Document vyJpddRbQ4Me30DeOn0J5E09
Estimating Human Risk from Exposure to VC
Quantification with FB-PK Modeling
Richard H. Reitz Michael L. Gargas McLaren/Hart, ChemRisk Division
for CMA Vinyl Chloride Panel
May 19,1994
044
Collaborators!
McLaren/Hart: R. H. Reitz M. L. Gargas
IC1 Toxicology Lab (Zeneca) T. L. Green W. M. Provan
U. S. E. P. A. (Res Tri Park) M. E. Andersen
2
BOR 0 1 1 9 1 6
VC History!
Low Acute Toxicity Occup. Expos. Limits - 500 ppm Viola (1970,1971)
Rats, Increased Tumor Incidence
Maltoni (1974)
Confirmed Viola's Results Identified Rare Liver Angiosarcoma Dose Response Flat > 1,000 ppm
Creech & Johnson (1974)
Found Same Cancer Type (Liver AngkKacroma) In Humans
Human Tumor Registry (to Present)
14,000 Subjects, 19 VC Plants
V2G/94
3
Objectives / Opportunity |
Develop A Process for Quantitatively Estimating Risk In Humans
+ Low, Non-Occupational Exposures - Superfund Sites - Fugitive Emission - Drinking Water
Test the Utility of our Cancer Risk Assessment Procedures
+ Rich Animal Data Set in Rats and Mke + Unique Opportunity to Compare Risk
Assessment with Actual Results In Humans
&W94
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Expectations for Pharmacokinetic Modeling
Modeling Cannot Eliminate ALL Uncertainty from Risk Assessments
Modeling Can Quantitatively Describe:
Metabolic Saturation Changes In Dose Route Physiological Differences in Species
PREMISE:
Risk Assessments based on Estimates of "Delivered Dose" will be More Reliable than Risk Assessments based Only on Administered Dose
s
Classical Pharmacokinetics:
"Stripping the Curve"
Curva Stripping fEimnnantlalsl C(t) - A) * tT a i1
5/2tm
6
BOR 0 1 1 9 1 8
dAO/dt - -ka*Doe dAl/dt - ka*Dos - K13 *Cl + 021*02 - ku*Cl
dU/dt - +021*01 - 021*02
dClia/dt - -k*Cl
SOW* 1
Advantages of PB-PK Models:
Compound Specific Information
Vapor Pressure Solubilities (Pardlkmlng) in Tissues
Species Specific Information
Physiology Metabolism
Route Specific Information
Oral Route, 1st Pass Through Liver
Allow Extrapolations
Betweea Dose Routes Between High Dose / Low Dose Betweea Species
mm s
BOR 0 1 1 9 1 9
A PB-PK Model for VC
Metabolites Bated om Raowey fc Aaderate, 1964
9
Capabilities of PB-PK Models
Will use examples from studies of Reitz et ai., at Dow Chemical Co., with 1,1,1-trichloroethane (Methylchloroform, MC)
Data used to Illustrate potential applications for VC PB-PK Model.
5/2IV94
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x z e tto
MC Rat Inhalation
(Blood Levels)
Methylchloroform, (MC) used as an example of the technique.
MC Mouse Inhalation
(Blood Levels)
8
Methylchloroform, (MC) used as an example of the technique.
U 5wm
12
MC Mouse Inhalation
(Other Endpoints)
2
1.5
1
0.5
0
BurdenFatLiver_______________Metab B 150 ppm 1500 ppm
420*4
13
MC Human Inhalation
(Exhaled Air)
Humans - Inhalation
420*4
14
BOR 0 1 1 9 2 2
MC Rat Water
(Exhaled Air)
snom
IS
Approach; VC PBPK Model]
(1) Parameterize Model
Physiological Constants - Andersen et al., 1987
Partition Coefficients - Vial Equilibration - Fat, Liver, Muscle, Blood
Metabolic Rate Constants - In Vivo (Rats, Mice)
(2) Validate Model
Independent Rat, Mouse and Human In Vivo Studies
(3) Extrapolate Risks
Rats to Mice Rats to Humans
SI1WM
BOR 0 1 1 9 2 3
BOR 0 1 1 9 2 4
VC Partition Coefficients Via! Equilibration
Measure:
Blood/Air Llver/Alr Fat/Alr Muscle/Alr
Calculate:
TIssue/Blood
VC Metabolic Rate Constants Gas Uptake Apparatus
mm
17 3/20/94
18
BOR 0 1 1 9 2 5
Gas Uptake Data
(Male Rats)
Gas Uptake Data
(Female Rats)
snvu
19 5non*
2D
r
Validation of Rat Model
