NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF KAVA KAVA EXTRACT (CAS No. 9000-38-8) IN F344/N RATS AND B6C3F1 MICE (GAVAGE STUDIES)

NTP Technical Report on the Toxicology and Carcinogenesis Studies Series

Volumn TR-571, Issue , 2012, Pages 1-192

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EID: 85052896178     PISSN: 23788917     EISSN: 23788925     Source Type: Book Series    
DOI: None     Document Type: Review

References (146)

1. ABC News (1998). The Kava Craze: The Herb that May Relieve Stress and Anxiety. More Information on Kava. 20/20 Airdate, June 22, 1998. http://www.herbsnmore.com/2020rpt.html
2. Allen, D.G., Pearse, G., Haseman, J.K., and Maronpot, R.R. (2004). Prediction of rodent carcinogenesis: An evaluation of prechronic liver lesions as forecasters of liver tumors in NTP carcinogenicity studies. Toxicol. Pathol. 32, 393-401.
3. Anke, J., and Ramzan, I. (2004a). Kava hepatotoxicity: Are we any closer to the truth? Planta Med. 70, 193-196.
4. Anke, J., and Ramzan, I. (2004b). Pharmacokinetic and pharmacodynamic drug interactions with Kava (Piper methysticum Forst. f.). J. Ethnopharmacol. 93, 153-160.
5. Ashby, J., and Tennant, R.W. (1991). Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat. Res. 257, 229-306.
6. Attia, M.A. (1985). Neoplastic and nonneoplastic lesions in aging female rats with special reference to the functional morphology of the hyperplastic and neoplastic changes in the pituitary gland. Arch. Toxicol. 57, 77-83.
7. Bailer, A.J., and Portier, C.J. (1988). Effects of treatment-induced mortality and tumor-induced mortality on tests for carcinogenicity in small samples. Biometrics 44, 417-431.
8. Basch, E., Ulbricht, C., Hammerness, P., Tsouronis, C., Sollars, D., Rogers, A., Basch, S., Bent, S., Boon, H., and Ernst, E. (2002). Kava monograph: A clinical decision support tool. J. Herb Pharmacother. 2, 65-91.
9. Bieler, G.S., and Williams, R.L. (1993). Ratio estimates, the delta method, and quantal response tests for increased carcinogenicity. Biometrics 49, 793-801.
10. Bilia, A.R., Gallon, S., and Vincieri, F.F. (2002). Kava-kava and anxiety: Growing knowledge about the efficacy and safety. Life Sci. 70, 2581-2597.
11. Boon, H.S., and Wong, A.H. (2003). Kava: A test case for Canada’s new approach to natural health products. Can. Med. Assoc. J. 169, 1163-1164.
12. Boorman, G.A., Montgomery, C.A., Jr., Eustis, S.L., Wolfe, M.J., McConnell, E.E., and Hardisty, J.F. (1985). Quality assurance in pathology for rodent carcinogenicity studies. In Handbook of Carcinogen Testing (H.A. Milman and E.K. Weisburger, Eds.), pp. 345-357. Noyes Publications, Park Ridge, NJ.
13. Brauer, R.B., Stangl, M., Stewart, J.R., Pfab, R., and Becker, K. (2003). Acute liver failure after administration of herbal tranquilizer kava-kava (Piper methysticum). J. Clin. Psychiatry 64, 216-218.
14. Bressler, R. (2005). Herb-drug interactions: Interactions between kava and prescription medications. Geriatrics 60, 24-25.
15. Bucher, J.R., Haseman, J.K., Herbert, R.A., Hejtmancik, M., and Ryan, M.J. (1998). Toxicity and carcinogenicity studies of oxazepam in the Fischer 344 rat. Toxicol. Sci. 42, 1-12.
16. Bujanda, L., Palacios, A., Silvariño, R., Sánchez, A., and Muñoz, C. (2002). Kava-induced acute icteric hepatitis [in Spanish]. Gastroenterol. Hepatol. 25, 434-435.
17. Campo, J.V., McNabb, J., Perel, J.M., Mazariegos, G.V., Hasegawa, S.L., and Reyes, J. (2002). Kava-induced fulminant hepatic failure. J. Am. Acad. Child Adolesc. Psychiatry 41, 631-632.
