“FWGE pulvis” is a powder consisting of an aqueous extract of fermented wheat germ, with the drying aids maltodextrin and silicon dioxide, standardized to contain approximately 200 µg/g of the natural constituent 2,6-dimethoxy-p-benzoquinone. The results of toxicological and clinical studies of this product demonstrate its safety for its intended use as a dietary supplement ingredient in the United States. FWGE pulvis has been used in Hungary since 1998 and is approved in that country, as well as in the Czech Republic, Bulgaria, and Romania, as a “medical nutriment for cancer patients.” Acute and subacute toxicity studies using rodents orally administered FWGE pulvis showed that dose levels (2000 to 3000 mg/kg body weight [bw]/day) exceeding the normal recommended oral dosage (8.5 g/day or 121 mg/kg bw/day for a 70-kg individual) by up to approximately 25-fold caused no adverse effects. The test substance showed no evidence of mutagenicity or genotoxicity in vitro or in vivo. Clinical studies using FWGE pulvis as a supplement to drug therapy in cancer patients at doses of 8.5 g/day not only showed no evidence of toxicity, but also showed a reduction in the side effects of chemotherapy. Overall, it was concluded that FWGE pulvis would not be expected to cause adverse effects under the conditions of its intended use as an ingredient in dietary supplements.

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. 

Half of the animals (10/sex/group) were followed for a 14-day recovery period. The animals were housed 2 per cage and were given rodent diet and tap water ad libitum. Body weights were recorded on the day of arrival, day of randomization, prior to treatment, on days 7, 14, 21, and 28 post dosing, and on days 7 and 14 of the recovery period. The rats were observed twice daily for any adverse clinical signs or mortality during the treatment and recovery periods. Feed consumption (g/day) was recorded weekly throughout the entire study and water intake (g/day) was recorded daily during weeks 1 and 4 of the treatment period and during week 2 of the recovery period. Prior to termination, fasting blood samples were taken from the femoral vein for hematological and clinical chemistry evaluations. 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. No statistically significant differences were observed in body weight, feed consumption, water intake, urinalysis, pathological examinations, organ weights, or histopathology between control and treated rats. Hematological parameters were similar between control and treated rats, with the exception of slight but statistically significant increases in hemoglobin content, MCH, and MCHC in treated females at the end of the 2-week recovery period. These small changes were considered not to be related to the test compound and of no biological importance. 

Although this study was not conducted under GLP or in accordance with OECD guidelines, histological samples were extracted and prepared under Registry of Industrial Toxicology Animal-Data (RITA) guidelines (Bahnemann et al. 1995). 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).