(Watanabe et a!., 1976)
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Estimating Mouse Metabolic Rate Constants*
Small, Halogenated Hydrocarbons Metabolized by CyP450 2EI
In Vivo VMax's from Experiments
Methylene Chloride (MeClj) (Rats, Mice, Humans)
Chloroform (CHCI,) (Rats, Mice)
Calculate VMax / grain Liver
Normalize to Rat In Vivo
MeCl2 chci3 Average
Mouse 2.57 2.71 2.64
Human 0.21 0.21
SflOtf*
22
BOR 0 1 1 9 2 6
BOR 0 1 1 9 2 7
Testing Estimated Mouse Metabolic Constants
Optimized Mouse Data|
*2tm
23 5/30/94
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Validation of Homan Model
(Baretlaetal., 1969)
wow
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Deriving Rat Potency)
Based on Maltont's Experiments
12 Months Exposure 0,1,5,10,25,50,100,150,209,250,500,
2500,5000,10000,30006 ppm tested Poor Survival 10000 and 30000; Use
Remaining 13 Dose Groups
Use PB-PK Model to Calculate Pose
Average Amount VC Metabolites per day per Liter of Liver Tissue
Howe & Crump's GLOBAL83 Multistage Model Dose Response (Maximum Likelihood Estimate)
Comparison: Linear Model Fitted to Top Two Doses (MTD, MTD/2)
S/20/94
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BOR 013-928
snxm
PK Dow
PPM Vinyl CMoiide
Extrapolating Rat > Mouse
(Maltoni, Swiss Albino Mice)_______
Cone 0 50
250 500 2,500
Males 0/80 1/30 9/30 6/30 6/29
Females 0/70 0/30 9/30 8/30 10/30
LADD 0.0 36.4
173.1 265.2 331.0
Equivalent Amounts erf* Metabolite produce Equivalent Tumor Yields
No Surface Area Correction Factor Used.
The 1(H RSD = 0.80 x 10-1
v SS2QS94
BOR 0 1 1 9 2 9
Comp^
Maltoni et al., (Rat) Maltoni et ai., (Mouse) Lee et ai., (Mouse)
0.177 0.080 0.120
Drew et al., (B6 Mouse) ^0.0032
Diagnostic Crlter
Drew
reported angiosacromas in Lee and Maltoni saw none.
B6C3F1 Ultrasensitive?
Reported to have partial oncogene activation in absence of any chemical treatment.
HO/M
29
Extrapolating Rat -> Humans
(Maltoni, Rat Potency)
Equivalent Amounts of Metabolite produce Equivalent Tumor Yields No Surface Area Correction Factor Used. Calculated "Unit Risk", Lifetime Exposure to lpg/m3,24 hr/day.
PBPK MLE = 4 x la7 PBPKUCL = 6xia7 IRIS Number = 840 x Kf7
Him
BOR 0 1 1 9 3 0
VC Tumor Registryl (Simonato et aill., 1991) |
12,706 Individuals from Population of 14,351
Completeness of Followups 97.7% Cohort has > 25 Years since 1st
Exposure to VC Exposure Groupings:
+ 0 > 2,000 ppm years + 2,000 - 4,000 ppu yean + 4,000 10,000 ppai years + > 14,000 ppm yean
Absolute Rides Estimated to Range from 6.2/100,000 to 280/100,000
sntm
31
PBPK. Risk Assessment Versus Simonato et al (1991)
ppm
PPM Yarn
Tea Yun Eimmh
SO 500
100 1,000
200 2,000
2000
500 5000
_ 2000
1000 10,000
>iaooo
2000
20,000
IWtdvYtm Eummw
so too 200
--
500
___
1000 2000
1,000 2000 4,000 sxno
ioooo
15,000 20.000 40000
PB-PK LADD
PB-PK Pmrfictiaa padOMM
Ohm4 Caaca
pulMtM*
343 6.63 1206
--
2668
--
3128
--
36.03
188 374 736
--
1,497
--
1,753
--
2532
-- (62J*
--
422
-- 152.3
--
280.0)*
--
666 1326 2611
--
53.35
--
6257 7207
376 747 1,465
--
2971
--
3,476 3,993
(623*
--
422 1524
280.0)6
sawM
*i
BOR 0 1 1 9 3 1
BOR 0 1 1 9 3 2
Summary)
Straight-Forward Modification of Existing PBPK Model
Based on Rat In Vivo Studies, Validated with Mouse and Human Data
Described Tumor Data 1-6,000 ppm in Rats and Predicted Tumor Data in Mouse Studies
Unit Risk Based on PBPK Principles 1 SO Fold Lower than Current IRIS Value.
Tumor Predictions Most Accurate WITHOUT Surface Area Correction Factor
When Mechanism is Known, PBPK Procedures Should Be Capable of Giving Much More Accurate Estimates of Risk.
SfiO/H