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Arsenic. Can This Toxic Metalloid Sustain Life?

  • Dean E. Wilcox
Part of the Metal Ions in Life Sciences book series (MILS, volume 13)

Abstract

It was recently reported that a bacterium, Halomonas species GFAJ-1, isolated from arsenic-rich Mono Lake and further selected for growth under conditions of high arsenate and low phosphate, is able to grow using arsenic instead of phosphorus. This claim, and subsequent studies to evaluate GFAJ-1, has brought new attention to the question of whether arsenic can play an essential or sustaining role for living organisms. If true, this would be in stark contrast to the well known toxicity of this element and its ability to cause a number of diseases, including cancer of the skin, lung, bladder, liver, and kidney. However, while deadly at high doses, arsenic oxide is also an approved and effective chemotherapeutic drug for the treatment of acute promyelocytic leukemia (APL). This review examines the evidence that arsenic may be a beneficial nutrient at trace levels below the background to which living organisms are normally exposed. It also examines whether arsenic can be used to sustain organisms growing under high arsenic conditions, specifically the results from recent studies of arsenic biochemistry motivated by the report of GFAJ-1. Both of these topics are considered in the context of the toxicity of this element and its ability to cause cancer and other diseases, yet its Janus-faced ability to effectively treat APL.

Keywords

acute promyelocytic leukemia arsenic beneficial nutrient GFAJ-1 toxicity 

Notes

Acknowledgments

I thank Brian Jackson for his contributions to the sections on chronic toxicity (2.2), deliberate human exposure (3.3.2), and pesticides (4.1). I am grateful for previous support from the Dartmouth Superfund Research Program, which is supported by the NIH (P42 ES07373). This contribution is dedicated to the late Paul Saltman.

