MODELS AND MODELING METHODS FOR ASSESSING HUMAN EXPOSURE AND DOSE TO TOXIC CHEMICALS AND POLLUTANTS
Contact
Impact/Purpose:
Research will be conducted to develop and apply integrated microenvironmental, and physiologically-based pharmacokinetic (PBPK) exposure-dose models and methods (that account for all media, routes, pathways and endpoints). Specific efforts will focus on the following areas:
1) Develop the Exposure Related Dose Estimating Model (ERDEM) System.
Includes: Updating the subsystems and compartments of the ERDEM models with those features needed for modeling chemicals of interest to risk assessors;
Designing and implementing the graphical user interface for added features.
Refining the exposure interface to handle various sources of exposure information;
Providing tools for post processing as well as for uncertainty and variability analyses;
Research on numerical and symbolic mathematical/statistical solution methods and computational algorithms/software for deterministic and stochastic systems analysis.
2) Apply ERDEM and other quantitative models to understand pharmacokinetics (PK) and significantly reduce the uncertainty in the dosimetry of specific compounds of regulatory interest.
Examples of the applications are:
exposure of children to pesticides
study design
route-to-route extrapolation
species extrapolation
experimental data analysis
relationship between parametric uncertainty and the distribution of model results
validity of scaling methods within species
validity of scaling methods from one species to another species
reduction of uncertainty factors for risk assessment
Description:
This project aims to strengthen the general scientific foundation of EPA's exposure and risk assessment, management, and policy processes by developing state-of-the-art exposure to dose mathematical models and solution methods. The results of this research will be to produce a modeling framework and integrated group of physiologically-based pharmacokinetic (PBPK) models.
This system called the Exposure Related Dose Estimating Model (ERDEM) can be easily modified for a variety of exposure assessment and risk characterization problems. The models interpret uptake into the body by multiple routes of entry (e.g., dermal, ingestion, and inhalation). Also, the modeling framework will be capable of incorporating the physiological changes of differing activity levels as well as the anatomic and physiological differences between infants and children during growth and development.
The development of mathematical methods includes parameter estimation methods and uncertainty analysis. These source-to-exposure-to-dose models provide the essential linkage between experimental data and assumptions established by regulation to dose-response models designed by toxicologists.
Record Details:
Record Type:PROJECTRelated Records:
PROPOSED MODELS FOR ESTIMATING RELEVANT DOSE RESULTING FROM EXPOSURES BY THE GASTROINTESTINAL ROUTERelationship Reason:PROPOSED MODELS FOR ESTIMATING RELEVANT DOSE RESULTING FROM EXPOSURES BY THE GASTROINTESTINAL ROUTE59760DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
USE OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL TO ESTIMATE ABSORBED CARBARYL DOSE IN CHILDREN AFTER TURF APPLICATION
Relationship Reason:USE OF A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL TO ESTIMATE ABSORBED CARBARYL DOSE IN CHILDREN AFTER TURF APPLICATION118164DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
USE OF EXPOSURE-RELATED DOSE ESTIMATING MODEL (ERDEM) FOR ASSESSMENT OF AGGREGATE EXPOSURE OF INFANT AND CHILDREN TO N-METHYL CARBAMATE INSECTICIDES
