EPA 520/4-76-013
HEALTH EFFECTS
OF ALPHA-EMITTING PARTICLES
IN THE RESPIRATORY TRACT
Report of Ad Hoc Committee on
"Hot Particles" of the Advisory Committee
on the Biological Effects of Ionizing Radiations
National Academy of Sciences
National Research Council
OFFICE OF RADIATION PROGRAMS
U. S. ENVIRONMENTAL PROTECTION AGENCY
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This report was prepared as an account of work sponsored by the
Environmental Protection Agency of the United States Government
under Contract No. 68-01-2230. Neither the United States nor
the United States Environmental Protection Agency makes any
warranty, express or implied, or assumes any legal liability or
responsibility for the accuracy, completeness or usefulness of
any information, apparatus, product or process disclosed, or
represents that its use would not infringe privately owned rights.
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Health Effects
of Alpha-Emitting Particles
in the Respiratory Tract
Report of Ad Hoc Committee on "Hot Particles"
of the Advisory Committee on the Biological Effects
of Ionizing Radiations
October 1976
NATIONAL ACADEMY OF SCIENCES
NATIONAL RESEARCH COUNCIL
Washington, D.C. 20006
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NOTICE
The project that is the subject of this report was approved
by the Governing Board of the National Research Council,
whose members are drawn from the Councils of the National
Academy of Sciences, the National Academy of Engineering,
and the Institute of Medicine. The members of the Committee
responsible for the report were chosen for their special
competences and with regard for appropriate balance.
This report has been reviewed by a group, other than the
authors according to procedures approved by a Report Review
Committee consisting of members of the National Academy
of Sciences, the National Academy of Engineering, and the
Institute of Medicine.
The work .presented in this report was supported by
the Office of Radiation Programs, Environmental Protection
Agency, under Contract No. 68-01-2230, Modification Nos. 2
and 5.
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FOREWORD
In the summer of 1974, the Environmental Protection
Agency asked the National Academy of Sciences for informa-
tion and evaluation of the health effects of alpha-emitting
particles ("hot particles") in the respiratory tract. This
report was prepared in response to that request.
The report presents a summary and analysis of current
knowledge concerning health effects of alpha-emitting par-
ticles in the respiratory tract. The report also reponds to
the questions raised by Drs. T. B. Cochran and A. R. Tamplin
of the Natural Resources Defense Council about the adequacy
of presently existing standards for "hot particles."
We want to thank the several people who helped in
preparation of this report and who have contributed material
for consideration by the Committee. We particularly want to
thank Ms. Leila Counts, Editor, Battelle, Pacific Northwest
Laboratories, who assisted in the preparation of the final
report.
lii
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PREFACE
This analysis of the cancer hazard to the lung from inhaled
plutonium particles was done under the auspices of the
National Academy of Sciences (NAS) at the request of the
Environmental Protection Agency (EPA). The report defines
the overall problem, describes its historical background, and
summarizes relevant current knowledge. Supporting docu-
mentation is included as Appendix A.
The Committee has endeavored to ensure that no
sources of pertinent knowledge or expertise were overlooked
in its study. During the course of its deliberations, the Com-
mittee solicited the opinions and counsel of several individual
scientists and others with information needed for a complete
overview of the problem.
Of special note is that the Committee met with
Drs. T. B. Cochran and A. R. Tamplin to specifically receive
their views and to discuss these views with them. A complete
transcript of this meeting is part of the NRC/NAS file of the
Committee.
Appendix B describes the procedure used to select the
Committee and gives biographical data about Committee
members. A listing of all meetings held and the participants
is given in Appendix C. Complete documentation, including
working papers used to prepare the report, is in the NRC/NAS
files.
IV
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MEMBERS OF AD HOC COMMITTEE ON "HOT PARTICLES"
Roy E. Albert, Chairman*
Institute of Environmental Medicine
New York University Medical Center
New York, NY
Edward L. Alpen
Donner Laboratory
University of California
Berkeley, CA
William J. Bair
Battelle, Pacific Northwest Laboratories
Richland, WA
George W. Casarett
Department of Radiation Biology
and Biophysics
University of Rochester Medical Center
Rochester, NY
Edward R. Epp
Department of Radiation Medicine
Massachusetts General Hospital
Boston, MA
Marvin Goldman
Radiobiology Laboratory
University of California
Davis, CA
Earle C. Gregg
Department of Radiology
University Hospital
Case Western Reserve University
Cleveland, OH
Edward B. Lewis
Biology Division
California Institute of Technology
Pasadena, CA
Roger O. McClellan
Inhalation Toxicology Research Institute
Lovelace Foundation
Albuquerque, NM
Edward P. Radford
Department of Environmental Medicine
Johns Hopkins University School of Hygiene
and Public Health
Baltimore, MD
Albert W. Hilberg, Senior Staff Officer
Division of Medical Sciences
Assembly of Life Sciences
National Academy of Sciences
National Research Council
*After the Committee had completed the study and formulated its
conclusions but before the final draft of the manuscript was com-
plete, Chairman Albert assumed a post with the Environmental Pro-
tection Agency. Although he remained a member of the Committee,
Dr. Albert thereafter limited his participation in the Committee's
activities. The Committee then asked Drs. Bair, Alpen, and Lewis
to assume responsibility for the task of incorporating into the
final manuscript the Committee's responses to the suggestions of
external reviewers. The entire Committee reviewed and assumes
responsibility for the final manuscript.
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CONTENTS
NOTICE ii
FOREWORD iii
PREFACE iv
COMMITTEE MEMBERSHIP v
SUMMARY AND CONCLUSIONS 1
DEFINITION OF THE PROBLEM 2
HISTORICAL BACKGROUND 3
THE COCHRAN-TAMPLIN RATIONALE AS THE BASIS FOR THE NRDC PETITION 5
A Critique of the Cochran-Tamplin Proposal 6
Summary Evaluation of the Cochran-Tamplin Rationale 8
CURRENT STATUS OF THE RADIATION BIOLOGY OF INHALED ALPHA-EMITTERS 9
Factors in Dose-Response Relationships 9
Animal Experiments 12
Experience with Human Beings 15
REFERENCES 16
APPENDIX A
I. RELEVANT PHYSICAL AND BIOLOGICAL DATA A.I
II. FACTORS IN DOSE-RESPONSE RELATIONSHIPS A.19
APPENDIX B PROCEDURES FOR COMMITTEE APPOINTMENTS AND
CONSIDERATION OF POTENTIAL BIAS OF MEMBERS B.I
APPENDIX C COMMITTEE MEETINGS AND ATTENDANCE '... C.I
vi I
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HEALTH EFFECTS OF ALPHA-EMITTING PARTICLES
IN THE RESPIRATORY TRACT
SUMMARY AND CONCLUSIONS
Since the early 1950's, various groups with
responsibility for determining the effects of
radiation sources on human health have recog-
nized the possibility that radioactive material
deposited in tissues of the body as high specific
activity particles might be a greater health
hazard than the same source distributed more
homogeneously. This has been referred to as
the "hot particle" problem [1-5].
In 1974 Cochran and Tamplin hypothesized
that the intense and highly localized dose
from inhaled insoluble plutonium particles
larger than a specified size causes greater
tissue damage, and is therefore more carcino-
genic, than more uniformly-delivered irradi-
ation [6]. On this basis Cochran and Tamplin
advocated a 115,000-fold reduction in the
current radiation standards governing expo-
sure to insoluble alpha-emitting ("hot") par-
ticles. With the support of the 1974 Cochran
and Tamplin report, the Natural Resources
Defense Council (NRDC) petitioned the
Environmental Protection Agency (EPA) to
reduce the current radiation protection guides
accordingly.
The National Academy of Sciences-National
Research Council Ad Hoc Committee on "Hot
Particles" has concluded that the evidence
does not support the NRDC petition for a
special, lower radiation protection standard
for inhaled alpha-emitting particles. The cur-
rent state of knowledge about the "hot particle"
problem can be summarized as follows:
1. In animals, all experimental data so far
obtained indicate that when insoluble
plutonium particles are inhaled, the major
radiation dose in the lungs occurs in the
pulmonary (i.e., alveolar) region. The
principal delayed effect in the lung of
breathing these particles is induction of
alveolar cancers. An analysis of mortality
from these cancers in beagle dogs indicates
that if there is a hot-particle effect,
Cochran and Tamplin have overestimated
the cancer risk per particle by at least two
orders of magnitude. However, analyses
indicate that the observed lung cancer mor-
tality in these dogs can be adequately
accounted for by the conventional method
of averaging the absorbed alpha radiation
dose over the entire lung. Therefore, it is
concluded that if there is a "hot particle"
risk, it is small by comparison with the lung
cancer risk attributable to the generalized
alpha radiation.
2. In human beings, epidemiological evidence
gained from experience with inhalation of
alpha-emitting radon daughters and with
external X or gamma irradiation of the
thorax strongly suggests that the radio-
carcinogenic sensitivity of the tracheo-
bronchial region is greater than that of
the alveolar regions where inhaled plu-
tonium is retained. Therefore, we would
not expect the human cancer risk from
alpha irradiation of the deep lung tissues
to be underestimated by applying risk
factors obtained from human experience
with cancer induced by irradiation of the
lining of the bronchial tree.
3. Current evidence indicates that the cancer
hazard from insoluble paniculate pluto-
nium deposited in the lungs is not markedly
greater than would be caused by the same
quantity of radioactivity distributed more
uniformly. The experimental evidence
suggests that the carcinogenic response is
more a function of the amount of radio-
activity in the lung than of its distribution.
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DEFINITION OF THE PROBLEM
In its simplest terms, the question addressed
by the Committee is: Does an insoluble,
highly radioactive particle small enough to
be taken into body tissues, especially the lung
tissues, have a greater probability of producing
a significant biological effect, such as cancer
induction, than does an internal source of
radiation of equivalent physical dose which is
distributed more uniformly?
Although the issue of the hazard from non-
uniform distribution of radioactive particles
is pertinent to all types of radiation, it is most
relevant to alpha radiation from the transuranic
elements, such as plutonium, americium, and
curium. Particles containing these elements
irradiate small regions around themselves,
extending not more than 50 /urn in solid tissues
and about 200 jum in the alveolar tissues of the
lungs. Moreover, many of these transuranic
elements have long half-lives and form highly
insoluble oxides which may persist in tissues
for long periods, even years. Local doses from
discrete small sources can reach very high
values, even when the computed mean tissue
dose in the organ is very low. Under these
conditions, the concept of dose as generally
used in radiation protection is not applicable.
The energy from a single alpha decay event,
with its short and well-defined range, will be
absorbed by one or, at most, several cells,
which may be killed or severely damaged.
Other cells, not actually traversed by alphas,
will suffer no direct alpha radiation injury.
Although insoluble particles move about within
the lungs as a result of cellular and other
clearance processes, it is not known how rap-
idly or freely the particles move. Since the
degree to which insoluble particles move
about in the lungs is unknown, the distribu-
tion of radiation dose within the lungs is uncer-
tain, but it probably varies from nearly uni-
form to highly localized, depending upon the
physical properties of the particles and the
degree of cellular interaction with the particles.
The "hot particle" issue arises from the possi-
bility that there might be no movement, or
relatively slow movement, of high specific
activity particles within the lungs.
Although radioactive particles may enter the
body through the integument or the intestinal
wall, the principal concern in this report is
with inhaled particles. This is so because inhal-
ation is likely to be a principal source of
exposure and because respiratory tissues are
particularly vulnerable to radioactive particles,
being directly exposed to airborne material
with immediate direct contact between parti-
cles and cells. In this report, therefore, the
hot particle problem is considered in relation
to the respiratory tract only. However, this
discussion could apply to any tissue where
particles may be translocated and retained
for a significant time.
In preparing this report the Committee drew
upon all relevant published data and the cur-
rent experience of nearly all laboratories
throughout the world doing research on this
problem. The data base used by the Committee
was far broader than that upon whfch the
Cochran-Tamplin rationale was developed.
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HISTORICAL BACKGROUND
During the early stages of the development of
radiation biology from a descriptive to a quan-
titative science, one of the first problems to
emerge was that of predicting the effects of
radiation exposure delivered in a nonuniform
manner. An early attempt to account for the
nonhomogeneous distribution of radioactive
substances deposited in body tissues was the
concept of "critical organ/' as explicitly stated
in National Council on Radiation Protection
and Measurements (NCRP) Handbook 52
(1953) [1] and in International Commission on
Radiological Protection (ICRP) recommenda-
tions (1955) [2]. The critical organ concept
assumes that different organs vary in uptake of
radionuclides and radiosensitivity. It also
assumes that the radionuclides are deposited
uniformly throughout the organ.
However, early NCRP and ICRP reports recog-
nized that for certain radionuclides the dose
may not be homogeneously deposited in critical
organs (NCRP Handbooks 52 [1953] [1] and
69 [1959] [3]). In 1961 the paniculate source
problem was noted explicitly by the NAS/NRC
Subcommittee on Inhalation Hazards of the
Committee on Pathologic Effects of Atomic
Radiation [4]. The Subcommittee considered
the issue of whether "mean dose to the lung" is
relevant when the source is particulate and
nonuniformly distributed. This of course in-
volves the distinction between the micro-
scopic dose in the paths of the ionizing particles
and the macroscopic dose which results from
averaging such events over the whole organ.
The Subcommittee also recognized the possi-
bility that radioactive material deposited as
high specific activity particles might be more
damaging to tissue than the same source homo-
geneously distributed. The Subcommittee
referred to the work of Passoneau [7], which
indicated that the carcinogenic potential
for 90Sr-90Y was lower when the activity was in
high specific activity beads. This model, which
was based on beta-emitting isotopes and
tumor production in rat skin, may not be
relevant to the case of much smaller alpha-
emitting particles in lung tissue.
In 1969, the International Commission on
Radiological Protection (ICRP) [5] defined
three categories for nonhomogeneous exposure
to ionizing radiation: Class 1 (Partial Irradi-
ation of Representative Tissue) - in which the
part irradiated is representative of the whole
organ or tissue, as in external irradiation of
skin or bone marrow; Class 2 (Partial Irradi-
ation of Nonrepresentative Tissue) - in which
the part irradiated is not representative of the
whole; and Class 3 (Irradiation from Radio-
active Materials in Particulate Form) - which
includes irradiation from discrete particles
containing radionuclides or from a highly
focal accumulation of radionuclides.
Again in 1972, the Committee on Biological
Effects of Ionizing Radiation (NAS/NRC) in
their report [8] raised the issue of "hot spots",
or particulate sources, as inducers of lung
cancer. The BEIR Committee referred to the
work of Grossman et al. [9], who compared
the carcinogenicity of 210Po in the lung when
the agent was administered by intratracheal
instillation with and without a particulate
carrier. Grossman et al. concluded that tumor
production was a function of total alpha dose,
whether the isotope was given with or without
a particulate carrier. The inference drawn
by the BEIR Committee was that "a higher
localized dose from alpha particles was not
more cancerogenic than the same mean tissue
dose delivered more uniformly to critical
cells" [8]. However, the biological effects of
intratracheally instilled polonium, which has a
relatively short half life (138 days), may be
quite different from those of inhaled insoluble
particles of plutonium, which has a much
longer half life.
In November of 1974 a report was published by
Cochran and Tamplin [6] in support of a peti-
tion made by the Natural Resources Defense
Council to the Environmental Protection
Agency and the Atomic Energy Commission.
The petition requested a reduction in the cur-
rent radiation standards governing the internal
exposure of man to insoluble alpha-emitting
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particles. The authors reviewed certain existing
data on carcinogenesis from point sources
of alpha radiation and drew on selected pub-
lished biological experiments to conclude
that the radiation protection guides should be
reduced by a factor of about 115,000.
Following publication of the Cochran and
Tamplin report, the question of alpha-emitting
particles in the lungs was addressed by Bair,
Richmond, and Wachholz [10], the British
Medical Research Council [11], the National
Council on Radiation Protection and Measure-
ments [12], and the National Radiological
Protection Board in the United Kingdom [13].
All of these sources have concluded that there
is no evidence that the risk of lung cancer
from alpha-emitting particles in the lungs is
greater than from equivalent amounts of alpha
radiation more uniformly distributed. They
also agreed that there is no compelling reason
to abandon the average lung dose convention
for radiation protection practices, which is
the same convention currently used to quantify
the radiation doses associated with plutonium-
induced lung cancer in experimental animals.
However, Cochran and Tamplin did not accept
these reports as refutation of their "hot par-
ticle thesis" [14].
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THE COCHRAN-TAMPLIN RATIONALE
AS A BASIS FOR THE NRDC PETITION
As Cochran and Tamplin noted in their 1974
report [6], the current ICRP occupational
exposure standard for insoluble plutonium in
air is 4 x KT11 juCi/mfi. This level of atmo-
spheric contamination would lead to a maxi-
mum permissible lung burden (MPLB) of
0.016 juCi and would be associated with a
maximum permissible lung dose of 15 rem/yr,
averaged over the entire lung.
Cochran and Tamplin [6] pointed out that in
the case of insoluble plutonium particles,
the dose is not delivered uniformly to the
entire lung:
It would take 53,000 particles . . . (1 M
in diameter, 0.28 pCi) ... to reach the
MPLB of 0.016 fiC\ which results in
15 rem/yr to the entire (1000 g) lung.
However . . these particles would
irradiate only 3.4 g of this 1000 g to
the lung, but at a dose rate of 4000
rem/yr . . . these particles result in an
intense but highly localized irradia-
tion. A fundamental question is, then:
is this intense but localized irradiation
more or less carcinogenic than uni-
form irradiation?
The Cochran-Tamplin approach to predicting
the cancer risk from hot particles is based on
the Geesaman Hypothesis [15,16], which in
turn is based almost wholly on the rat skin
irradiation experiments of Albert and his co-
workers [17-20]. Cochran and Tamplin's
interpretation of these experiments and the
rationale for their proposed standard are
described by the following excerpts from their
1974 report [6]:
A high incidence of cancer was ob-
served after intense local doses of
radiation, and the carcinogenesis
was proportional to the damage or
disordering of a critical architectural
unit of the tissue, the hair follicles.
(Page 23)
Certainly a reasonable interpretation
of these experimental results is:
when a critical architectural unit of
a tissue (e.g., a hair follicle) is irradi-
ated at a sufficiently high dosage, the
chance of it becoming cancerous is
approximately 10~3 to 10"". This has
become known as the Geesaman
hypothesis. (Page 26)
Geesaman indicates that the tissue
repair time in the lung is on the order
of one year. It therefore seems appro-
priate, but not necessarily conser-
vative, to accept as guidance that
this enhanced cancer risk occurs
when particles irradiate the surround-
ing lung tissue at a dose rate of 1000
rem/yr or more. (Page 33)
. . . using Geesaman's lung model, a
particle with an alpha activity be-
tween 0.02 pCi and 0.14 pCi is re-
quired to give a dose of 1000 rem/yr
to irradiated lung tissue. For purposes
of establishing a maximum permis-
sible lung particle burden we will
use 0.07 pCi from long half-lived
(greater than one year) isotopes as
the limiting alpha activity to qualify
as a hot particle. (Page 34)
The existing standards for uniform
radiation exposure of the whole body
or lung can be used as the basis for
establishing particle exposure stan-
dards by equating the risk of cancer
induction between the two types of
exposure (uniform versus grossly
nonuniform). The most recent assess-
ment of the risk associated with uni-
form irradiation of man was per-
formed by the NAS-NRC Advisory
Committee on the Biological Effects
of Ionizing Radiation. Their report,
published in 1972, is referred to as the
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BEIR Report . . . the existing occupa-
tional exposure standard for uniform
whole body irradiation is 5 rem/yr
and for the lung, 15 rem/yr. The BEIR
Report estimates that exposure of the
whole body of an individual to 5 rem/yr
would lead to a cancer risk between
4.5 x irr4 and 2.3 x IQ-Vyr. Their
best estimate is 10'Vyr. (Pages 41-42)
It is recommended here that the best
estimate of the effects of uniform
exposure by the BEIR Committee be
used together with a risk of cancer
induction of 1/2000 per hot particle
in determining the MPLPB for insolu-
ble alpha-emitting radionuclides in hot
particles. This is a somewhat arbitrary
compromise and is not the most con-
servative value that could be recom-
mended. Thus, the recommended
MPLPB for occupational exposure
from hot particles of alpha-emitting
radionuclides in the deep respiratory
zone is 2 particles. This corresponds
to a MPLB of 0.14 pCi and represents
a reduction of 115,000 in the existing
MPLB. (Pages 43-44)
In February 1975, in a supplemental sub-
mission [21] to the Environmental Protection
Agency's Public Hearing on Plutonium and
the Transuranium Elements, Cochran and
Tamplin added to their definition of a "hot
particle:"
In our petition and Hot Particle Report,
we concluded that, consistent with
the whole body exposure standard of
5 rem/year, the alpha-emitting hot
particle standard should be 2 particles
in the human lung. Using the estimated
minimum hot particle activity of 0.07
pCi, this resulted in the suggested
reduction of the MPLB by 115,000.
However, as we stated in our Hot
Particle Report, this factor of 115,000
would apply only when it was not
determined that the activity was not
on hot particles. Using the particle
size distribution determined for the
Rocky Flats fire, and allowing only
2 particles above 0.07 pCi would still
have required a reduction of the
MPLB by a factor of 16,000. (Page 22)
Based on their development of particle size
statistics for the exposure of personnel at the
time of the plutonium facility fire at Rocky
Flats, Colorado, Cochran and Tamplin "see
little justification for selecting a minimum
hot particle activity greater than 0.6 pCi/
particle ... a 2-particle limit at 0.6 pCi/
particle would still require a reduction of
the MPLB by a factor approaching 2000."
(Pages 22 and 24) [21].
A CRITIQUE OF THE COCHRAN-TAMPLIN
PROPOSAL
The Committee views the Cochran-Tamplin
thesis as based on three assumptions. Assump-
tions 1 and 2 together form the Geesaman
Hypothesis and Assumption 3 is the Hot Parti-
cle Hypothesis. The assumptions are described
and commented on below.
Assumption 1
The correlation between the induction of
atrophic hair follicles and the induction of
tumors in rat skin with ionizing radiation [17-
20] is assumed by Cochran and Tamplin to
indicate that the atrophic hair follicle causes
the skin tumors and that the role of ionizing
radiation is only to produce the structural
damage to the hair follicles.
Comment
Atrophic follicles are structures which have
lost the ability to produce hair, for any of a
number of reasons. When radiation is involved
in atrophy, however, the atrophy results from
the radiation-induced death of the hair germ
cells, which are the stem cells for hair produc-
tion normally found at the base of the resting
hair follicles. The most likely explanation for
the association between follicle atrophy and
tumor induction is that ionizing radiation
causes concomitant cell death and neoplastic
cell transformation.
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It is a generally established concept in the
etiology of cancer that the disease is initiated
by the neoplastic transformation of single
cells. The transformation of single cells by
carcinogens can be shown in tissue culture
studies, where it is evident that cell lethality
and cell transformation are concurrent effects.
However, the dose-response relationships for
the two effects vary sufficiently to indicate
that the processes are independent. It has
been shown that carcinogen-induced cell
death can be prevented without affecting the
yield of transformed cells [22]. And, while
tissue damage is commonly seen in association
with cancer formation, there is strong evidence
that the two effects represent different aspects
of carcinogenic action.
Assumption 2
Geesaman [15,16] generalized (Assumption 1)
that follicle atrophy causes skin tumors in
the rat. He expanded this assumption to con-
clude (as Assumption 2) that the probability of
cancer due to focal tissue damage in the lung
caused by a microscopic plutonium particle
will be 1/2000, which is the hypothesized ratio
of tumors-to-atrophic follicles in the rat skin.
Comment
This Geesaman Hypothesis, on which the
Cochran-Tamplin proposal is based, revives
one of the oldest cancer theories; namely,
that the cause of cancer is chronic tissue dam-
age. This is the chronic irritation theory pro-
pounded by Virchow in 1863. The theory, as
reviewed by Oberling [23], was in vogue for
about 50 years. It stemmed from the early
clinical observations that cancer rarely appears
in healthy tissue and is almost always pre-
• ceded by chronic inflammatory conditions
such as scars, ulcerations or fistulas. Post-
mortem observations in this era suggested
that the same association applies to internal
organs.
Virchow pointed out that every injury to tissues
is followed by a state of irritation in which
the cells are stimulated to multiply in order
to repair the damage. If the' injurious condi-
tions prolong the irritation, the cell prolifer-
ation grows more and more excessive and
irregular. Virchow argued that if such a condi-
tion persists year after year, cancer will occur.
The Virchow theory claimed that chronic
irritation was the sole, nonspecific cause of
cancer: i.e., that cancer was the outcome of
many widely differing conditions with no
features in common except chronic damage.
As related by Berenblum [24], Virchow's
theory was eventually demolished. Experi-
ments begun in 1918 showed that cancer
can be produced by some potent substances
that vary widely in their capacity to cause
damage; on the other hand, many agents
which cause substantial damage were shown
not to cause cancer.
Regarding radiation, analysis of the data on
induction of skin tumors in rats by alpha
rays [17-20] indicates that nearly all of the
potentially dividing cells (>99.9%) in each
hair follicle were sterilized by even the lowest
dose used. This means that increasing the dose
will produce only a negligible increase in the
number of destroyed cells. Since the number
of tumors increased very much more rapidly
with dose, these data negate the assumption
that follicle atrophy (or a nidus of dead cells)
is the only cause of tumor formation in rat
skin.
Assumption 3
On the basis of Assumption 2, Tamplin extend*
the Geesaman Hypothesis to make Assump-
tion 3: when the dose to the surrounding
tissue from the alpha-emitting particle exceeds
1000 rad/yr, focal damage will be produced
with a cancer risk of 1/2000. This is the Hot
Particle Hypothesis.
Comment
It is stated that 1000 rad/yr was selected as
the critical dose at which cancer risk from
ionizing radiation could be quantitatively
assessed in man because this dose is the mini-
mum that produces cancer in the rat skin and
lung, and the life span of lung cells is nor-
mally about one year. However, the logic of
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this reasoning is obscure because no system-
atic relationships are known to exist between
the rate of cell turnover and tissue damage
by alpha radiation in the lung or any other
organ. The selection of parameters appears
to have been arbitrary.
SUMMARY EVALUATION OF THE COCHRAN-
TAMPLIN RATIONALE
The exposure pattern in the deep lung to insol-
uble alpha-emitting particles always involves
focal irradiation. Particles deposited in the
alveoli are transported through the lymphatics
and concentrated around the respiratory and
terminal bronchioles [25]. Hence, the problem
for insoluble particles does not represent a
comparison of uniform and focal exposures,
but a comparison of the relative effects of
greater numbers of small particles compared
to smaller numbers of large particles for the
same total lung burden.
Radiobiologic theory supports the concept
that for respirable-sized particles distributed
in a tissue, the number of cells traversed by
alpha radiation, and probably also the carcino-
genic risk, increases with increasing particle
size or particle activity and reaches a maximum
at a given particle size or particle activity.
At particle sizes or particle activities above
this maximum the probability of multiple
traversals of single cells increases, thus in-
creasing lethality. This results in a reduced
carcinogenic risk since dead cells cannot
become cancer cells [12,26].
On the other hand, radiobiologic theory also
supports the concept that if the alpha activity
is distributed throughout the tissue, the num-
ber of cells that receive only single traversals
or sublethal events of some nature increases
with the amount of alpha-emitters present in
the lungs and the cancer risk increases simi-
larly. Of course, at very high concentrations
of alpha-emitters the number of cells receiving
multiple traversals increases and the risk of
radiation pneumonitis and fibrosis becomes
more significant, while the cancer risk de-
creases. Experimental efforts to verify these
concepts are continuing, but results to date
do not contradict this description [27].
In experimental animals the carcinogenic risk
is reasonably independent of the geometric
distribution of the particles in the lungs. In a
complex organ like the lung it is possible that
particle size may affect the distribution, and
hence the risks, among various tissues. How-
*ever, experimental evidence suggests that
because of competing tendencies in this distri-
bution, the overall tumorigenic response for
a variety of particle sizes is a function of the
total radioactive dose involved and is relatively
insensitive to differences in the distribution
in various tissues.
The Geesaman Hypothesis, on which the
Cochran-Tamplin rationale is based, has merit
only to the extent that tissue damage which
results in permanent structural disorganization
can have an enhancing effect on the tumori-
genic response to carcinogen exposure. The
postulate that structural disorganization, per
se, produces tumors has been shown to be true
only in the endocrine system where hormonal
feedback-regulating mechanisms operate
from one organ to another (e.g., the ovary and
pituitary glands). Under these circumstances
gross destruction of organs (not microscopic
focal derangements) can be a condition for a
tumorigenic response.
Geesaman's postulate, that the damage
produced in the lung by a single plutonium
particle would have the same probability
of causing lung cancer as that observed in
the irradiated rat skin, makes the following
unwarranted assumptions about the patho-
genesis of radiation-induced tumors in the
rat skin: a) that atrophic follicles, per se,
cause skin tumors (i.e., that structural dis-
organization of this type is tumorigenic) at
a relatively low probability of 1 in 2,000; and
b) that focal irradiation of hair follicles, as
would occur from stationary plutonium par-
ticles adjacent to hair follicles, causes atrophic
follicles and skin tumors. Since the Geesa-
man Hypothesis could hardly be taken as
the basis for predicting the yield of tumors,
even in the rat skin, from imbedded plutonium
particles, it would be purely fortuitous if it
accurately predicted the response of the
human lung to plutonium particles. Therefore,
the rationale for the NRDC petition appears
indefensible.
-------
CURRENT STATUS OF THE RADIATION BIOLOGY
OF INHALED ALPHA-EMITTERS*
The potential health effects caused by inhala-
tion of alpha-emitting radioactive particles
depend on the properties of the particles.
Particles released from the nuclear fuel cycle
may vary widely in radionuclide content,
from low specific activity particles (largely of
uranium) to high specific activity particles of
nearly pure plutonium, curium or americium.
The particles may contain beta and gamma-
emitting radionuclides in addition to the
alpha-emitting transuranics. Other particle
properties (such as chemical composition,
density, and size) can also vary over a wide
range, depending upon the mode of formation
and the route of release.
Only in extraordinary circumstances would
human beings be exposed to particles of a
fairly homogeneous size distribution (such as
pure plutonium oxide particles). Accidental
exposures would be to aerosols comprised of
randomly shaped particles with a variety of
physical and chemical properties and a wide
variation in sizes [28,29]. The particles would
most likely contain mixtures of uranium,
transuranic elements and fission products.
Thus, it is very difficult to assess the health
effects that could result from such an exposure.
FACTORS IN DOSE-RESPONSE
RELATIONSHIPS
Variations in anatomical and physiological
properties of the respiratory tract increase the
complexity of assessing the potential health
effects of exposures to aerosols containing
transuranic elements [30-35]. These differ-
ences, compounded by respiratory diseases,
exposures to other sources of radiation and
nonradioactive toxic substances, and differ-
ences in physical activity and (possibly) genetic
*More detailed supporting discussions are
included in Appendix A.
constitution among individuals, influence
susceptibility to the biological effects, includ-
ing lung cancer, of inhaled transuranic ele-
ments. Furthermore, since data on the effects
of transuranic elements in human lungs are
lacking, the assessment of potential health
effects depends largely on the results of animal
experiments.
Fate of Inhaled Particles
The chemical and physical properties of in-
haled alpha-emitting particles and their depo-
sition sites in the respiratory tract determine
the eventual fate of particles in the lung and
subsequent biological effects. Clearance of
particles deposited in the respiratory tract
occurs through the gastrointestinal tract,
through the lymphatic system or by disso-
lution and absorption into the blood. Clear-
ance from the upper respiratory tract is very
rapid, within a few hours, but clearance
from the lower respiratory tract and the alveo-
lar region may require weeks or even years.
Particles are cleared from the nasal regions
to the external environment or to the gastro-
intestinal tract within the first hours after
inhalation [36]. The process may be accel-
erated by sneezing and other mechanical
functions. Since absorption of transuranics
from particles in the gastrointestinal tract is
usually much less than 0.1% [37], nearly all
particles cleared from the respiratory passages
to the gastrointestinal tract are excreted.
Particles deposited in the tracheobronchial
region of the lungs are transported in the
layer of mucus, propelled by ciliary action
toward the esophagus. Interpretation of
experimentally-determined clearance curves
indicates that plutonium oxide particles are
probably cleared from the tracheobronchial
region with a half-time of up to about 3
days [38].
Particles deposited in the alveolar region may
be cleared by dissolution and absorption
-------
into the blood, by mucociliary action through
the tracheobronchial tree, or by transport via
the lymphatic system. The relative impor-
tance of each pathway for given particles
depends upon many factors, such as the parti-
cles' chemical and physical properties, specific
activity, cytotoxicity, and the state of health
of the respiratory tract. Estimates of the
retention half-time of plutonium in the lungs
of human beings accidentally exposed to
plutonium aerosols range from about 300 to
650 days [39]. The ICRP recommends that the
value of 500 days be used for radiation protec-
tion purposes [40].
Cigarette smoking has been reported to inhibit
ciliary activity of the respiratory tract, which
is an important mechanism for clearance of
particles from the lungs [41]. This raises the
question of whether plutonium would be
retained in the lungs of smokers to a greater
extent than in the lungs of nonsmokers.
Slowing of mucus flow along the major bronchi,
where movement is normally very rapid, does
occur in human smokers [42]. However, no
significant effects have been observed, in
human beings free of bronchitis, on mucus
transport in .the smaller bronchi where move-
ment is normally very slow [43]. There are
no data relating the effects of cigarette smok-
ing to clearance of particles from the human
alveolar region. There also is no information
available on residence times of particles
deposited in areas of the bronchial mucosa
which have been denuded of cilia, particularly
the bifurcations of the bronchi. However, a
recent report gives preliminary evidence for
long-term residence of 210Pb on the bronchial
epithelium of cigarette smokers [44]. How
this might relate to inhaled plutonium particles
is not known.
Particles are cleared from the lungs to re-
gional lymph nodes via the lymphatic vessels,
probably those adjacent to bronchioles and
bronchi. In experimental animals plutonium
particles have been identified in lymphatic
vessels beneath the pleural surface [25].
