Shellee Anderson

Team Leader, Nutrition Policy

Division of Dockets Management

Food and Drug Administration

5630 Fishers Lane, Room 1061 (A-305)

Rockville, MD 20852

June 14, 2004

**Docket \# 2004Q-0151 Solae Company Health Claim re Cancer**

Dear Ms. Anderson:

Please consider the attached information as you evaluate the petition
filed by the Solae Company regarding a health claim for
soy-protein-containing products and a reduced risk of certain cancers.

The petitioner Solae contends that its data is "based on the totality of
publicly available scientific evidence" when, in fact, their evidence
represents a very small portion of the available published studies. We
find that the petitioners were highly selective in their choice of
evidence and in their commentary, omitting many studies that show soy to
be ineffective as a cancer prevention agent, emphasizing favorable
outcomes in studies where results were mixed, and providing excuses for
results of the few unfavorable studies that they included to give the
illusion of balance. Solae states that "to the best of the knowledge of
the undersigned, this petition is a representative and balanced
submission" although it omitted all mention of the many well-designed
studies that have suggested that soy protein can contribute to, cause
and accelerate the growth of cancer.

The petitioner Solae contends that their data "establish that there is
scientific agreement among experts qualified by scientific training and
experience to evaluate such claims regarding the relationship between
soy protein products and a reduced risk of certain cancers." In fact, no
such consensus exists, and numerous experts qualified by scientific
training and experience \-- including scientists from the FDA's own
National Laboratory for Toxicological Research \-- have warned of soy
protein's carcinogenic potential and of the health dangers of excess
soy-food consumption. We are further concerned because the petitioner
fails to consider soy protein's well-documented risks to the digestive,
immune and neuroendocrine systems of the body as well as its high
allergenicity.

We have attached a response to Solae's petition to this letter for your
consideration. We have included an extended commentary, summaries of
important journal articles, quotations from qualified researchers and
complete references to publicly available studies, all of which raise
questions about or disprove the validity of the proposed health claim.

We maintain that the benefits cited by Solae are putative, not proven,
and that longstanding concerns in the scientific community about soy's
possible role in carcinogenesis need to be addressed. In the interest of
public safety, we therefore request that the Solae petition be declined
and the health claim be denied.

Sincerely,

Sally Fallon, President

The Weston A. Price Foundation

\(202\) 333-4801

westonaprice@msn.com

safallon@aol.com

Kaayla T. Daniel, PhD, CCN

wholenutritionist@earthlink.net

\(515\) 982-0887

William Sanda, Director of Public Affairs

The Weston A. Price Foundation

\(703\) 823-3153

bsanda@verizon.net

A. PRELIMINARY REQUIREMENTS

A 1 Solae provides basic information about the amount of soy protein in
various soyfoods and states that "soy products contain other nutrients
such as carbohydrates, vitamins and minerals, as well as naturally
occurring constituents such as fibers, isoflavones and saponins." It
neglects to mention here that isoflavones are listed as "carcinogens" in
the American Chemical Society's 1976 textbook *Chemical Carcinogens* as
well as other toxicology textbooks and that saponins have traditionally
been considered antinutrients.

Solae also does not mention that soy protein contains many other
constituents that have traditionally been considered antinutrients or
toxins. These include protease inhibitors (most notably trypsin
inhibitors), phytates, lectins, oxalates and oligosaccharides, which may
possess valuable pharmaceutical properties but which have also been
linked in more than 100 studies to digestive distress, intestinal
disorders, mineral deficiencies, flatulence and even cancer development
and growth.

Finally, Solae fails to note that genetically modified soybeans have not
been proven to be "substantially equivalent" to regular soybeans and
that safety issues have not been properly addressed. Yet soy foods made
with both GM and regular soybeans would be eligible for the proposed
health claim.

\* \* \* \* \*

In its discussion of types of soy foods, Solae states: 'Historically
soybean curd and soymilk have been viewed as "traditional" Asian foods.
This is only partially true. While tofu dates back to 164 BC, soy milk
has a much more recent history in Asia. The earliest historical
reference to soy milk as a beverage appears in 1866. *Chinese Medical
Journal* articles from the 1930s report that soy milk was not
traditional but had become popular as an occasional drink served to the
elderly by the 1920s and 1930s. Dr. Harry Miller, an American--born
Seventh Day Adventist physician and missionary, was the person in China
to invent a commercially feasible method to manufacture soy milk. Dr.
Miller also found out that soy milk was not traditional in Japan and in
1959 wrote an article for *Soybean Digest* entitled "Why Japan Needs Soy
Milk." Furthermore, soy milks in today's marketplace bear little
relationship to those made in Asia, for they are often made with soy
protein isolate and other non-traditional ingredients.

SOURCES

Shurtleff, William. Chronology of soymilk worldwide: Part 1, 220AD to
1949. Special Exhibit, Museum of Soy, 2001. Soyfoods Center, Lafayette,
CA.

Guy RA. The diets of nursing mothers and young children in Peiping.
*Chinese Med J,* 1936, 50, 434-442.

Guy RA, Yeh KS. Soybean 'milk' as a food for young infants. *Chinese Med
J,* 1938, 54, 1, 1-30.

Miller HW, Wen CJ. Experimental studies of soymilk in human nutrition.
*Chinese Med J,* 1936, 50, 4, 450-459.

Miller Harry W. Why Japan needs soymilk. *Soybean Digest*, April 1959,
16-17.

A1 b

::: Definition-Term
Although Solae claims that soy protein is "safe and lawful," it concedes
that soy protein isolate has never actually received GRAS (Generally
Recognized as Safe) status as an additive to food. Soy protein was
rejected for such status as late as 1999 when a petition submitted by
Archer Daniel s Midland for GRAS status for soy protein was returned by
CFSAN because of a failure to properly report adverse effects. The
petitioner also fails to note that unlike most GRAS substances in use
prior to 1958, soy protein isolate was not originally developed as a
food but as an industrial product to bind and seal paper products. It
therefore does not qualify as a product having a long history of safe
use in the food supply. More seriously, soy protein isolate is known to
include a number of toxins and carcinogens introduced by the high
temperatures, high pressures and chemicals used in its manufacture. In
1979, the Select Committee of GRAS Substances (SCOGS) examined safety
issues pertaining to the manufacture of soy protein isolate and
recommended that acceptable levels of the carcinogens nitrite and
nitrosamines and the toxic amino acid lysinoalanine be established "to
avoid future problems." To this date, safe levels have never been
established and levels of these substances in edible food products are
not closely monitored. The SCOGS committee determined that 150 mg per
day of soy protein was the maximum safe dose, an amount far less than
the 4.48 grams that is likely to be consumed by the average American
should Solae succeed in obtaining a soy protein and cancer health claim.
Solae claims that such "intakes are reasonable and present no safety
concerns."
:::

::: Definition-Term
SOURCES
:::

::: Definition-Term
Evaluation of the Health Aspects of Soy Protein Isolates as Food
Ingredients. Prepared by Life Sciences Research Office, Federation of
American Societies for Experimental Biology for the Bureau of Foods,
Food and Drug Administration, 1979. Contract \# FDA 223-75-2004.
:::

::: Definition-Term
Sheehan DM, Doerge DR. Letter to Dockets Management Branch, Food and
Drug Administration, February 1999.
:::

The SCOGS committee's recommendation of 150 mg of soy protein isolate
per day as a "safe dose" is far lower than Solae's estimate of per
capita consumption We maintain that soy protein at the higher intake
levels projected by Solae would present serious safety concerns, with
the biggest risk to people who are allergic to soy.

Soy is widely acknowledged as one of the top eight allergens, with one
prominent researcher putting soy in the "top six" and another in the
"top four." The increased soy protein in the food supply would not only
be found in well-known soyfoods such as tofu, soy milk and veggie
burgers -- foods that allergy sufferers know enough to avoid \-- but
also from soy proteins incorporated into the recipes for baked goods,
canned, packaged and other processed foods. This "hidden" soy poses a
danger to allergy sufferers, who may experience symptoms that range from
mild to life threatening, involving, the gastrointestinal, cutaneous and
respiratory systems. A recent Swedish study reported four fatalities as
the result of soy protein hidden in foods such as hamburgers.
Furthermore, allergy experts have warned that the increased use of soy
protein in food products is increasing the potential for sensitization.

S**OURCES:**

FAO Food Allergies Report of the Technical Consultation of the Food and
Agricultural Organization of the United Nations, Rome, November 13-14,
1995.

Besler, Matthias Allergen Data Collection: Soybean (Glycine max),
*Internet Symposium on Food Allergens* 1999, 1, 2, 51-79.
[www.food-allergens.de](http://www.food-allergens.de/)

Bousquet J, Bjorksten B et al. Scientific criteria and selection of
allergenic foods for labeling. *Allergy*, 1998, 53 (Suppl 47) 3-21.

Burks AW, Brooks JR, Sampson HA. Allergenicity of major component
proteins of soybean determined by enzyme-linked immunosorbent assay
(ELISA) and immunoblotting in children with atopic dermatitis and
positive soy challenges*. J Allergy Clin Immunol,* 1988, 81, 1135-1142.

Burks AW, Williams LW et al. Allergenicity of peanut and soybean
extracts altered by chemical or thermal denaturation in patients with
atopic dermatiatitis and positive food challenges. *J. Allergy Clin
Immunol*, 1992, 90 (6 pt 1), 889-897.

Sampson HA, McCaskill CM. Food hypersensitivity and atopic dermatitis:
evaluation of 113 pateints. J Ped. 1985, 107, 669. Documented soy
protein to be one of the major food antigens, wich inclueddes milk,
peanut, wheat, egg and fish.

Foucard T, Malmheden-Yman I. A study on severe food reactions in Sweden
-- is soy protein an underestimated cause of food anaphylaxis.
*Allergy,* 1999, 53, 3, 261-265.

[]{.mark}

[]{.mark}

We are also concerned that a claim that soy protein reduces cancer would
encourage many health conscious consumers to eat far more soy protein
than Solae's projected average of 4.48 g per day. People at special risk
are vegetarians and vegans who choose soy as their main source of
protein, individuals trying to prevent or reverse cancer and other
diseases, and those at risk for or afflicted with thyroid disease. The
Working Group of the British Committee on Toxicology (COT) recently
"identified individuals with hypothyroidism as a subgroup of potential
concern," noting that a "soy-rich diet may provide sufficient
concentrations of phytoestrogens to interfere with thyroxine replacement
therapy." Daniel Sheehan, Ph.D. and Daniel Doerge, Ph.D, of the FDA's
National Laboratory of Toxicological Research in Arkansas, have warned
that "Isoflavones are inhibitors of 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."

Solae has also not addressed the likelihood that increased genistein in
the food supply as a result of increased soy intake would have a
cumultative or exponential effect with other xenoestrogens in the
environment. Toxicologists at the Centre for Toxicology, The School of
Pharmacology at the University of London have stated that "estrogenic
agents are able to act together to produce significant effects when
combined at concentrations below their NOECs. . . Hazard assessments
that ignore the possibility of joint action of estrogenic chemicals will
almost certainly lead to significant underestimations of risk.

Later in this document, we will present a substantial number of studies
showing that soy can contribute to, cause and/or accelerate the growth
of cancer. Given the number of such studies and the strong warnings of
respected scientists, including the FDA's own Drs Sheehan and Doerge, we
find it highly disturbing that Solae would put its commercial interests
above public health and propose a cancer prevention health claim for soy
protein.

