ithnithm@BookC_StringPrint_SetupTPrintStartupSound_TabLISTBook_PrefsAct List Scene Drawing_Model Draw_Specs diagram_struct_arrayDependentsScriptPad_ListManuscriptPlayPlay_PrefsModelSubscript_Set_ListSubscript_SetArraySimulation_ModelRun_Specsentity_struct_arrayentity_structint16_arraydouble_arraytoken_type_arraytoken_type run_handle_array!Draw_Index"Poster_Info#queue$Units%diagram_struct&Point_array'movie_attach(Picture_Tab)Pad*Model_Index_array+Button_Type,Condition-Play_Where.Movie_Tab/Model_Index0slider_type1Log_Condn2Log_Page3lid_info_array4lid_info5slider_type_array6Dependent_Entry7graph_type8curve_type_array9curve_type:table_type;table_var_type_array<table_var_type=SET>AliasRecord?Pathname@PanelASector_SpecsBSense_SetupCselect_struct_arrayDselect_structEallow_struct_arrayFallow_structGPicture_arrayHPictureIEntity_Controller_MapJSection_ListKFont_MapLFont_Map_Record_ArrayMFont_Map_RecordNWindow_ListOModel_WindowPPad_WindowQ@@4223,33zf~2xxHH@\HH@d'O q pd>> ,,2V33     ,3r3    JJ@ drmd   3P3@@3243:30PP??A2    V2l 4H3 2g:33j*3 z7(1 Dim_Name_1 "jj@?əTimeH2'c ?S???S?S?S?????S?I dose_rateif ((MOD(TIME,spacing_between_cycles_in_hours*spacing_multiplier) < hours_per_cycle) and (TIME < duration_of_dosing_regimen_in_hours)) then concentration*concentration_multiplier else 0 0'=X  0   ,  '   =          !" #$%c??MR??S35v?MR?S35v?ϋѲ??MR?[;|?x- ???4?x- ?3?[5s?[;| CFU_GM_population_relative_sizeCFU_GM/2000000000~ ~ / Ae  !" #$%s@ ĽA?@ ĽA?%p @ ĽA???4?initiated_stem_cells0CC !" #$%c ?tzG{?tzG{@?@?tzG{?tzG{?tzG{?tzG{????tzG{? I?tzG{concentration0 !"1 #$%s?^U???-?^U&`;x????&1ZX ?2&`;xVOC_in_periphery0 !" #$%s  ?B 3[ ???B 5X?B 3[ &!????&1D#?2&! VOC_in_blood0   !" #$%f6 ?d4#P1???dm?d4#P1&1sE????2&1ZX K2172.9*VOC_in_periphery {from Cohen et. al., 1971, p.679}  @33 3333   !" #$%fH ?޸φ???޸Ї?޸φ&1 ((3????2&0AK12I4.2*VOC_in_blood {per hour, from Table 1 of Cohen, Jao, and Jusko, 1971}  @   !" #$%f ?m㈎v???m P?m㈎v%8E????2%=Omb#renal_clearance_of_VOCKe*VOC_in_blood     !" #$%s!? <??? t? <&F_*@????%Dh?3 &F_*@"CYP2E1&_MFO _metabolites_in_blood0  !" #$%f0?͙???˾?͙%ן}????3 %Iliver_MFO_metabolism1Kmet*hepatic_mixed_function_oxidase*VOC_in_blood        !" #$%s????????????????3 ?hepatic_mixed_function_oxidase1    !" #$%f ??????3  creation!0*hepatic_mixed_function_oxidase      !" #$%f ??????3  degradation!0*hepatic_mixed_function_oxidase      !" #$%c?ěS?ěS???ěS?ěS?ěS?ěS?ěS?ěS???? ?ěS? 3?ěSKmet0.262 {per hour, from Table 1 of Cohen, Jao, and Jusko, 1971. However, Sladek, page 315, suggests a plasma half life of about 7 hours (rate constant = 0.1) with a large interindividual variability}    ?ě S!"1 #$%c=?bM?bM???bM?bM?bM?bM?bM?bM?????bM?2?bMKe>0.032 {per hour, from Table 1 of Cohen, Jao, and Jusko, 1971}   ?bM !" #$%s! ?V;P???Ue?V;P&;[U֕C????&!3+?4&;[U֕C"reactive_metabolite_in_stem_cells0-z! !" #$%f ;!??????3 oxidation)??@<@wb>)@wb>)?????4@wb>) eliminated0 !" #$%f$.?u61???