Relationship Reason:USE OF EXPOSURE-RELATED DOSE ESTIMATING MODEL (ERDEM) FOR ASSESSMENT OF AGGREGATE EXPOSURE OF INFANT AND CHILDREN TO N-METHYL CARBAMATE INSECTICIDES118151DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
WORKER HAZARD POSED BY REENTRY INTO PESTICIDE-TREATED FOLIAGE: REASSESSMENT OF REENTRY LEVELS/INTERVALS USING FOLIAR RESIDUE TRANSFER - PERCUTANEOUS ABSORPTION PBPK/PD MODELS, WITH EMPHASIS ON ISOFENPHOS AND PARATHION
Relationship Reason:WORKER HAZARD POSED BY REENTRY INTO PESTICIDE-TREATED FOLIAGE: REASSESSMENT OF REENTRY LEVELS/INTERVALS USING FOLIAR RESIDUE TRANSFER - PERCUTANEOUS ABSORPTION PBPK/PD MODELS, WITH EMPHASIS ON ISOFENPHOS AND PARATHION87369DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
EXPOSURE TO DOSE MODELS: THEIR USES IN HELPING ACCESS RELEVANT DOSE IN CHILDREN
Relationship Reason:EXPOSURE TO DOSE MODELS: THEIR USES IN HELPING ACCESS RELEVANT DOSE IN CHILDREN87106DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
AN ADVANCED PBPK MODEL INPUT SYSTEM AND DATA REPOSITORY FOR COMPLEX MODELS WITH EXPORT FOR THE ACSL MODEL ENGINE
Relationship Reason:AN ADVANCED PBPK MODEL INPUT SYSTEM AND DATA REPOSITORY FOR COMPLEX MODELS WITH EXPORT FOR THE ACSL MODEL ENGINE86964DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
FUGACITY-BASED INDOOR RESIDENTIAL PESTICIDE FATE MODEL
Relationship Reason:FUGACITY-BASED INDOOR RESIDENTIAL PESTICIDE FATE MODEL85595DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
APPLICATION OF ERDEM IN RISK ASSESSMENT: HEALTH EFFECTS DIVISION'S RISK ASSESSOR TRAINING AND CERTIFICATION PROGRAM
Relationship Reason:APPLICATION OF ERDEM IN RISK ASSESSMENT: HEALTH EFFECTS DIVISION'S RISK ASSESSOR TRAINING AND CERTIFICATION PROGRAM85414DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
RECONSTRUCTING POPULATION EXPOSURES FROM DOSE BIOMARKERS: INHALATION OF TRICHLOROETHYLENE (TCE) AS A CASE STUDY
Relationship Reason:RECONSTRUCTING POPULATION EXPOSURES FROM DOSE BIOMARKERS: INHALATION OF TRICHLOROETHYLENE (TCE) AS A CASE STUDY85244DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
BETTER EXPOSURE-DOSE MODELS FOR PESTICIDES
Relationship Reason:BETTER EXPOSURE-DOSE MODELS FOR PESTICIDES84335DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
PHYSIOLOGICALLY-BASED PHARMACOKINETICS/PHARMACODYNAMIC MODELING AND CUMULATIVE RISK ASSESSMENT: CASE STUDY FOR THE N-METHYL CARBMATE PESTICIDES
Relationship Reason:PHYSIOLOGICALLY-BASED PHARMACOKINETICS/PHARMACODYNAMIC MODELING AND CUMULATIVE RISK ASSESSMENT: CASE STUDY FOR THE N-METHYL CARBMATE PESTICIDES83663DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
PHYSIOLOGICALLY-BASED PHARMACOKINETIC/PHARMACODYNAMIC MODELING AND CUMULATIVE RISK ASSESSMENT: CASE STUDY FOR THE N-METHYL CARBAMATE PESTICIDES
Relationship Reason:PHYSIOLOGICALLY-BASED PHARMACOKINETIC/PHARMACODYNAMIC MODELING AND CUMULATIVE RISK ASSESSMENT: CASE STUDY FOR THE N-METHYL CARBAMATE PESTICIDES83662DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
HARMONIZATION AND COMMUNICATION OF PBPK MODELS USING THE EXPOSURE RELATED DOSE ESTIMATION MODEL (ERDEM) SYSTEM: TRICHLOROETHYLENE
Relationship Reason:HARMONIZATION AND COMMUNICATION OF PBPK MODELS USING THE EXPOSURE RELATED DOSE ESTIMATION MODEL (ERDEM) SYSTEM: TRICHLOROETHYLENE83030DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
USE OF PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS IN ASSESSMENTS
Relationship Reason:USE OF PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS IN ASSESSMENTS82559DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
