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Index A Absorption extrapolation of, 139- 140 gastrointestinal, 122 rate of, 121 skin, 122-123 ACSL language, 232-233 Adenine arabinoside model, 58 Adenomas, hepatocellular, 459 Administered and delivered doses, 330, 447-455 ADSIM language, 232 Air, excretion into, 142- 143 Allometric equations, 66-67 Allometry, 65-78 valid and invalid extrapolations of, 141 Allyl chloride, 176-179 Alveolar space mass-balance equation, 262 Anatomical models, lower respiratory tract, 305-307 Angiosarcomas, 456-457 Animals no-observable-effect levels (NOELs) for, 4-5 477 pharmacokinetic studies in, 407- 408 polymorphisms in, 146 Anticancer therapy, prospective predictions and validations in, 431- 440 Apparent volume of distribution, 31 Area under tissue curve (AUTC), 11 Areas under concentration-time curves (AUCs), 256, 471-472 Armitage-Doll multistage model, 443 Arterial blood mass-balance equation, 262 AUCs (areas under concentration-time curves), 256, 471-472 AUTC (area under tissue curve), 11 Availability, systemic, 453 Average concentration, 97 Axial dispersion number, 87 B BASIC language, 231-232 Bayesian methods, 190 Bile excretion, 116, 122, 142-143 duct mass-balance equation, 53

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478 INDEX Binding affinity, 14 drug, 88-89 plasma, 90 tissue, 90 Bioavailability fraction of dose absorbed and, 122 gastrointestinal absorption and, 122 skin absorption and, 122-123 Birth rate for cells, 380 Blood carboxyhemoglobin, 169 pool mass balance, 46-47 Body clearance, total, 108, 115 mass dependent metric, 70-73 regions, 39-44 size, in pharmacokinetic models, 65-78 weight (BW), 18- 19, 209 Bolus administration, 43 C C language, 231 Cancer model, two-stage, 21 Carbon dioxide mass-balance equation, 263 Carbon monoxide mass-balance equation, 263 Carbon tetrachloride, model for, 312- 324 Carboxyhemoglobin, blood, 169 Carcass mass-balance equation, 262 Carcinogens and carcinogenesis chemical, quantitative risk assessment for, 6 DNA adducts and, 221-226 epigenetic, 16, 20-22 genotoxic, 16 inhibitors of, 222 models of, 443 multistage model of, 463, 467-468 risk assessment, 441-445 Carcinomas, hepatocellular, 371, 459 CCSL IV language, 232 Cell birth versus mutation accumulation, 277 Chronic bioassay, 6 Chronological time, 69, 73 Circulation time, mean, 41 Classical pharmacokinetics, 34-35, 37 Clearance, 17 hepatic, 125- 126 interface between PB-PK models and, 104-107 metabolic, 102 mucociliary, 329 renal, 128-131 total body, 108, 115 value, 81 Closed-chamber kinetics, 170, 172 Cofactor depletion, dose-dependent, 135-137 Compartments choice of, 39-44 deep, 195 linear models of, 104, 105 multicompartments, see Multicompartment model one, see One-compartment model three, see Three-compartment model two, see Two-compartment model Complexes, rates of formation of, 98- 99 Computational equipment needs, 233-234 resources, sharing, 246 Computer languages used in pharmacokinetic model, 230-232 see also specific languages Concentration -dependent metabolite elimination, 134-135 gradient, 27 models, versus experimental, 268- 270 -time curves, areas under (AUCs), 256, 471-472 -time data, 185 Confidence regions, 190- 191 linear, 200, 202

