Comments on the Review by Nguyen et al. (1999) Dear Sir: Dr. Nguyen's argument that low doses of plant stanols effects differ from those of plant sterols on blood cholesterol levels is incorrect. As indicated by Nguyen, an intake of "3g/d of sitosterol was sufficient to lower cholesterol levels" (Grundy and Mok 1976) . This intake level of plant sterols is similar to that of plant stanols in various clinical trials, for which similar degrees of cholesterol lowering were reported (Miettinen et

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... . 1995 , Nguyen et al. 1999 , Weststrate and Meijer 1998 . A difference in the reduction of cholesterol absorption between plant sterols and stanols does not necessarily lead to a parallel difference in plasma LDL cholesterol levels. An up-regulation in endogenous cholesterol synthesis is observed with plant sterol or stanol intake, which may well negate a difference in cholesterol absorption. Recently, Jones et al. (1999) reported that plant sterols and stanols affect cholesterol absorption and synthesis similarly. Only two published clinical trials , Weststrate and Meijer 1998) made a direct comparison between plant sterol-esters and plant stanol-esters. These studies clearly showed that both plant sterols and stanols have a significant and similar blood cholesterol-lowering effect at equal daily intake levels. Thus, Nguyen's conclusion that plant stanols are more efficacious than plant sterols is incorrect. Nguyen's assumption that plant sterols are atherogenic in hypercholesterolemics is misleading. Nguyen has based his suggestion on a publication by Bhattacharyya and Connor (1974) on homozygous phytosterolemics, who are characterized by a recessive genetic defect to chromosome 2p21. There is no proof in this study that plant sterols as such are atherogenic in phytosterolemia. Rather, it was speculated that sitosterol might have a role in the initiation of the development of xanthomas, and it was clearly stated that the reason for the xanthomatosis is unknown. Consequently, the link made by Nguyen between elevated plant sterol levels in blood and the development of atherosclerosis in hypercholesterolemic patients is flawed. The statement that plant sterols may increase the risk of coronary heart disease (CHD) in hypercholesterolemics is misleading. The blood plant sterol levels reported by Glueck et al. (1991) fall well within normal ranges (Ling and Jones 1995). Thus none of the subjects in the paper of Glueck et al. (1991) is "hyperphytosterolemic." Even at the 99th percentile, serum plant sterol levels were Ͻ1% of serum total sterol levels, which is a condition characterized as "normal." Higher plant sterol levels in the paper of Glueck et al. (1991) may indicate a higher efficiency of cholesterol absorption, very likely leading to higher blood cholesterol levels. Consequently, the association between serum plant sterols and risk of CHD is not necessarily causal but may reflect a causal relationship between the degree of cholesterol absorption and risk of CHD. Nguyen refers to animal studies, which have suggested that plant sterols may possess estrogenic activity. In the majority of these studies, crude plant extracts have been used and the purity of the plant sterols was not specified. Further, appropriate positive and negative controls were not always included in the studies. However, the estrogenic potential of a fully characterized mixture of plant sterols has been assessed by both in vitro and in vivo assays (Baker et al. 1999) . These studies clearly showed that plant sterols do not bind to the estrogen receptors and do not have estrogenic activity. In addition, there was no indication of estrogenicity in an uterotrophic assay or any side effects in a two-generation reproduction study (Baker et al. 1999 , Waalkens-Berendsen et al. 1999 . We agree with Nguyen's conclusion that plant sterols (and stanols) "are a helpful dietary adjunct to a prudent diet to lower cholesterol." However, we disagree with a number of misleading and incorrect statements. There are no published clinical trials that show that stanols have a greater cholesterollowering effect than sterols. In addition, there is extensive work to demonstrate that plant sterols, unlike stanols, have been part of the human diet for millennia, and are generally recognized as safe.