Soy Isoflavones, Panacea or Poison?

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Soy Isoflavones, Panacea or Poison?

by Mike Fitzpatrick, PhD, MNZIC

 

The following article was submitted to the FDA in an effort to block

inclusion of estrogen-like compounds called isoflavones, found in large

amounts in soy products, in the GRAS (Generally Recognized as Safe) list of

ingredients in foods and medicines.

 

Introduction

 

The Archer Daniels Midland Company (ADM) have provided the Food and Drug

Administration (FDA) with notice that it has determined that the substance

soy isoflavone is generally recognised as safe (GRAS). This notice was made

in accordance with the FDA proposed rule 'Substances Generally Recognized as

Safe' 21 CFR Parts 170, 184, 186 and 570. In support of this notice, ADM

have provided a document entitled " An information document reviewing the

safety of soy isoflavones used in specific dietary applications. "

 

In my opinion soy isoflavone (or more correctly, the soy isoflavones) should

not be granted GRAS status. In fact given the current state of knowledge in

the body of scientific literature it would make more sense, in terms of risk

assessment, to prohibit the addition of soy isoflavones to foods. Further,

manufacturers should act to minimise the exposure of the human and animal

population to these compounds that appear to occur in all foods that contain

soy protein. This opinion is based on my understanding of the scientific

literature on soy isoflavones and some experience as a researcher in the

field.

 

Soy Isoflavones: History of Use

 

In order to prove the GRAS status of soy isoflavones it is critical for ADM

to demonstrate that soy isoflavones have enjoyed a long and safe history of

use. Hence ADM claim that 'these isoflavone components...have been consumed

by millions of humans for over two thousand years'. However, their claim is

not based on fact and neither is there any evidence provided to substantiate

their claim.

 

The claim that isoflavones have been consumed for thousands of years has

become quite common in isoflavone scientific literature, however it is no

more than an assumption and appears based on the general perception that

historical soybean consumption was widespread in Asia.

 

Although soybean products have been consumed in some parts of Asia for many

hundreds of years (1) they did not form a significant part of the diet (2).

Also, the traditional soybean was quite different to the soybean as we know

it today.

 

Glycine soja , the wild soybean, is found in northern, north-eastern and

central China, adjacent areas of the former USSR, Korea, Taiwan and Japan.

Glycine soja is the species of soybean that was consumed traditionally and

is the ancestor of the modern cultivar, Glycine max (3).

 

The isoflavone content of Glycine max was first reported about 60 years ago

(4) but it is impossible to know with certainty whether Glycine soja

contained isoflavones. It is well established that Glycine max is,

compositionally, quite different to Glycine soja . For example, Glycine max

contains approximately 21.0% oil compared with 9.8% in Glycine soja and

Glycine max also contains more protein (3). This is quite expected because

Glycine max has been cultivated to have maximised economic potential.

 

It has also been shown that plants such as that as Glycine max produce

phytoestrogens such as the soy isoflavones as a defence mechanism in

response to pests (5). Increased disease resistance has been a consistent

goal of soybean breeders and it is quite conceivable that this goal has

served to increase the levels of isoflavones, and other naturally occurring

toxins, in Glycine max .

 

It is also well established that different cultivars of Glycine max can

contain widely variable levels of isoflavones (6). If this is so then it is

not implausible that the traditional Asian soybean, Glycine soja , contained

quite low levels of isoflavones, or perhaps none at all.

 

Therefore, a counter argument to the ADM claim of long and safe use could be

that isoflavones have entered the human food chain only in relatively recent

times. It has been the cultivation of Glycine max coupled with mass

production technology and incorporation of soy protein into numerous foods

that has resulted in these compounds being almost unavoidable in the human

diet. This mass exposure has only occurred in the last 30 years and it is

still undetermined whether isoflavones are safe or not.

 

In summary, ADM cannot show a long and safe history of use because there is

no evidence to substantiate their claim 'that isoflavones have been consumed

by millions of humans for over two thousand years'.

 

Soy Isoflavones: Safety of Use

 

ADM claim 'a long safe history of consumption for soy products and soy

foods'. The issue of the safety of soy products in relation to isoflavone

toxicity and risk:benefit considerations has been the subject of a recently

published paper (7) by a senior scientist at the FDA National Center for

Toxicological Research (NCTR), Dr Daniel Sheehan. Sheehan is 'unconvinced

that the long history of apparent safe use of soy products can provide

confidence that they are indeed without risk' and likens soy products to

herbal medicines stating that the 'confidence that soy products are safe is

clearly based more on belief than hard data'.

 

Even if ADM'S claims in relation to soy isoflavones, 'no toxic effects at

normal dietary levels', were correct (which they are not, see Section 4)

this does not provide evidence that soy products are safe. This is because

the potential harmful effects of soy isoflavones have never been thoroughly

investigated.

