PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
AEPA
United States Office of Chemical Safety and
Environmental Protection Agency Pollution Prevention
Draft Risk Evaluation for
Carbon Tetrachloride
Supplemental File:
Benchmark Dose Modeling and Source Code for PBPK
Model for Derivation of the IRIS Reference
Concentration (POD for Chronic Inhalation Exposures)
and Inhalation Unit Risk
CASRN: 56-23-5
ci
C""C|
cr
ci
January 2020
1
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
BENCHMARK DOSE MODELING FOR DERIVING THE REFERENCE
CONCENTRATION
MALE RAT:
Incidence data for fatty changes of the liver
Male F344 rats exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5, 25,125ppm
BMR = 10%
Model
Vmax = 0.4
vmax = 0.65
AIC
y?p-value3
BMC10
BMCL10
AIC
y2/;-value11
BMC10
BMCL10
MCA (jimol/L)
Gammab
144.336
0.0007
0.0793248
0.0551873
144.772
0.0005
0.0689847
0.051179
Logistic0
155.104
0.0000
0.170834
0.137191
156.51
0.0000
0.157857
0.126743
Log~Logisticc
137.403
0.4355
0.136715
0.0790319
137.463
0.4087
0.123076
0.0707077
Multistage
l-degreede
142.388
0.0074
0.0714015
0.0550523
142.778
0.0031
0.0665234
0.0511645
Probit0
169.521
0.0000
0.22329
0.17626
171.234
0.0000
0.21463
0.168317
Log-probitc
138.408
0.1761
0.124953
0.0755939
138.529
0.1581
0.112257
0.0803264
Quantal-linear
142.388
0.0074
0.0714017
0.0550523
142.778
0.0031
0.0665234
0.0511645
W eibullb
142.388
0.0074
0.0714016
0.0550523
142.778
0.0031
0.0665235
0.0511645
MRAMKL
fimol/hr-kg liver)
Gammab
137.468
0.4177
3.98707
2.6343
137.338
0.4760
5.31098
3.35649
Logistic0
136.747
0.3444
3.25675
2.58557
136.513
0.3671
4.60057
3.65284
Log-Logistic0
136.933
0.8012
4.56744
3.08461
136.996
0.7246
6.20422
4.00273
Multistage
2-degreeef
137.073
0.2702
3.55184
2.02617
138.991
0.0944
4.99656
2.5022
Probit0
138.891
0.0826
2.97807
2.41619
138.712
0.0728
4.23817
3.44383
Log-probitฐ
136.871
0.9538
4.27176
3.06539
136.872
0.9470
5.73628
3.97844
Quantal-linear
151.674
0.0008
1.01942
0.831472
148.898
0.0025
1.45532
1.18412
W eibullb
138.997
0.1316
3.34831
2.18252
138.601
0.1751
4.4781
2.81908
aValues <0.1 fail to meet conventional goodness-of-fit criteria;p value from the y} test.
''Power restricted to >1.
cSlope restricted to >1.
dUsed smallest degree polynomial available with an adequate fit; the 2-and 3-degree polynomials provided the
same fit as the 1-degree.
eBetas restrictedto >0.
fUsed smallest degree polynomial available with an adequate fit; the 3-degree polynomial providedthe same fit as
the 2-degree.
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
FEMALE RAT:
Incidence data for fatty changes of the liver
Female F344 rats exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5, 25,125ppm
BMR = 10%
None of the models in BMDS provided an adequate fit of the female rat data.
Incidence data for fatty changes of the liver
Female F344 rats exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5, 25ppm (high dose dropped)
BMR = 10%
v
* max
II
o
4^
V
'max
= 0.65
Model
AIC
y?p-value3
BMC10
BMCL10
AIC
y?p-value3
BMC10
BMCL10
MCA (jimol/L)
Gammab
92.9928
NA
0.187771
0.107455
92.9928
NA
0.170979
0.0971536
Logistic0
93.4185
0.1121
0.106984
0.0803379
93.3172
0.1201
0.0979754
0.0734707
Log-Logistic0
92.9928
a NA
0.182663
0.111838
92.9928
NA
0.166144
0.101213
Multistage*1'ฎ
2nd degree
92.4089
0.2442
0.123631
0.0851972
2nd degree
92.3049
0.2617
0.113721
0.0775873
3rd degree
94.9928
NA
0.213915
0.090506
3rd degree
92.9928
NA
0.195194
0.08177
Probit0
93.6833
0.0968
0.100288
0.0779817
93.5689
0.1043
0.0919928
0.0714911
Log-probit0
92.9928
NA
0.174053
0.112578
92.9928
NA
0.158234
0.101889
Quantal-linear
111.424
0.0000
0.0363563
0.0277405
111.025
0.0001
0.0332712
0.0253689
W eibullb
92.9928
NA
0.213201
0.102923
92.9928
NA
0.194228
0.0930656
MRAMKL
fimol/hr-kg liver)
Gammab
92.9928
NA
4.85516
3.42634
92.9928
NA
6.52318
4.43018
Logistic0
99.7262
0.0020
2.45785
1.90371
97.8675
0.0064
3.34536
2.58247
Log-Logistic0
92.9928
NA
4.84705
3.48106
92.9928
NA
6.48806
4.51798
Miltistaged'e
2nd degree
100.7
0.0039
2.43344
1.99357
2nd degree
98.1134
0.0124
3.42266
2.75565
3rd degree
92.2866
0.2650
3.76974
2.82488
3rd degree
91.5964
0.4421
5.42354
3.74923
Probit0
100.988
0.0013
2.16088
1.70134
98.8142
0.0044
2.98448
2.34695
Log-probit0
92.9928
NA
4.69168
3.49658
92.9928
NA
6.26103
4.54001
Quantal-linear
127.034
0.0000
0.817323
0.634088
123.548
0.0000
1.12472
0.870515
W eibullb
92.9928
NA
5.3798
3.29131
92.9928
NA
7.27174
4.24944
aValues <0.1 fail to meet conventional goodness-of-fit criteria;p value from the y} test.
''Power restricted to >1.
cSlope restricted to >1.
dUsed smallest degree polynomial available with an adequate fit.
eBetas restrictedto >0.
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Male Rat
Dose metric: MCA
Vmax = 0.4 mg/hour/kg BW0'07
Log-Logistic Model with 0.95 Confidence Level
0 0.5 1 1.5 2 2.5 3 3.5 4
dose
10:59 10/12 2007
Logistic Model. (Version: 2.9; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\MALE RAT\MCA-
VMAX= 0.4\RAT-FATTYLIVER-MCA-4.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\MALE RAT\MCA-
VMAX= 0.4\RAT-FATTYLIVER-MCA-4.pit
Fri Oct 12 10:59:34 2007
BMDS MODEL RUN
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))]
Dependent variable = FattyLiver
Independent variable = umol/L
Slope parameter is not restricted
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background = 0.08
intercept = 1.42536
slope = 1.89476
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Asymptotic Correlation Matrix of Parameter Estimates
background intercept slope
background 1 -0.077 0.34
intercept -0.077 1 0.54
slope 0. 34 0.54 1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
background 0.073606 * * *
intercept 1.74202 * * *
slope 1. 97967 * * *
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model Log(likelihood) # Param's Deviance Test d.f. P-value
Full model -65.434 4
Fitted model -65.7017 3 0.535433 1 0.4643
Reduced model -138.619 1 146.371 ^ <.0001
AIC: 137.403
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000 0.0736 3.680 4 50 0.173
0.1280 0.1559 7.796 7 50 -0.310
0.7080 0.7614 38.068 39 50 0.309
3.8920 0.9891 49.456 49 50 -0.621
Chi^2 = 0.61 d.f. = 1 P-value = 0.4355
Benchmark Dose Computation
Specified effect = 0.1
Risk Type Extra risk
Confidence level = 0.95
BMD = 0.136715
BMDL = 0.07 9 0319
5
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Male Rat
Dose metric: MCA
Vmax = 0.65 mg/hour/kg BW0'07
Log-Logistic Model with 0.95 Confidence Level
dose
11:12 10/122007
Logistic Model. (Version: 2.9; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\MALE RAT\MCA-
VMAX= 0.65\RAT-FATTYLIVER-MCA-65. (d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\MALE RAT\MCA-
VMAX=0.65\RAT-FATTYLIVER-MCA-65.pit
Fri Oct 12 11:12:25 2007
BMDS MODEL RUN
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))]
Dependent variable = FattyLiver
Independent variable = umol/L
Slope parameter is restricted as slope >= 1
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background = 0.08
intercept = 1.54201
slope = 1.8567 2
Asymptotic Correlation Matrix of Parameter Estimates
background intercept slope
-------
background
intercept
slope
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
1
-0.05
0. 33
-0. 05
1
0. 6
0. 33
0. 6
1
Variable
background
intercept
slope
Parameter Estimates
Estimate
0. 0733292
1.88323
1.94775
Std. Err.
Indicates that this value is not calculated.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
Deviance Test d.f.
Log(likelihood)
-65.434
-65.7316
-138.619
Param's
4
3
1
P-value
0.595159
146.371
(51. 44^
C. 0001
AIC
137.463
Goodness of Fit
Scaled
Dose
Est. Prob.
Expected Observed
Size
Residual
0.0000
0.0733
3.666 4
50
0.181
0.1160
0.1568
7.841 7
50
-0.327
0.6530
0. 7603
38.017 39
50
0. 326
3.7750
0.9895
49.476 49
50
-0.661
Chi/N2 = 0.
68
d.f.
= 1 P-value = 0.4087
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 0.12 3 07 6
BMDL = 0.0707077
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Male Rat
Dose metric: MRAMKL
Vmax = 0.4 mg/hour/kg BW0 07
Logistic Model with 0.95 Confidence Level
Logistic Model. (Version: 2.9; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\MALE RAT\MRAMKL-
VMAX=0.4\FATTY_LIVER_MRAMKL-4.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\MALE
RAT \ MRAMKL - VMAX= 0 . 4 \ FATTY_LIVER_MRAMKL-4 .pit
Fri Oct 12 11:17:49 2007
BMDS MODEL RUN
The form of the probability function is:
P[response] = 1/[1+EXP(-intercept-slope*dose)]
Dependent variable = FattyLiver
Independent variable = umol/hr-kgL
Slope parameter is not restricted
Total number of observations 3 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
1111ฆฆฆฆฆฆ1ฆฆฆฆฆฆฆฆฆ1ฆฆฆฆฆฆฆฆฆ1ฆฆฆฆฆฆฆฆฆ1ฆฆฆฆฆฆฆฆฆr
Logistic
BMDL BVID.
