DISCUSSION
DR. HAYNIE: By no special
pre-arrange-ment Mr. Hanson has discussed principally
cesium”7, and my discussion is on iodine’s’.
The problem of fallout depends a great
deal on the way you look at it. Because I
am a medical doctor and spend most of my
day in a clinical radioisotope laboratory
using radionuclides in the diagnosis and
treatment of disease, my outlook is
some-what different from Mr. Hanson’s.
I am going to try to be provocative
with-out being provoking. I am going to raise
questions, not answer them, because I think
we must first ask the right questions.
Let me review with you some of the
things that pass through the mind of a
per-son using radioisotopes daily in diagnosing
disease in his patients. These are all
mdi-viduals, and, as such, will suffer from
radia-tion no matter what the source. Patients
can be divided into those who benefit from
procedures and those who do not benefit.
Many times in research, patients may not
benefit directly, but medical science will.
That medical administration of
radioiso-topes may also result in environmental
spread is exemplified by an experience of
Lester Middlesworth. He was giving his
pa-tients iodine” for therapeutic reasons. He
asked them to mail in a questionnaire
con-cerning the effects of the treatment. In the
process, the envelopes mailed back were
counted; many exhibited considerable
amounts of iodine131. Whether we realize it
or not, iodine’s’ is escaping from
radioiso-tope laboratories. The fallout problem is
much less significant than this.
Dose estimates from internal
radionu-clides have undergone many changes and
no doubt will undergo many more. One
must know the dose accurately or he cannot
assess benefit versus risk. For medical
pur-poses where the exposure is a thousandfold
to a millionfold greater than fallout, the
risk evaluation is important. It is important
in an overall population to know this risk.
There are many problems that arise in
ac-curately determining the internal radiation
dose. For example, the
radiopharmaceuti-cals used are subject to variable intervals in
manufacture and storage limited only by
the radioactive half-life. Not only the total
activity that is administered, but also the
specific activity may be important too.
Variance in dosage can be caused by
pre-treatment of a patient with isotopes, the
pa-tient’s disease with its altered physiology,
and the size of the organ under study.
Different isotopes require the physician’s
judgement as to the relative biological
effectiveness and of the sensitivity of tissue which are so different.
Where do the medical and fallout
prob-lems merge? Where, and how, can one
ob-tam accurate information on internal
radia-tion dose? Over the last few years, internal
dose estimations from internal
radionu-clides have been increased. A better
appre-ciation of the variable factors associated
with concentration in cells, membrane
transport, and perfusion flow, and perhaps
in subcellular elements as well, have
negat-ed the use of simply assuming a diffuse
dis-tribution of the isotope in the organ. This is
a logical thing to do, but experience in
some cases has shown effects of small doses
which were previously considered
insig-nificant and which now are considered
significant.
We asked our epidemiologists to go
through the list of patients treated at M. D.
Anderson Hospital and run an analysis to
answer the question on what the iodine’3’
put in the child’s thyroid gland has done.
They found 60 children, ages 1 to 14 years
without thyroid disease, had received
studies of thyroid function and a total of
5,000 to 6,000 tests were performed on all
patients. So children, including the
adoles-cent, receive about 1 to 13% of the total
number of tests done. We do not know if
this percentage is valid for the whole
coun-try. Until better statistics are available, it is
all we have. As the number of childhood
diagnostic tests may rise into the thousands
per year, there may be a sizable group of
individuals who have received microcurie
Dn. YAMAzAKI: While the fetus cannot
speak for itself, there is one person who has
for some time studied the distribution,
re-tention, radiation dosimetry and
radionu-elide spectra in the fetus, Dr. Sikov.
DR. SIKov : Dr. Dennis Mahlum and I
have been investigating the cross placental
transfer of a number of radionuclides in the rat as well as their toxicity and distribution in the fetus and in the juvenile animals.
With radioiodine, the rat shows a
some-what different picture than was reported
here for the human in that the
concentra-tion
(
percent dose per gram)
increasesthroughout gestation. In the rat, the
con-centration in the fetal thyroid was
some-what less than that of the mother at all
times studied. On the other hand, we have
observed physiologic and morphologic
damage of the thyroid after exposure of the
prenatal or neonatal rat with radiation
doses substantially less than those which
produce comparable damage in the adult.
