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

2

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

3

Internal Dose in Risk Assessment Context

Exposure characteristics

Internal dose estimation

Dose distribution and fate in lung

Risk evaluation

4

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)

5

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

6

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

7

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.

8

Building a Computational Dosimetry Model

Exposure ‐> Inhalation ‐> Transport ‐> ‐> Clearance

Aerosol size distribution

ImpactionDiffusion

9

Four Components of Particle Respiratory Deposition Model

10

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)

11

First Component: URT Deposition Modeling

12

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

13

Second Component: Lower Respiratory Tract

Geometry

14

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

15

LRT GeometriesRats (Monopodial)

Asymmetric

Humans

Reconstructed

SymmetricTypical-path

Asymmetric lung

5 symmetric lobes

16

Third Component: Lung Ventilation

PInspiration Expiration

IntrapleuralPressure

AlveolarPressure

Inspiration

Expiration

17

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

18

Fourth Component: Particle Transport Modeling

19

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

20

Model Verifications (humans)

21

Comparison with MeasurementsOral:

Nasal:

TB PUL Total

22

Model Predictions (humans)

23

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

24

Regional Deposition

0

0.2

0.4

0.6

0.8

1

0.01 0.1 1 10

TBPUL

Particle Diameter, m

Regional Deposition

25

2 nm 5 nm 10 nm

Ultrafine Deposition Distribution

- More homogenous deposition with decreasing particle size (behave like gases)

26

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

27

(Deposition Fractions in an Eight-Year Old child)

LLRL

RURL

RM

Scaled with volume

Example 1: Age-Depended LRT Deposition

28

Adjusted Deposition Fraction at Different AgesDose metric: deposition per volume

29

Deposition Across Age GroupsDose metric: Deposition per unit surface area

30

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.

31

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

32

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

33

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

10

1

HEC/CA> 1 (HEC > CA ) Conservative exposure concentration

HEC/CA

34

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.