18. Clayton, N.P., Yoshizawa, K., Kissling, G.E., Burka, L.T., Chan, P.C., and Nyska, A. (2007). Immunohistochemical analysis of expressions of hepatic cytochrome P450 in F344 rats following oral treatment with kava extract. Exp. Toxicol. Pathol. 58, 223-236.
19. Clough, A.R., Bailie, R.S., and Currie, B. (2003). Liver function test abnormalities in users of aqueous kava extracts. J. Toxicol. Clin. Toxicol. 41, 821-829.
20. Code of Federal Regulations (CFR) 21, Part 58.
21. Cox, D.R. (1972). Regression models and life-tables. J. R. Stat. Soc. B34, 187-220.
22. Crawford, B.D. (1985). Perspectives on the somatic mutation model of carcinogenesis. In Advances in Modern Environmental Toxicology. Mechanisms and Toxicity of Chemical Carcinogens and Mutagens (M.A. Mehlman, W.G. Flamm, and R.J. Lorentzen, Eds.), pp. 13-59. Princeton Scientific Publishing Co., Inc., Princeton, NJ.
23. Denham, A., McIntyre, M., and Whitehouse, J. (2002). Kava – the unfolding story: report on a work-in-progress. J. Altern. Complement. Med. 8, 237-263.
24. Dentali, S.J. (1997). Herb Safety Review. Kava. Piper methysticum Forster f. (Piperaceae), p. 29. Herb Research Foundation, Boulder, CO.
25. De Smet, P.A. (2002). Safety concerns about kava not unique. Lancet 360, 1336.
26. DiSilvestro, R.A., Zhang, W., and DiSilvestro, D.J. (2007). Kava feeding in rats does not cause liver injury nor enhance galactosamine-induced hepatitis. Food Chem. Toxicol. 45, 1293-1300.
27. Dixon, W.J., and Massey, F.J., Jr. (1957). Introduction to Statistical Analysis, 2nd ed., pp. 276-278, 412. McGraw-Hill Book Company, Inc., New York.
28. Duffield, A.M., Jamieson, D.D., Lidgard, R.O., Duffield, P.H., and Bourne, D.J. (1989). Identification of some human urinary metabolites of the intoxicating beverage kava. J. Chromatogr. 475, 273-281.
29. Dunn, O.J. (1964). Multiple comparisons using rank sums. Technometrics 6, 241-252.
30. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Am. Stat. Assoc. 50, 1096-1121.
31. Ernst, E. (2002a). Recall of the herbal anxiolytic kava. Underestimation of its value or overestimation of its risks? [in German]. MMW Fortschr. Med. 144, 40.
32. Ernst, E. (2002b). Safety concerns about kava. Lancet 359, 1,865.
33. Ernst, E. (2006). Herbal remedies for anxiety – a systematic review of controlled clinical trials. Phytomedicine 13, 205-208.
34. Escher, M., Desmeules, J., Giostra, E., and Mentha, G. (2001). Hepatitis associated with Kava, a herbal remedy for anxiety. BMJ 322, 139.
35. Fong, H.H. (2002). Integration of herbal medicine into modern medical practices: Issues and prospects. Integr. Cancer Ther. 1, 287-293.
36. Food and Drug Administration (FDA) (2001). Letter to health care professionals about FDA seeking information on liver injury and kava products. (Accessed on December 2006).
37. Food and Drug Administration (FDA) (2002). Kava concerns. Botanical Council raises safety concerns. AWHONN Lifelines 6, 13-15.
38. Fu, P.P., Yang, Y.-C., Xia, Q., Chou, M.W., Cui, Y.Y., and Lin, G. (2002). Pyrrolizidine alkaloids – tumorigenic components in Chinese herbal medicines and dietary supplements. J. Food Drug Anal. 10, 198-211.
39. Fu, P.P., Xia, Q., Guo, L., Yu, H., and Chan, P.C. (2008a). Toxicity of kava kava. J. Environ. Sci. Health C Environ. Carcinog. Ecotoxicol. Rev. 26, 89-112.
40. Fu, S., Korkmaz, E., Braet, F., Ngo, Q., and Ramzan, I. (2008b). Influence of kavain on hepatic ultrastructure. World J. Gastroenterol. 14, 541-546.
41. Gardiner, P., Graham, R., Legedza, A.T., Ahn, A.C., Eisenberg, D.M., and Phillips, R.S. (2007). Factors associated with herbal therapy use by adults in the United States. Altern. Ther. Health Med. 13, 22-29.