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INDEX 479 Contour plots, 200-202 Covalent binding, 11 Critical exposure time, 435 toxicity reference (CTR) system, 354-357, 363-365 Curvilinear dose response, 448-450 Cytochrome P-450 isozymes, 148 Cytosine arabinoside pharmacokinetic model, 57-58 Cytotoxicity -hepatic, 275 modeling of, 273-279 mutation acumulation and, 273-283 D DCM (dichloromethane) (methylene chloride), 171-172, 217-219, 254-264, 392-408, 458-462 De minimus value, 155 Death rate for cells, 380 Dedrick plot, 74-75 Deep compartment, 195 Delivered and administered doses, 330, 447-455 Depletion, 11 cofactor, dose-dependent, 135- 137 glutathione, 175- 177, 178, 179 Detoxification, 452-453 Dibromomethane concentration, 168 Dichloromethane (DCM, methylene chloride), 171-172, 217-219, 254-264, 392-408, 458-462 Diffusion, 28 barriers, 99-102 index, 100 through thick membranes, 122-123 Direct decoupled method, 189 Dispersion number, axial, 87 Distribution intraorgan, extrapolation of, 140- 141 rate constants, 141 - 142 volume of, see Volume of distribution DNA adducts, 221-223 Dose/dosage, 471 administered and delivered, 160, 330, 447-455 dependencies, 120- 139 escalation, 433 extrapolations, 120-125, 170, 172- 173 fraction of, absorbed, 122 -incidence of response curve, 150- 151 log, versus percentage response, 4 low, risks at, 327-328, 444-445 -magnitude of response curve, 150- 151 maximum tolerated (MTD), 6, 432- 433, 449, 450 principle of fraction of, 128-131 response, 3-4, 221, 225-226, 375- 376, 448-450 -route extrapolation, 165- 167, 168, 216-219 safe starting, 433 scaling, 416-419 scheduling, 420-425, surrogates, 293-295 time-dependent, 467-468 time-weighted average, 454 virtually safe (VSD), 296-298 Dosimetry models, 230 comparisons, interspecies, 361-363 hazard assessment using, 353-367 lower respiratory tract mathematical, 357-363 physiologically based, 354-357 Drinking water exposures, modeling, 401-406 Drug binding, 88-89 development, 432-433 disposition, 43 solubility, 89-90 transport, 89-90

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480 INDEX E EAI Pacer 500 analog-digital hybrid computer, 335, 336 EDC (ethylene dichloride), 288-300 Efficiency number, 87 Elimination by excretion, 142- 143 half-life of, 30 location of organs of, 116-117 by metabolism, 143-148 organs, 83-86, 109, 112- 114 pulmonary, 385-387 rate constant, 28 species differences in, 142-148 Emphysema, 354 Endogenous precursors, 136 Energetics of muscle, 68-69 Environmental risk assessment, 431 Enzymes idealized distribution of, 127 inhibition, suicide, 173- 175 intraorgan localization of, 126- 128 Epigenetic carcinogens, 16, 20-22 Equilibrium constants, 99 Error analysis in model building, 188- 193 Ethical considerations, 431 Ethylene dichloride (EDC), 288-300 Exact method, l 90 Excess lifetime cancer risks, 6 Excretion biliary, 116, 122 elimination by, 42-143 Exercise, ozone uptake and, 308-310 Experimental error, 191 - 193 Exposure(s) 471 assessment, 8-9 drinking water, modeling, 401-406 intravenous injection, modeling, 406 scenario, extrapolation, 161, 167- 168, 169 time, critical, 435 time-dependent, see Time-dependent exposure Extraction ratio, 82, 85, 105 hepatic, 84 mathematical solution for, 87 Extrapolation, 312, 441-442 in absorption of substances, 139- 140 of allometric methods, 141 dose, 120-125, 170, 172-173 dose-route, 165-167, 168, 216-219 exposure scenario, 161, 167-168, 169 four types of 159 general aspects of, 96-155 from in vitro systems, 80-93 of interorgan distribution of substances, 140-141 interspecies, 212-216, 441-442 low-dose risk, 327-328, 444-445 pharmacokinetic, 161-162 physiologically based models for, 159-180 route-to-route, 114-119 species-to-species, 139- 142, 168- 170, 171, 396-401 F F-Ara-AMP (fludarabine phosphate), 437-438 Fat group (FG) of organs, 447 Feathering process, 29 Fick's First Law, 27, 32-33 Fick's Law of Diffusion, modified, 99-102 First-order rate constants, 90 First-pass elimination organs, 114 nonelimination organs, 113- 114 organs, 109 Flexible polygon method, 189 Flow diagrams, 40, 42 -limited models, 48-49, 446 rate, 32 Fludarabine phosphate (F-Ara-AMP), 437-438 Formaldehyde, 455-456