Table I presents a comparison of the
con-centrations of several nuclides in the fetus,
placenta, and fetal membranes after
intra-venous administration to the pregnant rat
after 19 days of gestation. It is obvious that
greatly varying fractions of the elements
studied are found in these structures.
Fur-ther, the physical form markedly influences
this relative distribution.
Several interesting aspects of the
metab-olism of these materials by the fetus have
been noted. Among these was the
observa-tion that the liver contains approximately
70% of the body burden of cerium in the
adult but only 20% in the fetus. This
dis-crepancy relates to a markedly increased
rel-ative concentration in the fetal skeleton.
Despite the overall low concentration of
plutonium in the fetus, the skeleton
con-tamed concentrations which may represent
a previously unrecognized hazard.
Dif-ferences in the metabolism of cesium
were also noted; there was little
localiza-tion in specific tissues of the fetus, such as
that seen in the adult. \Ioreover, it did not
Location Ce” (,137 Np23’
. ,i Colloi-do! p239 (233
Fetus 1.80 8.10 .4O 0.65 0.04 1.O() Placenta 39. 13.7 18. 91.0 .3 5.3 Membranes 160.0 7. 4.0 319.9 7.1 33.4
appear to concentrate in the fetal cartilage,
which contrasts with the results obtained in
the mouse by Nelson and his colleagues.’
DR. EVANS: I have two graphs which are
of interest in regard to the possible hazard
of ingested radioiodine at different times
during pregnancy and infancy. As shown in
Figure 31 the earliest stage at which
con-centration of iodine’s’ can be detected in
the fetal thyroid gland is at 3 months. The
gland at this time is not completely
differentiated and the uptake is restricted
to peripheral regions where follicles with a
small amount of colloid have been formed.
The percentage uptake by the thyroid
in-creases rapidly from the third to the sixth
month and more slowly from the sixth to
the ninth month. The values at 9 months
are based on two anencephalics whose
pi-tuitary and thyroid glands appeared to be
like those of the usual fetus of this age. The
weight of the thyroid gland increases most
rapidly from the sixth to the ninth month.
The percentage uptake at different times
during fetal life has been compared to that
during infancy and adulthood (Fig. 32). It
may be seen that the highest percent
up-take per gram is immediately following
birth. The value for the period between 30
and 35 weeks is taken from the literature.2’
These data will be presented in more detail
in a final report to the Division of Biology
and Medicine of the Atomic Energy
Com-mission, which has supported this
investiga-tion, and in a paper which is being
pre-pared for submission to the Journal of
Nu-clear Medicine.
DR. SAENGEB: I would like to address
some questions to Mr. Hanson because it
.1.2
2.0
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08
06
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05 2 315
Wks
Fic. 31. Radioiodine uptake in human fetal thyroid.
40.0
35.0 E
a 30.0
0
25.0
I)
20.0 0
Ui
15.0
I-I0.0
-i
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o
5.0
>-1.
0 5 10 $5 20 25 30 35 40 CHILD
FETAL AGE, in weeks AT BIRTH INFANT ADULT
would eventually want to make
observa-tions as to whether there is any deleterious
effects from the cesium. If so, then one
would consider supplying a replacement
diet which is reasonably free of cesium.
Last summer I had an opportunity to
visit Alaska and see the Eskimos at
Kotze-bue. Even Kotzebue, which is a pretty
refined place according to what Mr. Hanson
says, is a village of poverty, with problems
of sanitary disposal. There is, however, a
very handsome Public Health Service
los-pital. The question one should ask in the
light of other epidemiological questions is
how will these Eskimos and Indians be
studied in terms of control populations so
that maybe in 5 or 10 years an adequate
an-swer will be forthcoming to the question
whether the cesium did or did not make
any difference. In their health status I am
sure the Division of Biology and Medicine
of the Atomic Energy Commission has
con-sidered these problems, and I am sure the
Public Health Service has too. We really
should have a discussion about the proper
epidemiological design as I think it will be
an important aspect of this study.
MR. HANSON: First, I wish to comment on
dietary manipulation. Last summer we did
a biological half-time study of cesium in the
Eskimos. Dietary manipulation is no small
item and is not to be taken lightly. The
Eskimos like caribou and one cannot
re-place it arbitrarily. I think before
some-thing like that is attempted there should be
solid evidence that itmust be done, for this
is tampering with a culture and with a
peo-ple. We have no more right to change their
dietary habits than we do to expose them to
fallout. I don’t think either responsibility should be underestimated.
