Based on today’s knowledge preparations containing isoflavones must be regarded as safe and efficacious – as resulting from a symposium organized by the CRN (Council for Responsible Nutrition), which took place on the 13th and 14th of May 2009 in Milan under active participation of the EFSA. Topics of the debate were focused on the available data for isoflavones in the context of menopausal complaints, cancer and thyroidal disorders. As a conclusion of the symposium it was noted that, based on meta-analyses, the question of effects against menopausal complaints must by now clearly be positively answered. In addition, the recent clinical and toxicological data disprove concerns of regulatory authorities regarding hypothetical risks of hormonal origin. Soy preparations as “phyto-estrogens” do not favour the growth of hormone-sensitive cancer forms. In the contrary the data rather point to a protective effect from such diseases under the influence of isoflavones.
A congress report of the Isoflavone Research Initiative has been published in:
M. Schmidt: Soj-Isoflavone bei Wechseljahresbeschwerden. Welchen Nutzen, welche Risiken bergen Pflanzenestrogene? Ein Bericht zum diesjährigen Symposium zur Sicherheit und Wirksamkeit von Soja-Isoflavonen. Gyne 30(12): 25-34 (2009)
There is no question: our food should become even safer. In order to achieve this, toxicologists analyse and assess daily consumed food items for potential risks. When soy-containing food and extracts designed for consumption by menopausal women were criticized, the limitations of such a risk assessment became quite obvious. Distinct contradictions surfaced in the evaluation of isoflavone-containing soy preparations by the German Federal Institute for Risk Assessment (Bundesinstitut für Risikobewertung, BfR) in 2007 (Anon. 2007): Under certain conditions an increased risk of hormone-dependent cancer forms was observed in special animal models (Allred et al. 2004b), and was extrapolated to humans. However, this extrapolation is not in accordance with other experimental models (Zhou et al. 2004), and with data from epidemiological studies (Wu et al. 2008) and controlled clinical intervention trials (Maskarinec et al. 2009). In the contrary there are clear hints to a potentially protective effect of soy food.
The benefits and the clinically observed risks have been intensively discussed by experts as a consequence of the BfR pinpointing a possible risk for menopausal women consuming isoflavone-containing preparations (Messina 2008a; Messina et al. 2008; Messina 2008b; Messina et al. 2009b; Messina et al. 2009a). Following the assessment of the BfR, which was primarily based on publications which appeared well before the year 2006, a multitude of international studies covering these aspects have been presented. The topic had, however, meanwhile been shifted to the European level: in the beginning of 2009 the EFSA (European Food Safety Authority) published its mandate for the assessment of the safety of isoflavone-containing preparations (EFSA 2009b).
With this background it became necessary to have the available data discussed by toxicologists, epidemiologists, gynaecologists and representatives of the EFSA. Two days of intensive discussion resulted in a large step forward. It was, for example, noted that especially in the case of hormonal effects an extrapolation of observations from “simple” animal models to the complex situation in humans quickly reaches its limits. Human-clinical data must have priority over animal models when it comes to risk assessments. Already prior to the assessment by the BfR the connection between soy- and isoflavone-rich food and a lower risk of many diseases including various types of cancer was well-documented. The recent human trials presented in Milan deepened and confirmed this knowledge.
Isoflavones as „phyto-estrogens“
The aims of the symposium were presented by Dr. Antonello Sannia of the Italian Society of Phytotherapy (Sannia 2009). Soy counts among the best-researched food plants, with more than 10,000 relevant publications and 700 to 800 new contributions per year (Messina et al. 2009a). Soy is in first place known as a health food, but supplements aiming on the improvement of menopausal complaints are likewise commercially available. The application of isoflavone-containing supplements against menopausal disorders triggered a special interest, as the hormone therapy was correlated with undesired effects such as an increased rate of breast cancer, cardiac infarction and thromboembolism (Anderson et al. 2004). Meta-analyses and reviews have meanwhile confirmed the effects of isoflavones against menopausal complaints (Howes et al. 2006; Kurzer 2008; Nelson et al. 2006), among them an analysis newly presented on the Milan symposium. These positive aspects and the promising data from epidemiologic studies stand in contrast with recent concerns that phyto-“estrogens” might also induce the growth of hormone-sensitive cancer in the same way as the hormones (Wuttke et al. 2007). At first sight corresponding observations from animal studies (Allred et al. 2001; Allred et al. 2004a; Helferich et al. 2008) and in vitro-data (Bodinet et al. 2004; Hsieh et al. 1998) seem to confirm such concerns. The aim of the symposium was to explain the obvious discrepancy between results from animal studies and the positive experience from human application, and to eventually uncover the need for more research.
