Natural compound genistein

1. Introduction

In this report a risk assessment on the natural compound genistein will be done. A risk assessment is a powerful tool to determine the possible toxic effects on human beings. Present data on toxicity of genistein are used to extrapolate a possible risk from experimental animals to humans to establish an acceptable daily intake (ADI). Concentrations causing toxicity in these experiments are compared to daily intakes of genistein through human nutrition in different groups to quantify and qualify toxicity of genistein in humans.

2. Information on the compound

Table 1: Physochemical properties of genistein

Chemical property

Value (+ unit)


Molecular structure


ChemId plus website

Molecular weight


National Toxicology Program website, 2010

CAS number


Chemindex website, 2010

Log Kow

2.84 (est.)

National Toxicology Program website, 2010


Soluble in the usual organic solvents; soluble in dilute alkalies with yellow color. Practically insoluble in water.

National Toxicology Program website, 2010

Henry constant

5.1 x 10-17 atm-cu m/mole at 25 deg C (est)

National Toxicology Program website, 2010

Half-life (per medium, if relevant per condition)

5.7 +/- 1.3 h in human blood plasma

King et al. (1998)

What is (are) the main route(s) of (bio)degradation

Bacterial degradation of genistein (hydrolysis) followed by conjugation to glucuronic acid and sulfate, catalysed by phase II enzymes, leads to an excretion through bile and urine in human.

Yeh (2003)

Steensma (2006)

Special feature or use of the compound

Genistein is an isoflavone belonging to the group of phytoestrogens.


Genistein is an isoflavone that shares similarities in structure to estrogen and is able to interact with estrogen receptors (Mazur, 2000). Glycosides are the predominant form of genistein in unfermented soy products; glycosides (e.g. genistin) are formed by the conjugation of genistein to a sugar molecule (NTP, 2006; COT report, 2003). Unconjugated genistein (aglycones) represents only a small amount of total genistein in unfermented soy products, whereas in fermented food products aglycones are predominant (NTP, 2006; COT report, 2003). Genistein is a hydrophobic compound, and as a consequence nearly insoluble in water (National Toxicology Program website, 2010; COT report, 2003). Nevertheless, the water solubility may increase after conjugation to glucose, glucuronide or sulfate groups (COT report, 2003). After genistein is consumed, glycosides can be deconjugated by bacterial enzymes, β-glucuronidase or arylsulfatase, in the gut (Yeh, 2003 and references therein). After hydrolysis is completed, metabolites can be absorbed or further metabolized by microflora that are predominantly present in the colon (Yeh, 2003 and references therein). When aglycones reach the small intestine, they are quickly absorbed since these compounds have a lower polarity and molecular weight compared to the glycosides (Yeh, 2003 and references therein). In the colon, de-conjugated genistein and unabsorbed aglycones are metabolized to dihydrogenistein followed by the formation of 6'-hydroxy-demethylengolensin as is displayed in figure 1 (Yeh, 2003; Steensma, 2006). Further degradation may eventually lead to the metabolic product 4-ethyl phenol (Steensma, 2006). After absorption, genistein is conjugated in the liver for the greater part to glucuronic acid by UDPGT, conjugation to sulfate by sulfotransferase enzymes takes place to a smaller extend (Yeh, 2003; Steensma, 2006; NTP, 2006). The formed conjugated metabolites may enter the enterohepatic circulation and biliarly excretion may follow (Yeh, 2006; NTP, 2006). In the urine, genistein is excreted as a monoglucuronide, diglucuronide, and as a sulfoglucuronide (Steensma, 2006; Alderkreutz 1995). An overview of several chemical properties of genistein can be found in table 1.

3. Basic info: Framework of the risk assessment

Table 2: Basic information on genistein

Background info



Used for

Genistein can be acquired from soy and other legumes; it may be used in cancer treatment (i.e. as an anti-neoplastic and anti-tumor agent). Also used as supplements to releave post-menopausal symptoms e.g. hot flashes Osteoporosis, opvliegers

NTP-CERHR (2006)

ChemID plus website (2010)

Setchell (2001)

Sources (where/how is it produced and reaches food/drinking water)

Soybeans are the most important source of genistein. In addition, other legumes such as lentils and chickpeas comprise relatively low quantities of genistein.



COT report, 2003

Especially present in

Human exposure to genistein mainly occurs through the consumption of foods that consist of soybeans and/or soy protein, including dietary supplements and soy-based infant formula.



Specifically exposed people

Eastern populations, vegans and vegetarians may be specifically exposed to genistein as a result of higher dietary intakes.


