less than 4 mg. Human acute or sub chronic (two weeks) intake of red wine, dealcoholized red wine or red grape juice did not show effect on Tumor necrosis factor (TNF) a, Interleukin (IL)-2 or IL-4 levels, indicating no anti-inflammatory response of the wine but the presence of Resv in the wine was not proven [29,30]. Exposure of healthy volunteers to 36 mg Resv/day (combination of trans- and cis-Resv and cis-piceid) in the form of Chardonnay cava wine for 28 days caused a reduction of various inflammatory markers such as IL-6, high-sensitivity C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) [31]. Resveratrol is found to reduce the risk of colon cancer development in experimental animals (see below) using doses in the range of 0.2 to 8 mg/kg in rats and 2.4 to 60 mg/kg in mice. Applying the dose translations factors described by Reagan-Shaw et al. [32] the corresponding daily ‘human equivalent doses’ (HED) are around 2 mg–78 mg (based on rat data) or 12–290 mg (based on mouse data) for a 60 kg person. Enhanced insulin sensitivity by Resv was observed in experi- mental animals when exposed to 2.5–400 mg/kg in mice and 1–100 mg/kg in rats (see below). The corresponding HED are 12–1945 mg (based on mouse data) or 10–973 mg/day for a 60 kg person. The relevant effective dose of Resv needs to be established in humans in relation to the different diseases that it may counteract and the working group concludes (Table 3) that: N A relevant or optimal dose for resveratrol has yet to be established by human studies and will almost certainly vary depending on the effect being studied. N Doses in the range of hundreds of mg to several g per day have been proposed based on animal studies, but more human studies are needed to confirm these estimates. N Chronic human intake above the concentrations contained in natural food should be considered experimental until long- term human studies have been performed. Which valid data is available regarding an effect in various species of experimental animals? Cancer preventive activity. The initial paper by Jang et al. showed a cancer preventive effect of Resv on skin cancer in a mice model. Seven animal studies have been identified studying the effect of Resv on skin cancer (Table S1) all showing reduction of the incidence of chemically induced skin cancer [1,33–36], whereas no reduction was observed in a mouse line spontaneous to developing polyps [37]. Only mice have been used in these studies with different Resv concentrations, dose regimens and exposure times (up to 28 week). A recent study supported this by showing reduction of skin hyperplasia by Resv alone and in synergism with other dietary components [38]. To test the effect of Resv on breast cancer, four studies used mice where Resv showed a reducing effect in three experiments [1,39,40] (in chemical induced cancers, in a HER-2/neu transgenic mice model and injected Ehrlich ascites carcinoma cells), whereas Resv failed to show chemoprevention in a model where 4T1 mammary carcinoma cells were injected into the mice [41]. In rats, three studies showed a chemopreventive effect of Resv [26,42,43], whereas increased breast cancer incidence is observed in one study [44]. The reason for these contradictory results is not obvious. Resveratrol reduced chemically-induced liver cancer in rats [45] and in mice injected with carcinoma cells [46–48]. A single experiment showed no reduction of the incidence of esophagus Recommendations on the Use of Resveratrol carcinoma formation by Resv [49]. The effect of Resv on gastric cancers was evaluated with its effect on tumor growth after subcutaneous injection of cancer cells. Both studies in mice showed a reduced tumor volume as a consequence of Resv exposure [50,51]. To study the effect of Resv on colon cancer development in animals, four studies focus on chemically-induced colon cancer in rats or mice [52–55] and three studies evaluated the effect of Resv on colon cancer in APC/Min mice strains [56–58]. Three of the tests showed significant reduction of the aberrant crypt formation or incidence of adenomas, whereas two of the mouse studies did not show a significant reduction in colon cancer incidence or tumor load. Resveratrol showed a chemopreventive effect on development of prostate cancer using rat or mice strains prone to spontaneously developing prostate cancer [59–61] and a mouse model with injected prostate cancer cells [62] In other studies focusing on lung carcinogenesis, Resv showed a chemopreventive effect only in a single experiment out of a total of four experiments [63–66]. A single study focused on the effect of Resv on the development of neuroblastoma in mice, and found reduced tumor volume [67]. Cardioprotective effect of resveratrol. Risk reduction of cardiovascular events is one of the most well-known health promoting effects of Resv. It has been shown that Resv may modulate various aspects of cardio-vascular diseases, including atherosclerosis, hypertension, ischemia reperfusion injury and heart failure. Resveratrol reduced hypertension in various models (Table S2), including spontaneously hypertensive rats [68,69], salt induced hypertension [70], hypertension induced by monocrotaline [71,72], or obesity-induced hypertension [73–76]. In nine out of eleven studies, Resv (at levels of 10 mg/kg bw/day or higher) was found to reduce the elevated blood pressure. The blood pressure reducing effect of Resv was observed after 3 weeks and maintained for 10 weeks. Low exposure to Resv (2.5 mg/kg bw/day for 10 weeks) was described in two experiments using spontaneous hyper- tensive rat where one experiment showed a preventive effect on hypertension whereas the other did not. Several studies (five have been identified) showed a preventive effect of Resv on myocardial infarction induced by surgery. All studies showed a reduced infarct size effect and one experiment even at the low dose of 1 mg Resv/kg bw/day for four weeks [77–81]. Chronic treatment with Resv reduced infarct area after middle cerebral artery occlusion [82]. The diabetes-induced myocardial infarct size was significantly reduced by Resv (ranging from 1 to 5 mg/kg bw/day) in rats exposed to Resv for 5–15 days [83–85]. Further, Resv may precondition the heart in a nitric oxide (NO)-dependent manner, which would reduce heart damage from ischemia [85]. Resveratrol prevented the effects of ischemia at doses of 10 mg/kg, whereas higher doses were found to depress cardiac function and increase myocardial infarct size [86,87]. A single experiment was performed in swine where the reduced inferolateral function induced by hypercholesterolemic diet was prevented by 100 mg Resv/kg bw/day [88]. Obesity and type 2 diabetes. Animal studies focusing on the effect of Resv on obesity and diabetes are shown in Table S3. Some studies have indicated that intake of Resv may reduce body weight increase caused by high fat intake in mouse [89] and grey mouse lemurs [90] both exposed to high levels of Resv (200 or 400 mg/kg bw/day). Low doses, up to 60 mg/kg bw/day did not show any effect on body weight [21,73,76,91]. On the other hand, low doses did affect lipid accumulation observed as reduced size of white adipose tissue [91], reduced abdominal obesity [92], reduced abdominal fat in obese rats [73] and reduced grade of steatosis [93]. PLoS ONE | www.plosone.org 6 June 2011 | Volume 6 | Issue 6 | e19881