Multiple Path Particle Dosimetry Modeling (MPPD) · A four-component, multiple path, particle...
Transcript of Multiple Path Particle Dosimetry Modeling (MPPD) · A four-component, multiple path, particle...
Multiple Path Particle Dosimetry Modeling (MPPD)
Bahman Asgharian Applied Research Associates, Inc., Raleigh, NC
Granular Biopersistent Dust (GBS) and Translational Toxicology: Deriving HECs/ Occupational Limit Values
Berlin, GermanyDecember 9, 2016
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Application, challenges and assumptions Dosimetry modeling of environmental aerosols Example #1 – Internal dose as a function of age Example #2 – Interspecies extrapolation Summary and Conclusions
Outline
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Internal Dose in Risk Assessment Context
Exposure characteristics
Internal dose estimation
Dose distribution and fate in lung
Risk evaluation
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Dosimetry Modeling Applications in risk Assessment
Establishes comprehensive exposure-dose-response –characterization
Improves interspecies dose-metric adjustment and extrapolation by reducing uncertainty and variability
Interfaces with PBPK models to determine the dose to other tissues
Aids in design of inhalation exposure studies
Aids in design of toxicological and human clinical studies
Bio-defense: Dose assessment/risk evaluation from exposure to agents (Chemical, biological, radiological and nuclear)
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Modeling Challenges
Complex LRT geometry:- Multi-scale airway dimensions- Too many airways- Complicated airway geometry
Lung ventilation is not fully understood
- Need to make simplifying assumptions without compromising physics/physiology
- Accuracy of predictions depends on model assumptions
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Modeling Assumptions
Geometry Dichotomous branching structure Straight tube airways
Lung ventilation Forces for air transport (convective, resistive, etc.) are
independent Parabolic flow velocity (low Reynolds number)
Particle transport Average properties across airway cross sections (1D modeling) Simplified BCs: Losses are included as a sink term
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Calculate: Deposition fraction in the lung (per breath)- Regional (URT, TB, PUL, LRT, total)- Lobar- Site-specific
Given: Exposure environment - Aerosol concentration- Aerosol size distribution
Airway parametersLung and breathing parametersBreathing route & pattern
Reparatory Tract Deposition Modeling
Objective: Calculate internal dose in the respiratory tract.
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Building a Computational Dosimetry Model
Exposure ‐> Inhalation ‐> Transport ‐> ‐> Clearance
Aerosol size distribution
ImpactionDiffusion
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Four Components of Particle Respiratory Deposition Model
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1. URT deposition modeling- Deposition fractions are from measurements or numerical computations- Develop semi-empirical equations as a function non-dimensional
parameters
2. Respiratory tract geometry- Scanned imagery for large airways and morphometry for small airways- TB: symmetric or asymmetric- PUL (A): symmetric due to the large number and random orientations
3. Respiratory tract ventilation- Steady breathing: uniform expansion & contraction- Unsteady breathing: time varying flow
4. Particle transport modeling- Based on population (mass) balance per airway (Eulerian)
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First Component: URT Deposition Modeling
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Impaction:
Brownian Diffusion:
impdifimpdifnet )1()1(1
Compartmental model: The two mechanisms are assumed independent. Overall Deposition Fraction:
Deposition Mechanisms
Fit data to models Semi-empirical equations
Proportional to d2Q
Impaction Diffusion)( imp )( dif
)Qd(f 2imp
Proportional to D & Q. )Q,D(fd
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Second Component: Lower Respiratory Tract
Geometry
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LRT Geometry Tree-like branching structure: dichotomous branching pattern
made up of tracheobronchial tree and alveolar sub-tree.
Tree geometry: symmetric, asymmetric, and monopodialSymmetric: both daughters identical - typical pathAsymmetric/monopodial : daughters have different dimensions and orientations
Symmetric structure: Average deposition lung per depth
Asymmetric geometries:- Are more accurate representations that allow for site-specific dose prediction.
- Require better data sources (have for the rat) and are more involved mathematically
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LRT GeometriesRats (Monopodial)
Asymmetric
Humans
Reconstructed
SymmetricTypical-path
Asymmetric lung
5 symmetric lobes
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Third Component: Lung Ventilation
PInspiration Expiration
IntrapleuralPressure
AlveolarPressure
Inspiration
Expiration
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Two Ventilation Models Were Developed
Steady breathing (uniform lobe expansion):˗ Normal breathing – HEC calculations, risk assessment˗ Airflow rate is proportional to distal volume.
Unsteady breathing (RLC network analysis):˗ Diseased lung, HFV, more detailed calculations.˗ Flow rate is proportional to R, C, and L.˗ Flow splitting is proportional C of branches.