Evidence from experimental animals and from
human beings accidentally exposed to plu-
tonium indicates that plutonium particles
accumulate and are largely retained in the
lymph nodes. Thus, plutonium concentrations
in lymph nodes are usually several times
greater than those in lungs. However, lym-
phatic tissues have not been the site of pri-
mary cancers in experimental animals that
inhaled plutonium [45],
Physics of Energy Absorption
Heavy ions, such as alpha particles, lose
energy rapidly and produce a dense column of
ionization as they penetrate cells and tissues.
Because of this high rate of energy loss, their
range in cells and tissues is short. A 5.3 MeV
alpha particle emitted from plutonium has a
range in water of about 41 ^m with an average
ion density of about 3500 ion pairs//im. Due
to slowing of the alpha particle, the ion density
increases by about a factor of 2 at the end of
its range. Thus, compared with electrons,
energy from alpha particles is deposited in
cells and tissues in a highly concentrated
manner. An alpha particle which traverses
the nucleus of a cell deposits more than
enough energy, by several orders of magnitude,
to destroy the cell's reproductive capability.
Traversal through the cytoplasm, however,
can damage the cell but leave its reproductive
capacity unimpaired [46]. Therefore, when
dealing with the biological effects of alpha
irradiation, it is appropriate to consider the
probability that a cell, especially the nucleus,
might be traversed by an alpha particle, rather
than the amount of energy (usually expressed
in rad) deposited per unit mass of cells.
Calculations of the probability of epithelial
cells in the lung being traversed by alphas
emitted from plutonium particles lead to the
conclusion that the number of cells killed or
affected by such particulate sources will reach
a maximum after a relatively short interval,
regardless of the total activity involved, be-
cause a single traversal of a cell nucleus by an
alpha particle should be sufficient to kill or
affect the cell [25,26]. Thus, the probability
that plutonium particles will induce a lung
cancer is more likely to depend on the .number of
particles than on the specific activity of the
particles. This supports the hypothesis that
10
-------
greater tumorigenicity per unit of absorbed
dose results as the plutonium is more widely
distributed throughout the lungs in smaller
particles.
Cellular and Subcellular Effects
Knowledge of the mechanisms by which
cancer is induced by alpha irradiation would
help to resolve questions about the relative
hazards of inhaled alpha-emitting particles
of different sizes and specific activities. Unfor-
tunately, most of our knowledge about the
action of alpha irradiation at the cellular
and subcellular levels concerns cell mortality,
rather than cell transformation. Nevertheless,
since the physical processes leading to alpha-
induced cell transformation can be assumed to
be similar to those related to cell death, data
obtained from studies of cell mortality and
chromosomal aberration can be useful in
examining questions of spatial distribution of
alpha dose and carcinogenesis.
These data suggest that single alpha particles
that traverse the cytoplasm of a cell will have
minimal, if any, impact on the cell's ability
to survive and reproduce. Theoretical deduc-
tions, supported by studies of cells in tissue
cultures, indicate that when a single alpha
particle traverses a cell nucleus, it causes
sufficient irreparable molecular damage
to destroy the cell's reproductive capability
[47,48]. These killed cells do not become can-
cers. When a cell nucleus receives only a por-
tion of the energy from an alpha traversal and
survives, the cell may retain its reproductive
capability and pass on to its progeny certain
genetic alterations which may have a bearing
on subsequent events leading to cancer
induction.
Brooks et al. [49] studied the frequency of
chromosomal aberrations in the livers of
Chinese hamsters following injection of
239Pu citrate or 239PuO2 particles of various
sizes and numbers. The dose-response curves
for aberrations per cell were similar for low
total doses of 239Pu particles and uniformly
distributed 239Pu. However, with 239Pu particles
a large portion of the aberrations occurred in a
few cells that were considered by Brooks to be
reproductively dead. Brooks et al. concluded
that the 239Pu particles posed a lesser hazard
than did the more uniformly distributed 239Pu.
Insofar as cell death and chromosomal aber-
rations are related to cancer risk, the data
suggest that the more uniform the distribution
of the alpha flux, the greater the radiation
effect.
Mechanisms of Carcinogenesis
Because the basic mechanisms of carcino-
genesis are still essentially unknown, a discus-
sion of this subject can give little insight into
the hot particle problem. It is recognized, how-
ever, that the efficiency of carcinogenic action
depends upon the carcinogen reaching bio-
logical targets within cells, the susceptibility
of cells to transformation, and the extent to
which transformed cells acquire properties of
neoplasia, including unrestrained prolifera-
tion, invasiveness, and antigenicity.
The progeny of transformed cells have a variety
of neoplastic and non-neoplastic characteris-
tics; therefore, not all transformed cells lead
to tumor formation. In addition, selection
processes breed out some aberrant races of
cells and other transformed cells die naturally
(although this could conceivably facilitate the
election process for tumor cells).
Within the present insufficient body of knowl-
edge about carcinogenic processes and tumor
biology, the concept of "precancerous lesions"
has developed. Precancerous lesions are those
which may precede and may favor the devel-
opment of cancer but do not possess the essen-
tial elements of the disease [50]. However,
although most so-called precancerous lesions
have some neoplastic properties, such as cell
proliferation and distortion, it is impossible
to predict whether they will in fact develop
into cancer. Tumor induction is the result of
a series of critical events which are still imper-
fectly understood. The terms precancerous,
pre-adenoma, etc. are used to indicate
changes reminiscent of those preceding or
concomitant with tumor development, but they
do not have precise scientific meanings.
11
-------
ANIMAL EXPERIMENTS
Animal experiments [51,52] have shown two
responses at low levels of inhaled PuCh:
a reduction in the number of circulating lym-
phocytes and induction of lung cancer. Lung
cancer, the long-term consequence of greatest
concern, has been demonstrated in mice, rats,
dogs, and baboons. Although studies are limited
and still in progress, hamsters appear to be less
susceptible to induction of lung cancer by
inhaled plutonium than rats or dogs.
In all the animal experiments with inhaled
transuranic elements, bronchiole-alveolar
carcinoma, a variant of adenocarcinoma, is
the predominant resulting cancer type. The
tumors appear to originate in the periphery
of the lungs where, according to autoradio-
graphic evidence, the main portion of the
radiation dose is delivered.
In studies of inhaled plutonium it has been
the general practice to relate biological effects
to the total radiation doses delivered to the
lungs. The doses are calculated on the basis
that the deposited energy is absorbed by the
total lung mass, including the blood. Although
it has always been recognized that absorption
of alpha radiation energy emitted by plutonium
particles is not uniform, the actual distribution
of the absorbed energy has not been well
enough known to develop a more defensible
practice. On the positive side, there is merit
in using the same method for calculating
dose in animal experiments as is used in
setting standards for human exposure.
Animal experiments with inhaled plutonium
have involved both relatively soluble and
insoluble compounds. However, it should be
recognized that although both soluble and
insoluble compounds are deposited uniformly
throughout the lungs after inhalation, both
tend to become localized in "hot spots" as a
result of cellular action and other processes
acting to remove the foreign material. Soluble
plutonium compounds are removed from
the lungs more rapidly than insoluble com-
pounds, mostly by absorption into the blood.
The portion of soluble plutonium retained
in the lungs continues to be localized for long
periods of time. Even so, soluble plutonium
compounds are distributed more widely than
insoluble plutonium oxide particles and it
is reasonable to believe that the absorbed
radiation is also more widely distributed.
Thus, it is difficult, if not impossible, to com-
pare experimentally the effects of completely
uniformly-distributed alpha irradiation with
irradiation from particulate sources. It is
possible, however, to perform experiments
comparing more-uniform with less-uniform
irradiation, or more-particulate with less-
particulate irradiation. Experiments have
been completed which allow these kinds of
comparisons. The details of those experiments
are described in Appendix A.
The carcinogenic effect of ammonium-
plutonium pentacarbonate in rats has been
found to be no greater than that of less-
aggregated plutonium citrate [53]. Plutonium
nitrate given by intratracheal injection [54],
which results in highly localized deposition
in the lungs, was significantly less effective
than inhaled plutonium nitrate [55], plutonium
citrate, and ammonium-plutonium pentacar-
bonate. However, intratracheally administered
210Po in hamsters [56] has been more carcino-
genic than inhaled 210Po in rats [57] (although
the significance of this is difficult to assess
because of the different animal species used).
In another experiment in which Pu micro-
spheres of varying number and specific activity
were distributed throughout the vasculature
of the lungs of hamsters, no specific activity
particle or dose distribution was found to be
more carcinogenic than another, but a high
incidence of lung cancer was not observed
in any of the experimental groups [58]. A
recent analysis [59] shows that the risk of lung
cancer in rats from insoluble PuCh is about
double that from relatively soluble alpha-
emitters. In this analysis, data from experi-
ments with relatively soluble americium and
plutonium compounds were pooled. However,
the lung cancer risk per unit of absorbed dose
from some soluble alpha-emitters, such as
241Am(NO3)4, appeared to be equivalent to or
greater than that from PuO2 [59].
12
-------
These animal experiments indicate that the
carcinogenic response of lung tissue to alpha
irradiation is largely dependent on the total
amount of radioactivity without regard to its
distribution. The maximum difference between
the cancer risk from more particulate and
from less particulate sources appears to be a
factor of about 2. On the basis of these
lifespan experiments, mostly with rats, it is
possible to estimate that the absolute risk of
lung cancer to rats exposed to inhaled trans-
uranic elements is about 0.1% per rad over
the dose range studied [59]. At the present
time there is no basis for direct extrapolation
of this risk estimate to the human being.
Studies [60] extending over the entire lifespan
of beagle dogs conducted by Battelle, Pacific
Northwest Laboratories have shown that
bronchiole-alveolar cancer is the principal
type of lung tumor that develops in dogs after
inhalation of an aerosol containing insoluble
239PuO2 particles. More recently this same type
of cancer has also been found in dogs exposed
to aerosols of insoluble clay particles tagged
with 90Sr, 144Ce, and 91Y. In these experiments
[61-63], which were conducted at the Lovelace
Inhalation Toxicology Research Institute, the
beagle lung received a diffuse, low LET (linear
energy transfer) radiation exposure, as com-
pared to the localized, high LET exposure
produced by the 239Pu particles.
The likelihood of a hot particle effect such as
that envisioned by Cochran and Tamplin can be
directly assessed from the results of the Battelle
beagle dog study. The study was designed to
simulate the kind of exposure which occupa-
tional workers involved in processing Pu might
encounter; namely, inhalation of aerosols of
239PuO2 particles generated during processing
or accidental combustion of the metal. A group
of 40 dogs was exposed at a relatively early age
to an aerosol containing insoluble 239PuO2.
Lung cancer in the Battelle group may for the
purposes of the present discussion be thought
of as derived from two sources: 1) generalized
alpha irradiation of the lungs from 239PuO2
particles and 2) any hot particle effect of the
type proposed by Cochran and Tamplin. The
extent to which any such hot particle effect
contributed to lung cancer mortality in the
dogs can be judged by comparing the observed
number of lung cancer deaths with the number
expected on the basis of Cochran and Tamplin's
risk factor of 1/2000 per hot particle. The
results of the analysis, details of which are
presented in Appendix A, indicate that if there
is a hot particle effect the cancer risk per par-
ticle is lower by at least several orders of mag-
nitude than Cochran and Tamplin estimated.
The analysis also shows that all of the lung
cancer deaths in the Battelle group are readily
attributable to the absorbed lung dose from
the alpha radiation. In other words, if there is
a hot particle effect the beagle experience indi-
cates that it is dwarfed by the effect of the
generalized alpha irradiation the dogs experi-
enced. The results are summarized below.
As previously discussed, Cochran and Tamplin
have defined the hot particle in two different
ways. They originally described a hot particle
as one with an associated lung cancer death
risk of 1/2000 per particle and a specific activ-
ity of 0.07 pCi or more per particle. For brevity,
we shall refer to this as the Type 1 hot particle.
Later Cochran and Tamplin redefined the parti-
cle as one having the same cancer risk (1/2000
per particle) but they required that it have
nearly ten times the specific activity, namely
0.6 pCi or more, to produce that risk. We shall
refer to this redefined particle as their Type 2
hot particle. In order to avoid ambiguities in
the following discussion, cancer risks will be
assessed for both types of hot particles, since
it is not clear that Cochran and Tamplin have
completely abandoned the Type 1 definition.
The average animal in the Battelle group that
died of lung cancer is estimated to have had
deposited in the pulmonary lung regions
approximately 1.3 million Type 1 particles and
200,000 Type 2 particles. These numbers are
calculated on the basis of the measured particle
size distributions of the aerosols the dogs
inhaled.
13
-------
On the basis of Cochran and Tamplin's assumed
risk constant of 1/2000 per hot particle, it
follows that the average dog would be capable
of developing 650 lethal lung cancers, if they
were produced by the 1.3 million Type 1 parti-
cles, or 100 lethal lung cancers if they were
produced by the 200,000 Type 2 particles. It is
important to realize that the actual number of
primary lung cancers in an animal is not
directly observable, even at autopsy, because
lung tumors frequently metastasize, producing
multiple foci which cannot be distinguished
from multiple primary tumors. Nevertheless,
since primary tumors are expected to arise as
rare independent events and therefore to be
distributed in accordance with the Poisson
distribution [64], the mean number of lung
cancers can be indirectly inferred from the
observed cancer death rate. Thus, a lung cancer
death rate is a measure of the probability of
dying of lung cancer in a specified time period.
More precisely, it is the probability of dying
from at least one lung cancer in that period.
Cochran and Tamplin do not appear to have
specified over what time period their proposed
risk constant of 1/2000 would be realized. For
the purpose of testing their hot particle
hypothesis the mean life span of the normal
unirradiated beagle, about 11.5 years, may be
considered ample time for that constant to be
fully realized. Since the average animal in the
Battelle group was 560 days of age at the time
of inhalation of the aerosol, the mean life span
would be reached roughly 3600 days post-
inhalation. By Life Table methods it can be
calculated (as shown in Appendix A-ll) that if
the average animal in the Battelle group had
lived for 11.5 years, it would have had 1.9 pri-
mary lung cancers. According to the Cochran
and Tamplin hypothesis there should have
been 650 or 100 death-causing lung cancers in
such a dog depending on whether the cancers
were produced by Type 1 or Type 2 hot parti-
cles, respectively.
Thus the beagle data indicate that if there were a
hot particle effect and if that effect were
responsible for all of the lung cancer deaths in
the animals, the associated risk of a lung cancer
would still only be one chance per 670,000
per Type 1 particle, or one chance per 100,000
per Type 2 particle. These risks must be
compared with the risk of one chance per 2000
which Cochran and Tamplin have postulated
for either a Type 1 or Type 2 particle.
It remains to be considered whether the
observed lung cancer mortality in the Battelle
group can be accounted for solely on the basis
of the dose received from the generalized alpha
radiation. The effective half-life of this radio-
activity in their lungs averaged 960 days. For the
animals that died of lung cancer between 0 and
3600 days postinhalation, the initial lung bur-
dens averaged 1.07 yCi. The resultant total ac-
cumulated dose to the lungs at 3600 days post-
inhalation was 2575 rad. For chronic exposures
of this type, Marinelli has shown that tumor
response is expected to be a function of the
average accumulated dose [65], namely 1841
rad in the present case. Hence, the lung cancer
risk extending over the period 0-3600 days was
0.1% per rad (1.9/1841), or 0.01% per rem (if
a quality factor of 10 is assumed for the alpha
radiation from 239Pu). This estimate agrees
well with corresponding estimates for other
species under exposure conditions in which
hot particles would be absent [59]. Thus,
lung cancer mortality in the Battelle group
appears to be adequately accounted for by
the conventional method of averaging the
absorbed alpha dose over the entire lung.
Therefore it is concluded that if there is a hot
particle effect the lung cancer risk per par-
ticle has not only been greatly overestimated
but, more importantly, such a risk is small
by comparison with the lung cancer risk attri-
butable to the generalized alpha radiation.
It could be contended that the Cochran-Tamplin
risk constant of 1/2000 per hot particle still
applies to human beings, even though that
factor is too high by orders of magnitude to be
consistent with the beagle dog experience.
However, such a contention loses its force when
it is realized that Cochran and Tamplin derived
that constant on the basis of induction of tumors
in the rat. Moreover, these were not lung tumors
but skin tumors, and they were induced not by
localized alpha sources of the insoluble 239PuC»2
type but by a diffuse alpha irradiation.
14
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It could also be contended that the beagles had
far fewer hot particles in their lungs than esti-
mated. Although such a possibility cannot be
rigorously excluded, the beagle experiment
simulated in many ways the worst possible type
of exposure, in that the dogs inhaled a poly-
dispersed aerosol of 239PuC>2 particles immedi-
ately after the aerosol was generated. Thus, there
was a maximum opportunity for relatively large
particles, such as Type 2 particles, especially, to
reach the deep lungs. In contrast, in occupa-
tional accidents a worker would generally tend
to inhale aerosols depleted rather than
enriched in hot particles.
Finally, it should be stressed that sound radiation
protection practice requires that the limits of ex-
posure specified in a standard be expressed in
quantities which can be relatively easily mea-
sured. In the case of alpha emitters of the 239Pu
type, the amount of radioactivity, and in turn ex-
posure dose, which a person might acquire can
be assessed by determining excretion rates sup-
plemented where possible with whole body
scanning. On the other hand, there is no way of
measuring the number of hot particles which a
worker might have inhaled short of extirpation
of relatively large amounts of lung tissue.
It is further concluded on the basis of the Battelle
beagle study that the current method of
measuring the generalized alpha radiation
provides an adequate and practical method of
estimating potential lung cancer hazard. Studies
in progress involving lower levels of inhalation
of 239Pu in the beagle should help to settle
the question of whether there is any appre-
ciable residual lung cancer risk that cannot be
accounted for by the generalized alpha
radiation.
EXPERIENCE WITH HUMAN BEINGS
The predominant types of lung cancer observed
in human beings are epidermoid carcinomas,
small and large cell undifferentiated cancers,
adenocarcinomas, and mixtures of these types.
All of these generally occur in the hilar region
of the lungs and are more frequent in smokers,
persons exposed to chemical carcinogens, and
uranium miners [66].
Cancers in human beings have only rarely origi-
nated, under any circumstances, in the bron-
chiolo-alveolar regions [67]. Therefore, an
excess incidence of carcinomas in these tissues
as a result of occupational exposure to carcino-
gens would probably have been readily
detected. Data on the relative frequencies of
different tumor types in uranium miners and
Japanese atomic bomb survivors suggest that the
radiosensitivity of the bronchial epithelium for
cancer induction may be greater than that of
the alveolar or bronchiole-alveolar tissues.
in animals, it has been determined from ex-
periments that the bronchiole-alveolar epithe-
lium is the most likely site of primary lung
cancer following inhalation of plutonium, as
well as the predominant site of naturally-
occurring lung cancer. Since plutonium is not
known to have caused lung cancer in human
beings, we do not know where such cancers
might originate. The bronchial epithelium is
the predominant site of human lung cancers,
while cancers of the bronchiolo-alveolar epi-
thelium, the region of the lung expected to
receive the majority of the alpha dose from
inhaled plutonium, are rare [66-68]. Thus, the
site of plutonium-induced cancers in the human
being will depend upon the relative cancer sus-
ceptibilities of the bronchial epithelium and the
bronchiolo-alveolar epithelium, as well as the
magnitude of the radiation dose to these two
regions. If in human beings the region of the
bronchiolo-alveolar epithelium (where pluto-
nium is retained) is much less sensitive than the
bronchial epithelium (which may be subjected
to possible radiation exposure only during the
brief period when plutonium particles enter or
leave the lungs), then human beings might be
less sensitive to cancer induction by plutonium
than are experimental animals.
15
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REFERENCES
1. National Committee on Radiation Protection,
National Bureau of Standards. Maximum
Permissible Amounts of Radioisotopes in the
Human Body and Maximum Permissible Con-
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Superintendent of Documents, U.S. Govern-
ment Printing Office, Washington, DC 20402,
1953.
2. Recommendations of the International Com-
mission on Radiological Protection. British ).
of Radiology, Supplement 6,1955.
3. National Committee on Radiation Protection,
National Bureau of Standards. Maximum
Permissible Body Burdens and Maximum Per-
missible Concentrations of Radionuclides in
Air and Water for Occupational Exposure,
Handbook 69. Superintendent of Documents,
U.S. Government Printing Office, Washington,
DC 20402,1959.
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of the Subcommittee on Inhalation Hazards,
Committee on Pathologic Effects of Atomic
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ington, DC, 1961.
5. Radiosensitivity and Spatial Distribution of
Dose. Publication 14, International Commission
on Radiation Protection, Pergamon Press,
Oxford, England, 1969.
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18
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APPENDIXES
APPENDIX A — i. RELEVANT PHYSICAL AND BIOLOGICAL DATA
PARTICLES — R. O. McClellan A.1
RESPIRATORY TRACT STRUCTURE AND FUNCTION — R. O. McClellan A.7
REFERENCES A.14
APPENDIX A — II. FACTORS IN DOSE-RESPONSE RELATIONSHIPS
FATE OF INHALED PARTICLES — R. O. McClellan A.19
PHYSICS OF ENERGY ABSORPTION — E. C. Gregg A.23
BIOLOGICAL EFFECTS
Cellular and Subcellular Effects — M. Goldman A.30
Animal Experiments — W. J. Bair A.36
Analysis of Lung Tumor Mortality in the Battelle Beagle Lifespan Experiment —
E. B. Lewis A.54
Human Beings — E. P. Radford A.63
Comparison of Human and Animal Radiocarcinogen Effects — M. Goldman A.66
MECHANISMS OF CARCINOGENESIS — G. W. Casarett A.72
REFERENCES A.73
APPENDIX B — PROCEDURES FOR COMMITTEE APPOINTMENTS AND CONSIDERATION
OF POTENTIAL BIAS OF MEMBERS B.1
APPENDIX C — COMMITTEE MEETINGS AND ATTENDANCE C.I
-------
APPENDIX A
I. RELEVANT PHYSICAL AND BIOLOGICAL DATA
PARTICLES*
A number of characteristics of inhaled alpha-
emitting particles influence their potential
for producing deleterious health effects. These
factors (such as real size, aerodynamic size,
chemical form, specific activity, density, his-
tory of the material and solubility) may influ-
ence particle deposition, retention, transloca-
tion and ultimately the alpha dose to cells
and organs.
The elemental contents of alpha-emitting
aerosol particles that may be encountered
under accident conditions vary greatly. For
example, the elemental content depends
upon where in the nuclear fuel cycle the
aerosol is generated. At some stages in the
cycle transuranic elements are handled in
relatively pure forms; in other stages the mass
of the materials may be dominated by uranium.
Obviously, the elemental and isotopic contents
will change as functions of the specific fuel
cycle and the radiation history of the material,
including elapsed time since discharge from
the reactor.
The range of variations in the potential ele-
mental and isotopic content of particles that
might be released may be better understood
by considering various stages in different
fuel cycles.
1. An accident involving a uranium-fueled
light water reactor shortly after fueling
with fresh fuel would likely result in release
of low specific activity particles consist-
ing largely of uranium, with modest
quantities of beta-gamma-emitting fission
products and very small amounts of
alpha-emitting transuranics.
*Prepared for the Committeejs use by
R. O. McClellan and the staff of the Inhalation
Toxicology Research Institute'
2. An accident involving a uranium-fueled
reactor after a period of extended opera-
tion would likely release particles of
modest specific activity largely consisting
of uranium and beta-gamma-emitting
fission products with moderate amounts
of alpha-emitting transuranics. The alpha
specific activity might be on the order of
a few mCi/g.
3. An accident during certain stages of fuel
reprocessing could release material
similar to that described above; at other
stages it could yield relatively pure ele-
ments, including pure transuranics with
specific activities related to the nuclide
contents.
4. An accident involving uranium-plutonium
fuel assemblies, either during their fabri-
cation or during reactor operations, could
yield particles that are largely uranium
with significant quantities of plutonium
and, after irradiation, other transuranics
and fission products. The alpha specific
activity could be on the order of a few
mCi/g, perhaps approximately that of
pure 239Pu.
5. During reprocessing of the uranium-
plutonium fuel elements, releases could
be encountered at various stages that
would yield particles approximating the
fuel elements in radionuclide composition.
At some stages of the reprocessing rela-
tively pure elements with specific activi-
ties related to the radionuclide contents
might be handled.
The foregoing descriptions indicate that
accidents in most stages of nuclear fuel
cycles will probably yield particles with
specific activites no greater than that of
239Pu, and in many cases lower.
A.1
-------
The aerosol particles may vary greatly in
chemical form, depending upon the nuclear
fuel cycle stage from which they are released.
The forms being handled in the nuclear fuel
cycle vary from a nitrate solution to an
oxalate to an oxide of the various elements.
Aerosols released from these processes have
not been extensively studied but are likely to
be equally diverse. Conventional processes
and accident situations may also involve heat,
resulting in release of materials with varying
thermal histories.
Aerosols usually consist of particles with a
variety of physical and chemical properties.
In particular, a whole spectrum of physical
particle sizes is usually present in a given
aerosol, even when all the particles have the
same chemical composition. The' important
property, physical density, may differ among
different-size particles of a given chemical
form [1]. Hence, the density distribution with
respect to particle size must be considered in
characterizing an aerosol. Also, the specific
activities of particles may be different for
different sizes [2]. Due to lack of detailed
information, however, it is usually assumed
that all particles in a given actinide aerosol
under consideration are composed of material
of the same chemical form, specific activity
and physical density.
If particles in an aerosol are spherical or nearly
spherical in shape, their sizes can be con-
veniently described in terms of their respec-
tive diameters. However, for irregularly
shaped particles, physical size is more difficult
to describe satisfactorily. It is customary to
refer to irregular particles in terms of the
projected area diameter; that is, the diameter
of a circle whose area is the same as the
area of the particle as seen in two dimensions,
as in an optical or electron microscope
(Figure A.1-1).
The size distribution, using either the diam-
eter (D) of spherical particles or the projected
area diameter, is most conveniently described
as a mathematical function C(D) which is a
probability density with
OUTLINE OF PARTICLE
FIGURE A.I-1
Illustration of the Determination of the Projected
Area Diameter, Dp, of an Irregular Particle
/0°°C(D)dD=1 (1)
One such function which has been generally
useful in describing aerosol particle size
distribution is the log-normal function [3]
given by:
d(D) =
D/(2ir)lnag
(InD- lnCMD)2
e (2)
2(lnog)2
with In the natural logarithm, D the particle
diameter, CMD the median diameter of the
distribution (count median diameter or geo-
metric mean), and Og the geometric standard
deviation of the distribution.
Other physical characteristics of the particles
can be similarly described. For example, the
surface area of the particle is important to a
number of particle properties, including dis-
solution. An areal distribution with respect
to diameter might be described as log-normal
with an appropriate surface area median diam-
eter (SAMD) and ag. If the volume or mass
A.2
-------
distribution of the particles is being consid-
ered with respect to diameter, these might be
described with appropriate values for volume
median diameter (VMD) or mass median diam-
eter (MMD) and respective a g values. For
actinides and other radioactive materials, the
radioactivity distribution may be similarly
described in terms of an appropriate activity
median diameter (AMD).
Use of the log normal distribution function to
describe aerosol property distributions with
respect to size provides a number of useful
mathematical transformations, including:
In VMD = h CMD + 3(ln eog)2 (3)
In SAM = In CMD + 2(ln«ag)2 (4)
If the relationships among the volume, mass
and/or specific activity of particles are known,
Equation 3 can be used to calculate the MMD
or AMD from the CMD and Og.
Aerodynamic properties of aerosol particles
depend upon a variety of physical properties,
including the sizes and shapes of the particles
and their physical densities. When particles
are inhaled, their aerodynamic properties com-
bined with various aspects of respiratory me-
chanics determine their deposition in the res-
piratory tract, both in terms of fraction of
those inhaled which are deposited and the
location in the respiratory tract where they
deposit.
Two important aerodynamic propeties of
aerosol particles are the inertial properties
(describable in terms of the settling speed
in air under the influence of the earth's gravity
under normal conditions) and the diffusional
properties (describable in terms of the diffu-
sion coefficient).
It has been customary to use an aerodynamic
equivalent diameter (aerodynamic diameter,
AD) to describe the inertial properties of aero-
sol particles. The aerodynamic equivalent
diameter most generally used is defined as
the diameter of a unit density sphere which
has the same settling speed under gravity as
the particle under consideration. Such an aero-
dynamic equivalent diameter is affected by all
the factors (including shape, size and density)
that determine the inertial properties of a
particle. Under Stokes' Law for viscous settling
conditions, the settling speed of a spherical
particle is given by:
(5)
18n
and the aerodynamic equivalent diameter is
given as
'aeri -
/C(Daen)
(6)
with Dr the geometric (or real) diameter of
the sphere, p its density, C(Dr) its slip correc-
tion, Daen the aerodynamic diameter and
C(Daen) the slip correction associated with a
unit density sphere of diameter
The slip correction, C, is a semiempirical
factor that corrects the Stokes' Law of vis-
cous resistance for the effect of "slip" between
the air molecules when the aerosol particles
are almost as small as or smaller than the
free paths of the air molecules. The slip
correction is approximated for spheres by
with
C(Dr) = 1 + A
A=a+$exp
(7)
(8)
with X the mean free path as gas molecules,
aM.26, g ^0.45 and 8 M.08. At sea level the
mean free path, X, for air molecules is equal
to about 0.0646 ym for air at 21 °C.
A.3
-------
Another definition for aerodynamic equivalent
which has proved useful because of its sim-
plified form is:
(9)
Daeri and Daer2 are nearly equal (within
0.1 urn), as approximately given by
Daen=/[(Daer2.)2+(AA)2]-AX
(10)
where all dimensions are in micrometers, X
is the mean free path of air molecules and
A is a constant equal to about 1.26 (from Equa-
tion 8).
The geometric diameter of spherical particles
can also be calculated from the aerodynamic
equivalent diameter as approximately given
by:
- AA
(11)
All properties of the geometric diameter
described also apply to the aerodynamic diam-
eter. For example, one can refer to the count
median aerodynamic diameter (CMAD), the
mass median aerodynamic diameter (MMAD)
and radioactivity median aerodynamic
diameter (AMAD).
The rate of solubility of small, relatively in-
soluble particles is affected by the physical
property, surface-to-mass ratio. For a small
particle, the surface area is high relative to the
mass and this greater relative exposure to
the solvent will enhance dissolution. This
effect can be important in describing the
dissolution of inhaled particles deposited in
the lung.
Mercer [4] discussed the importance of parti-
cle size distribution in determining the
solubility of inhaled aerosol particles of
relatively insoluble forms. According to
Mercer, film diffusion kinetics do not control
the dissolution of sparingly soluble materials;
rather, the dissolution rate for a single parti-
cle is given by:
dM
dt
= -ks
(12)
where M is the particle mass, s is the particle
surface area, t is time and k is the dissolution
rate constant of specific solubility which
has units of mass or radioactivity dissolved
per unit time per unit surface area of the
particles. Equation 12 is equivalent to Equa-
tion 13:.
dt
D
(13)
where F is the mass fraction, D the particle
diameter and k' a constant equal to kas/pam
with k the rate constant of specific solubility,
DS the particle surface shape factor, am the
particle mass shape factor and p the particle
density.
Unfortunately, dissolution rate constants for
various chemical forms of familiar materials
are not readily available at this time because
chemists have customarily described solubility
in terms of the equilibrium solubility product,
which does not apply to nonequilibrium
dissolution as described by Equation 12. How-
ever, dissolution rate constants have been
measured under certain conditions [5].
Results reported by Raabe et al. [6] indicate
significant differences related to the specific
elements as well as differences between
238Pu and 239Pu (Table A.I-1) [7].
Aerosols usually consist of particles with
widely varying sizes, such as those which
might be described with log normal size distri-
butions. Such particle dispersions are called
polydisperse, to emphasize the various sizes
and types of particles that may be present.
When an aerosol consists of particles of only
one size, shape and type, it is referred to as
monodisperse. A practical definition of mono-
A.4
-------
TABLE A.M.
172 Reload Fuel Assemblies
(in g/1000 MW[e])
Nuclides
234(J
235U
236U
238U
238pu
239pu
240pu
241 pu
242Pu
Total
BWR
Uranium
7.57 x 10«
8.40 x 105
2.10 x 10*
3.14 x 107
1.15 SCR*
Recycled Pu
4.64 x 10*
5.93 x 105
1.26 x 10«
3.10 x 107
2.03 x 104
2.46 x 105
1.60 x 105
8.98 x 10*
6.92 x 1(H
3.22 x 107
3.22 x 107
*Self generating recycle assumes blending old plu-
tonium that has been recycled three times with new
plutonium formed in uranium fuel rods.
disperse is that the coefficient of variation
of the size distribution does not exceed 20%.
For a log-normally distributed aerosol, this is
about equivalent to a
less than 1.2.
distribution with a
g
Aerosol dispersions also depend for their prop-
erties on the state of the medium gas. Such
environmental conditions as relative humidity,
temperature, barometric pressure and fluid
flow conditions (wind velocity, for example)
will affect the aerodynamic phenomena asso-
ciated with aerosol particles.
Another property of a given aerosol dispersion
that can be of great importance in affecting
particle behavior is the state of electrostatic
charge. In some cases, aerosols released in
the nuclear industry might be expected to
have a significant charge per particle that
could be a major factor in determining their
deposition, collection or coagulation.
The most basic dispersion properties of aero-
sols are those that relate to the particle concen-
tration in air or other gaseous medium. The
number of particles per unit volume of gas
(#/cm3) indicates the coagulation rate of the
particles. The mass concentration (mg/m3) and
radioactivity concentration (pCi/2) provide the
quantitative information on which inhalation
exposure levels may be calculated.
Our knowledge of the specific characteristics
of aerosols encountered within containment
systems for normal operations is limited and
that of the characteristics of accidentally
released aerosols is even more limited. Elder
et al. [8] measured some parameters for
aerosols collected from the process or glove-
box ventilation ducts that make major contri-
butions to overall activity concentrations inci-
dent on exhaust HEPA filters. They found a
spectrum of aerosol sizes. A plutonium recov-
ery plant yielded aerosols in which over 70%
of the particles were under 1 //m AD; a fabri-
cating plant produced aerosols in which over
50% of the total activity was associated with
particles in the 1-5 ym AD range; and research
and development facilities produced a broad
spectrum of particle sizes, usually in the 1-2
pm AD range (Table A.I-2).
