Advertisement

Development of a human physiologically based pharmacokinetic (PBPK) model for inorganic arsenic and its mono- and di-methylated metabolites

  • Hisham A. El-MasriEmail author
  • Elaina M. Kenyon
Article

Abstract

A physiologically-based pharmacokinetic (PBPK) model was developed to estimate levels of arsenic and its metabolites in human tissues and urine after oral exposure to arsenate (AsV), arsenite (AsIII) or organoarsenical pesticides. The model consists of interconnected individual PBPK models for inorganic arsenic (AsV and AsIII), monomethylarsenic acid (MMAV), and, dimethylarsenic acid (DMAV). Reduction of MMAV and DMAV to their respective trivalent forms also occurs in the lung, liver, and kidney including excretion in urine. Each submodel was constructed using flow limited compartments describing the mass balance of the chemicals in GI tract (lumen and tissue), lung, liver, kidney, muscle, skin, heart, and brain. The choice of tissues was based on physiochemical properties of the arsenicals (solubility), exposure routes, target tissues, and sites for metabolism. Metabolism of inorganic arsenic in liver was described as a series of reduction and oxidative methylation steps incorporating the inhibitory influence of metabolites on methylation. The inhibitory effects of AsIII on the methylation of MMAIII to DMA, and MMAIII on the methylation of AsIII to MMA were modeled as noncompetitive. To avoid the uncertainty inherent in estimation of many parameters from limited human data, a priori independent parameter estimates were derived using data from diverse experimental systems with priority given to data derived using human cells and tissues. This allowed the limited data for human excretion of arsenicals in urine to be used to estimate only parameters that were most sensitive to this type of data. Recently published urinary excretion data, not previously used in model development, are also used to evaluate model predictions.

