Water, Assessment Tool);

AnnAGNPS (Annualized Agricultural Non-point Source Model); and

REMM (Riparian Ecosystem Management Model).

Details of two of these models, AnnAGNPS and REMM, were provided.  These models have also been used together to evaluate the impact of nutrient and sediment transport into adjacent streams and wetlands.  AnnAGNPS provides a continuous simulation (in daily time steps) of runoff processes.  Unlike other models, AnnAGNPS retains discrete spatial characteristics by dividing the landscape into cells, each of which individually contributes to the stream at user-defined locations.  Runoff processes in AnnAGNPS are affected by weather, precipitation, soil moisture, runoff (determined by curve number), and tile drainage.  Estimates of sediment yields, nutrient yields, and pesticide yields can be obtained.  REMM requires inputs for daily weather data (e.g., ppt), soil characteristics (e.g., Manning's N), vegetation types (e.g., rooting depth), site description (e.g., slope), and upland inputs.  REMM provides information on depth to water table, water flux, sediment yield, N flux, P flux, and groundwater nutrient content.  Outputs obtained from REMM, used in conjunction with AnnAGNPS, are most sensitive to changes in precipitation, slope, and Manning's N, and are least sensitive to vegetation parameters.  Results from these models can be used to assess the impact of agricultural management practices on the transport of potential contaminants.

Multivariate Analysis of Paired Watershed Data to Evaluate Agricultural BMP Effects on Stream Water P (W. Dean Hively, Ph.D. - USDA-ARS Environmental Quality Laboratory)

Dean Hively, USDA-ARS, presented his Ph.D. work on the effects of BMPs on phosphorus (P) loading in a small watershed that supports New York City's water supply (Bishop et al., 2005).   The multi-agency NYC Watershed Agriculture Program was founded to implement BMPs to pursue a 40% reduction in annual P loads to NYC reservoirs, where summertime eutrophication has been found to be largely limited by P concentrations originating from non-point sources, such as dairy farms.  Dr. Hively compared matched event stream quality data from two small paired watersheds located in the Cannonsville Reservoir basin (a forested "non-farm watershed" that served as a control and a 160-hectare "farm watershed" that was 38% dairy farm pasture, 53% forest, 7% row crops, and 2% impermeable) collected from 1993 to 2000, to analyze the impact of implemented BMPs on dissolved and particulate P loading from the farm watershed rich with non-point sources.

The BMPs were implemented from 1995 to 1996, separating the matched data into 2 years of pre-treatment data (pre-BMP) and 4 years of post-treatment data (post-BMP) covering event loads of total dissolved phosphorus (TDP) and particulate phosphorus (PP) from 231 precipitation events.  Post-BMP "large storm flows" outnumbered pre-BMP "large storm flows" by 7 to 1, but were not found to skew the study results.  Dr. Hively used the following five multivariate analysis of covariance (ANCOVA) models in an effort to compare their strengths for this analysis.

Univariate matched loads model:

  ln(Pf) = a + b ln(Pnf) + f k + ε

Pf = farm event P load

Pnf = non-farm event P load

k = 0 if PRE-BMP, k= 1 if POST-BMP

Bivariate matched loads model:

  ln(Pf) = a + b ln(Pnf) + c ln(Qf/Qnf) +  f k + ε

ln(Qf/Qnf) compensates for differences in matched event precipitation

Multivariate matched loads model:

  ln(Pf) = a + b ln(Pnf) + c ln(Qf/Qnf) +  d ln(QfPeak) + e ln(QRf) + f k + 	ε

ln(QfPeak) and ln(QRf) represent effects of event magnitude on P 		loading processes

Univariate single watershed model for TDP analysis:

  ln(Pf) = a + b ln(Qf) + f k + ε

ln(Qf) accounts for event flow volume, allowing a comparison of farm P 		concentrations in the pre- and post-treatment periods

Bivariate single watershed model for PP analysis:

  ln(Pf) = a + b ln(QfPeak) + c ln(QRf) + f k + ε

Bivariate and multivariate models outperformed univariate models in each season of the year in comparison of adjusted R2 and statistical power.  Calculation of percent load reduction was best performed by the multivariate matched loads model for PP year-round and for TDP in all seasons except winter, for which the bivariate matched loads model performed best.

