Development and specification of physiologically based pharmacokinetic models for use in risk assessment

Regulatory Toxicology and Pharmacology

Volumn 50, Issue 1, 2008, Pages 129-143

  Clewell, Rebecca A ^a   Clewell III, Harvey J ^a  

^a HAMNER INSTITUTES FOR HEALTH SCIENCES   (United States)

Author keywords

Biokinetic modeling; PBPK; Pharmacokinetics; Physiological modeling; Physiologically based pharmacokinetic modeling; Risk assessment; Toxicokinetic modeling

Indexed keywords

TOXIC SUBSTANCE;

ACCURACY; ARTICLE; ENVIRONMENTAL FACTOR; IN VITRO STUDY; MATHEMATICAL ANALYSIS; MEDICAL DOCUMENTATION; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; RISK ASSESSMENT; SUICIDE ATTEMPT; VALIDATION STUDY;

ANIMALS; HUMANS; MODELS, BIOLOGICAL; PHARMACOKINETICS; REPRODUCIBILITY OF RESULTS; RISK ASSESSMENT; UNCERTAINTY;

ANIMALIA;

EID: 37549042390     PISSN: 02732300     EISSN: 10960295     Source Type: Journal    
DOI: 10.1016/j.yrtph.2007.10.012     Document Type: Article

References (121)

