Page 1 **SOY INFORMATION SERVICE**

**P. O. Box 3285, Onerahi, Whangarei, NZ**

**Ph 09-4340564. Fx 09-4340567**

[www.soyonlineservice.co.nz](http://www.soyonlineservice.co.nz/)

Ms Shellee Anderson; April 27, 2004

Team Leader; Nutrition Policy,

Division of Dockets Management, By EMAIL and BY AIR-MAIL\
Food and Drug Administration,\
5630 Fishers Lane, Room 1061 (HFA-305)\
Rockville, MD 20852, USA

[Docket \# **2004Q-0151 Solae Corp Health Claim re Cancer**]{.underline}

Dear Ms Anderson,

In preparing this petition for filing we would like your staff to
consider the following information. These are all abstract references to
research published in the NIH Medline data base, and the full research
is available via these abstracts. You can see that these are from some
very reputable research institutions, and some like the Dept of Energy
and NCTR are Federally operated and funded. Soy Information Service is
shocked that a publicly held corporation would seek health **benefit**
claims- labeling, without revealing very well-documented **risks** of
cancer causation and acceleration by the same product

These are risks to consumers of cancers from the Solae (and other) soy
products, and do not include the other well-known risks to other organs
and bodily functions posed by soy consumption. For instance, FDA
scientists Dr D M Sheehan and Dr D Doerge have raised some of them in
the letter here \>.
<http://abcnews.go.com/onair/2020/2020_000609_soyfdaletter_feature.html>

\(1\)

  ------------------------------------------------------ ----------------
  ![](media/image1.wmf)**1:** Cancer Epidemiol           
  Biomarkers Prev. 2002 Dec;11(12):1674-7.               

  ------------------------------------------------------ ----------------

**Dietary soy and increased risk of bladder cancer: the Singapore
Chinese Health Study.**\
**Sun CL, Yuan JM, Arakawa K, Low SH, Lee HP, Yu MC.**\
USC/Norris Comprehensive Cancer Center, University of Southern
California Keck School of Medicine, Los Angeles, California 90089, USA.

**\"...**..the highest quartile of energy adjusted total soy intake was
associated with a 2.3-fold increase in bladder cancer.........the
soy-cancer risk relationship became stronger when the analysis was
restricted to subjects with longer duration of follow-up.\"

\(2\)

  ----------------------------------------------------- -----------------
  ![](media/image2.wmf)**1:** Environ Health Perspect.  
  1997 Apr;105 Suppl 3:633-6.                           

  ----------------------------------------------------- -----------------

**Dietary estrogens stimulate human breast cells to enter the cell
cycle.**\
**Dees C, Foster JS, Ahamed S, Wimalasena J.**\
Health Sciences Research Division, Oak Ridge National Laboratory,
Tennessee, USA.

\"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 human breast
cancer cells to enter the cell-cycle\" \"[women should not consume
particular foods (eg. soy-derived products) to prevent breast
cancer](../Refs/Dees.htm)\'.

Page 2

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  \(3\) ![](media/image2.wmf)**1:** Cancer Epidemiol     
  Biomarkers Prev. 1996 Oct;5(10):785-94.                

  ------------------------------------------------------ ----------------

**Stimulatory influence of soy protein isolate on breast secretion in
pre- and postmenopausal women.**\
**Petrakis NL, Barnes S, King EB, Lowenstein J, Wiencke J, Lee MM, Miike
R, Kirk M, Coward L.**\
Department of Epidemiology and Biostatistics, University of California,
San Francisco 94143-0560, USA.

\"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. 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\".

+---------------------------------------------------+------------------+
| ![](media/image2.wmf)                             |                  |
|                                                   |                  |
| \(4\) **:** J Natl Cancer Inst. 2001 Dec          |                  |
| 5;93(23):1791-8.                                  |                  |
+---------------------------------------------------+------------------+

**Breast cancer risk in women with abnormal cytology in nipple aspirates
of breast fluid.**\
**Wrensch MR, Petrakis NL, Miike R, King EB, Chew K, Neuhaus J, Lee MM,
Rhys M.**\
Dept. of Epidemiology and Biostatistics, School of Medicine, Box 1215,
University of California San Francisco, San Francisco, CA 94143, USA.\
\
\" We previously showed that women with abnormal cytology in breast
fluid obtained by nipple aspiration had an increased relative risk (RR)
of breast cancer compared with women from whom fluid was not obtained
and with women whose fluid had normal cytology. This study extends the
follow-up in the original study group ....The results obtained with the
newly followed women independently confirmed previous findings that
women with abnormal cytology in nipple aspirates of breast fluid have an
increased risk of breast cancer\".