METABOLISM OF 1,1- AND 1,3- DICHLOROPROPENE: A MECHANISM OF BIOACTIVATION BY GLUTATHIONE
Relationship Reason:METABOLISM OF 1,1- AND 1,3- DICHLOROPROPENE: A MECHANISM OF BIOACTIVATION BY GLUTATHIONE81456DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
DEMONSTRATION OF HUMAN EXPOSURE TOOLS
Relationship Reason:DEMONSTRATION OF HUMAN EXPOSURE TOOLS81454DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
HARMONIZATION AND COMMUNICATION OF PBPK MODELS USING THE EXPOSURE RELATED DOSE MODEL (ERDEM) SYSTEM: TRICHLOROETHYLENE
Relationship Reason:HARMONIZATION AND COMMUNICATION OF PBPK MODELS USING THE EXPOSURE RELATED DOSE MODEL (ERDEM) SYSTEM: TRICHLOROETHYLENE80989DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
TOWARDS A GENERIC PBPK MODEL OF PYRETHROID PESTICIDES: MODELING DELTAMETHRIN AND PERMETHRIN IN THE RAT
Relationship Reason:TOWARDS A GENERIC PBPK MODEL OF PYRETHROID PESTICIDES: MODELING DELTAMETHRIN AND PERMETHRIN IN THE RAT80200DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
COMPREHENSIVE PBPK MODELING APPROACH USING THE EXPOSURE RELATED DOSE ESTIMATING MODEL (ERDEM)
Relationship Reason:COMPREHENSIVE PBPK MODELING APPROACH USING THE EXPOSURE RELATED DOSE ESTIMATING MODEL (ERDEM)80193DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
A PBPK MODEL OF PYRETHROID PESTICIDES FOR APPLICATION IN RISK ASSESSMENT
Relationship Reason:A PBPK MODEL OF PYRETHROID PESTICIDES FOR APPLICATION IN RISK ASSESSMENT75892DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
ENVIRONMENTAL HEALTH
Relationship Reason:ENVIRONMENTAL HEALTH75060DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
A COMPREHENSIVE APPROACH FOR PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS USING THE EXPOSURE RELATED DOSE ESTIMATING MODEL (ERDEM) SYSTEM
Relationship Reason:A COMPREHENSIVE APPROACH FOR PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS USING THE EXPOSURE RELATED DOSE ESTIMATING MODEL (ERDEM) SYSTEM66380DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
TOWARDS A GENERIC PBPK MODEL OF PYRETHROID PESTICIDES: MODELING DELTAMETHRIN AND PERMETHIN IN THE RAT
Relationship Reason:TOWARDS A GENERIC PBPK MODEL OF PYRETHROID PESTICIDES: MODELING DELTAMETHRIN AND PERMETHIN IN THE RAT66378DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
CHEMOMORPHIC ANALYSIS OF MALATHION IN SKIN LAYERS OF THE RAT: IMPLICATIONS FOR THE USE OF DERMATOPHARMACOKINETIC (DPK) TAPE STRIPPING IN EXPOSURE ASSESSMENT TO PESTICIDES
Relationship Reason:CHEMOMORPHIC ANALYSIS OF MALATHION IN SKIN LAYERS OF THE RAT: IMPLICATIONS FOR THE USE OF DERMATOPHARMACOKINETIC (DPK) TAPE STRIPPING IN EXPOSURE ASSESSMENT TO PESTICIDES65641DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
ANALYSIS OF HOUSEHOLD WATER USE BEHAVIOR FOR USE AS IAQ MODEL PARAMETERS
Relationship Reason:ANALYSIS OF HOUSEHOLD WATER USE BEHAVIOR FOR USE AS IAQ MODEL PARAMETERS63538DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
INTEGRATED PROBABILISTIC AND DETERMINISTIC MODELING TECHNIQUES IN ESTIMATING EXPOSURE TO WATER-BORNE CONTAMINANTS: PART 1 EXPOSURE MODELING
Relationship Reason:INTEGRATED PROBABILISTIC AND DETERMINISTIC MODELING TECHNIQUES IN ESTIMATING EXPOSURE TO WATER-BORNE CONTAMINANTS: PART 1 EXPOSURE MODELING63535DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
INTEGRATED PROBABILISTIC AND DETERMINISTIC MODELING TECHNIQUES IN ESTIMATING EXPOSURE TO WATER-BORNE CONTAMINANTS: PART 2 PHARMACOKINETIC MODELING
Relationship Reason:INTEGRATED PROBABILISTIC AND DETERMINISTIC MODELING TECHNIQUES IN ESTIMATING EXPOSURE TO WATER-BORNE CONTAMINANTS: PART 2 PHARMACOKINETIC MODELING63504DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
