The dietary supplement ingredient FWGE pulvis consists of an aqueous extract of the germ of wheat (Triticum vulgare) fermented with baker’s yeast (Saccharomyces cerevisiae) combined with the drying aids maltodextrin and silicon dioxide, and standardized to contain approximately 200 µg/g of the naturally occurring constituent 2,6-dimethoxy-p-benzoquinone (2,6-DMBQ). The process by which the 2,6-DMBQ content of fermented wheat germ extract is standardized was invented by Hungarian biochemist Mate Hidvegi in the early 1990s. It is produced by fermenting a fixed amount of food-grade wheat germ and water with a fixed amount of baker’s yeast in stainless steel fermentation vessels. The ratio of these ingredients is similar to those commonly used in the preparation of whole-wheat baked products. Fermentation proceeds with continuous stirring at controlled pH, temperature, and flow of filtered air for approximately 18 h. The fermentation product is decanted, separated, and fine-filtered to a cell-free solution, which is condensed under vacuum to a specified weight percentage. Food-grade maltodextrin and colloidal silicon dioxide are added and the mixture is spray-dried. The final product, FWGE pulvis, comprises 63.2% fermented wheat germ, 35.0% maltodextrin, and 1.8% colloidal silicon dioxide. The product is manufactured under pharmaceutical good manufacturing practices (GMP) and its consistent 2,6-DMBQ content has been confirmed by analysis of multiple lots of product (Tomoskozi-Farkas and Daood 2004; Boros, Nichelatti, and Shoenfeld 2005). Flavors and sweeteners may be added to FWGE pulvis and the product sold under various trade names, including FWGE and Av´e.

The dietary supplement ingredient FWGE pulvis consists of an aqueous extract of the germ of wheat (Triticum vulgare) fermented with baker’s yeast (Saccharomyces cerevisiae) combined with the drying aids maltodextrin and silicon dioxide, and standardized to contain approximately 200 µg/g of the naturally occurring constituent 2,6-dimethoxy-p-benzoquinone (2,6-DMBQ). The process by which the 2,6-DMBQ content of fermented wheat germ extract is standardized was invented by Hungarian biochemist Mate Hidvegi in the early 1990s. It is produced by fermenting a fixed amount of food-grade wheat germ and water with a fixed amount of baker’s yeast in stainless steel fermentation vessels. The ratio of these ingredients is similar to those commonly used in the preparation of whole-wheat baked products. Fermentation proceeds with continuous stirring at controlled pH, temperature, and flow of filtered air for approximately 18 h. The fermentation product is decanted, separated, and fine-filtered to a cell-free solution, which is condensed under vacuum to a specified weight percentage. Food-grade maltodextrin and colloidal silicon dioxide are added and the mixture is spray-dried. The final product, FWGE pulvis, comprises 63.2% fermented wheat germ, 35.0% maltodextrin, and 1.8% colloidal silicon dioxide. The product is manufactured under pharmaceutical good manufacturing practices (GMP) and its consistent 2,6-DMBQ content has been confirmed by analysis of multiple lots of product (Tomoskozi-Farkas and Daood 2004; Boros, Nichelatti, and Shoenfeld 2005). Flavors and sweeteners may be added to FWGE pulvis and the product sold under various trade names, including FWGE and Av´e.

Wheat germ has a long history of consumption as a food. The germ is part of the wheat kernel, along with the bran and the endosperm. Like the bran, the germ is removed in the processing of wheat to yield white flour, but it is retained in whole-wheat products. The germ constitutes approximately 2.5% (range 2% to 4%) of the total weight of the wheat kernel (Tsen 1985; Nichelatti and Hidvegi 2002). A loaf of whole-wheat bread containing about 2 cups of whole-wheat flour (∼270 g) includes about 7 g of wheat germ. Additionally, wheat germ is used as an ingredient in a wide variety of foods formulated to provide advantageous nutritional characteristics. Although it is likely that the average American’s current consumption of wheat germ is <1 g/day, it appears probable that many Americans— particularly those with a preference for whole grain foods—may consume >5 g/day of wheat germ. Those consuming whole wheat at the estimated 95th percentile of wheat consumption (600 g/day, based on data from the U.S. Department of Agriculture’s Economic Research Service [USDA/ERS 2005]) have a daily intake of wheat germ of approximately 15 g (2.5% of 600 g). In addition to the wheat germ consumed in whole-wheat products, many Americans may ingest wheat germ marketed as a food supplement. Milled wheat germ has been sold for many years for incorporation into baked products, addition to breakfast cereals, use as a meat filler, and other applications.