McCauley (2005)

COT report, 2003 and references therein

Genistein is one of several known isoflavones. Isoflavones, such as genistein and daidzein, are found in a number of plants, being the primary food source. Genistein is a naturally occurring compound that can be found in legumes, principally soybeans (DELCLOS, 2007; NTP-CERHR, 2006; COT report, 2003). Consequently, genistein can be found in a wide variety of soy based foodstuffs. Some examples are tempeh, soy milk and tofu (NTP-CERHR, 2006 and references therein). Due to differences in food preparation, however, genistein levels within these products may differ (NTP-CERHR, 2006; COT report, 2003: and references therein). Moreover, not only the method of processing influences the quantity of genistein in soy products, differences in geographic location were the soy is grown, climate, and harvesting procedures, may cause wide variations in the level of genistein (NTP-CERHR, 2006; COT report, 2003: and references therein). Overall, the Asiatic population comprises relatively high intake levels of genistein as a result of notable amounts of soy in the traditional Asian diet (NTP-CERHR, 2006; McCauley, 2005; COT report, 2003 and references therein). A second group of people that are specifically exposed to genistein are vegetarians and vegans; both vegan and vegetarian diets consist of relative high quantities of soy-based foodstuffs as a replacement for meat and dairy products (NTP-CERHR, 2006; COT report, 2003: and references therein). Genistein and other isoflavones have been found to have other effects such as blocking the formation of new blood vessels, and may block the uncontrolled cell growth associated with diabetes, most likely by inhibiting the numberof substances in the body that regulate cell division and growth factors.

4. Hazard identification

Table 3: Overview of toxic effects of genistein

Toxic effects

Facts + species


General toxicity (what is found at high acute or at low chronic exposure)


Animal (lab)

Kijkuokool et al. (2006)

Enhancement of NMU-induced tumorigenesis in adult female rats after supplementation of genistein at a dosage comparable to the isoflavone consumption in humans.

Carcinogenic if exposure occurs during critical periods of differentiation in mice.

Newbold et al. (2001)

High dose of genistein throughout the lifespan led to decreased bone size in rats.

Hotchkiss et al. (2005)

High acute exposure resulted in lethargy and alopecia (baldness) in Wistar rats.

McClain et al. (2006)

Other animals

McClain et al. (2005)

Atrophy of the testes and prostate gland and absence of spermatozoa in the epididymus in beagle dogs after chronic exposure.

Specific toxicity (name mechanism of specific effects)

Estrogen agonist, with an estrogenicity 1/1000th to 1/10000th that of 17b-estradiol.

Genistein competes with estradiol for binding to estradiol receptors (ER) on specific cells or cytosol.

Whitten et al. (2001)

Causes DNA strand breaks by Inhibition of tyrosine kinase and topoisomerase II activity, which are involved in DNA replication and transcription.

Markovitz et al. (1989); Kiguchi et al. (1990)

Specific effects (are specific groups of people extra vulnerable for this compound?)

Estrogenic effect which make women with estrogen receptor-positive tumors, pregnant women, nursing mothers and men with prostate cancer extra vulnerable.

Toxnet website, 2010

Postmenopausal women who are treated with TAM (Tamoxifen) for estradiol responsive breast cancer.

Ju et al. (2002)

Individuals with hypothyroidism due to interference with thyroxine replacement therapy.

Toxnet website,


According to epidemiological studies genistein could be used as a chemo preventive agent for a variety of diseases and cancer. Although high consumption of foods containing considerable amounts of genistein did not show any adverse effect in epidemiological studies, increasing concern has emerged on potential adverse effects of genistein due to its estrogenic activity and some other activities (McClain, 2006). Few data are available on toxicity of genistein in humans since most of the experiments are done on laboratory animals and cell-lines. Animal and cell culture studies could be valuable for establishing guidelines on daily intake of genistein but comparison of cell culture studies with animal studies indicate highly variable and sometimes contrasting results which render them less useful.

Genistein can exert an estrogenic effect through interaction with estrogen receptors (ER-b in particular). Also actions involving growth factors, modulation of the action of endogenous estrogens and regulation of enzymes such as tyrosine kinase are attributed to genistein (Branca, 2003). Reviewing the available data, genistein mainly can do harm in vulnerable groups like neonates, women with estrogen-receptor positive tumors and postmenopausal women treated with Tamoxifen.

5. Hazard quantification & effects assessment

Table 4: Effects assessment


Doses tested






Ovariectomized mice

2-200 mg/kg/day

2 mg/kg/day

8 mg/kg/day

7 or 21 days

Decreased thymic weight and decreased thymic and splenic CD4CD8 T cell numbers.

Yellayi et al. (2002)

Neonatal Sprague-Dawley rats

12,5-100 mg/kg/day


12,5 mg/kg/day

5 days

Dysfunction of postpubertal reproductive performance and abnormal development of the gonads in female rats.

Nagao et al. (2001)

Wistar rats

0-500 mg/kg/day

5 mg/kg/day

50 mg/kg/day

52 weeks (chronic)

Reduced body weight gain accompanied by decreased food consumption at 500 mg/kg/day genistein

Mild hepatic effect at 500 mg/kg/day genistein.

Beagle dogs

0-500 mg/kg/day



150 mg/kg/day

52 weeks (chronic)

Transient effects on organ size and weight in the reproductive tract of male dogs treated with 150-500 mg/kg/day genistein

McClain et al. (2005)

Neonatal mice

50 mg/kg/day



5 days exposure, observation after 18 months

Uterine adenocarcinomas in 35% of the mice, indicating a carcinogenic effect if exposure occurs during critical periods of differentiation.