с|?u61&????4&TEl2cell_elimination%elimination_fraction*cell_metabolism     !" #$%c0???????????????? 4?elimination_fraction1 !"1 #$%g2??????Parent VOC Module!" #$%g3??????Hepatic metabolism module!" #$%g4??????Cellular Metabolism Module!" #$%f5?@{????@{%1u$????3%DhKel0.462*CYP2E1&_MFO__metabolites_in_blood {per hour, calculated from a 1.5 hr. half life cited by Colvin and Chabner, p. 296. Half-lives in adults range from about 1 to 5 hours.}    ?ݑh r   !" #$%f 8?Fh&???F Φf?Fh&&!xi????4&!3+ elimination4*0.08031*reactive_metabolite_in_stem_cells {adjusted from apparent, from mean phosphoramide half-life in plasma of 8.68 hours in human patients, cited by Colvin and Chabner, p. 295. But, see Sladek's discussion of apparent vs. actual half-lines, pp 316-317.}  * ?2 7    !" #$%fU> ?S???S?S?S????4?SIadministered_doseVif (AUC_of_admin_dose < target_total_AUC*target_AUC_multiplier) then dose_rate else 0#"$, # "         !" #$%s*@@0D?@0D@ vbl@0D@0D????4?4 @ vbl@0D+AUC_of_reactive_metabolite_in_target_cells0! !" #$%f!B?V;P???Ue?V;P&<az????4!&;[U֕Creactive_metabolite_amount"reactive_metabolite_in_stem_cells  !" #$%c C@@Aׄ?Aׄ@@@@????@? I"@target_total_AUC 100000000   Aׄ !"1 #$%sE?J@??J@?1&x?J@?J@????4?I#?J@AUC_of_admin_dose0$ !" #$%fG?S???S?S?S?????SI$dose_incrementadministered_dose# !" #$%gI??????%Administered Dose Sector !" #$%c K@??@@?l???????&?l sine_driver1 + SINWAVE(1, 24)    *   !" #$%cL@ @ ??@ @ @ @ @ @ ???@ ? I'@ hours_per_cycle24 !"1 #$%s PAx^KCYAg~,7?Ax^KCYAg~,7A@KݫAg~,7Ax^KCYAg~,7A1|gA]r@$??AQR4A]r?(A1|g cycling_HPCs4.9E7+,-.1j*8+,-   A]r !" #$%s QAu)A1A=eߥAK4v.A=eߥAA֨ABC????@$ABCx,AAtdifferentiated)differentiation_fraction*cycling_HPCs/10.(`( . (   !" #$%f IUA9 ??A1yKA9 'g????-'1KW!HPC_cell_death_from_cytotoxicityJcycling_HPCs*cytotoxic_potency_for_EHPC*reactive_metabolite_in_stem_cells(9( ( 9    !" #$%#cGX?$ xF?Nh???$ xF?\ ?$ xF?Nh??$ xF?????$ xF?.?differentiation_fractionH1-MAX(0,0.5 + 1.76E-9*(steady_state_HPCs - resting_HPCs-cycling_HPCs)) /)(+,H  , ? + >< M / )  (       !" #$%c#[A_ A_ ??A_ A_ A_ A_ A_ A_ ????A_ ?/A_ steady_state_HPCs$3.125E8 {PSC cells in steady state}.   A_ !" #$%c @8@8A L?A L@8@8@8@8???@8? I0@8 spacing_between_cycles_in_hours .01 {hours}   ?z G{!"1 #$%(c=_?Ms?h,{h???~n\?&qS?Ms?h,{h?]?W a?????W a?1?]recruitment_rate>k1*EXP(-v1*resting_HPCs-v1*cycling_HPCs) + k2*EXP(-v2*Z) + k353)(6427*G\ 5 3  )  3 (      6 4  2      7  !" #$%cDbB?-B'"??BA bҤB-%\B?-B'"B=pJ`%B>Nx????B>Nx?2B=pJ`%ZE(signal_Z + CFU_GM) {= 3.208E9 + 3.469E10 + 12.8E10 in steady state}A~1  A ~  !" #$%c d>rN>rN??>rN>rN>rN>rN>rN>rN????>rN? 3>rNv1 1.6955E-61   >r N!"1 #$%c e=$=$??=$=$=$=$=$=$???? =$? 4=$v2 3.1918E-111   = $!"1 #$%cf? =p ? =p ??? =p ? =p ? =p ? =p ? =p ? =p ????? =p ? 5? =p k1.36 {per hour}1   ? = p !"1 #$%cg?zG{?zG{???zG{?zG{?zG{?zG{?zG{?zG{?????zG{? 