Raabe et al. [6] recently evaluated the aerosols
present in a glovebox during a plutonium
oxide and uranium oxide mixing operation
and found the Activity Median Aerodynamic
Diameter to be 1 to 3 /j.m with a ag less
than 2 when the aerosol was drawn through an
electrostatic discharger (Table A.I-3). Prelimi-
nary studies by Raabe et al. have indicated
that the plutonium in these industrial aerosols
is much more soluble than laboratory-produced
23<>PuO2.
Mann and Kirschner [9] reported limited
data obtained from a fire in a plutonium
facility. They measured a Mass Median Diam-
eter of 0.32 pm with a geometric standard
deviation of 1.83 using an autoradiographic
technique on particles collected 15, 25 or
50 feet from the fire. Kanapilly et al. [10]
reported solubility data on a plutonium aerosol
collected in another accident and reported
that the plutonium was much more soluble than
laboratory-produced 239PuCh aerosols.
A.5
-------
TABLE A.I-2.
Plutonium Aerosol Size Characteristics [8]
Activity median aerodynamic diameter (AMAD)
At
Location — ,
A
B
C
D
E
— %
86
62
92
89
84
of — Observations
77
26
48
18
49
Fall in the Range
— ym — ym
1.0-3.0
1.0-4.0
3.0-5.0
0.1-1.0
2.0-4.0
Geometric Standard Deviation ( a g)
At
Location — ,
A
B
C
D
E
— %
86
81
92
67
71
of — Observations
77
26
48
18
49
Fall in this Range
1.5-3.0
1.5-3.5
1.5-2.5
1.5-4.0
1.5-3.0
TABLE A.I-3.
Data Summary for Samples from an Industrial Plutonium Glove Box [6]
Sample
Time AMAD Cone.
Day-Run (min) (y m) °g (nCi/l)
I. IMPACTOR SAMPLES
2-2 3 1.70 ± 0.05 S.E. 1.62 ± 0.04 S.E. 25
3-2 3 2.26 ±0.11 1.63+0.05 85
3-3 3 1.80 ±0.06 1.51 + 0.04 44
3-4a 3 5.02 ± 0.89 3.20 ± 0.53 2
3-5a 3 3.80 ±0.32 2.16 + 0.14 1
II. LAPS SAMPLES
1-1 45 1.56 ±0.03 S.E. 1.51 ± 0.02 S.E. 20
2-1 60 1.44 ±0.07 1.54 ±0.06 41
3-1 90 2.56+0.11 1.70+0.05 8
1 No 85Kr discharger, sample data not used.
A.6
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RESPIRATORY TRACT STRUCTURE AND
FUNCTION*
Basic Anatomy
Many anatomical features of the respiratory
tract influence deposition and retention of
inhaled aerosols, including lung volume, alve-
olar surface area, and structure and spatial
relationships of conducting airways and alve-
oli. The distribution of radiation doses and
effects of the inhalation of radioactive aerosols
depend on the characteristics of the aerosol-
emitted radiation and upon the deposited
particles' proximity to the cells at risk.
The respiratory tract may be considered as
having three major regions: the nasopharyn-
geal, the tracheobronchial, and the pulmon-
ary. The nasopharynx filters out large inhaled
particles and is the region in which the rela-
tive humidity is increased and the temperature
of the air is moderated. The trachea, bronchi,
and bronchioles serve as conducting airways
between the nasopharynx and alveoli, where
gas exchange occurs. The conducting airways
are lined with ciliated epithelium and coated
with a thin sheet of mucus. In addition to con-
ducting air to the regions of gas exchange, the
airways increase the relative humidity of air
and moderate its temperature. The surface of
the airways serves as a mucociliary escalator,
moving particles from the deep lung to the
oral cavity so that they may be swallowed.
The branching patterns and physical dimen-
sions of the airways are critically important in
determining deposition of particles in the lung.
They can be best demonstrated by a plastic
cast of the airways (Figure A.I-2).
An early model describing the physical dimen-
sions of the airways was developed by Fin-
deisen [11]. These early data (Table A.I-4)
were based more upon air flow considerations
than anatomical measurements. Landahl [12],
Davies [13] and Weibel [14] followed Findeisen
with improved anatomical models based upon
symmetrical airway branching. Weibel's model
i« shown in Table A.1-5.
FIGURE A.I-2
Front View of Human Lung Cast Trimmed Down
to the Level of Respiratory Bronchiole
*Prepared for the Committee's use by
R. O. McClellan and the staff of the Inhalation
Toxicology Research Institute'
A.7
-------
TABLE A.M.
Model of the Human Bronchial Tree [11]
Region
Trachea
Main Bronchi
First Order Bronchi
Second Order Bronchi
Third Order Bronchi
Terminal Bronchi
Respiratory Bronchioles
Alveolar Ducts
Alveolar Sacs
aTotal surface of the spherical alveolar sacs.
Number
1
2
12
100
700
5.4 x 10*
1.1 x 105
2.6 x 107
5.2 x 107
Diameter
cm
1.3
0.75
0.4
0.2
0.15
0.06
0.05
0.02
0.03
Length
cm
11.0
6.5
3.0
1.5
0.5
0.3
0.15
0.02
0.03
Total
Cross-Section
Area, cm2
1.3
1.1
1.5
3.1
14
150
220
8200
(147,000) a
TABLE A.I-5.
Weibel's Model of Regular Dichotomy [14] (Average Adult Lung
with Volume of 4500 mg at about 3/4 Maximal Inflation)
Region
Trachea
Main Bronchus
Lobar Bronchus
Segmental Bronchus
Bronchi with
cartilage in wall
Terminal Bronchus
Bronchioles with
muscle in wall
Terminal Bronchiole
Resp. Bronchiole
Resp. Bronchiole
Resp. Bronchiole
Alveolar Duct
Alveolar Duct
Alveolar Duct
Alveolar Sac
Alveoli
Genera-
tion
z
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Number per
Generation
n(z)
1
2
4
8
16
32
64
128
256
512
1,024
2,048
4,0%
8,192
16,384
32,768
65,536
131,072
262,144
524,288
1,048,576
2,097,152
4,194,304
8,388,608
300,000,000
Diameter
cm
1.8
1.22
0.83
0.56
0.45
0.35
0.28
0.23
0.186
0.154
0.130
0.109
0.095
0.082
0.074
0.066
0.060
0.054
0.050
0.047
0.045
0.043
0.041
0.041
0.028
Length
cm
12.0
4.76
1.90
0.76
1.27
1.07
0.90
0.76
0.54
0.54
0.46
0.39
0.33
0.27
0.23
0.20
0.165
0.141
0.117
0.099
0.083
0.070
0.059
0.050"
0.023
Total Cross
Section
cm2
2.54
2.33
2.13
2.00
2.48
3.11
3.96
5.10
6.95
9.56
13.4
19.6
28.8
44.5
69.4
113.0
180.0
300.0
534.0
944.0
1,600.0
3,220.0
5,880.0
11,800.0
Total
Volume
cm3
30.50
11.25
3.97
1.52
3.46
3.30
3.53
3.85
4.45
5.17
6.21
7.56
9.82
12.45
16.40
21.70
29.70
41.80
61.10
93.20
139.50
224.30
350.00
591.00
Accumul.
Volume
cm3
30.5
41.8
45.8
47.2
50.7
54.0
57.5
61.4
65.8
71.0
77.2
84.8
94.6
106.0
123.4
145.1
174.8
216.6
277.7
370.9
510.4
734.7
1,084.7
1,675.0
aAdjusted for complete generation.
A.8
-------
The acinus is the basic functional unit of the
mammalian lung and the primary location of
gas exchange between the environment and
blood. Anatomically, the acini consist of the
structures distal to and including the first-
order respiratory bronchiole, which is the
first bronchiole with alveoli. The acini, of
which there are about 200,000 in the adult
human, include 3 or 4 orders of respiratory
bronchioles, several orders of alveolar ducts
and alveolar sacs, hundreds of alveoli and
associated blood vessels, lymphatic tissues,
supportive tissues and nerve enervation. Air-
containing portions of the acinus are depicted
in Figure A.I-3 from reference to published
drawings [15-17] and from examination of
replica casts of the human lung [18]. Quanti-
tative anatomical information for these struc-
tures includes estimates of airway tube num-
bers, diameters, lengths, alveolar numbers
and diameters, surface areas and mean thick-
nesses for the air-blood barrier [13,14,19-23].
Variations in the acini from individual to indi-
FIGURE A.I-3
Air-Containing Portions of "the Acinus
vidual and from species to species during
growth, during breathing, and in healthy and
unhealthy states have been described quanti-
tatively by a number of authors [24-30].
Respiratory bronchioles are tubular structures
with diameters of about 0.5 mm and lengths
of about 1.0 mm in the adult man [15].
Bronchioles are lined with low cuboidal epi-
thelium and at times with ciliated epithelium.
Their walls contain collagen, smooth muscle,
and elastic fibers, but no cartilage, which
makes them quite distensible. One or more
alveoli open to their lumens along one side
while the other side is relatively smooth and
in contact with branches of the pulmonary
artery. In man, the number of alveoli open-
ing into the lumen increases with each sub-
sequent divison [15-17,20,31,32].
The alveolar ducts and sacs are thin-walled
tubes, literally covered with alveoli on all
sides. In adults their diameters are about
0.5 mm and lengths are about 0.7 mm [15].
Alveolar sacs, which are clusters of two or more
alveoli terminating in one or more alveolus,
branch from alveolar ducts and are essentially
closed-end versions of ducts. The total number
of alveolar ducts and sacs in man is estimated
to be about 10-25 million [13,14,33,34].
Alveoli are thin-walled, polyhedral pouches
with one side open to either a respiratory
bronchiole, alveolar duct or alveolar sac. Thin,
squamous pulmonary epithelial cells form
most of the continuous inner lining of the
alveolus. More rounded septal cells are also
located within the walls and free motile
phagocytic cells often lie in contact with the
inner surface of the alveolus. A dense capillary
vascular plexus covers the alveolus [31,35].
In man, the number of alveoli increases rapidly
after birth until about 8 years of age [24,30],
when approximately 300 million are present.
The value of 300 million alveoli in the adult
man is consistently reported, although recent
estimates have ranged from 100 million [22]
to over 500 million [13,36].
The alveolus of the adult human, though
not strictly spherical, has an equivalent diam-
eter of about 150-300 ym [13,14,21,22,24,37].
A.9
-------
The values of 250-350 ym given by Weibel [14]
are probably the most realistic. Alveolar
dimensions vary with degree of lung inflation
[38-40] and with their vertical positions within
the thorax [41].
The total surface area of the alveoli in the
adult man was reported by Von Hayek [37]
as 35 m2 during expiration and 100 m2 during
deep inspiration. Weibel [14] reported 70-
80 m2 at about 3/4 total lung capacity. The
alveolar surface areas for several mammals
are given by Tenney and Remmers [42].
The thickness of the air-blood barrier is
variable, even for an individual alveolus.
Weibel [43] summarized values for man from
the work of Meessen [44] as -follows: endo-
thelium, 0.02-0.4 jum; basement membrane,
0.11-0.16 Mm; alveolar epithelium, 0.04-0.065
urn; and total thickness, 0.36-2.5 Mm. Tissue
thickness between adjacent alveoli is deter-
mined by thicknesses of the alveolar wall,
basement membrane, interstitium and any
interposed capillaries. Weibel estimated that
the capillary diameter is 8 /im and that 90
to 95% of the alveolar surface is covered
by capillaries. Based on these data the mean
tissue thickness between adjacent alveoli is
about 9 Mm. However, Weibel may be over-
estimating the abundance of the alveolar
capillary network.
Lung Cytology
In addition to its major role as an organ for
external gas exchange, the lung also performs
numerous nonrespiratory functions [45], A
variety of cell types and systems are required
to perform these diverse physiologic functions.
One author [46] has listed well over 40 cell
types as identified by ultrastructure, not in-
cluding the circulating corpuscular elements
of blood. Although some of the cell types
are unique to the lung, many are present
elsewhere within the organism. These include
17 types of epithelium, 9 types of unspecified
connective tissue, 2 types of bone and carti-
lage, 7 types of cells related to blood vessels,
2 distinctive types of muscle cells, and 5
types associated with the pleural or nervous
tissue elements. The cells of greatest interest
are those that are unique to the respiratory
tract, such as ciliated bronchial epithelium,
nonciliated bronchiolar epithelium (Clara
cells), squamous alveolar (type I) pneumo-
cytes, great alveolar (type II) pneumocytes,
and alveolar macrophages. In addition, three
other cell types are of special interest: endo-
thelial cells and interstitial cells (fibroblasts
or fibrocytes), which comprise the greatest
percentage of total cells present; and lining
cells of the trachea and bronchi, which com-
prise only a small portion of the mass of the
total respiratory tract. These latter three cell
types are extremely susceptible to various types
of injury.
Ciliated Tracheobronchial Epithelial Cells
The ciliated tracheobronchial epithelial cells
are the predominant cells in the trachea,
bronchi and bronchioles down to 1 mm in
diameter, where they outnumber goblet cells
5 to 1. In the smaller airways they become
more cuboidal and smaller and decrease in
relative number. As the terminal bronchiole
diminishes in diameter and terminates into
the respiratory bronchiole, the cilia-bearing
cells gradually disappear. These cells are poly-
gonal and extend from the basal lamina to
the lumen. About 500 cilia are present on
each cell.
The ciliated epithelium functions to move a
fluid film, and thus particles that deposit on
it, from the lung to the nasopharynx [47-49].
Direct observations have shown that transport
rates in the trachea or large bronchi in several
species range from 1 to 3.5 cm/min. Thus,
mucociliary transport is capable of cleaning
inhaled particles from the conducting airways
in a few hours.
A number of cytokinetic studies of airways
have revealed a turnover time in the bronchial
epithelium of 7 to 28 days in both mice and
rats [50,51]. The turnover times of the bron-
chioles were generally longer. One study
identified specific cell types in the bronchi
and determined that the ciliated cell in the
rat has a turnover time of about 130 days [53].
A.10
-------
Nona/fated Bronchiolar Cells (Clara Cells)
Nonciliated bronchiolar cells are present only
in small bronchioles and usually can be identi-
fied with light microscopy by their bulging
into the bronchiolar lumen, by the absence
of cilia, and by the presence of apical cyto-
plasmic granules identified as peroxisomes
[53,54]. The ultrastructural characteristics [53]
reveal the presence of plasma membranes
that form complex interdigitations, including
desmosomes, with adjacent epithelial cells.
The general cytoplasmic features correspond
to those of most secretory cells.
The cytochemistry of Clara cells [53-56] shows
that lipids are present in cellular organelles
in the form of bound lipids and probably as
phospholipids. These, in turn, are firmly bound
to a nonlipid component, probably protein
in nature. Enzyme histochemical studies have
shown high activities of oxidative enzymes
[55-57] and the presence of acid phosphatase,
alkaline phosphatase, and nonspecific
esterase [56].
The function of the Clara cells is not known,
although ultrastructural and cytochemical
evidence indicates that they are metabolically
active, probably secretory and have charac-
teristics like merocrine-type secretory cells
[53]. It has been suggested [58] and later
supported [55] that Clara cells produce pul-
monary surfactant. However, there is also a
considerable body of evidence which supports
the premise that pulmonary surfactant is
largely a product of alveolar type II cells.
Recently it has been proposed that Clara cells
are the source of the hypophase (base layer)
components of the alveolar lining layer, as
opposed to the surface film (superficial layer)
containing the surface-active phospholipids
[53]. Another suggestion is that Clara cells
supply surfactant for bronchioles [59].
Type / Pulmonary Epithelial Cells (Squamous
Alveolar, Membranous Pneumocyte)
The surface of the pulmonary alveoli is largely
covered by the continuous exceedingly atten-
uated (0.1-0.2 ;um) cytoplasm of the squamous
epithelium, which has nuclei resembling those
of capillary endothelium. This cell is located
on the epithelial side of the basement mem-
brane and, together with the type II cells,
completely lines the alveolus. The junction
between the type I and type II cell is "tight",
forming a zonulae occludens. The surface
area of the type I cell has been calculated
as 2290 /urn2 and that of type II as 63 ;um2.
Thus, even though the ratio of type I to type
II cells in the alveolus is 40:60, the type I
cell makes up most of the barrier of the
blood/gas pathway [60].
The cytoplasm of type I cells is barely visible
with light microscopy and is equally unimpres-
sive with electron microscopy because of its
sparseness and paucity of organelles [61].
Except for pinocytotic vesicles, the cytoplasmic
extensions are practically devoid of organelles
except those concentrated in the perinuclear
cytoplasm.
The squamous alveolar cells function as a path-
way for gas exchange. Although they are
relatively inactive metabolically, as shown
by cytochemistry and electron microscopy,
much activity must be involved in maintaining
the membranes of such a large cell. Because
they are in close contact with the environ-
ment, the squamous alveolar cells serve as
the major epithelial barrier. Transport across
the squamous epithelial cell is presumably by
the pinocytotic vesicles [62]. Squamous alve-
olar cells have also been credited with phago-
cytic abilities under certain circumstances,
both for substances from the blood [63] and
from the alveolar lumen [64].
Type II Pulmonary Epithelial Cells (Great
Alveolar, Granular Pneumocyte)
With the light microscope type II pulmonary
epithelial cells are cuboidal. They are usually
located in corners of the alveoli. The nucleus
is spherical and the cytoplasm abundant with
vacuoles. Great alveolar cells from a number
of species have basically similar ultrastruc-
ture [65-67]. The cytoplasm has a loosely
A.11
-------
ordered granular endoplasmic reticulum, an
extensive Golgi apparatus, numerous multi-
vesicular bodies and many large osmophilic
multilamellated inclusions or cytosomes.
Together with the type I cell they line the
pulmonary alveolus, with "tight" junctions
between the cells. The surface area of the
alveolus covered by the type II cell is not
large compared to that covered by the type
I; 11,000 /urn2 versus 259,000 urn2 [60]. The
plasma membrane of the type II has charac-
teristic microvilli.
The numerous cytochemical studies of type
II cells [65,68-72] show that they are rich
in oxidative enzymes, acid hydrolases and
esterases and have peroxidase activity. This
indicates that the glycolytic scheme and the
pentose cycle are active pathways of carbo-
hydrate metabolism.
Type II cells are strongly implicated as pro-
ducers of pulmonary surfactant. The evidence
is .cytochemical [65,70,72], ultrastructural
[59,73,74], autoradiographic [74-77], and
functional [78,79]. The ultrastructural and
cytochemical characteristics indicate that
type II cells are very metabolically active and
are also secretory. The formation of the multi-
lamellated bodies from multivesicular bodies
with their subsequent excretion into the lumen
has been ultrastructurally determined. The
multilamellated bodies and associated enzymes
are found at the same time in embryonic
development of the individual that surfactant
is first detected. Radiolabeled precursors of
dipalmityl lecithin are found to concentrate
rapidly in the type II cells. Radiolabeled
leucine is rapidly taken up in the endoplasmic
reticulum and multilamellar bodies, indicating
that intracellular protein transport occurs
and that the lamellar bodies are storage
granules.
Other functions of this cell have not been
documented; however, the type II cell is
frequently the proliferative cell in the repair
of subtle diffuse injury to the squamous pul-
monary epithelium, such as results from
beryllium and oxygen toxicity [80-82]. The
type II cells have been classified as a renewing
cell population by several investigators [83],
with relatively long turnover times ranging
from 20 to 84 days.
Alveolar Macrophages
Alveolar macrophages are the phagocytic cells
of the lung and are found free in the alveoli.
With light microscopy, alveolar macrophages
in tissue sections are ovoid mononuclear
cells, 7-10 ^m in diameter. The nucleus is
5-6 jum in diameter and round, oval or kidney-
shaped. Macrophages washed from the
lungs look similar except they are larger
(15-25 jum) and flatter and have more defini-
tive cytologic detail.
Many authors have described the ultrastruc-
ture of the alveolar macrophage [84-90]. The
most notable features are the numerous single
membrane-bound vacuoles, which are either
scattered through the cytoplasm or arranged
about the centrosome. These vacuoles vary
in size, shape, internal structure and electron
density. While some have a homogeneous
matrix, others are multivesiculated and still
others are composed of concentric layers of
osmophilic membranes. The cytoplasmic
membrane characteristically has many broad
irregular extensions or pseudopodia.
The cytochemistry has been well studied by
a number of authors [65,71,91-94]. Alveolar
macrophages exhibit a high respiratory ac-
tivity and depend on oxidative metabolism
for energy required in phagocytosis. The
abundant lysosomes present contain acid
deoxyribonuclease, acid phosphatase, acid
ribonuclease, arylsulfatase, DPN hydrolase,
j3 galactosidase, /3 glucuronidase, /3-N-acetyl-
glucosaminidase, cathepsin D, lipase and
lysozyme.
The origin of alveolar macrophages has been
the subject of several recent reviews [93,95,%].
The relationship of the type II alveolar cell
and the alveolar macrophage has not been
definitively determined. Recent work using
radiation chimeras and chromosome or enzyme
A.12
-------
markers for determining the origin of pulmon-
ary washout cells shows that a majority of
cells come from the bone marrow [96-99].
A four-compartment scheme has been pro-
posed for the origin and maturation of alve-
olar macrophages based on evidence derived
by following blood leukocyte counts, number
of macrophages in lung washings and the
tritiated thymidine labeling of alveolar cells
after whole-body irradiation [100,101], The
postulate is that a stem cell in the bone
marrow produces a cell which travels by the
blood stream to the lung interstitium. Here
the cell divides, matures and then migrates
to the alveoli as a functional alveolar macro-
phage. Based on the radiographic indices, it
was estimated that the time from cell division
in the bone marrow to arrival in the lung
interstitium is about 10 days, with approxi-
mately 10 more days required for maturation
in the interstitium and arrival in the alveolus.
Cell renewal in the lung has been studied
with tritiated thymidine labeling techniques
[102,103] and with colchicine-stimulated
mitotic indices. Both techniques show two
populations in the alveolar wall, one with
a turnover time of 7 days and another of 28-
35 days. The cells in these populations have
not been definitively identified but the 7-day
cycle probably is representative of alveolar
macrophages. The 35-day cycle may represent
the type II or, less likely, the type I pulmon-
ary epithelial cells.
The major function of alveolar macrophages
is the ingestion of inhaled particulate material
[104]. Infectious particles are usually killed
by the macrophages, except in some chronic
bacterial and fungal infections, such as tuber-
culosis, and in some viral diseases where the
virus actually replicates in the macrophage
[105-107].
The ability of pulmonary macrophages to
ingest inanimate particulates has been docu-
mented many times [48,84,85,108-111]. Direct
semiquantitative relationships between the
number of phagocytes washed from lungs and
the amount of dust cleared from the lungs
have been demonstrated.
Endothelial Cells
The endothelial cells form a continuous cyto-
plasmic tube lining the pulmonary vasculature.
They have thin cytoplasmic extensions which
originate from a thicker central portion where
the nucleus is located and are unimpressive
with light microscopy. With electron micro-
scopy [60,61,112] the endothelium shows few
organelles except for numerous pinocytotic
vesicles. At the intercellular junctions the two
adjoining cells become closely approximated
or may interdigitate and overlap. In either
case, a narrow cleft exists which allows
the passage of small protein molecules from
the plasma to the extracellular space [112,113].
A small amount of protein is transferred via
pinocytotic vesicles. The endothelium of the
alveolar septa is separated from the epithelium
by an interstitial space of variable thickness.
Cytochemical studies [57,114,115] show that
the oxidative enzymes of the pulmonary endo-
thelial cells are similar to those in the type I
cells and are much less than those in other
pulmonary cells.
The pulmonary capillary endothelium functions
to exchange gases and volatile metabolites
between the blood and air. However, these
cells may also interact with the blood that
perfuses them and perform functions with
significant implications. For example, a lipo-
lytic system in or on the surface of endothelial
cells may be the source of a circulating lipo-
protein lipase [116] and fibrinolysin is acti-
vated by substances in or on the vascular
endothelium [117]. Five-hydroxytryptamine is
removed from circulation by pulmonary endo-
thelial cells, as indicated by autoradiographic
studies [118].
The pulmonary endothelial cells have been
classified as stem-cell, renewing cell popula-
tions [83]. The turnover time has not been
determined but must be long, a matter of
years [119].
A.13
-------
Pulmonary Fibroblast
The fibroblast is a cell of mesenchymal origin
which is responsible for production of inter-
cellular substances of connective tissues.
These are relatively undifferentiated cells and
it is probable that the fibroblasts found in
the lung are similar to those elsewhere in the
body. The young fibroblast, when viewed with
the light microscope, has abundant cytoplasm
surrounding the nucleus and less cytoplasm
in the attenuated processes which extend from
each end, giving the cell a spindle-shaped
appearance. The nucleus of the active fibro-
blast generally has a prominent nucleolus
and is somewhat elongated and oval-shaped.
Older fibroblasts or fibrocytes tend to have little
or indistinct cytoplasm; often all that can be
seen is a pale, ovoid nucleus' with a little
chromatin encased in the surrounding con-
nective tissue.
Ultrastructurally, the cytoplasm of active fibro-
blasts is rich in rough-surfaced endoplasmic
reticulum and free ribosomes. Mitochondria
and lysosomes are also common. The promi-
nence of ergastoplasm is clear evidence for
the secretory function of this cell and the cis-
ternae of the endoplasmic reticulum are
probably the sites of formation of the secretory
precursors. There is also a well-developed
Golgi apparatus. The secretory products are
extra-cellular and represented by collagen
and intracellular ground substances. Pinocy-
totic vesicles indicate active exchanges of
materials between this cell and its environment
[120].
In cytochemical observations of fibroblasts,
Thompson noted the presence of chondroitin
sulfates and hyaluronic acid, both of which are
generally believed to be synthesized by the
fibroblast. Fibroblasts also produce proteo-
glycans. Fibroblasts have been demonstrated
to contain stainable enzymes, including alka-
line phosphatase, beta-glucuronidase and
leucine amino peptidase, but they have been
shown to be negative for stainable acid phos-
phatase. Fibroblasts, when placed in a mixed
tissue culture, tend to overgrow other cell
types in the same culture, to synthesize col-
lagen [121-123], and to extrude synthesized
procollagen from the cell into the surrounding
media [124].
Functionally, it is evident that the fibroblast
is an active cell whose main function is the
production of collagen and intercellular
ground subtances. Extensive work has been
performed on these functions, both in vitro
and in v/vo [121,122,124,125].
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A.18
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APPENDIX A
II. FACTORS IN DOSE-RESPONSE RELATIONSHIPS
FATE OF INHALED PARTICLES*
A report of the Task Group on Lung Dynamics
of the International Commission on Radio-
logical Protection [1] describes models for the
deposition and retention of particles in the
human respiratory tract. In this report, the
respiratory tract was viewed as consisting of
three basic compartments: a) the naso-
pharynx, b) the tracheobronchial compart-
ment, and c) the pulmonary compartment. The
nasopharynx. (NP) begins with the anterior
nares and extends to the level of the larynx or
epiglottis. The tracheobronchial (TB) compart-
ment consists of the trachea and bronchial
tree, including terminal bronchioles. The
pulmonary compartment (P) consists of the
more distal portions of the lung which are
involved in functional gas exchange.
The model includes estimates of both the frac-
tional deposition of inhaled particles with
respect to aerodynamic size and the clearance
of deposited particles from the various regions
of the respiratory tract based on the particle
properties. Deposition, defined as the process
which accounts for the amount of inhaled or
inspired material that remains after expiration,
is accomplished by inertia! impaction, gravita-
tional settling and diffusion by Brownian
movement. Inertial impaction is greatest for
particles 5 /nm and larger in diameter and
occurs primarily in the NP and TB compart-
ments. Gravitational settling, involving parti-
cles in the range of 0.5 to 5 /im, is of some
significance in the NP and TB compartments
but is even more significant in the P compart-
ment. Diffusion, involving particles smaller
than about 0.5 pm, is of great significance for
deposition in the P compartment and, for very
small particles, may be the process by which
large quantities of radioactivity are deposited
in the N-P compartment.
*Prepared for the Committee's use by
R. O. McClellan and the staff of the Inhalation
Toxicology Research Institute
A comparison of the Task Group's deposition
model for inhaled particles with recent experi-
mental data from man has recently been
completed by Mercer [2]. In Figure A.II-1 the
total body deposition for two tidal volumes
(solid curves), based on the predictions of the
task group model, is compared with experi-
mental data, with good agreement. Fig-
ure A.11-2, which compares deposition in the
pulmonary compartment based on the task
group model to the very limited experimental
data available, suggests that the task group
model may underestimate somewhat the frac-
tion deposited in the pulmonary region from
nasal breathing. However, the model provides
a good working basis for estimation of the
deposition of inhaled particles, including
alpha-emitting radionuclides. Mercer's paper
also presents similar figures for the nasal and
tracheobronchical regions.
The retention of inhaled particles in the
respiratory tract was also addresssed by the
Task Group on Lung Dynamics Report [1].
FIGURE A.II-1
Total Deposition During Nasal Breathing [2]
A.19
-------
0.4
z
o
t
U)
g
g 0.2
O O
OLIPPMAN'S DATA
— TASK GROUP: 750 cm3 TIDAL VOLUME
-—TASK GROUP. 1450 cm'TIDAL VOLUME
NASOPHARYNGEAL REGION
FIGURE A.II-2
Deposition in the Pulmonary Region During
Nasal Breathing [2]
However, their model has been expanded by
others to include the retention of inhaled
material in the total body as well as in the lung.
Figure A.II-3 illustrates the application of such
a general model to transuranic elements in the
environment (both inhalation and ingestion
exposures) for man [3]. The cross-hatched
areas represent deposition of very insoluble
particles (i.e., 239PuO2) as opposed to moder-
ately soluble (i.e., 239Pu[NO3]4) aerosols which
are shown in the open compartments. Percent-
ages in each respiratory compartment
represent those portions of deposited aerosols
transferred by the associated pathways, as
indicated by the arrows.
Paniculate material deposited in the respira-
tory tract must eventually be cleared either
through the gastrointestinal tract, through the
lymphatic system, or by dissolution and absorp-
tion into blood. Clearance of the upper
respiratory tract is very rapid compared to that
of the deep pulmonary spaces. Nasal clearance
occurs within the first hour after particle
deposition in man [4] and during the first two
hours in dogs [5]. Eating, sneezing and other
mechanical functions speed nasal clearance,
either to the environment or (by swallowing)
FIGURE A.II-3
Inhalation and Ingestion Model for Transuranic
Elements in Man [3]
to the gastrointestinal tract. Absorption of
transuranic elements from the gastrointestinal
tract is considered to be very small, ranging
from 2 x 10~5 to 2 x 10~2 of the amount ingested
for plutonium [6]. Radiation damage to the
gastrointestinal tract itself from ingested
alpha-emitters (even in enormous quantities)
has not been demonstrated [7,8]. Thus the naso-
pharynx protects the lower respiratory tract
regions from inhaled alpha-emitting radio-
nuclides by diverting particles to clearance
pathways, such as the gastrointestinal tract,
that are not likely to be damaged.
Very similar considerations apply to material
deposited in the tracheobronchial tree. Clear-
ance times for these deposits, derived from
studies [9] in mouth-breathing humans, are
shown in Table A.I 1-1. Similar clearance rates
have been reported for donkeys [10], which
showed typical early clearance with a half-
time of about 30 minutes followed by slower
A.20
-------
additional clearance during the remainder of
the first day. Beagle dogs exposed to insoluble
oxide or fused clay particles showed similar
clearance of the tracheobronchial deposits
during the first day following inhalation [11].
These cleared particles were subsequently
swallowed and excreted in feces. For long-
lived alpha-emitting radionuclides, radiation
doses delivered to components of the respira-
tory tract or gastrointestinal tract during this
short-term clearance are of doubtful signifi-
cance, especially as related to long-term
irradiation of deep pulmonary structures.
Particles deposited in the pulmonary region
may be cleared via the lymphatic system, by
mucociliary movement through the tracheo-
bronchial tree, or by dissolution and
absorption into blood. The relative importance
of each pathway for a given aerosol depends
upon many factors, such as the chemical form,
particle size distribution, specific activity and
elemental form. Mercer [12] suggested that
dissolution of deposited particles in the deep
lung region is the major pathway for clear-
ance and that dissolution rates are directly
proportional to the surface areas of the
particles and their chemical compositions.
Figure A.II-4 illustrates the potential influence
of dissolution on the retention of inhaled
transuranic elements in the lung. Fig-
ures A.II-5 through A.II-8 illustrate the
variability in retention time in experimental
animals and man for various forms and par-
ticle size distributions of some transuranic
elements.
TABLE A.II-1
Average Bronchial Mucociliary Transit Times
(90% Clearance) in Humans [9]
Subjects
100
Male (non-smokers)
Male (smokers)
Female (smokers)
Clearance
Times
(min)
494
439
324
No.
Observa-
tions
14
15
6
S.D.
(min)
130
156
55
Q
CC
o
s
cc
5
o
tr
2.000 4,000
DAYS POST-EXPOSURE
FIGURE A.II-4
6.000
Theoretical Lung Retention Curves for Monodisperse
Plutonium Dioxide Aerosols of Various Sizes,
Assuming Lung Retention is Solely Dependent
Upon Particle Dissolution
ISOTOPE COMPOUND
13«pu
aipu
ORGANIC
COMPLEXES
NITRATE
FLUORIDE
DIOXIDE
NITRATE
DIOXIDE
200 400 600 SOO 1000 1200
LUNG RETENTION HALF TIME (DAYS)
FIGURE A.II-5
Retention of Plutonium in Pulmonary Region
of Lung [13]
A.21
-------
- »PuO,
100
1000
1OOO° 360° 450° 123° 900° 760°
OXALATE OXALATE METAL METAL OXALATE OXALATE
2 - 350°C
.46 .06 .05
1.3 .12 .1
1160 DAYS)
PARTICLE SIZE./
-------
lung burden per day and may be closer to 0.1%
per day [11]. Differences reported for effective
pulmonary clearance in the two experiments
with beagle dogs probably relate to differences
in particle solubility, although the effect of
alpha radiation upon pulmonary clearance
cannot be totally ruled out. Material that
leaves lung tissue by absorption into blood
distributes throughout other body tissues and
is excreted. For absorbed plutonium and other
actinide elements, ICRP Report 19 [15] suggests
that 45% deposits in liver, 45% in skeleton and
10% goes into other tissues or is excreted.
Effective half-times for plutonium in skeleton
and liver were recommended as 100 years and
40 years, respectively.
