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SCIENTISTS PROTEST FDA'S SOY PROTEIN RULING
Our publication of "Tragedy and Hype", an article by Sally Public Health Service Food and Drug Administration Fallon and Mary Enig on the politics and health implica- National Center For Toxicological Research tions of soy products (see NEXUS 7/03, April–May 2000), had quite an impact on readers, particularly those who had beenconsuming soy for many years without realising that it was related The article mentioned the work of Daniel Sheehan, PhD, and Division of Genetic and Reproductive Toxicology Daniel Doerge, PhD, from the US Food and Drug Administration's National Center for Toxicological Research, who wrote a protest letter ahead of a new FDA ruling "authorizing the use, on food labels and in food labeling, of health claims on theassociation between soy protein and reduced risk of coronary heart disease (CHD)". The FDA had come to the conclusion that"soy protein included in a diet low in saturated fat and cholesterol may reduce the risk of CHD by lowering blood cholesterol lev- els". However, the FDA disregarded contradictory evidence, and the new ruling came into effect on 26 October 1999. Drs Sheehan and Doerge were interviewed for the ABC's 20/20 program in the US, broadcast on 9 June and since screened widely We are writing in reference to Docket #98P-0683; "Food around the world. The program looked at the controversy over Labeling: Health Claims; Soy Protein and Coronary Heart the safety of soy products as a healthy source of protein, focusing Disease". We oppose this health claim because there is abun- on the relationship between soy and breast cancer in women, dant evidence that some of the isoflavones found in soy, accelerated brain ageing in men and developmental disorders in including genistein and equol, a metabolize of daidzein, infants. The two researchers told 20/20 that they had tried in vain demonstrate toxicity in estrogen-sensitive tissues and in the to stop the FDA's recommendation because it could be misinter- thyroid. This is true for a number of species, including preted as a broader general endorsement beyond solely having humans. Additionally, the adverse effects in humans occur in benefits for the heart. (For program summary, see http://abc- several tissues and, apparently, by several distinct mechanisms.
news.go.com/onair/2020/2020_000609_soy_feature.html.) Genistein is clearly estrogenic; it possesses the chemical The following is the text of their letter dated 18 February 1999.
structural features necessary for estrogenic activity (Sheehan (Please note that while it does refer to a number of studies involv- and Medlock, 1995; Tong et al., 1997; Miksicek, 1998) and ing animals, we would like to make it clear that NEXUS in no induces estrogenic responses in developing and adult animals way condones or supports the efficacy, validity or morality of ani- and in adult humans. In rodents, equol is estrogenic and acts as an estrogenic endocrine disrupter during development (Medlock et al., 1995a,b). Faber and Hughes (1993) showedalterations in LH regulation following developmental treatmentwith genistein. Thus, during pregnancy in humans, isoflavonesper se could be a risk factor for abnormal brain and reproduc-tive tract development. Furthermore, pregnant rhesus mon-keys fed genistein had serum estradiol levels 50–100 per centhigher than the controls in three different areas of the maternalcirculation (Harrison et al., 1998). Given that the rhesus mon-key is the best experimental model for humans, and that awoman's own estrogens are a very significant risk factor forbreast cancer, it is unreasonable to approve the health claimuntil complete safety studies of soy protein are conducted. Of equally grave concern is the finding that the fetuses of genistein-fed monkeys had a 70 per cent higher serumestradiol level than did the controls (Harrison et al., 1998).
Development is recognized as the most sensitive life-stage forestrogen toxicity because of the indisputable evidence of avery wide variety of frank malformations and seriousfunctional deficits in experimental animals and humans. In thehuman population, DES exposure stands as a prime exampleof adverse estrogenic effects during development. About 50per cent of the female offspring and a smaller fraction of maleoffspring displayed one or more malformations in thereproductive tract, as well as a lower prevalence (about one ina thousand) of malignancies. In adults, genistein could be a NEXUS • 11
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risk factor for a number of estrogen-associated diseases.
menstrual cycle length (Cassidy et al., 1994), it is unclear Even without the evidence of elevated serum estradiol levels whether the soy effects are beneficial or adverse. Furthermore, in rhesus fetuses, potency and dose differences between DES we need to be concerned about transplacental passage of and the soy isoflavones do not provide any assurance that the isoflavones, as the DES case has shown us that estrogens can soy protein isoflavones per se will be without adverse effects.
pass the placenta. No such studies have been conducted with First, calculations based on the literature show that doses of genistein in humans or primates. As all estrogens which have soy protein isoflavones used in clinical trials which demon- been studied carefully in human populations are two-edged strated estrogenic effects were as potent as low but active doses swords in humans (Sheehan and Medlock, 1995; Sheehan, of DES in rhesus monkeys (Sheehan, unpublished data).