42. Gart, J.J., Chu, K.C., and Tarone, R.E. (1979). Statistical issues in interpretation of chronic bioassay tests for carcinogenicity. JNCI 62, 957-974.
43. Girard, D.M., and Sager, D.B. (1987). The use of Markov chains to detect subtle variation in reproductive cycling. Biometrics 43, 225-234.
44. Gow, P.J., Connelly, N.J., Hill, R.L., Crowley, P., and Angus, P.W. (2003). Fatal fulminant hepatic failure induced by a natural therapy containing kava. Med. J. Aust. 178, 442-443.
45. Gruenwald, J., and Skrabal, J. (2003). Kava ban highly questionable: A brief summary of the main scientific findings presented in the “in depth investigation on EU member states market restrictions on kava products.” Semin. Integrative Med. 1, 199-210.
46. Guo, L., Li, Q., Xia, Q., Dial, S., Chan, P.C., and Fu, P. (2009). Analysis of gene expression changes of drug metabolizing enzymes in the livers of F344 rats following oral treatment with kava extract. Food Chem. Toxicol. 47, 433-442.
47. Guo, L., Shi, Q., Dial, S., Xia, Q., Mei, N., Li, Q.Z., Chan, P.C., and Fu, P. (2010). Gene expression profiling in male B6C3F1 mouse livers exposed to kava identifies – changes in drug metabolizing genes and potential mechanisms linked to kava toxicity. Food Chem. Toxicol. 48, 686-696.
48. Hall, R.L. (2007). Clinical pathology of laboratory animals. In Animal Models in Toxicology, 2nd ed. (S.C. Gad, Ed.), pp. 787-830. Taylor and Francis, Boca Raton, FL.
49. Hapke, H.J., Sterner, W., Heisler, E., and Brauer, H. (1971). Toxicological studies with Kavaform. Farmaco [Prat.] 26, 692-720.
50. Haseman, J.K., Young, E., Eustis, S.L., and Hailey, J.R. (1997). Body weight-tumor incidence correlations in long-term rodent carcinogenicity studies. Toxicol. Pathol. 25, 256-263.
51. Haseman, J.K., Hailey, J.R., and Morris, R.W. (1998). Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: A National Toxicology Program update. Toxicol. Pathol. 26, 428-441.
52. Heddle, J.A., Hite, M., Kirkhart, B., Mavournin, K., MacGregor, J.T., Newell, G.W., and Salamone, M.F. (1983). The induction of micronuclei as a measure of genotoxicity. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat. Res. 123, 61-118.
53. Hefner, D. (2002). FDA studying claims kava may be harmful. J. Natl. Med. Assoc. 94, 285.
54. Hoover, K.L., and Poirier, L.A. (1986). Hepatocyte-like cells within the pancreas of rats fed methyl-deficient diets. J. Nutr. 116, 1569-1575.
55. Hu, Z., Yang, X., Ho, P.C., Chan, S.Y., Heng, P.W., Chan, E., Duan, W., Koh, H.L., and Zhou, S. (2005). Herb-drug interactions: A literature review. Drugs 65, 1239-1282.
56. Humberston, C.L., Akhtar, J., and Krenzelok, E.P. (2003). Acute hepatitis induced by kava kava. J. Toxicol. Clin. Toxicol. 41, 109-113.
57. Institute for Nutraceutical Advancement (INA) (2001). Kavalactone Assay by HPLC, INA Method 101.006, (Accessed on July 23, 2001).
58. Ingelman-Sundberg, M. (2005). Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): Clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 5, 6-13.
59. Jamieson, D.D., and Duffield, P.H. (1990a). The antinociceptive actions of kava components in mice. Clin. Exp. Pharmacol. Physiol. 17, 495-507.
60. Jamieson, D.D., and Duffield, P.H. (1990b). Positive interaction of ethanol and kava resin in mice. Clin. Exp. Pharmacol. Physiol. 17, 509-514.
61. Jhoo, J.W., Ang, C.Y., Heinze, T.M., Deck, J., Schnackenberg, L.K., Beger, R.D., Dragull, K., and Tang, C.S. (2007). Identification of C-glycoside flavonoids as potential mutagenic compounds in kava. J. Food Sci. 72, C120-C125.