EARTH DAY 2003: LEARNING FROM THE EAST IN THE EPA: EASTERN PHILOSOPHY ENRICHING WESTERN SCIENTISTS
Relationship Reason:EARTH DAY 2003: LEARNING FROM THE EAST IN THE EPA: EASTERN PHILOSOPHY ENRICHING WESTERN SCIENTISTS63126DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
A COMPARATIVE INVESTIGATION OF THE INFLUENCE OF DERMAL APPENDAGES (HAIR FOLLICLES) ON THE PERCUTANEOUS ABSORPTION OF ORGANOPHOSPHORUS (OP) INSECTICIDES USING QSAR AND PBPK/PD MODELS FOR HUMAN RISK ASSESSMENT
Relationship Reason:A COMPARATIVE INVESTIGATION OF THE INFLUENCE OF DERMAL APPENDAGES (HAIR FOLLICLES) ON THE PERCUTANEOUS ABSORPTION OF ORGANOPHOSPHORUS (OP) INSECTICIDES USING QSAR AND PBPK/PD MODELS FOR HUMAN RISK ASSESSMENT63074DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
THE IMPORTANCE OF OBTAINING INFORMATION ON THE SPECIFIC CONTENT OF TISSUE ENZYMES METABOLIZING ORGANOPHOSPHORUS PESTICIDES, PRIOR TO DETERMINE VMAX, KM VALUES FOR USE IN PBPK MODELS
Relationship Reason:THE IMPORTANCE OF OBTAINING INFORMATION ON THE SPECIFIC CONTENT OF TISSUE ENZYMES METABOLIZING ORGANOPHOSPHORUS PESTICIDES, PRIOR TO DETERMINE VMAX, KM VALUES FOR USE IN PBPK MODELS62966DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
THE IMPORTANCE OF OBTAINING INFORMATION ON THE SPECIFIC CONTENT OF TISSUE ENZYMES METABOLIZING ORGANOPHOSPHORUS PESTICIDES, PRIOR TO DETERMINING VMAX, KM VALUES FOR USE IN PBPK MODELS
Relationship Reason:THE IMPORTANCE OF OBTAINING INFORMATION ON THE SPECIFIC CONTENT OF TISSUE ENZYMES METABOLIZING ORGANOPHOSPHORUS PESTICIDES, PRIOR TO DETERMINING VMAX, KM VALUES FOR USE IN PBPK MODELS62720DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
IN VITRO DETERMINATION OF KINETIC CONSTANTS FOR 1,3-DICHLOROPROPANE, 2,2-DICHLOROPROPANE, AND 1,1-DICHLOROPROPENE IN RAT LIVER MICROSOMES AND CYTOSOL
Relationship Reason:IN VITRO DETERMINATION OF KINETIC CONSTANTS FOR 1,3-DICHLOROPROPANE, 2,2-DICHLOROPROPANE, AND 1,1-DICHLOROPROPENE IN RAT LIVER MICROSOMES AND CYTOSOL62571DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
AN INDOOR PESTICIDE AIR AND SURFACE CONCENTRATION MODEL
Relationship Reason:AN INDOOR PESTICIDE AIR AND SURFACE CONCENTRATION MODEL62306DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) MODEL FOR PREDICTING THE DERMAL DOSE AND DISPOSITION OF ORGANOPHOSPHORUS INSECTICIDES
Relationship Reason:PHYSIOLOGICALLY-BASED PHARMACOKINETIC AND PHARMACODYNAMIC (PBPK/PD) MODEL FOR PREDICTING THE DERMAL DOSE AND DISPOSITION OF ORGANOPHOSPHORUS INSECTICIDES62301DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
VISUALIZATION-BASED ANALYSIS FOR A MIXED-INHIBITION BINARY PBPK MODEL: DETERMINATION OF INHIBITION MECHANISM
Relationship Reason:VISUALIZATION-BASED ANALYSIS FOR A MIXED-INHIBITION BINARY PBPK MODEL: DETERMINATION OF INHIBITION MECHANISM62291DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
PROPOSED SUITE OF MODELS FOR ESTIMATING DOSE RESULTING FROM EXPOSURES BY THE DERMAL ROUTE
Relationship Reason:PROPOSED SUITE OF MODELS FOR ESTIMATING DOSE RESULTING FROM EXPOSURES BY THE DERMAL ROUTE62186DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
RECONSTRUCTING EXPOSURE SCENARIOS USING DOSE BIOMARKERS - AN APPLICATION OF BAYESIAN UNCERTAINTY ANALYSIS
Relationship Reason:RECONSTRUCTING EXPOSURE SCENARIOS USING DOSE BIOMARKERS - AN APPLICATION OF BAYESIAN UNCERTAINTY ANALYSIS61418DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
THE INDOOR FUGACITY MODEL
Relationship Reason:THE INDOOR FUGACITY MODEL61333DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
A FUGACITY-BASED INDOOR RESIDENTIAL PESTICIDE FATE MODEL
