Guidance
Potassium Iodide as a Thyroid Blocking Agent in Radiation Emergencies
U.S. Department of Health
and Human
Services
Food and Drug Administration
Center for Drug Evaluation and
Research
(CDER)
November 2001
Procedural
Additional copies are
available from:
Office of Training and
Communications
Division of Communications
Management
Drug Information Branch, HFD-210
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
(Internet) http://www.fda.gov/cder/guidance/index.htm
TABLE OF CONTENTS
I. INTRODUCTION
II. BACKGROUND
III. DATA
SOURCES
IV. CONCLUSIONS
AND RECOMMENDATIONS
V. ADDITIONAL
CONSIDERATIONS IN PROPHYLAXIS AGAINST THYROID RADIOIODINE EXPOSURE
VI. SUMMARY
ACKNOWLEDGEMENTS
BIBLIOGRAPHY
Guidance
Potassium
Iodide as a
Thyroid Blocking
Agent in
Radiation Emergencies
This guidance represents the Food
and Drug
Administration's (FDA's) current thinking on this topic. It does not
create
or confer any rights for or on any person and does not operate to bind
FDA or the public. An alternative approach may be used if such approach
satisfies the requirements of the applicable statutes and regulations.
I. INTRODUCTION
The objective of this document is
to provide
guidance to other Federal agencies, including the Environmental
Protection
Agency (EPA) and the Nuclear Regulatory Commission (NRC), and to state
and local governments regarding the safe and effective use of potassium
iodide (KI) as an adjunct to other public health protective measures in
the event that radioactive iodine is released into the environment. The
adoption and implementation of these recommendations are at the
discretion
of the state and local governments responsible for developing regional
emergency-response plans related to radiation emergencies.
This guidance updates the Food
and Drug
Administration (FDA) 1982 recommendations for the use of KI to reduce
the
risk of thyroid cancer in radiation emergencies involving the release
of
radioactive iodine. The recommendations in this guidance address KI
dosage
and the projected radiation exposure at which the drug should be
used.
These recommendations were
prepared by
the Potassium Iodide Working Group, comprising scientists from the
FDA's
Center for Drug Evaluation and Research (CDER) and Center for Devices
and
Radiological Health (CDRH) in collaboration with experts in the field
from
the National Institutes of Health (NIH). Although they differ in two
respects
(as discussed in Section IV.B), these revised recommendations are in
general
accordance with those of the World Health Organization (WHO), as
expressed
in its Guidelines for Iodine Prophylaxis Following Nuclear
Accidents:
Update 1999 (WHO 1999).
II.BACKGROUND
Under 44 CFR 351, the Federal
Emergency
Management Agency (FEMA) has established roles and responsibilities for
Federal agencies in assisting state and local governments in their
radiological
emergency planning and preparedness activities. The Federal agencies,
including
the Department of Health and Human Services (HHS), are to carry out
these
roles and responsibilities as members of the Federal Radiological
Preparedness
Coordinating Committee (FRPCC). Under 44 CFR 351.23(f), HHS is directed
to provide guidance to state and local governments on the use of
radioprotective
substances and the prophylactic use of drugs (e.g., KI) to reduce the
radiation
dose to specific organs. This guidance includes information about
dosage
and projected radiation exposures at which such drugs should be used.
The FDA has provided guidance
previously
on the use of KI as a thyroid blocking agent. In the Federal
Register
of December 15, 1978, FDA announced its conclusion that KI is a safe
and
effective means by which to block uptake of radioiodines by the thyroid
gland in a radiation emergency under certain specified conditions of
use.
In the Federal Register of June 29, 1982, FDA announced final
recommendations
on the administration of KI to the general public in a radiation
emergency.
Those recommendations were formulated after reviewing studies relating
radiation dose to thyroid disease risk that relied on estimates of external
thyroid irradiation after the nuclear detonations at Hiroshima and
Nagasaki
and analogous studies among children who received therapeutic radiation
to the head and neck. Those recommendations concluded that at a
projected
dose to the thyroid gland of 25 cGy or greater from ingested or inhaled
radioiodines, the risks of short-term use of small quantities of KI
were
outweighed by the benefits of suppressing radioiodine-induced thyroid
cancer.1
The amount of KI recommended at that time was 130 mg per day for adults
and children above 1 year of age and 65 mg per day for children below 1
year of age. The guidance that follows revises our 1982 recommendations
on the use of KI for thyroid cancer prophylaxis based on a
comprehensive
review of the data relating radioioidine exposure to thyroid cancer
risk
accumulated in the aftermath of the 1986 Chernobyl reactor accident.