6?zG{k20.04 {per hour}1   ?z G{!"1 #$%ch?bM?bM???bM?bM?bM?bM?bM?bM?????bM? 7?bMk30.008 {per hour}1   ?bM !"1 #$%f oALI[AAI_"??AI$M~3A@ky ALI[AAI_"AAMAAL????AAL8AAㇶcell_divisionrecruited_into_cycle*( *!" #$%c#t?????????????? ?? 9?cytotoxic_potency_for_EHPC$0.1 {per cycling PSC cell per hour}-   ? !"1 #$%gx??????:Proliferative Sector!" #$%f {AZ`L0A&K???AΖפcnAĻ=gAZ`L0A&K?Aӱ1vA0????A0;Aӱ7= precursorsto_maturation_pool< !" #$%s|B,=sҒB Rs??B-TB(}}B,=sҒB RsB(y B'g????Aӱ B'g?<B(y maturation_pool5109E7?A;?   B'g !" #$%c# @@??@@@@@@???@? I=@$duration_of_dosing_regimen_in_hours 24 {hours} !"1 #$%sB(Dw 2Aޙ??B*eBK~+G!jB(Dw 2AޙB%+(.+B'????AӱbUB'?>B%+(.+marrow_reserve5123E7DA?D   B' !" #$%fFA֗\uAo1)??A*vASA֗\uAo1)Aӱ ARt????ARt?Aӱ maturedGmaturation_pool/transit_time_40_hr {fractional output = 1/40 per hour}<@<>  < @  !" #$%c@D@D??@D@D@D@D@D@D????@D?@@Dtransit_time_40_hr40 {hr}? (!" #$%c1B?~[wB&vC??B@5B,+JB?~[wB&vCB=B=%????B=%?AB= signal_Z2proliferating_pool+maturation_pool+marrow_reserve<>j2  <  >  !" #$%g??????BEarly HPC & Stem Cell Sector!" #$%$f#M????????C$elimination_of_initiated_stem_cellsif (stochastic_apoptosis) = 0 then initiated_stem_cells*initiated_stem_cell_elimination_rate else POISSON(initiated_stem_cells*initiated_stem_cell_elimination_rate/dt)L               /  !" #$%fAP!EAƟTv(x??AP!EACAP!EAƟTv(xAӱf|bAP!E????AP!EDAӱbUrelease_to_bloodmarrow_reserve*release_rate>MK>Q  > M  !" #$%g??????ENon-Proliferative Sector!" #$%s@8҄3??@C ӎ7@8҄3@8҄3?????F@8҄3cumulative_aging_of_HPCs0JG !" #$%f?Ms?h,{h???~n\?&qS?Ms?h,{h??W a?????W aG?]HPCs_recruited_into_cyclerecruitment_rate1F 1!" #$%sBֹ1??Boh_Bֹ1Bֹ1????HBֹ1AUC_Peripheral_Blood_Release0K !" #$%g??????IInternal Dosing Sector!" #$%c @8҄3??@C ӎ7@8҄3@8҄3?????J@8҄3Age_Statisticcumulative_aging_of_HPCsF F!" #$%fAP!EAƟTv(x??AP!EACAP!EAƟTv(xAӱf|bAP!E???AP!EKAӱbUnew_cells_into_bloodrelease_to_bloodDH D!" #$%f !AԻ+Dh=A-,??AA,tVlgAԻ+Dh=A-,AӱLšAԶm???AԶmLAӱH' blood_decay"peripheral_blood*blood_decay_rateQUQ  Q U  !" #$%c  ?xV%/(? ???9b=`?1ho:?xV%/(? ?&H"?&`~?????&`~?M?&H" release_ratek8-k9*EXP(-v3*GRF)VWXND( V W X  N      !" #$%s@[0bSɹ@&A.;K??@Nf^q@#\nb@[0bSɹ@&A.;K@*@(????:6M@(?N@*GRF12 {Steinbach et al. select the GRF scale to give a steady-state value of GRF = 10, but this appears to be low for dynamic consistency}MORO !" #$%f @%NC?* ??@~? @%NC?* ?:68?333334????333334O?:6M GRF_decayGRF*GRF_decay_rateNPN  N P  !" #$%c2??????????????? P?GRF_decay_rate30.1 {per hour. From Steinbach et al., 1980, p. 7}O   ? !"1 #$%sDB & Ap9\~??B .x+ǥBȓB & Ap9\~B䉚1B X???AӱH'B X?QB䉚1peripheral_bloodE1.39E10 {Steinbach et al., 1980, Table 1, p. 3 gives a value of 1.6}LRDL   B X!" #$%f@&B?Lǧx???@#򷏕?ގ!k@&B?Lǧx??: k9 = k8 - .0125 = 2 - .0125. See Steinbach et al., p. 6}M   ? !"1 #$%c?D_n`^?D_n`^???D_n`^?D_n`^?D_n`^?D_n`^?D_n`^?D_n`^????D_n`^? X?D_n`^v3 6.309E-4M   ?D_ n`^!"1 #$%b 8AP5h4]J??AR"u2彟3,AP5h4]J++QD+ qq????