Relationship Reason:A FUGACITY-BASED INDOOR RESIDENTIAL PESTICIDE FATE MODEL61332DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
SIMULATION MODELING OF GASTROINTESTINAL ABSORPTION
Relationship Reason:SIMULATION MODELING OF GASTROINTESTINAL ABSORPTION60727DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
USE OF PBPK/PD MODELS AND FOLIAR TRANSFER COEFFICIENTS IN ASSESSING REENTRY INTO PESTICIDE TREATED CITRUS AND TURF
Relationship Reason:USE OF PBPK/PD MODELS AND FOLIAR TRANSFER COEFFICIENTS IN ASSESSING REENTRY INTO PESTICIDE TREATED CITRUS AND TURF60579DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
CHEMOMORPHIC ANALYSIS OF MALATHION IN SKIN LAYERS: IMPLICATIONS FOR THE USE OF DERMATOPHARMACOKINETIC (DPK) TAPE STRIPPING IN EXPOSURE ASSESSMENT TO PESTICIDES
Relationship Reason:CHEMOMORPHIC ANALYSIS OF MALATHION IN SKIN LAYERS: IMPLICATIONS FOR THE USE OF DERMATOPHARMACOKINETIC (DPK) TAPE STRIPPING IN EXPOSURE ASSESSMENT TO PESTICIDES60573DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
UNCERTAINTY ANALYSIS OF TCE USING THE DOSE EXPOSURE ESTIMATING MODEL (DEEM) IN ACSL
Relationship Reason:UNCERTAINTY ANALYSIS OF TCE USING THE DOSE EXPOSURE ESTIMATING MODEL (DEEM) IN ACSL60572DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)
Relationship Reason:APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)60570DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR ROUTE TO ROUTE DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)
Relationship Reason:APPLICATION AND USE OF DOSE ESTIMATING EXPOSURE MODEL (DEEM) FOR ROUTE TO ROUTE DOSE COMPARISONS AFTER EXPOSURE TO TRICHLOROETHYLENE (TCE)60440DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
USE OF PBPK MODELS FOR ASSESSING ABSORBED DOSE AND CHE INHIBITION FROM AGGREGATE EXPOSURE OF INFANTS AND CHILDREN TO ORGANOPHOSPHORUS INSECTICIDES
Relationship Reason:USE OF PBPK MODELS FOR ASSESSING ABSORBED DOSE AND CHE INHIBITION FROM AGGREGATE EXPOSURE OF INFANTS AND CHILDREN TO ORGANOPHOSPHORUS INSECTICIDES60252DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
PREDICTIVE ORGANOPHOSPHORUS (OP) PESTICIDE QSARS AND PBPK/PD MODELS FOR RISK ASSESSMENT OF SUSCEPTIBLE SUB-POPULATIONS
Relationship Reason:PREDICTIVE ORGANOPHOSPHORUS (OP) PESTICIDE QSARS AND PBPK/PD MODELS FOR RISK ASSESSMENT OF SUSCEPTIBLE SUB-POPULATIONS59894DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
USE OF A CONVECTION-DIFFUSION MODEL TO UNDERSTAND GASTROINTESTINAL ABSORPTION OF ENVIRONMENTALLY-RELEVANT CHEMICALS
Relationship Reason:USE OF A CONVECTION-DIFFUSION MODEL TO UNDERSTAND GASTROINTESTINAL ABSORPTION OF ENVIRONMENTALLY-RELEVANT CHEMICALS59762DOCUMENT1.0A PRODUCT OF THE PROJECTREVIEWEDPUBLICORDNERL
Project Information:
Progress :The ERDEM modeling system has been released on the Web for evaluation and review. It consists of models for the various organs in the body.This includes two models for the lung as well as for the gastro-intestinal (GI) tract. The dermal model in this version is for skin exposure to chemical in water such as would occur in a shower. Multiple exposures can be modeled for multiple chemicals. Multiple metabolites can be modeled as circulating just as for each of the exposure chemicals.
A research version of the above model is able to perform enzyme inhibition calculations as well as dermal exposure from surfaces to skin.
This version of the ERDEM models has been placed on the HEASD web page for user code evaluation. The GUI interface for this version has been completed (March, 2004) as a demo version so that users can evaluate the new interface. It is not yet connected to the associated models.