0 5
11:17 10/122007
Default Initial Parameter Values
background = 0 Specified
intercept = -2.35241
slope = 0.249767
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -background
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
intercept slope
intercept 1 -0.82
slope -0.82 1
Parameter Estimates
Variable
intercept
slope
Estimate
-2.68587
0.309634
95.0% Wald Confidence Interval
Std. Err. Lower Conf. Limit Upper Conf. Limit
0.383165 -3.43685 -1.93488
0.0415113 0.228273 0.390994
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood)
-65.434
-66.3737
-138.619
136. 747
Param's
4
2
1
Deviance Test d.f.
1. 87944
146.371
P-value
0.3907
C. 0001
Dose
Goodness of Fit
Est. Prob.
Expected
Observed
Scaled
Residual
0.0000
3.8130
12.0920
24.3200
Chi^2
2 .13
0.0638
0.1816
0.7424
0.9922
d.f.
3.191
9. 082
37 .118
4 9.609
4
7
39
49
2
P-value
0.3444
50
50
50
50
0. 468
-0.764
0|^9
-0. 979
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 3.25 675
BMDL = 2.58 557
9
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Male Rat
Dose metric: MRAMKL
Vmax = 0.65 mg/hour/kg BW0'07
Logistic Model with 0.95 Confidence Level
1
0.8
"O
CD
0.6
a
o
o 0.4
CD
0.2
0
11:23
Logistic: Model. (Version: 2.9; Date: 02/20/2007)
Input Data File: G:\CARB0N TET\EMD\EMD MODELING 10-2007\RFC RAT LIVER\MALE RAT\MRAMKL-
VMAX=0. 65\MRAT_FATTY_LIVER_MRAMKL-65. (d)
Gnuplot Plotting File: G:\CARE0M TET\EMD\EMD MODELING 10-2007\RFC RAT LIVER\MALE
RAT\MRAMKL- VMAX= (J . 65\MRAT_FATTY_LIVER_MRAMKL-65 . pit
Fri Oct 12 11:23:29 2007
EMDS MODEL RUM
The form of the probability function is:
P[response] = 1/[1+EXP(-intercept-slope*dose)]
Dependent variable = FattyLiver
Independent variable = umol/hr-kgL
Slope parameter is not restricted
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
background = 0 Specified
intercept = -2.28912
slope = 0.166325
Asymptotic Correlation Matrix of Parameter Estimates
( The model parameter (s) -background
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
dose
10/12 2007
10
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
intercept slope
intercept 1 -0.8
slope -0.8 1
Variable
intercept
slope
Parameter Estimates
Estimate
-2.59592
0.207777
Std. Err.
0. 370821
0.0278282
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
-3.32272 -1.86913
0.153235 0.26232
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Deviance Test d.f.
Log(likelihood)
-65.434
-66.2567
-138.619
136.513
Param's
4
2
1
1. 64 536 \
146.371 3
P-value
0.4393
C. 0001
Goodness of Fit
Scaled
Dose
Est. Prob.
Expected Observed
Size
Residual
0.0000
0.0694
3.470 4
50
0.|ฃ9 5
4.9910
0.1738
8.690 7
50
-0.631
17 . 6260
0.7439
37.195 39
50
0. 585
36 .2660
0.9929
49.645 49
50
-1.085
Chi ^2 = 2.
.00 d.f. =
2 P-value = 0.3671
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 4.60 0 57
BMDL = 3.652 84
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Female Rat
Dose metric: MCA
Vmax = 0.4 mg/hour/kg BW0'07
1
0.8
"O
CD
% 0.6
| 0.4
Ll_
0.2
0
11:42
Multistage Model. (Version: 2.8; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\FEMALE RAT\MCA-
VMAX= 0.4\FRAT-FATTYLIVER-MCA-4.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\FEMALE
RAT\MCA-VMAX= 0.4\FRAT-FATTYLIVER-MCA-4.pit
Fri Oct 12 11:42:22 2007
BMDS MODEL RUN
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2 ) ]
The parameter betas are restricted to be positive
Dependent variable = FattyLiver
Independent variable = umol/L
Total number of observations =
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Multistage Model with 0.95 Confidence Level
dose
10/12 2007
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0746099
Beta(1) = 0
Beta(2) = 7.64624
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -Beta(l)
12
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Background Beta(2)
Background 1 -0.21
Beta (2) -0.21 1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
Background 0.0951491 * * *
Beta(1) 0 * * *
Beta(2) 6.89319 * * *
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model Log(likelihood) # Param's Deviance Test d.f. P-value
Full model -43.4964 3
Fitted model -44.2044 2 1.41613 1 0.234
Reduced model -101.707 1 116.422 2 <.0001
AIC: 92 .4089
Goodness of Fit
Dose
Est. Prob.
Expected
Observed
Si ze
Scaled
Residual
0.0000
0.0951
4 .757
6
50
0.599
0.1280
0.1918
9. 589
50
-0.930
0.7080
0.9714
48.571
49
50
0. 364
Chi^2 = 1.36 d.f. = 1 P-value = 0.2442
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 0.12 3 631
BMDL = 0. 0851972
BMDU = 0.148857
Taken together, (0.0851972, 0.148857) is a 90 % two-sided confidence
interval for the BMD
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Female Rat
Dose metric: MCA
Vmax = 0.65 mg/hour/kg BW0'07
Multistage Model with 0.95 Confidence Level
1
0.8
"O
CD
O
& 0.6
<
| 0.4
Ll_
0.2
0
11:47
Multistage Model. (Version: 2.8; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\FEMALE RAT\MCA-
VMAX= 0.65\FRAT-FATTYLIVER-MCA-65. (d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\FEMALE
RAT\MCA-VMAX= 0.6 5\FRAT-FAT TYLIVE R-MCA-6 5.p11
Fri Oct 12 11:47:23 2007
BMDS MODEL RUN
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/N2 ) ]
The parameter betas are restricted to be positive
Dependent variable = FattyLiver
Independent variable = umol/L
Total number of observations ^ 3
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
dose
10/12 2007
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0765787
Beta(1) = 0
Beta(2) = 8.98383
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -Beta(l)
14
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Background Beta(2)
Background 1 -0.21
Beta(2) -0.21 1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
Background 0.095736 * * *
Beta(1) 0 * * *
Beta(2) 8.14699 * * *
* - Indicates that this value is not calculated.
Analysis of Deviance Table
Model Log(likelihood) # Param's Deviance Test d.f. P-value
Full model -43.4964 3
Fitted model -44.1525 2 1.31215 1 0.252
Reduced model -101.707 1 116.422 2 <.0001
AIC: 92.3049
Goodness of Fit
Dose
Est. Prob.
Expected
Observed
Si ze
Scaled
Residual
0.0000
0.0957
4 .787
6
50
0. 583
0.1160
0.1896
9. 481
50
-0.895
0.6530
0.9720
48.599
49
50
0. 344
Chi^2 = 1.26 d.f. = 1 P-value = 0.2617
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 0.113721
BMDL = 0. 07 7 58 73
BMDU = 0. 137047
Taken together, (0.0775873, 0.137047) is a 90 % two-sided confidence
interval for the BMD
15
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Female Rat
Dose metric: MRAMKL
Vmax = 0.4 mg/hour/kg BW0 07
Multistage Model with 0.95 Confidence Level
Multistage Model. (Version: 2.8; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\FEMALE RAT\MRAMKL-
VMAX=0.4\FRAT_FATTY_LIVER_MRAMKL-4.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\FEMALE
RAT \ MRAMKL - VMAX= 0 . 4 \ FRAT_FATTY_LIVER_MRAMKL- 4 .pit
Fri Oct 12 11:52:42 2007
BMDS MODEL RUN
Observation # < parameter # for Multistage model.
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*doseL 2-beta3*dose/s3)
The parameter betas are restricted to be positive
Dependent variable = FattyLiver
Independent variable = umol/hr-kgL
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 4
Total number of specified parameters = 0
Degree of polynomial = 3
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0769299
Beta(1)
Beta(2)
Beta(3)
0
0
0.00216647
16
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -Beta(l) -Beta (2)
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Background
Beta(3)
Background
1
-0.21
Beta(3)
-0. 21
1
Parameter Estimates
Variable
Background
Beta(1)
Beta (2)
Beta(3)
Estimate
0.0958436
0
0
0. 00196673
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Log(likelihood)
-43.4964
Param's
3
Deviance Test d.f.
P-value
Fitted :
Reduced :
model
model
-44.
-101
1433 2 1.29386
.707 1 116.422
2
0.2553
r <.0001
AIC:
92 .
2866
Dose
Est
. Prob
Goodness of Fit
Expected Observed
Si ze
Scaled
Residual
0.0000
3.8130
12.0920
o o o
0958
1892
9721
4.792 6
9.462 7
48.603 49
L 50^
50
50
O CTi o
CD CD
lo co co
o o o
Chi ^2 = 1
.24
d.f.
= 1
P-value = 0.2650
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0.1
Extra risk
0. 95
3.76974
2^82 4 88
4. 26949
Taken together, (2.82488, 4.26949) is a 90
interval for the BMD
two-sided confidence
17
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Female Rat
Dose metric: MRAMKL
Vmax = 0.65 mg/hour/kg BW0'07
1
0.8
"O
CD
O
0.6
| 0.4
Ll_
0.2
0
0 2 4 6 8 10 12 14 16 18
dose
11:57 10/12 2007
Multistage Model. (Version: *2 . 8; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\FEMALE RAT\MRAMKL-
VMAX= 0.65\FRAT_FATTY_LIVER_MRAMKL-65. (d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\RFC RAT LIVER\FEMALE
RAT \ MRAMKL - VMAX= 0 . 65 \ FRAT_FATTY_LIVER_MRAMKL-65 .pit
Fri Oct 12 11:57:06 2007
BMDS MODEL RUN
Observation # < parameter # for Multistage model.
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/N2-beta3*dose/N3) ]
The parameter betas are restricted to be positive
Dependent variable = FattyLiver
Independent variable = umol/hr-kgL
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 4
Total number of specified parameters = 0
Degree of polynomial = 3
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(1) = 0
Beta(2) = 0
Beta(3) = 0.000714264
Asymptotic Correlation Matrix of Parameter Estimates
Multistage Model with 0.95 Confidence Level
Multistage
T
""^1
I
[ SMI)[
BMD
18
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Background
Beta(3)
*** The model parameter(s) -Beta(l) -Beta(2)
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Background Beta(3)
1 -0.19
-0.19 1
Parameter Estimates
Variable
Background
Beta(1)
Beta (2)
Beta(3)
Estimate
0.101433
0
0
0.000660435
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
- Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Param's Deviance Test d.f.
Log(likelihood
-43.4964
-43.7982
-101.707
91.5964
0.603632
116.422
P-value
0.4372
C. 0001
Goodness of Fit
Dose Est. Prob.