References

  1. 1.
    F. Wolfe-Simon, J. S. Blum, T. R. Kulp, G. W. Gordon, S. E. Hoeft, J. Pett-Ridge, J. F. Stolz, S. M. Webb, P. K. Weber, P. C. W. Davies, A. D. Anbar, R. S. Oremland, Science 2011, 332, 1163–1166.PubMedGoogle Scholar
  2. 2.
    W. R. Cullen, K. J. Reimer, Chem. Rev. 1989, 89, 713–764.Google Scholar
  3. 3.
    K. J. Reimer, I. Koch, W. R. Cullen, in Organometallics in Environment and Toxicology, Vol. 7 of Metal Ions in Life Sciences, Eds A. Sigel, H. Sigel, R. K. O. Sigel, Royal Society of Chemistry, Cambridge, 2010, pp. 165–229.Google Scholar
  4. 4.
    G. R. Willsky, M. H. Malamy, J. Bacteriol. 1980, 144, 356–365.PubMedCentralPubMedGoogle Scholar
  5. 5.
    G. R. Willsky, M. H. Malamy, J. Bacteriol. 1980, 144, 366–374.PubMedCentralPubMedGoogle Scholar
  6. 6.
    N. N. Rao, A. Torriani, Mol. Microbiol. 1990, 4, 1083–1090.PubMedGoogle Scholar
  7. 7.
    Z. J. Liu, J. Shen, J. M. Carbrey, R. Mukhopadhyay, P. Agre, B. P. Rosen, Proc. Natl. Acad. Sci. USA 2002, 99, 6053–6058.PubMedCentralPubMedGoogle Scholar
  8. 8.
    H. Fu, X. Jiang, B. P. Rosen, in Biological Chemistry of Arsenic, Antimony and Bismuth, Ed H. Sun, Wiley, Hoboken, 2011, pp. 181–207.Google Scholar
  9. 9.
    F. Challenger, Chem. Rev. 1945, 36, 315–361.Google Scholar
  10. 10.
    S. Lin, Q. Shi, F. B. Nix, M. Stybo, M. A. Beck, K. M. Herbin-Davis, L. L. Hall, J. B. Simeonsson, D. J. Thomas, J. Biol. Chem. 2002, 277, 10795–10803.PubMedGoogle Scholar
  11. 11.
    E. M. Leslie, A. Haimeur, M. P. Waalkes, J. Biol. Chem. 2004, 279, 32700–32708.PubMedGoogle Scholar
  12. 12.
    T. Maki, N. Takeda, H. Hasegawa, K. Ueda, Appl. Organomet. Chem. 2006, 20, 538–544.Google Scholar
  13. 13.
    W. J. Fitz, W. W. Wenzel in Managing Arsenic in the Environment, Eds R. Naidu, E. Smith, G. Owens, P. Bhattacharya, P. Nadebaum, CSIRO, Collingwood, 2006, pp. 209–222.Google Scholar
  14. 14.
    K. A. Francesconi, D. Kuehnelt, in Environmental Chemistry of Arsenic, Ed W. T. Frankenberger, Jr., Dekker, New York, 2002, pp. 51–94.Google Scholar
  15. 15.
    H. V. Aposhian, E. S. Gurzau, X. C. Le, A. Gurzau, S. M. Healy, X. F. Lu, M. S. Ma, L. Yip, R. A. Zakharyan, R. M. Maiorino, R. C. Dart, M. G. Tircus, D. Gonzalez-Ramirez, D. L. Morgan, D. Avram, M. M. Aposhian, Chem. Res. Toxicol. 2000, 13, 693–697.PubMedGoogle Scholar
  16. 16.
    Z. Drobna, W. B. Xing, D. J. Thomas, M. Stybo, Chem. Res. Toxicol. 2006, 19, 894–898.PubMedCentralPubMedGoogle Scholar
  17. 17.
    J. M. Carbrey, L. Song, Y. Zhao, M. Yoshinaga, A. Rojek, Y. Wang, Y. Liu, H. L. Lujan, S. E. DiCarlo, S. Nielsen, B. P. Rosen, P. Agre, R. Mukhopadhyay, Proc. Natl. Acad. Sci. USA 2009, 106, 15956–15960.Google Scholar
  18. 18.
    S. A. Moore, D. M. Moennich, M. J. Gresser, J. Biol. Chem. 1983, 258, 6266–6271.PubMedGoogle Scholar
  19. 19.
    Y. Xu, B. Ma, R. Nussinov, J. Phys. Chem. B 2012, 116, 4801–4811.Google Scholar
  20. 20.
    J. S. Pedrick, B. Jagadish, E. A. Marsh, H. V. Aposhian, Chem. Res. Toxicol. 2001, 14, 651–656.Google Scholar
  21. 21.
    T. Samikkannu, C.-H. Chen, L.-H. Yih, A. S. Wang, S.-Y. Lin, T.-C. Chen, K.-Y. Jan, Chem. Res. Toxicol. 2003, 16, 409–414.PubMedGoogle Scholar