Assessment of food safety by the EFSA: the European perspective
As a representative of the “Toxicology Forum” Prof. Arpad Somogyi explained the European perspective of risk assessment (Somogyi 2009). Prof. Somogyi outlined the history of the embodiment of questions of safety and consumer protection in the EU legislation since the treaty of Amsterdam in the year 2002. The trigger for the introduction of the precautionary principle and the foundation of the European Food Safety Authority (EFSA) as an independent European institution was primarily the BSE-scandal. Since then, the EFSA has to call for “strong scientific data” in the assessment of food benefits, as anchored in several EU legislative frameworks. The call for “strong science” is currently reflected in the extremely restrictive attitude of the EFSA towards health claims for food supplements of herbal origin.
In contrast to the “strong science” required for efficacy, the precautionary principle does not require scientifically sound criteria when it comes to risks. The authorities must point out insecurities should there remain doubts after the evaluation of the data, for example by stating that the available scientific data does not allow drawing a final conclusion. In such cases the authorities can apply precautionary measures. Such measures must, however, not have discriminatory effects for the market, and the measures taken must be comparable in similar situations.
By direct application of the general information given by Prof. Somogyi the EFSA’s recommendation will have to be measured against earlier decisions: Only recently the EFSA has published a safety assessment for products containing extracts from Medicago sativa (alfalfa). It was explicitly noted that no safety risk was perceived with a daily dose of 60 mg of isoflavones supplied by preparations containing alfalfa (EFSA 2009a).
According to Prof. Somogyi the recommendation given by the EFSA must be proportional to the desired degree of consumer protection. In addition, the decision must be based on an economic cost-benefit analysis.
Safety assessments can never be final: A previously taken decision must be questioned and eventually changed when new scientific evidence is available. Whether a decision is appropriate has to be assessed case by case, based on its effects on the concerned population. Recently it became evident that a zero-tolerance policy does not always make sense. Somogyi referred to the example of the potentially carcinogenic aflatoxins. The modern analytical techniques allow a constant lowering of limits of detection. The aflatoxins are, however, always present up to a certain threshold, and cannot fully be avoided. If the level of acceptance were zero, no more cereal products could be marketed based on today’s available analytical techniques.
The assessment of the isoflavones must be seen with this background in mind. However, Prof. Somogyi pointed out that the expected assessment by the EFSA will not be legally binding. The BfR would not be obliged to follow the vote of the EFSA. A decision against the EFAS’s assessment would, however, require a sound reasoning.
The BfR shifts the risk-benefit debate for soy to the European level
Dr. Miriam Jacobs, an EFSA representative, reported on the tasks of the EFSA in the ongoing risk assessment procedure on the European level (Jacobs 2009). She explicitly pointed to the position of the German BfR, which states that the use of soy preparations is “not without risk” (Anon. 2007). Positive effects of isoflavones on bone health (Ma et al. 2008a; Ma et al. 2008b), cholesterol levels (Taku et al. 2007), adiposity (Velasquez et al. 2007), menopausal complaints (Kurzer 2008) and the prevention of breast (Wu et al. 2008) or prostate cancer (Yan et al. 2009) have been demonstrated in epidemiological studies and human trials. In most cases the effects were related to the affinity of isoflavones to the estrogen receptors beta (ER-β) and alpha (ER-α) (McCarty 2006). Other mechanisms could, however, also be involved. The task of the safety assessment is based on concerns of the BfR regarding negative effects on the function of the thyroid gland, potential cancer-inducing effects, and the apprehension that isoflavones might interfere with the efficacy of tamoxifen in the treatment of breast cancer.
The task of the EFSA consists in an identification of potential risks related to soy food, as well as an assessment of existing data on food, extracts and isolated isoflavones. The emphasis will be on recent data on bioavailability and metabolism, questions of transferability and relevance of in vitro-data, and dose-effect relations specifically for the thyroid gland and for cancer, but also on the use of soy in infant nutrition. The report is expected to be available towards the end of the year 2009. Interested parties were invited to provide data for this assessment to the EFSA until Mid of June 2009.