Expected Observed Size
Scaled
Residual
0.0000 0.1014
4.9910 0.1723
17.6260 0.9759
5.072 6 50
8.613 7 50
48.793 49 50
0. 435
-0.604
0.191
Chi/N2 = 0.59 d.f.
= 1 P-value = 0.4421
Benchmark Dose Computation
Specified effect =
^0.1
Risk Type =
Extra risk
Confidence level =
0. 95
BMD =
5. 42354
BMDL =
3.74923
BMDU =
6. 17189
Taken together, (3.74923
interval for the BMD
, 6.17189) is a 90 % two-sided
confidence
19
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
CANCER ASSESSMENT: BMD MODELING OUTPUTS FOR LOW-DOSE LINEAR
EXTRAPOLATION APPROACH
Benchmark Dose Analysis
Liver tumors (adenoma or
carcinoma)
Female F344 rats exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5, 25,125ppm
Multistage; MCA: 2-stage model
MRAMKL: 4-stage model
Vmax = 0.4
Vmax= 0.65
BMR
BMR/
BMR/
(extrarisk)
AIC
X2/?-value1'
BMC
BMCL
BMCL
AIC
y?p-value3
BMC
BMCL
BMCL
MCA
(jimol/L)
0.05
61.6602
0.9842
0.609955
0.387377
0.129
61.5904
0.9916
0.588686
0.354766
0.141
MRAMKL
(jimol/hr-kg liver)
0.05
63.3399
0.6503
9.8151
8.40334
0.00595
62.8343
0.7440
14.582
12.2867
0.00407
aValues <0.1 fail to meet conventional goodness-of-fit criteria; /J-value from the x2 test.
Liver tumors (adenoma or
carcinoma)
Female F344 rats exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5, 25ppm
Multistage; 2-stage model
Vmax = 0.4
Vmax= 0.65
BMR
BMR/
BMR/
(extrarisk)
AIC
X2/?-value1'
BMC
BMCL
BMCL
AIC
y?p-value3
BMC
BMCL
BMCL
MCA
(jimol/L)
0.05
24.8957
0.9507
0.655398
0.345984
0.144
24.8889
0.9523
0.604144
0.317726
0.157
MRAMKL
(jimol/hr-kg liver)
0.05
25.2825
0.8571
11.5604
6.92352
0.00722
25.1734
0.8831
16.6986
9.76339
0.00512
aValues <0.1 fail to meet conventional goodness-of-fit criteria;/>-value from the y} test.
Note: 3-stage model did not proudc a sufficiently improved model fit.
20
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Liver tumors (adenoma or carcinoma)
Female BDF1 mouse exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5, 25ppm
Multistage; MCA: 2-stage model
MRAMKL: 2-stage model
BMR
Fisher
Thrall
(extra
BMR/
BMR/
risk)
AIC
y?p-value3
BMC
BMCL
BMCL
AIC
X2/?-value3
BMC
BMCL
BMCL
MCA
(jimol/L)
0.1
117.307
NA
0.10186
0.0467576
2.14
117.307
NA
0.194624
0.0885305
1.13
MRAMKL
(jimol/hr-kg liver)
0.1
115.912
0.4437
9.70893
6.3204
0.0158
117.341
0.1654
10.4557
7.59255
0.0132
aValues <0.1 fail to meet conventional goodness-of-fit criteria; /J-value from the %2 test.
Note: 3-stage model did not provide a sufficiently improved model fit.
Liver tumors (adenoma or
carcinoma)
Female BDF1 mouse exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5ppm
Multistage; 2-stage model
Fisher
Thrall
BMR
BMR/
BMR/
(extrarisk)
AIC
y?p-value3
BMC
BMCL
BMCL
AIC
y?p-value3
BMC
BMCL
BMCL
MCA
(jimol/L)
0.1
80.6149
NA
0.101967
0.044224
2.26
80.6149
NA
0.195666
0.0848621
1.18
MRAMKL
(jimol/hr-kg liver)
0.1
80.6149
NA
11.6352
5.04631
0.0198
80.6149
NA
14.1982
6.15788
0.0162
aValues <0.1 fail to meet conventional goodness-of-fit criteria; /J-value from the x2 test.
21
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Liver tumors (adenoma or
carcinoma)
Male BDF1 mouse exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5, 25ppm
Note: models could not fit data with all 4 dose groups; highest dose group dropped
BMR = 0.1
Multistage; 3-stage model
Fisher
Thrall
BMR
BMR/
BMR/
(extrarisk)
AIC
y?p-value3
BMC
BMCL
BMCL
AIC
X2 p-value3
BMC
BMCL
BMCL
MCA
(jimol/L)
0.1
151.192
0.3562
0.191106
0.063650
1.57
151.158
0.3660
0.388392
0.122027
0.819
MRAMKL
(junol/hr-kg liver)
0.1
152.089
0.1864
13.3804
7.30705
0.0137
152.924
0.1086
14.185
8.82145
0.0113
aValues <0.1 fail to meet conventional goodness-of-fit criteria;/>-value from the x2 test.
22
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Pheochromocytomas
Female BDF1 mouse exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5, 25,125ppm
Multistage; 2-stage model
BMR = 10%
BMR
(extrarisk)
Fisher
Thrall
AIC
X2 p-value3
BMC
BMCL
BMR/
BMCL
AIC
y?p-value3
BMC
BMCL
BMR/
BMCL
MCA
(jimol/L)
0.1
71.4077
0.7947
1.42662
1.13753
0.0879
71.3358
0.8039
2.94801
2.34113
0.0427
aValues <0.1 fail to meet conventional goodness-of-fit criteria; /J-value from the x2 test.
Note: 3-stage model did not provide a sufficiently improved model fit.
Pheochromocytomas
MaleBDFl mouse exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5, 25,125ppm
Cancer Multistage
BMR = 10%
Cancer Multistage (restricted mode) model did not provide an adequate fit of the male
pheochromocytoma data (1, 2, and 3 stage models provided the same outputs); therefore other
models inBMDS were used (see table below).
BMR
(extrarisk)
Fisher
Thrall
AIC
X2 p-value3
BMC
BMCL
BMR/
BMCL
AIC
X2 p-value3
BMC
BMCL
BMR/
BMCL
MCA
(jimol/L)
1st. 2nd & 3rd
0.1
139.129
0.0513
0.292123
0.230102
0.435
139.077
0.0488
0.600117
0.472644
0.212
aValues <0.1 fail to meet conventional goodness-of-fit criteria; /J-value from the x2 test.
23
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Pheochromocytomas
MaleBDFl mouse exposed to carbon tetrachloride vapor for 104 weeks (6 hours/day,
5 days/week)
Exposure concentrations modeled: 0, 5, 25,125ppm
Models other than Multistage
BMR = 0.1
Model
Fisher
Thrall
AIC
X2 p-value3
BMC
BMCL
BMR/
BMCL
AIC
X2 p-value3
BMC
BMCL
BMR/
BMCL
MCA ((amol/L)
Gammab
139.129
0.0513
0.292124
0.230102
0.435
139.077
0.0488
0.600118
0.472644
0.212
Gamma ~
unrestricted
140.755
0.0401
0.238028
0.10463
0.956
140.587
0.0428
0.473653
0.204957
0.488
Logistic0
161.228
0.0000
0.929566
0.75614
0.132
161.353
0.0000
1.9184
1.56019
0.064
Logistic
unrestricted
161.228
0.0000
0.929566
0.75614
0.132
161.353
0.0000
1.9184
1.56019
0.064
Log-logistic0
138.661
0.0978
0.24731
0.147398
0.678
138.467
0.1050
0.492945
0.297393
0.336
Log-logistic
unrestricted
138.661
0.0978
0.247311
0.130943
0.764
138.467
0.1050
0.492945
0.257935
0.388
Probit0
159.808
0.0000
0.851235
0.702221
0.142
159.949
0.0000
1.75643
1.44878
0.069
Pro bit -
unrestricted
159.808
0.0000
0.851235
0.702221
0.142
159.949
0.0000
1.75643
1.44878
0.069
Log-probit0
141.637
0.0044
0.423924
0.340228
0.294
141.988
0.0035
0.867906
0.696011
0.144
Log-probit
unrestricted
137.136
0.1533
0.264859
0.150882
0.663
136.945
0.1648
0.527758
0.297349
0.336
Quantal-linear
139.129
0.0513
0.292124
0.230102
0.435
139.077
0.0488
0.60012
0.472644
0.212
W eibullb
139.129
0.0513
0.292124
0.230102
0.435
139.077
0.0488
0.60012
0.472644
0.212
Weibull --
unrestricted
140.513
0.0497
0.226525
0.10562
0.947
140.316
0.0535
0.45102
0.207636
0.482
aValues <0.1 fail to meet conventional goodness-of-fit criteria;/>-value from the x2 test.
''Power restricted to >1.
cSlope restricted to >1.
24
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Female F344 rat hepatocellular adenomas or carcinomas (0, 5, 25,125 ppm dose groups)
Dose metric: MRAMKL
Vmax = 0.4 mg/hour/kg BW0 07
Multistage Cancer Model with 0.95 Confidence Level
1
0.8
1 0.6
% 0.4
5
LL
0.2
0
0 5 10 15 20 25
dose
10:00 10/162007
Multistage Cancer Model. (Version: 1.5; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS FEMALE RAT LIVER\MRAMKL-
VMAX=0.4\FRAT_LIVER_ADCAR_MRAMKL-4.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS FEMALE RAT
LIVER\ MRAMKL-VMAX=0 . 4 \ FRAT_LIVER_ADCAR_MRAMKL- 4 .pit
Tue Oct X16 10:00:27 2007
BMDS MODEL RUN
Observation # < parameter # for Multistage Cancer model.
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/N2-beta3*dose/s3-beta4*doseA4 ) ]
The parameter betas are restricted to be positive
Dependent variable = IncLiverTumor
Independent variable = umol/hr-kgL
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 5
Total number of specified parameters = 0
Degree of polynomial = 4
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(1) = 0
Beta(2) = 0
Beta(3) = 0
Beta(4) = 6.11699e-006
Asymptotic Correlation Matrix of Parameter Estimates
25
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
( *** The model parameter (s) -Background -Beta(l) -Beta (2) -Beta (3)
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Beta(4)
Beta(4) 1
Parameter Estimates
Variable
Background
Beta(1)
Beta (2)
Beta(3)
Beta(4)
Estimate
0
0
0
0
5.52 68 9e-006
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Deviance Test d.f.
Log(likelihood)
-2 9.6 94 6
-30.67
-109.05
63 .3399
Param's
4
1
1
1.95065
158.71
P-value
0.5827^
C. 0001
Dose
Est. Prob.