  22. 22.
    M. F. Hughes, Toxicol. Lett. 2002, 133, 1–16.PubMedGoogle Scholar
  23. 23.
    World Health Organization, Evaluation of Certain Food Additives and Contaminants. Thirty-third Report of the Joint FAO/WHO Expert Committee on Food Additives, Geneva, 1989, WHO Technical Report Series, No. 776.Google Scholar
  24. 24.
    D. K. Nordstrom, Science 2002, 296, 2143–2145.PubMedGoogle Scholar
  25. 25.
    A. H. Smith, P. A. Lopipero , M. N. Bates, C. M. Steinmaus, Science 2002, 296, 2145–2146.PubMedGoogle Scholar
  26. 26.
    C. H. Tseng, C. K. Chong, C. J. Chen, T. Y. Tai. Atherosclerosis 1996, 120, 125–133.PubMedGoogle Scholar
  27. 27.
    H. Y. Chiou, S. T. Chiou, Y. H. Hsu, Y. L. Chou, C. H. Tseng, M. L. Wei, C. J. Chen, Am. J. Epidemiol. 2001, 153, 411–418.PubMedGoogle Scholar
  28. 28.
    C. H. Tseng, T. Y. Tai, C. K. Chong, C. P. Tseng, M. S. Lai, B. J. Lin, H. Y. Chiou, Y. M. Hsueh, K. H. Hsu, C. J. Chen, Environ. Health Perspect. 2000, 108, 847–851.PubMedCentralPubMedGoogle Scholar
  29. 29.
    C. H. Tseng, C. K. Chong, C. P. Tseng, Y. M. Hsueh, H. Y. Chiou, C. C. Tseng, C. J. Chen, Toxicol. Lett. 2003, 137, 15–21.PubMedGoogle Scholar
  30. 30.
    Y. K. Huang, C. H. Tseng, Y. L. Huang, M. H. Yang, C. J. Chen, Y. M. Hsueh, Toxicol. Appl. Pharmacol. 2007, 218, 135–142.PubMedGoogle Scholar
  31. 31.
    M. Bates, O. Rey, M. L. Biggs, C. Hopenhayn, L. F. Moore, D. Kalman, C. Steinmaus, A. H. Smith, Epidemiology 2003, 14, S123.Google Scholar
  32. 32.
    C. Steinmaus, Y. Yuan, D. Kalman, O. A. Rey, C. F. Skibola, D. Dauphine, A. Basu, K. E. Porter, A. Hubbard, M. N. Bates, M. T. Smith, A. H. Smith, Toxicol. Appl. Pharmacol. 2010, 247, 138–145.PubMedGoogle Scholar
  33. 33.
    A. H. Smith, M. Goycolea, R. Haque, M. L. Biggs, Am. J. Epidemiol. 1998, 147, 660–669.PubMedGoogle Scholar
  34. 34.
    C. Ferreccio, C. Gonzalez, V. Milosavjlevic, G. Marshall, A. M. Sancha, A. H. Smith, Epidemiology 2000, 11, 673–679.PubMedGoogle Scholar
  35. 35.
    M. Argos, T. Kalva, P. J. Rathouz, Y. Chen, B. Pierce, F. Parvez, T. Islam, A. Ahmed, M. Rakibuz-Zaman, R. Hasan, G. Sarwar, V. Slavkovich, A. van Green, J. Graziano, H. Ahsan, Lancet 2010, 376, 252–258.PubMedCentralPubMedGoogle Scholar
  36. 36.
    A. H. Smith, G. Marshall, J. Liaw, Y. Yuan, C. Ferreccio, C. Steinmaus, Environ. Health Perspect. 2012, 120, 1527–1531.PubMedCentralPubMedGoogle Scholar
  37. 37.
    R. T. Nickson, J. M. McArthur, W. G. Burgess, K. M. Ahmed, P. Ravenscroft, M. Rahman, Nature 1998, 395, 338.PubMedGoogle Scholar
  38. 38.
    R. T. Nickson, J. M. McArthur, P. Ravenscroft, W. G. Burgess, K. M. Ahmed, Appl. Geochem. 2000, 15, 403–413.Google Scholar
  39. 39.
    A. H. Smith, E. O. Lingas, M. Rahman, Bull. World Health Org. 2000, 78, 1093–1103.Google Scholar
  40. 40.
    M. F. Naujokas, B. Anderson, H. Ahsan, H. V. Aposhian, J. H. Graziano, C. Thompson, W. A. Suk, Environ. Health Perspect. 2013, 121, 295–302.PubMedCentralPubMedGoogle Scholar
  41. 41.
    L. M. Del Razo, B. Quintanilla-Vega, E. Brambila-Colombres, E. S. Calderon-Aranda, M. Manno, A. Albores, Toxicol. Appl. Pharmacol. 2001, 177, 132–148.PubMedGoogle Scholar
  42. 42.