SOURCES:

Committee on Toxicology (UK) Draft Report on Phytoestrogens.
<http://www.foodstandards.gov.uk/multimedia/webpage/phytoreportworddocs>

::: Definition-Term
Silva E, Rajapakse N, Kortenkamp A. Something from "nothing' -- eight
weak estrogenic chemicals combined at concentrations below NOECs produce
significant mixture effects. *Environ Sc Technol*, 2002, 36, 8,
1751-1756.
:::

::: Definition-Term
Sheehan DM, Doerge DR. Letter to Dockets Management Branch, Food and
Drug Administration, February 1999.
:::

A2

Solae notes geographical differences in cancer morbidity and mortality,
and includes the striking fact that the death rate from breast cancer is
4-fold lower and from prostate cancer 18-fold lower in China than in the
United States. While soy may be a factor in these reduced rates, other
dietary and lifestyle factors are almost certainly involved. Certainly,
there is no direct evidence for beneficial cancer--reducing effects of
the phytoestrogens in soy protein foods. More importantly, we contend
that if the petitioners attributes decreased rates of breast, prostate
and colon cancer in Asia to soy consumption, then the same logic would
require them to blame higher rates of cancer of the esophagus, stomach,
thyroid, pancreas and liver in Asian countries on consumption of soy.
They have not done so.

Solae has also neglected to inform the FDA's examiners that proper use
of soy protein for cancer prevention requires sure knowledge of windows
of vulnerability -- or opportunity -- as found in utero, during infancy,
before puberty, during puberty, the reproductive years and beyond.
Ratther, this company proposes an indiscriminate increase in consumption
of soy protein for men, women and children with no admission of the fact
that a substance that might be helpful in one stage of the life cycle
could be harmful in another. Research to date is inconsistent and
contradictory, but leaves no doubt that the phytoestrogens in soy
protein exert their influence throughout the body in many different ways
and that they have the potential to exert adverse as well as beneficial
actions. Patricia L Whitten PhD of Emory University explains that "these
potential roles fall into three major areas: 1) estrogen agonists whose
activational actions could prove beneficial to postmenopausal women but
might be harmful to the degree that they contribute to carcinogenesis or
other adverse effects. 2) antiestrogens or antiproliferative agents that
could help to prevent estrogen-dependent carcinoma by antagonizing
estrogen action but could also contribute to infertility by suppressing
normal reproductive function and 3) developmental toxins that could
disrupt sexual differentiation by altering sex-specific patterns of
development but might also provide protection against environmental
estrogens by altering steroid response thresholds." We believe that it
is irresponsible of Solae to claim possible benefits of soy protein
without warning consumers of possible risks.

SOURCE

Whitten PL, Lewis C et al. Potential Adverse Effects of phytoestrogens.
*J Nutr,* 1995, 125, 771S-776S.

B. SCIENTIFIC EVIDENCE

B1

Solae states that "soy protein is a major source of dietary protein
worldwide." It is certainly true that soy protein consumption has been
increasing worldwide, but the claim that soy constitutes a "major source
of dietary protein" is inaccurate. In any case, high levels of soy
consumption is a recent phenomenon, the result of intense marketing
efforts by the soy industry and/or giveaways by government and
charitable organizations.

Soy foods have been a dietary component in some Asian countries for
centuries, not millennia, and are eaten there in small amounts as a
condiment, not as a staple. Furthermore, the types of soy foods eaten
traditionally in the countries of Asia are almost entirely whole soy
foods prepared by fermentation and precipitation methods, not
fractionated soy proteins produced by industrial food processing. This
difference is highly significant in that modern processing methods used
by the soy industry produce nitrosamines and other carcinogens. A recent
study from the University of Illinois at Urbana-Champaign indicates that
"highly processed soy may stimulate estrogen-dependent breast cancer."
According to Dr. Willliam Helferich, one of the study's authors, "Soy
has been correlated with low rates of breast cancer in Asian
populations, but soy foods in Asia are made from minimally processed
soybeans or defatted, toasted soy flour, which is quite different from
soy products consumed in the U.S." We include this important study later
in our section on Breast Cancer.

Solae boldly writes that "the totality of publicly available scientific
evidence supports the substance/disease relationship that consumption of
soy protein-containing foods is related to a lower risk of certain
cancers. The evidence is particularly strong in cancer of breast,
prostate and gastrointestinal tract." In fact, we will establish that
Solae has not presented "the totality" of publicly available evidence.
Nor have scientists reached a consensus regarding soy and cancer.
Indeed, many respected researchers believe that the isoflavones in soy
protein can contribute to, cause and/or accelerate the growth of cancer.

We also dispute the validity of Solae's claim that meta-analyses prove a
positive relationship between soy consumption and cancer risk.
Meta-analysts have been criticized by many in the scientific and
statistical communities for making faulty assumptions, indulging in
creative accounting and for leaving out studies that contradict or
dilute the conclusions desired. Solae has left out many such studies.

Finally, the petitioners further assert that animal studies support
their cancer claim and state that there are "39 studies available to
date." This number represents a fraction of the available studies, a
selection that Solae has weighed towards positive findings. Later in
this response, we will provide a sampling of the many animal studies
that suggest soy's ineffectiveness as a chemoprotective agent and its
possible role in carcinogenesis.

B3

B3 1 BREAST CANCER

This section of Solae's petition "considers the weight of scientific
evidence that relates dietary soy protein to the risk of breast cancer
in women" and concludes that "the totality of the publicly available
scientific evidence supports the substance/disease relationship that
consumption of soy protein-containing foods is associated with a lower
risk of breast cancer in women."

More accurately, this section presents scientific evidence suggesting
that soy protein is protective. A more comprehensive review of the
studies would reveal that the results are both inconsistent and
inconclusive. Solae does include several studies that show no effect
between soy intake and breast cancer risk but seems to have chosen them
because they were easy to dismiss for a variety of reasons. Most
seriously, Solae failed to include any studies that would substantially
undermine their premise that soy protein reduces breast cancer risk.

Later in this response we will present a number of well-designed studies
that rebut and refute Solae's position that soy is protective against
breast cancer. First, we would like to make a few points about some of
the studies cited by Solae.

**Nagata et al 2000** shows that soy protein intake is not associated
with lowered risk of breast cancer, prostate or lung cancer in Japanese
people. Soy protein was associated with a lowered risk of stomach cancer
but also with a higher risk of death from colorectal cancer. To its
credit, Solae did not omit either this study or this information. The
results, however, must not be minimized. This large-scale ecological
study resulted in statistically valid conclusions and provides strong
evidence of risk colorectal cancer from soy protein consumption. We do
not feel it is ethical to dismiss the validity of this study by rolling
it into a meta-analysis of all soy-and-cancer prevention studies.

**Key et al 1999**, a large prospective study of 34, 759 women in Japan,
found no significant association between breast cancer risk and
consumption of soy foods. Solae dismisses this study because it was
carried out in Hiroshima and Nagasaki, cities where women were exposed
to high levels of ionizing radiation because of the atomic bomb. The
fact that women consuming high levels of soy protein did not enjoy
special protection, however, is very significant. Proponents of soy
foods often claim that soy foods provide protection against the growing
numbers of carcinogens in the environment. The findings of Key et al
prove otherwise, and match the results of animal research in which
cancer was induced but soy-protein diets failed to confer protection.

**Ingram et al 1997** show that high excretion of both equol and
enterolactone were associated with a lowering of breast-cancer risk.
There were no associations with the parent phytoestrogens daidzein and
matairesinol. This suggests that metabolism of these compounds by the
gut microflora may be vitally important. If so, soy protein intake alone
would not be the most relevant factor in the lowering breast cancer
risk. In several studies Setchell and colleagues have found that some
women are equol producers and others are not. Given the fact that equol
production can be considered a marker of gastrointestinal health, this
study might support the role of a healthy gut in cancer prevention.
Recent studies -- most notably [*Journal of the American Medical
Association*](http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14970061&dopt=Abstract)
**(**February 18, 2004; 291(7):827-35)---have linked levels of breast
cancer risk to levels of antibiotic usage. Antibiotics can affect
bacteria in the intestine, which may impact the ways in which foods that
might prevent cancer are broken down in the body. Antibiotics may also
affect the body\'s immune response and response to inflammation, which
could also be related to the development of cancer Women with frequent
infections treated by antibiotics may also be generally less healthy as
those without such infections, and may therefore be more prone to the
development of breast cancer. The accompanying *JAMA* editorial noted
that the finding is particularly worrisome as exposure to antibiotics is
so prevalent, and often not necessary*. JAMA*'s editors raised the
question of whether the use of antibiotics is a risk factor for other
cancers, and point to a need for further research to address this
concern.

**Yuan et al 1995.** The researchers state their conclusion very
clearly. "Our study does not support the hypothesis that high intake of
soy protein protects against breast cancer." Women living in Shanghai
and Tianjin consumed 3.5 g/d and 2.8g/d, respectively, levels that are
approximately one-third of the average intake reported in the Shanghai
Breast Cancer Study (Dai et al 2001, Shu et al 2001). Solae comments:
"It is likely that the intake is underestimated in the Yuan study as the
study is not specifically designed to evaluate the effect of soyfoods
and soy intake ascertainment is incomplete." In fact, many researchers
have found that soy intake in many parts of China is lower than that
given in soy industry figures. Accordingly, factors other than soy need
to be looked at in connection with China's low breast cancer rate.

**Yamamoto et al 2003.** Solae points out the lack of significant
relationship between soyfoods and breast cancer here might be due to a
small number of breast cancer cases. The authors of the study state,
"possible associations between breast cancer risk and soyfoods that were
not statistically significant in our study may be detected among larger
sample sizes." This is speculation, and cannot properly be used in
defense of a soy protein/cancer reduction health claim.

**Wu et al 1996** indicate that the risk of breast cancer decreases
significantly with increased tofu intake, but that there is a lack of
statistical significance in postmenopausal women. Solae comments: "This
appears to be solely an effect of the larger number of premenopausal
than postmenopausal women since the magnitudes of effects are very
similar." However, the researchers found "the association was only
significant in women born in Asia and not among women of Asian origin
born in the US," suggesting the presence of other dietary and lifestyle
factors.

**Hakkak R, Korourian S et al.** Solae notes that "feeding rats a diet
containing 20% ISP for two generations significantly decreases tumor
incidence and increases tumor latency period in F2 offspring compared
with the controls fed a casein-based diet." The study, however,
indicates that both whey and SPI caused a reduction in tumour number and
increased tumour latency in both the F1 and F2 generations compared to
controls. Animals receiving whey exhibited a reduction in tumour
incidence but only animals in the subsequent generation fed SPI had a
reduced tumour incidence.

Solae also omits mention of Hakkak's finding of a 1-day advance in
vaginal opening observed in the animals fed soy protein isolate compared
to those fed whey or control. This is evidence of premature sexual
maturation and suggests that increased soy in the food supply could put
young girls at increased risk for precocious puberty, itself a
well-known risk factor for breast cancer.