+ qq3Y++QH6 cell_death_19(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_1zj__ z j  _  !" #$%b 8A;{glf; @??A`Q99A;{glf; @28M2N89????2N893Z28r cell_death_29(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_2zjaa z j  a  !" #$%b 8A0BzA0??AhߏAbA0BzA0: 9ʴ9qq????9qq3[: 9C cell_death_39(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_3zjcc z j  c  !" #$%c&? =p? =p??? =p? =p? =p? =p? =p? =p????? =p?3\? =pcytotoxic_potency_for_CFU_GM'0.13 {per proliferating cell per hour}z   ? =p!" #$%b 8A$kBGr'm??AHBe3 A$kBGr'mBū+A89????A893]Bū/h cell_death_49(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_4zjee z j  e  !" #$%b 8A)^LM*??A%`P147A)^LM*HH;q????H;q3^H; cell_death_59(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_5zjgg z j  g  !" #$%sAw1YNAu3p??AB aAu3pAw1YNAu3pA~(1A~????AHsA~?3_A~(1 CFU_GM_13.2E7Yb~`bY   A~ !" #$%fAK4v.A=eߥ??AHp&>A=eߥAK4v.A=eߥAA֨ABC????ABC3`AAt inflow_1differentiated,_ ,!" #$%sA@lAz??AiAzA@lAzA)!A????AP{A?3aA)! CFU_GM_24.4E7Zd~bdZ   A !" #$%fARWzAA2Zjm??AQ9*AA2ZjmARWzAA2ZjmAHsmAHj????AHj3bAHsflow_2CFU_GM_1/transit_time_10_i_a  _ i  !" #$%sA}tAI>9j??A#wAI>9jA}tAI>9jAL7KuAJ????AWp] *AJ?3cAL7Ku CFU_GM_36.1E7[f~df[   AJ !" #$%fAX͉#AE^ W$??AWF! AE^ W$AX͉#AE^ W$AP{9,AP????AP3dAP{flow_3CFU_GM_2/transit_time_10aiac  a i  !" #$%sA~*AAU??AJ{AUA~*AAUAH`UA^????A`:1A^?3eAH`U CFU_GM_48.44E7]h~fh]   A^ !" #$%fA`1AyAKd(.??A_N&3"AKd(.A`1AyAKd(.AWpY*l??A-AӰA!A>*lAqٓkAO????AoA\AO?3lAqٓk CFU_GM_616.2E7nu~knu   AO !" #$%sAw1??A4]_RʑA4][>1WY}Wc8????Wc83vWYA cell_death_79(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_7zjmm z j  m  !" #$%b 8A<^Ӏc bg??A<^Ӏeo^`A<^Ӏc bg`QX`l8????`l83w`Q cell_death_89(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_8zjoo z j  o  !" #$%b 8AD1jA O]A??AD1m UAD1jA O]AfaKfҪ????fҪ3xfed cell_death_99(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_9zjqq z j  q  !" #$%b 9AK74r0Q??AK74tP4AK74r0QoIkgo488????o4883yoIk!cell_death_10:(CFU_GM_cytotoxicity_death_rate-new_birth_rate)*CFU_GM_10zjss z j  s  !" #$%c> ?GB ???sc?GB & sw!e?????3z& sw!eCFU_GM_cytotoxicity_death_rate?reactive_metabolite_in_stem_cells*cytotoxic_potency_for_CFU_GM\YZ[]^uvwxy   \  !" #$%cW>/Hg#EY>/Hg#EY??>/Hg#EY>/Hg#EY>/Hg#EY>/Hg#EY>/Hg#EY>/Hg#EY????>/Hg#EY? 3{>/Hg#EYk4X3.6418E-9 {from Steinbach et. al., 1980, p. 5, calculated from steady-state conditions}j   >/Hg #EY!"1 #$%cX=am^=am^??=am^=am^=am^=am^=am^=am^????=am^? 3|=am^k5Y3.5476E-10 {from Steinbach et. al., 1980, p. 5, calculated from steady-state conditions}j   =a m^!"1 #$%cX=Fx=Fx??=Fx=Fx=Fx=Fx=Fx=Fx????=Fx? 3}=Fxk6Y6.9953E-12 {from Steinbach et. al., 1980, p. 5, calculated from steady-state conditions}j   = Fx!"1 #$%$cZ  AhcrM3A˵ӂl?A~nA+.YUAkAτP)AhcrM3A˵ӂlA Y0ZAޮ????Aޮ?3~A Y0ZCFU_GM[CFU_GM_1+CFU_GM_2+CFU_GM_3+CFU_GM_4+CFU_GM_5+CFU_GM_6+CFU_GM_7+CFU_GM_8+CFU_GM_9+CFU_GM_10_aceglmoqsj2L _ a  c  e  g  l  m  o  q  s  !" #$%g 3??????CFU-GM Sector!" #$%f5AIAtҵ4??AH0pQAwyn^C+AR[AH$bACx*A`????AynU]A`?ACx*P145.27E7   A `!" #$%fUAIAtҵ4??AH0pQAwyn^AuķA~fHAA_ A֤I%????A֤I%A_qflow_13P3/transit_time_56     !" #$%s]A|;8 AF??A+CHAŅ{BAA|;8 AFA} gqA????A%PA?A} gqP5154.3E7   A !" #$%f^A* IA;Ng??A~AϜzA* IA;NgAPA)BVm????A)BVmA flow_14P4/transit_time_56     !" #$%c, f@ffffff@ffffff??