Keywords

Arsenic Human PBPK MMA DMA 

Abbreviations

As

Inorganic arsenic

AsIII

Trivalent inorganic arsenic

AsV

Pentavalent inorganic arsenic

MMAIII

Monomethylarsonous acid

MMAV

Monomethylarsenic acid

DMAIII

Dimethylarsinous acid

DMAV

Dimethylarsinic acid

TMAO

Trimethylarsine oxide

PBPK

Physiologically based pharmacokinetic

AS3MT

Arsenic +3 oxidation state methyltransferase

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Yoshida T, Yamauchi H and Fan Sun G (2004). Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review. Toxicol Appl Pharmacol 198: 243–252 PubMedCrossRefGoogle Scholar
  2. 2.
    Navas-Acien A, Sharrett AR, Silbergeld EK, Schwartz BS, Nachman KE, Burke TA and Guallar E (2005). Arsenic exposure and cardiovascular disease: a systematic review of the epidemiologic evidence. Am J Epidemiol 162: 1037–1049 PubMedCrossRefGoogle Scholar
  3. 3.
    Khan MM, Sakauchi F, Sonoda T, Washio M and Mori M (2003). Magnitude of arsenic toxicity in tube-well drinking water in Bangladesh and its adverse effects on human health including cancer: evidence from a review of the literature. Asian Pac J Cancer Prev 4: 7–14 PubMedGoogle Scholar
  4. 4.
    Alam MG, Allinson G, Stagnitti F, Tanaka A and Westbrooke M (2002). Arsenic contamination in Bangladesh groundwater: a major environmental and social disaster. Int J Environ Health Res 12: 235–253 PubMedCrossRefGoogle Scholar
  5. 5.
    Mukherjee SC, Saha KC, Pati S, Dutta RN, Rahman MM, Sengupta MK, Ahamed S, Lodh D, Das B, Hossain MA, Nayak B, Mukherjee A, Chakraborti D, Dulta SK, Palit SK, Kaies I, Barua AK and Asad KA (2005). Murshidabad—one of the nine groundwater arsenic-affected districts of West Bengal, India. Part II: dermatological, neurological, and obstetric findings. Clin Toxicol (Phila) 43: 835–848 Google Scholar
  6. 6.
    (2001). National primary drinking water regulations; arsenic and clarification to compliance and new source contaminants monitoring; final rule. Federal Register 66: 6975–7066 Google Scholar
  7. 7.
    IPCS (2001) Arsenic and arsenic compounds, Vol. Envirnomental health criteria 224: 2nd edn, World Health Organization, International Programme on Chemical Safety (IPCS), GenevaGoogle Scholar
  8. 8.
    Waters SB, Devesa V, Del Razo LM, Styblo M and Thomas DJ (2004). Endogenous reductants support the catalytic function of recombinant rat cyt19, an arsenic methyltransferase. Chem Res Toxicol 17: 404–409 PubMedCrossRefGoogle Scholar
  9. 9.
    Waters SB, Devesa V, Fricke MW, Creed JT, Styblo M and Thomas DJ (2004). Glutathione modulates recombinant rat arsenic (3 oxidation state) methyltransferase-catalyzed formation of trimethylarsine oxide and trimethylarsine. Chem Res Toxicol 17: 1621–1629 PubMedCrossRefGoogle Scholar
  10. 10.
    Thomas DJ, Li J, Waters SB, Xing W, Adair BM, Drobna Z, Devesa V and Styblo M (2007). Arsenic (3 oxidation state) methyltransferase and the methylation of arsenicals. Exp Biol Med (Maywood) 232: 3–13 Google Scholar
  11. 11.
    Chowdhury UK, Zakharyan RA, Hernandez A, Avram MD, Kopplin MJ and Aposhian HV (2006). Glutathione-S-transferase-omega [MMA(V) reductase] knockout mice: enzyme and arsenic species concentrations in tissues after arsenate administration. Toxicol Appl Pharmacol 216: 446–457 PubMedCrossRefGoogle Scholar
  12. 12.
    Zakharyan RA and Aposhian HV (1999). Enzymatic reduction of arsenic compounds in mammalian systems: the rate-limiting enzyme of rabbit liver arsenic biotransformation is MMA(V) reductase. Chem Res Toxicol 12: 1278–1283 PubMedCrossRefGoogle Scholar
  13. 13.
    Gregus Z and Nemeti B (2002). Purine nucleoside phosphorylase as a cytosolic arsenate reductase. Toxicol Sci 70: 13–19 PubMedCrossRefGoogle Scholar
  14. 14.