62. JNC Corporation (1998). Kava – The National Drink of Fiji.
63. Johnson, B.M., Qiu, S.X., Zhang, S., Zhang, F., Burdette, J.E., Yu, L., Bolton, J.L., and van Breemen, R.B. (2003). Identification of novel electrophilic metabolites of piper methysticum Forst (Kava). Chem. Res. Toxicol. 16, 733-740.
64. Jonckheere, A.R. (1954). A distribution-free k-sample test against ordered alternatives. Biometrika 41, 133-145.
65. Kaplan, E.L., and Meier, P. (1958). Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 457-481.
66. Keledjian, J., Duffield, P.H., Jamieson, D.D., Lidgard, R.O., and Duffield, A.M. (1988). Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J. Pharm. Sci. 77, 1003-1006.
67. Kopp, B. (2003). Relevant hepatotoxic effects of kava still need to be proven: A statement of the Society for Medicinal Plant Research.
68. Kraft, M., Spahn, T.W., Menzel, J., Senninger, N., Dietl, K.H., Herbst, H., Domschke, W., and Lerch, M.M. (2001). Fulminant liver failure after administration of the herbal antidepressant Kava-Kava [in German]. Dtsch. Med. Wochenschr. 126, 970-972.
69. Lebot, V., Merlin, M., and Lindstrom, L. (1992). Kava: The Pacific Drug, p. 225. Yale University Press, New Haven, CT.
70. Lim, S.T., Dragull, K., Tang, C.S., Bittenbender, H.C., Efird, J.T., and Nerurkar, P.V. (2007). Effects of kava alkaloid, pipermethystine, and kavalactones on oxidative stress and cytochrome P450 in F-344 rats. Toxicol. Sci. 97, 214-221.
71. Lüde, S., Török, M., Dieterle, S., Jäggi, R., Büter, K.B., and Krähenbühl, S. (2008). Hepatocellular toxicity of kava leaf and root extracts. Phytomedicine 15, 120-131.
72. McComb, D.J., Kovacs, K., Beri, J., and Zak, F. (1984). Pituitary adenomas in old Sprague-Dawley rats: A histologic, ultrastructural, and immunocytochemical study. J. Natl. Cancer Inst. 73, 1143-1166.
73. McConnell, E.E., Solleveld, H.A., Swenberg, J.A., and Boorman, G.A. (1986). Guidelines for combining neoplasms for evaluation of rodent carcinogenesis studies. JNCI 76, 283-289.
74. MacGregor, J.T., Wehr, C.M., Henika, P.R., and Shelby, M.D. (1990). The in vivo erythrocyte micronucleus test: Measurement at steady state increases assay efficiency and permits integration with toxicity studies. Fundam. Appl. Toxicol. 14, 513-522.
75. Maronpot, R.R., and Boorman, G.A. (1982). Interpretation of rodent hepatocellular proliferative alterations and hepatocellular tumors in chemical safety assessment. Toxicol. Pathol. 10, 71-80.
76. Mathews, J.D., Riley, M.D., Fejo, L., Munoz, E., Milns, N.R., Gardner, I.D., Powers, J.R., Ganygulpa, E., and Gununuwawuy, B.J. (1988). Effects of the heavy usage of kava on physical health: Summary of a pilot survey in an aboriginal community. Med. J. Aust. 148, 548-555.
77. Mathews, J.M., Etheridge, A.S., and Black, S.R. (2002). Inhibition of human cytochrome P450 activities by kava extract and kavalactones. Drug Metab. Dispos. 30, 1153-1157.
78. Mathews, J.M., Etheridge, A.S., Valentine, J.L., Black, S.R., Coleman, D.P., Patel, P., So, J., and Burka, L.T. (2005). Pharmacokinetics and disposition of the kavalactone kawain: Interaction with kava extract and kavalactones in vivo and in vitro. Drug Metab. Dispos. 33, 1555-1563.
79. Miller, J.A., and Miller, E.C. (1977). Ultimate chemical carcinogens as reactive mutagenic electrophiles. In Origins of Human Cancer (H.H. Hiatt, J.D. Watson, and J.A. Winsten, Eds.), pp. 605-627. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.
80. Mills, E., Singh, R., Ross, C., Ernst, E., and Ray, J.G. (2003). Sale of kava extract in some health food stores. Can. Med. Assoc. J. 169, 1158-1159.
