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between consumption of plant stanols and reduced Vanhanen et al., 1993; and
LDL cholesterol, but not blood total cholesterol, in Weststrate and Meijer, 1998
the same category of subjects consuming diets (1 study); Hallikainen et al.,
within the range of a typical American diet. 2000; Jones et al., 1999,
2000; Miettinen et al., 1995;
Nguyen et al., 1999;
Vanhanen et al., 1994
 Two studies show a relationship between consump- Niinikoski et al., 1997; Plat 65 FR 54698
tion of plant stanols and reduced blood cholesterol and Mensink, 2000
in subjects with normal cholesterol concentrations
consuming a typical American diet.
Specificity: a specific  Given the variability of amounts and of food carriers 65 FR 54701
association is evidence in in which plant sterols and plant sterol esters were
favor of causality provided in the diets studied, the response of blood
cholesterol levels to plant sterols appears to be
consistent and substantial, except for plant sterols
from sheanut oil and ricebran oil.
40 Institute of Food Technologists
pounds (Jones et al., 2000; Vanstone et al., 2002; Weststrate organized by Hill s criteria, summarizes FDA s conclusions
and Meijer, 1998). A recent study has established the parity regarding the data supporting a health claim for stanol/sterol
of the two families of compounds (i.e., the stanols and the esters and coronary heart disease. In October 2000, FDA
sterols) in lowering LDL cholesterol (Vanstone et al., 2002) approved this health claim for certain foods and dietary
as well as the equivalency of free unesterified stanols and supplements containing plant stanol/sterol esters (FDA,
sterols in reducing cholesterol. It is clear that sterols and 2000c). FDA subsequently exercised its enforcement
stanols, free or esterified, are equivalent in lowering serum discretion to extend the claim to additional foods and
cholesterol levels and in interfering with intestinal absorp- also free forms and mixtures of stanols and sterols (FDA/
tion of cholesterol (Normen et al., 2000). Table 9 below, CFSAN/ONPLDS, 2003c). The data have led to the
Table 9. Case Study: Stanol/Sterol Esters and Coronary Heart Disease, continued
Hill Criteriaa Evidence Supporting/Against Studies Cited by FDA in References
FR Notice/FDA Papers
 Given the variability of amounts and food carriers 65 FR 54701
in which plant stanol esters were provided in the
diets studied, the response of blood cholesterol
levels appears to be consistent and substantial.
Time sequence: exposure FDA did not specifically address this, but the
to causative agent occurs results of intervention studies support the time
before endpoint of interest sequence.
Biologic gradient: Plant sterols  may be more effective in small doses Mattson et al., 1982 65 FR 54690
evidence of a dose- than previously believed.
response curve
 The investigators observed that the greater the Puska et al., 1998 65 FR 54700
self-reported daily use of the plant stanol ester
spread, the greater the serum cholesterol
reduction.
 Consumption of at least 0.8 g/d (grams/day) of Ayesh et al., 1991; Hendriks 65 FR 54704
free plant sterols, or 1.3 g/d of plant sterol esters, et al., 1999; Jones et al.,
has consistently been shown to lower blood total 2000; Maki et al., 1999; and
and LDL cholesterol. Maki et al., 1999 (1 study);
Sierksma et al., 1999;
Weststrate and Meijer, 1998
 The Agency was unable to find an intake level Andersson et al., 1999; 65 FR 54704
lower than 3.4 g/d that consistently showed Blomqvist et al., 1993;
cholesterol-lowering effects for both total and LDL Gylling and Miettinen, 1999;
cholesterol. At least 3.4 g/d of plant stanol esters Hallikainen and Uusitupa,
(equivalent to 2 g/d of free plant stanols) repre- 1999; and Vanhanen et al.
sents an amount that has been shown to be 1993; Weststrate and Meijer,
effective in reducing blood cholesterol. 1998 (1 study); Hallikainen
et al., 2000; Jones et al.,
2000; Miettinen et al., 1995;
Nguyen et al., 1991;
Niinikoski et al., 1997;
Plat and Mensink, 2000;
Vanhanen et al., 1994
Plausibility: association is  Long ago, plant sterols (beta-sitosterol and related Best et al., 1955; Davis, 65 FR 54690
biologically plausible compounds) were found to prevent absorption of 1955; Grundy and Mok,
dietary cholesterol apparently by blocking 1977; Farquhar and
absorption of cholesterol in the intestine. Sokolow, 1958; Farquhar et
al., 1956; Jandacek et al.,
1977; Lees et al., 1977;
Mattson et al., 1977;
Peterson et al., 1959
Coherence of explanation:  FDA concluded that it is generally accepted that 65 FR 54686
association is consistent blood total and LDL cholesterol levels are major
with current knowledge of risk factors for CHD, and that dietary factors
the disease/endpoint and affecting blood cholesterol levels affect the risk of
biomarkers known to be CHD.
associated with it
a
Friis and Sellers, 1999.
Two additional Hill criteria (experiment and analogy) were not included in the table as FDA did not discuss them in their review of the data for the health claim, and the report from the
Keystone Center (1996) did not include them either.
Expert Report 41
approved use of stanols/sterols in foods in several countries promoting the accessibility of systematic reviews of the
(Food Standards, 2001; Official Journal of the European effects of healthcare interventions. Jepson et al. (2004)
Communities, 2000). conducted a comprehensive review of all randomized or
quasi-randomized controlled trials of cranberry juice/
Case Study: Efficacy of Cranberry
products for the prevention of UTIs in susceptible popula-
The American cranberry (Vaccinium macrocarpon) has tions, including men, women or children. Seven trials (four
a rich history of use as one of America s earliest functional cross-over, three parallel groups) met the inclusion criteria.
foods (Leahy et al., 2001). Native Americans in New England Six trials evaluated the effectiveness of cranberry juice, and
used cranberries extensively in their diet, medicine and two trials investigated the effectiveness of cranberry tablets
commerce. Medically, the berries were used in poultices to (one trial evaluated both juice and tablets). The authors
treat wounds and blood poisoning, and the plant leaves were concluded that some evidence from two good quality [ Pobierz całość w formacie PDF ]