**den Tonkelaar I, Keinan-Boker L et al.** Solae states "A high urinary
genistein is associated with a lower risk breast cancer in this study
population, although results are not statistically significant." The
researchers conclusion is more definitive. "We were not able to detect
the previously reported protective effects of genistein and
enterolactone on breast cancer risk in our postmenopausal population of
Dutch women. Such an effect may be smaller than expected and/or limited
to specific subgroups of the population."

\* \* \* \* \*

We could raise many other questions about the validity of the results of
the studies chosen by Solae, but the most damaging evidence is found in
studies that Solae chose to exclude. We would like to draw attention to
a group of studies showing that soy protein causes the proliferation of
breast cancer cells. This not only increases a woman's risk of
developing breast cancer but poses special dangers to people already
afflicted with breast cancer. The latter group includes not only women
who have already been diagnosed with breast cancer, but those in the
early stages prior to diagnosis.

We are not alone in this concern. The British government's Committee on
Toxicology (COT) writes in Chapter 15 \-- Phytoestrogens and Cancer of
its "Working Draft on Phytoestrogen" that "Short term dietary
supplementation has been shown to cause a proliferative response in
premenopausal women with breast disease whereas a proliferative effect
was not reported in premenopausal women without breast disease. However,
phytoestrogen treatment did induce a weak estrogenic effect in these
women as shown by modulation of the levels of the oestrogen responsive
gene products apolipoprotein D and pS2 in nipple aspirate."

COT further states: "The animal data on breast cancer is conflicting. A
number of studies have shown that genistein has a protective effect in
animal models of chemically induced cancer. However, similar experiments
using tumour implant models showed that genistein stimulated the growth
of implanted mammary tumours both by dietary and subcutaneous
administration." The full text of this report can be found at
<http://www.foodstandards.gov.uk/multimedia/webpage/phytoreportworddocs>

\* \* \* \* \*

The following studies establish that soy protein (and its constituent
isoflavones) have the potential to increase breast cancer risk and
disease progression. All quotations included are from the original
journal articles.

**Dees C, Foster JS et al.** Dietary estrogens stimulate human breast
cells to enter the cell cycle. *Environ Health Perspect,* 1997, 105,
633-636.

"Genistein, a dietary estrogen, inhibits the growth of breast cancer
cells at low doses but additional studies have suggested that genistein
stimulates proliferation of breast cancer cells. . . Our findings are
consistent with a conclusion that dietary estrogens do not act as
anti-estrogens, but act like DDT and estradiol to stimulate breast
cancer cells to enter the cell cycle. Women should not consume
particular foods (soy derived products) to prevent breast cancer."

**Martin PM, Horwitz KB et al.** Phytoestrogen interaction with estrogen
receptos in human breast cancer cells. *Endocrinol,* 1978, 103, 5,
1860-1867**.**

**"**The interactions of phytoestrogens with estrogen receptors were
studied in the human breast cancer cell line, MCF-7. The phytoestrogens
are also biologically active; they can markedly enhance tumor cell
proliferation. In sum, phytoestrogens interact with the estrogen
receptors of human breast cancer cells in culture and, therefore, may
affect estrogen-mediated events in these cells."

**Allred CD, Ju YH et al.** Dietary genistein stimulates growth of
estrogen-dependent breast cancer tumors similar to that observed with
genistein*. Carcinogenesis,* 2001b, 22, 1667-1673.

"The estrogenic soy isoflavone, genistein, stimulates growth of
estrogen-dependent human breast cancer (MCF-7) cells in vivo. Dietary
genistein resulted in increased tumor growth, pS2 expression and
cellular proliferation similar to that observed with genistein. The
remaining mice were switched to diets free of genistein and genistein.
When mice were placed on isoflavone-free diets, tumors regressed over a
span of 9 weeks, metabolism of genistein to genistein occurred. .. . In
summary, the glycoside genistein, like the aglycone genistein, can
stimulate estrogen-dependent breast cancer cell growth in vivo. Removal
of genistein or genistein from the diet caused tumors to regress."

**Allred CD, Allred KF, et al.** Soy diets containing varying amounts of
genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a
dose dependent manner. *Cancer Res*, 2001, 61, 13, 5045-5050.

"We have demonstrated that genistein stimulates growth of
estrogen-dependent human breast cancer (MCF-7) cells in vivo (C.Y. Hsieh
et al, Cancer Res, 58, 3833-3838, 1998). The isoflavones are a group of
phytoestrogens that are present in high concentrations in soy. Soy
protein dits containing varying amounts of genistein increased
estrogen-dependent tumor growth in a dose dependent manner . . . Cell
proliferation was greatest in tumors of animals given estrogen or
dietary genistein (150 and 300 ppm). . . Here we present new information
that soy protein isolates containing increasing concentrations of
genistein stimulate the growth of estrogen-dependent breast cancer cells
in vivo in a dose-dependent manner.

**Allred CD, Allred KF et al.** Dietary genistein results in larger
MNU-induced, estrogen dependent mammary tumors following ovariectomy of
Sprague-Dawley rats. Carcinogenesis, 2004, 25, 2, 211-218.

"The data suggest that in an endogenous estrogen environment similar to
that of a postmenopausal woman, dietary genistein can stimulate the
growth of a mammary carcinogen MNU-induced estrogen-dependent mammary
tumours."

**Allred CD, Allred KF et al.** Soy processing influences growth of
estrogen-dependent breast cancer tumors in mice. *Carcinogenesis,* May
6, 2004.

"Soy-based products consumed in Asian countries are minimally processed
whereas in the U.S. many of the soy foods and soy ingredients are highly
processed. Soy foods contain complex mixtures of bioactive compounds
which may interact with one another. The objective of this study was to
evaluate the ability of various soy products containing genistein, the
glycoside form of genistein to affect growth of MCF-7 cells transplanted
into ovariectomized athymic mice. . . . Tumors in the negative control
animals regressed throughout the study while tumors in the soy flour-fed
animals remained basically the same size (neither grew nor regressed).
In animals consuming soy molasses, Novasoy ®, mixed isoflavones or
genistein alone tumor growth was stimulated when compared to animals
consuming a control diet devoid of soy. These same dietary treatments
resulted in increased cellular proliferation."

**Hsich CY, Santell RC, et al.** Estrogenic effects of genistein on the
growth of estrogen receptor-positive human breast cancer (MCF-7) cells
in vitro and in vivo. *Cancer Res,* 1998, 58, 3833-3838.

"Genistein, found in soy products, is a phytochemical with several
biological activities. In the current study, our research focused on the
estrogenic and proliferation-inducing activity of genistein. We have
demonstrated that genistein enhanced the proliferation of
estrogen-dependent human breast cancer (MCF-7) cells in vitro at
concentrations as low as 10nM, with a concentration of 100nM achieving
proliferative effects similar to those of 1 nM estradiol."

**Ju YH, Doerge DR et al.** Dietary genistein negates the inhibitory
effects of tamoxifen on growth of estrogen-dependent human breast cancer
(MCF-7) cells implanted in athymic mice. *Cancer Res,* 2002, 1, 62, 9,
2474-2477.

"We investigated interactions between the soy isoflavone, genistein, and
an antiestorgen, tamoxifen (TAM), on the growth of estrogen
(E)-dependent breast cancer (MCF-7) cells. Dietary genistein
negated/overwhelmed the inhibitory effect of TAM on MCF-7 tumor growth,
lowered E2 level in plasma and increased expression of E-resonsive genes
(.e.g. pS2, PR, and cyclin D1). Therefore caution is warranted for
postmenopausal women consuming dietary genistein while on TAM therapy
for E-responsive breast cancer."

**McMichael -Phillips DF, Harding C et al.** Effects of soy-protein
supplementation on epithelial proliferation in the histologically normal
human breast. *Am J Clin Nutr,* 1998, 68 (6 Suppl), 1431S-1435S.

This study examines the effects of dietary soy supplementation on the
proliferation rate of premenopausal histologically normal breast
epithelium and the expression of progesterone receptor. The
proliferation rate of breast lobular epithelium significantly increased
after 14d of soy supplementation when both the day of menstrual cycle
and the age of patient were accounted for. . . Short-term dietary soy
stimulates breast proliferation; further studies are required to
determine whether this due to estrogen agonist activity and to examine
the long-term effects of soy supplementation on the pituitary gland and
breast."

**de Lemos ML.** Effects of soy phytoestrogens genistein and daidzein on
breast cancer growth. *Ann Pharmacother*, 2001, 35, 9, 1118-1121.

"OBJECTIVE: To determine whether genistein and daidzein, the major
phytoestrogens in soy, can stimulate breast cancer growth. . . .
CONCLUSIONS: Genistein and daidzein may stimulate existing breast tumor
growth and antagonize the effects of tamoxifen. Women with current or
past breast cancer should be aware of the risks of potential tumor
growth when taking soy products."

**Wang C, Kurzer MS.** Phytoestrogen concentration determines effects on
DNA synthesis in human breast cancer cells. Nutr Cancer, 1997, 28, 3,
236-247.

"Our data suggest the possibility that, at typical concentrations in
humans, phytoestrogens and related flavonoids and lignans may stimulate,
rather than inhibit, growth of estrogen-dependent tumours. . . In
conclusion, most of the phytoestrogens and related compounds tested in
this study showed stimulation of DNA synthesis in estrogen-dependent
MCF-7 cells at low concentrations and inhibition of DNA synthesis in
MCF-7 and estrogen-independent MDA-MB-231 cells at high concentrations.
Although we observed inhibition at high levels, it is extremely
important to consider that, at concentrations close to probable levels
in humans, DNA synthesis was significantly induced in MCF-7 cells."

**Ju YH, Allred CD et al.** Physiological concentrations of dietary
genistein dose-dependently stimulate growth of estrogen-dependent human
breast cancer (MCF-7) tumors implanted in athymic nude mice. *J Nutr,*
2001, 131, 11, 2957-2962.

"In conclusion, dietary treatment with genistein at physiological
concentrations produces blood levels of genistein sufficient to
stimulate estrogenic effects, as breast tumor growth, cellular
proliferation and pS2 expression in athymic mice in a dose-resonsive
manner similar to that seen in vitro."

\* \* \* \* \*

Phytoestrogens such as genistein found in soy protein products can cross
the placenta, putting unborn children at risk. We present here two
studies that show that perinatal exposure could increase the risk of
babies developing breast cancer.

**Hilakivi-**Clark L, Cho E, Clark R. Maternal exposure to genistein
during pregnancy increases carcinogen-induced mammary tumorigenesis in
female rat offspring. *Oncol Rep,* 1998, 5, 609-616.

"Human and animal data indicate that a high maternal estrogen exposure
during pregnancy increases breast cancer risk among daughters. This may
reflect an increase in the epithelial structures that are the sites for
malignant transformation, i.e. terminal end buds (TEBs), and a reduction
in epithelial differentiation in the mammary gland. Some phytoestrogens,
such as genistein, which is a major component in soy-based foods, . . .
. have estrogenic effects on the reproductive system, breast and brain.
.. These findings indicate that maternal exposure to physiological doses
of genistein mimics the effects of E2 on the mammary gland and
reproductive systems in the offspring. Thus our results suggest that
genistein acts as an estrogen in utero, and may increase the incidence
of mammary tumors if given through a pregnant mother. "

**Yang J, Nakagama H et al.** Influence of perinatal genistein exposure
on the development of MNU-induced mammary carcinoma in female
Sprague-Dawley rats.

Cancer Lett, 2000, 149 (1-2), 171-179.