PHYSICS OF ENERGY ABSORPTION*
Basic Particle Dosimetry
Whenever a charged particle traverses a
medium, it leaves in its wake a number of ions,
directly broken molecular bonds and, ulti-
mately, free radicals (if the medium is
aqueous). In turn, these free radicals also
break molecular bonds, resulting in the largest
portion of biologic effects attributed to such
"indirect" causes.
The path of the particle and the distribution of
the ions and resultant radicals are determined
by the charge, mass, and velocity of the
original particle. Electrons, being of relatively
small mass and unity charge, produce some 6
ion pairs/jum of path (an energy loss of
210 eV/jum) when traveling with a velocity
near that of light (say, for a particle energy of
1 MeV and higher). However, as the electron
gradually loses energy, the path becomes very
tortuous due to atomic and nuclear deflections.
Also, the rate of energy loss increases because
of the decreased velocity and increased time
spent in the vicinity of atoms along the path.
This loss increases to about 66 ion pairs/Aim
(2300 eV/j;m) at an energy of 10 keV, which is
near the end of its range. However, by this
*Prepared for the Committee's use by
E. C. Gregg
time, the electron has migrated many hundreds
of micrometers from a co-linear projection of its
original direction.
Thus, for a circular beam of electrons incident
on a given medium, one visualizes a cylindrical
volume filled with a reasonably uniform
density of ions and/or free radicals. Consider
a one-square-centimeter, 0.01 microampere
beam of 5 MeV electrons incident on a water
medium for one second, resulting in a delivery
of 0.01 microcoulomb of charge. Thus, some
6 x 1010 electrons are delivered, depositing a,
total energy of 5 x 10s ergs. The range of these
electrons is about 2.4 cm, leading to an
irradiated volume of 2.4 mfi or an irradiated
mass of 2.4 g. Since the ions are distributed
uniformly due to scattering, this corresponds
to an energy deposition of 2 x 10s ergs/g or
2000 rad. The average energy loss is 5 MeV/2.4
cm or 5.6 ip///m, which implies that the end of
the range contributes little to the total loss.
One last figure of importance is that the total
beam produces 9 x 1015 ion pairs, which leads
to a spacing of about 0.06 /zm between ion pairs.
This in turn may be used to judge biologic
effects relative to critical biologic structure.
These considerations for electrons also hold
for x-rays or gamma rays whose biologic
actions are due to electrons produced by
photon absorption.
Since alpha particles are some 7200 times
heavier than electrons, their velocities are
much lower for the same initial energy.
Because of this, these heavy ions at nonrela-
tivistic energies lose energy quite rapidly and
produce a very dense column of ionization
with very little deflection from their original
path. Their range is also relatively short
because of this high rate of loss along the path.
In addition, due to statistical variations, there
is about a 2% spread in the overall range of
individual particles (straggling). A 5.3 MeV
alpha particle with a range of 41 jum in water
also has an average of of 129 keV/^m, or
about 3500 ion pairs///m. However, due to
slowing down (with little deflection) the ion
density increases by about a factor of 2 for
5 MeV particles at the end of their range. This
A.23
-------
is known as the Bragg effect and is much more
predominant for alpha particles than for
electrons.
The alpha particle track is cylindrical, 90% of
the ions remaining within a diameter of
0.01 /urn. The remaining 10% are recoil electrons
with sufficient energy to produce their own
ionizations (delta rays). Such ions are present
out to about 0.2 /urn. This concept can be
illustrated by considering a 5 MeV alpha
particle beam of 6 x 1010 particles and an area
of 1 cm2, as for the electron beam discussed
previously. Since the number of particles and
the per particle energy are the same as for the
electon beam, the same total energy of 5 x 105
ergs should be deposited. However, because
the range is only 40 jum, a smajler volume is
irradiated, resulting in a dose of 1.25 x 106
rad. To produce the same 2000 rad delivered by
the electrons only 108 particles/cm2 would be
needed, which is a spacing of 1 /zm, on the
average, between incident particles. At the
same time, the ion pairs are only about 3 Ang-
stroms apart along the path of the particle.
These calculations of the dose in rad for alpha
particles assume that the ionization is uni-
formly distributed throughout the volume, as
with electrons and x-rays. That this restriction
does not apply to alpha particles on the semi-
microscopic basis is rather obvious, as
discussed above. Furthermore, if the energy of
one alpha particle were assumed to be
deposited only in the volume of its path, this
would result in 8 x 10~6 ergs deposited in
4 x 10-"15 cm3, or a local dose of 2 x 107 rad.
Radiobiologic Effects
The dosimetric considerations described
above illustrate that the concept of dose in
rad is not applicable to biologic effects where
the volumes that are sensitive to radiation
(i.e., the cell nuclei) are small and far apart in
the milieu being radiated. It is well known
that the nuclei of mammalian cells are at least
a thousand times more sensitive to radiation
than the cytoplasm [20]. Furthermore, heavily
irradiating the cytoplasm seems to produce
prompt cessation of all cellular functions,
rather than just a loss of reproductive integrity,
as found with irradiating nuclei. Regarding
x-rays, a dose of 200 rad to a typical mam-
malian cell (e.g., Chinese hamster fibroblast)
will prevent division (a genetic or reproductive
death) half the time. Since typical masses of
cell nuclei are 2 x 10~10g, this corresponds to
a delivery of 4 x 10"6 ergs to the nucleus, which
in turn is 2.5 x 106 eV, or about 71,000 ion pairs.
It is important to remember that this energy
is distributed reasonably uniformly throughout
the nuclear volume and is not all used to
destroy critical molecules. Furthermore, the
local molecular damage produced by forming
one ion pair in the vicinity of a key molecule
may be slight enough to allow subsequent
repair or rejoining.
On the other hand, when an alpha particle
penetrates the nucleus, the damage in the
path of the particle is very high and repair is
quite unlikely. Furthermore, there is no oxygen
effect (enhanced production of free radicals
in the presence of oxygen) as with x-rays.
Thus, small doses of energy from alpha
particles as averaged over the whole irradiated
volume will produce the same effects as
larger doses from electrons. A relative biologic
effectiveness (RBE) ranging from 2 to 5 has
been found for loss of reproductive integrity
in mammalian cells by 5.3 MeV alpha particles,
which implies that 50 rad due to an alpha
particle averaged over the whole irradiated
volume will cause the same damage as 100 to
250 rad of x-rays. Since any one 5 MeV alpha
particle is depositing about 2 x 10~7 ergs/^m
of path (which amounts to about 4000 rad
when averaged over a cubical nucleus [7 jum x
7 (j.m x 7 jum]), even one particle will produce
"overkill." This has been shown experi-
mentally, in which only a 2 jum penetration of
one alpha particle into a nucleus of approxi-
mately the size described above was necessary
to kill the cell [20]. This data on "killing" or
destruction of reproductive integrity by alpha
particles can be explained on the basis that
50 rad corresponds to a spacing of 7 //m
between alpha particles. This means that on
the average a 7 jum-square nucleus will be hit
by an alpha particle just a little over half the
time.
A.24
-------
Thus, instead of referring to dose in rad when
dealing with alpha particles, we should more
properly consider the probability of a cell
nucleus being struck by such a particle.
Lung Model and Cells at Risk
To consider the lung, which is of immediate
concern in the "hot particle" problem, assume
the pieces of radioactive material are small
enough (about 1 jum) to become trapped at any
point in the lung and subsequently to radiate
alpha particles in all directions. While the
bronchial epithelium is probably more suspect
than the alveoli as the tissue at risk, the follow-
ing model of the epithelium in the alveoli is
assumed to approximate the bronchial epithe-
lium equally well.
An alpha particle that will traverse 40 /urn of
solid tissue will obviously travel much further
in the less dense lung tissue, as the range varies
inversely with the density (p). In addition,
even though the total mass traversed along
one path remains a constant, the number of
cells within the increased volume determined
by the range will be greater. The irradiated
volume (v) varies inversely as the cube of the
density while the total mass irradiated varies
as pv or 1/p2. Since the density of the actual cell
does not vary, the number of cells at risk must
vary as 1/p2.
Because the density of lung tissue changes
during breathing, a number of different values
are reported in the literature [21]. If the
average lung (for men and women) weighs
1000 g, has a residual volume of 4.0 I, and
inspires about 1 Ł under light exercise, a
minimum density of 0.2 g/cm3 is produced at
reasonable inspiration and a maximum density
of 0.25 g/cm3 at expiration. Rather than
average the density at this point, it will be
more correct to average the cells at risk later
in the calculations, even though the difference
is small.
Microscopic examination of lung tissue shows
that about 1/3 of the tissue traversed by an
alpha particle located in an alveolus consists
of epithelial cells; the rest of the tissue mass
consists of blood, plasma and connective
tissue. In spite of the fact that the cells are
very irregular and widely dispersed, the
volume of the cells and the projected cross-
sectional area of the nuclei are of more
concern. These are assumed to be 1500 /urn3 and
10 jum2, respectively, for typical epithelial cells.
The average cell, if forced into a cubical shape,
is 11 fjtm on a side; if spherical, it is 14 //m in
diameter. From the previous discussion,
alpha particle range (cm) = R = 4 x 10~3/P
lung volume - V(cm3) = 4500 + 500 sin Wt
angular respiratory frequency - W
= 27r x respiratory frequency
lung density (g/cm3) = P
= 1/(4.5 + 0.5 sin Wt)
mass of tissue within R = M(g) = 4frR3p/3
_ 8 x IP"7
number of epithelial cells within R = N
= M/(3) (1500) x 10-12 = ~
To find the average number of cells at risk due
to breathing we must average N:
Ndt
2VW
2TT/W
Ndt
sow r Z7I/vv
= -T-/ (4.5+ 0.5 sin Wt)2 dt
*• J 0
and evaluating,
where p is the linear average of the excursion
due to breathing. Thus weighting the influence
of breathing on the lung density only produces
a 1% correction, which is negligible.
A.25
-------
Using the originally assumed value for cell
size,
N = 1240 cells
R = 4x10Vp"=182Mm
This yields an average volume of lung tissue per
cell of 20,000 jum3, or one cell in a box 27 urn
on a side.
Probability Considerations
While the above calculations imply that six cells
can occur sequentially along a 180 urn path,
only three or four such cells can be penetrated,
since these would completely absorb the
energy of one alpha particle. Furthermore,
since the total effective tissue path is still
40 um, of which only 1/3 is cells, it follows that
on the average only one cell will actually be
in the path of an alpha particle, but the
number hit can vary between zero and three. •
Since the nucleus is the critical target and it
presents an area of 10 jttm2 to any incident
particle, it would follow that the probability
of not hitting a nucleus is 1 - 0.014 = 0.986. In
a 180 urn path there are roughly 7 (180/27 =
6.6) possible positions of nuclei, on the
average. The probability of not hitting any
nucleus in the total path is (0.986)7 = 0.9; the
probability of hitting one or more nuclei with
at least one particle in the total path is 1 - 0.9
= 0.1.
One pCi of activity will emit 0.37 particles/
sec or 3.2 x 10" particles/day. Considering the
calculations above, we see that if Q is the
activity in picocuries of any one source located
in the alveoli, D days will be required on the
average to sterilize all 1240 epithelial cells
within the range of the alpha particles as given
by QD = 1240/(3.2 x 104) (0.1) = 0.4. This is
plotted in Figure A.II-9. While a few cell nuclei
in the critical volume are hit by more than one
particle, delivery times longer than D days
for a given Q simply mean that nearly all cells
will be hit more than once (overkill region).
Times shorter than D days obviously lead to
underkill, as shown.
Since estimates of cell turnover in the lung
range from 5 days to 80 days, even with cell
u>
0.1
0.01
0.001
OVERKILL REGION
UNDERKILL REGION
0.1
LO
10
100
TIME, d
FIGURE A.II-9
Time Needed to Sterilize all Epithelial Cells
turnover the effects of this type of radiation
in terms of epithelial cell death will be the
same for activities above about 0.005 pCi,
as shown by the graph. There is no reason
to suspect a precipitous change in the biologic
effects at or near 0.07 pCi, as has been sug-
gested on the basis of dose (in rad). In fact,
this target treatment states that if turnover
is neglected, two plutonium particles of a
given activity located at different points in
the lung will sterilize twice as many cells
as one particle containing all the activity.
While this effect has been found to hold
approximately for tumor production in rat
skin [22], extrapolation to lungs is not war-
ranted because of turnover, particle migration,
and dependence of initial distribution on parti-
cle size. Nevertheless, there is no apparent
reason to support the concept of increased
risk with particle activity above a certain level
(-vp.005 pCi).
Irradiation of Rat Skin—Epithelial Cells
Albert et al. [23] found that irradiating the
skin of rats with alpha particles produced
tumors of the hair follicles only when the
range was 0.35 mm or larger. Neither 0.12 mm
penetration by alpha particles nor 0.16 mm
A.26
-------
penetration by protons produced any detec-
table tumors. Similarly, 0.2 MeV electrons did
not produce tumors but 0.7 MeV electrons
did [24]. Since the papilla which produces
the cells for the medulla of the hair, the
cortex, the cuticle and the internal root sheath
is located at this depth, it is most suspect
as the primary site of the induced tumors.
(Even though many of these cells were in the
telagen phase, they are capable of rapid re-
generation.) Some tumors also apparently
arose from the sebaceous gland located further
up the hair shaft, but these also depended
upon penetration of the radiation beyond
about 0.35 mm.
It was also observed that no higher production
of tumors was noted when the Bragg peak
(x5 in dose in rad) was located at or near
the papilla. The authors interpreted this to
mean that the whole follicle must be irradiated
to induce a tumor; it also seems logical to
accept this as proof of the single particle "hit"
hypothesis, which says that a single ionizing
event is sufficient to cause a tumor.
Finally, and most interestingly, it was
observed that no tumors originated in the
heavily irradiated epithelial cells between
the hair follicles. Data [25] on the epithelial
cells in the basal layer of the skin indicate
a population density in normal mouse skin of
1.4 x 106 cells/cm2. This leads to a cell area
of about 100 jum2 or a cell size of about 10 ^m
on a side, which is close to that measured
for most epithelial cells. Furthermore, the
average nucleus is about 3 nm x 3 Aim, which
produces a cross-sectional area of about 10
jum2. The alpha particle density used by Burns,
Albert and Heimbach [26] was lOVcm2, or
1 particle//um2, for a calculated dose of 520
rad. This is a density of approximately 10
alpha particles per nucleus. If x is the average
number of primary ionizations per target, then
e'x is the probability that no primary ioniza-
fions will occur in the target. It follows then
for x = 10 that the number of nuclei not
struck by an alpha particle is Ns = (1.4 x
106)e-io = 60 nuclei/cm2. From Withers' data
[25], 1300 rad of x-rays to the mouse skin
will leave 60 survivors per cm2, which leads
to an RBE of 2.5 for the killing of epithelial
cells by alpha particles if one measures the
dose in rad as averaged over the whole irradi-
ated volume. This is reasonably close to RBE
values reported for reproductive death and
other biologic effects produced by alpha parti-
cles [26].
In passing, it is interesting that Withers
reported that 10 to 20 surviving epithelial
cells were capable of preventing ulceration
by proliferating to cover a 1 cm2 area during
a 10-day postirradiation period. A most impor-
tant point in the alpha particle experiments
by Albert et al. [23] is that all doses delivered
to the rats killed about 106 epithelial cells
each. Since 6 cm2 were exposed per rat
and 210 rats were irradiated, then about 109
cells were killed without producing one tumor.
Thus the chance that one alpha particle
passing through one epithelial cell will pro-
duce a tumor is less than one in 109, assuming
that the probability of producing a tumor
is proportional to the number of cells irradi-
ated. This is equivalent to assuming tumors
result from "near" misses which in turn
produce appropriate genetic changes. Since
a 5.3 MeV alpha particle in the lung, will,
on the average, penetrate only one cell, the
probability of its producing a tumor is less
than 10~9 if the lung epithelial cells are like
those in mouse skin.
Applying these findings to the hot particle
concept, the probability of producing a tumor
near such a particle is less than 1.2 x 10"6.
Furthermore, this probability is not dependent
on the activity of the plutonium oxide parti-
cles, since for the ranges discussed no more
than 1200 cells will be killed per particle.
Only the number of particles is important.
Also, if the density or proximity of similar
cells is important in tumor formation, the
above probability limit becomes even smaller
since the epithelial cells in the skin are much
closer together than in lung tissue.
A.27
-------
Irradiation of Rat Skin—Hair Follicles
Tumor production in hair follicles has been
considered as a model for tumor production
in the lungs. Even though no structure in the
lungs corresponds to the papilla in the skin,
the epithelial cells in the alveoli appear to
be similar in tumorigenicity to the potentially
dividing cells in the papilla. This can be
partially explained on the basis that the cells
in the bulb of the hair follicle are an epidermal
derivative [27].
The bulb of an average hair follicle in the
rat is about 100 ^m in diameter and 150 nm
long, while the average cell in the papilla is
quite similar in size to the epithelial cells
described above [28]. Although not all of the
bulb consists of potentially dividing cells, cells
with measurable mitotic indices have been
found in the root sheath extending 170 Mm
upward from the papilla. Thus the typical
bulb can be approximated by a sphere 100 ^m
in diameter filled with about 1000 closely-
packed, potentially dividing cells.
There are 2500 follicles involving a total of
2.5 x 106 cell per cm2. This means that for an
incident alpha particle dose of 108/cm2 (520
rad), about 100 surviving cells should be
distributed among 2500 follicles. Even if one
surviving cell could regenerate a follicle, just
as one epithelial cell can regenerate mouse
skin [25], this would account for only a 4%
follicle survival compared with an observed
85%. The implications, of course, are: 1) that
many more cells are involved in a follicle
than is assumed above, 2) that active cells
migrate from unirradiated volumes to reform
follicles, and/or 3) that wholly killed follicles
appear "normal" due to the fact that most
of the cells remain in a resting phase and
are not challenged to divide. The latter is
probably the most acceptable explanation.
More importantly, the alpha irradiation data
indicate that one tumor is induced per 9000
abnormal hair follicles, or one tumor per 6 x
104 equally-irradiated hair follicles. Further-
more, for any of the doses used in these
experiments, virtually all the potentially
dividing cells in each follicle bulb are "killed"
or rendered incapable of division. Thus, if we
assume that 1000 closely packed cells or some
fraction thereof must be rendered reproduc-
tively inert to form a nidus for a tumor, then
tumor production should not depend on dose
in these experiments. Since it obviously does
depend on dose, the assumption of the
necessity of a core of sterilized cells to pro-
duce a tumor is not valid [29].
It is much more reasonable to assume that
the probability of producing a tumor is simply
proportional to the total number of sterilized
cells, since this will also be a measure of
near misses that may create the appropriate
genetic aberrations. The above example indi-
cates that for 1000 cells per follicle, there
should be a chance of creating 1 tumor per
6 x 107 sterilized cells. This leads to a probab-
ility of (1/6.) x 1(T7 = 1.6 x KT8 that a 5 MeV
alpha particle in the lung will produce a tumor
(assuming, of course, that the epithelial cells
in the human lung are identical to those in
the rat skin papilla). Thus, for the plutonium
oxide particles that kill at most 1200 cells
per particle, the probability of tumor induc-
tion is about 1 in 50,000 per particle, regardless
of its activity.
While this value is much greater than that
observed in either animals or man [30], most
important is that this model says that uni-
formly distributed activity has a much greater
tumorigenicity than that concentrated in a
hot particle. The probability that a 0.1 pCi
particle will induce a tumor in lungs con-
taining cells like those in rat skin papilla
increases from zero to 2 x 10~5 in 4 days,
after which it remains constant. If that same
activity is uniformly distributed in the lungs,
then the chance steadily increases with time,
becoming 2 x 10~4 at 4 days and 5 x 10"3
at 100 days. This illustrates an important
difference between irradiation by hot particles
and uniform distribution of radiation. In the
former, for a fixed cell population, the chances
of tumor production remain constant because
all viable cells in the vicinity of each particle
A.28
-------
can be "killed" only once. On the other
hand, with uniform distribution the chances
of tumor production increase with time since
cells are being continuously "killed". Cell
turnover and possible particle migration may
change the picture, but only slightly. How-
ever, if for no other reason than the fact
that observable rat skin tumors appeared as
early as 30 days after irradiation, it is most
unlikely that there are cells of this type and
sensitivity in the human and/or dog lungs in
which the latent period for lung cancer is
several years.
An exercise of interest is to determine the
area of a possible single hit target for tumor
production in the rat hair follicle. If A
represents the target area and D the dose in
particles/unit area, then AD is the average
number of primary events occurring in the
target. As before, the probability that a target
will not be hit is e'AD, producing for the
number of survivors NS - Noe~AD. From this
we see A = I/Da?, where Dn is the dose
required to reduce Ns to 0.37 No.
In the data shown in Figure A.II-10 (from
Heimbach et al. [31]) the percent of abnormal
follicles is plotted against dose (in rad). Since
the number of tumors is directly (and lin-
early) related to the number of abnormal
follicles, one minus the percent of abnormal
follicles is a measure of the number of sur-
vivors (i.e., those that do not get tumors).
A plot of Ns versus dose (as shown in Figure
A.II-10) shows that although the curve has
only a slight shoulder (indicating an almost
negligible extrapolation number but still
implying possible repair), the straight line
portion may still be used to determine A.
From the best straight line fit, Da; = 1000 rad,
or an incident dose of about 2 x 108 particles/
cm2. This leads to A = 0.52 /urn2. The probabil-
ity of one cell producing a tumor is finite
only when this particular area is hit by one
alpha particle. This might be an equivalent
area just outside the whole nuclear membrane
that will allow the cell to stay viable when
hit, yet allow penetration by free radicals
and/or delta rays to produce nonlethal genetic
abberations.
LO
0.9
0.8
J I
I I I
I
I I
0 200 400 600 800 1000
DOSE, rad
FIGURE A.II-10
Relationship Between Abnormal Hair Follicles and
Radiation Dose (in rad) [31]
Conclusions
Fundamental dosimetric and radiobiologic
considerations indicate that Cochran and
Tamplin's "hot particle" concept and the
Geesaman Hypothesis are invalid, for the
following reasons:
1. It is incorrect to explain mechanisms of
biologic effects of alpha particles in terms
of dose in rad or rem, particularly when
small, sensitive action sites are involved.
However, it is appropriate to use dose
in rad (or rem) for gross comparative
purposes, provided the microscopic
characteristics of the biologic media in-
volved are reasonably similar.
2. Local ("point") concentrations of alpha-
emitters can kill or affect only a fixed
A.29
-------
number of cells and their progeny, regard-
less of the total activity, due to the finite
range of the alpha particles and the fact
that a cell can only be sterilized once.
Thus, there is no reason to suspect in-
creased risk of tumor induction with
activity of a hot particle above a certain
level (-vO.005 pCi).
3. Had the proposed mechanism of a nidus
of dead cells forming a tumor applied to
tumors induced by alpha particles in the
rat skin, tumor production would have
been independent of dose for the doses
used in the experiments; however, this
was not observed. Further, there is no
direct experimental evidence that such a
nidus of dead cells will promote tumor
formation for an already transformed cell
in the lung. In fact, the lung tissue cells
now considered to be the initiators of
carcinogenesis have a reasonably short
replacement time without such stimuli.
4. There is no evidence—histological or
radiobiological—that any structures in the
lung are similar to the cells in the bulb
of the rat hair follicle. Thus, the proba-
bility of producing tumors in rat skin can-
not be extrapolated to the human lung.
5. Models based on current radiobiological
theory and experiments imply that the
risk of carcinogenesis from a uniformly
distributed alpha-emitter in lung tissue
is higher than if the activity were concen-
trated in a few discrete point sources.
BIOLOGICAL EFFECTS
Cellular and Subcellular Effects*
The spectrum of effects on and in cells tra-
versed by high LET radiations in general and
alpha particles in particular has been studied
in considerable detail. The general conclusion
* Prepared for the Committee's use by
M. Goldman
derived from these studies is that any particle
with a LET of about 100 keV/ium has an
exceedingly high probability of killing any
cell whose nucleus it traverses.
Since almost all studies on cell effects are
performed in vitro on cell suspensions or on
single cell preparations, the effects are gener-
ally "direct" ones, in that any potential modi-
fication of cell injury influenced by the pres-
ence of adjacent normal unirradiated cells is
likely to be absent or at least unphysiologic.
An additional possible complication is that
the mammalian cells studied in vitro are
frequently characterized by a relatively rapid
replication rate and morphologic uniformity.
However, although the "nonphysiologic"
nature of experimental culture media relative
to a mammalian tissue milieu may influence
the degree of response, in all likelihood it is
not of major significance.
Some fifteen years ago Barendsen et al. [32]
showed that cells irradiated by alpha particles,
unlike low-LET x-rays, showed in vitro sur-
vival curves which could be described by
simple exponentials of the form S = e-kD,
where S is fractional cell survival, D is the
dose in rad and k is a proportionality constant
describing the curve's slope. Assuming Poisson
distributions, k can be shown to equal 1/DO
(i.e., one hit per target) and if D/Do equals
1. (e-1), Do, is the 37% dose. Thus S = e-D/Do =
e~1 = 0.37. The smaller the value for DO,
the steeper the slope and the more effective
the radiation quality. For low LET radiations,
such as those of x-rays, cell type often
influences the precise value, but for mam-
malian cells DO is generally 100 to 150 rad
and 130 rad is a frequently quoted value
describing the exponential portion of the
survival curve [33].
Cells irradiated by alpha particles not only
fail to manifest the low dose shoulder charac-
teristic of x-ray exposures but also follow a
steeper slope, with values of Do ranging from
50 to 100 rad. A graphic comparison of cell
survival following irradiation by x-rays and
alpha particles (measured by cell cloning
potential) is shown in Figure A.I 1-11 [32],
in which the x-ray Do is about 135 rad and
A.30
-------
that for alpha particles is 65 rad (210Po). The
authors calculated the "cell sensitive" area
from the survival curve data as alphas per
unit area passing through cells. Thus for their
study, at 170 keV/jum (3.4 MeVas), one a per
Mm2 is equivalent to an average dose of 2720
rad. At a mean Do of 65 rad, they calculated
that the sensitive area was about 42 ;um2,
and if circular had a 7.4 nm diameter. Since
the human kidney cells used had optical diam-
eters of 6 to 10 Aim and (as will be shown
below) the cytoplasm is not the likely "target",
they concluded that
. . . the sensitive area is approxi-
mately equal to the area of the nu-
cleus. This implies that whenever
one a-particle penetrates the nucleus
anywhere, the cell is sufficiently dam-
aged to be prevented from developing
into a clone. This does not imply that
the sensitive volume is identical with
the whole nucleus. It is quite possible
that the sensitive structure is distri-
buted inside the nucleus in such a
way that the probability of an a-parti-
cle's passing through the nucleus
without hitting this structure is very
low.
. . .the passage of one a-particle
through the nucleus of a cell suffices
to inhibit this cell irreversibly from
developing into a clone, whereas cells
not hit in the sensitive volume may
be assumed to be damaged to such a
small extent by a-particles passing
through cytoplasm only that subse-
quent X-radiation will act on these
cells as if they had not been irradiated
at all. On the other hand, cells irradi-
ated with X-radiation first, but not
damaged sufficiently to be prevented
from developing into a clone, will
be expected to have the same sensi-
tive area as cells not damaged at all,
i.e., the cross sectional area of the
nucleus. Indeed their sensitivity to
a-radiation is not found to be in-
creased or decreased by the preceding
X-irradiation (curves 3 and 4, Figure
A.II-12 [32]).
!3
o
tc.
I
u.
O
UJ
I
111
o
DC
K
3
w
oc
UJ
CO
100
10
0.1
V \> 'J
-"--V-
—f
I .
I
2 4 6 8 10 12 14 16
»- DOSE IN RAD x 100
FIGURE A.IM1
Effects of a-, 0-, and X-Radiation
on Colony Formation [32]
Curve 1 obtained with a-radiation;
Curve 1' corrected for cells not adhering
to the bottom of the dishes;
Curve 2 obtained with ^-radiation, RBE 0.85;
Curve 3 obtained with X-radiation;
Curve 3' theoretical n/no = e-D;135 (1 + D/135)
A.31
-------
DOSE IN RAD x 100
FIGURE A.II-12
Effects of Combined a- and X-Radiation [32]
a and b, effects of a- and X-radiation, respectively;
Curve 1, effects of 50 rad of a-radiation + 0,100,
150, 200, 300 and 500 rad of X-radiation;
Curve 2, effects of 100-rad a-radiation + 0,100,
150, 200, 300 and 500 rad of X-radiation;
Curve 3, effects of 300 rad of X-radiation + 0, 50
and 100 rad of a-radiation;
Curve 4, effects of 500 rad of X-radiation + 0, 50
and 100 rad of a-radiation
An experiment by Munro [20] vividly illustrates
the relative insensitivity of the cell cytoplasm
to alpha irradiation and shows that Barendsen's
"sensitive area" is most likely the nucleus.
Using a micro-manipulator, Munro was able
to selectively irradiate single cultured Chinese
hamster ovarian fibroblasts with 210Po alpha
particles with a ballistic precision of about
1 nm (Figure A.II-13). The flux density (a/m2)
was equivalent to about 2000 rad/jum2 (Fig-
ure A.I 1-14). He showed that doses of 25,000
to 100,000 rad to the cytoplasm alone had
little effect on subsequent cellular growth and
proliferation, but that nuclear alpha irradi-
ation was lethal (Figure A.II-15). Lethality
seemed to correlate best with irradiation
within ±1 nm of the cell nuclear membrane.
The "partial" nuclear radiation doses used
for the 1.4 nm "tails" at an exposure to 0.18
a/Mm2 and 180 keV per tail over a 10 jum2
area of nuclear surface of a 200 nm3 volume
resulted in a dose estimate of about 26 rad.
These studies suggest that if a small portion
of the alpha particle energy is deposited at
or near the nuclear membrane, cell lethality
is quite likely. However, if the energy de-
posited within the nucleus is much below
100 keV (i.e., <1 nm) some cells may survive.
Thus, "near" or partial cell nucleus radiation
by alpha particles may have a lower relative
biologic effectiveness and, although spatially
different in terms of energy distribution, may
resemble the effects of lower LET radiation
traversals.
This low probability effect is inferred in the
recent work of Hall [34], in which synchro-
nized hamster cells manifested varying values
of DO as a function of the stage of the cell
cycle at the time of irradiation. While the
general response was qualitatively similar to
that found following x-radiation (Figure
A.II-16), with an "increase in radioresistance
to a maximum in late S, followed by a sensi-
tive period in late G? and M phases of the
cycle," it is tempting to speculate that the
spatial distribution of dose-to-nucleus may
not be as significant as the total number of
ionizations absorbed. There does not appear
to be an especially sensitive subnuclear volume,
but perhaps there is an ionization density
dependence. The relation of LET and RBE
for alpha particles found by Barendsen [35]
is depicted in Figure A.II-17, which compares
the unit dose to unit particle effectiveness.
A.32
-------
POLONIUM
SCALE OF CELL AND NEEDLE
FIGURE A.II-13
Irradiation of Part of the Cytoplasm of an Interphase Cell by Alpha Particles
from a Polonium-Tipped Microneedle [20]
60
40
o
x
20
10
20
97.000
83,000 |
D
a:
66,000
54.000
35,000
20,000
FIGURE A.II-14
uj Dose Rate, Rad/min, and Flux Density, Particles/
o pmVmin, Against Distance for a Typical Needle
(inset: end of the range on a larger scale, showing
the sharp cutoff) [20]
30
DISTANCE FROM NEEDLE,
100 r-
u
DC
01
CO
5
z
10
1
DAYS
FIGURE A.II-15
Alpha-Irradiation of Cell Cytoplasm
(Solid line—growth of three cells given
cytoplasmic alpha irradiation; broken line—
three similarly selected controls on the same
coverslip; points give extreme ranges of counts) [20]
A.33
-------
O EX. 121
A EX. 124
D EX. 142
10-3
0 200 400 600 800100012001400
DOSE (RAD) •
10-3
Ł
u
I i I
5 0
6 8 10
TIME (HOURS) AFTER
SYNCHRONIZATION WITH H. U.
FIGURE A.II-16
Survival Curves for Asynchronous Chinese Hamster
Cells Exposed to 210-keV X-rays or Alpha Particles [34]
He further calculates that at about 35 eV/
ionization, the experimental data are com-
patible with a track core relative effectiveness
of 10 to ISJpnizations (n) per 100 A but that
this is small compared to the effective cross
sections calculated per particle (^2-35 m2).
The implication is that "although the sensitive
structure, or molecules, in the cell comprises
a relatively large part of the cell or probably
of the cell nucleus, damage to reproductive
capacity is already produced if in a small part
of this structure or of such a molecule a large
amount of energy is deposited." His hypothesis
that a given number of n or more ionizations
is required in a certain small volume to initi-
ate the chain of events resulting in death of
a cell may be modified in such a way that
the total amount of damage produced in a
small volume must exceed a given minimum
value and that this total damage is on the
average produced by n ionizations.
The data on cell lethality in vitro following
alpha irradiation as predominantly a nuclear
event requiring a high ionization density is
further supported by the observation of an
efficient production of a-induced chromo-
somal aberrations. In a recent study by Vulpis
[36] on human lymphocytes in culture, 2.5
MeV alphas (0.5 rad/min) produced a spectrum
of aberrations similar to that following x-
irradiation. The yield of aberrations was
exponential between 3.5 and 17 rad of alphas
and "saturated" at higher doses (Table A.II-2).
Relative to x-rays, for example, the yield of
dicentrics per cell (0.1 to 2.5 range) showed
a reasonably constant RBE of about 23.
The data on the effects of alpha particles
at the cellular level, as typified by the above
studies, strongly suggest that single alphas
traversing a cell's cytoplasm will likely have
minimal, if any, impact on the cell's ability
to survive and reproduce. If, however, a single
A.34
-------
X
O
<
at
Z
UJ
«J
UJ
Of
O
Q
fc 1
oc
UJ
0.
