|
|
ADM GRAS Application Letter of Opposition
from Daniel
M. Sheenan
The first
page of this document is available here.
(continued).....
consumption in human infants (cf., Van Wyk et al., 1959; Hydovitz,
1960; Shepard et al., 1960; Pinchera et al., 1965; Chorazy et al.,
1995) and adults (McCarrison, 1933; Ishizaki, 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 autoimmune 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 thyroid
findings in infants receiving soy formula are a result of serum levels
of isoflavones 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 in humans or
primates. As all estrogens which have been studied carefully in human
populations are two-edged swords in humans (REF), 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
disease prevalence in the Hawaii 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, 1 996b). 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 ‘hat 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, 1998), 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, 1998)
Taken
together, the findings presented here are self-consistent and
demonstrate that genistein and other isoflavones 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
(REF). As the benefits are not under consideration, the addition of
isoflavones to foods needs to considered just as would the addition of
any estrogen to foods, which is a bad idea.
Finally,
NCTR is currently conducting a long-term multigeneration study of
genistein administered in feed to rats. The dose range-finding studies
were just completed. As preliminary data, which is still confidential,
may be relevant to your decision, I suggest you contact Dr. Barry
Delclos at the address on the letterhead, call him at 870-543-7372, or
email him at <bdelclos@nctr.fda.gov>.
|
HOME