"Perinatal genistein is an endocrine disrupter and increases
multiplicity of MNU-induced mammary carcinoma in rats."

\* \* \* \* \*

Women are at greater risk for breast cancer if they have abnormal
cytology in nipple aspirates of breast fluid. (Wrensch MR, Petrakis NL
et al. Breast cancer risk in women with abnormal cytology in nipple
aspirates of breast fluid. *J Natl Cancer Inst,* 2001, 5, 93, 23,
1791-1798.). The following study indicates that soy proteins increase
breast fluid, cause epithelial hyperplasia and contribute to other
abnormalities associated with increased risk of breast cancer.

**Petrakis NL. Barnes S et al.** Stimulatory influence of soy protein
isolate on breast cancer secretion in pre-and postmenopausal women.
*Cancer Epidemiol* *Biomarkers Prev,* 1996, 10, 785-794.

"Soy foods have been reported to have protective effects against
premenopausal breast cancer in Asian women. No studies have been
reported on potential physiological effects of dietary soy consumption
on breast gland function. We evaluated the influence of the long-term
ingestion of a commercial soy protein isolate on breast secretory
activity. We hypothesized that the features of nipple aspirate fluid
(NAF) of non-Asian women would be altered so as to resemble those
previously found in Asian women. . . . Of potential concern was the
cytological detection of epithelial hyperplasia in 7 of 24 women (29.2%)
during the months they were consuming soy protein isolate. The findings
did not support our a prior hypothesis. Instead, this pilot study
indicates that prolonged consumption of soy protein isolate has a
stimulatory effect on the premenopausal female breast, characterized by
increased secretion of breast fluid, the appearance of hyperplastic
epithelial cells and elevated levels of plasma estradiol. These findings
are suggestive of an estrogenic stimulus from the isoflavones genistein
and daidzein contained in soy protein isolate. "

**Hargreaves DF, Potten CS et al.** Two-week soy supplementation has an
estrogenic effect on normal premenopausal breast. *J. Clin Endocrinol
Metab,* 1999, 84, 4017-4024.

"Short term dietary soy has a weak estrogenic response on the breast, as
easured by nipple aspirate apolipoprotein D and pS2 expression. No
antiestrogenic effect of soy on the breast was detected."

\* \* \* \* \*

B3.2. Prostate Cancer

Solae states that "the totality of the publicly available scientific
evidence supports the substance/disease relationship that consumption of
soy protein-containing foods is related to a lower risk of prostate
cancer in men." We submit that the British Committee on Toxicity (COT)
is correct when it states in its "Working Draft on Phytoestrogens" that
"The epidemiological data on soy intake and prostate cancer are
inconsistent" and that concentrations used in animal experiments are
"very high compared with the likely dietary exposure levels in humans."
<http://www.foodstandards.gov.uk/multimedia/webpage/phytoreportworddocs>

Solae seems far more confident about the favorable conclusions in the
studies it cites than are the researchers themselves, who often qualify
their claims with phrases such as "the findings are not conclusive and
require further investigation.\" Two examples are: "Possible
associations between soy bean products, isoflavones and prostate cancer
risk should be further investigated." (Jacobsen, 1998) **"**More
research is needed on these dietary factors and the subsequent
development of prostate cancer before any firm conclusions can be
drawn." (Severson. 1989)

\* \* \* \* \*

We contend that many dietary factors may be involved in the reduced
rates of prostate cancer in Asia. The following studies indicate that
soy consumption is linked to reduced incidences of prostate cancer, but
suggest that soy is not the only dietary factor. Green tea, nuts,
grains, rice, fish and other foods alone or in combination with or
without soy might contribute to the reduced cancer risk. Severson,
Kolonel and Hebert are three researchers cited by Solae who help make
our case. All quotations in this and other sections are for the words of
the researchers.

**Severson,K, Nomura AM et al.** A prospective study of demographics,
diet, and prostate cancer among men of Japanese ancestry in Hawaii.
*Cancer Res.* 1989, 1, 49, 7, 1857-1860.

"Prostate cancer incidence was prospectively studied among 7999 men of
Japanese ancestry who were first examined between 1965 and 1968 and then
followed through 1986. During this surveillance period, 174 incident
cases of prostate cancer were recorded. Increased consumption of rice
and tofu were both associated with a decreased risk of prostate cancer .
. . "

**Kolonel LN, Hankin JH et al.** Vegetables, fruits, legumes and
prostate cancer: a multiethnic case-control study. *Cancer Epidemiol
Biomarkers Prev.* 2000, 8, 795-804.\
"The evidence for a protective effect of vegetables, fruits, and legumes
against prostate cancer is weak and inconsistent. We examined the
relationship of these food groups and their constituent foods to
prostate cancer risk in a multicenter case-control study of
African-American, white, Japanese, and Chinese men. Cases (n = 1619)
with histologically confirmed prostate cancer were identified through
the population-based tumor registries of Hawaii, San Francisco, and Los
Angeles in the United States and British Columbia and Ontario in Canada.
Controls (n = 1618) were frequency-matched to cases on ethnicity, age,
and region of residence of the case, in a ratio of approximately 1:1.
Intakes of yellow-orange and cruciferous vegetables were also inversely
related to prostate cancer, especially for advanced cases, among whom
the highest quintile OR for yellow-orange vegetables = 0.67 (P for trend
= 0.01) and the highest quintile OR for cruciferous vegetables = 0.61 (P
for trend = 0.006). Intake of tomatoes and of fruits was not related to
risk. Findings were generally consistent across ethnic groups. These
results suggest that legumes (not limited to soy products) and certain
categories of vegetables may protect against prostate cancer."

**Hebert JR, Hurley TG et al.** Nutritional and socioeconomic factors in
relation to prostate cancer mortality: a cross-national study. *Natl
Cancer Inst.* 1998, 90, 21, 1637-47.\
"CONCLUSIONS: The specific food-related results from this study are
consistent with previous information and support the current dietary
guidelines and hypothesis that grains, cereals, and nuts are protective
against prostate cancer. The findings also provide a rationale for
future study of soy products in prostate cancer prevention trials."

**Adlercreutz H.**Phyto-oestrogens and cancer**.** *Lancet Oncol.* 2002.
3, 6, 364-373.\
"Whether these observed protective effects are caused by the presence of
dietary phyto-oestrogens, or whether they are merely indicators of a
healthy diet in general, has not been established."

**Sonoda T, Nagata Y,** A case-control study of diet and prostate cancer
in Japan: possible protective effect of traditional Japanese diet.
*Cancer Sci.* 2004, 95, 3, 238-242.\
"The age-adjusted incidence of prostate cancer is low in Japan, and it
has been suggested that the traditional Japanese diet, which includes
many soy products, plays a preventive role against prostate cancer. We
performed a case-control study on dietary factors and prostate cancer in
order to assess the hypothesis that the traditional Japanese diet
reduces the risk of prostate cancer. . . Consumption of fish, all
soybean products, tofu (bean curds), and natto (fermented soybeans) was
associated with decreased risk. . . . Our results provide support to the
hypothesis that the traditional Japanese diet, which is rich in soybean
products and fish, might be protective against prostate cancer."\
\
**Zhou JR, Yu L, Zhong Y, Blackburn GL. Zhou** Soy phytochemicals and
tea bioactive components synergistically inhibit androgen-sensitive
human prostate tumors in mice, J Nutr. 2003, 133, 2, 516-21.

"Although high doses of single bioactive agents may have potent
anticancer effects, the chemopreventive properties of the Asian diet may
result from interactions among several components that potentiate the
activities of any single constituent. In Asia, where intake of soy
products and tea consumption are very high, aggressive prostate cancer
is significantly less prevalent in Asian men. The objective of the
present study was to identify possible synergistic effects between soy
and tea components on prostate tumor progression in a mouse model of
orthotopic androgen-sensitive human prostate cancer. . . . The
combination of SPC and green tea synergistically inhibited final tumor
weight and metastasis and significantly reduced serum concentrations of
both testosterone and DHT in vivo. Inhibition of tumor progression was
associated with reduced tumor cell proliferation and tumor angiogenesis.
This study suggests that further research is warranted to study the role
of soy and tea combination as effective nutritional regimens in prostate
cancer prevention."

\* \* \* \* \*

We would like to bring to your attention the following group of human
and animal studies omitted from Solae's "thorough review of the
literature." These studies not only show that soy foods are *not*
protective against prostate cancer or are less effective than other
dietary agents, but also that soy protein -- and its constituent
isoflavones \-- have been linked to *increased* prostate cancer risk. In
addition, these dietary compounds have caused undesirable side effects,
including changes to the dimorphic brain region and increased IGF-1
levels.

**Urban D, Irwin W et al.** The effect of isolated soy protein on plasma
biomarkers in elderly men with elevated serum prostate specific antigen.
*Clin Cancer Res,* 2001, 7, 1782-1789,

This was a randomized, double blind crossover study in which 34 elderly
men with elevated PSA received a soy beverage twice daily for six weeks.

"CONCLUSIONS: This study reveals that short-term exposure of elderly men
with elevated serum PSA values to soy protein containing isoflavones
decreases serum cholesterol but not the serum biomarkers PSA and
p105erbB-2."

**Adams KF, Chen C et al.** Soy isoflavones do not modulate
prostate-specific antigen concentrations in older men in a randomized
controlled trial. *Cancer Epidemiol biomarkers Prev*, 2004, 13, 4,
644-648.\
"Mortality rates for prostate cancer are low in Asia but high in the
West. One explanation is the high level of soy consumption in Asia. Soy
isoflavones reduce prostate tumor growth in many, but not all, animal
models. Elevated levels of serum prostate-specific antigen (PSA) are a
marker of prostate tumor growth. Our objective was to determine whether
12-month soy isoflavone supplementation would alter serum PSA
concentrations in healthy, older men. . . . We found no evidence that a
12-month 83 mg/day isoflavone treatment alters serum PSA concentration
or velocity in seemingly healthy men aged 50-80 years."

**Bylund A, Zhang JX et al.** Rye bran and soy protein delay growth and
increase apoptosis of human LNCaP prostate adenocarcinoma in nude mice.
*Prostate.* 2000, 1, 42, 4, 304-14.\
"CONCLUSIONS: Factors in rye bran and soy protein may inhibit prostate
cancer growth. The effect is more apparent for rye than for soy. Further
studies are needed to identify the effective substances and to explore
the mechanism."

**Hirayama T.** Epidemiology of prostate cancer with special reference
to the role of diet. *Natl Cancer Inst Monogr**,*** 1979, 53, 149-155.

"This was a prospective epidemiologic study of prostate cancer was
conducted in Japan. The 10-year follow-up study of 122,261 men aged 40
years and above, who constitute 94.5% of the census population of 29
Health Center Districts, revealed a significantly lower age-standardized
death rate for prostate cancer in men who daily ate green and yellow
vegetables. This association is consistently observed in each age-group,
in each socioeconomic class, and in each prefecture. Selected
epidemiologic phenomena, such as the upward trend of the prostate cancer
death rate in Japan, intracountry variation of death rate, the
significantly lower incidence rate in Japan compared with that of the
United States, and elevated risk in Japanese migrants to Hawaii, appear
to be explained by the variation in diet and change in amount of green
and yellow vegetables ingested. The possible role of vitamin A is
considered as a factor in preventing and inhibiting growth of prostate
cancer. Most of the other factors studied appear noncontributory, except
for marital status; a higher risk was observed in \'ever married\' men."