Goodness of Fit
Expected Observed Size
Scaled
Residual
0. 0000
3. 8130
12.0920
24.3200
Chi^2
0.0000
0.0012
0.1114
0.8554
1. 64
d.f.
0. 000
0. 058
5. 572
42.768
0
0
3
44
P-value
0.6503
50
50
50
50
0. 000
-0.242
-1.156
0. 495
Benchmark Dose Computation
Specified effect :
Risk Type
Confidence level :
BMD =
BMDL =
BMDU =
0. 05
Extra risk
0. 95
9.8151
8. 40334
10 .5331
Taken together, (8.40334, 10.5331) is a 90
interval for the BMD
two-sided confidence
Multistage Cancer Slope Factor
0.00595002
26
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Dose metric: MRAMKL
Vmax = 0.65 mg/hour/kg BW0'07
Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer Model. (Version: 1.5; Date: 02/20/2007)
Input Data File: G:\CARBON TET\EMD\EMD MODELING 1 0-2 0 07 \ TUMORS FEMALE RAT LIVER\MRAMKL-
VMAX=0.65\FRAT_LIVER_ADCAR_MRAMKL-65.(d)
Gnuplot Plotting File: G:\CARBON TET\EMD\EMD MODELING 10-2 0 07 \ TUMORS FEMALE RAT
LIVER\MRAMKL-VMAX=0 . 65\ FRAT_LIVER_ADCAR_MRAMKL-65 . pit
Tue Oct 16 10:05:09 2007
BMDS MODEL RUN
Multistage Cancer
Linear extrapolation
Dependent variable = I
Independent variable = umo
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 5
Total number of specified parameters = 0
Degree of polynomial = 4
0 5
13:09 12/142007
Observation
The form o
nd)*[1-EXP(
-beta3*doseA3-beta4*doseA 4)
The parameter betas
positive
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(1) = 0
Beta(2) = 0
Beta(3) = 0
Beta(4) = 1.23526e-006
27
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -Background -Beta(l) -Beta (2) -Beta (3)
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Beta(4)
Beta(4) 1
Parameter Estimates
Variable
Background
Beta(1)
Beta (2)
Beta(3)
Beta (4)
Estimate
0
0
0
0
1.13446e-006
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Deviance
Log(likelihood)
-2 9. 6 94 6
-30.4171
-109.05
62 .8343
Param's
4
1
1
Test d.f.
1. 44504 3X
158.71 3
P-value
0. 695
:. 0001
Goodness of Fit
Scaled
Dose
Est. Prob.
Expected
Observed
Size
Residual
0.0000
0.0000
^oAa
0
50
0. 000
4.9910
0.0007
0. 035
0
50
-0.188
17 . 6260
0.1037
5.186
3
50
-1.014
36 .2660
0.8595
42.97 4
44
50
0. 418
Chi ^2
1.24
d.f.
P-value
0. 7440
Benchmark Dose Computation
Specified effect =
Risk Type =
Confidence level =
BMD =
BMDL =
BMDU =
0. 05
Extra risk
0. 95
14 .582
12 .28 67
15.6526
Taken together, (12.2867, 15.6526) is a 90
interval for the BMD
two-sided confidence
Multistage Cancer Slope Factor
0.00406945
28
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Female F344 rat hepatocellular adenomas or carcinomas (0, 5, 25 ppm dose groups)
Dose metric: MRAMKL
Vmax = 0.4 mg/hour/kg BW0 07
Multistage Cancer Model with 0.95 Confidence Level
"O
CD
O
.(D
<
ฃ=
O
~o
CT3
0 2 4 6 8 10 12
dose
08:23 10/12 2007
Multistage Cancer Model. (Version: 1.5; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS FEMALE RAT LIVER\MRAMKL-
VMAX=0.4\FRAT_LIVER_ADCAR_MRAMKL-4.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS FEMALE RAT
LIVER\ MRAMKL-VMAX=0 . 4 \ FRAT_LIVER_ADCAR_MRAMKL- 4 .pit
Fri Oct 12 08:23:17 2007
BMDS MODEL RUN
The form of the probability function isx:
P[response] = background + (1-background)*[1-EXP(
-betal\*dose/sl-beta2*dose/N2 ) ]
The parameter betas are restricted to be positive
Dependent variable = IncLiverTumor
Independent variable = umol/hr-kgL
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(1) = 0
Beta(2) = 0.00044169
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -Background -Beta(l)
have been estimated at a boundary point, or have been specified by the user,
29
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
and do not appear in the correlation matrix
Beta(2)
Beta(2) 1
Parameter Estimates
Variable
Background
Beta(1)
Beta (2)
Estimate
0
0
0.000383811
95.0% Wald Confidence Interval
Std. Err. Lower Conf. Limit Upper Conf. Limit
Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Deviance Test d.f.
Log(likelihood
-11.3484
-11.6412
-14.7059
25.2825
Param's
3
1
1
0. 585705
6. 71498
P-value
0. 7461
0.03482
Goodness of Fit
Dose Est. Prob.
Expected Observed
Si ze
Scaled
Residual
0.0000 0.0000
0.000 0
50
0^00
3.8130 0.0056
0.278 0
50
^0. 529
12.0920 0.0546
2.729 3
50
0.169
Chi/N2 = 0.31 d.f.
= 2 P-value = 0.8571
Benchmark Dose Computation
Specified effect =
o
Cn
Risk Type =
Extra risk
Confidence level =
0. 95
BMD =
11.5604
BMDI^^
6. 92 3 52
BMDU =
30 .5183
Taken together, (6.92352
, 30.5183) is a 90 % two-
-sided
confidence
interval for the BMD
Multistage Cancer Slope
Factor = 0.00722176
30
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Dose metric: MRAMKL
Vmax = 0.65 mg/hour/kg BW0'07
Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer
Linear extrapolation
T3
o
ฃ
<
o
CO
0.15
0.1
0.05
08:35 10/12 2007
Multistage Cancer Model. (Version: 1.5; Date: 02/20/2007)
Input Data File: G:\CARB0N TET\EMD\EMD MODELING 1 0-2 0 07 \ TUMORS FEMALE RAT LIVER\MRAMKL-
VMAX=0. 65\FRAT_LIVER_ADCAR_MRAMKL-65. (d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS FEMALE RAT
LIVER\ MRAMKL-VMAX=0 . 65 \ FRAT_LIVER_ADCAR_MRAMKL - 65 .pit
Fri Oct 12 08:35:44 2007
BMDS MODEL RUN
The form of the probability function is:
background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2 ) ]
P[response]
The parameter betas are restricted to be positive
Dependent variable = IncLiverTumor
Independent variable = umojL/hr-kgL
Total number of observations =
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(1) = 0
Beta(2) = 0.000206402
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -Background -Beta(l)
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Beta(2)
31
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Beta(2)
Variable
Background
Beta(1)
Beta (2)
Parameter Estimates
Estimate
0
0
0. 000183949
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Deviance Test d.f.
Log(likelihood)
-11.3484
-11.5867
-14.7059
25.1734
Param's
3
1
1
0.476667
6. 71498
P-value
0. 7879
0.03482
Goodness of Fit
Dose
Est. Prob.
Expected
Observed
Si ze
Scaled
Residual
0.0000
0.0000
0. 000
0
0. 000
4.9910
0.0046
0. 229
0
50
-0.479
17.6260
0.0555
2 .777
3
50
0.137
Chi ^2
0. 25
d.f.
P-value
0.8831
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0. 05
Extra risk
0. 95
16 . 6986
9. 76339
43 .9237
Taken together, (9.76339, 43.9237) is a 90
interval for the BMD
two-sided confidence
Multistage Cancer Slope Factor
0.00512117
32
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Multistage Cancer Model. (Version: 1.5; Date: 02/20/2007)
Input Data File: G:\CARBON TET\EMD\EMD MODELING 10-2 0 07 \ TUMORS FEMALE MOUSE LIVER\MRAMKL-
FISHER\FMOUSE_LIVER_ADCAR_MRAMKL-FISHER.(d)
Gnuplot Plotting File: G:\CARBON TET\EMD\EMD MODELING 10-2 0 07 \ TUMORS FEMALE MOUSE
LIVER\MRAMKL-FISHER\FMOUSE_LIVER_ADCAR_MRAMKL-FISHER.pit
Fri Oct 12 08:54:44 2007
BMDS MODEL RUN
Female BDF1 mouse hepatocellular adenomas or carcinomas (0, 5, 25 ppm dose groups)
Dose metric: MRAMKL
Fisher model
Multistage Cancer Model with 0.95 Confidence Level
The form of th^\probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/N2 ) ]
The parameter betas are restricted to be positive
Dependent variable = IncLiverTumor
Independent variable = umol/hr-kgL
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
M u Itistage Cancer
Linear extrapolation
0 5
12:04 10/15 2007
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values Background =
0.0482072
Beta(1) = 0
Beta(2) = 0.00119035
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -Beta(l)
have been estimated at a boundary point, or have been specified by the user,
33
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Background
Beta (2)
and do not appear in the correlation matrix
Background Beta(2)
1 -0.38
-0.38 1
Variable
Background
Beta(1)
Beta (2)
Parameter Estimates
Estimate
0. 0693295
0
0.00111772
Std. Err.
Indicates that this value is not calculated.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Deviance Test d.f.
Log(likelihood)
-55.6537
-55.9559
-99.1295
115.912
Param's
3
2
1
P-value
0. 604318
86 . 9516
0.4369
C. 0001
Goodness of Fit
Dose
Est. Prob.
Expected
Observed
Si ze
Scaled
Residual
0.0000
0.0693
3. 466
4
50
0. 297
12.6660
0.2221
10.883
9
49
-0.647
41.6750
0.8664
43.321
44
50
0. 282
Chi ^2
0.59
d.f.