10
I
LET
50 100 500
Of UNITY DENSITY TISSUE)
1000
E
g
O
UJ
d
40
30
u
uj or*
if) ^U
10
I
10 50 100 500 1000
LET (keV//* OF UNIT DENSITY TISSUE)
D37
Energy
(MeV)
1.8
2.5
3.1
3.6
4.0
5.2t
8.3t
26.8t
LET
of Unit
Density Tissue)
200
166
141
123
110
± 40
±20
±15
±10
±10
85.8 ± 10
60.8 ± 5
24.6 ± 2
Rad
97 + 13
79 ± 9
62 ±
54 ±
57 +
64± 5t
107 ± 12t
197 + 30t
6
7
4
Particles
Per mm2
(x 101)
3.03 ± 0.41
2.98 ± 0.34
2.75 ± 0.26
3.25 ± 0.36
3.24 ± 0.23
4.66 ± 0.36
11.0 ±1.2
50 ±7.6
Relative
Per Unit Dose
(YD* in
ra«H x 10-*)
1.03 ± 0.14
1.27 ±0.14
1.61 ± 0.15
1.56 ±0.17
1.75 ± 0.12
1.56 ± 0.12
0.93 ± 0.10
0.51 ± 0.07
Effectiveness
Per Particle
(Cross Section
in mm2 x 10-')
33.0 ± 4.4
33.6 ±3.8
36.4 ± 3.5
30.8 1 3.4
30.8 ± 2.2
21.4 ± 1.7
9.111.0
2.0 ± 0.3
FIGURE A.II-17
Mean Lethal Dose and Relative Effectiveness of a-particles for Impairment of the Proliferative
Capacity of Cultured Human Cells [35]
A.35
-------
TABLE A.II-2.
Chromosome Aberration Frequencies Induced by Thermal Neutrons in Human Lymphocytes [36]
Chromosomal Aberrations per Cell
Exposure Time
(min)
7.5
12.5
25.0
35.0
50.0
Dicentrics
0.09
0.16
0.54
1.40
3.00
Centric Rings
0.006
0.020
0.050
0.310
1.200
Fragments
0.04
0.17
0.50
0.37
3.50
alpha particle traverses a cell nucleus (or its
membrane) so that an ionization density of
about 100 keV/jum is achieved, there is a
high likelihood of irreparable molecular dam-
age sufficient to kill the cell. There is com-
pelling evidence that a surviving cell whose
nucleus receives a "small" portion of the
alpha track energy may have the opportunity
to pass some nonlethal genetic lesion on to
its progeny, and this possibility may influence
the sequence of tissue events which leads to
the induction of a tumor. Furthermore, if an
ionizing event in a nucleus is not lethal,
the cell may also have minimal opportunity
for endogenous repair, thus causing efficient
replication of the "lesion" in this special
class of alpha-irradiated cells.
It is of further interest to speculate on the
applicability of these high dose rate studies
to a model in which a cell in its entire lifespan
may encounter only a single alpha particle.
The temporal distribution of dose in living
tissue may produce very different quantita-
tive estimates of effect and these may be
difficult to derive solely on the basis of in vitro
high dose rate studies. In particular, the spatial
distribution of cells around a "hot particle",
in comparison to the "uniform" distributions
used in cell culture, might suggest a major
sparing effect proportional to the frequency
with which a single cell is traversed by multi-
ple alpha particles. Insofar as cell killing
may be related to cancer risk, the in vitro
data would suggest that the radiation effect
is greatest when the alpha flux is diffusely
distributed.
Animal Experiments*
Clinical Responses to Inhaled Plutonium
Information on clinical responses to inhaled
plutonium has been derived entirely from
studies with experimental animals. (Chromo-
some aberrations have been observed in blood
lymphocytes of workers contaminated with
plutonium [37,38], but since these workers
were probably also exposed to external radi-
ation it is not clear that the aberrations were
due to the alpha radiation from the pluto-
nium.) Since the biological effects of inhaled
plutonium have been reviewed in several re-
cent reports [13,30,39-43], principal attention
will be given to delayed effects here.
Clinical responses to inhaled plutonium are
the result of alpha irradiation of the tissues in
which plutonium is transported or deposited
(primarily blood, lung, thoracic lymph nodes,
liver, and bone). The time of onset and the
magnitude of the response have been shown
to be dose-dependent. The principal clinical
responses to inhaled plutonium are shown in
Table A.II-3, with the approximate minimum
alveolar burdens of plutonium and tissue radi-
ation doses observed to cause these effects in
experimental animals. Extremely high doses
of alpha radiation from plutonium cause
severe hemorrhage and edema, resulting in
early death due to massive destruction of
*Prepared for the Committee's use by
W. J. Bair
A.36
-------
TABLE A.II-3
Clinical Responses to Inhaled Plutonium in Experimental Animals
Approximate Minimal Dose Observed
to Cause the Effect
Biological Effect
Lung Hemorrhage and Edema
Respiratory Insufficiency
Lung Fibrosis
Lymphopenia
Lung Cancer
Bone Cancer
Inhaled Dose
of lung)
0.5
0.02
0.005
0.001
0.002
0.01
Radiation Dose to Critical
Tissue or Organ (rad)
15,000
1,800
^200
(Critical tissue not known)
(rats)
000 (dogs)
3.6 (rats)
78 (dogs)
functional tissues. Lower doses may cause
fibrosis and metaplasia severe enough to lead
to respiratory insufficiency and eventual
death.
Fibrosis may or may not be accompanied by
metaplastic or neoplastic changes. Pulmonary
neoplasia has been observed in rats at cal-
culated cumulative radiation doses less than
about 10 rad. However, so far the lowest cal-
culated dose associated with pulmonary
neoplasia in dogs is about 1000 rad. Whether
neoplasia will occur at lower doses in dogs is
not yet known, since low dose experiments
have only been in progress for about five years.
Osteogenic sarcoma has occurred in dogs at
doses of about 78 rad and in rats at doses as
low as 3.6 rad.
In dogs lymphocytopenia is so far the most
prominent effect of plutonium deposition in
lungs. The degree to which circulating lympho-
cytes are reduced and the time span between
plutonium inhalation and lymphocyte reduc-
tion depend on the dose [44]. This is illustrated
by the results from current studies of inhaled
239PuO2 and 238PuO2 in beagle dogs [44].
Figure A.II-18 shows the leukocyte levels
in control beagle dogs and in dogs after inhal-
ation of six levels of 239PuO2. Lymphocytopenia
occurred in the four highest dose groups and
was related to the plutonium dose in both
time of appearance after exposure and magni-
tude. The decrease in neutrophil levels was
gradual and less pronounced than the decrease
in lymphocytes. No differences occurred in
either monocyte or eosinophil levels in
plutonium-exposed dogs and no effects were
seen in red cell levels.
The hematological changes in dogs exposed
to 238PuCh are similar to those observed in
dogs exposed to 239PuO2, except that there is a
greater decrease in neutrophil levels. This is
probably the result of the translocation of
238Pu to bone, which occurs more rapidly after
inhalation of 238PuO2 than after 239PuC>2.
The mechanism by which lymphocytopenia
occurs is unknown, but it may be due to direct
irradiation of lymphocytes circulating through
the lungs in which plutonium is deposited.
Wheiher the lymphocytopenia is related to
the accumulation of plutonium in thoracic
lymph nodes is not known, but lymphocyto-
penia has been observed in dogs before appre-
ciable amounts of plutonium have appeared
in the lymph nodes.
A.37
-------
e
X
(/I
Q.
s
o GROUP 1
• GROUP 2
• GROUP 3
a GROUP 4
A GROUP 5
GROUP 6
INITIAL ALVEOLAR
DEPOSITION, nCI
3.5 ± 1.3
22 ±4
79±14
300 ± 62
1100 ±170
5800 ± 3300
\*_/——
A^^ \ A^ .
V A-^A-A
0 4 8 12 16 20 24 28 32 36 40 44 48
TIME.MONTHS AFTER EXPOSURE
FIGURE A.II-18
Mean Lymphocyte, Leukocyte and Neutrophil Values from Dogs after Inhalation
of 239PuO2. (The shaded area represents mean values from age-related control
dogst the mean 95% confidence interval) [44]
A.38
-------
Neoplasia in Experimental Animals After
Inhalation of Plutonium and Other Transuranics
Inhaled plutonium and other transuranics
have been shown to cause pulmonary neoplasia
and osteosarcoma in several experimental
animal species. Pulmonary neoplasia is the
dominant carcinogenic response when the
plutonium is retained in the lung for a long
period. Osteogenic sarcoma also occurs when
inhaled plutonium is relatively soluble and is
translocated to bone. Liver also accumulates
plutonium translocated from respiratory
tissues, but liver cancer has not been a common
finding in studies of inhaled plutonium.
Leukemia has rarely been observed in pluto-
nium studies, although plutonium is trans-
ported in blood and deposited in lymphatic
tissues and has been associated with other
effects on blood elements, such as a reduc-
tion of lymphocytes and neutrophils [40].
The major experiments performed to date in
which pulmonary neoplasia has been observed
are summarized below.
Ammonium Plutonium-Rentacar bo nate
and Plutonium Citrate in Rats [45]. Pluto-
nium citrate is relatively soluble and does not
readily hydrolyze or form polymers. There-
fore, inhaled plutonium citrate deposited in
the lung is expected to be widely dispersed,
rapidly translocated to bone and other tissues
in the body, and excreted. Ammonium pluto-
nium-pentacarbonate hydrolyzes, readily
forming aggregates. Both compounds appear
to have similar translocation characteristics.
Thus, in this study the authors believed the
total radiation dose to the lung would be com-
parable for these two plutonium compounds,
but the distribution would be different (e.g.,
more localized in the case of ammonium
plutonium-pentacarbonate). However, this
difference was not documented in the report.
Throughout the duration of the experiment
autoradiograms showed plutonium aggregates
associated with hemosiderin deposits. Quan-
titative descriptions of this aggregation were
not provided by the authors for either plu-
tonium citrate or ammonium plutonium-
pentacarbonate.
The experiment involved 2232 rats, of which
376 were killed immediately after exposure
to determine the initial lung burden. The
characteristics of the aerosols were not pub-
lished. The experimental design and result";
are given in Table A.ii-4. (he two plutonium
compounds appeared to be equally effective
at the lower dose in causing lung cancer.
Differences may have occurred at doses above
500 rad.
Plutonium-239 Nitrate and Triacetate [46].
This experiment consisted of 1097 Wistar rats
weighing 140-160 g. Solutions (0.03 mi) of
plutonium nitrate (pH = 2), 0.01 N nitric acid
(pH = 2) and sodium plutonyl triacetate
(pH = 6.5) were given by intratracheal injec-
tion. From autoradiograms it was determined
that both plutonium compounds were present
for long times after administration as aggre-
gates in macrophages in sclerotic areas of the
peripheral lung, in interalveolar septas and
beneath the pleura. Although the surfaces of
the bronchi and lumens of the vessels were
free of plutonium, the greatest numbers of
large aggregates were in scar tissue in the
hilar region and were associated with iron-
containing pigment in connective tissue cells
or extracellularly between collagen fibers.
Nitric acid alone caused an increased inci-
dence of adenocarcinomas which was not
observed in the rats which received lower
levels of plutonium (Table A.II-5). Thus, if
nitric acid had any effect on the induction of
cancer by plutonium it was one of depressing
the response, rather than enhancing plutonium
carcinogenicity.
Intratracheally-injected plutonium increased
the total incidence of pulmonary neoplasia
but the response relative to dose was not as
great as observed after inhalation of pluto-
nium citrate and ammonium plutonium-
pentacarbonate (Table A.II-4). The authors
concluded that nitric acid scarring of the
lung tissue was an indirect cause of neoplasia.
However, there was no evidence that nitric
acid enhanced the carcinogenic effect of
plutonium.
A.39
-------
TABLE A.II-4
Frequency of Pulmonary Tumors in Rats After Inhalation of Plutonium Citrate
and Ammonium Plutonium-Pentacarbonate [45]
Number of Rats
Mean Survival Time (days)
Initial Lung Content (jLtCi)
Dose (rad)
Incidence of Tumors (%)
All Pulmonary Tumors
Squamous Cell Carcinoma
Adenocarcinomas
Adenomas
Hemangiosarcomas
Lymphosarcomas
Total: Squamous Cell,
Adenocarcinoma, and
Hemangiosarcoma
Number of Rats
Mean Survival Time (days)
Initial Lung Content (juCi)
Dose (rad)
Incidence of Tumors (%)
All Pulmonary Tumors
Squamous Cell Carcinoma
Adenocarcinomas
Adenomas
Hemangiosarcomas
Lymphosarcomas
Total: Squamous Cell,
Adenocarcinoma, and
Hemangiosarcoma
Controls
258 23
570.8 64.2
±
8.3 ± 2.1
0 1.03
0 3820
6.6
—
0.39
1.17
—
5.04
0.39
Controls
258 12
12 94
69.3 123.6
± 4.8 * 9.0
0.80 0.51
3090 2370
2.2
2.2
—
~
~
"
2.2
39
220.7
±12.9
0.362
1740
28.2
7.7
—
20.5
—
~~
7.7
Plutonium Citrate
113
415.6
±11.8
0.249
1390
47.9
16.8
3.6
23.0
3.6
0.9
24.0
105
463.6
±11.8
0.160
852
40.9
7.6
14.3
15.2
3.8
"
25.7
31
546.4
±22.3
0.080
467
48.5
9.7
16.1
6.5
9.7
6.5
35.5
203
544.9
±10.5
0.040
234
25.6
1.5
5.4
10.8
1.5
6.4
8.4
120
585.0
±11.5
0.020
117
18.3"'
—
2.5
8.3
—
7.5
2.5
157
635.0
±3.3
0.008
47
' 15.9
3.2
1.3
3.2
0.7
7.0
5.2
Amonium Plutonium-Pentacarbonate
23 69
22
126
83
126
91
101
48
570.8 77.3 77.8 138.9 247.4 360.9 484.3 581.8 583.9 571.6 570.9
±8.3 ±5.6 ±6.6 ±9.6 ±20.8 ±11.1 ±13.7 ±11.4 ±11.7 ±16.1 ±20.9
0 1.46 0.77 0.45 0.35 0.245 0.15 0.040 0.020 0.008 0.004
0 7320 3900 2780 2140 1615 1065 497 186 80 41
6.6
7.7
9.0 44.4 78.4 63.2 35.2 19.8 16.7
—
0.39
1.17
—
5.04
~
4.6
3.1
4.6
4.5
4.5
—
9.0
11.9
7.9
19.8
48
14.5
24.6
30.1
16.9
2.4
9.5
7.7
17.3
3.9
7.9
5.5
3.8
18.7
--
3.3
1.0
1.0
7.9
2.0
5.9
—
—
4.2
—
8.3
0.39
24.6 45.9 38.0 13.2 6.0 4.2
A.40
-------
TABLE A.II-5
Frequency of Pulmonary Tumors in Rats after Intratracheal Injection of 239Pu Triacetate [46]
x»Pu
Controls Triacetate
2WPu Nitrate
Number of Rats
Mean Survival Time (days)
Initial Lung Content (juCi)
Dose (rad)
Incidence of Tumors(%)
All Pulmonary Tumors
Squamous Cell Carcinoma
Adenocarcinomas
Adenomas
Hemangiosarcomas
Lymphosarcomas
Total: Squamous Cell,
Adenocarcinoma, and
Hemangiosarcoma
248
672.7
±7.7
0
0
52
391.5
36.54
42
94 110
87
93
93
93
89
586.2 289.6 417.5 535.0 599.4 578.6 586.7 628.0 625.4
±20 ±8.7 ±10 ±15.1 ±12.6 ±15.7 ±17.0+13.0 ±15.3
±17.1
1.0 HNCb 1.0 0.42 0.01 0.048 0.031 0.01 0.0042 0.00042
1570 0 5855 2756 620 317 205 62 28 2.8
38.45
32.69
1.92
1.92
1.92
0
7.2
0
2.4
0
0
4.8
21.27
19.15
1.06
1.06
0
0
39.07
16.4
12.7
7.27
0.9
1.8
21.84
5.75
3.45
8.05
4.6
0
22.13
1.1
5.38
14.6
1.1
0
8.33
1.04
3.12
2.08
0
2.08
10.76
0
2.15
0
0
8.6
7.54
1.1
0
3.23
0
3.23
11.24
2.25
0
3.37
0
5.62
2.4 20.21 30.0 13.79 7.53 4.17 2.16 1.08 2.25
The effect of plutonyl triacetate is difficult
to assess because there was only one dose
group. Since the pH of the injected solution
was more compatible with lung tissue than
the 0.01 N nitric acid in which the plutonium
nitrate was injected, there was probably less
scarring due to chemical action. However,
the neoplastic response was not less for plu-
tonyl triacetate than for plutonium nitrate.
It is impossible to compare the heterogenicity
of the distribution of plutonium and plutonium
aggregates in the lungs of the rats in these two
experiments; however, it is likely that intra-
tracheal administration of plutonium nitrate
solutions led to more nonuniformity than
inhalation of plutonium citrate and ammonium
plutonium-pentacarbonate. Since plutonium
nitrate given by intratracheal injection was
less effective than inhaled plutonium citrate
and ammonium plutonyl pentacarbonate in
causing pulmonary neoplasia, it does not
appear that scarring of the lung by nitric acid
or the greater aggregation of ' plutonium,
which occurred in the case of intratracheal
injection of plutonium nitrate, enhanced the
carcinogenic effect of plutonium.
Inhaled Plutonium Nitrate and Ca-DTPA
Treatment in Rats [47]. Male Wistar rats were
exposed to aerosols of 239Pu(NO3)4 generated
from a 0.27 N nitric acid solution. Beginning
after 28 days the rats were treated for one hour
at weekly intervals for six weeks by exposure
to aerosols of calcium diethylenetriamine-
pentaacetic acid (Ca-DTPA), a chelating agent
given clinically to plutonium-contaminated
human beings to increase the plutonium
excretion rate. The amount of Ca-DTPA
given the rats at each treatment was%5 mg/kg,
approximately equivalent to the dose given
human beings.
For long-term observation of biological effects
the experiment was comprised of 261 rats in
groups, as shown in Table A.II-6. Since Ca-
DTPA treatment did not appear to influence
the carcinogenic effect of plutonium, the
A.41
-------
incidence values were calculated for the com-
bined groups of Ca-DTPA and sham-treated
rats. In this experiment inhaled 239Pu(NO3)4
wai very effective in causing pulmonary
neopiasia. A 33% incidence was observed in
the dose range of 36-100 rad and a maximum
of 75% in the dose range of 1001-2000 rad.
This response was much greater than that
observed by Yerokhin et al. [46) with intra-
tracheally-injected plutonium nitrate, also
in Wistar rats. The difference in response may
be due to the method of administration, since
inhalation results in more uniform distribution
of plutonium in the lungs than does intra-
tracheal injection, or to the higher concen-
tration of nitric acid in the solution from which
Ballou generated his aerosol than in the solu-
tion given intratracheally by Yerokhin. The
distribution of HNOa deposited in the rat lungs
in the two experiments would also be different
for the two routes of administration; inhaled
HMOs would be more widely dispersed than
HNOa given by intratracheal injection.
Inhaled 239PuO2, 2MPu(NO*)4, and »»Pu(NO3)4
in Rats [48]. Sprague-Dawley S. P. F. rats
were exposed to aerosols of ^PufNOa)^
""PufNOaK and 239PuO2. The normality of the
nitric acid solutions from which the aerosols
were generated has not been reported. The
results are given in Table A.II-7. In this experi-
ment, about half of the pulmonary tumors
were bronchogenic carcinomas and about
half were bronchiole-alveolar carcinomas.
Plutonium-239 nitrate appeared to be more
effective than 238Pu(NOa)4. Both results agreed
better with the results of Ballou's inhaled
239Pu(NOa)4 experiment than with Yerokhin's
intratracheally-injected 239Pu(NOa)4.
Inhaled 239PuCh resulted in a high incidence of
lung cancer at doses ranging from 165 to 1300
rad. Over this dose range the tumor response
appeared to be independent of dose. This may
be due to the relatively small numbers of
animals in each dose group. At comparable
doses 239Pu(NOa) appeared to be more effec-
tive than 239PuO2, while the response to
238Pu(NOs)4 was similar to that observed for
23«PuO2.
Inhaled 241Am Oxide and Nitrate [48]. Sprague-
Dawley rats were given single exposures to
aerosols of 241Am oxide and 241Am nitrate
(Table A.II-8). Americium-241 oxide is relatively
soluble and is translocated from the lung
more rapidly than PuO2. Although information
about the distribution of these materials in
TABLE A.II-6
Lung Tumors in Rats After Inhalation of 239Pu(NO3)4 and Treatment with Ca-DTPA [47]
Dose Range
(rad)
36-100
101-300
301-500
501-1000
1001-2000
Ca-DTPA
Control
Number of
Rats
5 (1)a
13 (3)
16 (7)
8 (5)
1 (3)
70 (30)
99
Mean Number
Days at Risk
603 (888)
555 (546)
657 (608)
714 (699)
975 (641)
604 (591)
677
Rats with Lung Tumors
Number %b
1
5
5
6
1
1
0
(1)
(1)
(3)
(2)
(2)
(0)
33
38
35
62
75
1
0
^Numbers in parentheses are for rats sham treated with Ca-DTPA.
^Percentages calculated for combined Ca-DTPA and sham-treated rats.
A.42
-------
TABLE A.11-7
Lung Tumors in Rats after Inhalation of 239PuOJ( "«PuO(NO3)4 and 238Pu(NO3>4 [48]
Pu Deposited
in Lung
Treatment ( ju Ci)
239PuO2 0.045
0.050
0.080
0.095
0.135
0.170
0.350
239Pu(NO3>4 0.240
238Pu(NO3)4 0.315
Lung Dose
(rad)
165
200
265
340
550
650
1300
560
780
Mean
Survival
Time
(days)
735
720
700
650
550
525
375.
550
450
Number of
Rats
14
9
8
18
10
16
33
18
8
Lung Tumor Incidence
No. of Rats
with Tumor
7
3
5
13
6
9
22
16
4
%
50
33
62
72
60
56
66
89
50
TABLE A.II-8
Lung Tumors in Rats after Inhalation of 241Am Oxide and Nitrate [48]
24'Am
Compound
Oxide
Nitrate
J41Am
Deposited
in Lung
(A
-------
Inhaled 238Pu [49]. Female Sprague-Dawley
rats were given a single exposure to a 238Pu
aerosol generated from a physiological saline
suspension solution of 238Pu prepared from
the water supernatant of aged 238Pu crushed
microspheres further ground with mortar and
pestle. Electron micrographs showed the
presence of amorphous-like material rather
than the highly dense, sharply defined parti-
cles present in suspensions and aerosols of
PuO2. Autoradiograms showed few aggregates
in lung samples collected one day after expo-
sure. The alpha tracks were randomly distri-
buted throughout the lung. After a year the
small amount of 238Pu remaining was asso-
ciated with hemosiderin-like pigment granules
in peribronchiolar and perivascular regions
of the lungs. The incidences of pulmonary
neoplasia observed in these rats are shown in
Table A.I 1-9.
An increased incidence of neoplasia, mostly
bronchiolo-alveolar carcinomas, was observed
at 9 rad. However, the 6.6% incidence at 9 rad
was not significantly different from the 1.1%
incidence in the control group. At a dose of
32 rad, the tumor incidence was 20%, which
was significantly different from the controls
at the 99.9% confidence level. The author
attributed the high tumor incidence at these
low doses to the diffuse distribution of the
238Pu in the lungs, compared with PuOz. The
results from this experiment are fairly com-
patible with the results obtained by Ballou
with 239Pu(NOa)4 [47] and Lafuma with
238Pu(NO3)4 [48].
PuOz in Lung After Intraperitoneal Injec-
tion [50]. In a study of PuCh given to female
Sprague-Dawley rats by intraperitoneal injec-
tion it was found that some of the Pu particles
were transported to the lungs and deposited
in capillaries of the alveolar septae randomly
throughout the lungs. Autoradiography indi-
cated the median diameter of these particles
to be 0.3 (im. In addition to plutonium, one
group of animals was given benzo(a)pyrene
and another group asbestos. However, the
presence of these substances in the lungs was
not confirmed.
There was little evidence of pulmonary path-
ology in these rats, even though the dose to the
lungs of one group was estimated to be as high
as 600 rad (Table A.I 1-10). Pulmonary neo-
plasia was observed in only one rat. A
bronchiolo-alveolar carcinoma was found in
one rat 823 days after intraperitoneal injection
'of 72 nCi PuO2. Since pulmonary neoplasia is
occasionally seen in the control rats, <1%,
the finding of one neoplasia cannot unequiv-
ocably be attributed to 239Pu.
The author concluded that the lack of a signifi-
cant neoplastic response in this experiment
was due to the immobilization of the PuOa
particles in the lung capillaries and consequent
irradiation of a limited number of epithelial
cells in the lungs, fewer than would be the
case with inhaled plutonium.
Initial Alveolar
Deposition
(nCi)
Control
5
18
207
TABLE A.II-9
Lung Tumors in Rats after Inhalation of ^Pu [49]
Lung Dose
(rad)
0
9
32
375
Number of Rats
92
30
30
32
Tumor Incidence
No. of Rats
1
2
6
8
1.1
6.6
20
25
A.44
-------
TABLE A.II-10.
Effects of Plutonium Deposited in Lung After Intraperitoneal Injection of Pud: in Rats [50]
"'PuCh
Controls
2.9
0.36
0.072
0.36 + benzo(a)pyrene
0.072 + asbestos
Number of
Rats
Survival
Time (days)
»«Pu in
Lung (% of
Injected Dose)
108
35
38
36
18
24
200-300
200-500
200-500
200-500
200-500
—
0.39 ± 0.22
0.21 ± 0.13
0.33 ± 0.29
1.5 ±0.94
0.1310.11
Lung Dose
(rad)
600
40
10
170
20
No. of
Tumors
0
0
0
1
0
0
intratracheal Injection of 253EsCl [51]. Ein-
steinium is an alpha-emitting (6.6 MeV) radio-
nuclide with a half-life of 20.5 days. Thus, it is
capable of delivering a dose of alpha radiation
over a relatively short period of time com-
pared with the other transuranics and with
™Po, which has a half-life of 138 days.
Einsteinium-253 chloride in 0.01 N HCI (0.5 mC)
was given by intratracheal injection to male
Wistar rats for long-term observation of bio-
logical effects. Because of the small mass of
einsteinium present (the specific activity of
253Es is ~4 x 10-11 g/ju Ci), and especially the
method of administration, the distribution of
the einsteinium within the lung was probably
limited. The results are shown in Table A.II-11.
The incidence of pulmonary neoplasia was 4%
in rats with a lung dose of 38 rad and 12.5%
in rats receiving 1900 rad. It is highly probable
that the peak tumor response is somewhere
between these two doses. However, these
results are more comparable to those observed
with intratracheally administered 239Pu(NCb)4
(Table A.II-5) than to those observed in experi-
ments where the radionuclide was given by
inhalation.
TABLE A.II-11.
Lung Tumors in Rats After Intratracheal Instillation of 253EsCI [51]
«3EsCI Deposited
in Lung QuCi)
Control (0.01 N HCI)
0.05
2.5
12
38
1900
9800
Mean
Survival
Time
(days)
724
707
475
181
Number
of Rats
43
48
48
29
Lung Tumor Incidence
Number of
Rats with
Tumors %
0
2
6
0
0
4
12.5
0
A.45
-------
Inhaled 2"PuO2 in Dogs [52]. Beagle dogs
were given a single exposure to aerosols of
239PuO2. Thirty-five were held for lifetime
observation and 5 were sacrificed at times
after 800 days for determination of the tissue
distribution of the inhaled 239Pu. Data for the
35 dogs are given in Table A.II-12. Of these
dogs, 27 developed primary pulmonary neo-
plasia, 6 died of pulmonary fibrosis with no
evidence of neoplasia, one died of cardio-
vascular disease and another of encephalitis.
The latter two deaths did not appear to be re-
lated to the plutonium exposure. All dogs with
pulmonary neoplasia also showed extensive
pulmonary fibrosis at time of death. All dogs
with pulmonary neoplasia had bronchiolo-
alveolar carcinomas (histopathology is not com-
plete on 3 dogs). Some dogs had more than one
tumor but it is not known whether they were all
primary tumors or metastasis from a single pri-
mary tumor. Several dogs had additional neo-
plasms, as shown in Table A.II-12 [53]. Radio-
graphs showed that the tumors originated in the
lung periphery. Autoradiographs of lung sec-
tions taken from these and other dogs showed
PuCh had accumulated in subpleural regions of
the lungs in apparent association with the sub-
pleural lymphatics and, to a lesser extent, in
peribronchiolar and periovascular regions. The
location of the PuCh in the lungs appeared to
coincide with the peripheral origin of the
tumors. Although autoradiographs seldom
showed high concentrations of 239Pu within the
tumor mass, it was generally observed that rela-
tively large accumulations of ^Pu occurred in
fibrotic regions near the tumors.
Because this experiment involved relatively
high doses of plutonium, a large fraction of
the lung tissue was exposed to alpha irradi-
ation. This distribution of radiation dose was
enhanced by mobilization of the plutonium
in the lungs by macrophages, by transport
in the lymphatics, and by slow solubilization.
However, mobilization also caused plutonium
to accumulate in the subpleural and peri-
bronchiolar regions, with the result that these
regions of the lung received relatively high
doses. The results demonstrate the peripheral
origin of 239PuCh-induced neoplasia in the
lungs of dogs.
and Asbestos [54]. Female Sprague-
Dawley rats were given a single intratracheal
injection of 0.9 mg chrysotile asbestos, 29 nCi
239PuCh or 0.9 mg asbestos and 51 nCi 239PuO2
in saline. Asbestos tended to sequester the
PuCh in the peribronchiolar regions of the
lungs and signficantly reduced the rate of
PuO2 clearance from the lungs. The asbestos
tended to increase inflammation and scar-
ring of the lung tissue. Thus, the PuCh in the
presence of asbestos was located in areas of
greater scar formation than was the PuCh in
the lungs of rats which received no asbestos.
The mean cumulative radiation doses were
425 rad to the lungs of rats given PuCh and 1200
rad to the lungs of rats given PuCh plus asbestos.
The rates of mortality were similar in the two
groups. Table A.II-13 shows that there was no
difference in the incidences of pulmonary neo-
plasia in the PuCh and PuCh plus asbestos rats,
even though the radiation dose was three times
greater in the latter group.
The results of this experiment demonstrate that
the effectiveness of 239PuCh is not enhanced by
aggregation in scar tissue in lungs; rather, they
suggest a greater effectiveness when the239PuCh
is more widely distributed.
210Po Given by Intratracheal Injection to
Hamsters [55,56]. Syrian golden hamsters were
given intratracheal administrations of 210Po in
saline alone or with hematite. In this experi-
ment the hematite tended to cause aggregation
of the 210Po, while 210Po administered in saline
was more uniformly distributed throughout the
lung. It is probable that intratracheal administra-
tion of the 210Po resulted in less uniform distribu-
tion than would have occurred had the 210Po
been given by inhalation. The results of these
series of experiments are given in Table A.II-14
and Figure A.II-19. Included in Figure A.II-19are
data from an earlier experiment in which rats
were exposed to aerosols of 210Po in saline [57],
Neoplasia was not observed in the control ham-
sters or those given hematite alone. In rats given
210Po alone or with hematite the incidence of
pulmonary neoplasia ranged from 8 to 9%. At
low doses there does not appear to be any differ-
ence in the effectiveness of 210Po for inducing
neoplasia, whether it is given alone or with
A.46
-------
TABLE A.II-12.
Dog Mortality and Distribution of Inhaled 239PuO2 [53]
Dog
Number
1 182F
2 184F
3 272M
4 215F
5 83F
6 268F
7 173F
8 106F
9 183F
10 180F
11 76F
12 246M
13 259M
14 255F
15 213F
16 216F
17 85F
18258M
19 86F
20 281
Zl 81F
22 249M
23 283
24 212F
25 266F
26 273M
27 278M
28 254
29 IF
30 109F
31 252M
32 93F
33 277
34 264
35 267
Survival
(days)
855
933
988
1151
1184
1202
1339
1357
1379
1446
1549
1623
1629
1635
1720
1823
2015
2048
2050
2211
2229
2341
2356
2367
2412
2565
2792
2809
3079
3313
3441
4068
3664
3537
3676
Lesion
F
F
F
FT
FT
E
FT
FT
F
F
F
FT
FT
FT
FT
FT
FT
FT
C
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
FT
Alveolar
Deposit
frCI)
3.3
3.0
3.6
1.8
2.2
1.4
2.6
3.3
1.1
1.7
1.8
2.3
1.2
1.2
1.5
0.6
1.4
1.8
0.4
2.2
1.2
1.2
0.9
1.0
0.8
1.8
1.0
0.8
0.7
0.6
0.58
0.15
0.19
—
0.86
Final
Body
Burden
(HO)
2.7
2.5
2.9
1.4
1.8
1.1
2.1
2.7
0.9
1.4
1.4
1.8
1.0
1.0
1.2
0.5
1.1
1.4
0.3
1.7
0.9
1.0
0.8
0.8
0.7
1.5
0.8
0.6
0.6
0.4
0.46
0.12
0.15
—
0.67
Lungs
74
75
63
50
59
46
46
50
52
42
47
55
55
42
49
51
36
35
37
30
23
21
26
53
14
7
14
21
9
13
24
26
15
—
11
r«
Thoracic
Lymph
Nodes
21
17
17
42
28
25
48
37
38
49
45
24
23
24
27
26
30
37
49
44
54
32
29
39
41
56
41
45
56
56
36
57
24
—
18
TCcm ui m
Liver
2
5
14
2
6
20
2
6
6
5
3
16
15
26
15
15
21
19
6
15
19
32
23
3
32
21
23
21
21
16
22
8
31
—
61
wu v««7 mvn
Skeleton
1
1
4
4
2
3
2
2
3
3
4
3
6
3
5
7
6
4
5
5
4
6
12
2
7
5
10
5
7
6
9
6
9
—
6
acn
Abdom.
Lymph
Nodes
_
—
2.0
—
0.9
—
—
—
—
—
—
—
—
3.7
—
0.7
5.8
4
—
4
—
8
7
—
3
9
10
6
6
7
6
0.1
17.0
—
1.6
Spleen
_
—
—
0.5
0.1
—
—
—
—
—
—
—
—
1.0
—
0.3
0.7
0.4
—
0.2
—
0.7
1.2
—
1.2
0.6
1.4
0.7
1.0
0.6
0.7
0.1
2.6
—
1.7
Lung Tumors
B-A
B-A
B-A
B-A
B-A, "Bronchial care i^ia.
hemangiosaro. r>.