81. Mirasol, F. (1998). Botanicals industry posts strong growth in U.S. Chem. Market Rep. (Sept. 28) 4, 12-13.
82. Montgomery, C.A., Jr., and Seely, J.C. (1990). Kidney. In Pathology of the Fischer Rat: Reference and Atlas (G.A. Boorman, S.L. Eustis, M.R. Elwell, C.A. Montgomery, Jr., and W.F. MacKenzie, Eds.), pp. 127-153. Academic Press, Inc., San Diego, CA.
83. Morrison, D.F. (1976). Multivariate Statistical Methods, 2nd ed., pp. 170-179. McGraw-Hill Book Company, New York.
84. 1 Mice (Feed Studies). Technical Report Series No. 443. NIH Publication No. 93-3359. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
85. 1 Mice (Feed Studies). Technical Report Series No. 527. NIH Publication No. 05-4463. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
86. 1 Mice (Drinking Water Studies). Technical Report Series No. 537. NIH Publication No. 07-4475. National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, NC.
87. National Toxicology Program (NTP) (2011a). Toxicology and Carcinogenesis Studies of Ginseng (CAS No. 50647-08-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 567. NIH Publication No. 11-5909. National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, NC.
88. National Toxicology Program (NTP) (2011b). Toxicology and Carcinogenesis Studies of Milk Thistle Extract (CAS No. 84604-20-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 565. NIH Publication No. 11-5907. National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, NC.
89. National Toxicology Program (NTP) (2011c). Toxicology and Carcinogenesis Studies of Pulegone (CAS No. 89-82-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 563. NIH Publication No. 11-5905. National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services, Research Triangle Park, NC.
90. Natural Standard Monograph (NSM) (2010). Kava (Piper methysticum G. Forst).
91. Nerurkar, P.V., Dragull, K., and Tang, C.-S. (2004). In vitro toxicity of kava alkaloid, pipermethystine, in HepG2 cells compared to kavalactones. Toxicol. Sci. 79, 106-111.
92. Norton, S.A., and Ruze, P. (1994). Kava dermopathy. J. Am. Acad. Dermatol. 31, 89-97.
93. Parkman, C.A. (2002). Another FDA warning: Kava supplements. Case Manager 13, 26-28.
94. Piegorsch, W.W., and Bailer, A.J. (1997). Statistics for Environmental Biology and Toxicology, Section 6.3.2. Chapman and Hall, London.
95. Pittler, M.H., and Ernst, E. (2000). Efficacy of kava extract for treating anxiety: Systematic review and meta-analysis. J. Clin. Psychopharmacol. 20, 84-89.
96. Pittler, M.H., and Ernst, E. (2002). Kava extract for treating anxiety. Cochrane Database Syst. Rev. (2):CD003383.
97. Pittler, M.H., and Ernst, E. (2003). Kava extract for treating anxiety. Cochrane Database Syst. Rev. (1):CD003383.
98. Poolsup, N., Li Wan Po, A., and Knight, T.L. (2000). Pharmacogenetics and psychopharmacotherapy. J. Clin. Pharm. Ther. 25, 197-220.
99. Portier, C.J., and Bailer, A.J. (1989). Testing for increased carcinogenicity using a survival-adjusted quantal response test. Fundam. Appl. Toxicol. 12, 731-737.
100. Portier, C.J., Hedges, J.C., and Hoel, D.G. (1986). Age-specific models of mortality and tumor onset for historical control animals in the National Toxicology Program’s carcinogenicity experiments. Cancer Res. 46, 4372-4378.
101. Rao, G.N. (1996). New diet (NTP-2000) for rats in the National Toxicology Program toxicity and carcinogenicity studies. Fundam. Appl. Toxicol. 32, 102-108.
102. Rao, G.N. (1997). New nonpurified diet (NTP-2000) for rodents in the National Toxicology Program’s toxicology and carcinogenesis studies. J. Nutr. 127, 842s-846s.
103. Rasmussen, A.K., Scheline, R.R., and Solheim, E. (1979). Metabolism of some kava pyrones in the rat. Xenobiotica 9, 1-16.
104. Raucy, J.L. (2003). Regulation of CYP3A4 expression in human hepatocytes by pharmaceuticals and natural products. Drug Metab. Dispos. 31, 533-539.
105. Robinson, V., Bergfeld, W.F., Belsito, D.V., Klaassen, C.D., Marks, J.G., Jr., Shank, R.C., Slaga, T.J., Snyder, P.W., and Andersen, F.A. (2009). Final report on the safety assessment of Piper methysticum leaf/root/stem extract and Piper methysticum root extract, Cosmetic Ingredient Review Expert Panel. Int. J. Toxicol. 28, 175S-188S.
