PEER REVIEW DRAFT-DO NOT CITE OR QUOTE AEPA United States Office of Chemical Safety and Environmental Protection Agency Pollution Prevention Draft Risk Evaluation for Carbon Tetrachloride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Inhalation Exposures) and Inhalation Unit Risk CASRN: 56-23-5 ci C""C| cr ci January 2020 1 ------- PEER REVIEW DRAFT-DO NOT CITE OR QUOTE BENCHMARK DOSE MODELING FOR DERIVING THE REFERENCE CONCENTRATION MALE RAT: Incidence data for fatty changes of the liver Male F344 rats exposed to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. 2 ------- 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. 3 ------- 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 4 ------- 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 ------- 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 7 ------- 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 ) 8 ------- 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 ------- 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 ------- 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 11 ------- 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 ------- 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 13 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 64 ------- PEER REVIEW DRAFT-DO NOT CITE OR QUOTE 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 65 ------- PEER REVIEW DRAFT-DO NOT CITE OR QUOTE 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) 66 ------- PEER REVIEW DRAFT-DO NOT CITE OR QUOTE ! 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) 67 ------- PEER REVIEW DRAFT-DO NOT CITE OR QUOTE !***** 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) 68 ------- PEER REVIEW DRAFT-DO NOT CITE OR QUOTE !***** 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 69 ------- |