B-A
B-A, capillary hema •?,.•• .2,
mesothelioma
B-A
B-A
B-A
B-A; Squamous Cell
B-A, Epidermoid
B-A (oat cell) mesothelioma 1)
B-A (2)
B-A, Mesothelioma (2)
B-A
B-A, Epidermoid (3)
B-A
B-A, Epidermoid, Squamous c- ,i i '
B-A
B-A (3)
B-A
B-A, Epidermoid, Oat Cell,
Squamous Cell
B-A (3)
?
?
?
Lung Dose
(rad)»
4400
4600
4300
2700
3600
2000
6200
6700
70,.')
•i .(V|
• '. j
f!
"-;'-C
•.*• •
W
;oo
14Ci'
5>0:i
'70
4 :rri
2JOO
2201)
2«x;
1501:
-,7(X
.'7011
"90C
..DOU
1700
160'
voo
956
907
—
2300
T - Pulmonary Tumor; F - Pulmonary Fibrosis and Metaplasia; C- Cardiovascular; E- Encephalitis; B-A - Bronchiole-Alveolar Carcinoma
Other Tumors: (1) Lymphagiosarcoma in thoracic lymph nodes (2) Hemangiosarcoma in thoracic lymph node (3) Mammary gland adenocarcinoma
•Cumulative dose based on normal lung weight = 1.1% body weight. Retention half time for Pu in lung calculated for each dog based on final whole body burden =
deposition x r>OJ.
-------
TABLE A.II-13.
Neoplastic Response of Lung to Intratracheally Instilled Asbestos, 239PuO2 or Asbestos Plus ""PuOj [54]
Incidence of Pulmonary Tumors. %
Group
Saline
Asbestos
2MPuO2
"'PuO2 Plus Asbestos
Number
of Animals
26
22
22
27
Adenocarcinoma
0
4
21
21
Squamous
Carcinoma
0
0
11
0
Sarcoma
0
4
0
4
Total
0
9
32
25
TABLE A.II-14.
Lung Tumors in Hamsters After Intratracheal Instillation of 210Po [55,56]
Group
Control (no instillation)
Control - hematite (3 mg)a
21°Po (0.2 //Ci) in saline +
hematite (3 mg)a
210Po (0.2 i*C\) in saline +
hematite (3 mg)*5
210Po (0.01 juCi) in saline +
hematite (3 mg)a
Benzo(a)pyrene (3 mg) +
hematite (3 mg)a
Benzo(a)pyrene (0.3 mg) +
hematite (3 mg)a
21°Po (0.005 juCi) + hematite
(3 mg)a
21°Po (0.00125 //Ci) +
hematite (3 mg)a
^opo (0.00025 juGi) + hematite
(3 mg)a
™Po (0.1 juCi)b
21°Po (0.00125 juCi)a
5000
2000
300
300
75
15
1500
55
a15 weekly instillations
t*7 weekly instillations
hematite. Compared with the earlier work of
Yuile, inhaled 210Po in rats was less effective
than the intratracheally-injected 210Po in ham-
sters (Figure A.II-19). This is in contrast to the
results with 239Pu(NO3)4 in rats, where intra-
tracheal injection appeared to be much less
effective than inhalation of 239Pu(NO3)4.
Plutonium Microspheres Given Hamsters by
Intravenous Injection [58,59]. To determine
Number of
Rats
Autopsied
60
34
35
37
32
39
37
32
82
83
38
101
Number of
Rats with
Tumor
0
0
34
25
17
24
3
17
10
9
22
9
Tumor
Incidence
0
0
97
68
53
62
53
12
11
58
9
Ref.
55
55
55
55
55
55
55
56
56
56
56
56
whether the lung is susceptible to tumor induc-
tion by isolated alpha-emitting particles, 10 jum
ceramic microspheres were administered by
intravenous injection to Syrian golden ham-
sters. Various quantities of ^'Pu or 238Pu micro-
spheres of varying specific activity (Table
A.II-15) were administered to over 2300 ham-
sters. In addition, about 700 control hamsters
were given either none; 2,000; 4,000; 10,000;
100,000; or 500,000 nonradioactive microspheres.
A.48
-------
in umi
o mn IN SAUNE iHAMsnii-iii • unii
A Po IN SALINE IRAT-INHAUD) - YUIU
IB 400 to m TO BHWB I"* »»
CAICULAHO CUMULATIVE MEAN DOSE TO LIWCIKADI
FIGURE A.II-19
Lung Cancer after Inhalation or Intratracheal
Instillation of 210Po
Results of this experiment are available from
all but two groups of hamsters. Only four
deaths from neoplastic disease have occurred.
One animal that received 2000 microspheres
(0.84 nCi) developed a hemangiosarcoma in
the left lung and another developed a well
circumscribed adenoma in the left lung. Two
mucinous adenocarcinomas occurred in ham-
sters that received 6000 microspheres (354 nCi).
This experiment indicates that the hamster
lung is not very susceptible to tumor induction
by isolated plutonium particles deposited in
the capillaries. The results confirm an earlier,
smaller experiment with rats given plutonium
microspheres by the same technique in which
no neoplasia was observed. The results also
agree with the experiment of Sanders in which
239PuO2 particles deposited in lungs of rats
following intraperitoneal injection failed to
cause pulmonary neoplasia.*
*On July 29, 1976 additional information was received on this study from Dr. Ernest C. Anderson at Los Alamos
Scientific Laboratory.
Summary of Lung Tumor Incidence (LASL Data on Syrian Hamsters)
Specific
Activity
(pCi/sphere)
Number
of
Spheres
Lung
Burden
OiCi)
Approximate
Dow'
Tumors
Animals
Incidence
(% ± S.D.)
BA1>
Animals
Incidence
(% i S.D.)
"DIFFUSE" EXPOSURES (greater than 25% of lung mass exposed)
Intratracheal sol., "°Po
N.A.C N.A.
Intravenous spheres, iJBPu
2 70,000
Intravenous spheres, "'Pm
450 50,000
Intravenous spheres, iMPu
60 6,000
60 2,000
13 2,000
4 6,000
0.12°
0.14
1-2 krad total
13 krad/yr
14/47
17/163
30 ±8
10 ±3
22.0 28 krad/yr 12/54 2216
LOCALIZED EXPOSURES (less than 3% of lung mass exposed)
0.36
0.12
0.03
0.02
30 krad/yr 2/148 1 ± 1
10 krad/yr 0/72 0 ± 1
2 krad/yr 0/70 0 + 1
2 krad/yr 0/154 0 ± 0.5
CONTROLS
3/220 1.4 + 0.8
12/47
85/1636
16/54
3/148
0/72
0/70
9/154
1/220
^Maintained by weekly instillations for 7 weeks.
24 ±7
32 ±5
30±7
2±1
0+1
0+1
6 + 2
0.5 + 0.5
aTotal energy/total lung mass. , , .
"Bronchiolar adenomatoid lesion; regardless of whether graded eLow grade BAL 1 to 2+.
1+, 2+, 3+.
CN. A. = not applicable.
•In this table the tumor incidence observed in hamsters in which the lungs received relatively diffuse alpha irradiation
exposures is compared with the tumor incidence in hamsters given iMPu microspheres which irradiated less than 3% of the
lung mass. A 10-30% tumor incidence is observed in the hamsters which received relatively diffuse radiation exposure,
compared with only 1% in the group of hamsters that received JMPu microspheres. No tumors were found in three other
groups. This is taken by the Los Alamos staff as conclusive evidence that highly localized alpha irradiation of the lungs
is less effective in causing lung tumors than more diffuse alpha irradiation. The same conclusions can be drawn from
the incidences of bronchiolar adenomatoid lesions. It should be noted that the 2J*Pu microspheres in all four groups
qualify as "hot particles" according to Tamplin and Cochran's definitions, in that all were above 0.07 and 0.6 pCi/particle.
A.49
-------
TABLE A.II-15
Exposures of Hamsters to Intravenous Plutonium Microspheres [58]
Date of
Exposure
1971 May
May
May
June
June
June
June
Aug
Aug
Nov
Dec
1972 Feb
July
July
Dec
1973 April
April
April
May
June
June
July
July
Oct
Oct
Nov
Nov
1974 Jan
Jan
Jan
May
May
Number of
Animals
69
71
74
71
71
71
72
71
47
154
148
142
20
34
30
109
107
102
104
37
109
97
44
26
15
53
52
52
51
60
76
71
Spheres per
Animal
2,000
2,000
2,000
2,000
2,000
2,000
2,000
2,000
10,000
6,000
6,000
6,000
1,600,000
300,000
6,000
60,000
60,000
80,000
80,000
400,000
150,000
500,000
50,000
900,000
500,000
40,000
20,000
20,000
40,000
60,000
60,000
30,000
Specific
Activity
(pCi per sphere)
0.07
0.22
0.91
0.42
4.30b
13,30b
59.00b
2.10b
0.22
4.30b
59.00b
0.22
0.07
0.42
8.90b
0.91
8.90b
2.10b
0.22
0.42
0-.06
0.03
0.91
0.016
0.016
0.06
0.06
0.19
0.19
1.60
2.10b
0.19
1.30
112.00
126.00
53.00
55.00
710.00
168.00
18.00
170.00
9.00
15.00
45.00
14.00
8.00
2.40
1.20
3.80
7.60
96.00
126.00
11.00
Mean
Survival Time
(days of age»)
Other
Insults
630
795
765
670
635
620
650
720
830
720
615
695
715
655
(350)
490
395
515
680
505
455
470
440C
480
395
385
450
390
385
455
d
d
Cytoxin
Clf2C\4
Zymosan
Zymosan
fAnimals exposed at age 100 days.
bPlutonium-238; all others contain "»Pu.
^Weanlings exposed at age 30 days.
"No data yet available.
Inhaled ™PuCh, "'PuCfe, and "CmOz in
Rats [60]. The carcinogenic response to in-
haled ^PuOz, 239PuOa, and 244CmO2 was com-
pared in about 830 female PSF Wistar rats. The
experiment included 188 controls. The rats were
given a single exposure to the aerosol and
observed for the duration of their life span
(Table A.II-16).
The AMAD ranged from 1.2 to 2.6 urn for
23«PuO2, 1.7 to 3.4 /nm for 239PuO2, and 0.7
to 1.3 /^m for 244CmO2. Autoradiographs showed
that at doses above 10 nCi, ^PuOa and
239PuO2 were concentrated in subpleural and
peribronchiolar regions of the lungs within
several months after exposure. However,
single alpha tracks in the 244CmO2 animals
suggested a much more diffuse distribution
at all dose levels except for occasional aggre-
gates in macrophages and hemosiderin.
Particles were still present in 238PuO2 and
239PuO2 rats two years after exposure and were
concentrated in subpleural regions of the
lung and less frequently in peribronchiolar
regions. More than half the pulmonary neo-
plasias observed were bronchiole-alveolar
adenocarcinomas. About a third were squa-
mous cell carcinomas, occurring mostly in
plutonium rats at the higher doses. Six heman-
giosarcomas were seen in 239Pu rats.
A.50
-------
TABLE A.II-16
Pulmonary Neoplasia in Rats After Inhalation of 238PuO2,239PuO2 or 244CmO2[60]
1MPuO2*
"'PuOz
Lung Dose
(rad)a
No. of
Rats
Tumor
Incidence
Lung Dose
(rad) a
No. of
Rats
Tumor
Incidence
(%)
Lung Dose
(rad)a
No. of
Rats
Tumor
Incidence
(%)
0
<10
26 ±11
56+11
153 ±81
1720 + 990
8340 + 3240
^10,000
50
118
50
33
34
27
6
26
0
2.5
2.0
9.1
5.9
48.1b
100.0 b
19.2b
0
<10
27 ±12
78 + 17
255 ±132
680 ±120
2100 ±1210
MO 000
48
134
51
26
38
16
18
15
0
1.5
7.8
34.6
44.7b
31.3
66.70
46.7 b
0
0.4
6.0
32.0
710.0
1600.0
20
57
61
54
43
24
a Cumulative dose to 620 days postexposure: mean and standard deviation
bSignificantly greater from controls at P <0.05 level
*Data shown here were updated by Dr. Sanders from that appearing in the reference cited.
0
1.8
3.3
11.1
32.6
0
Pulmonary neoplasia was observed in groups
of rats which received lung doses somewhat
less than 10 rad. However, statistically signifi-
cant increases of tumor incidence occurred
only at higher doses. Of particular interest
in this experiment is the apparently greater
carcinogenic effectiveness of 239PuO2 than
238PuCh at comparable doses. Since both
plutonium isotopes were present as particles
in the lungs, the difference in their effective-
ness may be due to a difference in distribution
of the absorbed energy. Because the specific
activity of 238Pu is 280 times greater than that
of 239Pu, if the particles of both are equivalent
in size, one might expect equivalent radio-
active quantitities of 238Pu to be distributed
among 280 fewer particles than for 239Pu.
Thus, all other factors being equal, a specific
amount of 239Pu might be expected to irradiate
more cells than an equivalent amount of
238Pu. The same explanation might also apply
to the 244Cm; however, the results are still
incomplete.
The results of this experiment with 238PuOz
contrast markedly with Sanders' previous
experiment with "nonparticulate" 238Pu, in
which a statistically significant increase in
lung cancer incidence (20%) occurred at 32
rad (Table A.II-9).
Other Studies
A number of animal studies which bear on
the hot particle issue are in progress at several
laboratories. While these studies are not suffi-
ciently complete to draw conclusions of a
quantitative nature, some of the preliminary
data should be mentioned.
Ballou et al. [61] are studying the late effects
of inhaled 238Pu(NO3>4, 239Pu(NO3)4, and
253Es(NO3)3 in about 1,000 male Wistar rats.
Preliminary results indicate that the number
of lung tumors in these rats which inhaled
relatively soluble transuranic compounds
greatly exceeds the number of skeletal tumors.
Also, 253Es, which has a very short half-life
of 20.5 days, appears to be less effective in
causing cancer than the much longer half-
life 238Pu and 239Pu. This suggests a possible
dose rate effect. Ballou [62] is also conducting
A.51
-------
a similar experiment with 241Am(NO3)3. Com-
parison of the results of these experiments
with relatively soluble transuranics with the
results from the experiments with insoluble
transuranics will provide information relevant
to the hot particle issue.
Two current studies of inhaled transuranic
compounds in Syrian hamsters at Battelle,
Pacific Northwest Laboratories [63] and at
the Lovelace Foundation Inhalation Toxicology
Research Institute [64] are of special interest
to the general problem of the toxicity of in-
haled radionuclides. Sanders [63] at Battelle
has seen only three malignant lung tumors
in about 300 hamsters after inhalation of
238PuO2 or 239PuC»2. Mewhinney and Hobbs
[64] at Lovelace have not reported any malig-
nant lung tumors in experiments with about
2,500 hamsters which were exposed to Pu or
Am aerosols; however, it must be noted that
some of these experiments have not been in
progress very long. Nevertheless, the data
from both laboratories are adequate to suggest
that Syrian hamsters are much less suscep-
tible to the carcinogenic properties of inhaled
alpha-emitting transuranics than rats. These
negative results with hamsters are also in
contrast to the high incidences of lung tumors
in hamsters reported in the polonium intra-
tracheal injection experiments at Harvard
[55,56]. The reason for this difference is not
known, but it may be related to the mode of
administration of the radionuclide; i.e., a
single inhalation of the transuranics as opposed
to multiple intratracheal injections of polonium.
Conclusions
Experiments with animals have demonstrated
that alpha-emitting radionuclides deposited
in lungs have carcinogenic properties. Both
particulate as well as less paniculate radiation
sources have been found to cause pulmonary
neoplasia in rodents and dogs. None of these
experiments have indicated that the trans-
uranic alpha-emitting radionuclides are far
more effective in causing lung cancer when
the radiation dose to lung tissue is delivered
by particulate, as compared to less particulate,
sources.
Recently, attempts have been made to describe
mathematically the relevant experimental
animal data [65,66]. Because the data exhibit
a wide range even within an experiment, it
is not possible to argue for any particular
dose-response relationship. However, a linear
model was used in an analysis of the rat data
[67]. Only data from groups of animals for
which there was not an appreciable shorten-
ing of lifespan were used in the analysis; thus,
only data for doses less than about 800 rad
were included. The results are summarized in
Figure A.11-20, a and b, which shows the
relationship between the incidence of lung
cancer and radiation dose for inhaled soluble
transuranics and inhaled insoluble plutonium
dioxide, respectively. If the slope estimates
are taken as the best available, then the risk
of lung cancer for rats that inhaled soluble
transuranics was about 8 x 10~4 cases per
rad, while for rats that inhaled relatively in-
soluble PuO2 the risk was about 16 x 10'4.
Therefore, the risk to rats from insoluble
plutonium was about double that from soluble
alpha-emitters. Although the difference
is statistically significant, the authors cau-
tioned that "because of the biological problems
characteristic of these kinds of experiments,
the quality of the data and evidence of non-
linearity, the statistical power of such a test
is questionable."
An analysis of experimental animal data for
induction of lung cancer by external irradi-
ation and by internally deposited alpha and
beta-gamma-emitters has been recently com-
pleted [66]. Lung cancer effectiveness factors
were calculated for each type of radiation
exposure. Values of the ratio of effectiveness
of alpha irradiation compared with uniform
irradiation ranged from 0.35 to 110 with a
geometric mean of 4. For alpha-irradiation,
compared with beta irradiation, values ranged
from 0.06 to 25 with a geometric mean of
2.5. The wide range of values resulted from the
large variability of the data. While alpha
irradiation was generally more effective
than uniform irradiation and beta irradiation,
for all dose levels and all animal species the
mean differences were less than 10, the value
usually taken as the quality factor for alpha
irradiation.
A.52
-------
s
8
MO
90
n
TO
60
50
40
30
20
10
A(6)
•(30)
TUB
0(20)
A(13t
VBM)
>u CITRAH : KOSHHUBNIKOV*
fa AMMONIUM-Pu-PENTACARMNATt • KOSHNUDNIKOVA
S>u ' SANKRS
FIGURE A.ll-20a
Incidence of Lung Cancer in Rats
after Inhalation of Soluble Alpha-
Emitting Radionuclides [67]
(The number of animals in each
group is given in parentheses)
108 200 300400 500 600700 800
CALCULATED CUMULATIVE MEAN DOSE TO LUNGS, red
900 1000
FIGURE A.ll-20b
Incidence of Lung Cancer after
Inhalation of Insoluble Alpha-
Emitting Radionuclides [67].
(The number of animals in each
group is given in parentheses)
100 200 TOO 400 500 600 700 800
CALCULATED CUMULATIVE MEAN DOSE TO LUNGS, rad
900
A.53
-------
Analysis of Lung Tumor Mortality in the Battelle
Beagle Lifespan Experiment*
Forty beagles in the Battelle group between
12 and 43 months of age (mean age = 562 days)
were given "single, 10-30 minute inhalation
exposures to 239PuCh aerosols via a mask" [52].
Eighteen of the original 40 dogs died with lung
tumors as the primary cause of death. Seven-
teen died of other causes, primarily pulmonary
fibrosis, and in nine of these lung tumors
were in evidence even though they had not
developed to the point of causing death. Fi-
nally, five dogs were sacrificed for analysis
of tissue distribution of plutonium. Sacrificed
animals were asymptomatic for lung tumors
and none had lung tumors at autopsy. Details
of the experimental procedures and results
are given by Park et al. [52].
In order to use the Battelle beagle experiment
to test the Cochran and Tamplin Hot Particle
Hypothesis it is necessary to assess the lung
tumor mortality rate in these beagles in rela-
tion to the estimated number of hot particles
deposited in their lungs. It must first be noted
that the Cochran and Tamplin risk factor of
1/2000 per hot particle is a risk of death from
lung cancer. Thus, Cochran and Tamplin
used cancer death risks given in the BEIR
report [68] to calculate their estimate that
1/1000 is the lung cancer death risk which
would result from continuous lung exposure
at the current maximum permissible level for
workers. Since they went on to calculate that
such a risk would be generated by two hot
particles with a risk of 1/2000 each, it is clear
that the latter figure is a risk of death from
lung cancer, as opposed to a risk, for example,
that an individual will have an incipient lung
cancer developing.
For the purposes of the present analysis, the
risk of beagles in the Battelle study dying from
lung cancer will be assessed for a risk period
•Prepared for the Committee's use by
E. B. Lewis
extending from the time of the initial exposure
to the aerosol to 3600 days thereafter. At the
end of the risk period the animals would be
expected to have averaged 11.5 years of age,
since the average animal was 562 days of age
at the time of initial exposure. Although the
mean life span is not known accurately for
the normal unirradiated beagle in the Battelle
colony, 11.5 years is probably a reasonable
estimate.
Two methods will be used to derive the accu-
mulated risk of death from a lung cancer in
the Battelle group at 3600 days postinhalation.
The first method involves construction of a
survival table and analysis of the cumulative
proportion of survivors at 3600 days. The
results are shown in Table A. 11-17. Without
any assumptions about the nature of the
cancer induction process, the estimated cumu-
lative probability of dying from lung cancer,
Qx, at x days after inhalation of the aerosol
can be derived from the relationship:
where Px is the cumulative probability of
surviving x days after inhalation of the aerosol.
It is evident from Table A.II-17 that for the
animal that died of lung cancer at 3537 days
postinhalation, the probability of dying from
lung cancer was high enough, 0.82 (1-0.178),
to make it likely that the animal could have
had more than one primary lethal lung cancer.
A lethal lung cancer is defined as one that
has developed to the point at which it is
capable of causing the animal's death.
The probability of dying from lung cancer is
more strictly the probability of dying from at
least one lethal lung cancer. Since cancers
are expected to arise as rare independent
events it is appropriate to use the Poisson
distribution to estimate the frequency of multi-
ple primary cancers. It should be noted that
the actual number of primary cancers cannot
be directly observed since multiple cancer
foci may result either from metastases of a
single primary cancer or from multiple primary
cancers.
A.54
-------
TABLE A.II-17
Survival Table for the Battelle Group of Beagles
(1)
(2)
(3)
(4)
(5)
mx(a)
dx Px Calculated mean number
Time in days
after inhalation
of 239PuO2
1629
1635
1823
2211
2229
2341
2356
2412
2565
2792
2809
3079
3313
3441
3537
3664
3676
4068
"x
No. of dogs alive at
the start of the day, x
24
23
20
16
15
14
13
11
10
9
8
7
6
5
4
3
2
1
No. of dogs dying
of lung cancer
during the day, x
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Cumulative
probability of survival
at the end of day, x
0.958
0.917
0.871
0.816
0.762
0.708
0.653
0.594
0.534
0.475
0.416
0.356
0.297
0.238
0.178
0.119
0.059
0.000
of lethal lung cancers
per dog alive at end of
day, x
0.043
0.087
0.138
0.203
0.272
0.346
0.426
0.521
0.627
0.744
0.878
1.032
1.214
1.438
1.725
2.131
2.824
—
(a)mx=(-)loge(Px)
A.55
-------
The probability of surviving to x days without
a lung cancer is given by the first .term of the
Poisson distribution, e~m or [exp (-m)], where
m is the mean number of lethal lung cancers
that the average animal in the population
would possess at x days. It follows that the
cumulative probability of dying from at least
one lung cancer at x days is
Qx = 1 - [exp (-mx)] (2)
Combining Equations 1 and 2 gives
mx=(-)loge(Px)
(3)
Values of m calculated in this way are shown
in column 5 of Table A.II-17. For the animal
that died at 3537 days postinhalation the
value of m is 1.7. The next death occurred
at 3664 days, for which time the corresponding
value of m is 2.1 cancers. At 3600 days,
therefore, the average number of lethal
cancers per animal would have been approxi-
mately two.
For the purpose of making comparative risk
evaluations, it becomes essential to determine
also the rate at which the beagles died of
lung cancers as a function of the duration of
risk; that is, the elapsed time, t, since the initial
day of exposure to the radioactive aerosol.
For this purpose a life table method of analysis
was chosen, since this method has considerable
power to dissect the time course of tumor
development even when, as in the present
case, there are relatively small numbers of
animals at risk [69]. The probability of a
beagle in the Battelle group dying from lung
cancer, qx, in a given interval (arbitrarily,
100 days in length) is found to be adequately
expressed in terms of a simple power function
of t, namely:
q =a(t)b
(4)
where a and b are constants. Actually the
analysis has been carried out using the more
precise relationship,
qx=1-exp[-a(t)b]
(5)
where the quantity, a (t)b, is equivalent to mx
of Equation 2 and can be thought of as a rate,
Rm, at which lethal lung cancers develop in
a given interval. For a sufficiently small inter-
val, qx will in fact be equivalent to Rm for all
practical purposes, and in the present case
it turns out that a choice of an interval of 100
days in length satisfies this condition. By
analogy with Equation 2, Equation 5 allows for
the contingency that no matter how small the
interval in the life table there is a finite chance
that more than one lethal lung cancer will
develop in that interval.
Briefly, the method of fitting the constants
involved use of a computer to generate a life
table for each pair of values of a and b to be
tested and then to test goodness of fit between
observed and expected numbers of lung cancer
deaths by the Chi-squared criterion, first group-
ing such numbers into six successive 800-day
intervals. In this way the values of a and b
that result in a minimum value of Chi-squared
are found to be 9.0 x 10~15 and 3.2, respectively,
for t expressed in days. The life table based
on these values is shown in Table A.II-18 and
the resultant Chi-squared value is 3.8, which
for three degrees of freedom is not statistically
significant (P = 0.3). Even when a finer group-
ing into 400-day intervals is used, in none of
the 12 intervals does the difference between
observed and expected numbers of deaths give
cause for concern. If Equation 4 is used instead
of Equation 5, identical results, including
identical values of a and b, are obtained. Sub-
stitution of these values of a and b in the right
hand side of Equation 4 and integration over
the limits of 0 to 3600 days gives 1.9 for the
mean number of lethal lung cancers per animal
at 3600 days after exposure to the aerosol,
which is in good agreement with the number
calculated from the survival table (Table A.II-
17); namely, two, as shown above.
An approximate upper limit for the mean
number of lethal lung cancers at 3600 days
postinhalation has been derived by first esti-
mating an upper limit for the constant b.
When b is as high as 4.5, Chi-squared is at a
A.56
-------
TABLE A. 11-18
Life-Table Analysis of Lung Tumor Mortality
in the Battelle Group of Beagle Dogs
(1)
X
Mid-point in
days of each
successive
100-day inter-
val beginning
on the day of
exposure to
»PuO,
50
150
250
350
450
550
650
750
850
950
1050
1150
1250
1350
1450
1550
1650
1750
1850
1950
2050
2150
2250
2350
2450
2550
2650
2750
2850
2950
3050
3150
3250
3350
3450
3550
(2)
',
No. of dogs
alive at the
start of
interval
40
40
40
40
40
40
40
40
40
36
34
34
32
31
27
26
25
21
20
19
19
16
16
14
11
10
9
9
8
7
7
6
6
6
5
4
(3)
w«
No. of dogs dead
due to cause
other than cancer
(No. of dogs with
lung cancer which
was not the
primary cause
of death )
0
0
0
0
0
0
0
0
1
2
0
2(2)
1
3(2)
1
1
M1)
1(1)
0
0
3(2)
0
0
1(1)
0
0
0
0
0
0
0
0
0
0
0
0
(4)
»»
No. of dogs
sacrificed
(5)
d,
No. of dogs
dead with
primary lung
cancer during
interval
(6)
[d,]
Expected no.
of dogs dead
with lung
cancer (*)
[dx]
Mi'xiiqxi
(7)
[l.l
Expected no.
(8)
P'x]
No. of dogs
of dogs alive at al risk of
the start of
interval (b)
dying of lung
cancer during
interval (c)
(9) (10)
[qj d,
Probability Observed no.
that dog will of dogs dead
die of al least with primary
one lung lung cancer
cancer during in 400 day
interval(d) interval
(11)
[d,J
Expected no.
of dogs dead
with lung
cancer in
400 day
interval
during interval
0
0
0
0
0
0
0
0
3
0
0
0
0
1
0
0
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
0
1
0
0
0
2
2
1
1
0
1
1
0
1
0
0
1
1
1
0.00+
0.00+
0.00+
0.00+
0.01
0.02
0.04
0.06
0.08
0.11
0.14
0.18
0.22
0.26
0.30
0.35
0.39
0.43
0.49
0.57
0.59
0.60
0.66
0.70
0.72
0.77
0.80
0.83
0.84
0.85
0.83
0.81
0.77
0.72
0.66
0.60
40
40.0-
40.0-
40.0-
40.0-
40.0-
40.0-
40.0-
39.9
35.8
33.7
33.5
31.4
30.1
25.9
24.6
23.2
20.8
19.4
18.9
18.3
14.8
14.2
13.5
12.3
11.1
10.3
9.5
8.7
7.8
7.0
6.2
5.3
4.6
3.9
3.2
40
40.0-
40.0-
40.0-
40.0-
40.0-
40.0-
40.0-
37.9
34.8
33.7
32.5
30.9
28.1
25.4
24.1
22.2
20.3
19.4
18.9
16.8
14.8
14.2
13.0
11.8
11.1
10.3
9.5
8.7
7.8
7.0
6.2
5.3
. 4.6
3.9
3.2
0.00+
0.00+
0.00+ u
0.00+
0.00+
0.00+
0.00+ U
0.00+
0.00
0.00
0.00 °
0.01
0.01
0.01
0.01 °
0.01
0.02
0.02
0.03
0.03
0.04
0.04
0.05 4
0.05
0.06
0.07
0.08 J
0.09
0.10
0.11
0.12 L
0.13
0.14
0.16
0.17 J
0.19
A /\.
U.V+
0.1
n c
U. J
1 1
1 . 1
1Q
.y
2.6
3.1
3.3
2.8
A.57
-------
TABLE A.II-18 (Continued)
(1)
X
Mid-point in
days of each
successive
100-day inter-
val beginning
on the day of
exposure to
wpuo,
3650
3750
3850
3950
4050
4150
4250
4350
(2)
U
No. of dogs
alive at the
start of
interval
3
1
1
1
1
0
0
0
(3)
*x
No. of dogs dead
due to cause
other than cancer.
(No. of dogs with
lung cancer w. >ch
was not the
primary cause
of death.)
0
0
0
0
0
0
0
0
(4)
4X
No. of dogs
sacrificed
0
0
0
0
0
0
0
0
(5)
d,
No. of dogs
dead with
primary lung
cancer during
interval
2
0
0
0
1
0
0
0
(&)
[d,i
Expected no.
of dogs dead
with lung
cancer la'
[dxl
•nviiqj
during interval
0.52
0.45
0.38
0.31
0.25
0.20
0.15
0.11
(7\
[Ix]
Expected no.
(«)
[I'xl
No. of dogs
of dogs alive at at risk of
the start of
interval (b)
2.6
2.1
1.6
1.2
0.9
0.7
0.5
0.3
dying of lung
cancer during
interval
2.6
2.1
1.6
1.2
0.9
0.7
0.5
0.3
(9)
hxl
Probability
that dog will
die of at least
one lung
cancer during
interval
-------
minimum when a = 3.2 x 10~19 but the corres-
ponding value of P has dropped to 0.1; owing
to the small numbers involved, such a pro-
cedure can only provide a rough estimate
of 4.5 as the upper 90% confidence limit for b.
When these latter values of a and b are sub-
stituted in Equation A, integration over the
limits of 0 to 3600 days gives a value of 2.1
tumors. In a similar way an upper limit for the
constant a, when b is 3.2, is found to be 1.3 x
10~14, which yields an estimate of 2.7 lethal
lung cancers at 3600 days. By analogous
methods a lower limit for the mean number
of lethal lung cancers per animal at that time
is 1.2.
If the age of the animal is substituted for t in
Equation 4 by adding the mean age of the
animals at the time of exposure to the aerosol
(namely, 562 days), then the best fitting power
of the age is found to be 4.0. The purpose of
introducing age, as opposed to duration of risk,
is solely to permit comparison of these results
with the behavior of other cancer rates. Thus,
the natural incidence rates of many types of
cancers [70], including lung cancers [71],
have been shown to vary also in accord with
a power of the age of 4.0 or more. Doll [72]
has also shown that radiation-induced leuke-
mia rates in spondylitic patients increased
steeply as age at time of irradiation increased
and in a manner paralleling the increase in
natural leukemia incidence rates with age.
It is concluded that, in the case of lung cancer
induced by alpha radiation, risk evaluation
probably should be based upon the relative
risk rather than the absolute risk method.
This will be discussed more fully below.
The significance of the beagle findings will
be assessed first in relation to the Hot Particle
Hypothesis and then in relation to the problem
of estimating radiation-induced lung cancer
risks in human population groups. It is instruc-
tive to use the beagle experience to derive an
upper limit for the lung cancer death risk per
hot particle and then to compare that risk
with the one Cochran and Tamplin derived
from skin tumor data in rats. The estimate
based on the beagle experience is an upper
limit, in the sense that it is based on the arbi-
trary assumption that the average of two lethal
lung cancers per animal at 3600 days post-
inhalation results entirely from a hot particle
effect. For the animals that died of lung cancer
before that time, the mean initial lung burden
was 1.07 juCi. As shown in Table A.II-19, the
average animal with such a burden is likely
to have had deposited in its deep lungs at
least 1.3 million Type 1 particles or at least
200,000 Type 2. (Type 1 and Type 2 refer to
particles defined by Cochran and Tamplin
as having specific activities of 0.07 pCi and
0.6 pCi, respectively.)
It follows that if the beagle experience is used
to derive an estimate of the accumulated lung
cancer death risk associated with any hot
particle effect, then the upper limit for such a
risk per Type 1 hot particle is roughly 1.5 per
million (2 lethal lung cancers/1,300,000
particles), or one per 100,000 (2/200,000) per
Type 2 particle. These hypothetical risks could
be one or more orders of magnitude lower,
if not zero, if the bulk of the lung cancer risk
experienced by the beagles resulted from the
generalized alpha irradiation from the total
a9Pu activity in their lungs. These risk estimates
based on the beagle experience are thus strik-
ingly lower than the risk of one per 2,000 per
hot particle of either Type 1 or Type 2 which
Cochran and Tamplin derived on the basis of
their analysis of data on skin tumors in rats.
It is especially instructive to assess the induced
lung cancer risks experienced by the Battelle
beagle group in relation to estimates of lung
cancer risks in human beings based upon the
experience of occupational groups exposed to
alpha radiation. At the outset it should be
noted that the BEIR Committee suggested the
use of two methods of assessing cancer death
risks, including those from lung cancer;
namely, an absolute risk and a relative risk
method. There were insufficient data to decide
between the two methods and the committee
therefore calculated risks by both methods.