Second, I will comment on control
popu-lations. Last summer Dr. Shomon, who is
head of the Audubon Society and Nature
Centers Division of New York, was in the
barren grounds of Canada for 2 weeks. He
made the observation that he saw no
radia-tion damage in the caribou populations. I
other problems that we had better worry
about at home before we start worrying
about these in the Eskimos. I cannot
sug-gest what to do for control populations. I
don’t know how to hold all other factors
constant and do a considerable number of
genetic studies over a long period of time
and evaluate these extremely low levels of
exposure. We have no adequate control of
populations. I would say that the Eskimos
are manipulating their own diets probably
better than anyone else could do. They are
purchasing food in areas such as Kotzebue.
Where we find such a variety of diets none
can be taken as average for the Eskimo. At
Anaktuvuk Pass there is a closed economy
and dietary studies seem valid. These
ques-tions are terribly involved and, unless one
has been there for some time and knows the
situation intimately, decisions may be
arbi-trary rather than logical on this point.
DR. SAENGER: What does your
investiga-tion show? What is the pattern of your
in-vestigation? I am sure you can’t make an
arbitrary decision there.
MR. HANSON: Our investigation revolves
around trying to find why cesium behaves
as it does in the arctic environment and
trying to gain information about what
pop-ulation, what food habits, and what
season-al cycles are present in the arctic. The
pat-tern of our investigation is as follows: (1)
generally to describe what is there in the
environment, and (2) to concentrate on the
lichen, the people, and the caribou. Our
studies are not clinical in any way; they are
ecological.
DR. MAYS: I want to make two
com-ments, the first on iodine and the second on
cesium. With regard to iodine, I urge that
much stronger efforts be made to collect
in-formation in infants and children exposed
to diagnostic, therapeutic or fallout
io-dine’3’. This would complement the
ex-cellent follow-up studies by Dr.
Hemel-mann, Dr. Saenger, and their respective
col-leagues on children whose thyroids were
200
leo
60
40
120
‘ 00
z
80
a
“ 60
40
20
0
0
.
0 . .
0
0 10 20 30 40
AGE IN YEARS
.
[MALES
OFENALES
50 60 70
FIG. 33. Cs” half-time in normal humans. The line and shaded area are the
mean ± one standard deviation. The half-time increased with age from
19 ± 8 day’s in 5 infants to 97 ± 28 days in 40 adults (14 women plus 26
men). The equivalent biological half-time is defined as 0.693 (observed
body content/observed excretion rate).
With regard to cesium, the question
came tip earlier as to why there are
differences between the burdens of children
and adults. Figure 33 shows the half-times
we have measured in normal people using
the environmental cesium”7 present in the
diet. Our results confirm the initial
discov-ery by John Rundo at Harwell, England,
that the biological half-time of cesium’37 is
shorter in children than in adults. It is
fortu-nate for children that they excrete their
cesium burdens more rapidly. The
biologi-cal half-time of cesium’37 increases from
about 20 days in infants to about 100 days
in adults. Thereafter it appears to remain
relatively constant-except during
pregnan-cy.
A shorter half-time for cesium during
pregnancy than afterwards has been
re-ported.
Excited by the importance of this finding,
we evaluated the cesium half-time in 24
pregnant women (Fig. 34). In these
preg-nant women, the average half-time of 49
days was only 57% of that observed in 15
non-pregnant women.
Furthermore, among the six women we
measured, both before and after delivery,
five showed shorter half-times during
preg-nancy. Severe complications during the
pregnancy of the sixth may have caused her
half-time of 96 days evaluated 1 week
be-fore delivery to have exceeded her
non-pregnant value of 68 days. Bleeding and
cramping occurred throughout the final 3
months of her pregnancy, and hemorrhage
necessitated the artificial induction of labor
3 weeks early. For all six of these women,
the average half-time of 47 days while
pregnant was 66% of their non-pregnant
average. Excluding the sixth woman, the
half-times in the other five during
pregnan-cy averaged 38 days, or 53 of their
non-pregnant average.
These results show that pregnancy
accel-erates the excretion of cesium from the
body (except for infrequent special cases).
This effect is of special significance because
it reduces the radiation dose received by
the fetus.