III. DATA
SOURCES
A. Reliance
on Data from Chernobyl
In epidemiological studies
investigating
the relationship between thyroidal radioiodine exposure and risk of
thyroid
cancer, the estimation of thyroid radiation doses is a critical and
complex
aspect of the analyses. Estimates of exposure, both for individuals and
across populations, have been reached in different studies by the
variable
combination of (1) direct thyroid measurements in a segment of the
exposed
population; (2) measurements of 131I (iodine isotope)
concentrations
in the milk consumed by different groups (e.g., communities) and of the
quantity of milk consumed; (3) inference from ground deposition of
long-lived
radioisotopes released coincidentally and presumably in fixed ratios
with
radioiodines; and (4) reconstruction of the nature and extent of the
actual
radiation release.
All estimates of individual and
population
exposure contain some degree of uncertainty. The uncertainty is least
for
estimates of individual exposure based on direct thyroid measurements.
Uncertainty increases with reliance on milk consumption estimates; is
still
greater with estimates derived from ground deposition of long-lived
radioisotopes,
and is highest for estimates that rely heavily on release
reconstruction.
Direct measurements of thyroid
radioactivity
are unavailable from the Hanford, Nevada Test Site, and Marshall
Islands
exposures. Indeed, the estimates of thyroid radiation doses related to
these releases rely heavily on release reconstructions and, in the
former
two cases, on recall of the extent of milk consumption 40 to 50 years
after
the fact. In the Marshall Islands cohort, urinary radioiodine excretion
data were obtained and used in calculating exposure estimates.
Because of the great uncertainty
in the
dose estimates from the Hanford and Nevada Test Site exposures and due
to the small numbers of thyroid cancers occurring in the populations
potentially
exposed, the epidemiological studies of the excess thyroid cancer risk
related to these radioiodine releases are, at best, inconclusive. As
explained
below, the dosimetric data derived in the studies of individual and
population
exposures following the Chernobyl accident, although not perfect, are
unquestionably
superior to data from previous releases. In addition, the results of
the
earlier studies are inadequate to refute cogent case control study
evidence
from Chernobyl of a cause-effect relationship between thyroid
radioiodine
deposition and thyroid cancer risk.2
The Chernobyl reactor accident of
April
1986 provides the best-documented example of a massive radionuclide
release
in which large numbers of people across a broad geographical area were
exposed acutely to radioiodines released into the atmosphere.
Therefore,
the recommendations contained in this guidance are derived from our
review
of the Chernobyl data as they pertain to the large number of thyroid
cancers
that occurred. These are the most comprehensive and reliable data
available
describing the relationship between thyroid radiation dose and risk for
thyroid cancer following an environmental release of 131I.
In
contrast, the exposures resulting from radiation releases at the
Hanford
Site in Washington State in the mid-1940s and in association with the
nuclear
detonations at the Nevada Test Site in the 1950s were extended over
years,
rather than days to weeks, contributing to the difficulty in estimating
radioactive dose in those potentially exposed (Davis et al., 1999;
Gilbert
et al., 1998). The exposure of Marshall Islanders to fallout from the
nuclear
detonation on Bikini in 1954 involved relatively few people, and
although
the high rate of subsequent thyroid nodules and cancers in the exposed
population was likely caused in large part by radioiodines, the
Marshall
Islands data provide little insight into the dose-response relationship
between radioactive iodine exposure and thyroid cancer risk (Robbins
and
Adams 1989).
