The present
report critically reviews the available information related
to the safety of ephedra/ephedrine alkaloids and establishes
a safe upper intake based on the National Academy of Sciences
Upper Limit Model (UL) for nutrients. Information that was
evaluated included nNonclinical and clinical studies, published
case reports, and animal data, along with adverse event reports
(AERs) from the medical literature and the voluntary FDA reporting
system. called Special Nutritionals/Adverse Event Monitoring
System (SN/AEMS) under the direction of the Center for Food
Safety and Applied Nutrition (CFSAN) were evaluated. The term
Tolerable Upper Intake Level is defined as the maximum level
of total chronic daily intake of a substance judged unlikely
to pose a risk of adverse health effects to most members of
the healthy population, including sensitive individuals, throughout
the life stage, except in some discrete subpopulations (for
example, those with genetic predispositions or certain disease
states) that may be especially vulnerable to one or more adverse
effects. Although the model was developed for application
to nutrients, these food components are like all chemical
agents in that they can produce adverse health effects if
intakes are excessive. This UL is intended to provide a safety
standard for dietary supplements containing ephedrine ephedra
such that no significant or unreasonable risk of illness or
injury would arise at or below this intake level under specified
conditions of use.
The data
evaluation process for the UL method requires the selection
of the most appropriate or critical dataset(s) for deriving
the UL. In the data evaluation process, and high quality human
data are generally preferable to animal data; however, in
the absence of appropriate human data, information from an
animal species whose biological responses are most like those
of humans is used. The available human data provide the most
relevant kind of information for hazard identification potential
of ephedra/ephedrine alkaloids. In terms of assessing the
health effects of chemicals in humans, controlled, prospective
clinical investigations provide the most reliable source of
information. Following the assessment of the most critical
dataset(s), a NOAEL dose or intake level for humans is identified.
Based on the strengths of the study design, duration of study,
number of subjects enrolled, and endpoints evaluated, 19 studies
conducted in adultobese individuals were determined of sufficient
quality and extent for inclusion as the critical dataset for
the determination of a UL. A No Adverse Effect Level (NOAEL)
was identified as 90 mg/day of ephedrine alkaloids in an herbal
ephedra supplement, in a recent, well-conducted, placebo-controlled,
long-term 6-month investigation by Boozer et al. (2000).
Following
characterization of the NOAEL, safety factors or uncertainty
factors (UF) are typically applied. Judgments are made regarding
uncertainties associated with extrapolating from the observed
data to the healthy population. The UF is typically applied
to a NOAEL to derive the UL, which generally represents a
lower estimate of the threshold above which the there may
be a risk of adverse effects may increase. The UFs allocated
are dependent on the nature and extent of the toxicity safety
database. A UF of 1 was judged appropriate, based on considerations
of pharmacokinetics of ephedrine, use patterns, duration of
expected use, and animal studies, and the strong scientific
findings reported by Boozer et al. (2000) in the 6-month
ephedra study, and support ed by the of the clinical findings
on ephedrine from Pasquali et al. (1985), Krieger et
al. (1990), Astrup et al. (1992), Quaade et
al., (1992), Daly et al. (1993), Toubro et al.
(1993a,b), Nasser et al. (1999) and Molnár et
al., 2000.
Application
of the UF of 1 to the NOAEL of 90 derived a UL of 90 mg of
ephedrine alkaloids in ephedra per day for a generally
healthy population. This daily level of intake is unlikely
to pose a risk of adverse health effects. The UL for ephedrine
alkaloids in ephedra does not apply to specific groups of
persons, and other conditions of use include label instructions
that: consumers should check with their healthcare provider
about taking the product; direct the consumer to split the
daily dose into at least three parts, so that no dose exceeds
30 mg; the product is intended for use of not more than 6
months; and provide information to facilitate post-market
monitoring.