    Radabaugh TR, Sampayo-Reyes A, Zakharyan RA and Aposhian HV (2002). Arsenate reductase II. Purine nucleoside phosphorylase in the presence of dihydrolipoic acid is a route for reduction of arsenate to arsenite in mammalian systems. Chem Res Toxicol 15: 692–698 PubMedCrossRefGoogle Scholar
  15. 15.
    Nemeti B, Csanaky I and Gregus Z (2006). Effect of an inactivator of glyceraldehyde-3-phosphate dehydrogenase, a fortuitous arsenate reductase, on disposition of arsenate in rats. Toxicol Sci 90: 49–60 PubMedCrossRefGoogle Scholar
  16. 16.
    Nemeti B and Gregus Z (2004). Glutathione-dependent reduction of arsenate in human erythrocytes—a process independent of purine nucleoside phosphorylase. Toxicol Sci 82: 419–428 PubMedCrossRefGoogle Scholar
  17. 17.
    Thomas DJ, Waters SB and Styblo M (2004). Elucidating the pathway for arsenic methylation. Toxicol Appl Pharmacol 198: 319–326 PubMedCrossRefGoogle Scholar
  18. 18.
    Lerman S and Clarkson TW (1983). The metabolism of arsenite and arsenate by the rat. Fundam Appl Toxicol 3: 309–314 PubMedCrossRefGoogle Scholar
  19. 19.
    Georis B, Cardenas A, Buchet JP and Lauwerys R (1990). Inorganic arsenic methylation by rat tissue slices. Toxicology 63: 73–84 PubMedCrossRefGoogle Scholar
  20. 20.
    Healy SM, Casarez EA, Ayala-Fierro F and Aposhian H (1998). Enzymatic methylation of arsenic compounds. V. Arsenite methyltransferase activity in tissues of mice. Toxicol Appl Pharmacol 148: 65–70 PubMedCrossRefGoogle Scholar
  21. 21.
    Zakharyan RA, Ayala-Fierro F, Cullen WR, Carter DM and Aposhian HV (1999). Enzymatic methylation of arsenic compounds. VII. Monomethylarsonous acid (MMAIII) is the substrate for MMA methyltransferase of rabbit liver and human hepatocytes. Toxicol Appl Pharmacol 158: 9–15 PubMedCrossRefGoogle Scholar
  22. 22.
    Kenyon EM, Fea M, Styblo M and Evans MV (2001). Application of modelling techniques to the planning of in vitro arsenic kinetic studies. Altern Lab Anim 29: 15–33 PubMedGoogle Scholar
  23. 23.
    Easterling MR, Styblo M, Evans MV and Kenyon EM (2002). Pharmacokinetic modeling of arsenite uptake and metabolism in hepatocytes—mechanistic insights and implications for further experiments. J Pharmacokinet Pharmacodyn 29: 207–234 PubMedCrossRefGoogle Scholar
  24. 24.
    Schwerdtle T, Walter I, Mackiw I and Hartwig A (2003). Induction of oxidative DNA damage by arsenite and its trivalent and pentavalent methylated metabolites in cultured human cells and isolated DNA. Carcinogenesis 24: 967–974 PubMedCrossRefGoogle Scholar
  25. 25.
    Cohen SM, Arnold LL, Eldan M, Lewis AS and Beck BD (2006). Methylated arsenicals: the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Crit Rev Toxicol 36: 99–133 PubMedCrossRefGoogle Scholar
  26. 26.
    Mandal BK, Ogra Y and Suzuki KT (2001). Identification of dimethylarsinous and monomethylarsonous acids in human urine of the arsenic-affected areas in West Bengal, India. Chem Res Toxicol 14: 371–378 PubMedCrossRefGoogle Scholar
  27. 27.
    Valenzuela OL, Borja-Aburto VH, Garcia-Vargas GG, Cruz-Gonzalez MB, Garcia-Montalvo EA, Calderon-Aranda ES and Del Razo LM (2005). Urinary trivalent methylated arsenic species in a population chronically exposed to inorganic arsenic. Environ Health Perspect 113: 250–254 PubMedCrossRefGoogle Scholar
  28. 28.
    Del Razo LM, Styblo M, Cullen WR and Thomas DJ (2001). Determination of trivalent methylated arsenicals in biological matrices. Toxicol Appl Pharmacol 174: 282–293 PubMedCrossRefGoogle Scholar
  29. 29.
    Kenyon EM, Del Razo LM and Hughes MF (2005). Tissue distribution and urinary excretion of inorganic arsenic and its methylated metabolites in mice following acute oral administration of arsenate. Toxicol Sci 85: 468–475 PubMedCrossRefGoogle Scholar
  30. 30.
    Kenyon EM, Del Razo LM, Hughes MF and Kitchin KT (2005). An integrated pharmacokinetic and pharmacodynamic study of arsenite action 2. Heme oxygenase induction in mice. Toxicology 206: 389–401 PubMedCrossRefGoogle Scholar