::: Definition-Term
\(5\) **Phytoestrogen interaction with estrogen receptors in human
breast cancer cells.**
:::

::: Definition-Term
Martin PM, Horwitz KB, Ryan DS, McGuire WL
:::

::: Definition-Term
Endocrinology 1978 Nov 103:5 1860-7
:::

::: Definition-Term
\"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\".
:::

\(6\)

  -------------------------------------------------- --------------------
  ![](media/image2.wmf)**1:** Carcinogenesis. 2001   
  Oct;22(10):1667-73.                                

  -------------------------------------------------- --------------------

**Dietary genistin stimulates growth of estrogen-dependent breast cancer
tumors similar to that observed with genistein.**\
\
**Allred CD, Ju YH, Allred KF, Chang J, Helferich WG.**\
Department of Food Science and Human Nutrition and Division of
Nutritional Sciences, University of Illinois, at Urbana-Champaign, IL
61801, USA.

Page 3

**\"**The estrogenic soy isoflavone, genistein, stimulates growth of
estrogen-dependent human breast cancer (MCF-7) cells in vivo. Dietary
genistin 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 genistin and genistein. When mice
were placed on isoflavone free diets, tumors regressed over a span of 9
weeks. metabolism of genistin to genistein occurred ...In summary, the
glycoside genistin, like the aglycone genistein, can stimulate
estrogen-dependent breast cancer cell growth in vivo. Removal of
genistin or genistein from the diet caused tumors to regress\".

**(7)**

**Cancer Res. 2001 Jul 1;61(13):5045-50.**

**Soy diets containing varying amounts of genistein stimulate growth of
estrogen-dependent (MCF-7) tumors in a dose-dependent manner.**

Allred CD, Allred KF, Ju YH, Virant SM, Helferich WG.

Department of Food Science and Human Nutrition, University of Illinois,
Urbana, Illinois 61801, USA**.**

**We have demonstrated that the isoflavone, 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 diets 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.**

\(8\) **Estrogenic effects of genistein on the growth of estrogen
receptor-positive human breast cancer (MCF-7) cells in vitro and in
vivo.**

**Hsieh CY, Santell RC, Haslam SZ, Helferich WG.**

**Department of Food Science and Human Nutrition, Michigan State
University, East Lansing 48824,**

\"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 10 nM, with a concentration of 100 nM achieving
proliferative effects similar to those of 1 nM estradiol. \"

(9))

  ---------------------------------------------------- ------------------
  ![](media/image2.wmf)**1:** Am J Clin Nutr. 1998     
  Dec;68(6 Suppl):1431S-1435S.                         

  ---------------------------------------------------- ------------------

**Effects of soy-protein supplementation on epithelial proliferation in
the histologically normal human breast.**\
McMichael-Phillips DF, Harding C, Morton M, Roberts SA, Howell A, Potten
CS, Bundred NJ.\
Department of Epithelial Biology, Paterson Institute for Cancer
Research, Christie Hospital NHS Trust, Manchester, United Kingdom.\
\"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 14 d 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 is due to estrogen agonist activity
and to examine the long-term effects of soy supplementation on the
pituitary gland and breast\"

Page 4

\(10\) Cancer Res. 2002 May 1;62(9):2474-7. Related Articles, Links

Dietary genistein negates the inhibitory effect of tamoxifen on growth
of estrogen-dependent human breast cancer (MCF-7) cells implanted in
athymic mice.

Ju YH, Doerge DR, Allred KF, Allred CD, Helferich WG.

Department of Food Science and Human Nutrition, University of Illinois
at Urbana-Champaign, Urbana, Illinois 61801, USA.

\"The use of dietary isoflavone supplements by postmenopausal women with
breast cancer is increasing. We investigated interactions between the
soy isoflavone, genistein, and an antiestrogen, tamoxifen (TAM), on the
growth of estrogen (E)-dependent breast cancer (MCF-7) cells
MCF-7....... . Dietary genistein negated/overwhelmed the inhibitory
effect of TAM on MCF-7 tumor growth, lowered E2 level in plasma, and
increased expression of E-responsive 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\".