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INDEX 481 linear proportionality and, 328-330 FORTRAN programs, 230-231 Fraction of dose principle, 128-131 Free intrinsic clearance, 82 G Gas-uptake behavior, 175-177 Gastronintestinal absorption, 122 Gavage risk, 375-379 (;enotoxic carcinogens, 16 Glutathione depletion, 175-177, 178, 179 -S-transferase (GST) path, 459-462 Graphic output, 234 GST (glutathione-S-transferase) path, Inhibitors 459-462 Gut mass-balance equations, 53-54, 261 H Half-life, 28, 31 of elimination, 30 minimum, 106 of terminal phase, 106 Half-time to approach maximum concentration, 99 Hazard assessment, 8-9 using dosimetry modeling approach, 353-367 Hepatic clearance, 125- 126 cytotoxicity, 275 extraction ratio, 84 Hepatocellular adenomas, 459 carcinomas, 371, 459 Heteroscedasticity parameter, 193, 195 Humans inhalation, 216, 217 murine toxicity and, 434-435 no-observable-effect levels (NOELs) for, 5 polymorphisms in, 146-147 risk assessment, 369-370 Hybrid rate constants, 106 N-Hydroxy arylamines, urinary bladder exposure to, 334-348 I In vitro systems, extrapolation from, 80-93 Inaccuracy, degree of, 149 Inducers, 144-145 Inhalation model, 165- 167 risk, 375-379 of carcinogenesis, 222 suicide, 137- 139 Initiation index, 224 Intercalating agents, 19-20 Interspecies differences, 153- 155, 330-331 dosimetric comparisons, 361-363 extrapolation, 212-216, 441 -442; see also Extrapolation scaling, 16- 19, 36 . . . ntravenous 1nJectlon exposures, modeling, 406 Intrinsic clearance, 81-82 Isometry, 66 Isozymes, 143-144 cytochrome P-450, 148 interstrain differences in, 145- 146 J Joint risk assessment, 5 Judgmental decisions, 208 K Kidney mass-balance equation, 52, 262 partition coefficients, 91

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482 INDEX Kinetic models, see Pharmacokinetic models rate constants, 31 Kleiber equation, 66 Kliment zone model, 307 L Law of Mass Action, 149 Lawrence Solver for Ordinary Differential Equations (LSODE), 190 Lifetime cancer risks, excess, 6 Likelihood estimates, 188- 190 function, 188, 195 ~ . . Llnearlty compartment models, 104, 105 detoxification, 452-453 kinetics, 450 low-dose, 444 proportionality, formaldehyde and, 328-330 steady-state models, 117-118 Lineweaver-Burk plots, 192 Literature evaluation, 15 Liver mass-balance equation, 53, 261 partition coefficients, 91 Low dosage linearity, 444 risk extrapolation, 327-328, 444- 445 versus percentage response, 4 Lower respiratory tract (LRT) anatomical models, 305-307 mathematical dosimetry modeling, 357-363 ozone absorption in, 302-310 Lung administration, 115 dosimetry model, 235 mass-balance equation, 261-262 partition coefficients, 91 M Mammals, flow diagram for, 40 Mass action law, 20 Mass balances, 44 basic, 44, 46-47 blood pool, 46-47 equations for, 14, 51-54, 261-263 simplifications of, 47-56 tissue regions, 47, 48 Mass-specific rates, 73-74 Mathematical pharmacokinetic models, 445-446 Maximum concentration, 97, 99, 112 tolerated dose (MID), 6, 432-433, 449, 450 velocity of reaction, 14 Mean circulation time, 41 Membrane -limited model, 446-447 diffusion through thick, 122-123 permeability, 48-49 resistance, 41 Metabolism clearance, 81, 102 dose-dependent changes in, 125- 139 elimination by, 143-148 interorgan differences in, 145 interspecies differences in, 147-148 pathways, 14 production, 19 rate constants, 212, 288-290 role of, 392-396 sex differences in, 144 strain differences in, 143-144 urinary, 147 Metabolites concentration of, 120 elimination, concentration- dependent, 134- 135 formation and elimination of, 117- 118 functional classification of, 118 reactive nonisolatable, 17, 19