@ffffff@ffffff@ffffff@ffffff@ffffff@ffffff????@ffffff?@fffffftransit_time_56-5.6 {hr for each of 10 compartments = 56 hr}   @ff ffff!" #$%fjA<(A8 f??AG XA.A<(A8 fA%M+pAlWbI$????AlWbI$A%Pflow_15P5/transit_time_56     !" #$%slAm2RjAd%圧??AKtODA,mņAm2RjAd%圧AUu2A;????A\A;?AUu2P6209.6e7   A; !" #$%smAESBhA҂Mp??AyvA*ەuAESBhA҂MpA.XA8!????A%V+mA8!?A.XP7284.8e7   A8! !" #$%fnASOA&??ALkʺbsA)ASOA&AAO%I$????AO%I$A\flow_16P6/transit_time_56     !" #$%spAX??B]ifA#KBY%)AiwϿ>AA<????Aӱ7=A<?AP10714e7   A< !" #$%fuAܒLBAMt??ANŴ?AAܒLBAMtA{ۚARI$????ARI$A{flow_19P9/transit_time_56     !" #$%g??????GM Proliferation Sector!" #$%b Mt=BV{??t=BVC٠8t=BV{S~}OP????OPS~6cell_death_16N(cytotoxicity_death_rate_for_proliferating_cells-proliferation_birth_rate)*P6      !" #$%b M|I_*??|I_,-Z?|I_*mBo#????o#mcell_death_17N(cytotoxicity_death_rate_for_proliferating_cells-proliferation_birth_rate)*P7      !" #$%b M7vp<@s??7vpgǪ7vp<@s;'^7E????7E;(2cell_death_18N(cytotoxicity_death_rate_for_proliferating_cells-proliferation_birth_rate)*P8      !" #$%b MUTJ??UTc V UTJvP????Pv!Xcell_death_19N(cytotoxicity_death_rate_for_proliferating_cells-proliferation_birth_rate)*P9      !" #$%b NW ?qc??W9ӐRW ?qc5@ ~/????5@ ~/cell_death_20O(cytotoxicity_death_rate_for_proliferating_cells-proliferation_birth_rate)*P10      !" #$%c/E ?GB ???sc?GB & sw!e?????& sw!e0cytotoxicity_death_rate_for_proliferating_cellsFreactive_metabolite_in_stem_cells*cytotoxic_potency_for_proliferating     !" #$%$c B};Bye??Bh5&@B1 (B};ByeB!{NBg????Bg?B!{Nproliferating_poolP1+P2+P3+P4+P5+P6+P7+P8+P9+P10AL                    !" #$%fAZ`L0A&K???AΖפcnAĻ=gAZ`L0A&K?Aӱ1vA0????A0Aӱ7=to_maturation_poolP10/transit_time_56;     !" #$%c$ ?q?q???q?q?q?q?q?q????q??q%initiated_stem_cell_elimination_rate1/240 + initiated_cell_killing*cytotoxic_potency_to_initiated_cells*reactive_metabolite_in_stem_cells {baseline value = 1/(number of days to eliminate x 24)}C$         !" #$%0f N????????!creation_of_initiated_stem_cellsOif stochastic__initiation = 1 then POISSON((2000*reactive_metabolite_in_stem_cells)*HPCs_recruited_into_cycle*initiation_potency_per_recruited_HPC_per_hour/dt) else ((2000*reactive_metabolite_in_stem_cells)*HPCs_recruited_into_cycle*initiation_potency_per_recruited_HPC_per_hour) + background_initiation_rate*HPCs_recruited_into_cycle G|         G      /       G     G   !" #$%c-?zG{?zG{???zG{?zG{?zG{?zG{?zG{?zG{????zG{??zG{.initiation_potency_per_recruited_HPC_per_hour.01   ?z G{!" #$%f.?|6\???pyZ?|6\???initiated_cell_births/initiated_stem_cells*initiated_cell_birth_rate     !" #$%c?a?a???a?a?a?a?a?a????a??ainitiated_cell_birth_rate1/480 {mitoses per hour}   ?a !" #$%s?S???D ~?S>nJ5@???='?>nJ5@cytogenetic_damage0 !" #$%f6>F|̈́??