Isoflavone Research Initiative

Isoflavones have been examined in dedicated studies of repeated dose toxicity, reproduction toxicity, and genotoxicity, among others. None of these studies has given hints to carcinogenic effects of isoflavone-containing preparations in a relevant dose range. In most studies final doses by far exceeded any quantity which may possibly be ingested with nutrition.

The „No Effect Level“ of genistein (NOEL) was a daily dose of 50 mg/kg body weight in the dog, the „No Adverse Effect Level“ (NOAEL) was determined with > 500 mg/kg in repeated dose toxicity studies (McClain et al. 2005).

In the rat the NOEL of genistein was a daily dose of 5 mg/kg. This seemingly low dose was caused by the observation of estrogenic effects in higher doses, which was, however, not equivalent with undesired or adverse effects. The NOAEL was determined with a daily dose of 50 mg/kg body weight. Starting from 500 mg/kg body weight a change of liver function parameters was observed (McClain et al. 2006b).
 
Mutagenicity was excluded in the AMES-test with and without previous metabolic activation. Only in the mouse lymphoma test were clastogenic effects observed. However, due to the known effect of genistein on topoisomerase II in vitro (the relevance of the observation of an inhibition of this enzyme under in vitro conditions for the situation in the human organism is questionable) the observation of clastogenic effects in this model had to be expected. Such observations must necessarily be followed up by testing in vivo, for which data was also presented. Up to a dose of 20 mg/kg b.w. in the mouse and 2 g/kg in the rat genistein had no mutagenic effects (McClain et al. 2006a).

Reproduction toxicity was excluded for a relevant dose range of genistein in an examination in cultured rat embryos. Feeding of up to 1 g/kg to rats did not trigger teratogenic effects. The NOAEL for mother animals and adverse effects on embryonic development was determined with 100 mg/kg b.w. orally (McClain et al. 2007). Proliferation-enhancing effects were excluded with daily doses up to 300 mg/kg, and thus in a dose range far above of what can usually be reached by oral intake of soy preparations.

Already prior to the publication of the examinations of McClain on reproduction toxicity, reviews of corresponding data for genistein and soy preparations were published (Rozman et al. 2006a; Rozman et al. 2006b). These findings also confirm safety of application.

The studies in animals are paralleled by human interventions. A recent toxicological study, funded by the US-American National Institute of Health, documented the safety of application of up to 900 mg of isoflavones per day over a period of 84 days in postmenopausal women. There was no observation of a negative effect, and especially typical estrogenic effects (ER-α-mediated) could be excluded (Niculescu et al. 2007; Pop et al. 2008). This study was not a long-term trial, but the dose ingested for almost three months corresponded to an 18-fold of the average dietary intake. Under such circumstances the alleged risks extrapolated from experimental studies should have been observed.

One paper described the oral application of 300 mg of isoflavone aglycones to men with prostate cancer for a duration of 28 days, followed by 56 days with an oral dose of 600 mg/day. The genistein blood level reached 2.9 µM after 300 mg/day, and 10.7 µM after intake of 600 mg/day. The highest level measured for free genistein was 0.32 µM, which points to a physiological ceiling effect in the absorption of isoflavones. Despite of the extremely high doses applied in this study, no hint to a genotoxic potential was found (Miltyk et al. 2003).

Combined with further safety data from clinical trials safety of isoflavones is established. A hypothetical carcinogenic risk of isoflavones at hormone sensitive tissues can by now be ruled out – a conclusion which also includes postmenopausal women, which, according to the German BfR, are expected to be at risk by dietary ingestion of isoflavones.

References

McClain, M. R., Wolz, E., Davidovich, A., and Bausch, J. (2006a). Genetic toxicity studies with genistein. Food Chem. Toxicol 44 (1): 42-55.

McClain, M. R., Wolz, E., Davidovich, A., Pfannkuch, F., Edwards, J. A., and Bausch, J. (2006b). Acute, subchronic and chronic safety studies with genistein in rats. Food Chem. Toxicol 44 (1): 56-80.

McClain, R. M., Wolz, E., Davidovich, A., Edwards, J., and Bausch, J. (2007). Reproductive safety studies with genistein in rats. Food Chem. Toxicol 45 (8): 1319-1332.

McClain, R. M., Wolz, E., Davidovich, A., Pfannkuch, F., and Bausch, J. (2005). Subchronic and chronic safety studies with genistein in dogs. Food Chem. Toxicol 43 (10): 1461-1482.

Miltyk, W., Craciunescu, C. N., Fischer, L., Jeffcoat, R. A., Koch, M. A., Lopaczynski, W., Mahoney, C., Jeffcoat, R. A., Crowell, J., Paglieri, J., and Zeisel, S. H. (2003). Lack of significant genotoxicity of purified soy isoflavones (genistein, daidzein, and glycitein) in 20 patients with prostate cancer. Am J. Clin Nutr. 77 (4): 875-882.

Niculescu, M. D., Pop, E. A., Fischer, L. M., and Zeisel, S. H. (2007). Dietary isoflavones differentially induce gene expression changes in lymphocytes from postmenopausal women who form equol as compared with those who do not. J. Nutr. Biochem. 18 (6): 380-390.

Pop, E. A., Fischer, L. M., Coan, A. D., Gitzinger, M., Nakamura, J., and Zeisel, S. H. (2008). Effects of a high daily dose of soy isoflavones on DNA damage, apoptosis, and estrogenic outcomes in healthy postmenopausal women: a phase I clinical trial. Menopause 15 (4): 684-692.

Rozman, K. K., Bhatia, J., Calafat, A. M., Chambers, C., Culty, M., Etzel, R. A., Flaws, J. A., Hansen, D. K., Hoyer, P. B., Jeffery, E. H., Kesner, J. S., Marty, S., Thomas, J. A., and Umbach, D. (2006a). NTP-CERHR expert panel report on the reproductive and developmental toxicity of genistein. Birth Defects Res. B Dev. Reprod. Toxicol 77 (6): 485-638.

Rozman, K. K., Bhatia, J., Calafat, A. M., Chambers, C., Culty, M., Etzel, R. A., Flaws, J. A., Hansen, D. K., Hoyer, P. B., Jeffery, E. H., Kesner, J. S., Marty, S., Thomas, J. A., and Umbach, D. (2006b). NTP-CERHR expert panel report on the reproductive and developmental toxicity of soy formula. Birth Defects Res. B Dev. Reprod. Toxicol 77 (4): 280-397.