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INDEX 483 stable, 17, 18, 119 unstable, 119 Method of residuals, 29 Methotrexate (MIX), 410-425 pharmacokinetic model of, 53-56 Methylchloroform, 392-408 Methylene chloride (dichloromethane, DCM), 171-172, 254-264, 392- 408, 458-462 MFO (mixed-function oxidase) path, 459, 461 M-ice, old, 407-408 Michaelis-Menten kinetics, 81-83, 125-126 Microcomputers, 231-232, 234 Minimum concentration, 97, 112 half-life, 106 Mitotic rate, 380 Mixed-function oxidase (MFO) path, 459, 461 Models adenine arabinoside, 58 Armitage-Doll multistage, 443 anatomical, lower respiratory tract, 305-307 building, 187, 188- 193 cancer, two-stage, 21 carcinogenesis, 443 compartmental, 162 cytotoxicity, 274-277 dosimetry, see under Dosimetry drinking water exposures, 401-406 flow-limited, 446 inhalation, 165- 167 intravenous injection exposures, 406 kinetic, see Pharmacokinetic models Kliment zone, 307 linear compartment, 104, 105 linear steady-state, 117-118 lung dosimetry, 235 mathematical, 445-446 membrane-limited, 446-447 multicompartment, see Multicompartment model multispecies multroute, 391-408 multistage, see Multistage model one-compartment, see One- compartment model parallel tube, 86-87, 113 PB-PK, see Physiologically based pharmacokinetic models PBD, see Physiologically based dosimetry model perfusion-limited physiological, 82- 83 pharmacokinetic, see Pharmacokinetic models physiologically based, see Physiologically based pharmacokinetic models sinusoidal perfusion, 86-87 steady-state, linear, 117- 118 three-compartment, see Three- compartment model two-compartment, see Two- compartment model two-stage carcinogenicity, 21, 273- 274 venous-equilibration, of organ elimination, 83-86 well-stirred, of organ elimination, 83-86, 113 Moolgavkar-Knudson model, 276-277 MTD (maximum tolerated dose), 6, 432-433, 449, 450 MTX, see Methotrexate Mucociliary clearance, 329 Multicompartment model, 29, 235- 239 Multienzyme system, 86 Multispecies multiroute models, 391- 408 Multistage model, 150 of carcinogenesis, 463, 467-468 Murine and human toxicity, comparison of, 434-435 Muscle energetics of, 68-69 group (MG) of organs, 447 mass-balance equation, 51 partition coefficients, 91

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484 INDEX Mutation accumulation cell birth versus, 277 cytotoxicity and, 273-283 N National Ambient Air Quality Standards (NAAQs), 353-354 National Biomedical Simulation Resource (NBSR), 233, 246-247 National Toxicology Program (NTP), 449 Nickel injection, 237-239 NOELs (no-observable-effect levels), 4-5 Nonelimination organs, 109- 114 Non-first-pass elimination organs, 109, 112- 113 nonelimination organs, 109- 112 Nonlinear kinetics, 104 method, 190 No-observable-effect levels, see NOELs NTP (National Toxicology Program), 449 o Occupancy, 11 One-compartment model, 28-29, 55 Oral administration, 116 Organs availability, 104 classification of, 108- 110 elimination, 83-86, 109, 112-114 first-pass, 109 grouping of, 447 location of elimination of, 116- 117 nonelimination, see 109- 114 non-first-pass, 109- 113 rapidly equilibrated, 109 slowly equilibrated, 109 Oxidative pathway, saturable, 266 Ozone absorption in lower respiratory tract, 302-310 dosimetry modeling approach with, 353-367 exercise and uptake of, 308-310 uptake of, 360-363 p P (probability), 151 Parallel tube model, 86-87, 113 Parent chemicals, 16- 17 Partition coefficients, 33, 89-90, 91, 288,317,446 Pascal language, 2231, 232 PB-PK models, see Physiologically based pharmacokinetic models PBD (physiologically based dosimetry) model, 354-357 PCE (perchloroethylene), 210-217, 285-290, 369-382, 385-390, 462 Peeling process, 29 Percentage response, log dosage versus, 4 Perchloroethylene (PCE), 210-217, 285-290, 369-382, 385-390, 462 Perfusion-limited physiological model, 82-83 Permeability, membrane, 48-49 Perspectives, 471-475 Pharmacokinetic (PK) models, 13, 36, 162, 229-230, 442 body size in, 65-78 building, 185- 193 classical, 34-35, 37 computer languages used in, 230- 232 conventional approaches to, 234- 235 . . . . data in carcinogenic risk assessment, 441-463 description of, 209-212

