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4
A Model for the
Development of Tolerable
Upper Intake Levels
BACKGROUND
The Tolerable Upper Intake Level (UL) refers to the highest level of daily
nutrient intake that is likely to pose no risk of adverse health effects for
almost all individuals in the general population. As intake increases above
the UL, the risk of adverse effects increases. The term tolerable is chosen
because it connotes a level of intake that can, with high probability, be
tolerated biologically by individuals; it does not imply acceptability of that
level in any other sense. The setting of a UL does not indicate that nutri-
ent intakes greater than the Recommended Dietary Allowance (RDA) or
Adequate Intake (AI) are recommended as being beneficial to an indi-
vidual. Many individuals are self-medicating with nutrients for curative or
treatment purposes. It is beyond the scope of this report to address the
possible therapeutic benefits of higher nutrient intakes that may offset the
risk of adverse effects. The UL is not meant to apply to individuals who are
treated with the nutrient under medical supervision or to individuals with
predisposing conditions that modify their sensitivity to the nutrient. This
chapter describes a model for developing ULs.
The term adverse effect is defined as any significant alteration in the
structure or function of the human organism (Klaassen et al., 1986) or any
impairment of a physiologically important function that could lead to a
health effect that is adverse, in accordance with the definition set by the
joint World Health Organization, Food and Agriculture Organization of
the United Nations, and International Atomic Energy Agency Expert Con-
sultation in Trace Elements in Human Nutrition and Health (WHO, 1996).
In the case of nutrients, it is exceedingly important to consider the possi-
84
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A M ODEL FOR THE DEVELOPMENT OF ULs
bility that the intake of one nutrient may alter, in detrimental ways, the
health benefits conferred by another nutrient. Any such alteration
(referred to as an adverse nutrient–nutrient interaction) is considered an
adverse health effect. When evidence for such adverse interactions is avail-
able, it is considered in establishing a nutrient’s UL.
ULs are useful because of the increased interest in, and availability of,
fortified foods, the increased use of dietary supplements, and the growing
recognition of the health consequences of excesses, as well as inadequa-
cies of nutrient intakes. ULs are based on total intake of a nutrient from
food, water, and supplements if adverse effects have been associated with
total intake. However, if adverse effects have been associated with intake
from supplements or food fortificants only, the UL is based on a nutrient
intake from those sources only, not on total intake. The UL applies to
chronic daily use.
For many nutrients, there are insufficient data on which to develop a
UL. This does not mean that there is no potential for adverse effects result-
ing from high intake. When data about adverse effects are extremely limited,
extra caution may be warranted.
Like all chemical agents, nutrients can produce adverse health effects
if their intake from a combination of food, water, nutrient supplements,
and pharmacological agents is excessive. Some lower level of nutrient
intake will ordinarily pose no likelihood (or risk) of adverse health effects
in normal individuals even if the level is above that associated with any
benefit. It is not possible to identify a single risk-free intake level for a
nutrient that can be applied with certainty to all members of a population.
However, it is possible to develop intake levels that are unlikely to pose risk
of adverse health effects for most members of the general population,
including sensitive individuals. For some nutrients, these intake levels may
pose a risk to subpopulations with extreme or distinct vulnerabilities.
Whether routine, long-term intake above the UL is safe is not well
documented. Although members of the general population should not
routinely exceed the UL, intake above the UL may be appropriate for
investigation within well-controlled clinical trials. Clinical trials of doses
above the UL should not be discouraged as long as subjects participating
in these trials have signed informed consent documents regarding pos-
sible toxicity, and as long as these trials employ appropriate safety monitor-
ing of trial subjects.
A MODEL FOR THE DERIVATION OF TOLERABLE
UPPER INTAKE LEVELS
The possibility that the methodology used to derive Tolerable Upper
Intake Levels (ULs) might be reduced to a mathematical model that could
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86 DIETARY REFERENCE INTAKES
be generically applied to all nutrients was considered. Such a model might
have several potential advantages, including ease of application and assur-
ance of consistent treatment of all nutrients. It was concluded, however,
that the current state of scientific understanding of toxic phenomena in
general, and nutrient toxicity in particular, is insufficient to support the
development of such a model. Scientific information about various adverse
effects and their relationships to intake levels varies greatly among nutri-
ents and depends on the nature, comprehensiveness, and quality of avail-
able data. The uncertainties associated with the unavoidable problem of
extrapolating from the circumstances under which data are developed
(e.g., in the laboratory or clinic) to other circumstances (e.g., to the
healthy population) add to the complexity.
Given the current state of knowledge, any attempt to capture, in a
mathematical model, all of the information and scientific judgments that
must be made to reach conclusions about ULs would not be consistent
with contemporary risk assessment practices. Instead, the model for the
derivation of ULs consists of a set of scientific factors that always should be
considered explicitly. The framework by which these factors are organized
is called risk assessment. Risk assessment (NRC, 1983, 1994) is a systematic
means of evaluating the probability of occurrence of adverse health effects
in humans from excess exposure to an environmental agent (in this case, a
nutrient) (FAO/WHO, 1995; Health Canada, 1993). The hallmark of risk
assessment is the requirement to be explicit in all of the evaluations and
judgments that must be made to document conclusions.