1. Adolph E.F. Quantitative relations in the physiological constitutions of mammals. Science 109 (1949) 579-585
2. Allen B.C., Covington T.R., and Clewell H.J. Investigation of the impact of pharmacokinetic variability and uncertainty on risks predicted with a pharmacokinetic model for chloroform. Toxicology 111 (1996) 289-303
3. Andersen M.E. Saturable metabolism and its relation to toxicity. Crit. Rev. Toxicol. 9 (1981) 105-150
4. Andersen M.E., Clewell H.J., and Frederick C.B. Applying simulation modeling to problems in toxicology and risk assessment-a short perspective. Toxicol. Appl. Pharmacol. 133 (1995) 181-187
5. Andersen M.E., Clewell III H.J., Gargas M.L., MacNaughton M.G., Reitz R.H., Nolan R., and McKenna M. Physiologically based pharmacokinetic modeling with dichloromethane, its metabolite carbon monoxide, and blood carboxyhemoglobin in rats and humans. Toxicol. Appl. Pharmacol. 108 (1991) 14-27
6. Andersen M.E., Clewell H.J., Gargas M.L., Smith F.A., and Reitz R.H. Physiologically-based pharmacokinetics and the risk assessment for methylene chloride. Toxicol. Appl. Pharmacol. 87 (1987) 185-205
7. Andersen M.E., Clewell H.J., and Krishnan K. Tissue dosimetry, pharmacokinetic modeling, and interspecies scaling factors. Risk Anal. 15 (1995) 533-537
8. Andersen M.E., Clewell H.J., Tan Y.-M., Butenhoff J.L., and Olsen G.W. Pharmacokinetic modeling of saturable, renal resorption of perfluoroalkylacids in monkeys-probing the determinants of long plasma half-lives. Toxicology 227 1-2 (2006) 156-164
9. Andersen M.E., Gargas M.L., Jones R.A., and Jenkins Jr. L.H. Determination of the kinetic constants of metabolism of inhaled toxicant in vivo based on gas uptake measurements. Toxicol. Appl. Pharmacol. 54 (1980) 100-116
10. Andersen M.E., Gargas M.L., and Ramsey J.C. Inhalation pharmacokinetics: evaluating systemic extraction, total in vivo metabolism and the time course of enzyme induction for inhaled styrene in rats based on arterial blood:inhaled air concentration ratios. Toxicol. Appl. Pharmacol. 73 (1984) 176-187
11. Andersen M.E., Sarangapani R., Reitz R.H., Gallavan R.H., Dobrev I.D., and Plotzke K.P. Physiological modeling reveals novel pharmacokinetic behavior of inhaled octamethylcyclotetrasiloxane. Toxicol. Sci. 60 (2001) 214-231
12. Astrand P., and Rodahl K. Textbook of Work Physiology (1970), McGraw-Hill, New York p. 157-160, 206-211.
13. Barton H.A. Computational pharmacokinetics during developmental windows of susceptibility. J. Toxicol. Environ. Health A 68 11-12 (2005) 889-900
14. Barton H.A., and Clewell III H.J. Evaluating noncancer effects of trichloroethylene: dosimetry, mode of action, and risk assessment. Environ Health Perspect 108 suppl. 2 (2000) 323-334
15. Beliveau M., Lipscomb J., Tardif R., and Krishnan K. Quantitative structure-property relationships for interspecies extrapolation of the inhalation pharmacokinetics of organic chemicals. Chem. Res. Toxicol. 18 (2005) 475-485
16. Bischoff, K.B., 1987. Physiologically based pharmacokinetic modeling. National Research Council. In: Pharmacokinetics in Risk Assessment, Drinking Water and Health, vol. 8. National Academy Press, Washington, DC, pp. 36-61.
17. Bischoff K.B., and Brown R.G. Drug distribution in mammals. Chem. Eng. Prog. Symp. Ser. 62 66 (1966) 33-45
18. Bischoff K.B., Dedrick R.L., Zaharko D.S., and Longstreth J.A. Methotrexate pharmacokinetics. J. Pharm. Sci. 60 (1971) 1128-1133
19. Bois F. Statistical analysis of Clewell et al. PBPK model of trichloroethylene kinetics. Environ. Health Perspect. 108 suppl. 2 (2000) 307-316
20. Bois F.Y., Zeise L., and Tozer T.N. Precision and sensitivity of pharmacokinetic models for cancer risk assessment: tetrachloroethylene in mice, rats, and humans. Toxicol. Appl. Pharmacol. 102 2 (1990) 300-315
21. Brown R.P., Delp M.D., Lindstedt S.L., Rhomberg L.R., and Beliles R.P. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol. Ind. Health 13 4 (1997) 407-484