\(11\) Biochem Pharmacol. 1997 Nov 15;54(10):1087-96.

Anti-thyroid isoflavones from soybean: isolation, characterization, and
mechanisms of action.

Divi RL, Chang HC, Doerge DR.

National Center for Toxicological Research, Jefferson, AR 72079, USA.

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....... 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...\....This mechanism predicts that any
compound that inhibits TPO-mediated thyroid hormone synthesis is a
potential thyroid carcinogen\"

\(12\)

  --------------------------------------------------- -------------------
  ![](media/image2.wmf)**:** Trends Endocrinol Metab. 
  2001 Sep;12(7):320-7.                               

  --------------------------------------------------- -------------------

-   **Estrogens and cell-cycle regulation in breast cancer.**\
    **Foster JS, Henley DC, Ahamed S, Wimalasena J.**\
    Dept of OB/GYN, Graduate School of Medicine, University of
    Tennessee, Knoxville, TN 37920, USA.\
    \
    \"Clinical and experimental data have established that the leading
    cause of sporadic female breast cancer is exposure to estrogens,
    predominantly 17beta-estradiol.\"

-   \(13\)

  ------------------------------------------------- ---------------------
  ![](media/image2.wmf)**1:** Med Hypotheses. 1998  
  Jun;50(6):457-64.                                 

  ------------------------------------------------- ---------------------

**Xenoestrogens significantly enhance risk for breast cancer during
growth and adolescence.**\
\
**Ardies CM, Dees C.**\
\
Department of Biological and Exercise Sciences, Northeastern Illinois
University, Chicago 60625-4699, USA. cmardies@aol.com\
Page 5\
\"Breast cancer is one of the most common forms of cancer observed in
women, and endogenous estrogen is thought to play a major role in its
development. Because of this, any conditions or exposures which enhance
estrogenic responses would result in an increased risk for breast
cancer. The role of xenoestrogenic compounds, such as DDT, in the
etiology of breast cancer is still very controversial. In the following
paper we discuss recently-published observations by ourselves and others
which indicate that xenoestrogens may play a significant role in the
development of breast cancer. Specifically, we hypothesize that during
periods of high growth rates and during breast development the
sensitivity of breast cells to estrogenic compounds is sufficiently
great for xenoestrogens to significantly enhance risk for breast
cancer.\"

\(14\)

  ------------------------------------------------- ---------------------
  **1:** Cancer Res. 2001 Jun 1;61(11):4325-8.      

  ------------------------------------------------- ---------------------

**Uterine adenocarcinoma in mice treated neonatally with genistein.
Newbold RR, Banks EP, Bullock B, Jefferson WN.**

Developmental Endocrinology Section, Laboratory of Toxicology,
Environmental Toxicology Program, Division of Intramural Research,
National Institute of Environmental Health Sciences, Research Triangle
Park, NC 27709, USA.\
\"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\".

  ------------------------------------------- ---------------------------
  \(15\) Cancer Detect Prev.                  
  2001;25(6):527-32.                          

  ------------------------------------------- ---------------------------

Effects of the dietary phytoestrogens daidzein and genistein on the
incidence of vulvar carcinomas in 129/J mice.\
Thigpen JE, Locklear J, Haseman JK, Saunders H, Grant MF, Forsythe DB.\
Comparative Medicine Branch, National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina 27709, USA.\
\
The objective of this study was to determine the effect of dietary
phytoestrogens on the incidence of spontaneous vulvar carcinomas in
129/J mice using three natural ingredient diets and two purified diets
containing predetermined levels of daidzein and genistein. Vulvar
carcinomas in representative groups of mice were confirmed using routine
histological procedures. . We concluded that dietary levels of daidzein
and genistein were associated with an increase in the incidence of
vulvar carcinomas in mice and that the 129/J mouse may provide an animal
model for studying the development of vulvar carcinomas.

\(16\)

  -------------------------------------------- --------------------------
  **:** Oncol Rep. 1999 Sep-Oct;6(5):1089-95.  

  -------------------------------------------- --------------------------

Page 6

**Maternal exposure to genistein during pregnancy increases
carcinogen-induced mammary tumorigenesis in female rat offspring.**\
**Hilakivi-Clarke L, Cho E, Onojafe I, Raygada M, Clarke R.**\
Research Bldg., Lombardi Cancer Center, Georgetown University, NW,
Washington, DC 20007-2197, USA.