Beginning within a week after the
Chernobyl
accident, direct measurements of thyroid exposure were made in hundreds
of thousands of individuals, across three republics of the former
Soviet
Union (Robbins and Schneider 2000, Gavrilin et al., 1999, Likhtarev et
al., 1993, Zvonova and Balonov 1993). These thyroid measurements were
used
to derive, in a direct manner, the thyroid doses received by the
individuals
from whom the measurements were taken. The thyroid measurements were
also
used as a guide to estimate the thyroid doses received by other people,
taking into account differences in age, milk consumption rates, and
ground
deposition densities, among other things. The thyroid doses derived
from
thyroid measurements have a large degree of uncertainty, especially in
Belarus, where most of the measurements were made by inexperienced
people
with detectors that were not ideally suited to the task at hand
(Gavrilin
et al., 1999 and UNSCEAR 2000). However, as indicated above, the
uncertainties
attached to thyroid dose estimates derived from thyroid measurements
are,
as a rule, lower than those obtained without recourse to those
measurements.
It is also notable that the
thyroid radiation
exposures after Chernobyl were virtually all internal,
from
radioiodines. Despite some degree of uncertainty in the doses received,
it is reasonable to conclude that the contribution of external
radiation
was negligible for most individuals. This distinguishes the Chernobyl
exposures
from those of the Marshall Islanders. Thus, the increase in thyroid
cancer
seen after Chernobyl is attributable to ingested or inhaled
radioiodines.
A comparable burden of excess thyroid cancers could conceivably accrue
should U.S. populations be similarly exposed in the event of a nuclear
accident. This potential hazard highlights the value of averting such
risk
by using KI as an adjunct to evacuation, sheltering, and control of
contaminated
foodstuffs.
B. Thyroid
Cancers in the Aftermath of Chernobyl
The Chernobyl reactor accident
resulted in
massive releases of 131I and other radioiodines.
Beginning
approximately 4 years after the accident, a sharp increase in the
incidence
of thyroid cancer among children and adolescents in Belarus and Ukraine
(areas covered by the radioactive plume) was observed. In some regions,
for the first 4 years of this striking increase, observed cases of
thyroid
cancer among children aged 0 through 4 years at the time of the
accident
exceeded expected number of cases by 30- to 60-fold. During the ensuing
years, in the most heavily affected areas, incidence is as much as
100-fold
compared to pre-Chernobyl rates (Robbins and Schneider 2000;
Gavrilin
et al., 1999; Likhtarev et al., 1993; Zvonova and Balonov 1993). The
majority
of cases occurred in children who apparently received less than 30 cGy
to the thyroid (Astakhova et al., 1998). A few cases occurred in
children
exposed to estimated doses of < 1 cGy; however, the uncertainty of
these
estimates confounded by medical radiation exposures leaves doubt as to
the causal role of these doses of radioiodine (Souchkevitch and Tsyb
1996).
The evidence, though indirect,
that the
increased incidence of thyroid cancer observed among persons exposed
during
childhood in the most heavily contaminated regions in Belarus, Ukraine,
and the Russian Federation is related to exposure to iodine isotopes
is,
nevertheless, very strong (IARC 2001). We have concluded that the
best
dose-response information from Chernobyl shows a marked increase in
risk
of thyroid cancer in children with exposures of 5 cGy or greater (Astakhova
et. al., 1998; Ivanov et al., 1999; Kazakov et al., 1992). Among
children
born more than nine months after the accident in areas traversed by the
radioactive plume, the incidence of thyroid cancer has not exceeded
preaccident
rates, consistent with the short half-life of 131I.
The use of KI in Poland after the
Chernobyl
accident provides us with useful information regarding its safety and
tolerability
in the general population. Approximately 10.5 million children under
age
16 and 7 million adults received at least one dose of KI. Of note,
among
newborns receiving single doses of 15 mg KI, 0.37 percent (12 of 3214)
showed transient increases in TSH (thyroid stimulating hormone) and
decreases
in FT4 (free thyroxine). The side effects among adults and children
were
generally mild and not clinically significant. Side effects included
gastrointestinal
distress, which was reported more frequently in children (up to 2
percent,
felt to be due to bad taste of SSKI solution) and rash (~1 percent in
children
and adults). Two allergic reactions were observed in adults with known
iodine sensitivity (Nauman and Wolff 1993).
Thus, the studies following
the Chernobyl
accident support the etiologic role of relatively small doses of
radioiodine
in the dramatic increase in thyroid cancer among exposed children.