RISK ASSESSMENT AND FOOD SAFETY
Basic Concepts
Risk assessment is a scientific undertaking having as its objective a
characterization of the nature and likelihood of harm resulting from
human exposure to agents in the environment. The characterization of
risk typically contains both qualitative and quantitative information and
includes a discussion of the scientific uncertainties in that information. In
the present context, the agents of interest are nutrients, and the environ-
mental media are food, water, and nonfood sources such as nutrient
supplements and pharmacological preparations.
Performing a risk assessment results in a characterization of the rela-
tionships between exposure to an agent and the likelihood that adverse
health effects will occur in members of exposed populations. Scientific
uncertainties are an inherent part of the risk assessment process and are
discussed below. Deciding whether the magnitude of exposure is acceptable
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A M ODEL FOR THE DEVELOPMENT OF ULs
or tolerable in specific circumstances is not a component of risk assessment;
this activity falls within the domain of risk management. Risk management
decisions depend on the results of risk assessments, but may also involve
the public health significance of the risk, the technical feasibility of achiev-
ing various degrees of risk control, and the economic and social costs of
this control. Because there is no single, scientifically definable distinction
between safe and unsafe exposures, risk management necessarily incorpo-
rates components of sound, practical decision making that are not
addressed by the risk assessment process (NRC, 1983, 1994).
Risk assessment requires that information be organized in rather
specific ways, but it does not require any specific scientific evaluation
methods. Rather, risk assessors must evaluate scientific information using
what they judge to be appropriate methods and must make explicit the
basis for their judgments, the uncertainties in risk estimates, and, when
appropriate, alternative scientifically plausible interpretations of the avail-
able data (NRC, 1994; OTA, 1993).
Risk assessment is subject to two types of scientific uncertainties: those
related to data and those associated with inferences that are required when
directly applicable data are not available (NRC, 1994). Data uncertainties
arise during the evaluation of information obtained from the epidemio-
logical and toxicological studies of nutrient intake levels that are the basis
for risk assessments. Examples of inferences include the use of data from
experimental animals to estimate responses in humans and the selection
of uncertainty factors to estimate inter- and intraspecies variabilities in
response to toxic substances. Uncertainties arise whenever estimates of
adverse health effects in humans are based on extrapolations of data obtained
under dissimilar conditions (e.g., from experimental animal studies).
Options for dealing with uncertainties are discussed below and in detail in
Appendix L.
Steps in the Risk Assessment Process
The organization of risk assessment is based on a model proposed by
the National Research Council (NRC, 1983, 1994) that is widely used in
public health and regulatory decision making. The steps of risk assessment
as applied to nutrients follow (see also Figure 4-1).
• Step 1. Hazard identification involves the collection, organization,
and evaluation of all information pertaining to the adverse effects of a
given nutrient. It concludes with a summary of the evidence concerning
the capacity of the nutrient to cause one or more types of toxicity in humans.
• Step 2. Dose–response assessment determines the relationship
between nutrient intake (dose) and adverse effect (in terms of incidence
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88 DIETARY REFERENCE INTAKES
FIGURE 4-1 Risk assessment model for nutrient toxicity. NOAEL = no-observed-
adverse-effect level; LOAEL = lowest-observed-adverse-effect level; UF = uncertainty
factor.
and severity). This step concludes with an estimate of the Tolerable Upper
Intake Level (UL)—it identifies the highest level of daily nutrient intake
that is likely to pose no risk of adverse health effects for almost all indi-
viduals in the general population. Different ULs may be developed for
various life stage groups.
• Step 3. Intake assessment evaluates the distribution of usual total
daily nutrient intakes for members of the general population. In cases
where the UL pertains only to supplement use and does not pertain to
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A M ODEL FOR THE DEVELOPMENT OF ULs
usual food intakes of the nutrient, the assessment is directed at supple-
ment intakes only. It does not depend on Step 1 or 2.
• Step 4. Risk characterization summarizes the conclusions from
Steps 1 and 2 with Step 3 to determine the risk. The risk is generally
expressed as the fraction of the exposed population, if any, having nutri-
ent intakes (Step 3) in excess of the estimated UL (Steps 1 and 2). If
possible, characterization also covers the magnitude of any such excesses.
Scientific uncertainties associated with both the UL and the intake
estimates are described so that risk managers understand the degree of
scientific confidence they can place in the risk assessment.
The risk assessment contains no discussion of recommendations for
reducing risk; these are the focus of risk management.
Thresholds
A principal feature of the risk assessment process for noncarcinogens
is the long-standing acceptance that no risk of adverse effects is expected
unless a threshold dose (or intake) is exceeded. The adverse effects that
may be caused by a nutrient almost certainly occur only when the thresh-
old dose is exceeded (NRC, 1994; WHO, 1996). The critical issue con-
cerns the methods used to identify the approximate threshold of toxicity
for a large and diverse human population. Because most nutrients are not
considered to be carcinogenic in humans, approaches used for carcino-
genic risk assessment are not discussed here.
Thresholds vary among members of the general population (NRC,
1994). For any given adverse effect, if the distribution of thresholds in the
population could be quantitatively identified, it would be possible to estab-
lish ULs by defining some point in the lower tail of the distribution of
thresholds that would protect some specified fraction of the population.