    K. T. Kitchen, R. Conolly, Chem. Res. Toxicol. 2010, 23, 327–335.Google Scholar
  43. 43.
    J. E. Bodwell, L. A. Kingsley, J. W. Hamilton, Chem. Res. Toxicol. 2004, 17, 1064–1076.PubMedGoogle Scholar
  44. 44.
    H. Baumann, K. Paulsen, H. Kovacs, H. Berglund, A. P. H. Wright, J.-A. Gustafsson, T. Hard, Biochemistry 1993, 32, 13463–13471.PubMedGoogle Scholar
  45. 45.
    A. M. Spuches, D. E. Wilcox, J. Am. Chem. Soc. 2008, 130, 8148–8149.PubMedGoogle Scholar
  46. 46.
    A. M. Spuches, H. G. Kruszyna, A. M. Rich, D. E. Wilcox, Inorg. Chem. 2005, 44, 2964–2972.PubMedGoogle Scholar
  47. 47.
    F. D. Barr, L. J. Krohmer, J. W. Hamilton, L. A. Sheldon, PLoS One 2009, 4(8): e6766. doi: 10.1371/journal.pone.0006766.PubMedCentralPubMedGoogle Scholar
  48. 48.
    J. E. Bodwell, J. A. Goss, A. P. Nomikos, J. W. Hamilton, Chem. Res. Toxicol. 2006, 19, 1619–1629.PubMedCentralPubMedGoogle Scholar
  49. 49.
    K. Piatek, T. Schwerdtle, A. Hartwig, W. Bal, Chem. Res. Toxicol. 2008, 21, 600–606.PubMedGoogle Scholar
  50. 50.
    National Research Council, Arsenic in Drinking Water 2001 Update, National Academy, Washington, 2001.Google Scholar
  51. 51.
    S. H. Lamm, A. Engel, C. A. Penn, R. Chen, M. Feinleib, Environ. Health Perspect. 2006, 114, 1077–1082.PubMedCentralPubMedGoogle Scholar
  52. 52.
    E. T. Snow, P. Sykora, T. R. Durham, C. B. Klein, Toxicol. Appl. Pharmacol. 2005, 207, S557–S564.Google Scholar
  53. 53.
    M. Anke in Trace Elements in Human and Animal Nutrition, Vol 2, Ed W. Mertz, Academic, Orlando, 1986, pp. 347–372.Google Scholar
  54. 54.
    E. O. Uthus, Environ. Geochem. Health 1992, 14, 55–58.PubMedGoogle Scholar
  55. 55.
    S. S.-H. Tao, P. M. Bolger, Food Add. Contam. 1998, 16, 465–472.Google Scholar
  56. 56.
    F. H. Nielsen, J. Trace Elem. Exp. Med. 2000, 13, 113–129.Google Scholar
  57. 57.
    M. Lu, H. Wang, X.-F. Li, L. L. Arnold, S. M. Cohen, X. C. Le, Chem. Res. Toxicol. 2007, 20, 27–37.PubMedGoogle Scholar
  58. 58.
    M. Vahter, Sci. Prog. 1999, 82, 69–88.PubMedGoogle Scholar
  59. 59.
    K. N. Jeejeebhoy, R. C. Chu, E. B. Marliss, G. R. Greenberg, A. Bruce-Robertson, Am. J. Clin. Nutr. 1977, 30, 531–538.PubMedGoogle Scholar
  60. 60.
    M. M. Pluhator-Murton, R. N. Fedorak, R. J. Audette, B. J. Marriage, R. Y. Yatscoff, L. M. Gramlich, J. Parenteral Enteral Nutr. 1999, 23, 222–227.Google Scholar
  61. 61.
    W. E. Cornatzer, E. O. Uthus, J. A. Haning, F. H. Nielsen, Nutr. Reports Intl. 1983, 27, 821–829.Google Scholar
  62. 62.
    E. J. Calabrese, L. A. Baldwin, Crit. Rev. Toxicol. 2003, 33, 215–304.PubMedGoogle Scholar
  63. 63.
    A. A. Carbonell, M. A. Aarabi, R. D. DeLaune, R. P. Gambrell, W. H. Patrick, Jr., Sci. Total Environ. 1998, 217, 189–199.Google Scholar
  64. 64.
    N. Singh, L. Q. Ma, Environ. Poll. 2006, 141, 238–246.Google Scholar
  65. 65.
    Y. Gong, H.-N. Chou, C.-d. Tu, X. Liu, J. Liu, L. Song, J. Appl. Phycol. 2009, 21, 225–231.Google Scholar
  66. 66.
    M. S. Cox, P. E. Bell, J. Plant Nutr. 1996, 19, 1599–1610.Google Scholar
  67. 67.
    Z. Meng, N. Meng, Biol. Trace Elem. Res. 1994, 42, 201–208.PubMedGoogle Scholar
  68. 68.