 Naturally occurring 2,6-DMBQ has been identified in numerous plant families in addition to wheat, including several species that are consumed as food (e.g., Compositae [ettuce, endive, artichoke, chicory, sunflower, safflower, etc.], Leguminosae [soy, beans, peas, lentils, etc.], Proteaceae [macadamia], Gramineae [cereal grains], Ericaceae [blueberry, huckleberry, cranberry, wintergreen]) (Handa et al. 1983). Given that some of these plant families are widely consumed, frequently in large quantities, it is likely that humans have considerably greater exposure to 2,6-DMBQ in their diets than would result from consumption of wheat germ alone. 

Uses in Food

FWGE pulvis has been used in Hungary since 1998 as a dietary supplement and was approved in 2002 as a “medical nutriment for cancer patients.” It is classified by the European Union (EU) as a “dietary food for special medical purposes,” a category of foods specifically processed or formulated and intended for the dietary management of patients and to be used under medical supervision, and is sold with this designation in the Czech Republic, Bulgaria, and Romania.  It is also sold as a dietary supplement in Italy, Serbia, Switzerland, Cyprus, Russia, Israel, Austria, Slovakia, South Korea, Taiwan, Japan, Hong Kong, Australia, and New Zealand.  In the United States, FWGE pulvis is intended to be added to dietary supplements at a level of 8.5 g/dose for an average adult. For a 70-kg individual, this is equivalent to an intake of 121 mg FWGE pulvis/kg body weight (bw)/day. Because individuals weighing more than 90 kg (200 pounds) may increase the amount consumed up to a limit of 2 doses, it is anticipated that their intake of FWGE pulvis, in mg/kg bw/day, will generally be in the same range.

 Animals were housed 5 per cage and were given rodent diet and tap water ad libitum; intakes were not recorded. Body weights were recorded on the day of arrival, day of randomization, prior to treatment, and 24 h post dosing. Because some weight loss (not statistically significant) was noted among some animals in both the experimental and control groups at the 24-h interval (although there were no differences in the group mean weights), mice were weighed daily thereafter until an increase in body weight was noted. Animals also were weighed on days 7 and 14 post dosing. The animals were observed twice daily for any adverse clinical signs; after the observation period, the mice were killed for a postmortem examination. No deaths or abnormal clinical signs were reported. There were no statistically significant differences in body weight between control and treated mice. Pathological examination showed no macroscopic lesions. The LD50 of FWGE pulvis in male and female mice in this study was >2000 mg/kg bw. In a similar study, groups of 5-week-old Wistar rats (10/sex/group) were administered by gavage a single dose of 0 (vehicle control) or 2000 mg/kg bw of FWGE pulvis in distilled water and observed for up to 14 days (Csik´o, Semjen, and Ratz 1999). The rats were treated in the same manner as the mice in the previous study and the same parameters were examined as those in the mouse study. No deaths or abnormal clinical signs were reported. There were no statistically significant differences in body weight between control and treated rats. Pathological examination showed no macroscopic lesions. The LD50 of FWGE pulvis in male and female rats in this study was >2000 mg/kg bw. A third acute oral toxicity study was conducted using Wistar rats (IPCM 1999). 

 Hematological parameters included red blood cell count, white blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count, prothrombin time, and differential leucocyte count. Clinical chemistries included glucose, total protein, albumin, total bilirubin, urea nitrogen, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, cholesterol, triacylglycerols, Na, K, Ca, Cl, and P. Urine samples also were taken for urinalysis by test strip (Hemoket/GPH5) at the end of the treatment and recovery periods. Rats dying during the study and those terminated at end of the treatment and recovery periods underwent necropsy, including gross pathology and histopathological examination of the lymph nodes, mammary glands, salivary glands, sternebrae, femur (including marrow), pituitary, thymus, trachea, lungs, heart, thyroid,esophagus, stomach, small intestine, colon, liver, gall bladder, pancreas, spleen, kidneys, adrenals, bladder, prostate, testes, ovaries, uterus, brain, eyes, and spinal cord. Organ weights were recorded. Results were statistically analyzed using the t test. No adverse clinical signs were reported with the exception of one treated female rat which showed mild lethargy with decreased motor activity and piloerection 1 day prior to death on the first day of the recovery period. Two other rats from the FWGE pulvis–treated group died during the treatment period. Pathological examination revealed these deaths to be gavage errors rather than inherent toxicity of the test compound. 