>AL>F|̈́=+???='elimination_of_damaged_cells7cytogenetic_damage*cytogenetic_damage_elimination_rate     !" #$%c#?q?q???q?q?q?q?q?q????q??q$cytogenetic_damage_elimination_rate1/240   ?q !" #$%f)q?U訸M??>L\?U訸M%cKԯ/???%c|, *new_cytogenetic_damage_to_monitored_cellsrreactive_metabolite_in_stem_cells*HPCs_recruited_into_cycle*cytogenetic_damage_potency_per_recruited_HPC_per_hourG  G    !" #$%c5?zG{?zG{???zG{?zG{?zG{?zG{?zG{?zG{????zG{??zG{6cytogenetic_damage_potency_per_recruited_HPC_per_hour.01   ?z G{!" #$%c@%@%??@%@%@%@%@%@%???@%? I@%concentration_multiplier1 !"? #$%s@;?@;@°i@;@;???4?@;@;AUC_for_initiated_cells0 !" #$%f@ ĽA???%p @ ĽA???initiated_cell_hazardinitiated_stem_cells !" #$%c&??????????????? ?stochastic_ initiation'0 {1 = stochastic, 0 = deterministic} !" #$%c??????????????? I?target_AUC_multiplier1 !" #$%s)@Ik?@N@N@Ik@Ik???4?@Ik*AUC_of_recruited_proliferating_stem_cells0 !" #$%fF?oh?S-8‹"???gR9{?S-8‹"?oh?S-8‹"?U@?U ????U ?U@P cumulative_cycling_HPC_increaseGHPCs_recruited_into_cycle*((cycling_HPCs)/(cycling_HPCs+resting_HPCs))G() G ( ( )    !" #$%c@@??@@@@@@???@? I@spacing_multiplier1 !"C #$%g??????MVK and Cytogenetics Module!" #$%c??????????????? ?benzene_fraction1 !"P #$%c??????toluene_fraction0 !" #$%c ??????  DCM_fraction0 !"R #$%c??????m_xylene_fraction0 !" #$%c?????? styrene_fraction0 !"\ #$%c?????? butadiene_fraction0 !"Q #$%c ?????? PERC_fraction0 !"[ #$%c ?????? TCE_fraction0 !" #$%c??????chloroform_fraction0 !" #$%c?????? ethyl_benzene_fraction0 !"Y #$%c??????ethylene_oxide_fraction0 !" #$%c?????? methyl_chloroform_fraction0 !"Z #$%Bc 1????????????????Kmet_for_mixture_regression0*butadiene_fraction + 0*m_xylene_fraction+0*PERC_fraction+0*styrene_fraction+ 0*TCE_fraction+0*toluene_fraction+0*chloroform_fraction+0*DCM_fraction+0*ethylene_oxide_fraction+0*ethyl_benzene_fraction+0*methyl_chloroform_fraction+ benzene_fraction/(benzene_fraction + toluene_fraction)11                                       !" #$%s???????????????? lung_GSH1 !" #$%f ?????lung_GSH_depletionmin(.1, .4*butadiene_fraction)( ( ? , ?ٙ    !" #$%%f8?????lung_GSH_production9if (lung_GSH < 1) then MIN(.1*(1 - lung_GSH), .2) else 0P      ( ?     , ?ə     !" #$%c??????  sex_male1 !"M #$%c??????????????? ?stochastic_apoptosis1C !" #$%c?zG{?zG{???zG{?zG{?zG{?zG{?zG{?zG{????zG{??zG{background_initiation_rate.01 {0.01 default}   ?z G{!" #$%c2c @&A"ۖ??@&A"ۖ@&A"ۖ@&A"ۖ???4?@&A"ۖ@&A"ۖ3ratio_of_reactive_metabolite_AUC_to_admin_dose_AUCdif (AUC_of_admin_dose > 0) then AUC_of_reactive_metabolite_in_target_cells/AUC_of_admin_dose else 0# , #     #    !" #$%c9 @Y^ 0) then AUC_for_initiated_cells/AUC_of_reactive_metabolite_in_target_cells else 0 ,          !" #$%c5P @y??@ȣ+B@y@y???4?@+V @y6ratio_of_AUC_for_initiated_cells_to_AUC_of_admin_doseQif (AUC_of_admin_dose > 0) then AUC_for_initiated_cells/AUC_of_admin_dose else 0#, #     #    !" #$%c$$?陙?陙???陙?陙?陙?陙?陙?