1997), with both beneficial and adverse effects resulting from Second, we have recently shown that estradiol shows no the administration of the same estrogen, it is likely that the same threshold in an extremely large dose-response experiment characteristic is shared by the isoflavones. The animal data is (Sheehan et al., 1999), and we subsequently have found 31 also consistent with adverse effects in humans.
dose-response curves for hormone-mimicking chemicals that Finally, initial data from a robust (7,000 men), long-term is without risk; the extent of risk is simply a function of dose. These two features sup- port and extend the conclusion that it is and to Japanese (White et al., 1996a). In contrast, vascular dementia prevalence is Subsequently,
this same group
showed a significant
ancestry or environmental factors in Japan generate thyroid abnormalities, including dose-dependent risk
and Hawaii are responsible for the higher (up to 2.4-fold)
for development of
vascular dementia and
brain atrophy from
consumption of tofu,
a soy product rich
in isoflavones.
alyzed thyroid hormone synthesis i n vitro (Divi et al., 1997; Divi et al., 1996). The observed suicide enzymatic activity (Irvine, 1998), there is a mechanistic basis inactivation of TPO by isoflavones, through covalent binding to for the human findings. Given the great difficulty in discerning TPO, raises the possibility of neoantigen formation and the relationship between exposures and long-latency adverse because anti-TPO is the principal autoantibody present in effects in the human population (Sheehan, 1998b) and the autoimmune thyroid disease. This hypothetical mechanism is potential mechanistic explanation for the epidemiological consistent with the reports of Fort et al. (1986, 1990) of a dou- findings, this is an important study. It is one of the more bling of risk for autoimmune thyroiditis in children who had robust, well-designed prospective epidemiological studies received soy formulas as infants compared to infants receiving generally available. We rarely have such power in human studies, as well as a potential mechanism, and thus the results The serum levels of isoflavones in infants receiving soy formula are about five times higher than in women receiving Does the Asian experience provide us with reassurance that soy supplements who show menstrual cycle disturbances isoflavones are safe? A review of several examples led to the including an increased estradiol level in the follicular phase conclusion, "Given the parallels with herbal medicines with (Setchell, et al., 1997). Assuming a dose-dependent risk, it is respect to attitudes, monitoring deficiencies and the general unreasonable to assert that the infant findings are irrelevant to difficulty of detecting toxicities with long latencies, I am adults who may consume smaller amounts of isoflavones.
unconvinced that the long history of apparent safe use of soy Additionally, while there is an unambiguous biological effect on products can provide confidence that they are indeed without 12 • NEXUS
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risk" (Sheehan, 1998b). It should also be noted that the claim labeling of soy protein isolate for foods needs to be considered on p. 62978 that soy protein foods are GRAS [Generally just as would the addition of any estrogen or goitrogen to foods, Recognized As Safe] is in conflict with the recent return by CFSAN [Center for Food Safety and Applied Nutrition, FDA] to Estrogenic and goitrogenic drugs are regulated by FDA, and Archer Daniels Midland of a petition for GRAS status for soy are taken under a physician's care. Patients are informed of protein because of deficiencies in reporting adverse effects in risks, and are monitored by their physicians for evidence of the petition. Thus GRAS status has not been granted. Linda toxicity. There are no similar safeguards in place for foods, so Kahl can provide you with details. It would seem appropriate the public will be put at potential risk from soy isoflavones in for FDA to speak with a single voice regarding soy protein soy protein isolate without adequate warning and information.
Finally, NCTR is currently conducting a long-term multigen- Taken together, the findings presented here are self-consistent eration study of genistein administered in feed to rats. The and demonstrate that genistein and other isoflavones can have analysis of the dose-range-finding studies are near-complete or adverse effects in a variety of species, including humans.
complete now. As preliminary data, which is still confidential, Animal studies are the front line in evaluating toxicity as they may be relevant to your decision, I suggest you contact Dr predict, with good accuracy, adverse effects in humans. For the Barry Delclos at the address on the letterhead, or e-mail him.