Recent data on safety of application and effects in menopause
In the course of the symposium the main topics mentioned by the EFSA were all discussed by experts, with the exception of the question of safety of soy in infant nutrition. By no means was the data glossed over: the experimental and clinical data which, according to the BfR, point to potential risks were presented in detail and analysed in the general context. Thereby it became obvious that a real assessment of the situation is in fact only possible when the general context is respected. E.g., certain results from animal experiments pointing to a stimulation of hormone-dependent tumours by isoflavones can be converted to the contrary outcome already by small changes of the highly artificial study conditions. This leads to indications of cancer-protective effects by isoflavones, as they in fact correlate with the clinical observations.
The contributions to safety of application and the effects against menopausal disorders are presented in the corresponding sections of this website. Most recent meta-analyses and studies were presented for both aspects. Under the influence of soy isoflavones menopausal hot flushes and profuse sweating is significantly more reduced than with placebo, with an effect size considered as relevant and as a distinct alleviation by the concerned women. At the same time none of the studies demonstrated an estrogen-like impact on breast tissue or the mucosas of uterus and vagina, nor was any marker for increased proliferation of hormone-sensitive tissues influenced by isoflavones. This lack of hormonal effects was also explicitly observed in postmenopausal women with an increased risk of breast cancer: For this group of patients particularly stressed by the BfR there exist by now detailed clinical results from examinations lasting several years. Instead of a risk these examinations rather indicate protective effects of isoflavones.
At the end of the symposium the contributing scientists came to an unanimous conclusion: Based on the data by now available there can be no more doubt regarding long-term safety and health benefits of isoflavones. The artificial separation in “good” foodstuffs and “dangerous” extracts or even isolates is not supported by the multitude of clinical and experimental data by now covering the whole range of topics from questions of absorption, distribution, metabolism and excretion, via receptor effects, down to detailed clinical evaluations of desired and undesired effects. The data is congruent to experience from epidemiological examinations. The valuable database from hundreds of thousands of applications can and must therefore fully enter the risk-benefit analysis. From the part of the participating toxicologists there was no contradiction to these conclusions.
Whether the EFSA assessment panel will likewise follow this view remains to be seen. As a matter of fact, the composition of the panel may cause some doubts regarding the independence of the decision to be taken: the German BfR, which has made very clear that they are strongly opposed against isoflavone use in menopausal women, has a delegate in the EFSA risk assessment panel. Thus, the decision will be influenced by delegates who already before have turned a blind eye to the existing clinical evidence in order to hold up their extrapolation of hypothetical risks from experimental data.
Further reports from the Milan 2009 Soy Safety Symposium:
1. Plant “hormones”: Guilty by association with estrogens? International Symposium in Milan on the safety and efficacy of soy
2. Facts Related to Bioavailability
3. Lack of relevance of animal models for an extrapolation of risks of isoflavones
4. Isoflavones protect „menopausal” mice from breast cancer
5. Breast cancer risk is increased by synthetic gestagens
6. Breast tissue density remains unaltered with soy
7. Clinical studies demonstrate safety of soy in the breast
8. Study in more than 5,000 breast cancer patients: First positive tendencies with soy!
9. No effects of isoflavones on the endometrium
10. Isoflavones also safe at the thyroid gland
11. Backgrounds on Menopausal Hot Flushes
12. Clinical safety of isoflavone-containing preparations
13. Clinical effects of isoflavones against menopausal hot flushes
References
Anon. (2007). Isolierte Isoflavone in Nahrungsergänzungsmitteln und bilanzierten Diäten. Gesundheitliche Bewertung des BfR vom 30 11 2007.
EFSA (2009a). Opinion on the safety of "Alfalfa concentrate as food". Scientific opinion of the panel on dietetic products, nutrition and allergies. Parma: European Food Safety Authority.
EFSA (2009b). The use of dietary isoflavones and isolated isoflavones from soy or red clover in food and food supplements. Parma: European Food Safety Authority (EFSA).
Jacobs M (2009). The mandate for the EFSA scientific cooperation (ESCO) working group on the use of dietary isoflavones and isolated isoflavones from soy or red clover in food and food supplements: Potenzial hazards and health benefits. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.
Kurzer MS (2008). Soy Consumption for Reduction of Menopausal Symptoms. Inflammopharmacology 16:1-3.
Sannia A (2009). Goals and objectives of the symposium. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.
Somogyi A (2009). Evaluating isoflavone efficacy and safety from a policy perspective. Symposium on Evaluating the Efficacy and Safety of Isoflavones for Postmenopausal Women, 13-14 May. Milan (Italy): Council for Responsible Nutrition.
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