P-value
0.4437
Benchmark Dose Computation
Specified effect :
Risk Type
Confidence level :
BMD =
BMDL =
BMDU =
0.1
Extra risk
0. 95
9. 70893
6.3204
11^2 94 2
Taken together, (6.3204 , 11.2942) is a 90
interval for the BMD
two-sided confidence
Multistage Cancer Slope Factor
0.0158218
34
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Dose metric: MRAMKL
Thrall model
ง
0.8
0.6
tj 0.4
0.2
0
Multistage Model with 0.95 Confidence Level
1 Multistage
BMDL . BMP
0 5
12:10 10/152007
10 15 20 25 30 35 40
dose
45
Multistage Model. (Version: 2.8; Date: 02/20/2007)
Input Data File: G:\CARBON TET\EMD\EMD MODELING 10-2 0 07 \ TUMORS FEMALE
MOUSE LIVER\MRAMKL-THRALL\ FMOUSE_LIVER_ADCAR_MRAMKL-THRALL .(d)
Gnuplot Plotting File: G:\CARBON TET\EMD\EMD MODELING 10-2 0 07 \ TUMORS
FEMALE MOUSE LIVER\MRAMKL-THRALL\ FMOUSE_LIVER_ADCAR_MRAMKL-THRALL . pit
Fri Oct 12 09:01:03 2007
BMDS MODEL RUN
The form of the probability function is:
background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2 ) ]
P[response]
The parameter betas are restricted to be positive
Dependent variable = IncLiverTumor
Independent variable = umol/hr-kgL
Total number of observations =
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-00ฃ
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0162478
Beta(1) = 0
Beta(2) = 0.00110173
35
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -Beta(l)
have been estimated at a boundary point, or have been specified by the
36
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
and do not appear in the correlation matrix
Background Beta(2)
Background 1 -0.4
Beta (2) -0.4 1
Limit
Variable
Background
Beta(1)
Beta (2)
Parameter Estimates
Estimate
0.0643165
0
0.000963757
Std. Err.
- Indicates that this value is not calculated.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Deviance Test d.f.
Log(likelihood
-55.6537
-56.6705
-99.1295
117.341
Param's
3
2
1
2.03362
86 .9516
P-value
0.1539
C.0001
Goodness of Fit
Dose Est. Prob.
Expected Observed Size
Scaled
Residual
0.0000 0.0643
15.4560 0.2567
43.5990 0.8502
3.216 4 50
12.580 9 49
42.510 44 50
0. 452
-1.171
0. 590
Chi/N2 = 1. 92 d.f. :
= 1 P-value = 0.1654
Benchmark Dose Computation
Specified effect =
0.1
Risk Type =
Extra risk
Confidence level^=
0. 95
BMD =
10 .4557
BMDL =
7.59255
BMDU =
12.107
Taken together, (7.59255
interval for the BMD
, 12^107 ) is a 90 % two-sided
confidence
37
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Female BDF1 mouse hepatocellular adenomas or carcinomas (0, 5 ppm dose groups)
Dose metric: MRAMKL
Fisher model
0.35
Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer
Linear extrapolation
12:49 10/15 2007
Multistage Cancer Model. (Version: 1.5; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS FEMALE MOUSE LIVER\MRAMKL-
FISHER\FMOUSE_LIVER_ADCAR_MRAMKL-KISHER.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS FEMALE MOUSE
LIVER\MRAMKL-FISHER\FMOUSE_LIVER_ADCAR_MRAMKL-FISHER.pit
Fri Oct 12 09:15:17 2007
BMDS MODEL RUN
Observation # < parameter # for Multistage Cancer model.
The form of the probability function is:
P[response]
background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2 ) ]
The parameter betas are restricted to be positive
Dependent variable = IncLiverTumor
Independent variable = umol/hr-kgL
Total number of observations = 2
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.24898
Beta(1) = 0.0160225
Beta(2) = 0.001265
38
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l) Beta (2)
Background 1 -2.2e-008 8.3e-009
Beta (1) -6e-0 09 1 -1
Beta (2) -3.2e-009 -1 1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err. Lower Conf. Limit Upper Conf. Limit
Background 0.08 * * *
Beta (1) 0. 00471969 * * *
Beta (2) 0.000372627 * *
* - Indicates that this value is not calculated.
Error in computing chi-square; returning 2
Analysis of Deviance Table
Model Log(likelihood) # Param's Deviance Test d.f. P-value
Full model -37.3075 2
Fitted model -37.3075 3 2.84217e-014 -1 NA
Reduced model -38.4987 1 2.38238 1 0.1227
AIC: 80.6149
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000 0.0800 4.000 4 50 -0.000
12.6660 0.1837 9.000 9 49 0.000
Chi^2 = 0.00 d.f. = -1 P-value = NA
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 11^3 52
BMDL = 5.04 6 31
BMDU did not converge for BMR = 0.100000
BMDU calculation failed
BMDU = 3.56605e+007
Multistage Cancer Slope Factor = 0.0198165
39
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Dose metric: MRAMKL
Thrall model
Multistage Model with 0.95 Confidence Level
Multistage Model. (Version: 2. 8; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS FEMALE MOUSE LIVER\MRAMKL-
THRALL\FMOUSE_LIVER_ADCAR_MRAMKL-THRALL.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS FEMALE MOUSE
LIVER\MRAMKL-THRALL\FMOUSE_LIVER_ADCAR_MRAMKL-THRALL.pit
Fri Oct 12 09:17:46 2007
BMDS MODEL RUN
Dependent variable = I
Independent variable = umo
Total number of observations = 2^B
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
0.35
0.25
0.05
0 2
12:50 10/152007
Observation
The form o
P[response] =
The parameter betas
BMDL
positive
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values Background =
0.24898
Beta(1) = 0.0131302
Beta(2) = 0.000849523
Asymptotic Correlation Matrix of Parameter Estimates
Background Beta(l)
Beta(2)
40
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Background
Beta(1)
Beta(2)
NA
NA
NA
NA
NA
NA
NA - This parameter's variance has been estimated as zero or less.
THE MODEL HAS PROBABLY NOT CONVERGED!!!
Parameter Estimates
Variable
Background
Beta(1)
Beta (2)
Estimate
0. 08
0.00386773
0.000250241
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
* - Indicates that this value is not calculated.
At least some variance estimates are negative.
THIS USUALLY MEANS THE MODEL HAS NOT CONVERGED!
Try again from another starting point.
Error in computing chi-sguare; returning 2
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood)
-37.3075
-37.3075
-38.4987
80.6149
Param's Deviance Test d.f.
2
3 2.84217e-014 -1
1 2.38238 1
P-value
Est. Prob.
Goodness of Fit
Expected Observed Size
0.0000
15.4560
Chi ^2
0. 00
0.0800
0.1837
d.f.
4 . 000
9. 000
50
49
NA
0.1227
Scaled
Residual
-0.000
0. 000
-1
P-value
NA
Benchmark Dose Computation
Specified effect =
Risk Type =
Confidence level =
BMD =
BMDL =
BMDU =
0. 1
Extra risk
14 .1982
6.15788
2. 64 632e+ 014
Taken together, (6.15788, 2.64632e+014) is a 90
interval for the BMD
two-sided confidence
41
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Male BDF1 mouse hepatocellular adenomas or carcinomas (0, 5, 25 ppm)
Dose metric: MRAMKL
Fisher model
Multistage Cancer Model with 0.95 Confidence Level
BMDS MODEL RUN
Multistage Cancer Model. (Version: 1.5; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS MALE MOUSE
FISHER\MMOUSE_LIVER_ADCAR_MRAMKL-FISHER.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS MALE
LIVER\MRAMKL-FISHER\MMOUSE_LIVER_ADCAR_MRAMKL-FISHER.pit
Tue Dec 04 12:03:25 2007
LIVER\MRAMKL-
MOUSE
Observation # < parameter # for Multistage Cancer model.
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/N2-beta3*dose/s3) ]
The parameter betas are restricted to be positive
Dependent variable = IncLiverTumor
Independent variable = umol/hr-kgL
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 4
Total number of specified parameters = 0
Degree of polynomial = 3
Multistage Cancer
Linear extrapolation
BiyPL
02
12:03
0 5
12/04 2007
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.352068
Beta(1) = 0
Beta(2) = 0
Beta(3) = 4.77425e-005
Asymptotic Correlation Matrix of Parameter Estimates
42
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Background
Beta(3)
*** The model parameter(s) -Beta(l) -Beta(2)
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Background Beta(3)
1 -0.22
-0.22 1
Parameter Estimates
Variable
Background
Beta(1)
Beta (2)
Beta(3)
Estimate
0.41973
0
0
4 . 398 18e-005
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Log(likelihood)
-73.1699
-74.0443
-9 9.6 09 6
152.089
Param's Deviance Test d.f.
1. 74874
52 .87 95
P-value
0.186
:. 0001
Goodness of Fit
Dose
Est. Prob.
Expected
Observed
Si ze
Scaled
Residual
0.0000
0.4197
20.987
24
50
0. 864
12.6660
0.4693
23.467
20
50
-0.982
41.6750
0.9760
48.798
49
50
0.187
Chi ^2
1.75
d.f.
P-value
0.18 64
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0.1
Extra risk
0. 95
13.3804
7.30705
15.6428
Taken together, (7.30705, 15.6428) is a 90
interval for the BMD
two-sided confidence
Multistage Cancer Slope Factor
0.0136854
43
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Dose metric: MRAMKL
Thrall model
Multistage Cancer Model with 0.95 Confidence Level
0 5 10 15 20 25 30 35 40 45
dose
13:12 12/142007
Multistage Cancer Model. (Version: 1.5; Date: 02/20/2007)
Input Data File: G:\CARBON TET\EMD\EMD MODELING 1 0-2 0 07 \ TUMORS MALE MOUSE LIVER\MRAMKL-
THRALL\MMOUSE_LIVER_ADCAR_MRAMKL-THRALL.(d)
Gnuplot Plotting File: G:\CARBON TET\EMD\EMD MODELING 10-2 0 07 \ TUMORS MALE MOUSE
LIVER\MRAMKL-THRALL\MMOUSE_LIVER_ADCAR_MRAMKL-THRALL . P'lt
Tue Dec 04 12:19:57 2007
BMDS MODEL RUN
Observation # < parameter # for Multistage Cancer model.
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/N2-beta3*dose/N3) ]
The parameter betas are restricted to be positive
Dependent variable = IncLiverTumor
Independent variable = umol/hr-kgL
Total number of observations^a3
Total number of records with missing values = 0
Total number of parameters in model = 4
Total number of specified parameters = 0
Degree of polynomial = 3
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values Background =
0.317881
Beta(1) = 0
Beta(2) = 0
Beta(3) = 4.21166e-005
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -Beta(l) -Beta (2)
have been estimated at a boundary point, or have been specified by the user,
44
-------
PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
and do not appear in the correlation matrix
Background Beta(3)
Background 1 -0.26
Beta(3) -0.26 1
Variable
Background
Beta(1)
Beta (2)
Beta(3)
Parameter Estimates
Estimate
0.410703
0
0
3. 69143e-0 05
Std. Err.
Indicates that this value is not calculated.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Deviance Test d.f.
Log(likelihood)
-73.1699
-74.462
-9 9.6 09 6
152.924
Param's
3
2
1
2.58426
52 .87 95
P-value
0.1079
C. 0001
Goodness of Fit
Dose
Est. Prob.
Expected
Observed
Si ze
Scaled
Residual
0.0000
0.4107
20.535
24
50
0.996
15.4560
0.4858
24 .289
20
50
-1.214
43.5990
0.9724
48.618
49
50
0. 330
Chi ^2
2 . 57
d.f.