  31. 31.
    Yamauchi H and Yamamura Y (1983). Concentration and chemical species of arsenic in human tissue. Bull Environ Contam Toxicol 31: 267–270 PubMedCrossRefGoogle Scholar
  32. 32.
    Benramdane L, Accominotti M, Fanton L, Malicier D and Vallon JJ (1999). Arsenic speciation in human organs following fatal arsenic trioxide poisoning—a case report. Clin Chem 45: 301–306 PubMedGoogle Scholar
  33. 33.
    Saady JJ, Blanke RV and Poklis A (1989). Estimation of the body burden of arsenic in a child fatally poisoned by arsenite weedkiller. J Anal Toxicol 13: 310–312 PubMedGoogle Scholar
  34. 34.
    Brown RP, Delp MD, Lindstedt SL, Rhomberg LR and Beliles RP (1997). Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13: 407–484 PubMedGoogle Scholar
  35. 35.
    Yu DH (1999). A physiologically based pharmacokinetic model of inorganic arsenic. Regul Toxicol Pharmacol 29: 128–141 PubMedCrossRefGoogle Scholar
  36. 36.
    Mann S, Droz PO and Vahter M (1996). A physiologically based pharmacokinetic model for arsenic exposure. II. Validation and application in humans. Toxicol Appl Pharmacol 140: 471–486 PubMedCrossRefGoogle Scholar
  37. 37.
    Buchet JP, Lauwerys R and Roels H (1981). Comparison of the urinary excretion of arsenic metabolites after a single oral dose of sodium arsenite, monomethylarsonate, or dimethylarsinate in man. Int Arch Occup Environ Health 48: 71–79 PubMedCrossRefGoogle Scholar
  38. 38.
    Gentry PR, Covington TR, Mann S, Shipp AM, Yager JW and Clewell HJ (2004). Physiologically based pharmacokinetic modeling of arsenic in the mouse. J Toxicol Environ Health A 67: 43–71 PubMedCrossRefGoogle Scholar
  39. 39.
    Lin S, Shi Q, Nix FB, Styblo M, Beck MA, Herbin-Davis KM, Hall LL, Simeonsson JB and Thomas DJ (2002). A novel S-adenosyl-L-methionine:arsenic(III) methyltransferase from rat liver cytosol. J Biol Chem 277: 10795–10803 PubMedCrossRefGoogle Scholar
  40. 40.
    Styblo M, Delnomdedieu M and Thomas DJ (1996). Mono- and dimethylation of arsenic in rat liver cytosol in vitro. Chem Biol Interact 99: 147–164 PubMedCrossRefGoogle Scholar
  41. 41.
    Vahter M (1999). Methylation of inorganic arsenic in different mammalian species and population groups. Sci Prog 82(Pt 1): 69–88 PubMedGoogle Scholar
  42. 42.
    Vahter M and Marafante E (1983). Intracellular interaction and metabolic fate of arsenite and arsenate in mice and rabbits. Chem Biol Interact 47: 29–44 PubMedCrossRefGoogle Scholar
  43. 43.
    Styblo M, Del Razo LM, LeCluyse EL, Hamilton GA, Wang C, Cullen WR and Thomas DJ (1999). Metabolism of arsenic in primary cultures of human and rat hepatocytes. Chem Res Toxicol 12: 560–565 PubMedCrossRefGoogle Scholar
  44. 44.
    Kedderis GL, Elmore AR, Crecelius EA, Yager JW and Goldsworthy TL (2006). Kinetics of arsenic methylation by freshly isolated B6C3F1 mouse hepatocytes. Chem Biol Interact 161: 139–145 PubMedCrossRefGoogle Scholar
  45. 45.
    Csanaky I, Nemeti B and Gregus Z (2003). Dose-dependent biotransformation of arsenite in rats—not S-adenosylmethionine depletion impairs arsenic methylation at high dose. Toxicology 183: 77–91 PubMedCrossRefGoogle Scholar
  46. 46.
    Hayakawa T, Kobayashi Y, Cui X and Hirano S (2005). A new metabolic pathway of arsenite: arsenic-glutathione complexes are substrates for human arsenic methyltransferase Cyt19. Arch Toxicol 79: 183–191 PubMedCrossRefGoogle Scholar
  47. 47.
    Zakharyan RA, Tsaprailis G, Chowdhury UK, Hernandez A and Aposhian HV (2005). Interactions of sodium selenite, glutathione, arsenic species, and omega class human glutathione transferase. Chem Res Toxicol 18: 1287–1295 PubMedCrossRefGoogle Scholar
  48. 48.
    Aposhian HV, Zakharyan RA, Avram MD, Sampayo-Reyes A and Wollenberg ML (2004). A review of the enzymology of arsenic metabolism and a new potential role of hydrogen peroxide in the detoxication of the trivalent arsenic species. Toxicol Appl Pharmacol 198: 327–335 PubMedCrossRefGoogle Scholar