22. Carson E.R., Cobelli C., and Finkelstein L. Modeling and identification of metabolic systems. Am. J. Physiol. 240 3 (1981) R120-R129
23. Carson, E.R., Cobelli, C., Finkelstein, L., 1983. The mathematical modeling of metabolic and endocrine systems. Model formulation, identification, and validation. John Wiley and Sons, New York (p. 23-45, 113-127, 217-231).
24. Chiu W.A., Barton H.A., DeWoskin R.S., Schlosser P., Thompson C.M., Sonawane B., Lipscomb J.C., and Krishnan K. Evaluation of physiologically based pharmacokinetic models for use in risk assessment. J. Appl. Toxicol. 27 3 (2007) 218-237
25. Clark L.H., Setzer R.W., and Barton H.A. Framework for evaluation of physiologically based pharmacokinetic models for use in safety or risk assessment. Risk Anal. 24 (2004) 1697-1718
26. Clewell H.J. The use of physiologically based pharmacokinetic modeling in risk assessment: a case study with methylene chloride. In: Olin S., Farland W., Park C., Rhomberg L., Scheuplein R., Starr T., and Wilson J. (Eds). Low-Dose Extrapolation of Cancer Risks: Issues and Perspectives (1995), ILSI Press, Washington, DC 199-221
27. Clewell H.J., and Andersen M.E. Risk Assessment Extrapolations and Physiological Modeling. Toxicol. Ind. Health 1 4 (1985) 111-131
28. Clewell H.J., and Andersen M.E. Biologically motivated models for chemical risk assessment. Health Phys. 57 suppl. 1 (1989) 129-137
29. Clewell H.J., and Andersen M.E. Physiologically-based pharmacokinetic modeling and bioactivation of xenobiotics. Toxicol. Ind. Health 10 (1994) 1-24
30. Clewell H.J., and Andersen M.E. Use of physiologically-based pharmacokinetic modeling to investigate individual versus population risk. Toxicology 111 (1996) 315-329
31. Clewell H.J., Andersen M.E., Wills R.J., and Latriano L. A physiologically based pharmacokinetic model for retinoic acid and its metabolites. J. Am. Acad. Dermatol. 36 3 pt 2 (1997) S77-S82
32. Clewell H.J., Gearhart J.M., Gentry P.R., Covington T.R., VanLandingham C.B., Crump K.S., and Shipp A.M. Evaluation of the uncertainty in an oral reference dose for methylmercury due to interindividual variability in pharmacokinetics. Risk Anal. 19 (1999) 547-558
33. Clewell H.J., Gentry P.R., Allen B.C., Covington T.R., and Gearhart J.M. Development of a physiologically based pharmacokinetic model of trichloroethylene and its metabolites for use in risk assessment. Environ. Health Perspect. 108 suppl. 2 (2000) 283-305
34. Clewell H.J., Gentry P.R., Covington T.R., Sarangapani R., and Teeguarden J.G. Evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. Toxicol. Sci. 79 (2004) 381-393
35. Clewell H.J., Gentry P.R., Gearhart J.M., Allen B.C., and Andersen M.E. Comparison of cancer risk estimates for vinyl chloride using animal and human data with a PBPK model. Sci. Total Environ. 274 1-3 (2001) 37-66
36. Clewell H.J., and Jarnot B.M. Incorporation of pharmacokinetics in non-carcinogenic risk assessment: example with chloropentafluorobenzene. Risk Anal. 14 (1994) 265-276
37. Clewell H.J., Lee T., and Carpenter R.L. Sensitivity of physiologically based pharmacokinetic models to variation in model parameters: methylene chloride. Risk Anal. 14 (1994) 521-531
38. Clewell R.A., Merrill E.A., Gearhart J.M., Robinson P.J., Sterner T.R., Mattie D.R., and Clewell III H.J. Perchlorate and radioiodide kinetics across life-stages in the human: using PBPK models to predict dosimetry and thyroid inhibition and sensitive subpopulations based on developmental stage. J. Toxicol. Environ. Health A 70 5 (2007) 408-428
39. Clewell R.A., Merrill E.A., and Robinson P.J. The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species. Toxicol. Ind. Health. 17 5-10 (2001) 210-222
40. Cobelli C., Carson E.R., Finkelstein L., and Leaning M.S. Validation of simple and complex models in physiology and medicine. Am. J. Physiol. 246 (1984) R259-R266