 

There have been several studies that attempt to define the acute toxicity of

soy isoflavones in various experimental animals and these are cited in the

ADM document.

 

However, the prime concern in relation to estrogenic compounds such as the

soy isoflavones is the potential for chronic endocrine system and

reproductive toxicity and alterations to the immune system (8,9). As such

the harmful effects of soy isoflavones would not have been obvious if they

did exist. A compelling example is the estrogenic drug, diethylstilbestrol

(DES). Treatment with DES continued for over 20 years before physicians

fortuitously made the association between its use and the incidence of a

rare type of malignancy in DES daughters (10). In the case of soy

isoflavones, however, the fact that estrogenic compounds are present in soy

foods has not been general knowledge to health professionals until quite

recently. Therefore, any link between effect and cause is unlikely to have

been made.

 

Until more extensive epidemiological studies are undertaken with clearly

identified endpoints (such as breast cancer, thyroid disease or immune

system dysfunction) it must be concluded that there is no certainty that soy

isoflavones are safe at all.

 

Soy Isoflavones: Adverse Effects

 

ADM argue that 'these isoflavone components...have been consumed by millions

of humans for over two thousand years with no recorded adverse effects'.

Furthermore ADM claim that 'published epidemiology and feeding studies in

both animals and humans indicate no toxic effects at normal dietary levels'

and that 'soy isoflavones, as part of a soybean based diet, are not

associated with reports of adverse health effects'.

 

It is difficult to reconcile these statements with published scientific

literature which is replete with reports of adverse effects and toxicity of

isoflavones at dietary levels. In fact it was the toxicity of dietary levels

of isoflavones to animals that first raised the awareness of the scientific

community to the fact that soy isoflavones were endocrine disrupters (11).

 

Reproductive effects, infertility, thyroid disease or liver disease due to

dietary intake of isoflavones had been observed for several animals

including cheetah (12), quail (13), mice (14), rats (15), sturgeon (16) and

sheep (17).

 

With regard to sheep toxicity ADM claim that the 'adverse effects were

attributed to feeding on subterranean clover and are associated with

coumestrol and the isoflavone formononetin'. This is another example of

misinformation in the ADM document. In fact it is generally accepted that

sheep metabolise formononetin to the soy isoflavone daidzein. Daidzein is,

in turn, metabolised to equol which is believed to be responsible for the

type of infertility referred to as 'clover disease' (18). There can be no

doubt that if sheep were fed a diet supplemented with soy isoflavones they

would, depending on dose and duration, develop clover disease.

 

In another study it has also been reported that 9 out of 20 young calves

died when fed a soybean milk replacer (19). The authors implicated 'phenolic

compounds' as the reason of increased prostaglandin synthesis,

gastrointestinal disorders, tachycardia, bronchoconstriction and death. Soy

isoflavones have the potential to interfere with normal prostaglandin

synthesis and are, therefore, a likely explanation for this toxicity in

calves. It should be noted that in a control group of calves fed an ethanol

extracted soybean milk replacer, only 4 out of 20 deaths occurred. Ethanol

extraction reduced the amount of phenolics, which would have included

isoflavones, in the soybean milk replacer 2.18% to 1.00%.

 

ADM claim that 'infertility effects are not general to all animals ' citing

work by Lundh (20). However, this author does not even investigate

inter-species differences in reproductive toxicity due to isoflavones.

Rather, his work shows how different species metabolise isoflavones

differently. Although not all animals become infertile after consuming soy

isoflavones at normal dietary levels for restricted periods, feeding at such

levels does result in profound endocrine effects in all animals species

studied to date.

 

ADM also claim that 'soy isoflavones have been widely consumed and are

recognised to be non-toxic' citing Petrakis et al. (21) and Setchell et al.

(22). In fact, nowhere in either of these papers do the authors state that

soy isoflavones are recognised as non-toxic.

 

Petrakis et al. found that consumption of soy protein has a stimulatory

effect on the pre-menopausal breast. Although Setchell et al. state that

'there is no evidence to suggest that ingestion of isoflavones...has adverse

effects in human beings', they acknowledge 'the potential effect that these

bioactive compounds may produce...is unknown'.

 

It is incorrect to state that there is no evidence of harmful effects of soy

isoflavones on humans. In fact there is mounting evidence that dietary

levels of soy isoflavones cause thyroid disease and may increase the risk of

breast cancer.

 

Goitre and hypothyroidism were reported in infants fed soybean diets until

the early 1960's (23). In fact recent reports indicate that thyroid

disorders may be attributable to feeding soy-based infant formulas (24-25).

Further, a study on 37 adults showed that diffuse goitre and hypothyroidism

appeared in half of the subjects after consuming 30 g per day of pickled

roasted soybeans for three months (26). These findings are consistent with

the recently proposed mechanism by which soy isoflavones affect thyroid

hormone synthesis (27).