The method described here for identifying thresholds for a general popu-
lation is designed to ensure that almost all members of the population will
be protected, but it is not based on an analysis of the theoretical (but
practically unattainable) distribution of thresholds. By using the model to
derive the threshold, however, there is considerable confidence that the
threshold, which becomes the UL for nutrients or food components, lies
very near the low end of the theoretical distribution and is the end repre-
senting the most sensitive members of the population. For some nutrients
there may be subpopulations that are not included in the general distribu-
tion because of extreme or distinct vulnerabilities to toxicity. Data relating
to the effects observed in these groups are not used to derive ULs. Such
distinct groups, whose conditions warrant medical supervision, may not be
protected by the UL.
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The Joint FAO/WHO Expert Committee on Food Additives and vari-
ous national regulatory bodies have identified factors (called uncertainty
factors [UFs]) that account for interspecies and intraspecies differences in
response to the hazardous effects of substances and for other uncertainties
(WHO, 1987). UFs are used to make inferences about the threshold dose
of substances for members of a large and diverse human population from
data on adverse effects obtained in epidemiological or experimental
studies. These factors are applied consistently when data of specific types
and quality are available. They are typically used to derive acceptable daily
intakes for food additives and other substances for which data on adverse
effects are considered sufficient to meet minimum standards of quality
and completeness (FAO/WHO, 1982). These adopted or recognized UFs
have sometimes been coupled with other factors to compensate for defi-
ciencies in the available data and other uncertainties regarding data.
When possible, the UL is based on a no-observed-adverse-effect level
(NOAEL), which is the highest intake (or experimental oral dose) of a
nutrient at which no adverse effects have been observed in the individuals
studied. This is identified for a specific circumstance in the hazard identi-
fication and dose–response assessment steps of the risk. If there are no
adequate data demonstrating a NOAEL, then a lowest-observed-adverse-
effect level (LOAEL) may be used. A LOAEL is the lowest intake (or experi-
mental oral dose) at which an adverse effect has been identified. The
derivation of a UL from a NOAEL (or LOAEL) involves a series of choices
about which factors should be used to deal with uncertainties. Uncertainty
factors are applied in an attempt to deal both with gaps in data and with
incomplete knowledge about the inferences required (e.g., the expected
variability in response within the human population). The problems of
both data and inference uncertainties arise in all steps of the risk assess-
ment. A discussion of options available for dealing with these uncertainties
is presented below and in greater detail in Appendix L.
A UL is not, in itself, a description or estimate of human risk. It is
derived by application of the hazard identification and dose–response
evaluation steps (Steps 1 and 2) of the risk assessment model. To deter-
mine whether populations are at risk requires an intake or exposure assess-
ment (Step 3, evaluation of intakes of the nutrient by the population) and
a determination of the fractions of these populations, if any, whose intakes
exceed the UL. In the intake assessment and risk characterization steps
(Steps 3 and 4), the distribution of usual intakes for the population is used
as a basis for determining whether, and to what extent, the population is
at risk (Figure 4-1). A discussion of other aspects of the risk characteriza-
tion that may be useful in judging the public health significance of the risk
and in risk management decisions is provided in the final section of this
chapter “Risk Characterization.”
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A M ODEL FOR THE DEVELOPMENT OF ULs
APPLICATION OF THE RISK ASSESSMENT MODEL
TO NUTRIENTS
This section provides guidance for applying the risk assessment frame-
work (the model) to the derivation of Tolerable Upper Intake Levels (ULs)
for nutrients.
Special Problems Associated with Substances
Required for Human Nutrition
Although the risk assessment model outlined above can be applied to
nutrients to derive ULs, it must be recognized that nutrients possess some
properties that distinguish them from the types of agents for which the
risk assessment model was originally developed (NRC, 1983). In the appli-
cation of accepted standards for risk assessment of environmental chemi-
cals to risk assessment of nutrients, a fundamental difference between the
two categories must be recognized: within a certain range of intakes, nutrients
are essential for human well-being and usually for life itself. Nonetheless,
they may share with other chemicals the production of adverse effects at
excessive exposures. Because the consumption of balanced diets is consis-
tent with the development and survival of humankind over many millennia,
there is less need for the large uncertainty factors that have been used for
the risk assessment of nonessential chemicals. In addition, if data on the
adverse effects of nutrients are available primarily from studies in human
populations, there will be less uncertainty than is associated with the types
of data available on nonessential chemicals.
There is no evidence to suggest that nutrients consumed at the recom-
mended intake (the Recommended Dietary Allowance or Adequate Intake)
present a risk of adverse effects to the general population.1 It is clear,
however, that the addition of nutrients to a diet through the ingestion of
large amounts of highly fortified food, nonfood sources such as supple-
ments, or both, may (at some level) pose a risk of adverse health effects.
The UL is the highest level of daily nutrient intake that is likely to pose no
risk of adverse health effects for almost all individuals in the general popula-
tion. As intake increases above the UL, the risk of adverse effects increases.
If adverse effects have been associated with total intake, ULs are based
on total intake of a nutrient from food, water, and supplements. For cases
in which adverse effects have been associated with intake only from supple-
1It is recognized that possible exceptions to this generalization relate to specific
geochemical areas with excessive environmental exposures to certain trace ele-
ments (e.g., selenium) and to rare case reports of adverse effects associated with
highly eccentric consumption of specific foods. Data from such findings are gener-
ally not useful for setting ULs for the general North American population.