106. RTI International (2005). Final Study Report Kawain. Studies of Chemical Disposition in Mammals. RTI Report No. RTI/66U-08361.000.001. Health Sciences, Science and Engineering Group, RTI International, Research Triangle Park, NC.
107. Russmann, S., Lauterburg, B.H., and Helbling, A. (2001). Kava hepatotoxicity. Ann. Intern. Med. 135, 68-69.
108. Russmann, S., Barguil, Y., Cabalion, P., Kritsanida, M., Duhet, D., and Lauterburg, B.H. (2003). Hepatic injury due to traditional aqueous extracts of kava root in New Caledonia. Eur. J. Gastroenterol. Hepatol. 15, 1033-1036.
109. Sandusky, G.E., Van Pelt, C.S., Todd, G.C., and Wightman, K. (1988). An immunocytochemical study of pituitary adenomas and focal hyperplasia in old Sprague-Dawley and Fischer 344 rats. Toxicol. Pathol. 16, 376-380.
110. Schelosky, L., Raffauf, C., Jendroska, K., and Poewe, W. (1995). Kava and dopamine antagonism. J. Neurol. Neurosurg. Psychiatry 58, 639-640.
111. Schmid, W. (1975). The micronucleus test. Mutat. Res. 31, 9-15.
112. Schulze, J., Raasch, W., and Siegers, C.P. (2003). Toxicity of kava pyrones, drug safety and precautions – a case study. Phytomedicine 10, 68-73.
113. Shelby, M.D., and Witt, K.L. (1995). Comparison of results from mouse bone marrow chromosome aberration and micronucleus tests. Environ. Mol. Mutagen. 25, 302-313.
114. Shelby, M.D., Erexson, G.L., Hook, G.J., and Tice, R.R. (1993). Evaluation of a three-exposure mouse bone marrow micronucleus protocol: Results with 49 chemicals. Environ. Mol. Mutagen. 21, 160-179.
115. Shirley, E. (1977). A non-parametric equivalent of Williams’ test for contrasting increasing dose levels of a treatment. Biometrics 33, 386-389.
116. Shulgin, A.T. (1973). The narcotic pepper – the chemistry and pharmacology of Piper methysticum and related species. Bull. Narc. 25, 59-74.
117. Singh, Y.N. (1992). Kava: An overview. J. Ethnopharmacol. 37, 13-45.
118. Singh, Y.N. (2005). Potential for interaction of kava and St. John’s wort with drugs. J. Ethnopharmacol. 100, 108-113.
119. Singh, Y.N., and Devkota, A.K. (2003). Aqueous kava extracts do not affect liver function tests in rats. Planta Med. 69, 496-499.
120. Spillane, P.K., Fisher, D.A., and Currie, B.J. (1997). Neurological manifestations of kava intoxication. Med. J. Aust. 167, 172-173.
121. Stafford, N. (2001). Germany may ban kava kava herbal supplement. Reuter’s News Service, November 19, 2001, Germany.
122. Stickel, F., Baumüller, H.M., Seitz, K., Vasilakis, D., Seitz, G., Seitz, H.K., and Schuppan, D. (2003). Hepatitis induced by Kava (Piper methysticum rhizoma). J. Hepatol. 39, 62-67.
123. Straus, D.S. (1981). Somatic mutation, cellular differentiation, and cancer causation. JNCI 67, 233-241.
124. Symmetry (1998). Tranquility.
125. Tarone, R.E. (1975). Tests for trend in life table analysis. Biometrika 62, 679-682.
126. Tennant, R.W., Margolin, B.H., Shelby, M.D., Zeiger, E., Haseman, J.K., Spalding, J., Caspary, W., Resnick, M., Stasiewicz, S., Anderson, B., and Minor, R. (1987). Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 236, 933-941.
127. Teschke, R., Gaus, W., and Loew, D. (2003). Kava extracts: Safety and risks including rare hepatotoxicity. Phytomedicine 10, 440-446.
128. Teschke, R., Schwarzenboeck, A., and Hennermann, K.H. (2008). Kava hepatotoxicity: A clinical survey and critical analysis of 26 suspected cases. Eur. J. Gastroenterol. Hepatol. 20, 1182-1193.
