risa1927-sup-0001-suppmat
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Appendix A: Parameter Values Table A1: List of symbols Chemical Abbreviations: BZ: BO: PH: PH Conj: HQ: HQ Conj: MA: PMA: Cat: Cat Conj: BT: BT Conj: CT: benzene benzene oxide phenol phenol conjugates hydroquinone hydroquinone conjugates muconic acid phenylmercapturic acid catechol catechol conjugates benzenetriol benzenetriol conjugates creatinine Compartment Abbreviations: F: S: R: L: M: B: V: I: E: Blad: fat slowly perfused tissue rapidly perfused tissue liver bone marrow blood mixed venous blood inhaled air exhaled air bladder Chemical Concentrations: C ij : BZ A BZ V C C concentration of chemical i in tissue j : : concentration of benzene in arterial blood concentration of benzene in mixed venous blood CVi , j : concentration of chemical i in venous blood leaving tissue j CIBZ : concentration of benzene in inhaled air concentration of benzene in exhaled air C BZ E : 1 Table A2: Physiologic parameters used in the model Variable Value BW 70 QP 300 QC QP QL 0.25 × QC QM 0.04 × QC QF 0.05 × QC QS 0.22 × QC QR 0.44 × QC QU 1.5 VL 0.026 × BW VM 0.04 × BW VF 0.19 × BW VS 0.58 × BW VR 0.05 × BW VB 0.074 × BW VBlad 0.2 TL VL × 1,000 TM VM × 1,000 fDS 0.33 1 Reference weight 2 Travis et al.(5) 3 Medinsky et al.(25) 4 Fitzgerald and Brubaker(27) 5 Davies and Morris(26) 6 Hvarness et al.(32) 7 Organ Density = 1,000 g/l 8 Reddy et al.(31) Units kg l/h l/h l/h l/h l/h l/h l/h l/day l l l l l l l g g -- Description / Source body weight1 alveolar (pulmonary) ventilation rate2 total cardiac output3 blood flow to liver3 blood flow to bone marrow2 blood flow to fat2 blood flow to SPT2 blood flow to RPT2 urinary flow rate4 volume of liver2 volume of bone marrow2 volume of fat2 volume of SPT2 volume of RPT2 volume of blood5 volume of bladder4,6 total mass of the liver7 total mass of the bone marrow7 fraction of dead volume in the lungs 8 2 Table A3: Metabolic kinetic parameters used in the model Variable C CP C MP V2E1 C CYP Vh PH Max,1 Mouse 57.3 387 Human 58 14.5 Calibrated 58 52.3 Units mg/g tissue mg/g tissue Description concentration of cytosolic protein per gram of live tissue concentration of microsomal protein per gram liver tissue Source: Mouse Source: Human Cole et al. (14) Csanády et al.(34) Cole et al. (14) Lipscomb et al.(16,17) (14) Yokley et al.(15) 141 78.2 -- nmol/mg-hr CYP2E1 specific activity Cole et al. -- -- 0.056 nmol/mg specific activity concentration -- -- -- 240 1/hr Human calibrated velocity factor -- V 0.0221 0.0302 0.0005 µmol/mg-hr first maximum rate of PH metabolism Cole et al. PH VMax ,2 Lipscomb et al.(16,17) -(14) Yokley et al.(15) 0.295 0.4029 0.4029 μmol/mg-hr second maximum rate of PH metabolism Cole et al.(14) Yokley et al.(15) V HQ Max 1.0456 0.7484 0.7484 μmol/mg-hr maximum rate of conjugation for HQ Seaton et al.(61) Yokley et al.