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92 DIETARY REFERENCE INTAKES
ments and food fortificants, the UL is based on intake from these sources
only, rather than on total intake. The effects of nutrients from fortified
foods or supplements may differ from those of naturally occurring con-
stituents of foods because of the chemical form of the nutrient, the timing
of the intake and amount consumed in a single bolus dose, the matrix
supplied by the food, and the relation of the nutrient to the other con-
stituents of the diet. Nutrient requirements and food intake are related to
the metabolizing body mass, which is also at least an indirect measure of
the space in which the nutrients are distributed. This relation between
food intake and space of distribution supports homeostasis, which main-
tains nutrient concentrations in that space within a range compatible with
health. However, excessive intake of a single nutrient from supplements or
fortificants may compromise this homeostatic mechanism. Such elevations
alone may pose risks of adverse effects; imbalances among the nutrients
may also be possible. These reasons and those discussed previously sup-
port the need to include the form and pattern of consumption in the
assessment of risk from high nutrient or food component intake.
Consideration of Variability in Sensitivity
The risk assessment model outlined in this chapter is consistent with
classical risk assessment approaches in that it must consider variability in
the sensitivity of individuals to adverse effects of nutrients or food compo-
nents. A discussion of how variability is dealt with in the context of nutri-
tional risk assessment follows.
Physiological changes and common conditions associated with growth
and maturation that occur during an individual’s lifespan may influence
sensitivity to nutrient toxicity. For example, sensitivity increases with declines
in lean body mass and with the declines in renal and liver function that
occur with aging; sensitivity changes in direct relation to intestinal absorp-
tion or intestinal synthesis of nutrients; sensitivity increases in the new-
born infant because of rapid brain growth and limited ability to secrete or
biotransform toxicants; and sensitivity increases with decreases in the rate
of metabolism of nutrients. During pregnancy, the increase in total body
water and glomerular filtration results in lower blood levels of water-soluble
vitamins dose for dose, and therefore results in reduced susceptibility to
potential adverse effects. However, in the unborn fetus this may be offset
by active placental transfer, accumulation of certain nutrients in the amni-
otic fluid, and rapid development of the brain. Examples of life stage
groups that may differ in terms of nutritional needs and toxicological sen-
sitivity include infants and children, the elderly, and women during preg-
nancy and lactation.
Even within relatively homogeneous life stage groups, there is a range
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A M ODEL FOR THE DEVELOPMENT OF ULs
of sensitivities to toxic effects. The model described below accounts for the
normal expected variability in sensitivity, but it excludes subpopulations
with extreme and distinct vulnerabilities. Such subpopulations consist of
individuals needing medical supervision; they are better served through
the use of public health screening, product labeling, or other individual-
ized health care strategies. Such populations may not be at negligible risk
when their intakes reach the UL developed for the healthy population.
The decision to treat identifiable vulnerable subgroups as distinct (not
protected by the UL) is a matter of judgment and is discussed in the
individual nutrient chapters, as applicable.
Bioavailability
In the context of toxicity, the bioavailability of an ingested nutrient
can be defined as its accessibility to normal metabolic and physiological
processes. Bioavailability influences a nutrient’s beneficial effects at physi-
ological levels of intake and also may affect the nature and severity of
toxicity due to excessive intakes. The concentration and chemical form of
the nutrient, the nutrition and health of the individual, and excretory
losses all affect bioavailability. Bioavailability data for specific nutrients
must be considered and incorporated into the risk assessment process.
Some nutrients may be less readily absorbed when part of a meal than
when consumed separately. Supplemental forms of some nutrients may
require special consideration if they have higher bioavailability since they
may present a greater risk of producing adverse effects than equivalent
amounts from the natural form found in food.
Nutrient–Nutrient Interactions
A diverse array of adverse health effects can occur as a result of the
interaction of nutrients. The potential risks of adverse nutrient–nutrient
interactions increase when there is an imbalance in the intake of two or
more nutrients. Excessive intake of one nutrient may interfere with absorp-
tion, excretion, transport, storage, function, or metabolism of a second
nutrient. Possible adverse nutrient–nutrient interactions are considered as
a part of setting a UL. Nutrient–nutrient interactions may be considered
either as a critical endpoint on which to base a UL, or as supportive evi-
dence for a UL based on another endpoint.
Other Relevant Factors That Affect the Bioavailability of Nutrients
In addition to nutrient interactions, other considerations have the
potential to influence nutrient bioavailability, such as the nutritional status
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of an individual and the form of intake. These issues are considered in the
risk assessment. With regard to the form of intake, fat-soluble vitamins,
such as vitamin A, are more readily absorbed when they are part of a meal
that is high in fat. ULs must therefore be based on nutrients as part of the
total diet, including the contribution from water. Nutrient supplements
that are taken separately from food require special consideration because
they are likely to have different bioavailabilities and therefore may repre-
sent a greater risk of producing adverse effects.
STEPS IN THE DEVELOPMENT OF THE TOLERABLE
UPPER INTAKE LEVEL
Hazard Identification
Based on a thorough review of the scientific literature, the hazard
identification step outlines the adverse health effects that have been dem-
onstrated to be caused by the nutrient. The primary types of data used as
background for identifying nutrient hazards in humans are:
• Human studies. Human data provide the most relevant kind of infor-
mation for hazard identification and, when they are of sufficient quality
and extent, are given the greatest weight. However, the number of con-
trolled human toxicity studies conducted in a clinical setting is very limited
because of ethical reasons. Such studies are generally most useful for
identifying very mild (and ordinarily reversible) adverse effects. Observa-
tional studies that focus on well-defined populations with clear exposures
to a range of nutrient intake levels are useful for establishing a relation-
ship between exposure and effect. Observational data in the form of case
reports or anecdotal evidence are used for developing hypotheses that can
lead to knowledge of causal associations. Sometimes a series of case reports,
if it shows a clear and distinct pattern of effects, may be reasonably con-
vincing on the question of causality.