41. Corley R.A. Assessing the risk of hemolysis in humans exposed to 2-butoxyethanol using a physiologically-based pharmacokinetic model. Occup. Hyg. 2 (1996) 45-55
42. Corley R.A., Bormett G.A., and Ghanayem B.I. Physiologically based pharmacokinetics of 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in rats and humans. Toxicol. Appl. Pharmacol. 129 (1994) 61-79
43. Corley R.A., Mast T.J., Carney E.W., Rogers J.M., and Daston G.P. Evaluation of physiologically based models of pregnancy and lactation for their application in children's health risk assessments. Crit. Rev. Toxicol. 33 2 (2003) 137-211
44. Corley R.A., Mendrala A.L., Smith F.A., Staats D.A., Gargas M.L., Conolly R.B., Andersen M.E., and Reitz R.H. Development of a physiologically based pharmacokinetic model for chloroform. Toxicol. Appl. Pharmacol. 103 (1990) 512-527
45. Covington T.R., Gentry P.R., VanLandingham C.B., Andersen M.E., Kester J.E., and Clewell H.J. The use of Markov chain Monte Carlo uncertainty analysis to support a public health goal for perchloroethylene. Regul. Toxicol. Pharm. 47 1 (2007) 1-18
46. Davies B., and Morris T. Physiological parameters in laboratory animals and humans. Pharm. Res. 10 (1993) 1093-1095
47. Dedrick R.L. Animal scale-up. J. Pharmacokinet. Biopharm. 1 (1973) 435-461
48. Dedrick R.L., and Bischoff K.B. Species similarities in pharmacokinetics. Fed. Proc. 39 (1980) 54-59
49. Droz P.O., Wu M.M., Cumberland W.G., and Berode M. Variability in biological monitoring of solvent exposure. I. Development of a population physiological model. Br. J. Ind. Med. 46 (1989) 447-460
50. Droz P.O., Wu M.M., and Cumberland W.G. Variability in biological monitoring of solvent exposure. II. Application of a population physiological model. Br. J. Ind. Med. 46 (1989) 547-558
51. el-Masri H.A., Thomas R.S., Benjamin S.A., and Yang R.S. Physiologically based pharmacokinetic/pharmacodynamic modeling of chemical mixtures and possible applications in risk assessment. Toxicology 105 (1995) 275-282
52. Environmental Protection Agency (EPA) (1988). Reference physiological parameters in pharmacokinetic modeling. EPA/600/6-88/004. Office of Health and Environmental Assessment, Washington, DC.
53. Environmental Protection Agency (EPA) (1992). EPA request for comments on draft report of cross-species scaling factor for cancer risk assessment. Fed. Reg. 57: 24152.
54. Farrar D., Allen B., Crump K., and Shipp A. Evaluation of uncertainty in input parameters to pharmacokinetic models and the resulting uncertainties in output. Toxicol. Lett. 49 (1989) 371-385
55. Filser J.G., and Bolt H.M. Pharmacokinetics of halogenated ethylenes in rats. Arch. Toxicol. 42 (1979) 123-136
56. Fiserova-Bergerova, V., 1975. Biological - mathematical modeling of chronic toxicity. AMRL-TR-75-5, Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Ohio.
57. Fiserova-Bergerova V. Modeling of inhalation exposure to vapors: uptake distribution and elimination vol. 2 (1983), CRC Press, Boca Raton FL p. 108-130.
58. Fiserova-Bergerova V., Vlach J., and Cassady J.L. Predictable individual differences in uptake and excretion of gases and lipid soluble vapours: simulation study. Br. J. Ind. Med. 37 (1980) 42-49
59. Fisher J.W. Physiologically based pharmacokinetic models for trichloroethylene and its oxidative metabolites. Environ. Health Perspect. 108 suppl. 2 (2000) 265-273
60. Fisher J., Gargas M., Allen B., and Andersen M. Physiologically based pharmacokinetic modeling with trichloroethylene and its metabolite, trichloroacetic acid, in the rat and mouse. Toxicol. Appl. Pharmacol. 109 (1991) 183-195
61. Fisher J.W., Whittaker T.A., Taylor D.H., Clewell H.J., and Andersen M.E. Physiologically based pharmacokinetic modeling of the pregnant rat: a multiroute exposure model for trichlorethylene and its metabolite, trichloroacetic acid. Toxicol. Appl. Pharmacol. 99 (1989) 395-414