 In addition to FWGE pulvis, 900 mg vitamin C/kg bw/day was also administered to the animals by gavage. Animals were observed for any abnormal clinical signs and body weights were recorded on treatment days 1, 4, 8, 11, 17, 22, 29, 40, 52, 61, and 74 for rats and days 1, 7, 13, 18, 32, 39, 48, 61, 67, and 77 for mice. On day 77, all rats and mice were killed using anesthesia and underwent necropsy. No hematology or clinical chemistry was performed. Organ and tissue samples were taken from 3 randomly selected animals per species in both the experimental and control groups and prepared using hematoxylin and eosin staining for histopathological examination by a board-certified pathologist in a blinded setting. Organs (heart , lung, thymus spleen, liver, kidneys, and testicles) were removed and weighed for both species from the experimental groups only; organs from the control groups were not weighed. There were no statistically significant differences in body weight between treated animals and their corresponding controls. No pathological changes were noted in either rats or mice. Based on these findings, the NOAEL in this oral subchronic study was the tested dose of 3000 mg/kg bw/day of FWGE pulvis.

 The same research group (NICS 2004) also investigated the effect of FWGE pulvis on results with cobalt chloride, formaldehyde, and urethane in the Drosophila somatic mutation and recombination tests. Flies carrying one-one recessive mutations on their third chromosome (mwh/flr) were fed nutrient mixes containing the subject chemicals with or without FWGE pulvis or sucrose. As part of this study, groups of flies were also fed 10% FWGE pulvis or 10% sucrose alone. New mutations or somatic recombinations are visible in microscopic examination of the wings of adult flies. Mutation frequency was determined by dividing the number of visible mutations by the number of flies examined. The mutation frequency of flies fed 10% FWGE pulvis alone was similar to that of controls. FWGE pulvis showed no mutagenic potential in this study. 2,6-DMBQ Because 2,6-DMBQ is a constituent of wheat germ (100 µg/g), and consequently of FWGE pulvis (200 µg/g), the potential genetic toxicity of this substance was reviewed. When tested at concentrations of 0.1 to 100 µg/plate in Salmonella typhimurium strains TA98 and TA100, 2,6-DMBQ showed no significant increase in the number of revertant colonies in the presence or absence of metabolic activation (Mohtashamipur and Norpoth 1984). In Chinese hamster ovary (CHO) cells, 2,6-DMBQ was reported to cause a dose-dependent increase in DNA fragmentation following a 1-h exposure at concentrations of 0.5 to 0.125 mM (Brambilla et al. 1986). Similarly, when Chinese hamster lung cells (V79) or hepatocytes from Sprague-Dawley rats were exposed for 1 h to 2,6-DMBQ, a dose-dependent increase in DNA fragmentation was observed (Brambilla et al. 1988). 

All animal deaths were due to the inoculated tumors. No toxicity was seen from the administration of FWGE pulvis alone, and the combination of FWGE pulvis with the cytostatic drugs did not increase the toxicity of the cytostatic compounds and did not exert any toxic effect. In a study to examine the effect of FWGE pulvis alone and FWGE pulvis plus vitamin C on tumor growth and metastasis, 8- to 10-week-old inbred rats and mice had their spleens injected with tumor cells followed by gavage administration of 3000 mg FWGE pulvis/kg bw/day alone or with vitamin C (Hidvegi et al. 1998). Control animals were administered water. The animals were observed for 35, 45, and 65 days. No adverse reactions or test compound—related deaths were reported due to either FWGE pulvis alone or in combination with vitamin C. The effect of FWGE pulvis on blastic transformation of peripheral blood lymphocytes of 8-week-old C57BL mice was investigated (Hidvegi et al. 1999). Twenty mice were administered 3000 mg FWGE pulvis/kg bw/day, 5 days/week for 6 weeks. Spleen cells were harvested from treated and control mice and then exposed to concanavalin A to cause blastic transformation.  No adverse reactions or FWGE pulvis—related deaths were reported. In order to study the ability of FWGE pulvis to prevent colon cancer in laboratory animals, F344 rats were left untreated or given three injections of azoxymethane to induce colonic carcinogenesis, followed by 3000 mg FWGE pulvis/kg bw/day administered by gavage, and observed for 32 weeks (Zalatnai et al. 2001).  Thirty-two rats received the induction injections plus FWGE pulvis, 48 rats received the induction injections only, 10 rats received FWGE pulvis only, and 10 rats served as untreated controls.

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