• Animal data. Most of the available data used in regulatory risk assess-
ments come from controlled laboratory experiments in animals, usually
mammalian species other than humans (e.g., rodents). Such data are used
in part because human data on nonessential chemicals are generally very
limited. Moreover, there is a long-standing history of the use of animal
studies to identify the toxic properties of chemical substances, and there is
no inherent reason why animal data should not be relevant to the evalua-
tion of nutrient toxicity. Animal studies offer several advantages over
human studies. They can, for example, be readily controlled so that causal
relationships can be recognized. It is possible to identify the full range of
toxic effects produced by a chemical, over a wide range of exposures, and
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Causality
The identification of a hazard is strengthened by evidence of causality.
As explained in Chapter 2, the criteria of Hill (1971) are considered in
judging the causal significance of an exposure–effect association indicated
by epidemiological studies.
Relevance of Experimental Data
Consideration of the following issues can be useful in assessing the
relevance of experimental data.
Animal Data. Some animal data may be of limited utility in judging
the toxicity of nutrients because of highly variable interspecies differences
in nutrient requirements. Nevertheless, relevant animal data are consid-
ered in the hazard identification and dose–response assessment steps
where applicable, and, in general, they are used for hazard identification
unless there are data demonstrating they are not relevant to humans, or it
is clear that the available human data are sufficient.
Route of Exposure.2 Data derived from studies involving oral exposure
(rather than parenteral, inhalation, or dermal exposure) are most useful
for the evaluation of nutrients. Data derived from studies involving
parenteral, inhalation, or dermal routes of exposure may be considered
relevant if the adverse effects are systemic and data are available to permit
interroute extrapolation.
Duration of Exposure. Because the magnitude, duration, and frequency
of exposure can vary considerably in different situations, consideration
needs to be given to the relevance of the exposure scenario (e.g., chronic
daily dietary exposure versus short-term bolus doses) to dietary intakes by
human populations.
Pharmacokinetic and Metabolic Data
When available, data regarding the rates of nutrient absorption, distri-
bution, metabolism, and excretion may be important in derivation of
Tolerable Upper Intake Levels (ULs). Such data may provide significant
information regarding the interspecies differences and similarities in
2The terms route of exposure and route of intake refer to how a substance enters the
body (e.g., by ingestion, injection, or dermal absorption). These terms should not
be confused with form of intake, which refers to the medium or vehicle used (e.g.,
supplements, food, or drinking water).
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A M ODEL FOR THE DEVELOPMENT OF ULs
nutrient behavior, and so may assist in identifying relevant animal data.
They may also assist in identifying life stage differences in response to
nutrient toxicity.
In some cases, there may be limited or even no significant data relating
to nutrient toxicity. It is conceivable that in such cases pharmacokinetic
and metabolic data may provide valuable insights into the magnitude of
the UL. Thus, if there are significant pharmacokinetic and metabolic data
over the range of intakes that meet nutrient requirements, and if it is
shown that this pattern of pharmacokinetic and metabolic data does not
change in the range of intakes greater than those required for nutrition, it
may be possible to infer the absence of toxic risk in this range. In contrast,
an alteration of pharmacokinetics or metabolism may suggest the poten-
tial for adverse effects. There has been no case encountered thus far in
which sufficient pharmacokinetic and metabolic data are available for
establishing ULs in this fashion, but it is possible such situations may arise
in the future.
Mechanisms of Toxic Action
Knowledge of molecular and cellular events underlying the produc-
tion of toxicity can assist in dealing with the problems of extrapolation
between species and from high to low doses. It may also aid in understand-
ing whether the mechanisms associated with toxicity are those associated
with deficiency. In most cases, however, because knowledge of the bio-
chemical sequence of events resulting from toxicity and deficiency is still
incomplete, it is not yet possible to state with certainty whether these
sequences share a common pathway.
Quality and Completeness of the Database
The scientific quality and quantity of the database are evaluated.
Human or animal data are reviewed for suggestions that the nutrient has
the potential to produce additional adverse health effects. If suggestions
are found, additional studies may be recommended.
Identification of Distinct and Highly Sensitive Subpopulations
The ULs are based on protecting the most sensitive members of the
general population from adverse effects of high nutrient intake. Some
highly sensitive subpopulations have responses (in terms of incidence,
severity, or both) to the agent of interest that are clearly distinct from the
responses expected for the healthy population. The risk assessment process
recognizes that there may be individuals within any life stage group who
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are more biologically sensitive than others, and thus their extreme sensi-
tivities do not fall within the range of sensitivities expected for the general
population. The UL for the general population may not be protective for
these subgroups. As indicated earlier, the extent to which a distinct sub-
population will be included in the derivation of a UL for the general
population is an area of judgment to be addressed on a case-by-case basis.
Dose–Response Assessment
The process for deriving the UL is described in this section and out-
lined in Box 4-1. It includes selection of the critical data set, identification
of a critical endpoint with its no-observed-adverse-effect level (NOAEL) or
lowest-observed-adverse-effect level (LOAEL), and assessment of uncertainty.
