Scientists Protest Soy Approval In Unusual Letter, FDA Experts Lay Out Concerns

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Scientists Protest Soy Approval In Unusual Letter, FDA Experts Lay Out

Concerns

 

 

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609_soyfdaletter_feature.html

 

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., Estrogen Base Program

Division of Genetic and Reproductive Toxicology

and

Daniel R. Doerge, Ph.D.

Division of Biochemical Toxicology

 

February 18, 1999

 

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 fi-om 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

Iatencies, 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.

Finally, NCTR is currently conducting a long-term multigeneration study

of genistein administered in feed to rats. The analysis of the dose

range-finding studies are near-complete or complete now. As preliminary

data, which is still confidential, maybe relevant to your decision, I

suggest you contact Dr. Barry Delclos at the address on the letterhead, or

email him.

 

Sincerely,

Daniel M. Sheehan

Daniel R. Doerge

 

Enclosures

cc: Dr. Bernard Schwetz, Director, NCTR

Dr. Barry Delclos

 

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Chorazy, P.A., Himelhoch, S., Hopwood, N, J., Greger, N. G., and Postellon,

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Divi, R. L., Chang, H. C., and Doerge, D.R. Identification, characterization

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Divi, R.L. and Doerge, D.R. Inhibition of thyroid peroxidase by dietary

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