The data from this study indicate a significantly increased risk of
prostate cancer associated with the consumption of miso.

Solae states that it chose to exclude studies on miso because it is
relatively low in soy protein. However, miso does include soy
isoflavones. We therefore believe that the results from this large-scale
study are relevant In addition, Dr. Hirayama offers a convincing
alternative explanation as to why the Japanese have lower rates of
prostate cancer.

**Doerge D, Chang H**. Inactivation of thyroid peroxidase by soy
isoflavones in vitro and in vivo. *J Chromatogr B. Analyt Technolo
Biomed Life Sci,* 2002, 777 (1-2), 269.

Drs. Doerge and Chang review the evidence in humans and animals for
anti-thyroid effects of soy and its principal isoflavones, genistein and
daidzein. They note that genistein interferes with estrogen receptors in
rat prostate glands which " . . . may have implications for reproductive
toxicity and carcinogenesis that warrant further investigation."

**Lephart ED, Adlercreutz H, Lund TD.** Dietary soy phytoestrogen
effects on brain structure and aromatase in Long-Evans rats.
*Neuroreport.* 2001, 16; 12, 16,:3451-3455.\
"We found that dietary phytoestrogens: significantly decrease body and
prostate weights, do not alter brain aromatase levels and significantly
change during adulthood the structure of the sexually dimorphic brain
region (i.e. anteroventral periventricular nucleus; AVPV) in male, but
not in female rats. Since most commercial animal diets contain
significant concentrations of phytoestrogens their influence on brain
structure should be considered."

**Spentzos D, Mantzoros C et al.** Minimal effect of a low-fat/high soy
diet for asymptomatic, hormonally naive prostate cancer patients. *Clin
Cancer Res*. 2003 15, 9, 9, 3282-3287.\
"PURPOSE: The effects of a low-fat diet or a low-fat diet with the
addition of a soy supplement were investigated in a pilot Phase II study
for asymptomatic, hormonally naive prostate cancer patients with rising
prostate-specific antigen (PSA) levels. . . CONCLUSIONS: A low-fat diet
with the subsequent addition of a soy supplement did not result in a
significant decline in PSA levels. The addition of soy protein had a
modest effect on TTP. A potentially undesirable effect associated with
the administration of soy was an increase in IGF-I serum levels."

**Cohen LA, Zhao Z, Pittman B, Scimeca J.** Effect of soy protein
isolate and conjugated linoleic acid on the growth of Dunning
R-3327-AT-1 rat prostate tumors. *Prostate.* 2003, 54, 3, 169-180.\
\
"BACKGROUND: Epidemiologic and animal model studies suggest that
consumption of soy isoflavones may be associated with reduced risk of
prostate cancer (PC). In addition, animal model studies suggest that
conjugated linoleic acid (CLA), a natural positional isomer of linoleic
acid, inhibits tumor growth in various models, including models of PC.
RESULTS: The results of this study indicate that neither an
isoflavone-rich soy protein isolate (SPI), nor CLA inhibit the in vivo
growth and development of prostate tumor cells when administered in the
diet either singly or in combination. Moreover, at the highest
concentrations SPI and CLA (i.e., 20% SPI, 1% CLA), there was a
statistically significant increase in tumors volume over controls.
Administration of SPI at 10% in the diet also enhanced tumor growth,
whereas at 5%, SPI exerted no measurable effect. CLA administration
alone had no observable effects on AT-1 tumor growth. . . CONCLUSION:
These results, in an established rat model, suggest caution in using
isoflavone-rich SPI in human studies involving advanced
hormone-refractory prostate cancer until further investigation of these
effects are completed. "

**Probst-Hensch NM, Wang H et al.** Determinants of circulating
insulin-like growth factor I and insulin-like growth factor binding
protein 3 concentrations in a cohort of Singapore men and women. *Cancer
Epidemiol Biomarkers Prev.* 2003, 8, 739-746.\
"Variation in the circulating concentrations of the insulin-like growth
factor (IGF) system has been implicated in the etiology of chronic
diseases including cancer (prostate, breast, colon, and lung), heart
disease, type 2 diabetes, and osteoporosis. We searched for
sociodemographic, anthropometric, reproductive, lifestyle, and dietary
determinants of IGF-I and insulin-like growth factor binding protein
(IGFBP) -3 serum concentrations . . . Intake of soy was associated
positively with IGF-I and molar ratio concentrations, but only in men.
The results of this study lend additional support to the hypothesis that
circulating IGF-I concentrations increase the risk of prostate, bladder,
colorectal, and breast cancer."

**Jenkins DJ, Kendall CW et al.** Soy consumption and phytoestrogens:
effect on serum prostate specific antigen when blood lipids and oxidized
low-density lipoprotein are reduced in hyperlipidemic men. *J Urol.*
2003, 169, 2, 507-511.\
"PURPOSE: Herbal remedies high in phytoestrogens have been shown to
reduce serum prostate specific antigen (PSA) and have been proposed as a
treatment for prostate cancer. Soy proteins used to lower serum
cholesterol are rich sources of phytoestrogens. Therefore, we assessed
the effect of soy consumption on serum PSA in men who had participated
in cholesterol lowering studies. . . MATERIALS AND METHODS: For 3 to 4
weeks 46 healthy middle-aged men with a range of starting PSA values
took soy (mean 44 gm. soy protein daily, 116 mg. isoflavones daily) or
control foods, and a subgroup of men took a lower level of soy
supplements for 3 months. PSA was measured at the start and end of each
treatment. RESULTS: Soy had no significant effect on serum total or free
PSA, independent of PSA starting value or isoflavone intake. . . "

**Cohen LA, Zhao Z, Pittman B, Scimeca J.** Effect of soy protein
isolate and conjugated linoleic acid on the growth of Dunning
R-3327-AT-1 rat prostate tumors. *Prostate*. 2003, 54, 3, 169-180.\
"BACKGROUND: Epidemiologic and animal model studies suggest that
consumption of soy isoflavones may be associated with reduced risk of
prostate cancer (PC). In addition, animal model studies suggest that
conjugated linoleic acid (CLA), a natural positional isomer of linoleic
acid, inhibits tumor growth in various models, including models of PC. .
. .RESULTS: The results of this study indicate that neither an
isoflavone-rich soy protein isolate (SPI), nor CLA inhibit the in vivo
growth and development of prostate tumor cells when administered in the
diet either singly or in combination. Moreover, at the highest
concentrations SPI and CLA (i.e., 20% SPI, 1% CLA), there was a
statistically significant increase in tumors volume over controls.
Administration of SPI at 10% in the diet also enhanced tumor growth,
whereas at 5%, SPI exerted no measurable effect. CLA administration
alone had no observable effects on AT-1 tumor growth. CONCLUSION: These
results, in an established rat model, suggest caution in using
isoflavone-rich SPI in human studies involving advanced
hormone-refractory prostate cancer until further investigation of these
effects are completed."

**Santti** Developmental estrogenization and prostatic neoplasia.
*Prostate,* 1994, 24, 2, 67-78.

"Evidence indicates that estrogen exposure during development may
initiate cellular changes in the prostate which would require estrogens
and/or androgens later in life for promotion of prostatic hyperplasia or
neoplasia. . . The critical time for estrogen action would be during the
development of prostatic tissue. We further suggest that
estrogen-sensitive cells may remain in the prostate and be more
responsive to estrogens alter in life or less responsive to the normal
controlling mechanisms of prostate growth" In other words, a male fetus
exposed to soy phytoestrogens from his mother's diet would be more
likely to develop prostate cancer later in life.

\* \* \* \* \*

**Pollard M, Wolter W, Sun L.** Diet and the duration of
testosterone-dependent prostate cancer in Lobund-Wistar rats. *Cancer
Lett.* 2001, 173, 2, 127-131.\
In its petition Solae sums this study up as follows: "Providing rats an
ISP diet during age 12-24 months, the stage of spontaneous prostate
tumor development, significantly reduces tumor incident compared with
the controls on a soy meal diet."\
The researchers, however, conclude their abstract with this revealing
statement: "Dietary soymeal found in most natural ingredient diets may
promote PC tumorigenesis, but only in L-W rats." L-W rats were
developed, in the words of these researchers as "a unique model of
spontaneous prostate cancer (PC)" that "shares many of its
characteristics with the natural. history of PC in man, including (a)
inherent predisposition, high production of testosterone and aging risk
factors, (b) endogenous tumorigenic mechanisms, and (c) early stage
testosterone-dependent and late stage testosterone-independent tumors."

> \* \* \* \* \*

Several studies suggest that if soy reduces rates of prostate cancer it
might do so only for equol producers. If so, all males in the population
would not stand to benefit from soy protein consumption. Also, green tea
might be a factor in equol production.

**Akaza H, Miyanaga N et al.** Comparisons of percent equol producers
between prostate cancer patients and controls: case-controlled studies
of isoflavones in Japanese, Korean and American residents**.** *Jpn J
Clin Oncol*. 2004, 34, 2, 86-89.\
BACKGROUND: Our previous case-control study revealed that the Japanese
residents in Japan could be divided into those who are able to degrade
daidzein, a soybean isoflavone, to equol and those without this ability,
and that the incidence of prostate cancer is higher in the latter group.
. . CONCLUSIONS: These results suggest that the ability of producing
equol or equol itself is closely related to the lower incidence of
prostate cancer.

**Miyanaga N, Akaza H et al. Higher consumption of green tea may enhance
equol production.** *Asian Pac J Cancer Prev*. 2003, 4, 4, 297-301

BACKGROUND: Our previous case-control study revealed that Japanese
living in Japan and Koreans living in Korea can be divided into equol
producers who have an ability to metabolize daidzein to equol and
non-producers, and that the incidence of prostate cancer is higher in
the latter group. In the present study, we examined relationships
between type of food intake and the capacity for equol production in
Japanese subjects. CONCLUSIONS: Our results suggest that higher
consumption of soybean and green tea are strongly related to the
establishment of a capacity for equol production.\
 \
**Akaza H, Miyanaga N et al. Is daidzein non-metabolizer a high risk for
prostate cancer? A case-controlled study of serum soybean isoflavone
concentration.** *Jpn J Clin Oncol.* 2002, 32, 8, 296-300\
"Equol itself or some unknown factor regulating the metabolism of
daidzein is deeply involved in the biology of prostate cancer. Future
studies are urgently needed to compare the incidence of daidzein
metabolizers among various countries."

\* \* \* \* \*

Finally, Solae has omitted discussion of the prevailing theories about
why soy might be protective against the development of prostate cancer.
Prostate cancer is generally thought to be dependent on exposure to male
reproductive hormone. If soy confers protection, it is by altering
endogenous hormone concentrations -- by decreasing testosterone and
androgen levels and estrogenizing men. While this might have valid
pharmaceutical applications in cancer treatment, it seems inadvisable as
a preventative treatment for the entire male population.

B.3.3. Gastro-Intestinal Cancer

In this section Solae states that a "thorough review of these studies
reveals that consumption of soyfoods is related to a lower incidence of
gastro-intestinal cancer in humans." To reach this conclusion, Solae had
to omit numerous studies showing adverse effects.