Data Selection and Identification of Critical Endpoints
The data evaluation process results in the selection of the most appro-
priate or critical data sets for deriving the UL. Selecting the critical data
set includes the following considerations:
• Human data, when adequate to evaluate adverse effects, are prefer-
able to animal data, although the latter may provide useful supportive
information.
• In the absence of appropriate human data, information from an
animal species with biological responses most like those of humans is most
valuable. Pharmacokinetic, metabolic, and mechanistic data may be avail-
able to assist in the identification of relevant animal species.
• If it is not possible to identify such a species or to select such data,
data from the most sensitive animal species, strain, and gender combina-
tion are given the greatest emphasis.
• The route of exposure that most resembles the route of expected
human intake is preferable. This consideration includes the digestive state
(e.g., fed or fasted) of the subjects or experimental animals. When this is
not possible, the differences in route of exposure are noted as a source of
uncertainty.
• The critical data set defines a dose–response relationship between
intake and the extent of the toxic response known to be most relevant to
humans. Data on bioavailability are considered and adjustments in expres-
sions of dose–response are made to determine whether any apparent dif-
ferences in response can be explained.
• The critical data set documents the route of exposure and the
magnitude and duration of the intake. Furthermore, the critical data set
documents the NOAEL (or LOAEL).
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A M ODEL FOR THE DEVELOPMENT OF ULs
Identification of a NOAEL (or LOAEL)
A nutrient can produce more than one toxic effect (or endpoint),
even within the same species or in studies using the same or different
exposure durations. The NOAELs and LOAELs for these effects will ordi-
narily differ. The critical endpoint used to establish a UL is the adverse
biological effect exhibiting the lowest NOAEL (e.g., the most sensitive
indicator of a nutrient’s toxicity). Because the selection of uncertainty
factors (UFs) depends in part upon the seriousness of the adverse effect, it
is possible that lower ULs may result from the use of the most serious
(rather than most sensitive) endpoint. Thus, it is often necessary to evaluate
several endpoints independently to determine which leads to the lowest UL.
For some nutrients, there may be inadequate data on which to develop
a UL. The lack of reports of adverse effects following excess intake of a
nutrient does not mean that adverse effects do not occur. As the intake of
any nutrient increases, a point (see Figure 4-2) is reached at which intake
begins to pose a risk. Above this point, increased intake increases the risk
of adverse effects. For some nutrients and for various reasons, there are
inadequate data to identify this point, or even to estimate its location.
Because adverse effects are almost certain to occur for any nutrient at
some level of intake, it should be assumed that such effects may occur for
nutrients for which a scientifically documentable UL cannot now be
derived. Until a UL is set or an alternative approach to identifying protec-
Risk of Adverse Effects
1.0 1.0
Risk of Adverse Effects
Risk of Inadequacy
0.5 0.5
0.0 0.0
Observed Level of Intake
FIGURE 4-2 Theoretical description of health effects of a nutrient as a function of
level of intake. The Tolerable Upper Intake Level (UL) is the highest level of daily
nutrient intake that is likely to pose no risk of adverse health effects for almost all
individuals in the general population. At intakes above the UL, the risk of adverse
effects increases.
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100 DIETARY REFERENCE INTAKES
tive limits is developed, intakes greater than the Recommended Dietary
Allowance (RDA) or Adequate Intake (AI) should be viewed with caution.
The absence of sufficient data to establish a UL points to the need for
studies suitable for developing ULs.
Uncertainty Assessment
Several judgments must be made regarding the uncertainties and thus
the uncertainty factor (UF) associated with extrapolating from the
observed data to the general population (see Appendix L). Applying a UF
to a NOAEL (or LOAEL) results in a value for the derived UL that is less
than the experimentally derived NOAEL unless the UF is 1. The greater
the uncertainty, the larger the UF and the smaller the resulting UL. This is
consistent with the ultimate goal of the risk assessment: to provide an
estimate of a level of intake that will protect the health of virtually all
members of the healthy population (Mertz et al., 1994).
Although several reports describe the underlying basis for UFs (Dourson
and Stara, 1983; Zielhuis and van der Kreek, 1979), the strength of the
evidence supporting the use of a specific UF will vary. Because the impreci-
sion of these UFs is a major limitation of risk assessment approaches, con-
siderable leeway must be allowed for the application of scientific judgment
in making the final determination. Because data are generally available
regarding intakes of nutrients in human populations, the data on nutrient
toxicity may not be subject to the same uncertainties as are data on non-
essential chemical agents. The resulting UFs for nutrients and food
components are typically less than the factors of 10 often applied to non-
essential toxic substances. The UFs are lower with higher quality data and
when the adverse effects are extremely mild and reversible.
In general, when determining a UF, the following potential sources of
uncertainty are considered and combined in the final UF:
• Interindividual variation in sensitivity. Small UFs (close to 1) are used
to represent this source of uncertainty if it is judged that little population
variability is expected for the adverse effect, and larger factors (close to
10) are used if variability is expected to be great (NRC, 1994).
• Extrapolation from experimental animals to humans. A UF to account
for the uncertainty in extrapolating animal data to humans is generally
applied to the NOAEL when animal data are the primary data available.
While a default UF of 10 is often used to extrapolate animal data to humans
for nonessential chemicals, a lower UF may be used because of data showing
some similarities between the animal and human responses (NRC, 1994).