  49. 49.
    Harrison R (2004). Physiological roles of xanthine oxidoreductase. Drug Metab Rev 36: 363–375 PubMedCrossRefGoogle Scholar
  50. 50.
    Harrison R (2002). Structure and function of xanthine oxidoreductase: where are we now?  . Free Radic Biol Med 33: 774–797 PubMedCrossRefGoogle Scholar
  51. 51.
    Hoidal JR (2001). Reactive oxygen species and cell signaling. Am J Respir cell Mol Biol 25: 661–663 PubMedGoogle Scholar
  52. 52.
    Boveris A (1998). Biochemistry of free radicals: from electrons to tissues. Medicina 58: 350–356 PubMedGoogle Scholar
  53. 53.
    Wildfang E, Zakharyan RA and Aposhian HV (1998). Enzymatic methylation of arsenic compounds. VI. Characterization of hamster liver arsenite and methylarsonic acid methyltransferase activities in vitro. Toxicol Appl Pharmacol 152: 366–375 PubMedCrossRefGoogle Scholar
  54. 54.
    Clewell HJ, Covington TR, Gearhart JM and Gentry PR (2000). Development of a physiologically based pharmacokinetic model of trichloroethylene and its metabolites for use in risk assessment. Environ Health Perspect 108(Suppl 2): 283–305 PubMedGoogle Scholar
  55. 55.
    Clewell HJ, Gentry PR, Gearhart JM, Allen BC and Andersen ME (2001). Comparison of cancer risk estimates for vinyl chloride using animal and human data with a PBPK model. Sci Total Environ 274: 37–66 PubMedCrossRefGoogle Scholar
  56. 56.
    Corley RA, Bartels MJ, Carney EW, Weitz KK, Soelberg JJ, Gies RA and Thrall KD (2005). Development of a physiologically based pharmacokinetic model for ethylene glycol and its metabolite, glycolic Acid, in rats and humans. Toxicol Sci 85: 476–490 PubMedCrossRefGoogle Scholar
  57. 57.
    Hughes MF, Devesa V, Adair BM, Styblo M, Kenyon EM and Thomas DJ (2005). Tissue dosimetry, metabolism and excretion of pentavalent and trivalent monomethylated arsenic in mice after oral administration. Toxicol Appl Pharmacol 208: 186–197 PubMedCrossRefGoogle Scholar
  58. 58.
    Bridges CC and Zalups RK (2005). Molecular and ionic mimicry and the transport of toxic metals. Toxicol Appl Pharmacol 204: 274–308 PubMedCrossRefGoogle Scholar
  59. 59.
    Kumagai Y and Sumi D (2007). Arsenic: signal transduction, transcription factor and biotransformation involved in cellular response and toxicity. Annu Rev Pharmacol Toxicol 47: 243–262 PubMedCrossRefGoogle Scholar
  60. 60.
    Kala SV, Kala G, Prater CI, Sartorelli AC and Lieberman MW (2004). Formation and urinary excretion of arsenic triglutathione and methylarsenic diglutathione. Chem Res Toxicol 17: 243–249 PubMedCrossRefGoogle Scholar
  61. 61.
    Marafante E, Vahter M, Norin H, Envall J, Sandstrom M, Christakopoulos A and Ryhage R (1987). Biotransformation of dimethylarsinic acid in mouse, hamster and man. J Appl Toxicol 7: 111–117 PubMedCrossRefGoogle Scholar
  62. 62.
    Lee E (1999) A physiologically based pharmacokinetic model for the ingestion of arsenic in humans. In: Environmetnal toxicology. University of California, Irvine, IrvineGoogle Scholar
  63. 63.
    Buchet JP, Lauwerys R and Roels H (1981). Urinary excretion of inorganic arsenic and its metabolites after repeated ingestion of sodium metaarsenite by volunteers. Int Arch Occup Environ Health 48: 111–118 PubMedCrossRefGoogle Scholar
  64. 64.
    Sheiner BL and Beal SL (1981). Evaluation of methods for estimating population pharmacokinetic parameters. II. Biexponential model and experimental pharmacokinetic data. J Pharmacokinet Biopharm 9: 635–651 PubMedCrossRefGoogle Scholar
  65. 65.
    Gustafsson LL, Ebling WF, Osaki E, Harapat S, Stanski DR and Shafer SL (1992). Plasma concentration clamping in the rat using a computer-controlled infusion pump. Pharm Res 9: 800–807 PubMedCrossRefGoogle Scholar
