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Read The
Natural Law Party's comments on this letter.
In
Unusual Letter, FDA Experts Lay Out Concerns
Researchers Daniel Doerge and Daniel
Sheehan, two of the Food and Drug Administration's experts
on soy, signed a letter
of protest, which points to studies that show
a link between
soy and health problems in certain animals.
The two say they tried in vain to stop the FDA approval
of soy because it could be misinterpreted as a broader general
endorsement beyond benefits for the heart. The text of the
letter follows.
Department of Health and Human Services
Public Health Service
Food and Drug Administration
National Center For Toxicological Research
Jefferson, Ark. 72079-9502
Daniel M. Sheehan, Ph.D.
Director, Estrogen Base Program
Division of Genetic and Reproductive Toxicology
and Daniel R. Doerge, Ph.D.
Division of Biochemical Toxicology
Dockets Management Branch (HFA-305)
Food and Drug Administration
Rockville, MD 20852
To whom it may concern,
We are writing in reference to Docket
# 98P-0683; "Food Labeling: Health Claims; Soy Protein
and Coronary Heart Disease." We
oppose this health claim
because there is abundant evidence that some of the isoflavones
found in soy, including genistein and equol, a metabolize
of daidzen, demonstrate toxicity in estrogen sensitive tissues
and in the thyroid.
This is true for a number of species,
including humans. Additionally, the adverse effects in humans
occur in several tissues and, apparently, by several distinct
mechanisms.
Genistein is clearly estrogenic; it
possesses the chemical structural features necessary for
estrogenic activity (; Sheehan and Medlock, 1995; Tong,
et al, 1997; Miksicek, 1998) and induces estrogenic responses
in developing and adult animals and in adult humans.
In rodents, equol is estrogenic and
acts as an estrogenic endocrine disruptor during development
(Medlock, et al, 1995a,b). Faber and Hughes (1993) showed
alterations in LH regulation following developmental treatment
with genistein.
Thus,
during pregnancy in humans, isoflavones per se could be
a risk factor for abnormal brain and reproductive tract
development.
Furthermore, pregnant Rhesus monkeys
fed genistein had serum estradiol levels 50- 100 percent
higher than the controls in three different areas of the
maternal circulation (Harrison, et al, 1998). Given that
the Rhesus monkey is the best experimental model for humans,
and that a women's own estrogens are a very significant
risk factor for breast cancer, it
is unreasonable to approve the health claim until 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 percent
higher serum estradiol level than did the controls (Harrison,
et al, 1998). Development is recognized as the most sensitive
life stage for estrogen toxicity because of the indisputable
evidence of a very wide variety of frank malformations and
serious functional deficits in experimental animals and
humans.
In the human population, DES exposure
stands as a prime example of adverse estrogenic effects
during development. About 50 percent of the female offspring
and a smaller fraction of male offspring displayed one or
more malformations in the reproductive tract, as well as
a lower prevalence (about 1 in a thousand) of malignancies.
In adults, genistein could be a risk factor for a number
of estrogen-associated diseases.
Even without the evidence of elevated
serum estradiol levels in Rhesus fetuses, potency and dose
differences between DES and the
soy isoflavones do not provide any assurance that the soy
protein isoflavones per se will be without adverse effects.
First, calculations, based on the literature,
show that doses of soy protein isoflavones used in clinical
trials which demonstrated estrogenic effects were as potent
as low but active doses of DES in Rhesus monkeys (Sheehan,
unpublished data).
Second, we have recently shown that
estradiol shows no threshold in an extremely large dose-response
experiment (Sheehan, et al, 1999), and we subsequently have
found 31 dose-response curves for hormone-mimicking chemicals
that also fail to show a threshold (Sheehan, 1998a).
Our conclusions are that no
dose is without risk; the extent of risk is simply
a function of dose. These two features support and extend
the conclusion that it is inappropriate to allow health
claims for soy protein isolate.
Additionally, isoflavones are inhibitors
of the thyroid peroxidase which makes T3 and T4. Inhibition
can be expected to generate thyroid abnormalities, including
goiter and autoimmune thyroiditis. There exists a significant
body of animal data that demonstrates goitrogenic and even
carcinogenic effects of soy products (cf., Kimura et al.,
1976).
Moreover, there are significant reports
of goitrogenic effects from soy consumption in human infants
(cf., Van Wyk et al., 1959; Hydovitz, 1960; Shepard et al.,
1960; Pinchers et al., 1965; Chorazy et al., 1995) and adults
(McCarrison, 1933; Ishizuki, et al., 1991).
Recently, we have identified genistein
and daidzein as the goitrogenic isoflavonoid components
of soy and defined the mechanisms for inhibition of thyroid
peroxidase (TPO)-catalyzed thyroid hormone synthesis in
vitro (Divi et al., 1997; Divi et al., 1996).