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INDEX 485 for drinking water exposures, 401- 406 equipment needs for, 233-234 extrapolation, 161-162; see also Extrapolation flow chart of development of, 15 introduction, 27-35 mathematical, 445-446 objective of, 96 physiologically based, see Physiologically based pharmacokinetic models for thiopental, 50-54 uncertaintly in, using SIMUSOLV, 185-207 Physiological time, 69-76 Physiologically based dosimetry (PBD) model, 354-357 Physiologically based pharmacokinetic (PB-PK) models, 13- 14, 36-59, 162-165, 273-274, 442, 446- 447, 472-475 abbreviations and symbols used in specific, 211 for adenosine arabinoside, 58 biological basis of, 38-39 for carbon tetrachloride, 312-324 construction of, 385-390 for cytosine arabinoside, 57-58 description of specific, 209-212 development of, 39, 287-288 diagram of generic, 163 diagram of specific, 210 dose, species, and route extrapolation using, 159- 180 for ethylene dichloride, 288-300 fundamental equation of, 33 general, 96-104 interface between clearance and, 104-107 of intravenous injection exposures, 406 limitations of, 282-283 linear, 107-113 linear compartmentalized, 104, 105 for methotrexate, 53-56, 414-416 Moolgavkar-Knudson, 276-277 multispecies multiroute, 391-408 in old aminals, 407-408 of ozone absorption in lower respiratory tract, 302-310 for percholoroethylene, 285-290, 369-382 physiological and biochemical parameters used in specific, 213 potential of, 35 Ramsey-Andersen, 274-275 risk assessment and, 295-296, 474 route-of-exposure differences and, 298 route-to-route extrapolation of dichloromethane using, 254-264 schematic representation of, 287 sensitivity analysis in, 265-272 simple, 102-103 simplification of, 98 validation of, 283, 317-319 virtually safe doses and, 296-298 Plasma binding, 90 mass-balance equation, 51 membranes, 100 Poly-input availability, 114 Ploymorphisms in animals, 146 in humans, 146-147 Precursors, endogenous, 136 Predictions, prospective, in anticancer therapy, 431-440 Probability (P), 151 Problem identification, 15 Prospective predictions in anticancer therapy, 431-440 Pulmonary fibrosis, 354 uptake and elimination, 385-387 Q Quantitative risk assessment, for chemical carcinogenesis, 6

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486 INDEX R R parameter, 103-104 organ/blood, 141-142 Ramsey-Andersen PB-PK model, 274-275 Rapidly equilibrated organs, 109 Rate constants, 99, 106 distributional, 141- 142 hybrid, 106 metabolic, 212 metabolism, 288-190 Rats ingestion by, 214-215 inhalation by, 212-214 old, 407 Reactive nonisolatable metabolites, 17, 19 Reactivity equations, chemical, 11 Receptor binding equations, 11 Reitz-Andersen optimization procedure, 265-272 Renal clearance, 128- 131 Residence time, 139- 140 Residuals, method of, 29 Respiratory tract, see Lower respiratory tract; Upper respiratory tract Response dosage versus, 3-4 percentage, log dosage versus, 4 Risk assessment, 208 at low doses, 327-328, 444-445 carcinogen-DNA adducts in, 221- 226 carcinogenic, 441-463, 443-445 combination techniques, 7 elements of, 9 environmental, 431 extrapolation, low-dose, 327-328 historical perspectives, 3-7 human, 369-370 joint, 5 major elements of, 355 management, major elements of, 355 objective of, 471 PB-PK model and, 295-296, 474 quantitative, see Quantitative risk assessment tissue dosimetry in, 8-23 with time-dependent exposure patterns, 453-455 Route-of-exposure differences, PB-PK model and, 298 Route-to-route extrapolation, 114- 119 S Safe starting dose, 433 Safety factor (SF), 5 Saturable detoxification, 452-453 oxidative pathway, 266 Scaleup, see Extrapolation Scaling interspecies, 16- 19, 36 formulas, 209, 212 SCoP (Simulation Control Program), 232, 233 example program, 239-246 Semipermeable membranes, 100 Sensitivity analysis, 265-272 Sex differences in metabolism, 144 SIMNON language, 232 Simulation, 229 future trends in, 249 general approaches to, 229-230 languages, 232-233 in toxicology, 229-250 training in, 246 Simulation Control Program, see SCoP SIMUSOLV, 185, 186, 233 applications of, 193-205 statistical analysis using, 204 statistical output for, 206-207 uncertainty using, 185-207 Sinusoidal perfusion model, 86-87 Skin absorption, 122- 123 administration, 115

