d e B r i e f i n g s 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.
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 d e B r i e f i n g s
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
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 nvitro (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 d e B r i e f i n g s
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
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NEXUS • 13
authors stated that there was no scalp numbness afterthey injected their solutions which contained Xylocaı¨neÒWith great interest we have read the article: ÔSuboccip-2% 0.5 ml. This could indicate that the injection site wasital injection with a mixture of rapid- and long-actingnot close enough to the greater occipital nerve or theysteroids in cluster headache: A double-blind placebo-
Opúsculo informativo para el solicitante del status de refugiado 1. ¿EN CUALES CASOS PUEDO PEDIR EL RECONOCIMIENTO Italia, por la ley 30 julio 2002 n. 189, se ha dado nueva normativa en cuestión de inmigración y asilo. En particular, en cuestión del asilo, el art. 32 de esa ley, y relativo reglamento de actuación (D.P.R. 16/09/2004 n. 303), han establecido nueva disposición para el