The observed suicide inactivation of
TPO by isoflavones, through covalent binding to TPO, raises
the possibility of neoantigen formation and because anti-TPO
is the principal autoantibody present in auto immune thyroid
disease. This hypothetical mechanism is consistent with
the reports of Fort et al. (1986, 1990) of a
doubling of risk for autoimmune thyroiditis in children
who had received soy formulas as infants compared
to infants receiving other forms of milk.
The serum levels of isoflavones in infants
receiving soy formula that are about five times higher than
in women receiving soy supplements who show menstrual cycle
disturbances, including an increased estradiol level in
the follicular phase (Setchell, et al, 1997). Assuming a
dose-dependent risk, it is unreasonable to assert that the
infant findings are irrelevant to adults who may consume
smaller amounts of isoflavones.
Additionally, while there is an unambiguous
biological effect on menstrual cycle length (Cassidy, et
al, 1994), it is unclear whether the soy effects are beneficial
or adverse. Furthermore, we need to be concerned about transplacental
passage of isoflavones as the DES case has shown us that
estrogens can pass the placenta. No such studies have been
conducted with genistein in humans or primates.
As all estrogens which have been studied
carefully in human populations are two-edged swords in humans
(Sheehan and Medlock, 1995; Sheehan, 1997), with both beneficial
and adverse effects resulting from the administration of
the same estrogen, it is likely that the same characteristic
is shared by the isoflavones. The animal data is also consistent
with adverse effects in humans.
Finally, initial data from a robust
(7,000 men) long-term (30+ years) prospective epidemiological
study in Hawaii showed that Alzheimer's disease prevalence
in Hawaiian men was similar to European-ancestry Americans
and to Japanese (White, et al, 1996a). In contrast, vascular
dementia prevalence is similar in Hawaii and Japan and both
are higher than in European-ancestry Americans.
This suggests that common ancestry or
environmental factors in Japan and Hawaii are responsible
for the higher prevalence of vascular dementia in these
locations. Subsequently, this
same group showed a significant dose-dependent risk (up
to 2.4 fold) for development of vascular dementia and brain
atrophy from consumption of tofu, a soy product rich in
isoflavones (White, et al, 1996b).
This finding is consistent with the
environmental causation suggested from the earlier analysis,
and provides evidence that soy (tofu) phytoestrogens causes
vascular dementia.
Given that estrogens are important for
maintenance of brain function in women; that the male brain
contains aromatase, the enzyme that converts testosterone
to estradiol; and that isoflavones inhibit this enzymatic
activity (Irvine, 1998), there is a mechanistic basis for
the human findings. Given the great difficulty in discerning
the relationship between exposures and long latency adverse
effects in the human population (Sheehan, 1998b), and the
potential mechanistic explanation for the epidemiological
findings, this is an important study.
It is one of the more robust, well-designed
prospective epidemiological studies generally available.
We rarely have such power in human studies, as well as a
potential mechanism, and thus the results should be interpreted
in this context.
Does the Asian experience provide us
with reassurance that isoflavones are safe? A review of
several examples lead to the conclusion "Given the
parallels with herbal medicines with respect to attitudes,
monitoring deficiencies, and the general difficulty of detecting
toxicities with long latencies, I
am unconvinced that the long history of apparent safe use
of soy products can provide confidence that they are indeed
without risk." (Sheehan, 1998b).
It should also be noted that the claim
on p. 62978 that soy protein foods are GRAS is in conflict
with the recent return by CFSAN to Archer Daniels Midland
of a petition for GRAS status for soy protein because of
deficiencies in reporting adverse effects in the petition.
Thus GRAS status has not been granted. Linda Kahl can provide
you with details. It would seem appropriate for FDA to speak
with a single voice regarding soy protein isolate.
Taken together, the findings presented
here are self-consistent and demonstrate that genistein
and other isoflavones can have adverse effects in a variety
of species, including humans. Animal studies are the front
line in evaluating toxicity, as they predict, with good
accuracy, adverse effects in humans.
For the 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 assumed to 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 labeling of soy protein isolate for foods needs to
considered just as would the addition of any estrogen or
goitrogen to foods, which are bad ideas.
Estrogenic and goitrogenic drugs are
regulated by FDA, and are taken under a physician's care.
Patients are informed of risks, and are monitored by their
physicians for evidence of toxicity. There are no similar
safeguards in place for foods, so the public will be put
at potential risk from soy isoflavones in soy protein isolate
without adequate warning and information.
Sincerely,
Daniel M. Sheehan
Daniel R. Doerge
ABC
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