129. Thomsen, M., Vitetta, L., Schmidt, M., and Sali, A. (2004). Fatal fulminant hepatic failure induced by a natural therapy containing kava. Med. J. Aust. 180, 198-199.
130. Ulbricht, C., Basch, E., Boon, H., Ernst, E., Hammerness, P., Sollars, D., Tsourounis, C., Woods, J., and Bent, S. (2005). Safety review of kava (Piper methysticum) by the Natural Standard Research Collaboration. Expert Opin. Drug Saf. 4, 779-794.
131. Unger, M., Holzgrabe, U., Jacobsen, W., Cummins, C., and Benet, L.Z. (2002). Inhibition of cytochrome P450 3A4 by extracts and kavalactones of Piper methysticum (Kava-Kava). Planta Med. 68, 1055-1058.
132. United States Pharmacopeia (USP) (2000). Powdered Kava Extract. Pharmacop. Forum 26, 779-784.
133. United States Pharmacopeia (USP) (2002). Powdered Kava Extract. Thin-layer chromatographic identification test. Pharmacop. Forum 28, 816.
134. Wanwimolruk, S., Bhawan, S., Coville, P.F., and Chalcroft, S.C. (1998). Genetic polymorphism of debrisoquine (CYP2D6) and proguanil (CYP2C19) in South Pacific Polynesian populations. Eur. J. Clin. Pharmacol. 54, 431-435.
135. Welsch, C.W., Goodrich-Smith, M., Brown, C.K., and Roth, L. (1981). The prophylaxis of rat and mouse mammary gland tumorigenesis by suppression of prolactin secretion: A reappraisal. Breast Cancer Res. Treat. 1, 225-232.
136. Whittaker, P., Clarke, J.J., San, R.H., Betz, J.M., Seifried, H.E., de Jager, L.S., and Dunkel, V.C. (2008). Evaluation of commercial kava extracts and kavalactone standards for mutagenicity and toxicity using the mammalian cell gene mutation assay in L5178Y mouse lymphoma cells. Food Chem. Toxicol. 46, 168-174.
137. Whitton, P.A., Lau, A., Salisbury, A., Whitehouse, J., and Evans, C.S. (2003). Kava lactones and the kavakava controversy. Phytochemistry 64, 673-679.
138. Williams, D.A. (1971). A test for differences between treatment means when several dose levels are compared with a zero dose control. Biometrics 27, 103-117.
139. Williams, D.A. (1972). The comparison of several dose levels with a zero dose control. Biometrics 28, 519-531.
140. Williams, D.A. (1986). A note on Shirley’s nonparametric test for comparing several dose levels with a zero-dose control. Biometrics 42, 183-186.
141. Witt, K.L., Knapton, A., Wehr, C.M., Hook, G.J., Mirsalis, J., Shelby, M.D., and MacGregor, J.T. (2000). Micronucleated erythrocyte frequency in peripheral blood of B6C3F1 mice from short-term, prechronic, and chronic studies of the NTP Carcinogenesis Bioassay Program. Environ. Mol. Mutagen. 36, 163-194.
142. Zeiger, E., Haseman, J.K., Shelby, M.D., Margolin, B.H., and Tennant, R.W. (1990). Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: Confirmation of earlier results with 41 additional chemicals. Environ. Mol. Mutagen. 16 (Suppl. 18), 1-14.
143. Zeiger, E., Anderson, B., Haworth, S., Lawlor, T., and Mortelmans, K. (1992). Salmonella mutagenicity tests: V. Results from the testing of 311 chemicals. Environ. Mol. Mutagen. 19 (Suppl. 21), 2-141.
144. Zou, L., Harkey, M.R., and Henderson, G.L. (2002). Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity. Life Sci. 71, 1579-1589.
145. Zou, L., Henderson, G.L., Harkey, M.R., Sakai, Y., and Li, A. (2004). Effects of kava (Kava-kava, 'Awa, Yaqona, Piper methysticum) on c-DNA-expressed cytochrome P450 enzymes and human cryopreserved hepatocytes. Phytomedicine 11, 285-294.
146. Zou, L., Harkey, M.R., and Henderson, G.L. (2005). Synthesis, in vitro, reactivity, and identification of 6-phenyl-3-hexen-2-one in human urine after kava-kava (Piper methysticum) ingestion. Planta Med. 71, 142-146.