The British Committee on Toxicology (COT) states that epidemiological
studies exploring the relationship between soy consumption and the risk
of stomach and colo-rectal cancer have "provided inconsistent results."
<http://www.foodstandards.gov.uk/multimedia/webpage/phytoreportworddocs>

Solae has found consistency, in part, because it purposely eliminated
all studies pertaining to fermented soy products on the grounds that
they are not as high in protein as other soy foods. Increased rates of
stomach and colorectal cancer have been found among people eating many
fermented foods, including miso and other fermented soy products.

Solae has also incorporated all negative findings into its
meta-analyses. This had the effect of obscuring the conclusions of
**Nagata et al 2000,** an important study which showed that soy protein
was associated with a lowered risk of stomach cancer but also with a
higher risk of death from colorectal cancer. It hardly seems appropriate
to claim benefit for a food that might prevent stomach cancer but put a
person at higher risk for colon cancer.

Solae has also claimed benefits for soy protein based on studies in
which the authors found their most significant associations with raw
vegetables, green vegetables and allium-containing foods such as garlic
and onions. We have summarized below important findings from several
important studies pertaining dietary intake and gastrointestinal cancer.
The studies by Gao, Ji, Lee, Hoshiyama, Shinchi, Takezaki, Nogoan and
Ahn are studies in which the soy protein findings were exaggerated by
Solae. Indeed, most provide excellent support for the FDA's health claim
for fruits and vegetables preventing cancer, but cannot be used to
support a health claim for soy protein.

**Gao CM, Takezaki T et al.** Protective effect of allium vegetables
against both esophageal and stomach cancer: a simultaneous case-referent
study of a high-epidemic area in Jiangsu Province, China. *Jpn J Cancer
Res*. 1999 Jun;90(6):614-21.

To study the relation between allium vegetable intake and cancer of the
esophagus (EC) and stomach (SC) in Yangzhong city, which is one of the
highest-risk areas for these cancers in Jiangsu province, China . . . .
The results showed that frequent intake of allium vegetables (including
garlic, onion, Welsh onion and Chinese chives), raw vegetables, tomatoes
and snap beans, and tea consumption were inversely associated with the
risk for EC and SC. . .. The main results in the present study suggested
that allium vegetables, like raw vegetables, may have an important
protecting effect against not only stomach cancer, but also esophageal
cancer.

**Ji BT, Chow WH et al.** Dietary habits and stomach cancer in Shanghai,
China. *Int J Cancer.* 1998, 76, 5, 659-64.

". . . . Risks of stomach cancer were inversely associated with high
consumption of several food groups, including fresh vegetables and
fruits, poultry, eggs, plant oil, and some nutrients, such as protein,
fat, fiber and antioxidant vitamins. By contrast, risks increased with
increasing consumption of dietary carbohydrates. . . Similar increases
in risk were associated with frequent intake of noodles and bread in
both men . . . and women . . . In addition, elevated risks were
associated with frequent consumption of preserved, salty or fried foods,
and hot soup/porridge, and with irregular meals, speed eating and binge
eating. . . . Our findings add to the evidence that diet plays a major
role in stomach cancer risk and suggest the need for further evaluation
of risks associated with carbohydrates and starchy foods as well as the
mechanisms involved."

**Lee JK, Park BJ et al.** Dietary factors and stomach cancer: a
case-control study in Korea. *Int J Epidemiol*. 1995, 24, 1, 33-41.

". . An increased risk of stomach cancer was noted among those with high
consumption of stewed foods such as soybean paste stew and hot
pepper-soybean stew, broiled fish, and those who liked salty food.
However, mung bean pancake, tofu (soybean curd), cabbage, spinach, and
sesame oil decreased the risk of stomach cancer. Stratified analysis by
salt in combined foods, such as stewed foods and pickled vegetables,
disclosed salt as being an important risk factor. . . " .

**Takezaki T, Gao CM et al**. Comparative study of lifestyles of
residents in high and low risk areas for gastric cancer in Jiangsu
Province, China; with special reference to allium vegetables. *J
Epidemiol*. 1999, 9, 5, 297-305.

"There is a low risk area for gastric cancer in Jiangsu Province, China,
where people frequently consume raw allium vegetables. The results of
the survey suggest that frequent consumption of allium vegetables, in
addition to other anticancer foods, may be a factor in low mortality for
gastric cancer."

**Ngoan LT, Mizoue T et al**. .Dietary factors and stomach cancer
mortality. *Br J Cancer.* 2002;87, 1, :37-42.

"The present study examined the relationship between stomach cancer and
the low intake of fresh fruit and vegetables and/or a high intake of
pickled, preserved or salted foods and frequent use of cooking oil.
During 139,390 person-year of follow-up of over 13,000 subjects, 116
died from stomach cancer. . . . . controlling for age, sex, smoking and
other dietary factors, a significant decline was found with a high
consumption of green and yellow vegetables . . . . Reductions of between
40 and 50% were also observed with a high consumption of fresh foods
(fruit, cuttle fish, tofu, and potatoes), but these associations were
not statistically significant. The risk was significantly increased by
the high consumption of processed meat . . "

**Shinchi K, Ishii H et al.** .Relationship of cigarette smoking,
alcohol use, and dietary habits with Helicobacter pylori infection in
Japanese men. Scand J Gastroenterol. 1997 32, 7, 651-655. .

". . . . Unexpectedly, the consumption of tofu (soybean curd) was
significantly, negatively related to the infection . . . The
seropositivity was unrelated to the consumption of pickled vegetables,
soy paste soup, green tea, or garlic. . . The findings suggest that
fresh vegetables may be protective against H. pylori infection. The
study does not support either an increased risk of the infection
associated with salty foods or a protective effect of green tea or
garlic."

{H pylori is a major risk factor in stomach cancer\]

**Ahn YO.** Diet and stomach cancer in Korea. *Int J Cancer*. 1997;
Suppl 10, 7-9.

"An increased risk of stomach cancer was noted among people who
frequently consume broiled meats and fishes, salted side dishes
(salted/fermented fish products) and salty stewed foods, such as soybean
paste thick stew. Frequent consumption of mung bean pancake, tofu,
cabbage, spinach and sesame oil decreased the risk. In a recent cohort
study in Seoul, green vegetables and soybean foods were associated with
a decreased risk of stomach cancer. Case-control and cohort studies have
reported that ginseng intake decreased the risk of gastric cancer."

**Nomura AM, Hankin JH et al.** Case-control study of diet and other
risk factors for gastric cancer in Hawaii (United States). *Cancer
Causes Control*. 2003, 14, 6, 547-558.

"The consumption of all vegetables, mainly dark green, light green, and
yellow vegetables, reduced risk. Many of these vegetables contain
beta-carotene, vitamin C, vitamin E or folate, which were also inversely
related to gastric cancer risk. When these nutrients were analyzed
simultaneously, the inverse association was mainly with beta-carotene. .
. . These findings provide additional support that the consumption of
dark green and yellow vegetables are protective against adenocarcinoma
of the distal stomach."

.

**Hoshiyama Y, Sasaba T** A case-control study of stomach cancer and its
relation to diet, cigarettes, and alcohol consumption in Saitama
Prefecture, Japan. *Cancer Causes Control.* 1992 3, 5, 441-448.

" . . . The consumption of raw vegetables was inversely related to the
risk of stomach cancer, with a dose-response relation observed
consistently in the comparisons with both sets of controls. In the
multiple logistic regression, the consumption of raw vegetables showed a
protective effect on stomach cancer while cigarette smoking had no

significant association, in both sets of controls.

**Lee HH, Wu HY, et al.** Epidemiologic characteristics and multiple
risk factors of stomach cancer in Taiwan *Anticancer Res.* 1990, 10, 4,
:875-81

"Comparison of the incidence of stomach cancer among Chinese in
different countries showed a much lower incidence among Chinese in the
USA than those in southeastern Asia. A hospital-based matched
case-control study carried out in Taipei metropolitan areas showed a
positive association of stomach cancer with blood type A, chronic
gastric diseases, cigarette smoking, alcohol drinking, green tea
drinking as well as consumption of salted meat, cured meat, smoked food,
fried food and fermented beans. There was also a significant negative
association between the disease and the consumption of milk."

**McKeown-Eyssen, GE, Bright-See E.** Dietary factors in colon cancer:
international relationships. *Nutr Cancer,* 1984, 6, 160-170.

This cross-cultural study of 38 countries found no association between
soybean intake and risk of colon cancer.

**Chyou PH, Nomura AM et al**. A case-cohort study of diet and stomach
cancer. *Cancer Res.* 1990, 50, 23, 7501-7504.

". . . We found that the consumption of all types of vegetables was
protective against stomach cancer.. . . Similar but weaker protective
effects from consumption of green and cruciferous vegetables were also
observed. In addition, an inverse association between stomach cancer
risk and intake of fruits was noted . . . but this inverse trend was
weakened after the effect of cigarette smoking was taken into account.
There were no other dietary factors significantly associated with the
risk of gastric cancer

**You WC, Blot WJ et al**. Diet and high risk of stomach cancer in
Shandong, China. *Cancer Res.* 1988; 48, 12, 3518-23.

". . . A case-control investigation involving interviews with 564
stomach cancer patients and 1131 population-based controls was conducted
to evaluate reasons for the exceptionally high rates of stomach cancer
in Linqu, a rural county in Shandong Province in northeast China. Daily
consumption of sour pancakes, a fermented indigenous staple, was
associated with a 30% increase in risk. . . . risks tended to decrease
in proportion to increasing consumption of fresh vegetables and fruits.
This protective effect was more pronounced for vegetables, with those in
the highest quartile of intake at less than one-half the risk of those
in the lowest. Stomach cancer risks also declined with increasing
dietary intake of carotene, vitamin C, and calcium, but not retinol. "

**Galanis DJ, Kolonel LN et al**. Intakes of selected foods and
beverages and the incidence of gastric cancer among the Japanese
residents of Hawaii: a prospective study. *Int J Epidemiol*. 1998, 27,
2, 173-180

". .. . The combined intake of fresh fruit and raw vegetables was
inversely associated with the risk of gastric cancer in the total
cohort, and among the men no significant relationships were found
between gastric cancer incidence and the intake of pickled vegetables,
miso soup, dried or salted fish, or processed meats among either gender.
. ."

**Hu JF, Lin YY et al.** Diet and cancer of the colon and rectum: a
case-control study in China. *Int J Epidemiol*, 1991, 20, 362-367.

. . . Vegetables, particularly green vegetables, chives and celery, have
a strong protective effect against colorectal cancer. Reduced
consumption of meat, eggs, bean products and grain was associated with
increasing risk for cancer of the rectum. Alcohol intake was found to be
an important risk factor for developing colon cancer and male rectal
cancer. . . "

> \* \* \* \* \*

Solae omitted several key studies that link soy protein to the
development of intestinal cancers or that document precancerous damage
caused by soy protein.

**McIntosh GH, Regester GO et al.** Dairy proteins protect against
dimetylhydrazine-induced intestinal cancers in rats. *J Nutr,* 1995,
125, 809-816.