ERDEM was used to determine dose due to exposure to Malathion from a lice treatment application to the scalp. Experimental urine data for the diakyl-phosphates from male and female rats was used Carbaryl, one of the N-Methyl Carbamates was modeled. Enzyme inhibition was calculated and parameters were adjusted to compare with experimental data for amount of active enzyme for rat brain and blood.
Simulations were performed for methyl-tertiary butyl ether (MTBE) and comparisons were made with multiple sources of experimental data for oral and inhalation exposure routes. Sensitivity and Monte Carlo analyses were performed and reported for use in MTBE risk assessment.
The ERDEM modeling architecture was designed as a graphical software platform to assist exposure and risk assessors. The ERDEM was initially coded with exposure modules and portal of entry descriptions.
In FY99, a model was developed to estimate dose resulting from repeated exposure to trichloroethylene (TCE). The TCE model has been used to study the dose equivalence between two different routes of exposure (inhalation versus oral). Model output was compared with data from human volunteers.
Also in FY 99, sensitivity and uncertainty modules were developed, tested, and applied to the TCE model. The TCE model was also reformulated to allow for time-history of exposure concentrations to be used as inputs.
In FY 99, the ERDEM framework was expanded to where it could simulate circulating metabolites in response to exposure to multiple compounds. In FY 00, equations describing binding in the body's organs were added.
Also, in FY 00 equations were introduced to specifically handle inhibition of brain acetylcholinesterase (AChE) and plasma cholinesterase (ChE) by organophosphorus (OP) pesticides (chlorpyrifos, parathion, and isofenphos). For the last three compounds the model was designed to estimate dose for a single compound or multiple compounds. For these pesticides (singly or in combination), model output included estimates of enzyme metabolism and inhibition, tissue distribution, and elimination of biomarkers.
The initial OP model was based on occupational exposure of farm workers as related to agricultural health initiatives. In FY 01, the OP model was specifically designed to simulate exposure scenarios for children in various age classes in support of FQPA. The model was used to test conservative (protective) assumptions against amassed exposure and toxicokinetic data in an effort to identify data gaps and assess model structure. In the absence of empirical data, provisional estimates of biological factors were derived from Quantitative Structure Activity Relationships for 31 OP pesticides of interest to EPA.
The OP model successfully examined aggregate exposure of infants and children resulting from combined and sequential interaction with various sources, food and water, indoor air, and indoor and outdoor surfaces, by way of oral, inhalation and dermal pathways.
Relevance :Relevance/Significance/Impact: Exposure related physiologically-based pharmacokinetic (PBPK) and pharmacodynamic (PBPD) models as developed in ERDEM hold the very real promise of aiding risk assessors and policy experts in making informed judgements about the scientific validity of safety factors, reference doses, and dose extrapolations involving aggregate exposure to chemicals with additive (cumulative) and synergistic toxicity. The adaptable framework as developed within ERDEM for such diverse chemicals as TCE and the OP insecticides may be expanded to other toxic substances of interest within EPA, e.g., OPPTS and OPP, and other national, e.g., NIOSH and NIEHS, and international agencies, e.g., Organization for Economic Cooperation and Development (OECD). By better characterizing the exposure to dose to response continuum risk assessments will be based on better interpretations of scientific data. A user-friendly front-end attached to the ERDEM model will facilitate the implementation of models by a large audience and will allow people to examine the output for whatever exposure scenarios are of interest to them. External collaborators (such as investigators at the Environmental and Occupational Health Sciences Institute (EOHSI) and Lawerence Berkeley National Laboratory (LBNL)) have joined with ERDEM modelers and scientists developing second generation aggregate exposure modules. This collaboration involves sharing of data, stochastic and deterministic models and theories. What has emerged from this collaboration is an expansive characterization of uncertainty surrounding the accuracy and precision of measurements, the comparability and representativeness of extant data, and the completeness and reasonableness of assumptions. Thus the outcomes from the ERDEM can be verified and data gaps can be identified to where more advanced experimental protocols and procedures can be applied. We expect the future will involve the use of PBPK models in conjunction with "weight-of- the-evidence" procedures to formulate state-of-the science analyses.
Clients :OPPTS, OPP, OSWER, ORD, NERL, NCEA, NHEERL, Scientific Community
Project IDs:
ID Code :3906Project type :OMIS