Dr. Hively concluded that ANCOVA provided estimates of P load reductions with confidence intervals and that the use of multiple covariates substantially increased model precision, which allowed separation of data into seasons.  Implementation of farm BMPs was associated with overall reductions in event based loading of TDP (40%) and PP (29%).  The small watershed approach evaluated the net effect of BMP implementation on P loading processes on farms.  Farm P loading rates (252 kg TDP ha-1 yr-1 PRE-BMP, 164 kg ha-1 yr-1 POST-BMP) remained high in comparison to the control (18 and 23 kg ha-1 yr-1).

Bishop, Hively, Stedinger, Bloomfield, Rafferty, and Lojpersberger.  2005.  Journal of Environmental Quality 34(3): 1087-1101.

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Wrap up

Next Meeting

The next meeting will be October 26th, 2005.

OPP Conference Room 1126

1801 S. Bell St. - Crystal Mall 2

Arlington, VA  22202

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May 4 6, 2004 1 PROPOSED HAZARD IDENTIFICATION METHODOLOGY FOR ASSESSMENT OF DERMAL SENSITIZATION RISK Timothy F. McMahon, Ph. D Jonathan Chen, Ph. D.

Office of Pesticide Programs U. S. EPA, Washington D. C. May 4 6, 2004 2 Outline Current regulatory approaches Biology of dermal sensitization Methods for induction thresholds Methods for elicitation thresholds Scientific uncertainty Populations of concern May 4 6, 2004 3 Acknowledgements Norm Cook ( OPP)

Nader Elkassabany, Ph. D. ( OPP)

Timothy Leighton ( OPP)

William Jordan ( OPP)

Winston Dang, Ph. D. ( OPP)

Denise Sailstad, Ph. D. ( ORD)

Michele Burgess, Ph. D.( OSWER)

Lee Hoffman, Ph. D., D. A. B. T ( OSWER)

Joseph Merenda ( OSCP)

Karen Hamernik, Ph. D. ( OSCP)

Nancy Chiu, Ph. D. ( OW) May 4 6, 2004 4 ° USEPA, § 40 CFR 798.4100:

" Information derived from tests for skin sensitization serves to identify the possible hazard to a population repeatedly exposed to a test substance."

° USFDA: FFDCA Section 601 ( cosmetics)

Prohibits distribution of cosmetics in interstate commerce which are adulterated or misbranded. A cosmetic is considered adulterated if it contains a substance which may make the product harmful or injurious to consumers under customary conditions of use.

DERMAL SENSITIZATION CURRENT APPROACHES May 4 6, 2004 5 ° USFDA cosmetics cont.

If tests are needed to determine dermal sensitization potential, classical animal tests or in vitro lternatives are used.

° USFDA: drugs In published guidance, the Buehler and GPMT tests are cited as reliable assays for determining the sensitization potential of topically applied drugs. The LLNA is cited as a " quantitative rather than essentially subjective" test.

DERMAL SENSITIZATION CURRENT APPROACHES ( Continued) May 4 6, 2004 6 DERMAL SENSITIZATION CURRENT APPROACHES ( Continued)

° CPSC 1500.3( b)( 9)

Before designating any substance as a strong sensitizer, the Commission, upon consideration of the frequency of occurrence and severity of the reaction,

shall find that the substance has a significant potential for causing hypersensitivity.

To determine whether a substance is a    strong'`

sensitizer, the Commission considers the available data for a number of factors, including but not limited to " the result of experimental assays in animals or humans ( considering dose response factors), with human data taking precedence over animal data." May 4 6, 2004 7 A registered pesticide is incorporated into an article to protect the integrity of the article or substance itself.

Treated articles such as treated wood do not bear pesticide labels or other communication methods to inform the public about potential hazards, including dermal sensitization. Treated Articles May 4 6, 2004 8 EPA's Office of Pesticides Programs ( OPP) is seeking expert advice on how to evaluate general population exposure to a pesticide that is recognized to cause dermal sensitization. Specifically, the Agency is interested in better understanding how such exposures may induce sensitization in the general population and how to establish criteria to protect against unacceptable dermal reaction.

The Agency is also seeking guidance from the SAP on how such exposures impact individuals already sensitized.