• LOAEL instead of NOAEL. If a NOAEL is not available, a UF may be
applied to account for the uncertainty in deriving a UL from the LOAEL.
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A M ODEL FOR THE DEVELOPMENT OF ULs
The size of the UF involves scientific judgment based on the severity and
incidence of the observed effect at the LOAEL and the steepness (slope)
of the dose–response.
• Subchronic NOAEL to predict chronic NOAEL. When data are lacking
on chronic exposures, scientific judgment is necessary to determine whether
chronic exposures are likely to lead to adverse effects at lower intakes than
those producing effects after subchronic exposures (exposures of shorter
duration).
Derivation of a UL
The UL is derived by dividing the NOAEL (or LOAEL) by a single UF
that incorporates all relevant uncertainties. ULs, expressed as amount per
day, are derived for various life stage groups using relevant databases,
NOAELs, LOAELs, and UFs. In cases where no data exist with regard to
NOAELs or LOAELs for the group under consideration, extrapolations
from data in other age groups or animal data are made on the basis of
known differences in body size, physiology, metabolism, absorption, and
excretion of the nutrient.
Generally, any age group adjustments are made based solely on differ-
ences in body weight, unless there are data demonstrating age-related dif-
ferences in nutrient pharmacokinetics, metabolism, or mechanism of action.
The derivation of the UL involves the use of scientific judgment to
select the appropriate NOAEL (or LOAEL) and UF. As shown in Figure 4-3,
when using the same critical endpoint there is a greater level of uncer-
tainty in setting the UL based on a LOAEL compared with a NOAEL. The
risk assessment requires explicit consideration and discussion of all choices
made regarding both the data used and the uncertainties accounted for.
These considerations are discussed in the nutrient chapters.
Characterization of the Estimate and Special Considerations
If the data review reveals the existence of subpopulations having dis-
tinct and exceptional sensitivities to a nutrient’s toxicity, these subpopula-
tions are explicitly discussed and concerns related to adverse effects are
noted; however, the use of the data is not included in the identification of
the NOAEL or LOAEL, upon which the UL for the general population is
based.
Circumstances in Which No UL Is Established
There are two general conditions under which ULs are not established.
In some cases, the availability of insufficient evidence regarding a
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RDA UL NOAEL LOAEL
Risk of Adverse
100%
Effects
50%
NOAEL
RDA UL LOAEL
100%
Risk of Adverse
Effects
50%
Increasing Intake
FIGURE 4-3 Effect of uncertainty assessment on the Tolerable Upper Intake Level
(UL). Dashed line represents a hypothetical no-observed-adverse-effect level
(NOAEL). Solid lines represent available data used to set the UL. Area containing
diagonal lines represents theoretical range of uncertainty. LOAEL = lowest-
observed-adverse-effect level; RDA = Recommended Dietary Allowance.
nutrient’s capacity to cause adverse effects prohibits the application of the
UL model. In other cases, the evidence is available, but meeting the UL
derived from such evidence will necessarily result in the introduction of
undesirable health effects because of the required adjustments in dietary
patterns.
Insufficient Evidence of Adverse Effects
The scientific evidence relating to adverse effects of nutrient excess
varies greatly among nutrients. The type of data and evidence of causation
used to derive ULs have been described earlier in this chapter, but such
data and evidence are simply unavailable for some nutrients. In some cases
(e.g., the individual amino acids), some data relating to adverse effects
may be available, but are of such uncertain relevance to human health that
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A M ODEL FOR THE DEVELOPMENT OF ULs
their use in deriving ULs is scientifically insupportable. In every instance in
which ULs are not derived because of lack of adequate evidence, the
specific limitations in the database are described.
Offsetting Benefits Reduction
In the case of macronutrients, particularly, problems arise because of
the adjustments in dietary patterns that would be required to meet a
derived UL. For saturated and trans fatty acids and dietary cholesterol, for
example, there is evidence that any intake greater than zero will increase
serum levels of low density lipoprotein cholesterol, an established risk for
cardiovascular disease. In such cases, the UL model calls for the establish-
ment of a UL of 0. But it is clear that, because saturated fat and cholesterol
are both unavoidable in ordinary diets, achieving such a UL will require
extraordinary changes in patterns of dietary intake. Such extraordinary
adjustments may introduce other undesirable health effects (e.g., elimina-
tion of foods containing saturated fats may result in a large excess intake
of carbohydrate and insufficient intake of micronutrients). In addition,
unknown and unquantifiable health risks may also be introduced. For
these reasons, no UL will be proposed in circumstances in which imple-
mentation of measures to achieve the UL may lead to undesirable dietary
adjustments. In all such cases, the basis for failing to propose a UL will be
described.
Lack of ULs for Macronutrients and Implications
ULs were not set for macronutrients because (1) there was insufficient
evidence for identifying an adverse effect, and therefore a LOAEL, upon
which to determine a UL (e.g., protein), (2) data relating to adverse effects
were available (e.g., amino acids), but were of uncertain relevance to
human health because their use in deriving ULs was not scientifically sup-
portable, (3) macronutrients are interrelated in providing energy and
therefore it is not known whether the adverse effect is due to a high intake
of one macronutrient (e.g., fat), due to a low intake of another macro-
nutrient (e.g., carbohydrate, which is usually low in a high fat diet), or
both (high fat, low carbohydrate diet), and (4) adjustments of dietary
patterns to prevent exceeding a UL of near 0 g/d (e.g., trans and saturated
fatty acids and cholesterol), resulting in inadequate intakes of certain micro-
nutrients (e.g., iron and zinc). In addition, the UL method is not applicable
to energy since any intake above the requirement would be expected to
result in weight gain and an increased risk of premature mortality.