If we understood how pregnancy
short-ens the biological half-time of cesium, it
might be possible to accelerate the removal
Cs HALF-TIMES IN PREGNANT WOMEN
140
120
- 100
.,r’ 80
I-S
S
0 0 20 30 40 50
AGE IN YEARS
Fic. 34. Cs’3’ half-times in pregnant women. The line and shaded area
show the mean ± one standard deviation for non-pregnant females. The average half-time of 49 ± 16 days for the 24 pregnant women was signifi-cantly lower than our value of 84 ± 27 days for 15 non-pregnant women. In only one pregnant woman did the half-time exceed the normal mean, and
this woman had severe complications during pregnancy.
How does pregnancy decrease the
reten-tion of cesium? Is it due to: (1) elevations
in estrogen and progesterone levels, (2) the
presence of a rapidly growing mass of
tis-sue, (3) accelerated metabolic rate, or (4)
other factors? We studied the effects of
ele-vated hormone levels in six normal women
orally given 1 mg of ethinyl estradiol per
day, for times up to a month, concurrent
with 2 gm of progesterone per day for the
last 5 days; little, if any, changes in
half-times occurred. We are studying the effect
of rapidly growing tissue in cancer patients
and the effect of accelerated metabolic rate
in hyperthyroid patients, but more cases
must be observed before firm conclusions
can be drawn. A detailed report on our
studies is available from me on request.
A closing comment on cesium
metabo-lism: we have discovered very short
half-times in children disabled by muscular
dys-trophy. The average half-time in 10 boys
with Duchenne muscular dystrophy was
healthy children.
DR. BRILL: Since 1960, the Division of
Radiological Health has been doing what
Doctor Mays has suggested. A clinical
fol-low-up study of approximately 40,000
thy-rotoxicosis patients, more than half of
whom were treated with radioactive iodine
in the years following 1945, is being
con-ducted. Results of the first cycle of
exam-inations should be forthcoming within the
next year. The evaluation of the potential
hazards of diagnostic doses in children is
more difficult. Several pilot studies have
been conducted in the past 3 years, but as
yet no feasible plan for a large study has
been developed. The problem is that it is
an exceptional circumstance in which
nor-mal children, and especially infants, are
given diagnostic doses for the simple
pur-pose of establishing ranges of normal. The
establishment of a suitable control group
and the identification of sufficient numbers
of properly matched index and control
z
60
0
U 40
20
0
S.
.
a.
.
a
.cases has to date precluded the institution
of the large scale effort that would be
re-quired to discern a hazard at the dose
lev-els used in diagnosis in such a population. I
should like to add a remark concerning the
data presented by Dr. Evans on fetal
ac-cumulation of radioactive iodine in the
thy-roid. It should be pointed out that my
ear-lier remarks in the discussion following Dr.
Eisenbud’s paper were related to the
iden-tification of a theoretical hazard, which I
believe is not possible to resolve at this
time with the data on hand or with the
present technology. The exponential rise in
radioactivity in the thyroid gland with
ges-tational age following 12 weeks is not
sur-prising, since as more calls are present, if
they function, more iodine is trapped. The
question I raised concerned a potential
haz-ard at the earliest stages of development
prior to the appearance of a recognizable
thyroid anlage. At that early time, when
there are relatively few young cells which
go on to form the thyroid gland, a
significant cellular derangement in a single
primordial cell by amplification in
subse-quent development may come to have a
significant numerical representation in the
adult thyroid gland. The numbers of events
required for such damage to a small
num-ber of primordial cells is well below the
level of detectability of radiation and hence
it does not seem possible to dismiss this
theoretically plausible hazard from the data
at hand.
REFERENCES
1. Nelson, A. S., Ullberg, H. K., and R#{246}nnb#{228}ck, C.: Distribution of radiocesium in mice. Acta Radiol., 55:374, 1961.
2. Chapman, E. M., Corner, G. W., Jr., Robin-son, D., and Evans, R. D.: The collection of radioactive iodine by the human fetal thyroid. J. Clin. Endocr., 8:717, 1948. 3. Hodges, R. E., Evans, T. C., Bradbury, J. T.,
and Keettel, W. C.: The accumulation of radioactive iodine by human fetal thyroids.
J.
Clin. Endocr. 15:661, 1955.4. Morrison, R. T., Birkbeck, M. B., Evans, T. C., and Routh, J. I.: Radioiodine uptake studies
in newborn infants. J. Nuci. Med., 4:162,
1963.
5. Evans, T. C.: Radioactive iodine in the study
of thyroid disorders. J. Iowa Med. Soc., p.