ISSUE BEFORE THE SAP PANEL May 4 6, 2004 9 Allergic Contact Dermatitis ( ACD)

Contact Hypersensitivity Contact Allergy Delayed Contact Hypersensitivity:

  A delayed, immunologically mediated inflammatory skin disease consisting of various degrees of erythema,

edema, and vesiculation.  ( Marzulli and Maibach, 1996)

  stimulation by chemical allergen ( in an inherently susceptible individual) of an immune response of the quality and vigor required to permit the provocation of an elicitation reaction upon subsequent encounter with the same chemical.  ( Kimber, 2004) May 4 6, 2004 10 Allergic Contact Dermatitis Characterized by two phases:

Induction:

An exposure of sufficient magnitude and/ or duration to activate specific immune mechanisms resulting in the acquisition of sensitization Elicitation/ challenge :

Responses induced in sensitized individuals upon exposure to the allergen by a relevant route. May 4 6, 2004 11 Dermal Irritation vs. ACD Edema Erythema Reaction time:

immediate Response on 1st exposure No immune memory Edema Erythema Reaction time: 24   72 hrs No response on 1st exposure Requires immune memory Irritation Irritation ACD ACD INDUCTION ELICITATION LOW MOLECULAR WT ALLERGEN MIGRATION TO LOCAL LYMPH NODE IL 1  , IL 6, IL 12 IL 1  ,

TNF  ,

GM CSF T CELL LYMPHOCYTE PROLIFERATION ICAM 1 LANGERHANS CELL ( LC) " PRIMED" LYMPHOCYTES SPECIFIC INFLAMMATORY RESPONSE CYTOKINES, COSTIMULATORY,

ADHESION MOLECULES INCREASE CELLULAR INFLUX EDEMA AND ERYTHEMA Contact Hypersensitivity*

Reprinted with permission from Sailstad, 2003 May 4 6, 2004 13 ° ACD is generally recognized as a threshold phenomenon, i. e.

below a certain concentration, ACD will not be expected to occur.

° However, thresholds are largely determined by the potency of the allergen, and induction/ elicitation thresholds vary mongIndividuals ( Kimber et al., 2003) Dose response relationships are observed for both induction and elicitation ( Scott et al., 2002).

° In addition, induction of ACD may occur after a single exposure, after contact with a sufficiently large area of skin, or as a consequence of repeated skin exposures ( Marzulli and Maibach., 1996). In some cases ( i. e. DNCB) a single contact can be sufficient for sensitization ( Griem et al., 2003).

Allergic Contact Dermatitis ( Continued) May 4 6, 2004 14 METHODS Contact Hypersensitivity Animal Models for Hazard ID GPMT and Buehler Test GPMT GPMT ID injection w/ and without ID injection w/ and without FCA FCA plus topical application:

plus topical application:

Days 0 and Days 5 Days 0 and Days 5 8 Day 20 Day 20 22 topical challenge 22 topical challenge Read Read: 24,48 h after challenge : 24,48 h after challenge Topical application Topical application  closed closed patch:

patch:

Days 0, 6 Days 0, 6 8, and 13 8, and 13 15 15 Day 27 Day 27 28 topical challenge 28 topical challenge of the untreated flank for 6 h of the untreated flank for 6 h Read Read: 24,48 h after : 24,48 h after removing patch removing patch BT BT Induction Induction Challenge Challenge Endpoint Endpoint May 4 6, 2004 16 Animal Models for Hazard ID The Buehler test and the maximization test are best suited for providing information on whether a substance is a skin sensitizer or not. The Local Lymph Node Assay ( LLNA) is a more recent method for assessing the induction phase of sensitization. Local Lymph Node Assay Days 1, 2 & 3 Apply Sensitizer Day 6  Inject H Thymidine 3 5 h Make Cell Suspension Determine H Thymidine Incorporation by Liquid Scintillation Counting 3 Reprinted with permission From Sailstad, 2003. May 4 6, 2004 18 Local Lymph Node Assay ( LLNA)

As an alternative to traditional tests, the LLNA provides:

Potential for determining a NOAEL

Use of fewer animals

Evaluation of induction phase

Biological basis for the endpoint of concern

Extensive assay data available May 4 6, 2004 19 LLNA cont.