(15) V Cat Max HQ Max HQ Max HQ Max μmol/mg protein-hr maximum rate of metabolism for Cat Equivalent to HQ kinetics Equivalent to HQ kinetics HQ VMax μmol/mg protein-hr maximum rate of metabolism for BT Equivalent to HQ kinetics Equivalent to HQ kinetics V V BT VMax PH m,1 V 1.4 1.4 1.4 μmol/l first concentration at half-saturation of PH Seaton et al. K mPH, 2 220 220 220 μmol/l second concentration at half-saturation of PH Seaton et al.(61) Seaton et al.(61) K mHQ 746 746 746 μmol/l concentration at half-saturation for HQ Seaton et al.(61) Seaton et al.(61) K mCat K mHQ K mHQ K mHQ μmol/l concentration at half-saturation for Cat Equivalent to HQ kinetics Equivalent to HQ kinetics K mHQ μmol/l concentration at half-saturation for BT Equivalent to HQ kinetics Equivalent to HQ kinetics 0.0397 l/μmol K K BT m A BZ A PH AHQ A Cat A BT 0.0397 0.0397 affinity parameter for CYP2E1 for BZ (61) Seaton et al.(61) Nedelcheva et al. (62) Nedelcheva et al.(62) 0.013 0.013 0.013 l/μmol affinity parameter for CYP2E1 for PH Lovern et al. 1E-07 1E-07 1E-07 l/μmol affinity parameter for CYP2E1 for HQ Lovern et al.(63) Lovern et al.(63) 1E-05 l/μmol affinity parameter for CYP2E1 for Cat Lovern et al. (63) Lovern et al.(63) Cat 1E-05 1E-05 (63) Lovern et al.(63) l/μmol affinity parameter for CYP2E1 for BT Equivalent to Cat kinetics Equivalent to Cat kinetics k1 4.20E-05 4.20E-05 2E-05 l/nmol efficiency of BZ to BO conversion Lovern et al.(63) Lovern et al.(63) k2 32.16 32.16 32.16 1/hr first-order rate constant for the conversion of BO to PH Lovern et al.(63) Lovern et al.(63) k3 2.045 15 3 1/hr first-order rate constant for the conversion of BO to MA Cole et al.(14) Yokley et al.(15) (14) Yokley et al.(15) k4 k5 k6 A 0.85 4E-05 2.13E-06 0.7 4E-05 2.13E-06 0.2 4E-05 4E-05 1/hr l/nmol l/nmol first-order rate constant for the conversion of BO to PMA efficiency of PH to HQ conversion efficiency of PH to CAT conversion Cole et al. Lovern et al. (63) Lovern et al.(63) Lovern et al. (63) Lovern et al.(63) (63) Lovern et al.(63) k7 2.03E-07 2.03E-07 5E-07 l/nmol efficiency of HQ to BT conversion Lovern et al. k9 29.58 0.1163 0.1163 1/hr binding constant of PH to tissue macromolecules Cole et al.(14) Yokley et al.(15) binding constant of HQ to tissue macromolecules (14) Yokley et al.(15) k10 k11 Mfrac 421 1E-09 -- 0.1443 -0.04 0.1443 1E-09 0.04 1/hr l/nmol -- efficiency of CAT to BT conversion metabolic rate of BZ to BO in bone marrow relative to liver Cole et al. Lovern et al. Travis et al. (63) (5) Lovern et al.(63) Travis et al.(5) 3 Table A4: Partition coefficients used in the model Variable PSBZ Values 7.4 406 / PB 11 / PB 15 / PB PLBZ PRBZ BZ M BO F BO R P 120 / PB P P PFBZ PRBZ PSBO PSBZ PLBO PMBO PLBZ PMBZ PFPH PRPH PSPH 27.63 2.17 1.22 PLPH PMPH PRPH PRPH PFHQ PRHQ PSHQ 4.06 1.04 0.94 PLHQ PMHQ PRHQ PRHQ PFCat PRCat PSCat PFHQ PRHQ PSHQ PLCat PMCat PLHQ PMHQ PFBT PRBT PSBT PFHQ PRHQ PSHQ PLBT PLHQ PMHQ PB PFBZ PRBZ BT M P Units -------------------------------- Description BZ blood/air BZ fat/blood BZ RPT/blood BZ SPT/blood BZ liver/blood BZ marrow/blood BO fat/blood BO RPT/blood BO SPT/blood BO liver/blood BO marrow/blood PH fat/blood PH RPT/blood PH SPT/blood PH liver/blood PH marrow/blood HQ fat/blood HQ RPT/blood HQ SPT/blood HQ liver/blood HQ marrow/blood Cat fat/blood Cat RPT/blood Cat SPT/blood Cat liver/blood Cat marrow/blood BT fat/blood BT RPT/blood BT SPT/blood BT liver/blood BT marrow/blood Source Travis et al.