Furthermore, it appears that the increased risk occurs with a
relatively
short latency. Finally, the Polish experience supports the use of KI as
a safe and effective means by which to protect against thyroid cancer
caused
by internal thyroid irradiation from inhalation of contaminated air or
ingestion of contaminated food and drink when exposure cannot be
prevented
by evacuation, sheltering, or food and milk control.
IV.
CONCLUSIONS AND RECOMMENDATIONS
A. Use
of KI in Radiation Emergencies: Rationale, Effectiveness, Safety
For the reasons discussed above,
the Chernobyl
data provide the most reliable information available to date on the
relationship
between internal thyroid radioactive dose and cancer risk. They suggest
that the risk of thyroid cancer is inversely related to age, and that,
especially in young children, it may accrue at very low levels of
radioiodine
exposure. We have relied on the Chernobyl data to formulate our
specific
recommendations below.
The effectiveness of KI as a
specific blocker
of thyroid radioiodine uptake is well established (Il'in LA, et al.,
1972)
as are the doses necessary for blocking uptake. As such, it is
reasonable
to conclude that KI will likewise be effective in reducing the risk of
thyroid cancer in individuals or populations at risk for inhalation or
ingestion of radioiodines.
Short-term administration of KI
at thyroid
blocking doses is safe and, in general, more so in children than
adults.
The risks of stable iodine administration include sialadenitis (an
inflammation
of the salivary gland, of which no cases were reported in Poland among
users after the Chernobyl accident), gastrointestinal disturbances,
allergic
reactions and minor rashes. In addition, persons with known iodine
sensitivity
should avoid KI, as should individuals with dermatitis herpetiformis
and
hypocomplementemic vasculitis, extremely rare conditions associated
with
an increased risk of iodine hypersensitivity.
Thyroidal side effects of stable
iodine
include iodine-induced thyrotoxicosis, which is more common in older
people
and in iodine deficient areas but usually requires repeated doses of
stable
iodine. In addition, iodide goiter and hypothyroidism are potential
side
effects more common in iodine sufficient areas, but they require
chronic
high doses of stable iodine (Rubery 1990). In light of the preceding,
individuals
with multinodular goiter, Graves' disease, and autoimmune thyroiditis
should
be treated with caution, especially if dosing extends beyond a few
days.
The vast majority of such individuals will be adults.
The transient hypothyroidism
observed in
0.37 percent (12 of 3214) of neonates treated with KI in Poland after
Chernobyl
has been without reported sequelae to date. There is no question that
the
benefits of KI treatment to reduce the risk of thyroid cancer outweigh
the risks of such treatment in neonates. Nevertheless, in light of the
potential consequences of even transient hypothyroidism for
intellectual
development, we recommend that neonates (within the first month of
life)
treated with KI be monitored for this effect by measurement of TSH (and
FT4, if indicated) and that thyroid hormone therapy be instituted in
cases
in which hypothyroidism develops (Bongers-Schokking 2000; Fisher 2000;
Calaciura 1995).
B.
KI Use in Radiation Emergencies: Treatment Recommendations
After careful review of the data
from Chernobyl
relating estimated thyroid radiation dose and cancer risk in exposed
children,
FDA is revising its recommendation for administration of KI based on
age,
predicted thyroid exposure, and pregnancy and lactation status (see
Table).
|
|
|
|
|
Threshold Thyroid
Radioactive Exposures
and
Recommended Doses of KI
for Different
Risk Groups
|
|
Predicted
Thyroid exposure(cGy)
|
KI dose (mg)
|
# of 130 mg tablets
|
# of 65
mg tablets
|
Adults
over 40
yrs |
>500 |
130 |
1 |
2 |
Adults
over 18
through 40 yrs |
>10 |
Pregnant
or lactating
women |
>
5 |
Adoles.
over 12
through 18 yrs* |
65 |
1/2 |
1 |
Children
over 3
through 12 yrs |
Over
1 month through
3 years |
32 |
1/4 |
1/2 |
Birth
through 1
month |
16 |
1/8 |
1/4 |
*Adolescents approaching adult
size (>
70 kg) should receive the full adult dose (130 mg).
The protective effect of KI
lasts approximately
24 hours. For optimal prophylaxis, KI should therefore be dosed daily,
until a risk of significant exposure to radioiodines by either
inhalation
or ingestion no longer exists.