The Immunotoxicity Working Group of ICCVAM in 1999 recommended the LLNA as a stand alone alternative for contact sensitization hazard provided certain protocol modifications were made At that time the ICCVAM IWG considered that the LLNA was not appropriate for certain classes of chemicals, including metals, strong irritants, and aqueous soluble materials. May 4 6, 2004 20 LLNA cont.

In 2001, the FIFRA SAP agreed with the Agency proposal that the LLNA was applicable for testing chemicals for contact sensitization and should be considered a preferred,

standalone assay.

The SAP also noted that expanding application of the LLNA to metals, strong irritants, and aqueous soluble materials should be considered based on additional data published since the 1999 ICCVAM peer review. May 4 6, 2004 21 INDUCTION THRESHOLDS  METHODS Approaches for quantitative determination of induction thresholds have been published using LLNA data ( Gerberick et al., 2001; Felter et al., 2003;

Griem et al., 2003).

As reviewed by Felter et al. ( 2003),

Gerberick et al. ( 2001) proposed a methodology for derivation of a ` sensitization reference dose' ( S RfD) May 4 6, 2004 22 This method employs the same fundamental concepts of a risk assessment, i. e. hazard identification,

doseresponse assessment, exposures assessment, and risk characterization.

Hazard is first identified from the available data,

Including animal and human test results. May 4 6, 2004 23 Gerberick et al. 2001 Dose response is then done using a weight of evidence approach, in which chemicals can be categorized into potency classes. For each potency class,

a ` default NOAEL' is assigned, as available NOAELs in the literature do not have a high degree of precision. May 4 6, 2004 24 Gerberick et al., cont.

May 4 6, 2004 Hazard Assessment   Murine LLNA data

Default NOAEL for Use in Risk Assessment  Gerberick ( 2000, 2001)

1

10 Potent

10 1,000 1000   10,000 Weak 1000   10,000 10 10  100 Strong 10   100 100 100  1000 Moderate 100   1000 10,000 > 10,000 Extremely Weak > 10,000 NA NC Non Sensitizing NC Default NOAEL (

g/ cm2)

Experimental Human NOAEL (

g/ cm 2)

Sensitization Potential A LLNA EC3 (

g/ cm2)

NC = Not Calculated, No Positive response is obtained at any concentration tested. An EC3 value cannot be calculated.

NA = Not Applicable. The Material is non sensitiser. A default NOAEL is not needed for risk assessment. May 4 6, 2004 25 Uncertainty factors are then considered to account for:

 Intra species variation ( age, genetic factors, skin integrity)

 Vehicle or product matrix effects ( e. g., soil, wood)

 Exposure considerations ( formulations, repeated exposures)

 Maximum UF for each area is 10, with a maximum UF of 1000  No inter species extrapolation UF, as LLNA data are currently used only for potency classification and not for determination of an actual NOAEL.

Gerberick et al., cont. May 4 6, 2004 26 Gerberick et al., cont.

S RfD = Default NOAEL uncertainty factor Comparison of S RfD to calculated exposure to Determine a Margin of Safety Principle could be potentially be applied to induction and/ or elicitation May 4 6, 2004 27 Griem et al. ( 2003)

Proposed an an approach to derive a ` safe area skin dose' for induction based on use of LLNA data. Comparison was made between EC3 values from LLNA tests and NOAEL/ LOAEL values from HRIPT or HMT tests for known human sensitizers. May 4 6, 2004 28 Griem et al ( 2003) cont. May 4 6, 2004 29 Uncertainty factors were then applied for derivation of safe area Induction doses Interspecies extrapolation UF of 3x Intraspecies variability UF of 10x 10x to account for a possible higher inducing potency of a chemical upon repeated exposure Division of the LLNA EC3 by the total UF of 300 results in an area dose which " should not induce sensitization in the vast majority of humans."

Griem et al. ( 2003) Cont. May 4 6, 2004 30 Elicitation thresholds Methods Methods have also been proposed for determination of concentrations or safe area doses for protection against elicitation in sensitized individuals. By inference, protection against elicitation would also be protective of induction,

as thresholds for induction are generally higher than those for elicitation ( Kimber et al., 2003) May 4 6, 2004 31 Griem et al. ( 2003)

Theoretically, a correlation should be expected between Sensitizing and elicitation potency of a chemical However, elicitation thresholds have been determined for only a small number of sensitizers.