" . . . The tumor data indicated that dietary whey protein and casein
were more protective against the development of intestinal cancers in
rats than were the red meat and soybean diets. No statistically
significant difference was observed between the effects of casein and
the effects of whey protein In addition, no significant difference in
tumor incidence or burden could be measured between the animals fed the
red meat diet and those fed the soybean protein diet. . . . Our data
also suggest that, like meat, soybean may not be an optimal source of
protein for the gastrointestinal tract,

**Govers MJ, Lapre JA et al.** Dietary soybean protein compared with
casein damages colonic epithelium and stimulates colonic epithelial
proliferation in rats. *J Nutr* 1993, 123, 1709-1713.

". . . epithelial cell damage and proliferation of colonic epithelium
(measured as in vivo incorporation of tritiated thymidine into DNA) were
greater in rats fed soybean protein. The stimulation of colonic
proliferation by soybean protein is consistent with the observed
increase in luminal cytolytic activity and epithelial cell damage. We
conclude that the stimulatory effect of soybean protein on endogenous
magnesium excretion is due to a soybean protein-specific damage of
colonic epithelial cells, which results in a compensatory epithelial
cell hyperproliferation. "

{Cell proliferation has been identified as an early biomarker of colon
cancer risk.}

**Davies MJ, Bowey EA et al.** Effects of soy or rye supplementation of
high-fat diets on colon tumour develop in azoxymethane-treated rats.
*Carcinogenesis*, 1999, 20,

927-931.

". . . Demonstrated that soy (250 mg isoflavones/kg diet) did not
protect against experimentally induced colon cancer in rats. Indeed
those given isoflavones had increased numbers of small ACF, thought to
be markers for the disease, at 12 weeks.

However a diet containing 30% rye bran significantly reduced the number
of colon tumors. Although there was no change in the total number of ACF
at 12 weeks, with the rye diet, the total number of large ACF was
reduced. . . These results suggest that soy isoflavones have no effect
on the frequency of colonic tumours in this model while rye bran
supplementation decreases the frequency of colon cancer. This effect is
due not to a decrease in early lesions but in their progression to
larger multi-crypt ACF. The study also supports the hypothesis that
larger ACF are more predictive of subsequent tumorigenicity."

Soybeans also contain antinutrients known as lectins that bind to the
villi and crypt cells of the small intestine. Lectin binding contributes
to cell death, a shortening of the villi, a diminished capacity for
digestion and absorption, cell proliferation in the crypt cells,
interference with hormone and growth factor signaling and unfavorable
population shifts among the microbial flora. All these factors
contribute towards intestinal cancers.

The following studies are relevant:

**Jindal S, Soni GL, Singh R.** Biochemical and histopathological
studies in albino rats fed on soyabean lectin. *Nutr Rep Inter*, 1984,
29, 95-106.

> **Torres-Pinedo R.** Lectins and the intestine. *J Pediatr
> Gastroenterol Nutr*, 1983, 2, 588-594.
>
> **Ament ME, Rubin CE**. Soy protein -- another cause of the flat
> intestinal lesion. *Gastroenterol*, 1972, 62, 2, 227-234.
>
> **Poley JR, Klein AW.** Scanning electron microsocopy of soy
> protein-induced damage of small bowel mucosa in infants. *J. Pediatr
> Gastroenterol Nutr*, 1983, 2, 2, 271-287
>
> \* \* \* \* \*

Finally, Solae claims that soy protein is a high-quality, complete
protein, containing all the essential amino acids. The sulfur containing
amino acid methionine, however, is so underrepresented in soy protein
that it must be added to soy infant formula and to soy-based animal
feeds. This deficiency makes soy protein a questionable food for colon
cancer prevention. As the following studies indicate, methionine has
been shown to be prevent colon cancer.

**Fuchs CS, Willett WC et al.** The influence of folate and multivitamin
use on the familial risk of colon cancer in women. *Cancer Epidemiol
Biomarkers Prev.* 2002 Mar;11(3):227-34.

Low intake of folate and methionine and heavy alcohol consumption have
been associated with an increased overall risk of colon cancer, possibly
related to their role in methylation pathways. . . . Our results suggest
that higher intake of folate and methionine, regular use of
multivitamins containing folate, and avoidance of moderate to heavy
alcohol consumption may diminish the excess risk of colon cancer
associated with a family history of the disease.

**Giovannucci E, Stampfer MJ et al.** ,Folate, methionine, and alcohol
intake and risk of colorectal adenoma. *J Nutr.* 1993
Oct;123(10):1709-13J.

" . . . The apparent protective effect of fresh fruits and vegetables,
the major folate sources, on colorectal cancer incidence suggests that a
methyl-deficient diet contributes to occurrence of this malignancy. Low
dietary folate and methionine and high intake of alcohol may reduce
levels of S-adenosylmethionine, which is required for DNA methylation. .
.CONCLUSIONS: Folate, alcohol, and methionine could influence methyl
group availability, and a methyl-deficient diet may be linked to early
stages of colorectal neoplasia. A dietary pattern that increases methyl
availability could reduce incidence of colorectal cancer. . . "

APPENDIX III: SCIENTIFIC EVIDENCE -- OTHER CANCERS

Solae provides summaries of a number of studies that "reflect a trend
that consumption of soyfoods is related to a lower risk of cancerous
diseases. However, the number of studies is limited and findings are not
consistent in certain types of cancers."

We would agree that the studies are inconsistent and sometimes
contradictory. However,we do not agree that the number of studies is
limited; in fact, there are a large number of studies related to thyroid
and pancreatic cancers as well as two studies that implicate soy in the
development of childhood leukemia.

The American Cancer Society reports that overall thyroid cancer
incidence across all ages and races is now increasing at 1.4 percent per
year and that incidences rose 42.1 percent between 1975 and 1996, with
the largest increases among women. Thyroid carcinoma is one of the most
common cancers among US children and adolescents, with approximately 75
percent occurring to adolescents between the ages of 15 and 19. The
National Cancer Institute (NCI) comments that "the preponderance of
thyroid cancer in females suggest that hormonal factors may mediate
disease occurrence." \"Hormonal factors" could include the
phytoestrogens in soy protein products.

There is also substantial body of evidence proving that the
antinutrients known as protease inhibitors (or trypsin inhibitors) in
soy causes pancreatic hyperplasia, a precursor to pancreatic cancer. It
may not be coincidental that pancreatic cancer recently moved up to
fourth place as a cause of cancer deaths in men and women in the United
States as consumption of soyfoods in this country has increased. In the
1970s and 1980s, several researchers studying protease-inhibitor damage
on the pancreas noted that pancreatic cancer had then moved up to fifth
place and wondered whether there might be a soybean-protease inhibitor
connection. The fact that this ongoing rise has occurred along with a
rise in the human consumption of soybeans does not prove cause and
effect. However, looking at the increase in pancreatic cancer cases
alongside pertinent animal studies is suggestive \-- and sobering. No
one appreciates the safety issues better than Irvin E. Liener, Ph.D, a
leading expert on plant toxins and antinutrients. In 1998, he warned
that "Soybean trypsin inhibitors do in fact pose a potential risk to
humans when soy protein is incorporated into the diet.\" (Liener IE.
Letter to Dockets Management Branch, Food and Drug Administration,
December 31, 1998).

Finally, Solae fails to open a discussion about soy protein's link to
immune system suppression, a possibility that further undermines any
assertion that soy protein affords protection against cancer.

The following studies support our position that the claim that soy
protein prevents cancer cannot be justified.

**Divi RL, Chang HC, Doerge DR.** Anti-thyroid isoflavones from soybean:
isolation, characterization, and mechanisms of action. *Biochem
Pharmacol*. 1997. 10, 1087-96.\
"The soybean has been implicated in diet-induced goiter by many studies.
The extensive consumption of soy products in infant formulas and in
vegetarian diets makes it essential to define the goitrogenic potential.
In this report, it was observed that an acidic methanolic extract of
soybeans contains compounds that inhibit thyroid peroxidase- (TPO)
catalyzed reactions essential to thyroid hormone synthesis. . . .
Because inhibition of thyroid hormone synthesis can induce goiter and
thyroid neoplasia in rodents, delineation of anti-thyroid mechanisms for
soy isoflavones may be important for extrapolating goitrogenic hazards
identified in chronic rodent bioassays to humans consuming soy
products."

**Divi RL, Doerge DR Inhibition of thyroid peroxidase by dietary
flavonoids.** *Chem Res Toxicol*. 1996, 9, 1, 16-23.\
"Flavonoids are widely distributed in plant-derived foods and possess a
variety of biological activities including antithyroid effects in
experimental animals and humans. . . . These inhibitory mechanisms for
flavonoids are consistent with the antithyroid effects observed in
experimental animals and, further, predict differences in hazards for
antithyroid effects in humans consuming dietary flavonoids. In vivo,
suicide substrate inhibition, which could be reversed only by de novo
protein synthesis, would be long-lasting. However, the effects of
reversible binding inhibitors and alternate substrates would be
temporary due to attenuation by metabolism and excretion. The central
role of hormonal regulation in growth and proliferation of thyroid
tissue suggests that chronic consumption of flavonoids, especially
suicide substrates, could play a role in the etiology of thyroid
cancer."

**Sheehan DM.** Herbal medicines, phytoestrogens and toxicity:
risk:benefit considerations. *Proc Soc Exp Biol Med.* 1998, 217, 3,
379-85.

"There are several suggested health benefits of phytoestrogens,
particularly those found in soy products. Herbal medicines are also
widely thought to confer health benefits. Additionally, drugs are
prescribed to improve human health, but unlike phytoestrogens and herbal
medicines, toxicities are defined in experimental animals and monitored
in humans before and after marketing. Knowledge of toxicity is crucial
to decrease the risk:benefit ratio; this knowledge defines appropriate
conditions for use and strategies for development of safer products.
However, our awareness of the toxicity of herbal medicines and
phytoestrogen-containing foods is dramatically limited compared to
drugs. Some aspects of the toxicity of herbal medicines are briefly
reviewed; it is concluded that virtually all of our knowledge is derived
from human exposures leading to acute toxicities. Importantly, detection
of toxicity is sporadic, and little information is available from prior
animal experimentation. Additionally, well-organized monitoring of human
populations (as occurs for drugs) is virtually nonexistent. Important
toxicities with long latencies are particularly difficult to associate
with a causative agent during or even after large scale exposures, as
exemplified by tobacco smoking and lung cancer; estrogen replacement
therapy and endometrial cancer; diethylstilbestrol and reproductive
tract cancers; and fetal alcohol exposure and birth defects. These
considerations suggest that much closer study in experimental animals
and human populations exposed to phytoestrogen-containing products, and
particularly soy-based foods, is necessary. Among human exposures,
infant soy formula exposure appears to provide the highest of all
phytoestrogen doses, and this occurs during development, often the most
sensitive life-stage for induction of toxicity. Large, carefully
controlled studies in this exposed infant population are a high
priority."

**Newbold RR, Banks EP et al**. Uterine adenocarcinoma in mice treated
neonatally with genistein. *Cancer Res.* 2001 Jun 1;61(11):4325-8.\
\
"The developing fetus is uniquely sensitive to perturbation with
estrogenic chemicals. The carcinogenic effect of prenatal exposure to
diethylstilbestrol (DES) is the classic example. Because phytoestrogen
use in nutritional and pharmaceutical applications for infants and
children is increasing, we investigated the carcinogenic potential of
genistein, a naturally occurring plant estrogen in soy, in an
experimental animal model previously reported to result in a high
incidence of uterine adenocarcinoma after neonatal DES exposure. Outbred
female CD-1 mice were treated on days 1-5 with equivalent estrogenic
doses of DES (0.001 mg/kg/day) or genistein (50 mg/kg/day). At 18
months, the incidence of uterine adenocarcinoma was 35% for genistein
and 31% for DES. These data suggest that genistein is carcinogenic if
exposure occurs during critical periods of differentiation. Thus, the
use of soy-based infant formulas in the absence of medical necessity and
the marketing of soy products designed to appeal to children should be
closely examined."