Individuals intolerant of KI
at protective
doses, and neonates, pregnant and lactating women (in whom repeat
administration
of KI raises particular safety issues, see below) should be given
priority
with regard to other protective measures (i.e., sheltering, evacuation,
and control of the food supply).
Note that adults over 40 need
take KI only
in the case of a projected large internal radiation dose to the thyroid
(>500 cGy) to prevent hypothyroidism.
These recommendations are meant
to provide
states and local authorities as well as other agencies with the best
current
guidance on safe and effective use of KI to reduce thyroidal
radioiodine
exposure and thus the risk of thyroid cancer. FDA recognizes that, in
the
event of an emergency, some or all of the specific dosing
recommendations
may be very difficult to carry out given their complexity and the
logistics
of implementation of a program of KI distribution. The recommendations
should therefore be interpreted with flexibility as necessary to allow
optimally effective and safe dosing given the exigencies of any
particular
emergency situation. In this context, we offer the following critical
general
guidance: across populations at risk for radioiodine exposure,
the
overall benefits of KI far exceed the risks of overdosing, especially
in
children, though we continue to emphasize particular attention to dose
in infants.
These FDA recommendations differ
from those
put forward in the World Health Organization (WHO) 1999 guidelines for
iodine prophylaxis in two ways. WHO recommends a 130-mg dose of KI for
adults and adolescents (over 12 years). For the sake of logistical
simplicity
in the dispensing and administration of KI to children, FDA recommends
a 65-mg dose as standard for all school-age children while allowing for
the adult dose (130 mg, 2 X 65 mg tablets) in adolescents approaching
adult
size. The other difference lies in the threshold for predicted exposure
of those up to 18 years of age and of pregnant or lactating women that
should trigger KI prophylaxis. WHO recommends a threshold of 1 cGy for
these two groups. As stated earlier, FDA has concluded from the
Chernobyl
data that the most reliable evidence supports a significant increase in
the risk of childhood thyroid cancer at exposures of 5 cGy or greater.
The downward KI dose adjustment
by age
group, based on body size considerations, adheres to the principle of
minimum
effective dose. The recommended standard dose of KI for all school-age
children is the same (65 mg). However, adolescents approaching adult
size
(i.e., >70 kg) should receive the full adult dose (130 mg) for
maximal
block of thyroid radioiodine uptake. Neonates ideally should receive
the
lowest dose (16 mg) of KI. Repeat dosing of KI should be avoided in the
neonate to minimize the risk of hypothyroidism during that critical
phase
of brain development (Bongers-Schokking 2000; Calaciura et al., 1995).
KI from tablets (either whole or fractions) or as fresh saturated KI
solution
may be diluted in milk, formula, or water and the appropriate volume
administered
to babies. As stated above, we recommend that neonates (within the
first
month of life) treated with KI be monitored for the potential
development
of hypothyroidism by measurement of TSH (and FT4, if indicated) and
that
thyroid hormone therapy be instituted in cases in which hypothyroidism
develops (Bongers-Schokking 2000; Fisher 2000; Calaciura et al., 1995).
Pregnant women should be given KI
for their
own protection and for that of the fetus, as iodine (whether stable or
radioactive) readily crosses the placenta. However, because of the risk
of blocking fetal thyroid function with excess stable iodine, repeat
dosing
with KI of pregnant women should be avoided. Lactating females should
be
administered KI for their own protection, as for other young adults,
and
potentially to reduce the radioiodine content of the breast milk, but
not
as a means to deliver KI to infants, who should get their KI directly.
As for direct administration of KI, stable iodine as a component of
breast
milk may also pose a risk of hypothyroidism in nursing neonates.
Therefore,
repeat dosing with KI should be avoided in the lactating mother, except
during continuing severe contamination. If repeat dosing of the mother
is necessary, the nursing neonate should be monitored as recommended
above.