Kijkuokool et al. (2006)

Most of the findings of toxicity studies are related to the estrogenic effect of genistein and are reversible. The most relevant toxicity studies are depicted in the table above. For instance in a study with mice which were ovariectomized to mimic endocrine conditions in human infants (circulating estrogen levels are minimal in both males and females), low doses of genistein had a considerable adverse effect on thymic and splenic CD4 CD8 T cell numbers. In the study of Nagao et al. (2001), where neonatal rats were tested with low doses of genistein, gonadal development and reproductive functioning were disturbed. These results both suggest toxicity of low doses of genistein in neonates. In studies done on adult animals the doses of genistein that caused toxic effects were considerably higher than the doses that caused toxic effects in neonates. Therefore we cannot select one ADI that will cover both groups and thus we will determine an ADI for adults and one for neonates. For determining the ADI's the studies where the lowest NOEL was found will be used (Yellayi et al. (2002) and McClain et al. (2006)), since the lowest concentrations already caused a toxic effect and with selecting these studies we will include all the other studies as well. Since we have to do with a natural compound a safety factor of 10 (instead of 100) will be used. Doing so an ADI of 0,2 mg/kg/day for neonates and 0,5 mg/kg/day for adults can be obtained.

6. Exposure assessment

Table 5: Genistein levels in different foods

Food product

Analytical method


in product (mg/100 g)

Max Intake dose (µg/kg bw) 1, 2


Dairy and eggs


0.02 - 2.58

1.3 - 173

USDA database
Umpress (2005)
Horn-Ross (2006)

Baby food (ready-to eat-foods)


1.37 - 2.69

Sorted by age 3:

1 week: 2170 - 4260

1 month: 3060 - 6022

2 months:2307 - 4530

4 months: 2005 - 3937

USDA database

Johns (2003)
Murphy (1997)

Nguyenle (1995)

Setchell (1998)

Poultry products


0.25 - 0.30

3.57 - 4.2

USDA database
Umpress (2005)

Soups, sauces and gravies


0.00 - 4.04

0.00 - 86.57

USDA database
Umpress (2005)
Thompson (2006)
Horn-Ross (2006)

Sausages and luncheon meals


0.05 - 1.00

1.4 - 28.57

USDA database Umpress (2005)
Thompson (2006)

Breakfast cereals


0.01 - 7.70

0.07 - 55

USDA database Umpress (2005)

Liggins (2002)

Fruits and fruit juices


0.01 - 0.06

0.57 - 3.4

USDA database

Thompson (2006)
Mazur (2000)
Horn-Ross (2006)
Liggins (2000)

Vegetables and vegetable products


0.00 - 22.57

0.00 - 644.86

USDA database
Antonelli (2005)

Thompson (2006)

Horn-Ross (2006)
Liggins (2000)

Nuts and seeds


0.01 - 1.75

0.57 - 10

USDA database
Thompson (2006)

Gentile (2007)
Liggins (2000)
Simonne (2000)

Finfish and shellfish


0.05 - 0.15

0.71 - 2.4

USDA database

Umpress (2005)

Thompson (2006)

Legumes and legume products


0.00 - 114.71

0.00 - 1229

USDA database

Wang (1990)
Achouri (2005)
Antonelli (2005)

Fast foods


0.01 - 13.10

2.85 - 374.29

USDA database Umpress (2005)

Thompson (2006)



0.00 - 13.60

0.00 - 194.29

USDA database Umpress (2005)





Life extension website, 2010

1 portion sizes are based on the website of ‘'het voedingscentrum''. 2 daily intakes are based on 70 kg bw .

3 daily intakes are based on average bw per age (Setchell (1998)).

Especially the group of legumes and legume products contains the largest quantities of genistein per 100 g product among the food groups displayed in table 5. This group consists partly of soy and soy based products. When the concentration of individual foodstuffs within this group is evaluated, it can be seen that soy and soy-based products contain substantial amounts of genistein, while other foods such as beans hardly contain any genistein. When corrected for the maximal daily intake, this food group results in a high exposure level. Surprisingly, babies that are fed soy based infant formula are highly exposed. Noteworthy, levels of genistein intake can vary widely since it's concentration in food(products) depends on several variables (section 3). As mentioned in section 3, people consuming a soy-rich diet are mainly exposed to genistein (table 5b).

Table 5b: Genistein exposure levels of different groups


Daily intake (mg/kg bw/day)


Patients in clinical studies (US)

< 0.014

De Kleijn (2001)

Strom (1999)



Kirk (1999)



Kirk (1999)



Wakai (1999)

Arai (2000)



Kim et al. (2001)



Chen (1999)

Seow (1998)

Infants fed soy formula


NTP-CERHR, 2006 CERHR Expert Panel Report on Soy Formula

Please be aware that the free essay that you were just reading was not written by us. This essay, and all of the others available to view on the website, were provided to us by students in exchange for services that we offer. This relationship helps our students to get an even better deal while also contributing to the biggest free essay resource in the UK!