\"A high estrogenic environment in utero may increase subsequent breast
cancer risk. It was therefore determined whether a maternal exposure
during pregnancy to the phytoestrogen genistein or zearalenone, both of
which exhibit estrogenic activities in vitro and in vivo, alters breast
cancer risk among female offspring......\... The results indicate that
in utero exposure to genistein, but not to zearalenone, dose-dependently
increased the incidence of DMBA-induced mammary tumors, when compared
with the controls. Tumor growth characteristics were not altered...\...
. Our results suggest that a maternal exposure to subcutaneous
administration of genistein can increase mammary tumorigenesis in the
offspring, mimicking the effects of in utero estrogenic exposures.
Further, increased ER protein levels and reduced PKC activity in the
mammary gland may be involved in increasing susceptibility to
carcinogen-induced mammary tumorigenesis in rats exposed to genistein in
utero.\"

\(17\) Oncol Rep. 1998 May-Jun;5(3):609-16.

Maternal genistein exposure mimics the effects of estrogen on mammary
gland development in female mouse offspring.

Hilakivi-Clarke L, Cho E, Clarke R.

Lombardi Cancer Center, Research Bldg., Room W405, Georgetown
University, 3970 Reservoir Road, NW, Washington, DC, 20007-2197, USA.

\"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, and zearalenone, a mycotoxin found in agricultural
products, 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. The
estrogenic effects of zearalenone on the mammary gland, in contrast, are
probably counteracted by the permanent changes in estrus cycling.\"

::: Definition-Term
\(18\)
:::

::: Definition-Term
**Infantile leukemia and soybeans\--a hypothesis \[editorial\]** Abe T
:::

::: Definition-Term
Leukemia 1999, 13:317-20
:::

::: Definition-Term
\"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\"
:::

Page 7

(19) Exp Biol Med (Maywood). 2004 Jan; 229(1):108-17. **Effects of
     genistein or soy milk during late gestation and lactation on adult
     uterine organization in the rat.** Hughes CL, Liu G, Beall S,
     Foster WG, Davis V.

Department of Medical and Scientific Services, Quintiles, Inc., Research
Triangle Park, North Carolina 27709, USA.

In utero and lactational exposure to estrogenic agents has been shown to
influence morphological and functional development of reproductive
tissues. Thus, consumption of dietary phytoestrogens, such as
isoflavones, during pregnancy and lactation could influence important
periods of development, when the fetus and neonate are more sensitive to
estrogen exposure. In this study, reproductive outcomes after
developmental exposure to isoflavones were examined in Long-Evans rats
maternally exposed to isoflavones via a commercial soy beverage or as
the isolated isoflavone, genistein. ....... These experiments
demonstrate that developmental exposure to dietary isoflavones, at
levels comparable to the ranges of human exposure, modify expression of
the estrogen-regulated PR in the uterus of sexually mature rats weeks
after exposure ended. Since the PR is essential for regulating key
female reproductive processes, such as uterine

proliferation, implantation, and maintenance of pregnancy, its increased
expression suggests that soy phytoestrogen exposure during reproductive
development may have long-term reproductive health consequences.

+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

Concern about the potential carcinogenesis of modern soy is not new. For
example, the Committee for Food Safety was worried about it in 1966, the
definitive textbook \"Chemical Carcinogens\" published by the American
Chemical Society in 1976 had a chapter titled \"Plant Carcinogens\" that
identified soy isoflavones as known carcinogens, the Life Sciences
Committee of FASEB in its 1978 \" Evaluation of Soy Products for Human
Consumption\" for the Food and Drug Administration (SCOGS-101 under
contract to the FDA \# 223-75-2004) declined GRAS determination because
of the risks of carcinogenic nitrosamines, lysinoalanines, and nitrite
occurring during the modern processing

> Moreover in 1999, an application by Archer Daniels Midland Corp for
> GRAS determination of GRAS (GRN 00001) for isoflavones was declined
> due to the failure of the applicant to reveal health risks.
>
> This is exactly the present situation, and Soy Information Service
> urges you to follow the same course now and to decline to file this
> present application.
>
> Yours Sincerely,
>
> Soy Information Service,
>
> pp Richard F James MBA LLB
>
> Director.
>
> Encls..........Downloaded Abstracts as Above