(5) Travis et al.(5) Travis et al.(5) Travis et al.(5) Same as RPT Travis et al.(5) Same as BZ Same as BZ Same as BZ Same as BZ Same as BZ Leung et al.(64) Leung et al.(64) Leung et al.(64) Same as RPT Same as RPT Leung et al.(64) Leung et al.(64) Leung et al.(64) Leung et al.(64) Leung et al.(64) Same as HQ Same as HQ Same as HQ Same as HQ Same as HQ Same as HQ Same as HQ Same as HQ Same as HQ Same as HQ 4 Table A5: Background metabolite parameters used in the model Variable Value Units Description / Source CTProd/BW 15.5 ± 2.3a mg/kg/day creatinine prod. / BW1 CTProd CTProd/BW × BW mg creatinine /day daily creatinine prod. CPMA/CT 0.00088 mg/g creatinine Specific PMA conc.2 CMA/CT 0.31 mg/g creatinine Specific MA conc.2 CHQ/CT 4.34 mg/g creatinine Specific HQ conc.2 CCat/CT 2.84 mg/g creatinine Specific Cat conc.2 CPH/CT 11.9 mg/g creatinine Specific PH conc.2 MWPMA 239.29 g/mol PMA molecular weight MWMA 142.11 g/mol MA molecular weight MWHQ 110.11 g/mol HQ molecular weight MWCat 110.11 g/mol Cat molecular weight MWPH 94.111 g/mol PH molecular weight a Assuming normally distributed with Mean ± SD, based on 2.5%-ile and 97.5%-ile values of 11 and 20 mg/kg/day from Cecil et al.(33) 5 Appendix B: Mathematical Model In the liver and bone marrow, the rate of conversion of benzene to benzene oxide in µmol/hr is modeled as shown in Equations B1 and B2, where k1 is a kinetic rate constant, πβ is a human velocity calibration factor, πΆ πΆππ is the concentration of cytosolic protein, C LBZ and CMBZ are the concentrations of benzene in the liver and bone marrow, CMP is the amount of microsomal protein per milligram of liver, TL and TM are the total masses of the liver and bone marrow, and π·πΏ and π·π are saturation factors. The mean concentration of cytosolic protein, πΆ πΆππ , of 0.0499 ± 0.017 nmol of CYP2E1 per mg of microsomal protein, is based on a dataset from 20 individuals reported by Lipscomb et al.(17) Additionally, Lipscomb et al.(16) report a more extensive dataset containing 60 samples, with a similar mean of 0.0545 ± 0.0241 nmol CYP2E1 per mg microsomal protein. The expressions for DL and DM (Equations B11 and B12) and the affinity coefficients ABZ, APH, AHQ, and ACat were empirically derived by Lovern et al.(63) The affinity coefficient ABT was set equal to ACat. Together, these parameters account for both the saturability of enzyme active sites and competition for active sites between the five compounds. Rate expressions for the conversion of phenol to hydroquinone, phenol to catechol, hydroquinone to benzenetriol, and catechol to benzenetriol in the liver are similarly defined. Travis et al.