Vitamins 43 A.(c) The third study was the Physicians Health Study, in which 22071 US male lysicians were randomised to get 50mg B-carotene or aspirin(325 mg), or both or neither every other day for 12 years. There was no evidence of a significant beneficial or harmful effect on cancer or cardiovascular disease. but the number of smokers in the study was too small to be certain whether B-carotene was harmful in the group or not(Hennekens et al, 1996) One other study should also be mentioned. The Cancer Prevention Study Il,a prospective study on more than one million US adults investigated the effect of ommercially available multivitamins and/or vitamins A, C, and/or E on mortal ity during a 7 year follow-up. The use of multivitamins plus A, C and/or E sig nificantly reduced the risk of lung cancer in former smokers and in those who never smoked but increased the risk in men who smoked and used vitamins a C and/or E compared with men who reported no supplement use. Thus the antioxidant vitamins A, C and E only appear to benefit male non-smokers. No association with smoking was seen in women(Watkins et al, 2000). 3.6.3 Reasons for increased cancer risk associated with B-carotene supplementation The mechanism for the increased risk associated with B-carotene supplementa tion in smokers is unclear. One suggestion is that the subjects of the studies already had a ' high risk ' of developing lung cancer and many might have had undetected tumours at the start. The stage of carcinogenesis that B-carotene might affect is not known but if mediated by the immune system the effect might be at the promotional stages preceding the formation of a malignant tumour(Hughes, Immune cells rely heavily on cell-to-cell communication, particularly via mea s 2001). The immune system appears to be particularly sensitive to oxidative stress brane bound receptors, to work effectively. Cell membranes are rich in polyun saturated fatty acids and if peroxidised, can lead to a loss of membrane integrity, altered membrane fluidity and result in alterations in intracellular signalling and cell function. It has been shown that exposure to reactive oxygen species(ROS) can lead to a reduction in cell-membrane expression(Hughes, 2001). In addition, the production of Ros by phagocytic immune cells can damage the cells them selves if not adequately protected by antioxidants such as B-carotene, lycopene and lutein One of the major unresolved dilemmas of B-carotene research is the required to optimise immune function and provide other health benefits(Hr nd it is not clear whether different intakes are associated with different outcomes It is also possible that supplemental B-carotene might be interfering with intesti- nal absorption of other possible chemopreventive nutrients e.g. B-carotene can inhibit absorption of lutein, a-carotene and canthaxanthin, all of which show good antioxidant properties(Olson, 1999). Another explanation might be that B- carotene is acting as a pro-oxidant in the presence of high oxygen tension in(c) The third study was the Physicians Health Study, in which 22 071 US male physicians were randomised to get 50 mg b-carotene or aspirin (325 mg), or both or neither every other day for 12 years. There was no evidence of a significant beneficial or harmful effect on cancer or cardiovascular disease, but the number of smokers in the study was too small to be certain whether b-carotene was harmful in the group or not (Hennekens et al, 1996). One other study should also be mentioned. The Cancer Prevention Study II, a prospective study on more than one million US adults investigated the effect of commercially available multivitamins and/or vitamins A, C, and/or E on mortal￾ity during a 7 year follow-up. The use of multivitamins plus A, C and/or E sig￾nificantly reduced the risk of lung cancer in former smokers and in those who never smoked, but increased the risk in men who smoked and used vitamins A, C and/or E compared with men who reported no supplement use. Thus the ‘antioxidant’ vitamins A, C and E only appear to benefit male non-smokers. No association with smoking was seen in women (Watkins et al, 2000). 3.6.3 Reasons for increased cancer risk associated with b-carotene supplementation The mechanism for the increased risk associated with b-carotene supplementa￾tion in smokers is unclear. One suggestion is that the subjects of the studies already had a ‘high risk’ of developing lung cancer and many might have had undetected tumours at the start. The stage of carcinogenesis that b-carotene might affect is not known but if mediated by the immune system the effect might be at the promotional stages preceding the formation of a malignant tumour (Hughes, 2001). The immune system appears to be particularly sensitive to oxidative stress. Immune cells rely heavily on cell-to-cell communication, particularly via mem￾brane bound receptors, to work effectively. Cell membranes are rich in polyun￾saturated fatty acids and if peroxidised, can lead to a loss of membrane integrity, altered membrane fluidity and result in alterations in intracellular signalling and cell function. It has been shown that exposure to reactive oxygen species (ROS) can lead to a reduction in cell-membrane expression (Hughes, 2001). In addition, the production of ROS by phagocytic immune cells can damage the cells them￾selves if not adequately protected by antioxidants such as b-carotene, lycopene and lutein. One of the major unresolved dilemmas of b-carotene research is the intake required to optimise immune function and provide other health benefits (Hughes, 2001). Most studies have been done using pharmacological doses of b-carotene and it is not clear whether different intakes are associated with different outcomes. It is also possible that supplemental b-carotene might be interfering with intesti￾nal absorption of other possible chemopreventive nutrients e.g. b-carotene can inhibit absorption of lutein, a-carotene and canthaxanthin, all of which show good antioxidant properties (Olson, 1999). Another explanation might be that b￾carotene is acting as a pro-oxidant in the presence of high oxygen tension in the lung. Vitamins 43