Comparison of sensitization and elicitation area doses showed no obvious correlation.

ELICITATION THRESHOLDS METHODS May 4 6, 2004 32 Griem et al. ( 2003) cont. May 4 6, 2004 33 Griem et al ( 2003) cont.

Relevant for assessing elicitation is the ratio of the induction to elicitation threshold. A linear correlation was used to describe the relationship between log( induction/ elicitation threshold ratio) and log( elicitation threshold).

Based on this, it is proposed that the induction/ elicitation threshold ratio can be predicted on the basis of an established induction threshold. Griem et al., 2003 May 4 6, 2004 35 Uncertainty factors for derivation of the safe area dose for elicitation  Griem et al. 2003 ( cont.)

When based upon the EC3 induction threshold from an LLNA, the total UF = 300 ( 3x interspecies, 10x intraspecies, 10x repeated exposure)

When based upon a NOAEL/ LOAEL from one time HRIPT or sensitization potency from LLNA, total UF =

100 1000 ( 10x interspecies, 10x intraspecies, 3 10x LOAEL to NOAEL), plus inclusion of variable UF based on induction/ elicitation ratio. May 4 6, 2004 36 Uncertainty factors for derivation of the safe area dose for elicitation  Griem et al. SAP Comment To an EC3 value of 8.8 ug/ cm 2 were applied Uncertainty factors of:

1x interspecies 10x intraspecies 10x time ( repeated exposure)

15x Induction/ elicitation factor Total UF = 1500 ` safe area dose for Cr( VI) = 8.8/ 1500 = 0.006 ug/ cm 2 May 4 6, 2004 37 Griem et al., 2003 ( cont.)

To a benchmark value of 0.05 ug/ cm 2 from human patch test data were applied uncertainty factors of:

10x intraspecies 3x time ( repeated exposure)

Total UF = 30 ` safe area dose' = 0.05/ 30 = 0.002 ug/ cm 2 May 4 6, 2004 38 MET Approach Minimum Elicitation Threshold Based on the concept that there is an ` elicitation threshold'

Below which sensitization is not expected MET usually derived from tests in sensitized individuals Uniform scientific criteria for establishing the MET are not yet established, i. e. what is the appropriate response Level ( 5%? 10%?). Further, it is not known whether this concept can be applied to all chemical sensitizers. May 4 6, 2004 39 Uncertainty factors May 4 6, 2004 40 Areas of Uncertainty Inter species extrapolation Intra species variation Product matrix effects Exposure considerations May 4 6, 2004 41 Inter species extrapolation Intended to account for differences in response between animals and humans Griem et al. ( 2003) reported that sensitizing area doses are similar for murine LLNA and human data;

therefore, the inter species factor may be less than 10 May 4 6, 2004 42 Inter species factor, cont.

Not all proposals use this factor Felter et al. ( 2003) recognizes this factor but also recognizes that the murine LLNA has not been yet used for derivation of a NOAEL for use in quantitative assessment May 4 6, 2004 43 Intra species variation A 10x factor is proposed to account for variability based on age ( children vs.

adults), race, sex, and genetic make up ( Gerberick et al., 2001; Griem et al.,

2003; Felter et al, 2002). May 4 6, 2004 44 Product Matrix Effects Range of of 1 10x proposed ( Gerberick et al., 2001; Felter et al., 2002)

Accounts for exposure to the contact allergen in the product matrix vs. results from experimental studies Various components of the product may affect sensitizing potency of the allergen, e. g.

dermal irritation can increase the sensitizing potency.

Smaller factors may be considered for mild formulations. May 4 6, 2004 45 Exposure Variables Uncertainty factor proposed ( 1 10x) to account for:

Site of the body exposed

Repeated exposures

Bioavailability in matrix ( soil/ wood/ patch) May 4 6, 2004 46 Populations of Concern Non sensitized individuals Sensitized individuals Relative susceptibility of children vs.

adults ( Paustenbach et al., 1992; Felter et al. 2003; Wohrl et al., 2003) May 4 6, 2004 47 Worhl et al., 2003 May 4 6, 2004 48 Worhl et al., 2003 May 4 6, 2004 49 End