The National Academies Press

Currently Skimming:

Index
Pages 477-488

The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.

From page 477... ... , 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 Read the entire page →
From page 478... ... , 256, 471-472 -time data, 185 Confidence regions, 190- 191 linear, 200, 202 Read the entire page →
From page 479... ... , 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, 140141 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, 172173 fraction of, absorbed, 122 -incidence of response curve, 150151 log, versus percentage response, 4 low, risks at, 327-328, 444-445 -magnitude of response curve, 150151 maximum tolerated (MTD) , 6, 432433, 449, 450 principle of fraction of, 128-131 response, 3-4, 221, 225-226, 375376, 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) Read the entire page →
From page 480... ... , 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, 167168, 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, 139140 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, 168170, 171, 396-401 F F-Ara-AMP (fludarabine phosphate) Read the entire page →
From page 481... ... 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 . Read the entire page →
From page 482... ... 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, 125139 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, concentrationdependent, 134- 135 formation and elimination of, 117118 functional classification of, 118 reactive nonisolatable, 17, 19 Read the entire page →
From page 483... ... 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 Onecompartment model parallel tube, 86-87, 113 PB-PK, see Physiologically based pharmacokinetic models PBD, see Physiologically based dosimetry model perfusion-limited physiological, 8283 pharmacokinetic, see Pharmacokinetic models physiologically based, see Physiologically based pharmacokinetic models sinusoidal perfusion, 86-87 steady-state, linear, 117- 118 three-compartment, see Threecompartment model two-compartment, see Twocompartment model two-stage carcinogenicity, 21, 273274 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, 235239 Multienzyme system, 86 Multispecies multiroute models, 391408 Multistage model, 150 of carcinogenesis, 463, 467-468 Murine and human toxicity, comparison of, 434-435 Muscle energetics of, 68-69 group (MG) Read the entire page →
From page 484... ... , 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) Read the entire page →
From page 485... ... models, 13- 14, 36-59, 162-165, 273-274, 442, 446447, 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 Read the entire page →
From page 486... ... , 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 Read the entire page →
From page 487... ... 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) Read the entire page →
From page 488... ... , 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) Read the entire page →

From page 477...

... , 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

Read the entire page →

From page 478...

... , 256, 471-472 -time data, 185 Confidence regions, 190- 191 linear, 200, 202

Read the entire page →

From page 479...

... , 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, 140141 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, 172173 fraction of, absorbed, 122 -incidence of response curve, 150151 log, versus percentage response, 4 low, risks at, 327-328, 444-445 -magnitude of response curve, 150151 maximum tolerated (MTD) , 6, 432433, 449, 450 principle of fraction of, 128-131 response, 3-4, 221, 225-226, 375376, 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)

Read the entire page →

From page 480...

... , 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, 167168, 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, 139140 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, 168170, 171, 396-401 F F-Ara-AMP (fludarabine phosphate)

Read the entire page →

From page 481...

... 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 .

Read the entire page →

From page 482...

... 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, 125139 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, concentrationdependent, 134- 135 formation and elimination of, 117118 functional classification of, 118 reactive nonisolatable, 17, 19

Read the entire page →

From page 483...

... 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 Onecompartment model parallel tube, 86-87, 113 PB-PK, see Physiologically based pharmacokinetic models PBD, see Physiologically based dosimetry model perfusion-limited physiological, 8283 pharmacokinetic, see Pharmacokinetic models physiologically based, see Physiologically based pharmacokinetic models sinusoidal perfusion, 86-87 steady-state, linear, 117- 118 three-compartment, see Threecompartment model two-compartment, see Twocompartment model two-stage carcinogenicity, 21, 273274 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, 235239 Multienzyme system, 86 Multispecies multiroute models, 391408 Multistage model, 150 of carcinogenesis, 463, 467-468 Murine and human toxicity, comparison of, 434-435 Muscle energetics of, 68-69 group (MG)

Read the entire page →

From page 484...

... , 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)

Read the entire page →

From page 485...

... models, 13- 14, 36-59, 162-165, 273-274, 442, 446447, 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

Read the entire page →

From page 486...

... , 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

Read the entire page →

From page 487...

... 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)

Read the entire page →

From page 488...

... , 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)

Read the entire page →

← Previous Chapter Skim

This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More information on Chapter Skim is available.

Index Pages 477-488

Index
Pages 477-488