The BEIR Committee suggested that if the
absolute risk method is adopted a risk constant
of one lung cancer death per million person-
years per rem should be used, this constant
A.59
-------
TABLE A.II-19
Estimated Number of Hot Particles Deposited in the Pulmonary Regions of the Battelle Group of 15 Beagles
That Died Between 0 and 3600 Days of Lung Cancer. [Calculated on the assumption of (1) a log normal
frequency distribution with respect to particle size before inhalation of the aerosol; and (2) a constant
deposition frequency in the pulmonary regions; that is, any particle is equally likely to reach the
pulmonary regions regardless of its size.]
Type of Aerosol
Number of Dogs Exposed That
Died of Lung Cancer
Mean Initial Lung Burden (ILB),juCi
Estimated Number of Type 1
Hot Particles (> 0.07 pCi)
Estimated Number of Type 2
Hot Particles (>0.6 pCi)
A
CMDb = 0.5,
ag c = 2.3
1.01
4.1 x 10s
1.4 x 105
B
CMD = 0.25 urn
a a = 2.1
10
1.10a
1.8x10*
2.1 x 10=
Weighted
Means
1.07
1.3 x 106
1.9 x 105
aFor one of the dogs exposed to aerosol "B" the initial lung burden has not been determined. Therefore,
the initial lung burdens and particle number estimates are based upon 10 instead of 11 dogs; the omitted
dog died with a lung cancer as cause of death 3537 days after exposure to the aerosol.
= Count Median Diameter
c O = Geometric Standard Deviation
NOTE: When allowance is made for" differential pulmonary deposition (see Figure A.II-2), the numbers
of Type 1 and Type 2 particles deposited in the deep lungs are likely to have been higher than those
shown in this table.
to take effect after a 15-year latent period
and to remain in effect for either (a) a 30-year
period or (b) indefinitely. An estimate can
then readily be derived for the accumulated
lung cancer risk a person might be expected
to acquire by age 70, for example, if he had
been continuously exposed over his working
life to the maximum permissible occupational
level as currently set (15 rem per year to the
lung). The accumulated dose over a 48-year
work span extending from age 18 to 65 inclu-
sive amounts to 720 rem (48 x 15) and the
duration over which the risk constant is
assumed to apply is either (a) 30 years or (b)
36 years (from age 34, after a 15-year latent
period, to the start of age 70). For present
purposes the more conservative assumption (b)
is desired. The resultant accumulated lung
cancer death risk is 0.026 (1 x 10'6 x 720 x 36).
(Strictly speaking, for chronic exposures at
a constant dose rate the effective dose is one-
half of the total accumulated dose, as shown
by Marinelli [73]; however, since the risk
constant used in the BEIR Report was derived
on the basis of the accumulated rather than
the effective dose, it is necessary to use the
A.60
-------
accumulated dose in applying that risk
constant.)
The BEIR Committee suggested that if the
relative risk method is used, a value of 0.29%
should be adopted for the incremental
relative risk per rem. For present purposes,
before the relative risk constant can be applied
it is necessary to estimate the accumulated
lung cancer death risk by age 70 for adult
males in the general population. That is,
such males constitute the population from
which the occupational groups under consid-
eration are expected to be largely drawn;
namely, groups that mine or process heavy
alpha-emitting elements. From age-specific
death rates that have been averaged over
the years 1962-1967 and tabulated by Burbank
[74], the accumulated lung cancer death risk
by age 70 can be estimated from the cumula-
tive proportion of survivors at that age and is
found to be 0.036. Such an estimate must be
used with caution since it is known that it is
markedly influenced by such factors as the
smoking habits which characterized different
age groups in the population at risk. With this
reservation in mind, the accumulated lung
cancer death risk at age 70 can be estimated
as 0.075 (0.036 x 720 x 0.0029) for the hypo-
thetical case of continuous occupational
exposure of the lungs at the maximum per-
missible level. It should be emphasized that
in applying the relative risk as well as the
absolute risk method the underlying assump-
tion is that of a linear dose-response relation-
ship over the range of exposures being consid-
ered. (Again it should be stressed that since
the BEIR Committee used the cumulative dose,
as opposed to the effective mean dose, to derive
the relative risk constant in the case of chronic
exposures, it obviously is necessary when
applying their estimate of that constant to
use the cumulative dose experienced by the
population under consideration.)
To recapitulate, 0.026 and 0.075 are estimates
based on absolute risk and relative risk meth-
ods, respectively, of the accumulated death
risk from lung cancer by age 70 for the case
of continuous occupational exposure of the
lungs at 15 rem per year. As already indicated,
the steepness with which lung cancer death
rates in the Battelle beagles rose as a function
of age strongly suggests that the relative risk
estimate is the appropriate one to use in the
present context of assessing lung cancer risk
from alpha emitters.
The relative risk of 0.075, calculated for
humans, will be used as a basis for testing
whether the generalized alpha radiation to
which the beagle's lungs were exposed can
account for the observed lung cancer mortality
in those animals. The effective lung dose of
alpha radiation which the beagles had accumu-
lated by 3600 days postinhalation amounted to
approximately 51 times* the corresponding
dose accumulated by age 70 in the hypothetical
case of a worker exposed continuously at the
occupational maximum permissible level
(that is, the dose upon which the estimate of
0.075 is based). Hence on the basis of linear
extrapolation (0.075 x 51) there should have
been an average of 3.8 lethal lung cancers
*The mean initial lung burden of the 15 animals
that died of lung cancer between 0 and 3600 days
postinhalation was 1.07 nC\, which corresponds to
an initial dose rate of 2.05 rad per day. The effective
half-life of this activity in the lungs of these beagles
averaged 970 days. The total accumulated lung
dose at 3600 days is found to be 2575 rad, or 25,750
rem if a quality factor of 10 is used for converting
rad of alpha radiation to rem. Marinelli [73] has
shown that, in determining a linear dose-response
relationship, the effective dose is given by the
mean accumulated dose, which in the present
case is found to be 18,410 rem. For occupational
exposure at 15 rem per year for 48 years the total
accumulated dose to the lungs is 720 rem, which
corresponds to a mean accumulated dose of 360
rem. Hence the ratio of the effective dose to the
lungs of the Battelle beagles that died of lung cancer
and the effective dose to human lungs from occupa-
tional exposure at the maximum permissible level
is 51 (18,410/360).
A.61
-------
per animal at 3600 days compared to. the two
previously calculated tumors per animal esti-
mated by the life table method. Since the
relative risk constant is itself subject to consid-
erable uncertainty, being based on sets of data
for which the calculated values of that constant
ranged from 0.0016 and 0.0068 [68], it can
be inferred that the expected number of lethal
lung cancers for the case of exposure of the
human lung could have ranged from 2 to 9.
For present purposes it suffices to note that
the beagle lung cancer death risk is not
markedly different from, and may have been
less than, that which would be calculated on
the basis of averaging alpha radiation doses
over the entire lung.
Finally, it may be of interest to analyze
Cochran and Tamplin's original statement
that the maximum permissible lung burden
(MPLB) should be reduced by a factor of
115,000. This factor, it will be recalled, was
derived by dividing the maximum permissible
lung burden of ^'Pu required to give a dose
rate of 15 rem per year (0.016 juCi) by the
total activity contained in two of their Type 1
hot particles (0.14 pCi). Their choice of two
particles, as already noted, was based on two
assumptions: 1) that the lung cancer death
risk associated with continuous lung exposure
at the rate of 15 rem per year was 1/1,000,
and 2) that the lung cancer death risk per hot
particle was 1/2,000. The present analysis
indicates that the appropriate value for the
first of these risks is 1/13 (0.075), rather
than 1/1,000; while the value for the second
risk is not 1/2,000 but instead has an upper
limit of 1.5/1,000,000 per Type 1 and 1/100,000
per Type 2 hot particle. It follows that at least
50,000 Type 1 particles would be required to
give the predicted lung cancer death risk of
0.075. That number of particles would con-
stitute a total activity of 0.004 juCi or more
and therefore would represent a factor of no
less than 1/5, rather than one of 1/115,000,
of the maximum permissible occupational
level. Nor is the problem changed appreciably
with the more recently defined Type 2 particle,
since at least 7,500 of such particles would
be required, corresponding to a total activity
of 0.005 /xCi or a factor of no less than 1/4,
not 1/115,000. Since all of the lung cancer
deaths in the Battelle group of beagles can
be accounted for on the basis of the generalized
alpha radiation, the actual risks associated
with any hot particle effect may be so low as to
be negligible when compared to the risk from
the generalized alpha radiation.
Radiation standards, as currently applied, are
not tied directly to any particular method of
calculating risks but instead are set in terms
of various absorbed dose levels to the whole
body or to critical organs, depending upon the
type of population group exposed. In relating
such levels to risks, it is appropriate to use
the methods outlined in the BEIR Report.
Indeed, the relative risk method in the present
case may be expected to predict adequately
not only lung cancer risks from generalized
alpha radiation but also those from insoluble
particulates.
Summary
An analysis of lung cancer mortality rates in
the Battelle group of beagles indicates that (1)
the generalized alpha radiation from the
total a9Pu activity in their lungs is sufficient
to account for all of the lung cancer deaths
which occurred in these animals, and (2) if
there is a hot particle effect of the type postu-
lated by Cochran and Tamplin, the risk of a
lung cancer death per particle when calculated
on the basis of the beagle experience is orders
of magnitude smaller than they estimated
and could well be so small that the contribution
from any hot particle effect to the total lung
cancer mortality is negligible. The beagle
results also indicat<> that the relative risk
method of asse .& risks, as opposed to the
absolute risk method, is likely to be the appro-
priate one for estimating lung cancer risks in
human populations exposed to radiation.
A.62
-------
Human Beings*
Lung cancer is the common designation for
a number of types of cancer arising in the
respiratory tract. By far the most frequent
type in man is cancer arising from bronchial
epithelial cells in the first few branches of the
bronchial tree. On histological grounds, these
bronchial tumors are divided into epidermoid
cancers, small and large cell undifferentiated
cancers, adenocarcinomas, and mixed types.
There are also rare tumors, carcinoids, that
arise from argentaffin cells in the bronchial
wall. .
There remains a controversy about the origin
cells of the epidermoid and undifferentiated
cancers and adenocarcinomas. Most authors
believe that these all derive from epithelial
stem cells, with the final histological type
depending on the degree of differentiation
achieved by the cell line that makes up the
tumor [75]. Regardless of whether these can-
cer cells have different parent cells, the impor-
tant point is that all three types are increased
in those exposed to certain environmental
agents, such as cigarette smokers [76,77]
or persons occupationally exposed to carcino-
gens [78]. Smokers have an especially large
increase in epidermoid cancers while undiffer-
entiated cancers usually predominate among
persons who develop bronchial cancers from
occupational exposures.
Tumors also arise from alveolar cells [79]
and cells in the bronchiole-alveolar region.
Some authors have concluded that the bron-
chiolo-alveolar tumors arise from terminal bron-
chial cells such as the Clara or the argentaffin
cells [80]. These are rare cancers in man [81]
and, unlike the bronchial epithelial cancers,
have not been found to be increased in smokers
or in groups exposed to environmental car-
cinogens. Thus they constitute a higher pro-
portion of tumors in nonsmokers than in
smokers, but they represent at present no
more than a few percent of all lung cancers
observed in the population at large.
*Prepared for the Committee's use by
E. P. Radford
Finally, there are cancers derived from plural
elements such as the mesotheliomas. Recent
work has shown that these rare tumors are
nearly always associated with exposure to
asbestos. In addition, and very rarely in the
lung tissues, tumors may occur from connec-
tive tissues or other cell types, such as fibro-
sarcomas, leiomyomas, and angiosarcomas.
These tumors are not now known to be related
to environmental exposures to carcinogens.
The number of agents known to induce human
bronchial cancers continues to grow. With
the past few years, evidence has been obtained
that occupational inhalation of bis-
chloromethyl ether, nickel compounds and
arsenic compound is associated with increased
risk of bronchial cancer. Bis-chloromethyl
ether, an extremely potent carcinogen in
experimental animals, leads especially to small
cell undifferentiated bronchial cancers in
man. Thus, these agents join exposure to
ionizing radiation, asbestos, mustard gas,
chromate dust and, of course, cigarette smoke
as environmental agents capable of causing
bronchial cancer, now the most common cause
of cancer in males in the United States.
Sensitivity of Lung Tissue Cells to Induction
of Cancer by Environmental Agents, Including
Ionizing Radiation
Exposure of lung tissues to most of the numer-
ous chemical and physical agents associated
with increased lung cancer risk has been by
inhalation; an exception, discussed below, is
exposure to ionizing radiation experienced
by the Hiroshima survivors and patients who
received x-ray treatment for ankylosing spon-
dylitis. The exposure dose of the gases (e.g.,
mustard gas or bis-chloromethyl ether) to
various tissues of the lungs will depend on
their water solubility (highly soluble gases
will be removed in the upper respiratory tract)
and the surface area of the tissues exposed
(since diffusion governs uptake). Mustard
gas is sparingly soluble in water and thus its
uptake is determined by the surface area.
Similar considerations apply to the poorly-
soluble respirable dusts such as arsenic trioxide
and chromates. In the particle size range
A.63
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which can reach the lungs and. tracheo-
bronchial tree, diffusion also governs most
of the deposition process. This means that,
on inhalation, initial deposition of these
materials occurs predominantly in the alveoli
of the lung, rather than in the ciliated bron-
chial region, because of the very much larger
surface area of the alveoli (more than 100
times greater).
The important datum, however, is the dose
delivered to cells. Since the cells of the alveolar
surface are much more attenuated than those
of the ciliated epithelium, if deposition of a
carcinogen is proportional to the gas-liquid
surface area then obviously the alveolar cells
will receive a larger dose of a diffusing agent
than the bronchial epithelial cells. On the
basis of this reasoning, therefore, if the sensi-
tivity to cancerous transformation of the
epithelial cells of the respiratory tract is equal
throughout, then the cells of the alveoli,
especially the type I cells (since they receive
the highest dose of these agents) should give
rise to many more cancers than the bronchial
epithelium. This reasoning applies equally
to cigarette smoke. In fact, there is no evidence
that alveolar or bronchocell cancers are
associated with inhalation of these carcino-
genic gases, submicron dusts, or cigarette
smoke. Although the groups exposed to occu-
pational carcinogens have been relatively
small, if alveolar or bronchiolo-alveolar cancers
had increased they would have been immed-
diately detected because these cancers are so
rare in the general population. (Pleura! and
peritoneal mesotheliomas, the first type of
cancer shown conclusively to be related to
asbestos exposure, were noted precisely
because they are so rare and thus the increase
observed in workers handling asbestos was
especially striking.)
This report, of course, is concerned with the
hazard from inhaled apha-emitting elements.
We have extensive evidence, both for cancer
risk and site of cancer origin, in one human
group exposed to alpha-emitters, underground
uranium miners. Data on origin and cell type
of the cancers are especially complete for
the U.S. uranium miners studied by Sacco-
manno and his associates {77]. Before consid-
ering this group in some detail, however, it
is worthwhile to review the lung cancer
experience in populations exposed to external
radiation.
In British studies of patients treated with
x-rays for ankylosing spondylitis [82] the
x-ray was directed principally at the thoracic
and lumbar spine. From analysis of the dose to
the lung tissues, it is reasonable to conclude
that much of the lung parenchyma received
the same x-ray dose as did the bronchial
tissues. In the Hiroshima survivors who were
exposed to both neutrons and penetrating
gamma radiation, the neutron dose to the
bronchial tissues, because of shielding effects,
would have been somewhat lower than to
the alveolar tissues closest to the direction
of the bomb. In both groups, with well over
100 excess cancers observed, there is only a
slight indication of an increase in alveolar
cancers [83].
The U.S. uranium miner study offers the best
quantitative evidence of the relative sensi-
tivities of different lung tissues to alpha irradi-
ation [84]. These miners are exposed to radi-
ation from the daughters of radon; the half-
lives of these daughters are short, up to 30
minutes, and most of them are inhaled on
respirable dust particles in the submicron
size range. These particles are deposited in
the respiratory tract, where movement is
primarily by diffusion. The time period during
which they move about in the respiratory
tract is limited by their physical decay rate.
Calculation of the alpha dose to bronchial
epithelium and lung tissue is complex but
Albert estimates that the number of alpha
emissions in the alveoli from inhalation of a
typical mine atmosphere is approximately
10 times higher than that released in the
bronchial tree in the regions where tumors
form.
Saccomanno has examined histologically
the lung tissues of approximately 200 lung
cancer cases among these miners and reports
that only one bronchiolo-alveolar cancer has
been observed. Considering the population
A.64
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at risk, this is somewhat Fess than might be
expected on the basis of the frequency of these
cancers in the male population but, even if we
accept this case as a radiogenic cancer, it
would appear that the radiosensitivity of the
bronchial epithelium in man is at least 100
times that of the alveolar or bronchiole-alveolar
tissues. In fact, the relative sensitivity may be
much greater.
For alpha irradiation therefore, as well as for
exposure to dusts and chemical agents in man,
alveolar and bronchiole-alveolar tissues appear
to be very much more resistant to cancer induc-
tion than the bronchial epithelial cells. This
conclusion varies somewhat from experience
with cancer induction in experimental animals
(discussed in the previous section). Some
possible explanations for the special sensitivity
of the bronchial epithelium in man are:
a) the bronchial epithelium is more rapidly
renewed by cell division than are the alveolar
epithelium or connective tissue elements and
radiosensitivity is related to this quality;
b) most (but not all) occupational bronchial
cancers have been observed in cigarette
smokers who had been exposed to irritants
in smoke and many of whom had chronic
bronchitis, both of which may make the epi-
thelium more sensitive to carcinogens;
c) human populations are commonly and
repeatedly exposed to viral infections of the
respiratory epithelium which cause rapid
loss of epithelial cells, requiring rapid pro-
liferation of stem cells to repopulate the
mucosa. Moreover, these viruses could directly
contribute to the process of transformation
to a cancer; and d) other inhaled pollens, dusts,
and gases in the general environment may
contribute to bronchial irritation. Regardless
of the reasons for this sensitivity, the tissue
at special risk in man from inhaled transuranic
elements is probably the bronchial epithelium,
especially in the more proximal regions of
the bronchial tree.
Dose-Response Data for Cancer Induction by
Alpha Radiation Exposure in Man
An extensive review of dose-response data
for cancer induction by alpha radiation was
presented in the BEIR Report in 1972 [68].
The Committee's position as reflected in that
document is summarized below, followed by
an account of recent developments relevant
to the issue of toxicity of alpha-emitters.
Dose-response data have been obtained from
a number of underground mining groups ex-
posed to relatively high levels of radon daugh-
ters in the past and to individuals exposed
to thoron exhaled as a daughter from body
burdens of thorium salts given for diagnostic
purposes. The best data have been from the
U.S. uranium miners [84] and the Newfound-
land fluorspar miners [85]. From the analysis
done in 1972, these two groups showed similar
risk estimates per rem of exposure to the
bronchial epithelium, although the fluorspar
miners gave an estimate of 1.65 excess lung
cancer cases/rem/106 person-years, while the
figure for the uranium miners was 0.63 cases/
rem/106 person-years. It was pointed out in
the BEIR Report that all of these populations
are still at increased lung cancer risk and,
thus, these figures are likely to be revised
upward. The similarity of risk estimates for
lung cancer based on the gamma and neutron-
irradiated Hiroshima survivors and the miners
supported the conclusion that the radiosensi-
tivity of the lung tissues was consistent with
well-known radiobiological principles.
Documentation of new underground mining
populations exposed to elevated radon daugh-
ter concentrations and an updating of the
experience of the U.S. uranium miner group
have contributed new evidence on the ques-
tion of risk from alpha irradiation. The new
mining populations that have been studied are
in iron and zinc mines in Sweden [86,87].
The cumulative dose response data in these
miners are comparable to those of the other
groups but the most significant aspect of these
mines is that the radon daughter concentra-
tions were relatively low, with exposures in
some cases below 1 Working Level. This evi-
dence, therefore, extends our documentation
of increased cancer risk to lower dose rates
than had been observed previously in the
uranium and fluorspar miners.
A.65
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Finally, it has been possible to update the
U.S. uranium miners study group to 1972
[88]. As expected, the cancer incidence rate
has remained high, at roughly 30 times the
rate in the remainder of the U.S. population.
Adding the new lung cancer cases, modifying
the definition of period at risk from 5 years
after beginning of mining (used in the Inter-
agency and BEIR Reports) to 10 years after
beginning of mining, and eliminating three
cases which occurred during the 5-10 year
period (which is probably less time than the
latent period for lung .cancer) results in a
revised absolute risk of about 2 cases/rem/
106 person-years. The new data suggest that
the straight-line fit of the dose-response curve
used in the BEIR Report is in error, with
the risk in the lower dose categories, higher
per rad than in the highest dose groups.
Since the lowest dose category (< 120 WLM)
contains few cases and the statistical range
of uncertainty is very large as a result, there
is a corresponding uncertainty in the exact
basis for calculating the risk in this group.
It should be noted that these risk estimates
may continue to increase if more cases occur,
especially if with advancing age, relative
risk compared to the general population
remains high.
Comparison of Human and Animal Radio-
carcinogen Effects*
While responses to "toxic" levels of external
radiation and internal emitters in people and
experimental animals have been studied over
the past 75 years, uncertainties regarding the
quantitation of effect and appropriate methods
to scale dosage, time and effect (risk) still
exist. Furthermore, human experience has
been limited and usually has been observed
through epidemiological, retrospective studies
while laboratory studies on animals are pros-
pective in nature. There is no radionuclide
*Prepared for the Committee's use by
M. Goldman
(or any other agent) for which toxic levels
cannot be determined. The lungs in which
the radionuclide is deposited do not appear
to be uniquely sensitive or resistant to
radiation-induced effects, including cancer,
when compared to other comparably exposed
tissues. However, despite intensive study,
the exact mechanisms of radiation-induced
cancer are still unknown. Many theories have
been proposed, usually invoking a series of
initiating and promoting factors for which
some data are available, but it appears likely
that no single model is universally acceptable
[89].
In the absence of human data, the relationship
between radiation dose and biological effects
determined in animal experiments have been
used to predict human consequences [90].
The most common parameters used have been
the organ-averaged cumulative radiation dose
and the crude excess incidence of effect (i.e.,
the number of animals manifesting the effect
divided by the total number of dosed or dead
animals at each exposure level). This statistic
provides an estimate of fraction or percent
effect per unit dose, but is fairly species (e.g.,
lifespan) dependent. While some long-lived
animals, such as dogs and nonhuman primates,
have been and are being studied, most of our
animal data have been derived from relatively
short-lived rodents [91,92].
A comparison of the interspecies radio-
biology of inhaled alpha particles is hampered
by the lack of direct human experience. Several
indirect approaches can be used which attempt
to "normalize" the spatial and temporal dose
and metabolic and anatomic factors as well
as differences in pathologic appearance, spon-
taneous disease and life expectancy. People
are larger and live longer than experimental
animals in the laboratory; however, there are
probably fewer differences than similarities.
The special case of lung cancer in people is
somewhat obscured by problems relating to
use of tobacco products and perhaps other
occupational and environmental atmospheric
pollutants. Table A.II-20 gives some quantita-
tive interspecies comparisons.
A.66
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Life Span (yr)
Adult Mass (kg)
Lung Mass (g)
Bone Mass (g)
Liver Mass (g)
Lymph Node (TB) Mass (g)
PuO2 Lung Ret., ?b (da)
TABLE A.II-20
Some Species Intercomparisons
Mice
3
0.03
0.4
3
4
200-
500
Rats
^•Wi^B^^H
4
0.4
2
40
10?
250
550
Dogs
13
10
75
1000
375
35
300-
1000
Human
Beings
72
70
1000
7000
1700
250
240-
650
Conventional Approach
The interspecies comparison most used in risk
assessments is time independent and attempts
to use the linear dose to risk approach to
calculate the absolute percent increase in
effect per unit of dose [68,93]. For bronchial
lung cancer, absolute estimates range from 0.6
(ABCC) to 1.61 (fluorspar miners) cases per
yr/rem/106 persons, with an average of I/
106/yr/rem. Since the data are as yet incom-
plete, the risk may be twice as high in the
final analysis (i.e., 2/106/yr/rem). If a 30
year "plateau" for risk obtains, the total
excess yield might be 30 yr x 2/106/yr/rem
or about 0.006%/rem; if a 50 year plateau
obtains, the value could be about 0.01%/rem.
Since all the radiation dose is not absorbed
initially and there may be an effective latency
per effective rem of about 20 years, it would
appear that a reasonable estimate might be
about 0.005%/rem.
Rodent inhalation studies with alpha-emitting
radionuclide particles have yielded a variety of
lung cancer risk estimates. Bair and Thomas
[67] recently summarized many of these and
derived a rodent lung cancer linear estimate
of about 0.1%/rad. The single completed dog
study at Battelle provides a crude upper limit
of about 90%/1500 rads or 0.006%/rem which,
although derived from very high doses, is not
markedly different from the human and rodent
estimates. In all three estimates, the lung
dose is averaged over the entire lung volume
and, as stated above, does not account for
lifespan differences in survival rates at each
dose level. Thus the classical approach suggests
a rodent-dog-person risk of about 10'3 -
lO-^/rem of lung irradiation.
The Radium-Bone Standard Approach
For many years the human experience with
radium poisoning has been a benchmark for
radionuclide standard-setting. Based primarily
on studies of painters of watch dials, data
on this bone-seeking alpha-emitting nuclide
have been reviewed often and to date it
would appear that doses in excess of several
hundred ( > 700) rad of cumulative exposure
have increased the risk for induction of skeletal
tumors [94]. Furthermore, studies in rodents
and dogs have attempted to simulate the
human experience and provide a basis for
further interspecies comparisons of the effects
of alpha particles in mammals [95,%].
In addition, plutonium has also been admini-
stered to animals to provide data on plutonium
in the skeleton [97,98]. One obvious compar-
ison, therefore, would relate the effects of
these two nuclides in one organ for different
species. Jacobi [99] recently related the 226Ra
data for bone sarcomas in beagles and humans
and attempted to account for temporal factors
A.67
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by use of an age-specific mortality rate for
beagle bone cancer and an estimate of_an
induction period Tj (Tj = 2.0 + 5A-°-67; T =
years, A = yCi/kg injected). His dog-human
comparison is shown in Figure A.I 1-21 and
suggests a 5-10-fold lower risk to humans than
to dogs at each mean alpha rad dose level.
Using a somewhat similar approach, Goldman
et al. [90] compared mouse, dog, and man.
Results are shown in Figure A.II-22.
Osteosarcomas in animals following injection
of plutonium are summarized in Figure A.II-
23 [40]. Except for the dog data (open circles),
these data are derived from rodents. The dogs
clearly are more responsive per rad than the
rodents. An attempt to quantify the difference
is shown in Figure A.II-24, which compares
the plutonium in mice studies conducted by
Finkel [100] at Argonne National Laboratory
and the beagle plutonium study at Utah [101].
There is about a 30-fold difference between
the two species over most of the range of
plutonium injections, but only about a 2-fold
difference for these two species for radium
[90]. If one applies the distribution factor
100
Ł
*
tn
a:
8
cc
O
oo
10
0.1
BEAGLES
A EXPERIMENTAL
CALCULATED
/
10'
10* 103
MEAN SKELETON a-DOSE (RAD)
10«
(DF) of 5 for plutonium relative to radium
and uses, for example, the 10% risk (in rad)
estimate for beagles and humans from Jacob!,
a relationship such as the following can be
derived.
Ra dog bone
Ra human bone
440 = 440/5
1500 X
,x ^
Pu dog bone
Pu human bone
rac|/io% plutonium bone
tumors in man
If linear, this would be an estimate of about
3 x 10'3%/rem. To further extend the analogy
of radium:plutonium, dogrman to estimate
relation of lung cancers according to species
requires assuming that both organs manifest
the same ratio of sensitivity to tumor induction
in each species. The comparison might be:
Ra Dog . Pu Dog
(bone) = —
Ra Man Pu Man
(lung)
The 10% lung cancer incidence due to pluto-
nium exposure in dogs is from the Battelle
data of 90%/1500 rad. Thus the 10% yield
I
ui
U
100
80
111
u 60
t 40
3
B 20
5
i
0"
0.01
DOG
0.05 0.1 0.5 1
INJECTED DOSE,
FIGURE A.II-22
10
FIGURE A.II-21
Bone Sarcoma Incidence in Humans and Beagle
Dogs from Exposure to 266Ra [99]
Estimate of Incidence of Osteosarcomas in Man
Based on Osteosarcoma Data Obtained from Mice
and Dogs, Allowing for Differences in Radium
Retention [90]
A.68
-------
100
| 80
1
2 60
8
LL.
o
0 40
S
Q
O
~ 20
0
_
-
•
" 111! ,
1 10
* ,it J
(
b
'
•\
r,l4
100
(
I
r?
I
<
I
1
o
•I
f
k 1
1
V'
p
o
II
i
.
,1 1
(
)
1 1 llllll
1.000 10.000
CALCULATED CUMULATIVE MEAN DOSE TO BONE (RAD)
FIGURE A.II-23
Plutonium-Induced Osteosarcoma in Experimental Animals [40]
FIGURE A.II-24
Comparison of Plutonium-
Induced Osteosarcomas
in Mice and Dogs [90]
INJECTED ACTIVITY (pCi/kg)
A.69
-------
might be 10/0.006%/rerTT1 or 1666 rem
(167 rad)*; 440/1500 = 167/x, or x = 570
rad/10%. The human lung cancer estimate
related to the bone comparison would be
0.0018%/rem.
The Quality Factor Model
The relative carcinogenicity of alpha parti-
cles in animal lungs can be compared to
effects from low LET (B-Y,X) irradiation,
but the human radionuclide data to complete
the comparison is lacking. The precision and
accuracy of the dosimetry in the uranium
and fluorspar miner data are severely defi-
cient and the possible role of inhaled co-
carcinogens is unknown [93]. Most of the
dose estimates for effects range from. 2,000
to 20,000 rem.
That the incidence of lung tumors in animals
is not linear with respect to dose is seen
in Figure A.I 1-25 for low LET radiation and
Figure A.I 1-26 for alpha-emitters [92]. A
comparison of the effectiveness of the two
types of radiation is shown in Figure A.11-27
where for the same level of effect the two
types of radiation differ by a factor of about
5 for the low doses and by about 20 for
high doses. If the QF of 10 is applied to
the alpha dose curve (and a QF of 1 for 0,
Y and x-rays), it would appear that the two
curves would almost superimpose. Again noting
the 10% incidence merely for comparative
purposes, the 100 rad alpha value multiplied
by the QF of 10 is about equal to the 3 - Y
value of about 1000 rad (rem). The inconstancy
of the relationship is shown by the lack of
complete parallelism between the two curves
in Figure A.II-27.
As in Jacobi's bone comparison for radium,
lungs also may respond nonlinearly when
subjected to continued low dose rate alpha
irradiation. The limited data on uranium
miners also suggest a nonlinear response [99].
CALCULATED DOSE TO LUNG (RAD)
FIGURE A.II-25
Fractional Incidence of Lung Cancer in Animals Exposed to low LET ()3,X,7) Radiation from
Implanted Sources and X-Radiation from External Sources [92]
*ln computing this from the 90% incidence
value in dogs, no consideration is given to
the occurrence of multiple tumors in the dogs.
A.70
-------
10
100.000
100 1000 10.000
CALCULATED CUMULATIVE MEAN BETA-GAMMA DOSE TO LUNG. RAD
FIGURE A.II-26
Relationship Between Incidence of Lung Cancer and Radiation Dose to
Lung from Inhaled Beta-Gamma Emitting Radionuclides in Experimental Animals [4t]
U
o
1
8
o
u
60
50
40
30
20
10
ALPHA EMITTERS
(BASED ON UNIFORM
ABSORPTION OF
ENERGY)
ALPHA EMITTERS
(ENERGY ABSORBED IN
CRITICAL VOLUMES.
0.1% OF LUNG)
10 100 1.000 10.000 100.000 1,000.000
CALCULATED CUMULATIVE MEAN BETA-GAMMA DOSE TO LUNG. RAD
FIGURE A.II-27
Comparative Relationships Between the Incidences of Lung Cancer and
Radiation Doses from Inhafed Beta-Gamma and Alpha Emitters in Experimental Animals [92]
A.71
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MECHANISMS OF CARCINOGENESIS*
Carcinogenic Mechanisms at the Intracellular
Level
The cellular processes that cause neoplastic
transformations are unknown. The efficiency
of carcinogenic action is clearly affected by
factors that determine the extent to which
a given carcinogen actually reaches target
cells and the susceptibility to transformation.
Susceptibility depends on a variety of factors
which determine the extent of initial injury
and the effectiveness of repair.
At present, it is not clear whether there is
a common pathway for different carcinogens
for cellular neoplastic transformation, although
this has been suggested in terms of the acti-
vation of a latent viral oncogen [102,103]. It is
also not clear whether the inheritable abnor-
malities transmitted to successive generations
of proliferating cancer cells are caused by
genetic damage or abnormal differentiation
involving deranged expression of the normal
genome. Neoplastic transformation at the
cellular level is not a simple all-or-none
phenomenon. Transformed cells show differ-
ences in the extent to which they acquire
the several independent properties of neo-
plasia: unrestrained proliferation, invasive-
ness, and antigenicity.
Neoplasia is also not an immutable property
which is transmitted equally to all the pro-
geny of a transformed cell. The clonal out-
growth of single cultured cells shows a
spectrum of neoplastic and nonneoplastic
properties amongst progeny cells which has
been related to chromosomal balance. Single
cells isolated from malignant teratomas also
produce clones of cells, some of which are
neoplastic and others of which undergo normal
differentiation. The neoplastic character of a
tumor, therefore, appears to depend on the
average behavior of its component cells.
*Prepared for the Committee's use by
G. W. Casarett
It is possible that the carcinogenic process
will prove to be similar to that of species
evolution, in that random genetic damage of
somatic cells produced by carcinogens is
combined with selection pressures to breed
out a race of cells having growth advantages
over their normal counterparts. It would be
expected that the process would be generally
slow, progressive in character and wasteful
of cells due to lethal injury; cell lethality,
however, could undoubtedly facilitate the
selection process, especially in tissues which
normally have a low proliferative rate.