P-value
0.1086
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
BMDU
0.1
Extra risk
0. 95
14 .185
8. 82145
16 .5171
Taken together, (8.82145, 16.5171) is a 90
interval for the BMD
two-sided confidence
Multistage Cancer Slope Factor
0.011336
45
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
BDF1 mouse (female) pheochromocytomas
Dose metric: MCA
Fisher model
Multistage Cancer Model with 0.95 Confidence Level
BMDL
Multistage Cancer Model. (Version: 1.5; Date: 02/20/2007)
Input Data File: G:\CARBON TET\EMD\EMD MODELING 10-2 0 07 \ TUMORS FEMALE
PHEOCHROMOCYTOMAS\FISHER\FMOUSE_PHEOCHROMOCYTOMA_MCA-FISHER.(d)
Gnuplot Plotting File: G:\CARBON TET\EMD\EMD MODELING 10-2 0 07 \ TUMORS FEMALE
PHEOCHROMOCYTOMAS\FISHER\FMOUSE_PHEOCHROMOCYTOMA_MCA-FISHER.pit
Fri Oct 12 09:49:11 2007
BMDS MODEL RUN
Multistage Cancer
Linear extrapolation
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose'\2 ) ]
The parameter betas are restricted to be positive
Dependent variable = Pheochrom
Independent variable = umol/L
0 0.5
09:49 10/12 2007
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(1) = 0
Beta(2) = 0.0548062
46
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -Background -Beta(l)
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Beta(2)
Beta(2) 1
Parameter Estimates
Variable
Background
Beta(1)
Beta (2)
Estimate
0
0
0.0517683
Std. Err.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
Log(likelihood)
-33.7087
-34.7039
-69.0688
Param's
4
1
1
Deviance Test d.f.
1.99041
70 .7202
P-value
0.5744
C. 0001
AIC:
71.4077
Dose
Est. Prob.
Goodness of Fit
Expected Observed
Scaled
Residual
0. 0000
0.1110
0.6030
3.3150
Chi^2
1. 03
0.0000
0.0006
0.0186
0.4338
d.f.
0. 000
0. 031
93^
21.259
0
0
0
22
50
49
50
49
0. 000
-0.177
-0.975
0. 214
P-value
0. 7947
Benchmark Dose Computation
Specified effect =
Risk Type =
Confidence level =
BMD =
BMDL =
BMDU =
0.1
Extra risk
M. 95
1. 42662
1. 13753
1. 72224
Taken together, (1.13753, 1.72224) is a 90 % two-sided confidence
interval for the BMD
Multistage Cancer Slope Factor = 0.08791
47
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Dose metric: MCA
Thrall model
Multistage Cancer Model with 0.95 Confidence Level
Multistage Cancer Model. (Version: 1.5; Date: 02/20/2007)
Input Data File: G:\CARBON TET\EMD\EMD MODELING 10-2 0 07 \ TUMORS FEMALE
PHEOCHROMOCYTOMAS\THRALL\FMOUSE_PHEOCHROMOCYTOMA-MCA-THRALL.(d)
Gnuplot Plotting File: G:\CARBON TET\EMD\EMD MODELING 10-2 0 07 \ TUMORS FEMALE
PHEOCHROMOCYTOMAS\THRALL\FMOUSE_PHEOCHROMOCYTOMA-MCA-THRALL.pit
Fri Oct 12 09:53:23 2007
BMDS MODEL RUN
T3
-S3
O
ฃ
<
0.4
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal\*dose/sl-beta2*dose/N2 ) ]
The parameter betas are restricted to be positive
Dependent variable = Pheochrom
Independent variable = umol/L
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 3
Total number of specified parameters = 0
Degree of polynomial = 2
Multistage Cancer
Linear extrapolation
BVCL
HVD
0 1
09:53 10/12 2007
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0
Beta(1) = 0
Beta(2) = 0.0128084
Asymptotic Correlation Matrix of Parameter Estimates
48
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
( *** The model parameter (s) -Background -Beta(l)
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Beta(2)
Beta(2) 1
Parameter Estimates
Variable
Background
Beta(1)
Beta (2)
Estimate
0
0
0. 0121232
Std. Err.
Indicates that this value is not calculated.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Log(likelihood)
-33.7087
-34. 6679
-69.0688
71.3358
Param's
4
1
1
Deviance Test d.f.
1.91847
70 .7202
P-value
0.5895
C. 0001
Dose
Goodness of Fit
Est. Prob.
Expected
Observed
Scaled
Residual
0.0000
0.2130
1.2260
6.8560
Chi^2
0. 99
0.0000
0.0005
0.0181
0.4344
d.f.
0. 000
0. 027
0. 903
21 hgQ5
0
0
0
22
P-value
0.8039
50
49
50
49
0. 000
-0.164
-0.959
0. 206
Benchmark Dose Computation
Specified effect =
Risk Type =
Confidence level =
BMD =
BMDL =
BMDU =
0.1
Extra risk
0. 95
2.94801
2.34113
3.55893
Taken together, (2.34113, 3.55893) is a 90
interval for the BMD
two-sided confidence
Multistage Cancer Slope Factor
0.0427144
49
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
BDF1 mouse (male) pheochromocytomas
Dose metric: MCA
Fisher model
Probit Model with 0.95 Confidence Level
Probit Model. (Version: 2.8; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS MALE
PHEOCHROMOCYTOMAS\FISHER\MMOUSE_PHEOCHROMOCYTOMA_MCA-FISHER.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS MALE
PHEOCHROMOCYTOMAS\FISHER\MMOUSE_PHEOCHROMOCYTOMA_MCA-FISHER.pit
Fri Nov 30 12:55:04 2007
BMDS MODEL RUN
The form of the probability function is:
P[response] = Background
+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose) ) ,
where CumNorm(.) is the cumulative normal distribution function
Dependent variable = Pheochrom
Independent variable = umol/L
Slope parameter is not restricted
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Probit
0 0.5
12:55 11/30 2007
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -0.416734
slope = 0.792244
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -background
50
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
intercept
slope
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
intercept
1
-0 .092
slope
-0.092
1
Variable
background
intercept
slope
Estimate
0
-0.358995
0.694404
Parameter Estimates
Std. Err.
NA
0.125298
0.110458
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
-0.604574
0.47791
-0.113416
0. 910899
Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
Log(likelihood)
-64.0144
-66.5682
-110.216
Param's
4
2 t
1
Deviance Test d.f.
5.10756 2
92.4032 3
137.136
Dose
Est. Prob.
Goodness of Fit
Expected Observed Size
P-value
0.07779
<.0001
Scaled
Residual
0.0000
0.1110
0.6030
3.3150
Chi ^2
3.75
0.0000
0.0297
0.2388
0.6820
d.f.
0. 000
1.484
11.939
34.099
0
0
16
32
2
P-value
0.1533
50
50
50
50
0. 000
-1.237
1. 347
-0.637
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level =
BMD =
BMDL =
0. 95
0.264859
0.150882
51
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
Dose metric: MCA
Thrall model
Probit Model with 0.95 Confidence Level
Probit Model. (Version: 2.8; Date: 02/20/2007)
Input Data File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS MALE
PHEOCHROMOCYTOMAS\THRALL\MMOUSE_PHEOCHROMOCYTOMA_MCA-THRALL.(d)
Gnuplot Plotting File: G:\CARBON TET\BMD\BMD MODELING 10-2007\TUMORS MALE
PHEOCHROMOCYTOMAS\THRALL\MMOUSE_PHEOCHROMOCYTOMA_MCA-THRALL.pit
Fri Nov 30 13:15:12 2007
The form of the probability function is:
P[response] = Background
+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)),
where CumNorm(.) is the cumulative normal distribution function
Dependent variable = Pheochrom
Independent variable = umol/L
Slope parameter is not restricted
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Probit
BMDL
BMD
0 1
13:15 11/30 2007
E'.MDS MODEL RUM
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0
intercept = -0.965049
slope = 0.776315
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter (s) -background
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
52
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
intercept slope
intercept 1 -0.58
slope -0.58 1
Parameter Estimates
Variable
background
intercept
slope
Estimate
0
-0.844448
0. 683918
Std. Err.
NA
0.153761
0.109119
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
-1.14581
0. 470048
-0.543082
0.897787
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Deviance Test d.f.
Log(likelihood)
-64.0144
-66.4723
-110.216
136.945
Param's
4
2
1
4.91585
92 .4 032
P-value
0.08561
k<. 0001
Goodness of Fit
Scaled
Dose
Est. Prob.
Expected
Observed
Size
Residual
0.0000
0.0000
0. 000
0
50
0. 000
0.2130
0.0286
1. 429
0
L 50
-1.213
1.2260
0.2404
12.019
16
50
1. 318
6.8560
0.6816
34 .ฃ18 0
32
50
-0.631
Chi ^2
3. 61
d.f.
P-value
0.1648
Benchmark Dose Computation
Specified effect =
Risk Type =
Confidence level =
BMD =
BMDL =
0.1
Extra risk
0. 95
0.527758
0.29734 9
53
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
SOURCE CODE FOR PHYSIOLOGICALLY BASED
PHARMACOKINETIC MODELS
%
%
% File: HUMINH.M
0/
/O
% Programmed by Gary Diamond
% Syracuse Research Corporation, 02/2005
0/
/O
%Tliis run time file implements CCL4.CSL for inhalation exposure
%(human parameters)
0/
/O
%Prepare time history variables
prepare @clear @all
%Set communication interval
CINT=1.;
%Set simulation stop (lir)
TSTOP=17250.;
%hitegration error check
!!SET WESITG=.F.
%Air Exposure Parameters
AIRC=2.27; %ppm
AIRON=0.; %lir
AIROFF=l 000000.; %17520.; %hr
CIOFF=0.; %ppm
APERl=24.;%lir
AWID1=24.; %hr
APER2= 168.; %lir
AWID2= 168.; %lir
%Oral Exposure Parameters
RGIL=0.0;
FGIL=1.0;
%Human Parameters
BW=70.;
VLC=0.04;
WC=0.30; %Revisedfrom 0.1 (03/2007)
VSC=0.62;
VRC=0.05;
54
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
QCC=15.;
QPC=15.;
QSF=0.74;
QLC=0.25;
QFC=0.06;
QSC=0.18;
QRC=0.51;
PBLD=2.64;
PL=3.14;
PF=79.42;
PS=1.0;
PR=3.14;
%Chemical Parameters
MW=153.8;
VMAXC=1.49;
KMX =0.25;
VMAXSF=0.7;
Al=0.065;
A2=0.095;
A3=0.84;
Kl=0.25;
K2=0.03;
K3=0.025;
K4=0.;
K5=0.0004;
!! START /NC
%Output
HUMl=|_time day air ca ramkb mcl _cf_af, _cl];
HUM2=rot90(fliplr(HUMl));
out=fopen('HUMAN.out','w');
fprintf(out '%f,%f,%f,%e ,%e ,%e,%e ,%e,%e\ii",HUM2);
fclose(out);
55
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
0/
/o
%
% File: HUMOR.M
0/
/O
% Programmed by Gary Diamond
% Syracuse Research Corporation, 10/2007
%
%Tliis run time file implements CCL4.CSL for "oral" exposure (RGIL)
%(human parameters)
0/
/o
%Prepare time history variables
prepare @clear @all
%Set communication interval
CINT=24.;
%Set simulation stop (lir)
TSIDP=5000.;
%hitegration error check
!!SET WESITG=.F.