isoflavones, we additionally have evidence of two types of adverse effects in humans, despite the very few studies that have addressed this subject. While isoflavones may have beneficial effects at some ages or circumstances, this cannot be assumedto be true at all ages. Isoflavones are like other estrogens in that they are two-edged swords, conferring both benefits and risk (Sheehan and Medlock, 1995; Sheehan, 1997). The health References
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in isoflavones on the menstrual cycle of pre- of soybeans administered experimentally to • Sheehan, D.M., "Isoflavone content of breast menopausal women", Am. J. Clin. Nutr. 60:333- healthy subjects", Nippon Naibunpi gakkai milk and soy formulas: Benefits and risks", • Chorazy, P.A., Himelhoch, S., Hopwood, N.J., • Kimura, S., Suwa, J., Ito, B. and Sate, H., • Sheehan, D.M. and Medlock, K.L., "Current Greger, N.G. and Postellon, D.C., "Persistent "Development of malignant goiter by defatted issues regarding phytoestrogens", Polyphenols hypothyroidism in an infant receiving a soy for- soybean with iodine-free diet in rats", Gann. mula: Case report and review of the literature", • Sheehan, D. M., Willingham, E., Gaylor, D., • Levy, J.R., Faber, F.A., Ayyash, L. and Bergeron, J. M. and Crews, D., "No threshold • Divi, R.L., Chang, H.C. and Doerge, D.R., Hughes, C.L., "The effect of prenatal exposure dose for oestradiol-induced sex reversal of tur- "Identification, characterization and mecha- to phytoestrogen genistein on sexual differentia- tle embryos: How little is too much?" nisms of anti-thyroid activity of isoflavones tion in rats", Proc. Soc. Exp. Biol. Med. 208:60- Environmental Health Perspectives, February from soybean", Biochem. Pharmacol. 54:1087- • McCarrison, R.,"The goitrogenic action of • Shepard, T.H., Pyne, G.E., Kirschvink, J.F.
• Divi, R.L. and Doerge, D.R., "Inhibition of soybean and groundnut", Indian J. Med. Res. and McLean, C.M., "Soybean goiter", New Eng. thyroid peroxidase by dietary flavonoids", Chem. Res. Toxicol. 9:16-23, 1996.
• Medlock, K.L., Branham, W.S. and Sheehan, • Tong, W., Perkins, R., Xing, L., Welsh, W.J.
• Fort, P., Lanes, R., Dahlem, S., Reeker, B., D.M., "The effects of phytoestrogens on neona- and Sheehan, D.M., "QSAR models for binding Weyman-Daum, M., Pugliese, M. and Lifshitz, tal rat uterine growth and development", Proc. of estrogenic compounds to estrogen receptor F., "Breast feeding and insulin-dependent dia- Soc. Exp. Biol. Med. 208:307-313, 1995.
alpha and beta subtypes", Endo. 138:4022- betes mellitus in children", J. Am. Coll. Nutr. • Medlock, K.L., Branham, W.S. and Sheehan, D.M., "Effects of coumestrol and equol on the • Van Wyk, J.J., Arnold, M.B., Wynn, J. and • Fort, P., Moses, N., Fasano, M., Goldberg, T.
developing reproductive tract of the rat", Proc. Pepper, F., "The effects of a soybean product on and Lifshitz, F., "Breast and soy-formula feed- Soc. Exp. Biol. Med. 208:67-1, 1995. thyroid function in humans", Pediatrics 24:752- ings in early infancy and the prevalence of • Miksicek, R.J., "Estrogenic flavonoids: autoimmune thyroid disease in children", J. Am. Structural requirements for biological activity", • White, L., Petrovitch, H., Ross, G.W. and Proc. Soc. Exp. Biol. Med. 208:44-50, 1995.
Masaki, K.H., "Association of mid-life con- • Harrison, R.M., Phillippi, P.P. and Henson, • Pinchers, A., MacGillivray, M.H., Crawford, sumption of tofu with late life cognitive impair- M.C., "Effects of genistein on estradiol produc- J.D. and Freeman, A.G., "Thyroid refractoriness ment and dementia: The Honolulu-Asia Aging tion in pregnant rhesus monkeys (Macaca in an athyreotic cretin fed soybean formula", Study", The Neurobiol. of Aging 17(suppl.
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• Hydovitz, J.D., "Occurrence of goiter in an • Setchell, K.D.R., Zimmer-Nechemias, L., Cai, • White, L., Petrovich, H., Ross, G.W., Masaki, infant on a soy diet", New Eng. J. Med. J. and Heubi, J.E., "Exposure of infants to K.H., Abbot, R.D., Teng, E.L., Rodriguez, B.L., phytoestrogens from soy-based infant formula", Blanchette, P.L., Havlik, R.J., Wergowske, G., • Irvine, C.H.G., Fitzpatrick, M.G. and Chiu, D., Foley, D.J., Murdaugh, C. and Curb, Alexander, S.L., "Phytoestrogens in soy-based • Sheehan, D.M., "Literature analysis of no- J.D., "Prevalence of dementia in older infant foods: Concentrations, daily intake, and threshold dose-response curves for endocrine Japanese–American men in Hawaii", JAMA possible biological effects", Proc. Soc. Exp. disrupters", Teratology 57:219, 1998a.
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