(5) found that using a metabolic rate of benzene in the marrow of roughly four percent that of the liver adequately matched rodent data sets. Therefore, to characterize the rate of benzene oxidation in the bone marrow, the rate expression in Equation B2 was multiplied by Mfrac = 0.04. Product inhibition of the conversion of benzene oxide to phenol, muconic acid, and phenylmercapturic acid is considered negligible, and rate expressions are assumed to be first order, and of the form shown in Equations B13 – B18, where k2, k3 and k4 are kinetic rate 6 constants, C LBO and C MBO are the concentrations of benzene oxide in the liver and bone marrow, and VL and VM are the volumes of the liver and bone marrow compartments, respectively. The conversions of hydroquinone, catechol, and benzenetriol to their respective conjugated metabolites were modeled using Michaelis-Menten kinetics based on data published by Seaton et al.,(61) with forms shown in Equations B19 – B24. The conversion of phenol to its conjugates, however, was modeled using the experimental data from Seaton et al.(61), who postulate that the rate of phenol sulfation can be described as the sum of two saturable terms, as shown in Equations B25 and B26 for metabolism in the liver and bone marrow, respectively. Metabolic Rate and Mass Balance Equations Metabolic rates are indicated by the form RM ij ,L or RM ij ,M and represent the rate at which compound i is metabolized into product j. The subscripts L and M represent metabolic rates in the liver and bone marrow, respectively. π΅π π ππ΅π,πΏ = π1 πβ πΆ πΆππ πΆπΏπ΅π π΅π π ππ΅π,π = πππππ π1 π΅π πβ πΆ πΆππ πΆπ π·π πβ πΆ πΆππ πΆπΏππ» ππ» π ππ»π,πΏ = π5 ππ» π ππΆππ‘,πΏ = π6 ππ» πβ πΆ πΆππ πΆπ πβ πΆ πΆππ πΆπΏππ» ππ» π ππΆππ‘,π = π6 π»π πβ πΆ πΆππ πΆπΏ π·πΏ (B2) (B3) (B4) πΆ ππ ππΏ (B5) ππ» πβ πΆ πΆππ πΆπ π·π (B1) πΆ ππ ππ π·π π·πΏ πΆ ππ ππ πΆ ππ ππΏ π·πΏ ππ» π ππ»π,π = π5 π»π π ππ΅π,πΏ = π7 πΆ ππ ππΏ π·πΏ πΆ ππ ππ πΆ ππ ππΏ (B6) (B7) 7 π»π πβ πΆ πΆππ πΆπ π»π π ππ΅π,π = π7 π·π πΆππ‘ π ππ΅π,πΏ = π11 πΆ ππ ππ πβ πΆ πΆππ πΆπΏπΆππ‘ π·πΏ πΆππ‘ π ππ΅π,π = π11 πΆ ππ ππΏ πΆππ‘ πβ πΆ πΆππ πΆπ π·π πΆ ππ ππ (B8) (B9) (B10) DL ο½ 1 ο« A BZ C LB ο« A PH C LPH ο« A HQ C LHQ ο« ACat C LCat ο« A BT C LBT DM ο½ 1 ο« A BZ C MB ο« A PH C MPH ο« A HQ C MHQ ο« ACat C MCat ο« A BT C MBT (B11) (B12) BO BO RM PH , L ο½ k 2CL VL (B13) BO BO RM PH , M ο½ k 2 C M VM (B14) BO BO RM MA , L ο½ k3CL VL (B15) BO BO RM MA , M ο½ k 3 C M VM (B16) BO BO RM PMA , L ο½ k 4 C L VL (B17) BO BO RM PMA , M ο½ k 4 C M VM (B18) RM HQ HQ Conj , L HQ HQ VMax C ο½ HQ L HQ C MPTL K m ο« CL HQ HQ VMax CM C MPTM HQ HQ K m ο« CM HQ RM HQ Conj ,M ο½ Cat RM Cat Conj , L ο½ Cat Cat VMax CL C MPTL Cat Cat K m ο« CL Cat RM Cat Conj , M ο½ RM BT BT Conj , L Cat Cat VMax CM C MPTM Cat Cat K m ο« CM BT VMax C LBT ο½ BT C MPTL BT K m ο« CL BT RM BT Conj , M ο½ BT VMax C MBT C MPTM K mBT ο« C MBT PH PH PH PH ο¦ VMax οΆ CP VMax ,1C L , 2C L ο§ ο·C TL RM ο½ ο§ PH ο« PH PH PH ο· K ο« C K ο« C L m,2 L ο¨ m ,1 οΈ PH PH PH PH ο¦ VMax,1C M VMax, 2C M οΆ CP PH ο§ ο· RM PH ο½ ο« Conj , M ο§ K PH ο« C PH K PH ο« C PH ο·C TM M m, 2 M οΈ ο¨ m,1 PH PH Conj , L Total Mass of liver and bone marrow: TL ο½ VL ο΄ 103 g l TM ο½ VM ο΄ 103 g l (B19) (B20) (B21) (B22) (B23) (B24) (B25) (B26) (B27) (B28) 8 Blood Flow Concentration of benzene in the mixed venous blood: C BZ Q ο« CVBZ,S QS ο« CVBZ, R QR ο« CVBZ, L QL ο« CVBZ,M QM CVBZ ο½ V , F F QC Pseudo-steady-state gas exchange equation for benzene concentration in arterial blood: C BZ Q ο« CVBZ QC C ABZ ο½ I P QP PB ο« QC Concentration of benzene in the exhaled breath: BZ CEBZ ο½ f DS CIBZ ο« ο¨1 ο f DS ο©C AL Concentration of chemical i in venous blood leaving compartment j: C ij i CV , j ο½ i Pj (B29) (B30) (B31) (B32) Area under the curve of chemical i in tissue j: t AUC ο½ ο² C ij ο¨t ο©dt i j (B33) 0 Benzene ο¨ ο© dC FBZ ο½ QF C ABZ ο CVBZ,F dt dCSBZ VS ο½ QS C ABZ ο CVBZ,S SPT: dt dC RBZ VR ο½ QR C ABZ ο CVBZ, R RPT: dt dCLBZ BZ ο½ QL C ABZ ο CVBZ, L ο RM BO Liver: VL ,L dt dCMBZ BZ ο½ QM C ABZ ο CVBZ, M ο RM BO Marrow: VM ,M dt Fat: VF ο¨ ο© ο¨ ο¨ ο© ο© ο¨ ο© (B34) (B35) (B36) (B37) (B38) Benzene Oxide dCBBO ο½ QF CVBO,F ο« QS CVBO,S ο« QRCVBO,R ο« QLCVBO,L ο« QM CVBO,M ο QC CBBO Blood: VB dt dCFBO VF ο½ QF CBBO ο CVBO, F Fat: dt ο¨ ο© (B39) (B40) 9 ο¨ ο© (B41) ο¨ ο© (B42) ο¨ ο© (B43) dCSBO ο½ QS CBBO ο CVBO, S dt dC BO VR R ο½ QR CBBO ο CVBO, R RPT: dt dC BO BZ BO BO BO Liver: VL L ο½ QL CBBO ο CVBO, L ο« RM BO , L ο RM PH , L ο RM MA, L ο RM PMA, L dt dCMBO BZ BO BO BO ο½ QM CBBO ο CVBO, M ο« RM BO Marrow: VM , M ο RM PH , M ο RM MA, M ο RM PMA, M dt SPT: VS ο¨ ο© (B44) Phenol dCBPH ο½ QF CVPH,F ο« QS CVPH,S ο« QRCVPH,R ο« QLCVPH,L ο« QM CVPH,M ο QC CBPH ο k9VBCBPH (B45) dt dCFPH VF ο½ QF CBPH ο CVPH,F ο k9VF CFPH Fat: (B46) dt dCSPH VS ο½ QS CBPH ο CVPH,S ο k9VS CSPH SPT: (B47) dt dCRPH VR ο½ QR CBPH ο CVPH,R ο k9VRCRPH RPT: (B48) dt dCLPH BO PH PH PH PH ο½ QL CBPH ο CVPH,L ο« RM PH Liver: VL (B49) , L ο RM HQ, L ο RM Cat , L ο RM PH Conj , L ο k9VL CL dt dCMPH BO PH PH PH PH ο½ QM CBPH ο CVPH,M ο« RM PH Marrow: VM ,M ο RM HQ,M ο RM Cat ,M ο RM PH Conj ,M ο k9VM CM (B50) dt Blood: VB ο¨ ο© ο¨ ο© ο¨ ο© ο¨ ο© ο¨ ο© Hydroquinone dC BHQ HQ HQ HQ HQ HQ HQ ο½ QF CVHQ , F ο« QS CV , S ο« QR CV , R ο« QL CV , L ο« QM CV , M ο QC C B ο k10VB C B dt dC FHQ HQ VF ο½ QF ο¨C BHQ ο CVHQ Fat: , F ο© ο k10VF C F dt dC SHQ HQ VS ο½ QS C BHQ ο CVHQ SPT: , S ο k10VS C S dt dC RHQ HQ VR ο½ QR ο¨C BHQ ο CVHQ RPT: , R ο© ο k10VR C R dt dC LHQ PH HQ HQ HQ ο½ QL C BHQ ο CVHQ Liver: VL , L ο« RM HQ, L ο RM BT , L ο RM HQ Conj , L ο k10VL C L dt dCMHQ PH HQ HQ HQ ο½ QM ο¨C BHQ ο CVHQ Marrow: VM , M ο© ο« RM HQ, M ο RM BT , M ο RM HQ Conj , M ο k10VM C M dt Blood: VB ο¨ ο¨ ο© ο© (B51) (B52) (B53) (B54) (B55) (B56) 10 Catechol dC BCat Cat Cat Cat Cat Cat ο½ QF CVCat , F ο« QS CV , S ο« QR CV , R ο« QL CV , L ο« QM CV , M ο QC C B dt dC FCat VF ο½ QF C BCat ο CVCat, F Fat: dt dC SCat VS ο½ QS C BCat ο CVCat SPT: ,S dt dC RCat VR