%Air Exposure Parameters
AIRC=0.; %ppm
AIRON=0.; %lir
AIROFF= 1000000. ;%17520.; %hr
CIOFF=0.; %ppm
APERl=24.;%lir
AWID1=24.; %hr
APER2=168.;%lir
AWID2=168.;%lir
%Oral Exposure Parameters
RGILC=10.0;
FGIL=1.0;
%Human Parameters
BW=70.;
VLC=0.04;
WC=0.30; %Revisedfrom0.1
VSC=0.62;
VRC=0.05;
QCC=15.;
QPC=15.;
QSF=0.74;
56
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
QLC=0.25;
QFC=0.06;
QSC=0.18;
QRC=0.51;
PBLD=2.64;
PL=3.14;
PF=79.42;
PS=1.0;
PR=3.14;
%Chemical Parameters
MW=153.8;
VMAXC=0.40;
KMX =0.25;
VMAXSF=0.7;
Al=0.065;
A2=0.095;
A3=0.84;
Kl=0.25;
K2=0.03;
K3=0.025;
K4=0.;
K5=0.0004;
!! START /NC
%Output
HUM 1=[_time _rgil mca mramkl];
HUM2=rot90(fliplr(HUMl));
out=fopen('HUMAN.out7w');
fprintf(out '%e ,%e ,%e ,%e\n",HUM2);
fclose(out);
57
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
0/
/o
%
% File: MOUINH_JF.M
0/
/O
% Programmed by Gary Diamond
% Syracuse Research Corporation, 10/2007
0/
/O
%Tliis run time file implements CCL4.CSL for inhlation exposure
%(mouse parameters. Fisher et al. 2004)
0/
/o
%Prepare time history variables
prepare @clear @all
%Set communication interval
CINT=24.;
%Set simulation stop (lir)
TSTOP=17520.;
%Integration error check
!!SET WESnXKF.
%Air Exposure Parameters:
AIRC=125.; %ppm
AIRON=0.; %lir
AIROFF=17520;%lir
CIOFF=0.; %ppm
APERl=24.;%lir
AWID1=6.; %lir
APER2= 168.; %lir
AWID2= 120.; %lir
%Mouse Parameters:
BW=0.036;
VLC=0.04;
VFC=0.04;
VSC=0.69;
VRC=0.14;
QCC=30.;
QPC=30.;
QSF=0.75;
QLC=0.24;
QFC=0.05;
QSC=0.17;
QRC=0.54;
58
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
PBLD=3.8;
PL=4.8;
PF=91.4;
PS=2.5;
PR=4.8;
%Chemical Parameters:
MW=153.8;
VMAXC=1.;
KMX = 0.3;
VMAXSF=0.75;
%From Hirall et al 2000
Al=0.065;
A2=0.095;
A3=0.84;
Kl=0.25;
K2=0.03;
K3=0.025;
K4=0.;
K5=0.00042;
!! START /NC
%Output
%MOU=[AIR MCA MRAMKB MCL MRAMKL]
MOU1=|_time day air mramkl mca mramkb mcl mramkl]; %output matrix
%formatingof output for printed comma-dilimited file:
MOU2=rot90(fliplr(MOU 1));
out=fopen('MOU.out7w');
%fprintf(out,'%f,%f,%f,%f,%f,%f,%f\n",MOU2);
%fprintf(out. "%f,%f,%f,%e ,%e ,%e,%e ,%e\n",MOU2);
fprintf(out '%e\n",MOU);
fclose(out);
59
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
0/
/o
%
% File: MOUINHJCT.M
0/
/O
% Programmed by Gary Diamond
% Syracuse Research Corporation, 3/2007
0/
/O
%Tliis run time file implements CCL4.CSL for inhlation exposure
%(mouse parameters. Thrall et al. 2000)
0/
/o
%Prepare time history variables
prepare @clear @all
%Set communication interval
CINT=24.;
%Set simulation stop (lir)
TSTOP=17520.;
%Integration error check
!!SET WESITG=.F.
%Air Exposure Parameters:
AIRC=2.5; %ppm
AIRON=0.; %lir
AIROFF=17520;%lir
CIOFF=0.; %ppm
APERl=24.;%lir
AWID1=6.; %lir
APER2= 168.; %lir
AWID2= 120.; %hr
%Mouse Parameters:
BW=0.036;
VLC=0.04;
VFC=0.04;
VSC=0.78;
VRC=0.05;
QCC=28.;
QPC=28.;
QSF=0.74;
QLC=0.24;
QFC=0.05;
QSC=0.19;
QRC=0.52;
60
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
PBLD=7.83;
PL=2.08;
PF=23.0;
PS=0.61;
PR=2.08;
%Chemical Parameters:
MW=153.8;
VMAXC=0.79;
KMX =0.46;
VMAXSF=0.7;
Al=0.065;
A2=0.095;
A3=0.84;
Kl=0.25;
K2=0.03;
K3=0.025;
K4=0.;
K5=0.00042;
!! START /NC
%Output
%MOU=[AIR MCA MRAMKB MCL MRAMKL]
MOUl=[_time dayairmramklmcamcl]; %output matrix
%formatingof output for printed comma-dilimited file:
MOU2=rot90(fliplr(MOU 1));
out=fopen('MOU.out7w');
fprintf(out "%f,%f,%e ,%e ,%e ,%e\n",MOU2);
fprintf(out "%e\n",MOU);
fclose(out);
61
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
0/
/o
%
% File: RATTNH.M
0/
/O
% Programmed by Gary Diamond
% Syracuse Research Corporation, 02/2005
0/
/O
%Tliis run time file implements CCL4.CSL for inhalation exposure
%(rat parameters)
0/
/o
%Prepare time history variables
prepare @clear @all
%Set communication interval
CINT=1.;
%Set simulation stop (lir)
TSTOP=17250.;
%hitegration error check
!!SET WESITG=.F.
%Air Exposure Parameters:
AIRC=4.; %ppm
AIRON=0.; %lir
AIROFF=17520;%lir
CIOFF=0.; %ppm
APERl=24.;%lir
AWID1=6.; %6.; %hr
APER2=168.;%lir
AWID2= 120.; %120.; %hr
%Rat Parameters:
BW=0.452;
VLC=0.04;
WC=0.08;
VSC=0.74;
VRC=0.05;
QCC=15.;
QPC=15.;
QSF=0.74;
QLC=0.25;
QFC=0.04;
QSC=0.20;
QRC=0.51;
62
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
PBLD=4.52;
PL=3.14;
PF=79.42;
PS=1.0;
PR=3.14;
%Chemical Parameters:
MW=153.8;
VMAXC=0.4;
KMX =0.25;
VMAXSF=0.7;
Al=0.065;
A2=0.095;
A3=0.84;
Kl=0.25;
K2=0.03;
K3=0.025;
K4=0.;
K5=0.00042;
!! START /NC
%Output
RATI=|_timc day air mca mramkl mcl]; %outputmatrix
%formating of output for printed comma-dilimited file:
%RAT2=rot90(fliplr(RATl));
%out=fopen('RAT.out7wl);
%fprintf(out, '%f,%f,%f,%e ,%e ,%e\n",RAT2);
%fclose(out);
63
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PEER REVIEW DRAFT-DO NOT CITE OR QUOTE
PROGRAM: CCL4R
IThis program simulates the pharmacokinetics of carbon tetrachloride
!The program is based onlTRICCTAACSL, developed by KD THRALL 9/98; ACSL code provided to
GDiamond, 04/2004
!The above code was translated with minor modifications, by GDiamond, 05/2004
INITIAL
VARIABLE TIME = 0.0 ! Set independent variable to be TIME
ALGORITHM IALG = 2 [Numerical integration algorithm - Gear for stiff systems
CINTERVAL CINT=100. [Communication interval
NSTP = 1000 ! Set initital integration cycle length at CINT/1000
MERROR AL=0.0001 !Set error tolerance for Gear
I*****BODyAND TISSUE MASSES*****
CONSTANT BW = 0.2 IBody weiglit (kg)
CONSTANT VLC =0.04 ! Li\cr fraction of body weight
CONSTANT VFC = 0.08 ! Adipose fraction of body weiglit
CONSTANT VSC =0.74 ! Slowly-perfused fraction of body weiglit
CONSTANT VRC = 0.05 IRapdily-perfused fraction of body weight
VL=VLC*BW ILivcr (kg
W=WC*BW !Adipose (kg)
VS=VSC*BW !Slowly-perfused (kg)
VR=VRC*BW IRapidly-perfused (kg)
l*****BLOOD FLOWS*****
CONSTANT QCC=14 ICardiac output (L/lir-BWASF)
CONSTANT QPC=14 ! Alveolar ventilation (L/lir-BWASF)
CONSTANT QLC = 0.25 ILiver fraction of cardiac output
CONSTANT QFC = 0.09 ! Adipose fraction of cardiac output
CONSTANT QSC = 0.15 ! Slowly-perfused fraction of cardiac output
CONSTANT QRC = 0.51 IRapidly-perfused fraction of cardiac output
CONSTANT QSF = 0.74 !QC and QP scaling factor (SF)
QC=QCC*BW**QSF!Cardiac output (L/lir)
QP=QPC*BW**QSF! Alveolar ventilation (L/lir)
QL = QLC*QC ILiver (L/lir)
QF = QFC*QC lAdipose (L/lir)
QS = QSC*QC ! Slowly-perfused (L/lir)
QR= QRC*QC IRapidly-perfused (L/lir)
!***** PARTITION COEFFICIENTS* * * * *
CONSTANT PBLD = 4.52 !Blood:air partition coefficient
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CONSTANT PL = 3.14 !Liver:bloodpartitioncoefficient
CONSTANT PF = 79.42 !Adipose:bloodpartitioncoefficient
CONSTANT PS = 1.0 !Slowly-perfused:blood partition coefficient
CONSTANT PR = 3.14 !Rapidly-perfused:bloodpartitioncoefficient
!***** METABOLISM and EXCRETION* * * * *
CONSTANT MW=153.8 IMolecular weight of CC14
CONSTANT VMAXC = 0.40 !VMAX for metabolism in liver (mg/lir-BWASF)
CONSTANT KMX= 0.25 !KM for metabolism in liver (mg/L)
CONSTANT VMAXSF=0.7 ! Scaling factor for VMAXC (SF)
CONSTANT Al=0.085 IFraction of metabolism rate to Ml pool
CONSTANT A2=0.095 IFraction of metabolism rate to M2 pool
CONSTANT A3=0.84 IFraction of metabolism rate to M3 pool
CONSTANT Kl=0.123 IRate constantforconversionofMl to exhaled metabolite (C02) (lir-1)
CONSTANT K2=0.03 IRate constant for conversion ofM2 to urinary metabolite (lir-1)
CONSTANT K3=0.0252 IRate constant for conversion of M3 to fecal metabolite (hr-1)
CONSTANT K4=0. IRate constantforconversionofM2toMl (lir-1)
CONSTANT K5=0.00042 IRate constantfor conversion of M3 to Ml (hr-1)
VMAX = 1000* VMAXC* BW**VMAXSF/MWI Maximum rate of metabolism in liver (umol/hr)
KM = 1000*KMX/MW IMichaelis constant for metabolism in liver (umol/L)
|*****EXPOSURE-AIR*****
CONSTANT AIRC = 1.1 Air exposure concentration (ppm)
AIR = AIRC; I Air exposure concentration (ppm)
AIRCM = AIR/24.45 I Air exposure (umol/L)
mgAIR = AIR*MW/24.45 I Air exposure (mg/m3)
ugAIR=AIR*MW/24.45 I Air exposure concentration (ug/L)
CONSTANT TSTOP = 700. ILengthofsimulaion(lir)
CONSTANT AIRON=0. ITime air exposure starts (lir)
CONSTANT AIROFF=700. ITime air exposure stops (lir)
CONSTANT CIOFF=0. IConcentrationininlialedairwhen exposure is off (ppm)
CONSTANT APER1=24. IPulse period 1 for air exposure (e.g., hours in a day)
CONSTANT AWID1=24. IPulse width 1 for air exposure (e.g., 6 hours each day)
CONSTANT APER2=168. IPulse period 2 for air exposure (e.g., hours in a day)
CONSTANT AWID2=168. IPulse width 2 for air exposure (e.g., 6 hours each day)
!*****EXPOSURE-ORAL ******GD08/2007
CONSTANT RGILC=0. IRate of uptake from GI to liver (umol/hr)
RGIL=RGILC IRate of uptake from GI to liver (umol/hr)
lUse for simuulating constant rate of uptake from Gl-tract
MGRGIL=RGIL*MW/1000 IRate of uptake from GI to liver (mg/lir)
MGRGILKGD=RGIL*24*MW/(1000*BW)IRate ofuptake to liver (mg/kg-day)
CONSTANT GILF=1. I Absorption fraction
ICONSTANT POINTS = 96.