  66. 66.
    Gustafson DL, Rastatter JC, Colombo T and Long ME (2002). Doxorubicin pharmacokinetics: macromolecule binding, metabolism, and excretion in the context of a physiologic model. J Pharm Sci 91: 1488–1501 PubMedCrossRefGoogle Scholar
  67. 67.
    Krishnan K, Haddad S and Pelekis M (1995). A simple index for representing the discrepancy between simulations of physiological pharmacokinetic models and experimental data. Toxicol Ind Health 11: 413–422 PubMedGoogle Scholar
  68. 68.
    Kligerman AD, Doerr CL and Tennant AH (2005). Oxidation and methylation status determine the effects of arsenic on the mitotic apparatus. Mol Cell Biochem 279: 113–121 PubMedCrossRefGoogle Scholar
  69. 69.
    Kligerman AD, Doerr CL, Tennant AH, Harrington-Brock K, Allen JW, Winkfield E, Poorman-Allen P, Kundu B, Funasaka K, Roop BC, Mass MJ and DeMarini DM (2003). Methylated trivalent arsenicals as candidate ultimate genotoxic forms of arsenic: induction of chromosomal mutations but not gene mutations. Environ Mol Mutagen 42: 192–205 PubMedCrossRefGoogle Scholar
  70. 70.
    Mass MJ, Tennant A, Roop BC, Cullen WR, Styblo M, Thomas DJ and Kligerman AD (2001). Methylated trivalent arsenic species are genotoxic. Chem Res Toxicol 14: 355–361 PubMedCrossRefGoogle Scholar
  71. 71.
    Aposhian HV, Gurzau ES, Le XC, Gurzau A, Healy SM, Lu X, Ma M, Yip L, Zakharyan RA, Maiorino RM, Dart RC, Tircus MG, Gonzalez-Ramirez D, Morgan DL, Avram D and Aposhian MM (2000). Occurrence of monomethylarsonous acid in urine of humans exposed to inorganic arsenic. Chem Res Toxicol 13: 693–697 PubMedCrossRefGoogle Scholar
  72. 72.
    (2005). Toxicological profile for arsenic. Public Health Service, US Department of Health and Human Services, Atlanta Google Scholar
  73. 73.
    Vahter M, Concha G, Nermell B, Nilsson R, Dulout F and Natarajan AT (1995). A unique metabolism of inorganic arsenic in native Andean women. Eur J Pharmacol 293: 455–462 PubMedCrossRefGoogle Scholar
  74. 74.
    Concha G, Nermell B and Vahter MV (1998). Metabolism of inorganic arsenic in children with chronic high arsenic exposure in northern Argentina. Environ Health Perspect 106: 355–359 PubMedCrossRefGoogle Scholar
  75. 75.
    Drobna Z, Waters SB, Walton FS, LeCluyse EL, Thomas DJ and Styblo M (2004). Interindividual variation in the metabolism of arsenic in cultured primary human hepatocytes. Toxicol Appl Pharmacol 201: 166–177 PubMedCrossRefGoogle Scholar
  76. 76.
    Meza MM, Yu L, Rodriguez YY, Guild M, Thompson D, Gandolfi AJ and Klimecki WT (2005). Developmentally restricted genetic determinants of human arsenic metabolism: association between urinary methylated arsenic and CYT19 polymorphisms in children. Environ Health Perspect 113: 775–781 PubMedCrossRefGoogle Scholar
  77. 77.
    Yu L, Kalla K, Guthrie E, Vidrine A and Klimecki WT (2003). Genetic variation in genes associated with arsenic metabolism: glutathione S-transferase omega 1–1 and purine nucleoside phosphorylase polymorphisms in European and indigenous Americans. Environ Health Perspect 111: 1421–1427 PubMedGoogle Scholar
  78. 78.
    Marnell LL, Garcia-Vargas GG, Chowdhury UK, Zakharyan RA, Walsh B, Avram MD, Kopplin MJ, Cebrian ME, Silbergeld EK and Aposhian HV (2003). Polymorphisms in the human monomethylarsonic acid (MMA V) reductase/hGSTO1 gene and changes in urinary arsenic profiles. Chem Res Toxicol 16: 1507–1513 PubMedCrossRefGoogle Scholar
  79. 79.
    Milton AH, Rahman H, Smith W, Shrestha R and Dear K (2006). Water consumption patterns in rural Bangladesh are we underestimating total arsenic load. Journal of water and health 4: 431–436 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Experimental Toxicology Division, National Health and Environmental Effects Research LaboratoryU. S. Environmental Protection AgencyResearch Triangle ParkUSA

Personalised recommendations