V. ADDITIONAL
CONSIDERATIONS IN PROPHYLAXIS AGAINST THYROID RADIOIODINE EXPOSURE
Certain principles should guide
emergency
planning and implementation of KI prophylaxis in the event of a
radiation
emergency. After the Chernobyl accident, across the affected
populations,
thyroid radiation exposures occurred largely due to consumption of
contaminated
fresh cow's milk (this contamination was the result of milk cows
grazing
on fields affected by radioactive fallout) and to a much lesser extent
by consumption of contaminated vegetables. In this or similar
accidents,
for those residing in the immediate area of the accident or otherwise
directly
exposed to the radioactive plume, inhalation of radioiodines may be a
significant
contributor to individual and population exposures. As a practical
matter,
it may not be possible to assess the risk of thyroid exposure from
inhaled
radioiodines at the time of the emergency. The risk depends on factors
such as the magnitude and rate of the radioiodine release, wind
direction
and other atmospheric conditions, and thus may affect people both near
to and far from the accident site.
For optimal protection against
inhaled
radioiodines, KI should be administered before or immediately
coincident
with passage of the radioactive cloud, though KI may still have a
substantial protective effect even
if
taken 3 or 4 hours after exposure. Furthermore, if the release of
radioiodines
into the atmosphere is protracted, then, of course, even delayed
administration
may reap benefits by reducing, if incompletely, the total radiation
dose
to the thyroid.
Prevention of thyroid uptake of
ingested
radioiodines, once the plume has passed and radiation protection
measures
(including KI) are in place, is best accomplished by food control
measures
and not by repeated administration of KI. Because of radioactive decay,
grain products and canned milk or vegetables from sources affected by
radioactive
fallout, if stored for weeks to months after production, pose no
radiation
risk. Thus, late KI prophylaxis at the time of consumption is not
required.
As time is of the essence in
optimal prophylaxis
with KI, timely administration to the public is a critical
consideration
in planning the emergency response to a radiation accident and requires
a ready supply of KI. State and local governments choosing to
incorporate
KI into their emergency response plans may consider the option of
predistribution
of KI to those individuals who do not have a medical condition
precluding
its use.
VI. SUMMARY
FDA maintains that KI is a safe
and effective
means by which to prevent radioiodine uptake by the thyroid gland,
under
certain specified conditions of use, and thereby obviate the risk of
thyroid
cancer in the event of a radiation emergency. Based upon review of the
literature, we have proposed lower radioactive exposure thresholds for
KI prophylaxis as well as lower doses of KI for neonates, infants, and
children than we recommended in 1982. As in our 1982 notice in the Federal
Register, FDA continues to recommend that radiation emergency
response
plans include provisions, in the event of a radiation emergency, for
informing
the public about the magnitude of the radiation hazard, about the
manner
of use of KI and its potential benefits and risks, and for medical
contact,
reporting, and assistance systems. FDA also emphasizes that emergency
response
plans and any systems for ensuring availability of KI to the public
should
recognize the critical importance of KI administration in advance of
exposure
to radioiodine. As in the past, FDA continues to work in an ongoing
fashion
with manufacturers of KI to ensure that high-quality, safe, and
effective
KI products are available for purchase by consumers as well as by state
and local governments wishing to establish stores for emergency
distribution.
KI provides protection only for
the thyroid
from radioiodines. It has no impact on the uptake by the body of other
radioactive materials and provides no protection against external
irradiation
of any kind. FDA emphasizes that the use of KI should be as an adjunct
to evacuation (itself not always feasible), sheltering, and control of
foodstuffs.
ACKNOWLEDGEMENTS
The KI Taskforce would like to
extend special
thanks to our members from the NIH: Jacob Robbins, M.D., and Jan Wolff,
Ph.D., M.D., of the National Institute of Diabetes, Digestive, and
Kidney
Diseases and Andre Bouville, Ph.D., of the National Cancer Institute.
In
addition, we would like to thank Dr. David V. Becker of the Department
of Radiology, Weill Medical College (WMC) of Cornell University and The
New York Presbyterian Hospital-WMC Cornell Campus, for his valuable
comments
on the draft
.
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1 For
the radiation
emitted by 131 I (electrons and photons), the
radiation-weighting
factor is equal to one, so that the absorbed dose to the thyroid gland
expressed in centigrays (cGy) is numerically equal to the thyroid
equivalent
dose expressed in rem (1 cGy = 1 rem).
2 We
have included
in this guidance an extensive bibliography of the sources used in
developing
these revised recommendations.
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