ICINT = TSTOP/POINTS ISets communication for 96 times in the simulation
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END !of INITIAL section of program
DYNAMIC
DERIVATIVE
DAY=TTME/24
YEAR=DAY/365
I * * * * * CONCENTRATION IN INHALED AIR (umol/L)*****
CION = AIRCM*PULSE( AIRON, APER1, AWID1) * PULSE( AIRON, APER2, AWID2)
CI = RSW(TIME.LE.AIROFF,CION,CIOFF)
RAI = QP*(CA/PBLD-CI)!Rate inhaled (uinol/lir)
CP =CI*24.45 IConcentration in chamber (ppm)
l*****AMOUNTTAKEN IN BY ONE ANIMAL (umol)*****
RIN = QP*CI
AIN = INTEG(RIN,0.0)
I***** LIVER* * * * *
!Use for simulation of constant rate of uptake from Gl-tract (GD 08/2007)
RAL = QL*(CA-CVL)+RGIL-RAM !Rate of change in amount (umol/hr)
!Use for simulation of inhalation exposure
!RAL = QL*(CA-CVL)-RAM !Rate of change in amount (umol/lir)
AL = WIEG(RAL, 0.0)!Amount (umol)
CVL = CL/PL IConcentration in venous blood (umol/L)
CL = AL/VL IConcentration (umol/L)
AUCCL = INIEG(CL,0.) IAUC concentration (umol/L xlir)
I Average concentration in li\er (umol/L) -MCL(GD 05/2004)
IF (TIME .GT. 0.) THEN
MCL = AUCCL/TTME
ELSE
MCL= 0.
END IF
ugCL = CL*MW/1000 IConcentration (ug/g)
MugCL = MCL*MW/1000 I Average concentration (ug/g)
AUCugCL = AUCCL*MW/1000 IAUC concentration (ug/g xlir)
I ***** METABOLIZED* *** *
RAM = (VMAX*CVL)/(KM+CVL) IRate, total (umol/lir)
RAMKB= RAM/BW IRate, total (umol/hr xkq body)
RAMKL=RAM/VL IRate. total (umol/hr x kg liver)
AUCRAM=INIEG(RAM,0.0) IAUC rate (umol/hr xlir)
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! Ave rage rate of metabolism (umol/hr) - MRAM (GD 05/2004)
IF (TIME .GT. 0.) THEN
MRAM = AUCRAM/UME
ELSE
MRAM= 0.
END IF
MRAMKB=MRAM/BW ! Average rate, total (umol/hr x kg body) (GD 05/2004)
MRAMKL=MRAM/VL ! Ave rage rate, total (umol/hr x kg liver) (GD 05/2004
RAXA = RAM*A1-K1*AXA+K4*AXU+K5*AXF !Rate to air pool (umol/hr)
RAXF = RAM*A3-K3* AXF-K5* AXF !Rate to feces pool (umol/hr)
RAXU = RAM*A2-K2*AXU-K4* AXU !Rate to urine pool(umol/hr)
AM = INTEG(RAM,0.) lAmount total (umol)
AMK = AM/BW ! Amount total (umol/kgbw)
AMKL=AM/VL !Amount total (umol/kg liver)
AXA = WIEG(RAXA0.) ! Amount in air pool (umol)
AXF = INTEG(RAXF,0.) ! Amount in feces pool (umol)
AXU = WIEG(RAXU,0.) ! Amount in urine pool (umol)
RA = AXA*kl !Rate to air (umol/hr)
RU = AXU*k2 !Rate to urine (umol/hr)
RF = AXF*k3 !Rate to feces (umol/hr)
ugRA = RA*MW !Rate to air (ug/lir)
ugRU = RU*MW !Rate to urine (ug/lir)
ugRF = RF*MW !Rate to feces (ug/lir)
CAX = RA/((3/2)*QP) IConcentration of metabolite inexlialedair (umol/L)
CAXM = CAX*24.45 IConcentration of metabolite in exhaled air (ppm)
(***** pAT* * * * *
RAF = QF*(CA-CVF) IRate of change in amount (umol/hr)
AF = WIEG(RAF, 0.0) lAmount (umol)
CVF = CF/PF IConcentration in venous blood (umol/L)
CF=AF/VF IConcentration (umol/L)
AUCCF =WIEG(CF, 0.) IAUC concentration (umol/L xlir)
lAverage concentration in fat (umol/L) - MCF (GD 03/2007)
IF (TIME .GT. 0.) THEN
MCF = AUCCF/UME
ELSE
MCF=0.
END IF
ugCF = CF*MW/1000 !Concentration(ug/g)
MugCF =MCF*MW/1000 I Average concentration (ug/g)
AUCugCF = AUCCF*MW/1000 IAUC concentration (ug/g x lir)
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!***** SLOWLY PERFUSED TISSUES* * * * *
RAS = QS*(CA-CVS) !Rate of change in amount (uinol/lir)
AS = INTEG(RAS, 0.0)! Amount (uinol)
CVS = CS/PS IConcentration in venous blood (uinol/L)
CS = AS/VS IConcentration in uinol/L
ugCS = CS*MW/1000 IConcentration inug/g
l*****RICHLYPERFUSED TISSUES*****
RAR = QR*(CA-CVR) IRate of change in amount (umol/hr)
AR = WIEG(RAR0.0) !Amount (umol)
CVR = CR/PR IConcentration in venous blood (umol/L)
CR= AR/VR IConcentration in umol/L
ugCR = CR*MW/1000 !Concentrationinug/g
|*****MIXED VENOUS BLOOD*****
CV = (QF*CVF+QL*CVL+QS*CVS+QR*CVR)/QC IConcentration (umol/L)
AUCCV=INTEG(CVO.) IAUC concentration (umol/L xlir)
lAverage concentration in venous blood (umol/L) - MCV (GD 05/2004)
IF (TIME .GT. 0.) THEN
MCV = AUCCV/TTME
ELSE
MCV=0.
END IF
ugCV = CV*MW/1000 IConcentration (ug/g)
MugCV =MCV*MW/1000 lAverage concentration (ug/g)
AUCugCV = AUCCV*MW/1000 IAUC concentration (ug/g xlir)
!*****ARTERIAL BLOOD*****
CA= (QC*CV+QP*CI)/(QC+(QP/PBLD)) IConcentration(umol/L)
AUCCA=INTEG(CA0.) IAUC concentration (umol/L xlir)
I Average concentration in atrerial blood (umol/L) - MCA (GD 05/2004)
IF (TIME .GT. 0.) THEN
MCA = AUCCA/TTME
ELSE
MCA=0.
END IF
ugCA=CA*MW/1000 IConcentration (ug/g)
MugCA=MCA*MW/1000 lAverage concentration (ug/g)
AUCugCA=AUCCA*MW/1000 IAUC concentration (ug/g xlir)
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!***** AMOUNT EXHALED*****
CX=CA/PBLD IConcentration in alveolar air (umol/L)
CXPPM= (0.7*CX+0.3*CI)*24.45 IConcentration in exhaled air (ppm)
ITotal ventilation is 0.7 of alveolar ventilation
RAX= QP*CX !Rae of change in amount (umol/hr)
AX=INTEG(RAX,0.) lAmount (uinol)
!**** *NET AMOUNT ABOSORBED* * * * *
DOSEX = AIN-AX !Net amount absorbed(umol)
BODY=AL+AF+AS+AR ! Amount in body (umol)
MASSB = BODY+AM+AX !Mass balance (umol)
END !of DERIVATIVE section of program
TERMT(HME .GE. TSTOP) [Termination condition
END !of DYNAMIC section of program
TERMINAL
END !of TEMINAL section of program
END !of program
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