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INDEX 487 Slowly equilibrated organs, 109 Solubility of drug, 89-90 Species differences, 38-39 in elimination, 142- 148 Species-to-species extrapolations, 139-142, 168-170, 171, 396- 401 Stable metabolities, 17, 18, 119 Starting dose, safe, 433 Steady statefs) concentration, 107, 118 - conditions, 98-99 distribution ratio, 288 models, linear, 117- 118 term, 107 virtual, see Virtual steady states Suicide enzyme inhibition, 173- 175 inhibitors, 137- 139 Surface area adjustment, 17-19, 160 Systemic availability, 453 T TO (tracheobronchial) liquid lining, 357-361 Terminal half-lives, 106 Thiopental pharmacokinetics model, 50-54 Three-compartment model, 334, 336, 337 Threshold effect, 435-436 Time chronological, 69, 73 integral of tissue exposure, 10 -dependent dosing, 467-468 -dependent exposure, 451-455 physiological, 69-76 -weighted average dose, 454 - weighted average receptor occupancy, 20 , - ~ssue binding, 90 dosimetry in risk assessment, 8-23 exposure, time integral of, 10 mass balance, 48 partition coefficients, 91 perfusion, 49 regions, 45-47 total concentration, 49-50 volume, 19 Tolerated dose, maximum (MTD), 6, 432-433, 449, 450 Toxicity assessment of, 410-425 comparision of human and murine, 434-435 mechanism of, 412-414 nonsaturable pathway, 266 Toxicology Information Network (TOXIN), 247-248 Toxiphors, 265 Tracheobronchial (TB) liquid lining, 357-361 Transfer constant, 27 Transition rate, 380 Transport, drug, 89-90 Tumor promoters, 21 Tumorigenesis, 5-6 Two-compartment model, 30-31, 32, 43, 194 Two-stage carcinogenicity model, 21, 273-274 TYMNET data communications network, 247 U Unbound concentration, 103, 108 fractions, 88-92, 103 Uncertainty~ies) error analysis and, 188- 193 inherent, 473 using SIMUSOLV, 185-207 Unstable metabolites, 119 Upper respiratory tract (URT), 303 morphology of, 358 Urinary bladder exposure to N-hydroxy arylamines, 334-348 metabolism, 147

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488 1 NDEX Urine, excretion into, 142- 143 URT, see Upper respiratory tract V Validations of PB-PK models, 283, 317-319 prospective, in anticancer therapy, 431-440 Variance of error, 191 - 193 VCM (vinyl chloride monomer), 456- 458 Velocity of reaction, minimum, 14 Venous blood mass-balance equation, 262 -equilibration model of organ elimination, 83-86 Vessel-poor group (VPG) of organs, 447 Vessel-rich group (VRG) of organs, 447 Vial equilibration, 164 Vinyl chloride monomer (VCM), 456-458 Virtual steady states, 98-99 validity of assumption of, 105-106 Virtually safe doses (VSD), 296-298 Volume of distribution, 31 VPG (vessel-poor group) of organs, 447 VRG (vessel-rich group) of organs, 447 VSD (virtually safe doses), 296-298 W Well-stirred model of organ elimination, 83-86, 113