    T.-C. Lee, M. Oshimura, J. C. Barrett, Cacrinogenesis 1985, 6, 1421–1426.Google Scholar
  69. 69.
    P. Sykora, E. T. Snow, Toxicol. Appl. Pharmacol. 2008, 228, 385–394.PubMedGoogle Scholar
  70. 70.
    A. Stoica, E. Pentecost, M. B. Martin, Endocrinology 2000, 141, 3595–3602.PubMedGoogle Scholar
  71. 71.
    W. P. Norwood, U. Borgmann, D. G. Dixon, Environ. Poll. 2007, 147, 262–272.Google Scholar
  72. 72.
    J. L. Brown, K. T. Kitchen, Cancer Lett. 1996, 98, 227–231.PubMedGoogle Scholar
  73. 73.
    P. Mushak, Environ. Health Perspect. 2007, 115, 500–506.PubMedCentralPubMedGoogle Scholar
  74. 74.
    J. M. Santini, L. I. Sly, R. D. Schnagl, J. M. Macy, Appl. Environ. Microbiol. 2000, 66, 92–97.PubMedCentralPubMedGoogle Scholar
  75. 75.
    D. Ahmann, A. L. Roberts, L. R. Krumholz, F. M. Morel, Nature 1994, 371, 750.PubMedGoogle Scholar
  76. 76.
    R. S. Oremland, J. F. Stolz, Science 2003, 300, 939–944.PubMedGoogle Scholar
  77. 77.
    F. H. Westheimer, Science 1987, 235, 1173–1178.PubMedGoogle Scholar
  78. 78.
    Science 2011 332, 1149a-j.Google Scholar
  79. 79.
    M. I. Fekry, P. A. Tipton, K. S. Gates, ACS Chem. Biol. 2011, 6, 127–130.PubMedGoogle Scholar
  80. 80.
    D. S. Tawffik, R. E. Viola, Biochemistry 2011, 50, 1128–1134.Google Scholar
  81. 81.
    S. Silver, L. T. Phung, FEMS Microbiol. Lett. 2011, 315, 79–80.PubMedGoogle Scholar
  82. 82.
    B. P. Rosen, A. A. Ajees, T. R. McDermott, Bioessays 2011, 33, 350–357.PubMedCentralPubMedGoogle Scholar
  83. 83.
    M. L. Reaves, S. Sinha, J. D. Rabinowitz, L. Kruglyak, R. J. Redfield, Science 2012, 337, 470–473.PubMedGoogle Scholar
  84. 84.
    T. J. Erb, P. Kiefer, B. Hattendorf, D. Gunther, J. A. Vorholt, Science 2012, 337, 467–470.PubMedGoogle Scholar
  85. 85.
    L. T. Phung, S. Silver, W. L. Trimble, J. A. Gilbert, J. Bacteriol. 2012, 194, 1835–1836.PubMedCentralGoogle Scholar
  86. 86.
    G. N. Basturea, T. K. Harris, M. P. Deutscher, J. Biol. Chem. 2012, 287, 28816–28819.PubMedCentralPubMedGoogle Scholar
  87. 87.
    M. A. Zundel, G. N. Basturea, M. P. Deutscher, RNA 2009, 15, 977–983.PubMedCentralPubMedGoogle Scholar
  88. 88.
    M. Elias, A. Wellner, K. Goldin-Azulay, E. Chabriere, J. A. Vorholt, T. J. Erb, D. S. Tawfik, Nature 2012, 491, 134–137.PubMedGoogle Scholar
  89. 89.
    E. J. Denning, A. D. MacKerell, Jr, J. Am. Chem. Soc. 2011, 133, 5770–5772.PubMedCentralPubMedGoogle Scholar
  90. 90.
    A. Mladek, J. Sponer, B. G. Sumpter, M. Fuentes-Cabrera, J. E. Sponer, J. Phys. Chem. Lett. 2011, 2, 389–392.Google Scholar
  91. 91.
    J. Gu, J. Wang, Y. Xie, J. Leszczynski, H. F. Schaefer, III, J. Comp. Chem. 2012, 33, 817–821.Google Scholar
  92. 92.
    M. Toulouze, J. Pilme, F. Pauzat, Y. Ellinger, Phys. Chem. Chem. Phys. 2012, 14, 10515–10522.PubMedGoogle Scholar
  93. 93.
    J. Sponer, A. Mladek, J. E. Sponer, D. Svozil, M. Zgarbova, P. Panas, P. Jurecka, M. Otyepka, Phys. Chem. Chem. Phys. 2012, 14, 15257–15277.PubMedGoogle Scholar
  94. 94.
    C. D. Baer, J. O. Edwards, P. H. Rieger, Inorg. Chem. 1981, 20, 905–907.Google Scholar
  95. 95.
    G. K. Schroeder, C. Lad, P. Wyman, N. H. Williams, R. Wolfenden, Proc. Natl. Acad. Sci. USA 2006, 103, 4052–4055.PubMedCentralPubMedGoogle Scholar