62. Fisher J.W., Whittaker T.A., Taylor D.H., Clewell H.J., and Andersen M.E. Physiologically based pharmacokinetic modeling of the lactating rat and nursing pup: a multiroute exposure model for trichlorethylene and its metabolite, trichloroacetic acid. Toxicol. Appl. Pharmacol. 102 (1990) 497-513
63. Gargas M.L., and Andersen M.E. Metabolism of inhaled brominated hydrocarbons: validation of gas uptake results by determination of a stable metabolite. Toxicol. Appl. Pharmacol. 66 (1982) 55-68
64. Gargas M.L., and Andersen M.E. Determining kinetic constants of chlorinated ethane metabolism in the rat from rates of exhalation. Toxicol. Appl. Pharmacol. 97 (1989) 230-246
65. Gargas M.L., Andersen M.E., and Clewell H.J. A physiologically-based simulation approach for determining metabolic constants from gas uptake data. Toxicol. Appl. Pharmacol. 86 (1986) 341-352
66. Gargas M.L., Burgess R.J., Voisard D.E., Cason G.H., and Andersen M.E. Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol. Appl. Pharmacol. 98 (1989) 87-99
67. Gargas M.L., Clewell H.J., and Andersen M.E. Metabolism of inhaled dihalomethanes in vivo: differentiation of kinetic constants for two independent pathways. Toxicol. Appl. Pharmacol. 82 (1986) 211-223
68. Gargas M.L., Clewell H.J., and Andersen M.E. Gas uptake techniques and the rates of metabolism of chloromethanes, chloroethanes, and chloroethylenes in the rat. Inhal. Toxicol. 2 (1990) 295-319
69. Gargas M.L., Seybold P.G., and Andersen M.E. Modeling the tissue solubilities and metabolic rate constant (Vmax) of halogenated methanes, ethanes, and ethylenes. Toxicol. Lett. 43 (1988) 235-256
70. Gearhart J.M., Jepson G.W., Clewell III H.J., Andersen M.E., and Conolly R.B. Physiologically based pharmacokinetic model for the inhibition of acetylcholinesterase by organophosphate esters. Environ. Health Perspect. 102 (1994) 51-60
71. Gearhart J.M., Mahle D.A., Greene R.J., Seckel C.S., Flemming C.D., Fisher J.W., and Clewell H.J. Variability of physiologically-based pharmacokinetic (PB-PK) model parameters and their effects on PB-PK model predictions in a risk assessment for perchloroethylene. Toxicol. Lett. 68 (1993) 131-144
72. Gelman A., Bois F., and Jiang J. Physiological pharmacokinetic analysis using population modeling and informative prior distributions. J. Am. Stat. Assoc. 91 436 (1996) 1400-1412
73. Gentry P.R., Covington T.R., and Clewell H.J. Evaluation of the potential impact of pharmacokinetic differences on tissue dosimetry in offspring during pregnancy and lactation. Reg. Toxicol. Pharmacol. 38 1 (2003) 1-16
74. Gentry P.R., Haber L.T., McDonald T.B., Zhao Q., Covington T., Nance P., Clewell III H.J., Lipscomb J.C., and Barton H.A. Data for physiologically based pharmacokinetic modeling in neonatal animals: physiological parameters in mice and Sprague-Dawley rats. J. Children Health 2 3-4 (2004) 363-411
75. Gerlowski L.E., and Jain R.K. Physiologically based pharmacokinetic modeling: principles and applications. J. Pharm. Sci. 72 (1983) 1103-1126
76. Gerrity T.R., and Henry C.J. Principles of Route-to-Route Extrapolation for Risk Assessment (1990), Elsevier, New York, NY p. 1-12.
77. Gueorguieva I.I., Nestorov I.A., and Rowland M. Fuzzy simulation of pharmacokinetic models: case study of whole body physiologically based model of diazepam. J. Pharmacokinet. Pharmacodyn. 31 3 (2004) 185-213
78. Hack C.E., Chiu W.A., Zhao Q.J., and Clewell H.J. Bayesian population analysis of a harmonized physiologically based pharmacokinetic model of trichloroethylene and its metabolites. Reg. Toxicol. Pharmacol. 46 1 (2006) 63-83
79. Himmelstein K.J., and Lutz R.J. A review of the application of physiologically based pharmacokinetic modeling. J. Pharmacokinet. Biopharm. 7 (1979) 127-145
80. International Commission on Radiological Protection (ICRP). (1975). Report of the Task Group on Reference Man. ICRP Publication 23 (p. 228-237, 280-285, 325-327).