陙????陙??陙%cytotoxic_potency_to_initiated_cells0.8   ?陙 !" #$%c'?????? initiated_cell_killing0 !" #$%  _\  |_&a PP2PlH'(Parent VOC Module)*+ &PR3RJ!'(Hepatic metabolism module)*+ &Po!4 o!R K'(Cellular Metabolism Module)*+ &P,RI ,R^Jf'(Administered Dose Sector )*+ &PFxFxp)x '(Proliferative Sector)*+ &Fb@'()*+ &C@'()*+ &CJ@*#'  !()*+ &FhM@V}>'^s()*+ &P  $ )23 J'(Early HPC & Stem Cell Sector)*+ &P5T5Tl Lt2'(Non-Proliferative Sector)*+ &Pp yx '(Internal Dosing Sector)*+ &F&& t@ ;;T'&0&()*+ &C  @ s'()*+ &C&? @7;TYq'?0?()*+ &C :@v'()*+ &F*  @"?U'**()*+ &C{ @c*}'k"k()*+ &C @'()*+ &P*3*"' '(CFU-GM Sector)*+ &CJ@b'ZZ()*+ &C @ ,0:'()*+ &CqV@i'qq()*+ &Pq"q"T )3'(GM Proliferation Sector)*+ &N|D|/t7'()*,ZZ AnT n -." /TABLES0+ &C=2@jd'r\r()*+ &CwJ@1k'!ww"()*+ & t@<D'()High Level Concept Map*+ &N!D!GO'()*, AnT n -./BACK0+ &N#&D#&IrQz'()*,A(nT n -." /HOME0+ &J[''()*1hh ???d3?023." " + &Nd(Dd(t\ |'()*, AnT n -./BACK0+ &W@ '()*1?3?023." " + &D2 @!I'() Graph 1*+ & t@Ca"_Ki'()`_VOC Hematotoxicity Risk Simulation Model 1.0 (c) Cox Associates, 2003 (c) Cox Associates, 2003*+ &N#D#,z#4'()*,$A2 nT n -.F" / MODEL LOGIC0+ &N(D(t$ |'()*,xAnT n -.b" /RUN0+ &NszDsz%kr'()*,6ADnT n -." /INPUTS0+ &M@.X&'()*+ &M@PR' )'()*+ &Mo@4N(>'()*+ &Cw J@)>'  ww()*+ & t`)* 2'() SET SCENARIO*+ &N2$D2$Xp +*`x'()*,LAZnT n -." /HOME0+ &Nk&Dk&r ,cz'()*, AnT n -./BACK0+ & t`-  '() VIEW TABLES*+ &N#D#I .Q'()*,AnT n -." /HOME0+ &N\D\ /T'()*, AVnT n -./BACK0+ &D@0z'() Table 1*+ &L.(+]| 1#e'()*40 5ոƑModel Parameters6 1 @?3?023." " 1 @??3?023." " 1 >/Hg#EY@}!>/Hg#EY?3{?0{23." " 1 =am^@ 0=am^?3|?0|23." " 1 =Fx@==Fx?3}?0}23." " 1 ? =p @Gz? =p ?35?0523." " 1 ?zG{@QR?zG{?36?0623." " 1 ?bM@bM?bM?37?0723." " 1 >rN@>rN?33?0323." " 1 =$@=$?34?0423." " 1 ? =p@ =p ? =p?3?023." " 1 =fqrRO@ =fqrRO3?023." " 1 ?ěS@tj?ěS3?023." " 1 ?@??39?0923." " 1 ?@?3U?0U23." " 1 ?@?3P?0P23." " 1 @h@i @i?3T?0T23." " 1 ?@@?3V?0V23." " 1 ?@fffff??3W?0W23." " 1 ?D_n`^@J?D_n`^?3X?0X23." " 1 =<|@ =<|3S?0S23." " 55ԑ⑲Dosing Constants621 @@?tzG{3?023." " 1 ?@È@ 3'?0'23." " 1 A_ @830?0023." " 1 @È@3=?0=23." " 1 Aׄ@3"?0"23." " + &C,  @2A' ,,  ()*+ &C @3^' ||()*+ &&ND5 '()*,`Ann& n -. " /MODULES0+ &ND7 X6? `'()*,A ’n& n -.j:" /Pharmacokinetics Model0+ & t2@2o 7*w '()VOC Risk Model Module Browser*+ &&& th@h n:` v'()Pharmacokinetics modules*+ &N D 0; 8'()*,@ANn& n -.j " /CFU-GM Cytotoxicity0+ &N cD c < [ '()*,hAvn& n -.j " /Clastogenic Damage0+ &NS DS | =K z '()*,dA rn& n -." /HOME0+ &ND U> ]'()*,\Ajn& n -.j:" /Dosing Module0+ &J?[6'()*1@4@%?63?023." " + &RX@@'()*13?023." " + &NG$DG$lxA?t'()*, Aؓn& n -./CLEAR0+ &W@ B'()*1?3?023." " + &J&  CZt'()*1@@?d3?023." " + &N D / 4D 7 <'()*,VA dn& n -.j<" /Proliferating cells0+ & tj ~@j ~ 5Eb v ='()Hematotoxity modules*+ &N fD f1 F ^9 '()*,ƔA Ԕ n& n -.j" / MVK module0+ &NK DK ~ 8GC  @'()*,A(n& n -.jN" /Non-proliferating cells0+ & tj S@j S Hb K $'()Carcinogenicity*+ &Ppu puISm!JK'(MVK and Cytogenetics Module)Cytogenetics & MVK*+ &C IR@J'()*+ &CmIR@Ke}%'mmu()*+ &NR DR LJ '()*, A$:n& n -./Human;This button will give access to human data and parameters.0+ &W< @< P  M, P '()*1?3?023." " + &N{D{Ns'()*,An n -." /MIXTURE0+ &"J/yIOEu'()*1@Y@Y@Y@Yd@Y023." " +80000000 &J^yf@LLPItB'()*1@Y?