ο½ QR C BCat ο CVCat RPT: ,R dt dC LCat PH Cat Cat ο½ QL C BCat ο CVCat Liver: VL , L ο« RM Cat , L ο RM BT , L ο RM Cat Conj , L dt dC MCat PH Cat Cat ο½ QM C BCat ο CVCat Marrow: VM , M ο« RM Cat , M ο RM BT , M ο RM Cat Conj , M dt Blood: VB (B57) ο¨ ο© (B58) ο¨ ο© (B59) ο¨ ο© (B60) ο¨ ο© (B61) ο¨ ο© (B62) Benzenetriol dC BBT ο½ QF CVBT, F ο« QS CVBT,S ο« QR CVBT,R ο« QL CVBT, L ο« QM CVBT,M ο QC C BBT dt dC FBT VF ο½ QF C BBT ο CVBT, F Fat: dt dC SBT VS ο½ QS C BBT ο CVBT,S SPT: dt dC RBT VR ο½ QR C BBT ο CVBT,R RPT: dt dC LBT HQ Cat BT ο½ QL C BBT ο CVBT,L ο« RM BT Liver: VL , L ο« RM BT , L ο RM BT Conj , L dt dCMBT HQ Cat BT ο½ QM C BBT ο CVBT,M ο« RM BT Marrow: VM , M ο« RM BT , M ο RM BT Conj , M dt Blood: VB (B63) ο¨ ο© ο¨ ο© (B65) ο¨ ο© (B66) ο¨ ο© (B67) ο¨ ο© (B64) (B68) Muconic Acid dM MA BO BO ο½ RM MA , L ο« RM MA, M dt MA dCBlad BO BO MA ο½ RM MA Bladder: VBlad ,L ο« RM MA,M ο« CMA / CT CTProd ο QU C Blad dt MA Initial: CBlad t ο½0 ο½ CMA / CT CTProd QU Amount: (B69) (B70) (B71) Phenylmercapturic Acid Amount: dM PMA BO BO ο½ RM PMA , L ο« RM PMA, M dt (B72) 11 PMA dCBlad BO BO PMA ο½ RM PMA ,L ο« RM PMA,M ο« C PMA / CT CTProd ο QU C Blad dt PMA CBlad t ο½0 ο½ CPMA/ CT CTProd QU Bladder: VBlad (B73) Initial: (B74) Catechol Conjugates dM Cat Conj Cat Cat ο½ RM Cat Conj , L ο« RM Cat Conj , M dt Cat Conj dCBlad Cat Cat Cat Conj ο½ RM Cat Bladder: VBlad Conj ,L ο« RM Cat Conj ,M ο« CCat / CT CTProd ο QU C Blad dt Cat Conj Initial: CBlad t ο½0 ο½ CCat / CT CTProd QU Amount: (B75) (B76) (B77) Phenol Conjugates dM PH Conj PH PH ο½ RM PH Conj , L ο« RM PH Conj , M dt PH Conj dCBlad PH PH PH Conj ο½ RM PH Bladder: VBlad Conj ,L ο« RM PH Conj ,M ο« CPH / CT CTProd ο QU CBlad dt PH Conj Initial: CBlad t ο½0 ο½ CPH / CT CTProd QU Amount: (B78) (B79) (B80) Benzenetriol Conjugates Amount: dM BT Conj BT BT ο½ RM BT Conj , L ο« RM BT Conj , M dt (B81) Hydroquinone Conjugates dM HQ Conj HQ HQ ο½ RM HQ Amount: Conj ,L ο« RM HQ Conj ,M dt HQ Conj dCBlad HQ HQ HQ Conj ο½ RM HQ Bladder: VBlad Conj ,L ο« RM HQ Conj ,M ο« C HQ / CT CTProd ο QU C Blad dt HQConj Initial: CBlad t ο½0 ο½ CHQ / CT CTProd QU (B82) (B83) (B84) 12 Appendix C: Additional validation studies 1 Benzene in Breath (ppm) 0.1 0.01 0.001 0.0001 0 1 2 3 4 5 6 7 Time (days) Figure C1: Breath measurements following cessation of occupational exposure, as reported by Berlin et al.(36) Model results are for 8 hours of exposure to 0.5 ppm benzene, followed by a background exposure of 0.005 ppm. 13 100 Women Breath Concentration (ppm) Men 10 1 0.1 0 4 8 12 Time (hr) 16 20 24 Figure C2: Breath concentrations measured by Nomiyama and Nomiyama during four hours of exposure to 57 ppm benzene.(37,38) 14 100 1 hr @ 99 ppm Model Curves: 1 hr @ 99 ppm 4.8 hr @ 25 ppm 8 hr @ 13.5 ppm 8 hr @ 6.4 ppm 4.8 hr @ 25 ppm 10 8 hr @ 13.5 ppm Concentration (ppm) 8 hr @ 6.4 ppm 1 0.1 0.01 0.001 0 20 40 60 80 100 Time (hr) Figure C3: Results of Sherwood(40) and model predictions for four exposure scenarios. 15
