In an assessment by the German BfR of October 2007 the following statement can be found:

"Considering the special sensitivity of women in and after menopause, the safety of products with isolated isoflavones from soy or red clover is not sufficiently substantiated. In this context potential undesired carcinogenic and goitrogenic (goitre-forming) effects as well as other undesired effects on the hormonal status are of special importance. As health risks of such food supplements and balanced diets are possible in women in and after menopause with a low probability, the BfR sees the necessity for taking action, e.g., by an increased information of women with breast cancer or a disposition for it."

The BfR already starts from an erroneous assumption: their argumentation is based on the assumption of estrogenic (proliferation enhancing) effects of isoflavones via activation of ER-α. The partly corrected version of October 2007 mended this error which was already made in the introduction, but still the BfR did not draw the logical conclusions for the subsequent argumentation. The chain of arguments is still based on the assumption of ER-α effects.

In addition, the BfR does not substantiate the risk, but talks about a “small probability” (in other words the BfR could not provide evidence for their hypothesis). In fact, the hypothesis of a cancer risk inherent to isoflavones is not plausible. Most supplements containing soy preparations do not provide more or other isoflavones as ingested daily by a major part of the world’s population – quite obviously without a risk.

In debates reference is frequently made to a recent review which seems to support the risk hypothesis (Wuttke et al. 2007). The author, Prof. Wuttke, has no clinical experience with isoflavones, but has tested isoflavones in pure ER-α-models such as cell cultures with MCF-7 breast cancer cells or examinations in ovarectomized athymic nude mice. For more details on these topics see the contributions related to risks derived from in vitro- and from in vivo-models.

As was amply discussed on a recent symposium on the safety of isoflavones, these in vitro and in vivo models are of no relevance for the assessment of a carcinogenic risk of isoflavones (Messina 2009b; Zhou 2009).

In principle other reviews could also be used in seeming support of the hypothesis of a risk (Duffy et al. 2007). All such reviews have in common that they speak of alleged proofs of a carcinogenic risk derived from human clinical data. These clinical findings can all be traced back to the very same studies:

• - The assumed observation of an increase of breast tissue density in the pilot study of Petrarkis (Petrakis et al. 1996); and
  - An increased rate of endometrial hyperplasia in a clinical trial (Unfer et al. 2004).

When a closer look at these publications is taken it quickly becomes clear that none of the cited papers supports the alleged effect. This is not simply an isolated opinion of the Isoflavone Research Initiative, but is also discussed in recent publications (Messina 2008; Messina and Wood 2008), and was amply and unanimously debated on the isoflavone safety symposium in Milan in May 2009 (Lundstrom 2009; Messina 2009a; Shu 2009; Tice 2009).

When all available data from human exposure are taken together, soy isoflavones must be regarded as extraordinarily safe even on long-term application in dose ranges corresponding to the usual range of dietary intake with soyfood, i.e., up to a minimum of 100-120 mg per day. This conclusion is supported by new long-term data with several years of uninterrupted ingestion of isoflavones including women with a high risk of breast cancer or an impaired thyroid function (Marini et al. 2008; Maskarinec et al. 2009; Shu 2009; Squadrito 2009), and by a recent meta-analysis of adverse events observed in clinical trials with isoflavones presented on the isoflavone symposium in Milan in May 2009 (Tempfer 2009).

References

Duffy, C., Perez, K., and Partridge, A. (2007). Implications of phytoestrogen intake for breast cancer. CA Cancer J. Clin 57 (5): 260-277.

Lundstrom, E. (2009). Effects of isoflavones on in vivo breast cell proliferation in normal subjects and breast cancer patients. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.

Marini, H., Bitto, A., Altavilla, D., Burnett, B. P., Polito, F., Di, Stefano, V, Minutoli, L., Atteritano, M., Levy, R. M., D'Anna, R., Frisina, N., Mazzaferro, S., Cancellieri, F., Cannata, M. L., Corrado, F., Frisina, A., Adamo, V., Lubrano, C., Sansotta, C., Marini, R., Adamo, E. B., and Squadrito, F. (2008). Breast Safety and efficacy of genistein aglycone for post-menopausal bone loss: A follow-up study. J. Clin Endocrinol. Metab 93 (12): 7487-7496.

Maskarinec, G., Verheus, M., Steinberg, F. M., Amato, P., Cramer, M. K., Lewis, R. D., Murray, M. J., Young, R. L., and Wong, W. W. (2009). Various Doses of Soy Isoflavones Do Not Modify Mammographic Density in Postmenopausal Women. J. Nutr. 139: 981-986.

Messina, M. (2008). Conclusion that isoflavones exert estrogenic effects on breast tissue and may raise breast cancer risk unfounded. Mol. Nutr. Food Res. 52 (2): 299-300.

Messina, M. (2009a). Effects of isoflavones on endometrial tissue and endometrial cancer risk. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.

Messina, M. (2009b). Isoflavones and breast cancer: What is the basis for concern? Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.

Messina, M. and Wood, C. E. (2008). Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary. Nutr. J. 7: 17-29.

Petrakis, N. L., Barnes, S., King, E. B., Lowenstein, J., Wiencke, J., Lee, M. M., Miike, R., Kirk, M., and Coward, L. (1996). Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women. Cancer Epidemiol. Biomarkers Prev. 5 (10): 785-794.

Shu, X.O. (2009). Soyfood consumption and breast cancer prognosis: Review of the epidemiologic data. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.

Squadrito, F. (2009). Effects of isoflavones on thyroid function. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.

Tempfer, C.B. (2009). Side effects of phytoestrogens - a meta-analysis of randomized trials. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.

Tice, J.A. (2009). Effects of isoflavones on mammographic breast density in pre- and postmenopausal women. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.

Unfer, V., Casini, M. L., Costabile, L., Mignosa, M., Gerli, S., and Di Renzo, G. C. (2004). Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil. Steril. 82 (1): 145-148.

Wuttke, W., Jarry, H., and Seidlova-Wuttke, D. (2007). Isoflavones - safe food additives or dangerous drugs? Ageing Res. Rev. 6 (2): 150-188.

Zhou, J.R. (2009). Soy, isoflavones, and mammary cancer: Overview of results from animal studies. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.