81. Jepson G.W., Hoover D.K., Black R.K., McCafferty J.D., Mahle D.A., and Gearhart J.M. A partition coefficient determination method for nonvolatile chemicals in biological tissues. Fundam. Appl. Toxicol. 22 (1994) 519-524
82. Johanson G. Physiologically based pharmacokinetic modeling of inhaled 2-butoxyethanol in man. Toxicol. Lett. 34 (1986) 23-31
83. Jonssonm F., Bois F., and Johanson G. Physiologically based pharmacokinetic modeling of inhalation exposure of humans to dichloromethane during moderate to heavy exercise. Toxicol. Sci. 59 2 (2001) 209-218
84. Johanson G., and Filser J.G. A physiologically based pharmacokinetic model for butadiene and its metabolite butadiene monoxide in rat and mouse and its significance for risk extrapolation. Arch. Toxicol. 67 (1993) 151-163
85. Jonsson F., and Johanson G. A Bayesian analysis of the influence of GSTT1 polymorphism on the cancer risk estimate for dichloromethane. Toxicol. Appl. Pharmacol. 174 2 (2001) 99-112
86. Kedderis G.L., and Lipscomb J.C. Application of in vitro biotransformation data and pharmacokinetic modeling to risk assessment. Toxicol. Ind. Health. 17 5-10 (2001) 315-321
87. King F.G., Dedrick R.L., Collins J.M., Matthews H.B., and Birnbaum L.S. Physiological model for the pharmacokinetics of 2,3,7,8-tetrachlorodibenzofuran in several species. Toxicol. Appl. Pharmacol. 67 (1983) 390-400
88. Kohn M.C. Achieving credibility in risk assessment models. Toxicol. Lett. 79 (1995) 107-114
89. Kohn M.C. The importance of biological realism for validation of physiological models of disposition of inhaled toxicants. Toxicol. Appl. Pharmacol. 147 (1997) 448-458
90. Lam G., Chen M., and Chiou W.L. Determination of tissue to blood partition coefficients in physiologically-based pharmacokinetic studies. J. Pharm. Sci. 71 4 (1981) 454-456
91. Leung H.W. Development and utilization of physiologically based pharmacokinetic models for toxicological applications. J. Toxicol. Environ. Health 32 (1991) 247-267
92. Lilly P.D., Thornton-Manning J.R., Gargas M.L., Clewell H.J., and Andersen M.E. Kinetic characteristics of CYP2E1 inhibition in vivo and in vitro by the chloroethylenes. Arch. Toxicol. 72 (1998) 609-621
93. Lipscomb J.C., and Kedderis G.L. Incorporating human interindividual biotransformation variance in health risk assessment. Sci. Total Environ. 288 1-2 (2002) 13-21
94. Lipscomb J.C., Meek E., Krishnan K., Kedderis G.L., Clewell H., and Haber L.T. Incorporation of pharmacokinetic and pharmacodynamic data into risk assessments. Toxicol. Mech. Methods 14 (2004) 145-158
95. Mann S., Droz P.O., and Vahter M. A physiologically based pharmacokinetic model for arsenic exposure. I. Development in hamsters and rabbits. Toxicol. Appl. Pharmacol. 137 (1996) 8-22
96. Mann S., Droz P.O., and Vahter M. A physiologically based pharmacokinetic model for arsenic exposure. II. Validation and application in humans. Toxicol. Appl. Pharmacol. 140 (1996) 471-486
97. McDougal J.N., Jepson G.W., Clewell H.J., MacNaughton M.G., and Andersen M.E. A physiological pharmacokinetic model for dermal absorption of vapors in the rat. Toxicol. Appl. Pharmacol. 85 (1986) 286-294
98. Monro A. What is an appropriate measure of exposure when testing drugs for carcinogenicity in rodents?. Toxicol. Appl. Pharmacol. 112 (1992) 171-181
99. Mork A.K., and Johanson G. A human physiological model describing acetone kinetics in blood and breath during various levels of physical exercise. Toxicol. Lett. 164 1 (2006) 6-15
100. O'Flaherty, E.J., 1987. Modeling: an introduction. National Research Council. In: Pharmacokinetics in Risk Assessment. Drinking Water and Health, vol. 8. National Academy Press, Washington, DC, pp. 27-35.
101. O'Flaherty E.J. Interspecies conversion of kinetically equivalent doses. Risk Anal. 9 (1989) 587-598
102. O'Flaherty E.J. Physiologically based models for bone seeking elements. V. Lead absorption and disposition in childhood. Toxicol. Appl. Pharmacol. 131 (1995) 297-308