P
d1
d2
p
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Fourth Component: Particle Transport Modeling
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Depositiontransport
massNettransport
massNetchange
number/Mass
ConvectionDiffusion
Particle Transport Equations
Calculate particle concentration from a mass balance in an airway:
Particle concentration and deposition are calculated for all airways of the lung from the above models
P
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Model Verifications (humans)
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Comparison with MeasurementsOral:
Nasal:
TB PUL Total
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Model Predictions (humans)
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0
0.1
0.2
0.3
0.01 0.1 1 10
RU
Dep
ositi
on F
ract
ion
Particle Diameter, m
0
0.1
0.2
0.3
0.01 0.1 1 10
RM
Dep
ositi
on F
ract
ion
Particle Diameter, m
0
0.1
0.2
0.3
0.01 0.1 1 10
RL
Dep
ositi
on F
ract
ion
Particle Diameter, m
0
0.1
0.2
0.3
0.01 0.1 1 10
LL
Dep
ositi
on F
ract
ion
Particle Diameter, m
0
0.1
0.2
0.3
0.01 0.1 1 10
LU
Dep
ositi
on F
ract
ion
Particle Diameter, m
Overall Deposition- Typical-path- Five-lobe symmetric- 30 stochastic (asymmetric)
0
0.2
0.4
0.6
0.8
1
0.01 0.1 1 10
stochastic5-lobe symmetrictypical-path symmetric
Particle Diameter, m
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Regional Deposition
0
0.2
0.4
0.6
0.8
1
0.01 0.1 1 10
TBPUL
Particle Diameter, m
Regional Deposition
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2 nm 5 nm 10 nm
Ultrafine Deposition Distribution
- More homogenous deposition with decreasing particle size (behave like gases)
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Multiple Path, Particle Dosimetry Model (MPPD)
˗ Lung geometry˗ Particle characteristics˗ Breathing parameters ˗ Breathing route˗ Lung parameters (FRC, URT volume)
Input:
- Textual: Input parameters, predictions - Graphical: Deposition per generation/lobe/region- Data files: Export to other graphical packages
and spreadsheets
Output:
V1.0 CIIT (B. Asgharian, F.J. Miller, R. Subramaniam, O.T. Price), Dutch Ministry ofHealth (RIVM) (J. Frier, Flemming Cassee) Funding: CIIT, RIVM, EPA
V2.0, 3.04 ARA (B. Asgharian, F.J. Miller, O.T. Price) Funding: CDC/NIOSH, NIH, ONR, ICA
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(Deposition Fractions in an Eight-Year Old child)
LLRL
RURL
RM
Scaled with volume
Example 1: Age-Depended LRT Deposition
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Adjusted Deposition Fraction at Different AgesDose metric: deposition per volume
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Deposition Across Age GroupsDose metric: Deposition per unit surface area
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Example 2: Interspecies Dose Extrapolation
Calculate human equivalent concentration (HEC) based on a dose-metric.
Exposure concentration & biological responses are known in animals from inhalation studies.
Use MPPD to calculate regional, total, lobar, and deposition per airway or retained dose (i.e., dose-metric) in animals.
Assume the same biological response for the same dose-metric.
Can calculate HEC for a dose-metric based on deposition or retained dose-metric.
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HEC Calculations based on Deposited Mass
A
H
A
H
A
HE
AE Ctt
SA/DFSA/DF
VV
HEC
time
osureexpvolume
uteminionconcentrat
osureexpfraction
depositionmass
deposited
tVCDFMass E
AH SAMass
SAMass
Dose metric based on deposited mass/surface area
MassTimeTime
VolumeVolume
MassDF
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Laboratory AnimalExposure(g/m3)
Human EquivalentExposure (HEC)
(g/m3)
Laboratory AnimalEffective
Internal Dose Metric
Human Effective Internal Dose Metric
Laboratory AnimalDosimetry Model
Human Dosimetry Model
Laboratory AnimalExposure(g/m3)
Human EquivalentExposure (HEC)
(g/m3)
Laboratory AnimalEffective
Internal Dose Metric
Human Effective Internal Dose Metric
Laboratory AnimalDosimetry Model
Human Dosimetry Model
Step 1. Step 2.
Step 3.Step 4.
(By trial and error)
HEC Calculations based on Retained Mass
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Dose metric : Deposited Mass/Surface Area
TB region
10-3
10-2
10-1
0.5 1 6
Deposition/Area in large TB airwaysDeposition/Area in small TB airwaysDeposition/Area in all TB airways
Particle Diameter, m0.3
Dose Metric
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1
HEC/CA> 1 (HEC > CA ) Conservative exposure concentration
HEC/CA
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Summary & Closing Remarks
A four-component, multiple path, particle dosimetry model was developed to predict regional and local deposition of particles.
Model predictions were in good agreement with regional and total deposition in humans.
MPPD was developed with a user-friendly GUI based on the dosimetry model.
MPPD can be used for interspecies extrapolating (HEC) and risk assessment.