@Y@Y3@YO023." "O + &Jyf@LLQxJ'()*1@Y@Y@Y3@YO023." "O + &Jyf@LLR.'()*1@Y@Y@Y3@YO023." "O + & t"@"K'SS/'()Mixture Definition *+ &N D T '()*, A┲8n& n -./Rat9This button will give access to rat data and parameters.0+ &N D  U '()*, A:n& n -./Mouse;This button will give access to mouse data and parameters.0+ &NDVw'()*,dArn& n -." /HOME0+ &N@iD@ikW8as'()*,AƗn& n -." /HOME0+ & t @ RX Z'()Under Construction*+ &Jyf@Y^'()*1@Y@Y@Y3@YO023." "O + &Jyf@Z0u'()*1@Y@Y@Y3@YO023." "O + &JIyf@[4_5'()*1@Y@Y@Y3@YO023." "O + &Jxyf@\c;'()*1@Y@Y@Y3@YO023." "O + &W+@+Q ]y'()*1?3?023." " + &D @^v '() Graph 2*@+ !drmdD 7plwh.)7plwh.7plwh. 7plwh. 7plwh. W7plwh. )7plwh./7plwh. E7plwh. 7plwh. 7plwh. i7plwh. 7plwh.7plwh. 7plwh. 7plwh. B  ))   /)& tT \'()A simplified compartmental model of target cell metabolism and pharmacokinetics, including its principle circulating metabolites*+ &cr;Um eO'()*+ &auI>I@ pD'()*+ &c@z*'()*+ &a 3@ '()*+ &s@ i~'()*+ &cUmideCFU_4[c'()*+ &a\k*eeWp'()*+ &sj  '()*+ &s>f c'()*+ &fy; 2'*()'*+ &f}< 120'*()'  *+ &f]R iM ' E]E]()' "9{9{*+ &d_ 2B Vh'()*+ &s2  oT m#7<'()*+ &f  ~ L$'T()'F*+ &aT 2 tYO'()*+ &sG  H !yZ#'()*+ &a6 3 G"";'()*+ &dI~ 3\ @uR'()*+ &fJ   9{iw'JJ()'gg*+ &fH  ~ 7gv'HH()'ff*+ &dI 3 @R'()*+ &aT 3 1 J_'()*+ &aK 3g mssFY'()*+ &a2 N e'()*+ &a 2 2 Jd ++/'()*+ &c  '()*+ &a 3 '()*+ &a5 2 V }kg;'()*+ &c~+3 qM'()*+ &aA62 a">  'l%'()*+ &s[:TC %:?2i#'()*+ &fc ; !>Aa';' F9()' F}Y}*+ &f]w "g B, #)+/=':o()'.c*+ &a- 3" 9!!#2'()*+ &d&B>I F $9/K'()*+ &cq #= %d{''()*+ &sHz  &69~'()*+ &ag& %3!` 1^^'!le'()*+ &c/r ("P)'()*+ &a$(4"  {77))'()*+ &c E *8.+'()*+ &a9*4" }//+%>'()*+ &s)C ,<'()*+ &d(?.49 -61H'()*+ &f)  .GFU-/1')7)()'E+E*+ &a"4.( ,TT/-'()*+ &ci) 0\^1'()*+ &a_#04.2 ``1?d('()*+ &gTTi 2Hu'(Parent VOC Module)*+ &gr r+ 3f'(Hepatic metabolism module)*+ &g  4'(Cellular Metabolism Module)*+ &f7 H 5,3C)C67;'7+7()' 3I3*+ &d37 538 6*.<@'()*+ &a. 35CA h???73A'()*+ &fmlH 8 G`9:' OmOm()' -CC~*+ &dn848 9ew'()*+ &a[ 48id q^^:Vin'()*+ &a? 53!^ |XX;:c'()*+ &sB4w <}'()*+ &dB"4w =9 K'()*+ &f@8t >&!~$HJD'.@@()' n3n::*+ &a  4B ? cp>'()*+ &sc 0l @.Wv'()*+ &d]B4/vkz ATf'()*+ &fdB! ?{ BS~+A?'ddv()'yyS*+ &c""Q^U C}D'()*+ &aCI>7 (~~DI'()*+ &sb#$-`1 E<xuJ'()*+ &dZ/GI \ FQ&c8'()*+ &f[$0eli G5gJFH'['[()'oo*+ &a8>IGa "!^%HjJ'()*+ &gl% l I`'(Administered Dose Sector )*+ &ahEI>8 [11JcI'()*+ &cYA&6r KL4g'()*+ &c?'*LMO'()*+ &f sC@M sN~' ()' *+ &d M@ N '()*+ &aILhQippODm'()*+ &s(b| P9WYs9'()*+ &sA) Q+g Va]+'()*+ &f * RLV`p' T ()'T*+ &f+}" SL>(WZ'T()'T*+ &fu, ) T&*wqYy'()'*+ &f{- ed U urusv' ()' *+ &aWQR oVP'()*+ &aPS j''W0'()*+ &cd.% XWv Z\q]'()*+ &aPTl cjj((Yq'()*+ &aZXS( 11Z3^'()*+ &cd;/