 

It is concluded that soy isoflavones can be the cause of thyroid disorders

in soy consumers and, hence, there is every indication that cases of goitre

and hypothyroidism in infants were caused by the soy isoflavones. Unless

diets that include soy isoflavones are adequately supplemented with iodine,

goitre will result. In this regard Kay et al. discuss the minimum safety

iodine requirement for a soybean diet (28).

 

However, even if iodine supplementation does occur, under conditions of high

chronic doses of isoflavones persistent inhibition of thyroid hormone

synthesis could potentially lead to thyroid cancer (27).

 

With regard to breast cancer, Dees et al. have shown that dietary

concentrations of genistein may stimulate breast cells to enter the cell

cycle; this finding led these authors to conclude that women should not

consume soy products to prevent breast cancer (29). This work is consistent

with an earlier report by Petrakis et al. who expressed concern that women

fed soy protein isolate have an increased incidence of epithelial

hyperplasia (21).

 

There is no doubt that soy isoflavones are biologically active in humans.

The first report of a definitive experiment which showed this involved the

consumption of 60g of soy protein per day for one month by pre-menopausal

women (30). The soy isoflavones disrupted the menstrual cycle during, and

for up to three months after, administration. With regard to this study the

ADM document claims 'no adverse effects were noted' but the authors of the

original paper did not state this. It is appreciated that there are varying

opinions in the scientific community as to what constitutes toxicity. In

recent times, however, there has evolved a greater understanding of

endocrine disrupters and their effects. Many now view the multiplicity of

effects that endocrine disrupters can induce as toxic effects (8).

 

The inclusion of endocrine disrupters in human diets should not be taken

lightly. With specific reference to soy-based infant formulas the high soy

isoflavone intake of this population group has led Dr Sheehan to note that

infants fed soy-based formulas have been placed at risk in a 'large,

uncontrolled, and basically unmonitored human infant experiment' (31). If

soy isoflavones are granted GRAS status this experiment would spread to the

greater population and millions would be exposed to compounds which are

increasingly being shown to have adverse effects.

 

Also, the synergistic effects that soy isoflavones may induce when combined

with other xenoestrogens that the human population are exposed are beyond

the scope of this document. However, there is a general thesis that because

of the potential for synergistic effects, human exposure to all endocrine

disrupters, such as the soy isoflavones, requires urgent reduction (8).

 

Soy Isoflavones: Benefits

In recent times there have been numerous claims that isoflavones prevent

hormone related diseases such as breast cancer. Under some conditions

genistein has been found to inhibit breast cancer cell growth (32). However,

there is no consensus amongst scientists that isoflavone ingestion reduces

breast cancer risk.

 

Recently the UK government published a definitive review assessing the

effects of phytoestrogens in the human diet (33). This study found that

there was almost no evidence linking health benefits from foods containing

isoflavones to the isoflavones themselves.

 

Similarly in their review of phytoestrogens and western diseases,

Adlercruetz and Mazur assert that any benefits from soy products are not due

to isoflavones specifically. They conclude that the combination of a high

phytoestrogen intake with a western diet may not be beneficial (34).

 

ADM state that 'epidemiological studies between Western and Far Eastern

populations suggest that components of soybeans may contribute to important

health effects'. However an epidemiological study in China has shown that

high soy intake is not protective against breast cancer (35).

 

Based on evidence to date it is concluded that there is little evidence for

the beneficial effects of soy isoflavones. Indeed authorities in the field

do not support the ADM thesis that soy isoflavones 'provide positive health

maintenance benefits'.

 

Summary and Conclusions

In conclusion, the recognition by the Archer Daniels Midland Company that

soy isoflavones are generally recognised as safe (GRAS) is seriously flawed.

The supporting document entitled 'An information document reviewing the

safety of soy isoflavones used in specific dietary applications' contains

factual errors, misrepresents cited authors and does not present the full

body of current scientific evidence. The conclusions reached in the ADM

document are not based on fact:

 

There is no evidence of a long and safe history of use or that 'these

isoflavone components...have been consumed by millions of humans for over

two thousand years'.

 

It is not correct that 'published epidemiology and feeding studies in both

animals and humans indicate no toxic effects at normal dietary levels' or

that 'soy isoflavones, as part of a soybean based diet, are not associated

with reports of adverse health effects'.

 

Benefits of dietary intake soy isoflavones have not been proven. To the

consumer, dietary soy isoflavones represent a clear risk whereas the

benefits are highly questionable. Rather than accept that soy isoflavones

are GRAS, it is my opinion that regulatory agencies such as the FDA should

give full attention to consumer protection and deny GRAS status to soy

isoflavones.

 

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