**Doerge DR, Sheehan DM**. Goitrogenic and estrogenic activity of soy
isoflavones. *Environ Health Perspect*, 2002, 110, suppl 3, 349-353.

"Soy is known to produce estrogenic isoflavones. Here we briefly review
the evidence for binding of isoflavones to the estrogen receptor, in
vivo estrogenicity and developmental toxicity, and estrogen
developmental carcinogenesis in rats. . . Although safety testing of
natural products, including soy products, is not required, the
possibility that widely consumed soy products may cause harm in the
human population via either or both estrogenic and goitrogenic
activities is of concern."

**Whitten PL, Lewis C et al.** Potential Adverse Effects of
phytoestrogens. *J Nutr,* 1995, 125, 771S-776S.

"Evaluation of the potential benefits and risks offered by naturally
occurring plant estrogens requires investigation of their potency and
sites of action when consumed at natural dietary concentrations. . . . .
These findings illustrate the broad range of actions of these natural
estrogens and the variability in potency across endpoints. This
variability argues for the importance of fully characterizing each
phytoestrogen in terms of its sites of action, balance of agonistic and
antagonistic properties, natural potency, and short-term and long-term
effects."

\` **Strauss L, Santti R et al.** Dietary phytoestrogens and their role
in hormonally dependent disease. *Toxicol Lett,* 1998, 28, 102-103,
349-354.\
"Epidemiological studies suggest that diets rich in phytoestrogens
(plant estrogens), particularly soy and unrefined grain products, may be
associated with low risk of breast and prostate cancer. It has also been
proposed that dietary phytoestrogens could play a role in the prevention
of other estrogen-related conditions, namely cardiovascular disease,
menopausal symptoms and post-menopausal osteoporosis. However, there is
no direct evidence for the beneficial effects of phytoestrogens in
humans. All information is based on consumption of phytoestrogen-rich
diets, and the causal relationship and the mechanisms of phytoestrogen
action in humans still remain to be demonstrated. In addition, the
possible adverse effects of phytoestrogens have not been evaluated. It
is plausible that phytoestrogens, as any exogenous hormonally active
agent, might also cause adverse effects in the endocrine system, i.e.
act as endocrine disrupters."

**Whitten PL, Patisaul HB.** Cross-species and interassay comparisons of
phytoestrogen actions. *Envir Health Perspect*, 2001, 109, Suppl 1,
5-20.

"In vivo data show that phytoestrogens hav ea wide range of biologic
effects doses and plasma concentrations seen with normal human diets.
Signfiicant in vivo resonses have been observed in animal and human
tests for bone, breast, ovary, pituitary, vasculature, prostate and
serum lipis. . Steroidogenesis and hypothalmamic-pituitary-gonadal axis
appear to be important loci of phytoestrogen actions, but these
inferences must be tentative because good dose-response data are not
available for many end-points."\
\
**Anderson D, Dobrzynska MM, Basaran N.** Effect of various genotoxins
and reproductive toxins in human lymphocytes and sperm in the Comet
assay. *Teratog Carcinog Mutagen*. 1997;17(1):29-43.\
\
"There have been conflicting reports as to whether the mean sperm count
in some men has diminished over the last 50 years. The downward trend
has been suggested to coincide with an increase in exposure to
estrogen-like compounds. These estrogenic substances are ubiquitous in
the environment. We have examined the effect of such substances
(diethylstilbestrol, beta-estradiol, daidzein, genestein, and
nonylphenyl) in the single cell gel electrophoresis assay (Comet assay)
in human sperm and compared responses with those from human peripheral
lymphocytes in the same donor and in peripheral lymphocytes from a
female donor. In addition, effects from the estrogens have been compared
to those from known reprotoxins and genotoxins. These include lead
sulfate, nitrate and acetate, dibromochloropropane, ethylene glycol
monoethyl ether, 1,2-epoxybutene, and 1,2,3,4-diepoxybutane. All
compounds produced positive responses, but ethylene glycol monoethyl
ether only produced positive responses in sperm cells in the male and
not in peripheral lymphocytes, and similarly the phytoestrogens
(genistein, daidzein) were less responsive in the peripheral lymphocytes
in the male than in the sperm. This may be due to greater sensitivity of
sperm cells because of their lack of repair. However, since damage was
generally seen over a similar dose range, a one-to-one ratio of somatic
and germ cell damage was observed and has implications for man for risk
assessment purposes."

**Yellayi S, Naaz A et al. The phytoestrogen genistein induces thymic
and immune changes: a human health concern?** *Proc Natl Acad Sci* U S
A. 2002 99, 11, 7616-7621.\
"Use of soy-based infant formulas and soy/isoflavone supplements has
aroused concern because of potential estrogenic effects of the soy
isoflavones genistein and daidzein. Here we show that s.c. genistein
injections in ovariectomized adult mice produced dose-responsive
decreases in thymic weight of up to 80%. Genistein\'s thymic effects
occurred through both estrogen receptor (ER) and non-ER-mediated
mechanisms, as the genistein effects on thymus were only partially
blocked by the ER antagonist ICI 182,780. Genistein decreased thymocyte
numbers up to 86% and doubled apoptosis, indicating that the mechanism
of the genistein effect on loss of thymocytes is caused in part by
increased apoptosis. Genistein injection caused decreases in relative
percentages of thymic CD4(+)CD8(-) and double-positive CD4(+)CD8(+)
thymocytes, providing evidence that genistein may affect early thymocyte
maturation and the maturation of the CD4(+)CD8(-) helper T cell lineage.
Decreases in the relative percentages of CD4(+)CD8(-) thymocytes were
accompanied by decreases in relative percentages of splenic CD4(+)CD8(-)
cells and a systemic lymphocytopenia. In addition, genistein produced
suppression of humoral immunity. Genistein injected at 8 mg/kg per day
produced serum genistein levels comparable to those reported in soy-fed
human infants, and this dose caused significant thymic and immune
changes in mice. Critically, dietary genistein at concentrations that
produced serum genistein levels substantially less than those in soy-fed
infants produced marked thymic atrophy. These results raise the
possibility that serum genistein concentrations found in soy-fed infants
may be capable of producing thymic and immune abnormalities, as
suggested by previous reports of immune impairments in soy-fed human
infants."

The following studies offer a good cross section of the evidence that
soy protein stresses the pancreas and may contribute to or cause cancer.

**Rackis JJ, Gumbmann MR, Liener IE**. The USDA Trypsin Inhibitor
Study,I. Background, objectives and procedural details. *Qual Plant
Foods Hum Nutr*, 1985, 35, 213-242.

**Liener IE, Nitsan Z et al.** The USDA Trypsin inhibitor study, II.
Timed release biochemical changes in the pancreas of rats. *Qual Plant
Foods Hum Nutr,* 1985, 35, 243-257.

**Spangler WL, Gumbmann MR et al.** The USDA Trypsin Inhibitor Study,
III. Sequential development of pancreatic pathology in rats. *Qual Plant
Foods Hum* *Nutr,* 1985, 35, 359-274.

**Gumbmann MR, Spangler WI et al.** The USDA Trypsin Inhibitor Study,
IV. The chronic effects of soy flour and soy protein isolate on the
pancreas in rats after two years. *Qual Plant Foods Hum Nutr,* 1985, 35,
275-314.

**Roebuck BD.** Trypsin Inhibitors: potential concern for humans? *J.
Nutr*, 1987, 117, 398-400.

**Myers BA, Hathcock J et al.** Effects of dietary soya bean trypsin
inhibitor concentrate on initiation and growth of putative preneoplastic
lesions in the pancreas of the rat. *Food Chem Toxic*, 1991, 29, 7,
437-443.

**Liener IE.** Letter to the editor: Soybean protease inhibitors and
pancreatic carcinogenesis, *J. Nutr*, 1996, 126, 582-583.

Studies implicating soy and leukemia are as follows:

**Strick R, Strissel PL et al.** Dietary bioflavonoids induce cleavage
in the MLL gene and may contribute to infant leukemia. *Proc Natl Acad
Sci* USA, 2000, 25, 97, 9, 4790-4795.\
"Chromosomal translocations involving the MLL gene occur in about 80% of
infant leukemia. In the search for possible agents inducing infant
leukemia, we identified bioflavonoids, natural substances in food as
well as in dietary supplements, that cause site-specific DNA cleavage in
the MLL breakpoint cluster region (BCR) in vivo. The MLL BCR DNA
cleavage was shown in primary progenitor hematopoietic cells from
healthy newborns and adults as well as in cell lines; it colocalized
with the MLL BCR cleavage site induced by chemotherapeutic agents, such
as etoposide (VP16) and doxorubicin (Dox). Both in vivo and additional
in vitro experiments demonstrated topoisomerase II (topo II) as the
target of bioflavonoids similar to VP16 and Dox. Based on 20
bioflavonoids tested, we identified a common structure essential for
topo II-induced DNA cleavage. Reversibility experiments demonstrated a
religation of the bioflavonoid as well as the VP16-induced MLL cleavage
site. Our observations support a two-stage model of cellular processing
of topo II inhibitors: The first and reversible stage of topo II-induced
DNA cleavage results in DNA repair, but also rarely in chromosome
translocations; whereas the second, nonreversible stage leads to cell
death because of an accumulation of DNA damage. These results suggest
that maternal ingestion of bioflavonoids may induce MLL breaks and
potentially translocations in utero leading to infant and early
childhood leukemia."

> **Editorial \--** Infantile Leuemia and soybeans -- a hypothesis
> *Leukemia,* 1999, 13, 317-320.
>
> "Recent molecular-genetic studies have revealed that in the majority
> of patients with secondary leukemia induced by topoisomerase II (topo
> II) inhibitors and also with infantile acute leukemia (IAL), the
> breakpoints are clustered within scaffold attachment regions (SARS) of
> 3"-MLL-bcr near exon 9. Genistein, abundant in soybeans, is reported
> to be a potent nonintercalative topo II inhibitor. It interferes with
> the break-reseal reaction of topo II by stabilizing a cleavable
> complex, which in the presence of detergents, results in DNA strand
> breaks. The present study revealed that genistein induced
> chromatid-type aberrations in which chromatid exchanges are often
> observed. Genistein seems to act in a manner very similar to that of
> VP-16, although the latter is reported to produce both
> chromatid-and-chromosome-type aberrations. In view of this
> pharmacological similarity between genistein and VP-16, and also the
> similarity of breakpoint clustering regions within the MLL gene in
> reported cases with secondary leukemia and IAL, genistein may be
> largely responsible for the development of IAL."
>
> \* \* \* \* \* \* \* \* \*
>
> IN CONCLUSION: We have provided abundant scientific evidence
> indicating that consumption of soy protein/soy isoflavones can
> contribute to various types of cancer. Allowance of a claim that soy
> prevents cancer would be false and misleading and would constitute a
> betrayal of public trust.