103. Peck C.C., Beal S.L., Sheiner L.B., and Nichols A.I. Extended least squares nonlinear regression: a possible solution to the "choice of weights" problem in analysis of individual pharmacokinetic data. J. Pharmacokinet. Biopharm. 12 5 (1984) 545-558
104. Plotzke K.P., Crofoot S.D., Ferdinandi E.S., Beattie J.G., Reitz R.H., McNett D.A., and Meeks R.G. Disposition of radioactivity in fischer 344 rats after single and multiple inhalation exposure to [(14)C]octamethylcyclotetrasiloxane ([(14)C]D(4)). Drug Metab. Dispos. 28 2 (2000) 192-204
105. Portier C.J., and Kaplan N.L. Variability of safe dose estimates when using complicated models of the carcinogenic process: a case study: methylene chloride. Fundam. Appl. Toxicol. 13 (1989) 533-544
106. Poulin P., and Krishnan K. Molecular structure-based prediction of the toxicokinetics of inhaled vapors in humans. Int. J. Toxicol. 18 (1999) 7-18
107. Ramsey J.C., and Andersen M.E. A physiological model for the inhalation pharmacokinetics of inhaled styrene monomer in rats and humans. Toxicol. Appl. Pharmacol. 73 (1984) 159-175
108. Reddy M.B., Yang R.S.H., Clewell III H.J., and Andersen M.E. Physiologically Based Pharmacokinetic Modeling: Science and Applications (2005), John Wiley & Sons, Hoboken, New Jersey
109. Reitz R.H., Mendrala A.L., Corley R.A., Quast J.F., Gargas M.L., Andersen M.E., Staats D.A., and Conolly R.B. Estimating the risk of liver cancer associated with human exposures to chloroform using physiologically based pharmacokinetic modeling. Toxicol. Appl. Pharmacol. 105 (1990) 443-459
110. Reitz R.H., Mendrala A.L., and Guengerich F.P. In vitro metabolism of methylene chloride in human and animal tissues: use in physiologically-based pharmacokinetic models. Toxicol. Appl. Pharmacol. 97 (1989) 230-246
111. Rescigno A., and Beck J.S. Perspectives in pharmacokinetics. The use and abuse of models. J. Pharmacokinet. Biopharm. 15 3 (1987) 327-344
112. Roth W.L., Weber L.W., Stahl B.U., and Rozman K. A pharmacodynamic model of triglyceride transport and deposition during feed deprivation or following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the rat. Toxicol. Appl. Pharmacol. 120 1 (1993) 126-137
113. Sarangapani R., Gentry P.R., Covington T.R., Teeguarden J.G., and Clewell H.J. Evaluation of the potential impact of age- and gender-specific lung morphology and ventilation rate on the dosimetry of vapors. Inhal. Toxicol. 15 10 (2003) 987-1016
114. Sato A., and Nakajima T. Partition coefficients of some aromatic hydrocarbons and ketones in water, blood and oil. Br. J. Ind. Med. 36 (1979) 231-234
115. Sato A., and Nakajima T. A vial equilibration method to evaluate the drug metabolizing enzyme activity for volatile hydrocarbons. Toxicol. Appl. Pharmacol. 47 (1979) 41-46
116. Teorell T. Kinetics of distribution of substances administered to the body. I. The extravascular mode of administration. Arch. Int. Pharmacodyn. 57 (1937) 205-225
117. Teorell T. Kinetics of distribution of substances administered to the body. I. The intravascular mode of administration. Arch. Int. Pharmacodyn. 57 (1937) 226-240
118. U.S. Environmental Protection Agency (USEPA). (2006). Approaches for the Application of Physiologically Based Pharmacokinetic (PBPK) Models and Supporting Data in Risk Assessment. EPA/600/R-05/043F. Available from: .
119. Utell M.J., Gelein R., Yu C.P., Kenaga C., Geigel E., Torres A., Chalupa D., Gibb F.R., Speers D.M., Mast R.W., and Morrow P.E. Quantitative exposure of humans to an octamethylcyclotetrasiloxane (D4) vapor. Toxicol. Sci. 44 2 (1998) 206-213
120. Watanabe P., Mc Gown G., and Gehring P. Fate of [14] vinyl chloride after single oral administration in rats. Toxicol. Appl. Pharmacol. 36 (1976) 339-352
121. Yates F.E. Good manners in good modeling: mathematical models and computer simulations of physiological systems. Am. J. Physiol. 234 (1978) R159-R160