Implementing food-based dietary guidelines for - United Nations ...

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ent under study; a diet may have to be artificially
constructed to attain a goal of negligible amounts
of the study nutrient. The effects of the diet lacking
the nutrient are followed in a group of subjects until
observable signs or symptoms of inadequacy appear;
early signs may be abnormal biochemical or neurological
measures indicating abnormal metabolism. Once
the effects of mild depletion are ascertained, the nutrient
is given to the group of individuals under study in
incremental amounts to see at what dose (intake) the
abnormal signs or measures return to normal. With
this type of study, it is possible to identify candidates for
the appropriate indicator or criterion of adequacy, as
well as see how responsive the criterion is to repletion
of the nutrient. This type of study is useful for nutrients
for which it is not possible to collect excretion products
that would represent turnover of the nutrient.
Animal studies. For a few nutrients, there may be
few quantitative data available that relate dietary intake
in human subjects to specific functional outcomes,
whereas significant data from animal models may be
available. Such data are particularly useful in establishing
the probable mechanism of action and resulting
adverse effects that will be experienced in humans as
a result of inadequacy; however, without human correlates,
such data have not been considered sufficient
to define a quantitative relationship between intake
and a noted criterion of adequacy. Because evidence of
inadequacy for such a nutrient in humans consuming
typical diets is lacking, there has been a hesitation to
use animal studies to establish quantitative reference
intakes. This is the case for nutrients such as silicon and
possibly boron in the dietary reference intake (DRI)
reviews [7]; animal models have been used to identify
the essential role of a nutrient in metabolism for one or
more species, but the lack of demonstrated deficiency
or inadequacy in humans due to the ubiquitous nature
of the nutrient has precluded the establishment of a
reference standard for adequacy by extrapolation to
estimate human requirements. However, in the case
of potential adverse effects due to overconsumption,
animal data have been used when human data are
not available, with appropriate uncertainty factors to
extrapolate from animals to humans (see Aggett [12]
in this issue).
Clinical signs and symptoms. Functional outcomes of
inadequacy of a nutrient, such as a deficiency disease
like scurvy, are easy to detect at advanced stages and
even at early stages if they present with unique and
well-known symptoms; such symptoms can be considered
good indicators of adequacy, since symptoms such
as bleeding gums and loose teeth are observable and
taken together are not associated with other nutrient
deficiencies. Other functional outcomes and their relationship
to nutrients are less well understood and characterized,
such as risk of fracture and calcium intake or
potassium intake and hypertension. Although there is a
relationship, it is not well understood due either to lack
of data or to multiple causative factors that prevent the
demonstration of a direct dose–response relationship
between intake and outcome.
Although the most valuable endpoints may be
observable events, such as fracture, stroke, or myocardial
infarction, studies of this type can take much
longer and require many more subjects than studies
in which surrogate markers are evaluated. The use of
biomarkers or surrogate markers must be validated as
clinically useful [13], in which mechanisms of action
are established that support the relationship between
the nutrient and the functional outcome [14].
Epidemiologic associations. In 1971 Hill identified six
important factors useful in establishing relationships
between diet and disease [15] (table 2); although they
have been modified slightly by others, they continue to
aptly describe the required components of the relationship
desired between a nutrient or bioactive food component
and functional or disease outcome. Although
they were developed for epidemiologic associations
to assist in determining causation, they are equally
applicable to experimental studies in which outcomes
are evaluated when the level of nutrients is varied in
diets. This type of information is particularly useful in
evaluating the role of diet in chronic disease onset.
Observations in healthy populations. Nutrient intakes
of populations in which individuals show no signs,
symptoms, or indicators of inadequacy can also be used
as the basis for setting nutrient standards; the nutrient
intakes of a representative sample of individuals
in the population are estimated and then assumed to
be typical of all those in the population. Since there is
no evidence of inadequacy, the amount consumed on
average is assumed to be adequate for all. This is the
basis for establishing most of the default recommended
intake values in the DRI process, termed adequate
intakes (AIs), a recommended intake reference standard
used when it was not possible to determine a level
at which half of a population group would have their
needs met [7].
It is possible to set a nutrient reference standard
using observational information from a representative
sample of a healthy population group if the following
conditions are met:
» There is a comprehensive food and supplement
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TABLE 2. Diet and disease relationships
Strength of association
Dose–response relationship
Temporally correct association
Consistency of association
Specificity of association
Biological plausibility
Source: Hill [15].
A. A. Yates