  96. 96.
    G. Przygoda, J. Feldmann, W. R. Cullen, Appl. Organomet. Chem. 2001, 15, 457–462.Google Scholar
  97. 97.
    L. Tremolizzo, M. A. Riva, C. Ferrarese, Med. Hypothesis 2010, 75, 677.Google Scholar
  98. 98.
    Y.-N. Zhang, G.-X. Sun, Q. Huang, P. N. Williams, Y.-G. Zhu, Environ. Intl. 2011, 37, 889–892.Google Scholar
  99. 99.
    E. A. Murphy, M. Aucott, Sci. Total Environ. 1998, 218, 89–101.Google Scholar
  100. 100.
    L. L. Embrick, K. M. Porter, A. Pendergrass, D. J. Butcher, Microchem. J. 2005, 81, 117–121.Google Scholar
  101. 101.
    D. C. Elfving, K. R. Wilson, J. G. Ebel, K. L. Manzell, W. H. Gutenmann, D. J. Lisk, Chemosphere 1994, 29, 407–413.Google Scholar
  102. 102.
    C. E. Renshaw, B. C. Bostick, X. Feng, C. K. Wong, E. S. Winston, R. Karimi, C. L. Folt, C. Y. Chen, J. Environ. Qual. 2006, 35, 61–67.PubMedGoogle Scholar
  103. 103.
    B. P. Jackson, J. C. Seaman, P. M. Bertsch, Chemosphere 2006, 65, 2028–2034.PubMedGoogle Scholar
  104. 104.
    S. Gibaud, G. Jaouen, Top. Organomet. Chem. 2010, 32, 1–20.Google Scholar
  105. 105.
    Z. X. Shen, G. Q. Chen, J. H. Ni, X. S. Li, S. M. Xiong, Q. Y. Qui, J. Zhu, W. Tang, G. L. Sun, K. Q. Yang, Y. Chen, L. Zhou, Z. W. Fang, Y. T. Wang, J. Ma, P. Zhang, T. D. Zhang, S. J. Chen, Z. Chen, Z. Y. Wang, Blood 1997, 89, 3354–3360.PubMedGoogle Scholar
  106. 106.
    L. C. Platanias, J. Biol. Chem. 2009, 284, 18583–18587.PubMedCentralPubMedGoogle Scholar
  107. 107.
    J. Zhu, M. H. M. Koken, F. Quignon, M. K. Chelbi-Alix, L. Degos, Z. Y. Wang, Z. Chen, H. de The, Proc. Natl. Acad. Sci. USA 1997, 94, 3978–3983.Google Scholar
  108. 108.
    X.-W. Zhang, X.-J. Yan, Z.-R. Shou, F.-F. Yang, Z.-Y. Wu, H.-B. Sun, W.-X. Liang, A.-X. Song, V. Lallemand-Breitengach, M. Jeanne, Q.-Y. Zhang, H.-Y. Yang, Q.-H. Huang, G.-B. Zhou, J.-H. Tong, Y. Zhang, J.-H. Wu, H.-Y. Hu, H. de The, S.-J. Chen, Z. Chen, Science 2010, 328, 240–243.PubMedGoogle Scholar
  109. 109.
    N. Zhang, P. Wang, P. D. Jeffrey, N. P. Pavletich, Cell 2000, 102, 533–539.Google Scholar
  110. 110.
    S.-J. Chen, G.-B. Zhou, X.-W. Zhang, J.-H. Mao, H. de The, Z. Chen, Blood 2011, 117, 6425–6437.PubMedCentralPubMedGoogle Scholar
  111. 111.
    J.-H. Mao, X.-Y. Sun, J.-X. Liu, Q.-Y. Zhang, P. Liu, Q.-H. Huang, K. K. Li, Q. Chen, Z. Chen, S.-J. Chen, Proc. Natl. Acad. Sci. USA 2010, 107, 21683–21688.PubMedCentralPubMedGoogle Scholar
  112. 112.
    J. O. Nriagu, in Environmental Chemistry of Arsenic, Ed W. T. Frankenberger, Jr., Dekker, New York, 2002, pp. 1–26.Google Scholar
  113. 113.
    R. Baastrup, M. Sorensen, T. Balstrom, K. Frederiksen, C. L. Larsen, A. Tjonneland, K. Overvad, O. Raaschou-Nielsen, Environ. Health Perspect. 2008, 116, 231–237.PubMedCentralPubMedGoogle Scholar
  114. 114.
    World Health Organization, Summary and Conclusions of the 72nd Meeting of the Joint FAO/WHO Expert Committee on Food Additives, Geneva, 2010.Google Scholar

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© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of ChemistryDartmouth CollegeHanoverUSA

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