The failure to establish a UL for any nutrient should not be inter-
preted as a lack of concern for adverse health effects (i.e., it is not equiva-
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lent to a recommendation that the nutrient can be consumed without
limit). Lack of data regarding adverse effects is not evidence of safety.
Indeed, in some cases (the previous example of saturated fat) there is
clearly evidence of adverse health effects, but a UL is not established to
avoid the need for drastic changes that may introduce undesirable health
effects.
In every instance in which a UL is not established, it is necessary to
offer specific advice regarding the need to avoid deficiency, or in some
cases, to reduce intakes, consistent with the need to maintain healthy
dietary patterns.
INTAKE ASSESSMENT
In order to assess the risk of adverse effects, information on the range
of nutrient intakes in the general population is required. As noted earlier,
in cases where the Tolerable Upper Intake Level (UL) pertains only to
supplement use and not to usual food intakes of the nutrient, the assess-
ment is directed at supplement intake only.
RISK CHARACTERIZATION
As described earlier, the question of whether nutrient intakes create a
risk of toxicity requires a comparison of the range of nutrient intakes
(from food, supplements, and other sources, or from supplements alone,
depending upon the basis for the Tolerable Upper Intake Level [UL])
with the UL.
Figure 4-4 illustrates a distribution of chronic nutrient intakes in a
population; the fraction of the population experiencing chronic intakes
above the UL represents the potential at-risk group. A policy decision is
needed to determine whether efforts should be made to reduce risk. No
precedents are available for such policy decisions, although in the areas of
food additives or pesticide regulations, federal regulatory agencies have
generally sought to ensure that the 90th or 95th percentile of intake falls
below the UL (or its approximate equivalent measure of risk). If this goal
is achieved, the fraction of the population remaining above the UL is
likely to experience intakes only slightly greater than the UL and is likely
to be at little or no risk.
For risk management decisions, it is useful to evaluate the public
health significance of the risk, and information contained in the risk char-
acterization is critical for this purpose.
Thus, the significance of the risk to a population consuming a nutri-
ent in excess of the UL is determined by the following:
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A M ODEL FOR THE DEVELOPMENT OF ULs
FIGURE 4-4 Illustration of the population at risk from excessive nutrient intakes.
The fraction of the population consistently consuming a nutrient at intake levels in
excess of the Tolerable Upper Intake Level (UL) is potentially at risk of adverse
health effects. See text for a discussion of additional factors necessary to judge the
significance of the risk. NOAEL = no-observed-adverse-effect level; LOAEL = lowest-
observed-adverse-effect level.
1. the fraction of the population consistently consuming the nutri-
ent at intake levels in excess of the UL,
2. the seriousness of the adverse effects associated with the nutrient,
3. the extent to which the effect is reversible when intakes are reduced
to levels less than the UL, and
4. the fraction of the population with consistent intakes above the
no-observed-adverse-effect level or even the lowest-observed-adverse-effect
level.
Thus, the significance of the risk of excessive nutrient intake cannot
be judged only by reference to Figure 4-4, but requires careful consider-
ation of all of the above factors. Information on these factors is contained
in sections of the nutrient chapters that describe the bases for each of
the ULs.
REFERENCES
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uncertainty (safety) factors. Regul Toxicol Pharmacol 3:224–238.
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FAO/WHO (Food and Agriculture Organization of the United Nations/World
Health Organization). 1982. Evaluation of Certain Food Additives and Contami-
nants. Twenty-sixth report of the Joint FAO/WHO Expert Committee on Food
Additives. WHO Technical Report Series No. 683. Geneva: WHO.
FAO/WHO. 1995. The Application of Risk Analysis to Food Standard Issues. Recom-
mendations to the Codex Alimentarius Commission (ALINORM 95/9,
Appendix 5). Geneva: WHO.
Health Canada. 1993. Health Risk Determination—The Challenge of Health Protection.
Ottawa: Health Canada, Health Protection Branch.
Hill AB. 1971. Principles of Medical Statistics, 9th ed. New York: Oxford University
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Klaassen CD, Amdur MO, Doull J. 1986. Casarett and Doull’s Toxicology: The Basic
Science of Poisons, 3rd ed. New York: Macmillan.
Mertz W, Abernathy CO, Olin SS. 1994. Risk Assessment of Essential Elements. Wash-
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NRC (National Research Council). 1983. Risk Assessment in the Federal Government:
Managing the Process. Washington, DC: National Academy Press.
NRC. 1994. Science and Judgment in Risk Assessment. Washington, DC: National Acad-
emy Press.
OTA (Office of Technology Assessment). 1993. Researching Health Risks. Washing-
ton, DC: OTA.
WHO (World Health Organization). 1987. Principles for the Safety Assessment of Food
Additives and Contaminants in Food. Environmental Health Criteria 70. Geneva:
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WHO. 1996. Trace Elements in Human Nutrition and Health. Geneva: WHO.
Zielhuis RL, van der Kreek FW. 1979. The use of a safety factor in setting health-
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Representative terms from entire chapter:
animal data