Pitot and Heidelberger [104] have formulated
an epigenetic scheme for neoplasia based on
abnormal differentiation. Braun [105] has also
elaborated on this alternative based on plant
tumorigenesis experiments. These studies
show that plant tumors can arise from an
epigenetic differentiation abnormality which
is characterized by the production of large
amounts of growth hormone by the tumor
cells. These anaplastic tumors, after years
of propagation in tissue culture, can per-
manently revert to normal plant tissue when
grown under certain conditions.
The Problem of So-Called "Precancerous"
Lesions
The problem of so-called "precancerous"
lesions applies also to terms such as "preneo-
plastic", "pretumorous", and "preadenoma-
tous" and to the question of whether benign
tumors should be considered precancerous
lesions.
According to Ewing [106], precancerous
lesions are those which precede and favor
the development of cancer but do not possess
the essential elements of the cancerous
process.
It must be pointed out that there is nothing
in the histologic picture of these lesions that
indicates which of them will "precede and
favor the development of cancer." It is the
ulterior development of similar lesions that
is brought to mind when such a prediction
is made [107]. The concept of precancerous
A.72
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lesions is purely statistical and certainly not
applicable pathognomonically in individual
cases.
Although most so-called precancerous lesions
are proliferative in nature, there are many other
lesions, even more proliferative, which are
not precancerous [108]. Likewise, in addition
to proliferative changes, many of the so-
called precancerous lesions are also charac-
terized by tissue disorganization, vascular
changes and fibrosis, but so are many other
lesions which are not precancerous. These
changes, or combinations of changes, might
have tumorigenic-enhancing or promoting
influence, but they more likely represent the
various ways in which tissues can respond
to severe acute or chronic damage rather
than essential changes that assure cancer
development. If the latter were true, the
cancer incidence would be vastly greater
than it is.
Perez-Tamayo [107] lists many diseases which
have been regarded as precancerous, about
half of which (in the total list) have been
shown to be incorrect. Not even the presence
of a benign tumor is necessarily indicative
of increased probability of cancer development.
In order to qualify strictly as a precancerous
lesion, even in the statistical sense, there
must be a clear quantitative relationship
between the precisely defined lesion (which
must not possess essential elements of the
cancerous process) and consequently a signi-
ficantly enhanced incidence of cancer.
Once the statistical relationship has been
established through observation of behavior
of different lesions, the microscopic diagnosis
may aid in assessing the possibility of cancer
development, but not because of any peculiar
histologic markings.
The terms "precancerous", "preadenoma" and
the like have been used somewhat casually
to indicate changes reminiscent of those pre-
ceding or concomitant with tumor develop-
ment, to enhance descriptions of certain
changes by describing them as "precancerous"
or "preadenomatous", or to imply the possi-
bility of subsequent tumor development when
there is uncertainty as to the presence of
essential features of the tumorous process
in the lesions.
REFERENCES
1. Task Group on Lung Dynamics. Deposition
and Retention Models for Internal Dosimetry
of the Human Respiratory Tract. Health Phys.
12:173-207,1966.
2. T. T. Mercer. The Deposition Model of the
Task Group on Lung Dynamics: A Compari-
son with Recent Experimental Data. Health
Phys. 29:673-680,1975.
3. R. G. Cuddihy, L. D. Chapman, J. R. Wayland,
V. L. Dugan and R. O. McClellan. General
Characteristics of a Mathematical Model
for Predicting Environmental and Human
Health Effects of Developing Nuclear Reactor
Programs. In: Inhalation Toxicology Re-
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APPENDIX B
PROCEDURES FOR COMMITTEE APPOINTMENTS AND
CONSIDERATION OF POTENTIAL BIAS OF MEMBERS
As a general rule, individuals are appointed
to NRC committees by the chairman, staff
officers, and members of the NRC division
and assembly concerned. (Division members
are nominated by scientific societies in their
relevant fields and, less frequently, by govern-
mental agencies.)
The appointment process usually involves two
or three layers of personal consultation
between the selectors and people who are
actively working in the pertinent fields. Typi-
cally, the assembly/division chairman or
executive director approaches an individual
in academia or industry whom he believes to
be well informed about activities in his field
and solicits his help in identifying potential
members for the committee or panel. On the
basis of such suggestions, the chairmen select
a balanced membership and recommend it
to the President of the National Academy of
Sciences for his approval.
The President's office examines the nomina-
tion list with the following criteria in mind:
balance, qualifications, and present commit-
ments of the nominees to other committees
and panels of the Academy and Research
Council. Although a number of persons serve
on two or even more NRC committees at a
time, it is a general practice to limit the
assignments to prevent overburdening a com-
mittee member.
NRC committee members are, in general,
chosen for their technical qualifications,
recognized communication skills, and judg-
mental qualities, but other more subjective
factors, such as motivation and temperament,
are not overlooked. The identification of pos-
sible members and the final committee selec-
tion are often preceded by an extensive
analysis of the various competences needed
to deal with the subject and issues being
considered.
The appointing function is thus carried out at
two levels: at the assembly and division level,
where there is professional expertise in the
scientific fields and the specific problems,
and in the Executive Office of the Academy,
where the above-mentioned screening pro-
cedure takes place. The Executive Office
maintains a complete file of all current task
appointments for all activities of the National
Academy of Sciences and the National
Research Council.
CONFLICT OF INTEREST
Organizations avoid knowingly appointing a
person to a committee if his interests, or those
of his employer, will be affected by actions
of the committee. Awards committees, for
example, should not include scientists whose
academic departments are applicants for
awards in the programs being considered.
Industrial scientists should not sit as members
of committees when the recommendations are
likely to affect the business interests of their
companies. Other forms of conflict of inter-
est—ownership of equities in a company,
industrial consultancies, and the like—also
must be considered.
The problem becomes especially difficult
when a field is so highly specialized that
only a few top quality advisers can be found,
and when the activities of the agency request-
ing advice are so pervasive in a field of
expertise that almost all advisers with the
technical competence required are or have
B.1
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been related to the agency in some way. This
is a far from rare occurrence; examples are
the relationship of the Atomic Energy Commis-
sion (now Energy Research and Development
Administration) to the field of nuclear reactor
development, of the National Institute of
Health to policies for the support of biomedi-
cal education, and of the National Aeronautics
and Space Administration to exobiology.
Where, for any reason, conflicts of interest
must be accepted in order to obtain adequate
expertise, it is important that they be known
to all members of the committee and to the
sponsoring and requesting agencies. This not
only ensures that possible biases are recognized,
but also assists members who have such con-
flicts to make necessary compensations in
their own thinking and judgment.
Clear statements of the task assigned the
committee, and of any possible conflicts of
interest among its members, can do much to
assure the likelihood of public confidence
in its conclusion.
The following brief biographical sketches of
the members of the ad hoc Committee on
"Hot Particles" are included to demonstrate
the expertise and competence of each member.
Some of these may, in their background,
demonstrate sources of possible bias, as
discussed above. However, NAS/NRC and
the Committee itself believe that in all official
deliberations, the members have exercised
their best scientific judgements. If any bias
existed, it was manifested in a critical exami-
nation of each member's prior public state-
ments and positions.
B.2
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ALBERT, ROY E.
DATE OF BIRTH: 1924
EDUCATION:
A.B. 1944 Columbia College
M.D. 1946 New York University College of Medicine
1946-47 Internship, Bellevue Hospital, Third Medical Division
1949-51 USPHS Fellowship in Cardiovascular Hemodynamics, New York
University College of Medicine
1951-52 Residency in Medicine, University of the State of New York at
Syracuse University Hospital
PAST POSITIONS:
1959-66 Associate Professor, Institute of Environmental Medicine, New York University
Medical Center.
1956-59 Assistant Clinical Professor of Medicine (Geographical Full-Time) and Assistant
Director of the Radioisotope Laboratory, George Washington University School
of Medicine.
1954-56 Assistant Chief (1954-55), Chief (1955-56), Medical Branch, U.S. Atomic Energy
Commission, Division of Biology and Medicine.
1952-54 Medical Officer, Health Safety Laboratory, New York Operations Office, U.S.
Atomic Energy Commission.
1947-49 A.U.S. Medical Field Research Laboratory, Fort Knox, Kentucky (Military Service).
PRESENT POSITION:
Director, Office of Health Ecological Effects, Environmental Protection Agency (July 1975 - ).
Professor of Environmental Medicine (1966 - )—on sabbatical leave.
Vice Chairman and Deputy Director of Institute of Environmental Medicine, New York Univ.
Medical Center (1973 - )—on sabbatical leave.
PUBLICATIONS:
Sixty-three journal articles, chiefly on physiology, biology, carcinogenesis, radiation biology, and
radiation effects.
CONSULTANTSHIPS:
Task Force II, National Conference on Preventive Medicine (1975 - ) (American College of
Preventive Medicine and NIH Fogarty Center).
AIBS Life Sciences Study Team for Assessment of Ecological Impact (1974- ) (American Institute of
Biological Sciences).
Study on Principles of Decision-Making for Regulating Chemicals in the Environment (1974 - )
(National Academy of Sciences—National Research Council).
B.3
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CONSULTANTSHIPS (Continued):
Task Group on the Influence of Radiobiological Factors in the Estimation of Risks of Cancer
Induction for Purposes of Radiation Protection (1974 - ) (International Commission on
Radiological Protection).
Committee on Biologic Effects of Atmospheric Pollutants - Panel on Arsenic (1973 - ) (National
Academy of Sciences—National Research Council).
Advisory Committee to the Radiation Registry of Physicians (1972 - ) (National Academy of
Sciences—National Research Council).
NCRP Scientific Committee 38 - Task Group on Krypton-85 (1972 - ) (National Council on
Radiation Protection and Measurements).
Committee on Biologic Effects of Atmospheric Pollutants - Panel on Airborne Particles (1972 - )
(National Academy of Sciences—National Research Council).
Committee on Toxicology, ad hoc Panel on Carbon Monoxide (1971 - ) (National Academy
of Sciences—National Research Council).
Committee on Biologic Effects of Atmospheric Pollutants, Panel on Polycyclic Organic Matter
(1970-72) (National Academy of Sciences—National Research Council).
Ad hoc Committee on Environmental Health Research, Panel on Hazardous Trace Substances
(1970-72) (Office of Science and Technology, Executive Office of the President).
Ad hoc Subcommittee on Asbestos Hazards (1970) (Air Pollution Working Group of the New
York City Health Research Council).
Ad-hoc Committee on Air Quality Standards in Space Flight (1967) (National Academy of
Sciences—National Research Council).
Committee on Research in the Life Sciences, Panel on Environmental Health (1967) (National
Academy of Sciences—National Research Council).
Air Pollution Advisory Committee (1967-70) (New York City Department of Health).
Division of Biology and Medicine Committee on Space Nuclear Systems and Radiological
Safety Matters (1967 - ) (U.S. Atomic Energy Commission).
Technical Advisory Committee on Uranium Mining Studies (1966) (Department of Health,
Education, and Welfare).
Consultant to the Surgeon General's Advisory Committee on Smoking and Health (1963).
B.4
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ALPEN, EDWARD L.
DATE OF BIRTH: 1922
EDUCATION:
B.S. 1946 Chemistry, University of California, Berkeley
Ph.D. 1950 Pharmaceutical Chemistry and Pharmacology, University of California,
San Francisco
PAST POSITIONS:
1972-75 Director, Pacific Northwest Division, Battelle Memorial Institute, Richland,
Washington.
1971-72 Associate Director, Pacific Northwest Laboratories, Battelle Memorial Institute,
Richland, Washington.
1969-71 Manager, Environmental and Life Sciences Division, Battelle Pacific Northwest
Laboratories.
1958-69 Head, Biological and Medical Sciences Division, Naval Radiological Defense
Laboratory.
1954-58 Head, Biophysics Branch, Naval Radiological Defense Laboratory.
1951-54 Scientific Investigator, Naval Radiological Defense Laboratory.
1950-51 Assistant Professor of Pharmacology, George Washington University School
of Medicine, Washington, D.C.
1946-47 Research Chemist, Cutter Laboratories, Berkeley, California.
PRESENT POSITION:
Director, Donner Laboratory, University of California, Berkeley, California.
PUBLICATIONS:
Approximately 70 journal publications chiefly on radiation effects, biology, aging, neuro-
physiology, psychology, biophysics, and immunology.
HONORS AND/OR CITATIONS:
Senior Post-Doctoral Fellow of the National Science Foundation, Oxford University, Oxford,
England (in residence 1958-59).
Sustaining Members Award for Creative Research of the Association of Military Surgeons (1961).
Distinguished Achievement in Science Gold Medal and Citation, Department of the Navy (1962).
Distinguished Service Gold Medal and Citation, Department of Defense (1963).
B.S
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PROFESSIONAL AFFILIATIONS:
National Councillor, Radiation Research Society (1952 - ).
Member, Board of Editors, Society for Experimental Biology and Medicine.
Member, American Physiological Society (1952 - ).
Member, National Environmental Council, Dept. of HEW (1970-74).
Chairman, Biological Effects Advisory Panel, Bureau of Radiological Health (1968-74).
Member, Sigma Xi. Local chapter president (1963-64).
Fellow, California Academy of Sciences.
Foreign Associate Member, Royal Society of Medicine (1962 - ).
Member, Radiation Study Section, National Institutes of Health (1960-72).
Member, Advisory Panel to Collaborative Radiological Health Laboratory, U.S. Public Health
Service (1965-70).
Member, Quadripartite Technical Cooperation Panel (U.S., U.K., Canada, Australia, Scientific
Cooperation Group of Defense).
Councillor, National Council on Radiation Protection (1955-74).
Board of Directors, National Council on Radiation Protection (1972-74).
Member, NCRP Scientific Committees 14 and 24: Chairman, NCRP SC 39.
Consultant to the Director, Clinical Investigation Center, U.S. Naval Hospital, Oakland (1956 - ).
Member, 'Failla' Panel to the Department of Defense on Radiological Instrumentation (1955-61).
B.6
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BAIR, WILLIAM J.
DATE OF BIRTH: 1924
EDUCATION:
B.A. 1949 Chemistry, Ohio Wesleyan University
Ph.D. 1954 Radiation Biology, University of Rochester
PAST POSITIONS:
1973-75 Director, Life Sciences Program, Pacific Northwest Laboratories, Battelle Memorial
Institute, Richland, Washington.
1968-75 Manager, Biology Department, Pacific Northwest Laboratories, Battelle Memorial
Institute, Richland, Washington.
1956-68 Manager, Inhalation Toxicology Section, Biology Department, General Electric
Company, Richland, Washington (prime contractor changed to Battelle Memorial
Institute in 1965 - position unchanged).
1954-56 Biological Scientist, General Electric Company, Richland, Washington.
1950-54 Research Associate, Radiation Biology, University of Rochester.
1949-50 National Research Council, AEC Fellowship in radiological physics, University
of Rochester.
PRESENT POSITION:
Manager, Environmental and Safety Research Program, Pacific Northwest Laboratories of Battelle
Memorial Institute, Richland, Washington (March 1975 - ).
PUBLICATIONS:
87 journal articles or books chiefly on radiation biology, with emphasis on toxicity of inhaled
radionuclides and pulmonary effects in experimental animals.
HONORS AND/OR CITATIONS:
E. O. Lawrence Memorial Award by the U.S. Atomic Energy Commission for research on radiation
biology of inhaled radionuclides (1970).
AEC Fellowship in Radiological Physics, U. of Rochester, 1949-50.
PROFESSIONAL AFFILIATIONS:
Staff Member, Joint Center for Graduate Study at Hanford (operated by Oregon State University,
Washington State University, and University of Washington). Lecturer in Radiation Biology
(1955- ).
Member, International Commission on Radiological Protection, Committee 2 (1973 - ).
B.7
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PROFESSIONAL AFFILIATIONS (Continued):
Chairman, Task Group on the Biological Effects of Inhaled Radioactive Particles, International
Commission on Radiological Protection (1969 - ).
Chairman, Transuranium Technical Group (organized by the American Institute of Biological
Sciences to advise the U.S. Atomic Energy Commission on biomedical research on transuranium
elements) (1972 - ).
Member of National Council on Radiation Protection and Measurement (NCRP) (1974 - ).
Member, Board of Directors, National Council on Radiation Protection and Measurement
(NCRP) (1976 - ).
Member of Scientific Committee 1 (NCRP) on Basic Radiation Protection Criteria (1975 - ).
Member of Scientific Committee 34 (NCRP) on Maximum Permissible Concentration for
Occupational and Non-Occupational Exposure (1970- ).
Chairman of NCRP ad hoc Committee on "Hot Particles" (1974-75).
Member of Subcommittee on Inhalation Hazards of the Committee on Pathologic Effects of
Atomic Radiation, National Academy of Science (1957-64).
Member of National Academy of Sciences/National Research Council ad hoc Committee on
"Hot Particles" of the Advisory Committee on the Biological Effects of Ionizing Radiation (1974 - ).
Chairman, Mound Laboratory Internal Emitter Working Group, Division of Biomedical and
Environmental Research, U.S. Energy Research and Development Administration (1975-76).
Member, the Nevada Applied Ecology Group ad hoc Pu Committee, AEC-ERDA (1970 - ).
Member, Joint Space Nuclear System/Biomedical and Environmental Research Working Group,
Atomic Energy Commission (1967-73).
Member, Radiation Research Society (1954 - ).
Member, the Health Physics Society (1956 - ). Board of Directors (1970-73).
Member, Society for Experimental Biology and Medicine (1973 - ). Vice Chairman, Northwest
Section (1967-70,1974-76).
Member, Sigma Xi (1953 - ). Vice Chairman, Tri-Cities, Washington Club (1973-74).
Member, Reticuloendothelial Society (1960 - ).
B.8
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CASARETT, GEORGE W.
DATE OF BIRTH: 1920
EDUCATION:
1938-41 University of Toronto (pre med.)
1943-45 University of Rochester (pre med.)
1948-52 University of Rochester (graduate school in medicine)
1952 Ph.D.
PAST POSITIONS:
1959-63 Associate Professor in Radiation Biology. Chief, Radiation Pathology Section,
Atomic Energy Project. Chief, Radiation Pathology Section, Radiation Therapy
Department.
1957-59 Assistant Professor in Radiation Biology Department Scientist (Rad. Path.)
Atomic Energy Project.
1953-57 Instructor in Radiation Biology Department. Scientist (Rad. Path.) Atomic Energy
Project.
1947-53 Chief of Pathology Unit and Assistant Chief of Radiation Tolerance Section,
Atomic Energy Project.
1943-47 Research Assistant in Pathology Division, Manhattan Project.
PRESENT POSITION:
Professor of Radiology (secondary appointment). Director of Experimental Research in Clinical
Radiation Research Center.
Professor of Radiation Biology and Biophysics (primary appointment). Head of Radiation
Pathology Section of Atomic Energy Project.
PUBLICATIONS:
175 Journal articles, book chapters, reports, or books, chiefly on radiation pathology, radiation
biology, carcinogenesis, cancer biology, and gerontology.
HONORS AND/OR CITATIONS:
Co-winner (with collaborators) of First Award and Silver Roentgen Medal, Meeting of American
Roentgen Ray Society Meeting, 1959.
Co-winner (with collaborators) of First Award (cum laude) for Fundamental Research, Annual
Meeting of Radiological Society for North America, 1959,1964,1971.
B.9
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CURRENT CONSULTANTSHIPS:
Chairman of National Academy of Sciences Advisory Committee on Biological Effects of Ionizing
Radiations. (Formerly member of NAS Advisory Committee to Federal Radiation Council.)
Member of Board of Directors of National Council on Radiation Protection and Measurement
(NCRP).
Chairman of Scientific Committee 14 of National Council on Radiation Protection and
Measurement (NCRP).
Chairman of NCRP ad hoc Committee on Comparison of Radiation Protection Philosophies.
Member of National Cancer Institute Cancer Research Training Committee. (Committee
inactive at present.)
Consultant to Task Group on Biological Effects of Inhaled Particulates, of International Commission
on Radiological Protection.
B.10
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EPP, EDWARD R.
DATE OF BIRTH: 1929
EDUCATION:
B.A. 1950 University of Saskatchewan
M.A. 1952 University of Saskatchewan
Ph.D. 1955 McGill University
PAST POSITIONS: _ , _. , . cl „ „ . _. . .
Dept. of Biophysics, Sloan-Kettermg Division,
Sloan-Kettering Institute Graduate School of Medical Sciences,
for Cancer Research Cornell University
1973—74
1969-74
1968-72
1964-69
1960-64
1957-60
Laboratory Head
Member
Chief, Div. of Physical Biology
Assoc. Member
Associate
Assistant
1970-74
1966-72
1966-70
1960-66
1958-60
1957-58
Professor (Dept.)
Chairman (Dept.)
Assoc. Professor
Asst. Professor
Associate
Assistant
1967-74 Associate Attending Physicist, Dept. of Medical Physics, Memorial Hospital
for Cancer and Allied Diseases.
1956-57 Consultant Physicist, Dept. of Radiology, Montreal Children's Hospital.
1955-57 Radiation Physicist, Department of Radiology, Montreal General Hospital.
1952-53 Scientific Staff, National Research Council of Canada
1949-50 Summer Research Assistant, Physics Dept., University of Saskatchewan.
PRESENT POSITION:
Radiation Biophysicst and Head, Division of Radiation Biophysics, Massachusetts General
Hospital (1974 - ).
Professor of Radiation Therapy (Radiation Biophysics), Faculty of Medicine, Harvard University
(1974- ).
PUBLICATIONS:
33 Journal articles chiefly on radiation physics and radiation biology.
CURRENT CONSULTANTSHIPS:
Radiation Study Section of NIH (1971-75).
Editorial Board, Radiation Research Journal (1972-75).
Chairman, Scientific Program Committee-AAPM (1972 - ).
Councillor in Physics, Radiation Research Society (1974 - ).
B.11
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GOLDMAN, MARVIN
DATE OF BIRTH: 1928
EDUCATION:
A.B. 1949 Adelphi University (Biology)
M.S. 1951 University of Maryland (Zoology-Physiology)
Ph.D. 1957 University of Rochester (Radiation Biology)
PAST POSITIONS:
1972-73 Principal Investigator, Studies on Canine Bone Density, NASA, (NAS2-6763),
University, of California, Davis.
Biophysicist-Physiologist, Division of Biomedical and Experimental Research,
U.S. Atomic Energy Commission.
Associate Director for Sciences, UCD
1971-72 . Consultant, General Electric Company
1970-71 Principal Investigator, Studies on 89Sr Toxicity in Mice, USPHS, UCD.
1968-71 Collaborator, Orbital Flight Effects on Calcium Kinetics and Fracture Healing
Repair, NASA (NAS2-5057), UCD.
1958-64 Associate Radiobiologist, UCD.
PRESENT POSITION:
Director, Radiobiology Laboratory, UCD (1973 - ).
Professor of Radiobiology, Department of Radiological Sciences, School of Veterinary Medicine
and Department of Radiology, School of Medicine, UCD (1973 - ).
Research Radiobiologist, Radiobiology Laboratory, UCD (1964 - ).
PUBLICATIONS:
101 Journal articles, book chapters, reports, or books, chiefly on radiation pathology, radiation
biology and carcinogenesis.
HONORS AND/OR CITATIONS:
E. O. Lawrence Memorial Award presented by the U.S. Atomic Energy Commission (1972).
CURRENT CONSULTANTSHIPS:
Council Member, National Council on Radiation Protection and Measurements (1974 - ).
Chairman, U.S. Atomic Energy Commission, DSNS/DBER Biomedical Working Group (1973 - ).
Member, University of California Cancer Research Coordinating Committee (1973 - ).
Co-principal Investigator, Tumor Biology Training Grant, NIH/NCI (1972 - ).
Member, Advisory Committee, Crocker Nuclear Laboratory, University of California, Davis
(1971- ).
B.12
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GREGG, EARLE C.
DATE OF BIRTH: 1918
EDUCATION:
B.S. 1940 Case Institute of Technology, Cleveland
M.S. 1942 Case Institute of Technology, Cleveland
Ph.D. 1949 Case Institute of Technology, Cleveland (Physics)
PAST POSITIONS:
1958-65 Associate Professor of Radiology (Radiation Physics), Case Western Reserve
University.
1952-58 Associate Professor of Physics, Case Institute of Technology
1949-52 Assistant Professor of Physics, Case Institute of Technology
1946-49 Instructor in Physics, Case Institute of Technology
1943-46 Research Associate, Columbia University
1942-43 Research Associate, Massachusetts Institute of Technology
PRESENT POSITION:
Professor of Radiology (Radiation Physics), Case Western Reserve University (1965 - ).
Chief, Radiologic Physics, Department of Radiology, University Hospitals.
Chief, Biophysics Section, Division of Radiation Biology, Case Western Reserve University.
Chairman, Biophysics Graduate Study Program, Case Western Reserve University.
Committee on Human Use of Radioisotopes, University Hospitals.
Chairman, Committee on Biophysics, Case Western Reserve University.
Visiting Staff, Metropolitan General, St. John's, Highland View, and Lutheran Hospitals.
PUBLICATIONS:
107 Journal articles chiefly on biophysics, ultrasonics, radiologic physics and nuclear physics.
HONORS AND/OR CITATIONS:
Member of Editorial Board, Investigative Radiology.
Fellow, American Physical Society.
Standards Committee, American College of Radiology.
Past Editor, Journal Applied Physics.
Scientific Committee, American Association Physics in Medicine.
B.13
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HONORS AND/OR CITATIONS (Continued):
Registered Professional Engineer, State of Ohio.
Member, Radiation Study Section, National Institutes of Health.
Committee on Radiology, National Academy of Sciences.
Member, Cancer Research Center Review Committee, National Institutes of Health.
Member, Advisory Committee on the Biological Effects of Ionizing Radiations (BEIR), National
Academy of Sciences.
Chairman, Division of Biological Physics, American Physical Society.
'B.14
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LEWIS, EDWARD B.
DATE OF BIRTH: 1918
EDUCATION:
B.S. 1939 University of Minnesota
Ph.D. 1942 California Institute of Technology
PAST POSITIONS:
1956-66 Professor, California Institute of Technology.
1949-56 Associate Professor, California Institute of Technology.
1948-49 Assistant Professor, California Institute of Technology
1948-49 Rockefeller Foundation Fellow, School of Botany,Cambridge University, Cambridge,
England.
1946-48 Instructor in Genetics, California Institute of Technology.
1942-45 U.S. Army Air Force meteorologist and oceanographer.
PRESENT POSITION:
Thomas Hunt Morgan Professor, California Institute of Technology (1966 - ).
PUBLICATIONS:
21 Journal articles chiefly on genetics of drosophila and carcinogenic effects of ionizing radiation
on human populations.
HONORS AND/OR CITATIONS:
Member, National Academy of Sciences (1968 - ).
Genetics Society of America (Secretary 1962-64) (Vice President 1966) (President 1967).
Fellow, American Association for the Advancement of Science.
American Academy of Arts and Sciences.
American Society of Human Genetics.
CONSULTANTSHIPS:
National Council for Radiation Protection and Measurements.
Advisory Committee on the Biological Effects of Ionizing Radiation, National Research Council -
National Academy of Sciences.
B.15
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McCLELLAN, ROGER O.
DATE OF BIRTH: 1937
EDUCATION:
1960 Doctor of Veterinary Medicine with Highest Honors, Washington State
University
PAST POSITIONS:
1966-73 Assistant Director of Research and Director, Fission Product Inhalation Program,
Lovelace Foundation for Medical Education and Reasearch, Albuquerque,
New Mexico.
1965-66 Scientist, Medical Research Branch, Division of Biology and Medicine, U.S. Atomic
Energy Commission, Washington, D.C.
1965- Senior Scientist, Biology Department, Pacific Northwest Laboratories, Battelle
Memorial Institute, Richland, Washington (leave of absence to the U.S.A.E.C.)
1963-64 Senior Scientist, Biology Laboratory, Hanford Laboratories, General Electric
Company, Richland, Washington.
1959-62 Biological Scientist, Biology Laboratory, Hanford Laboratories, General Electric
Company, Richland, Washington.
1957-58 (Summers) - Junior Scientist, Biology Laboratory, Hanford Laboratories, General
Electric Company, Richland, Washington.
1957-60 Research Assistant, Department of Veterinary Microbiology, Washington State
University, Pullman, Washington.
PRESENT POSITIONS:
Vice President and Director of Research Administration and Director, Inhalation Toxicology
Research Institute, Lovelace Foundation for Medical Education and Research, Albuquerque,
New Mexico.
PUBLICATIONS:
192 Scientific publications, technical reports or abstracts on various aspects of the metabolism,
toxicity and internal dosimetry of radionuclides in experimental animals.
HONORS AND/OR CITATIONS:
Elda E. Anderson Award, Health Physics Society (1974).
CONSULTANTSHIPS:
Member, ad hoc Committee on "Hot Particles", Advisory Committee on the Biological Effects
of Ionizing Radiations (BEIR), National Research Council (1974 - ).
Member, North American Late Effects Group Steering Committee (1974 - ).
B.16
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CONSULTANTSHIPS (Continued):
Chairman, Environmental Radiation Exposure Advisory Committee Member, Scientific Advisory
Board, Environmental Protection Agency (1974 - ).
Member, National Institutes of Health, Animal Resources Advisory Committee (1974-78).
Member, Environmental Radiation Exposure Advisory Committee of the Environmental
Protection Agency (1972 - ).
Member, Transuranium Technical Group (Advisory to U.S. Atomic Energy Commission,
Division of Biomedical and Environmental Research) (1972 - ).
Member, National Council on Radiation Protection and Measurements (1971 - ).
Program Committee Member and Chairman, Health Physics Society (1970-73).
President, American Board of Veterinary Toxicology (1970-73).
Member, Subcommittee on Whole Animal Radiobiology and Pathology, Los Alamos Meson
Physics Facility (LAMPF) (1970 - ).
Chairman, Scientific Committee #30 of National Council on Radiation Protection and
Measurements (1969 - ).
Member, Toxicology Study Section, National Institutes of Health (1969-73).
Consultant, National Institute of Environmental Health Sciences, National Institutes of Health
(1968-71).
Councilman, American College of Veterinary Toxicologists (1968-71).
Advisor, Laboratory Animal Biology and Medicine Training Program, University of California,
Davis (1968-70).
Member, Joint Space Nuclear Systems/Biomedical and Environmental Research Working
Group (1967-73).
B.17
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RADFORD, EDWARD P.
DATE OF BIRTH: 1922
EDUCATION:
1937-40
1940-43
1943-46
M.D. 1946
Phillips Exeter Academy, Exeter, New Hampshire
Massachusetts Institute of Technology
Harvard Medical School
Harvard Medical School
PAST POSITIONS:
1965-68
1959-65
1955-59
1952-55
1950-52
1949-50
1947-49
1946-47
Professor and Director, Department of Environmental Health
Director of Kettering Laboratory
Professor of Physiology, College of Medicine, University of Cincinnati.
Associate Professor of Physiology, Harvard School of Public Health.
Physiologist, Haskell Laboratory for Toxicology and Industrial Medicine, E. I. duPont
de Nemours and Company, Newark, Delaware.
Associate, Department of Physiology, Harvard School of Public Health.
Instructor, Department of Physiology, Harvard Medical School.
Teaching Fellow, Department of Physiology, Harvard Medical School.
Active Duty, U.S. Air Force, Chief of Medical Service, Maxwell Air Force Base,
Montgomery, Alabama.
Rotating Internship, Geisinger Memorial Hospital, Danville, Pennsylvania.
PRESENT POSITION:
Professor of Environmental Medicine, School of Hygiene and Public Health, Johns Hopkins
University (1968 - ).
PUBLICATIONS:
Several scientific journal articles and published testimony before legislative bodies chiefly on
radiation biology, health effects of environmental pollutants, and carcinogenesis.
HONORS AND/OR CITATIONS:
National Scholar, Harvard Medical School (1943-46).
Macy Faculty Scholar Award (1975-76).
CONSULTANTSHIPS:
Medical Consultant to Council on Environmental Quality, Washington, D.C. (1975 - ).
Consultant in Occupational Health, State of Maryland, Division of Labor and Industries (1973 - ).
B.18
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CONSULTANTSHIPS (Continued):
Faculty Member, Westinghouse International School of Environmental Management,
Ft. Collins, Colorado (1972 - ).
Consultant to Department of Anesthesiology, Massachusetts General Hospital, Boston,
Massachusetts (1963 - ).
National Academy of Sciences Committee on Medical and Biological Effects of Environmental
Pollutants, Subcommittee on Carbon Monoxide.
National Academy of Sciences Advisory Committee on the Biological Effects of Ionizing Radiations,
ad hoc Committee on "Hot Particles."
Advisory Council, Bureau of Air Quality Control, State of Maryland.
Radiation Control Advisory Board, State of Maryland.
Chairman, Power Plants and Human Health and Welfare Studies Group, Department of Natural
Resources, State of Maryland (1972-73).
Member, National Academy of Sciences Advisory Committee on the Biological Effects of Ionizing
Radiation (1970-72).
Member, The Governor's Advisory Council on Nuclear Reactors, State of Pennsylvania (1973-74).
B.19
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APPENDIX C
COMMITTEE MEETINGS AND ATTENDANCE
November 14, 1974
Committee Members
Albert, Dr. Roy E., New York University Medical
Center, New York, N.Y.—Chairman
Alpen, Dr. Edward L, Battelle Pacific Northwest
Laboratory, Richland, Wash.
Bair, Dr. William J., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Casarett, Dr. George W., University of Rochester
Medical Center, Rochester, N.Y.
Epp, Dr. Edward R., Massachusetts General Hos-
pital, Boston, Mass.
Goldman, Dr. Marvin, University of California,
Davis, Calif.
Gregg, Dr. Earle C., University Hospital, Cleveland,
Ohio
Lewis, Dr. Edward B., California Institute of Tech-
nology, Pasadena, Calif.
McClellan, Dr. Roger O., Lovelace Foundation,
Albuquerque, New Mexico
Guests
Ellett, Dr. William H., Environmental Protection
Agency, Washington, D.C.
Mills, Dr. William A., Environmental Protection
Agency, Washington, D.C.
Wachholz, Dr. Bruce W., Atomic Energy Commis-
sion, Washington, D.C.
National Academy of Sciences—Assembly of Life
Sciences—Division of Medical Sciences
Hilberg, Dr. Albert W., Senior Staff Officer
McConnaughey, Dr. David A., Senior Staff Officer
January 30 - 31, 1975 - (Jan. 30)
Committee Members
Albert, Dr. Roy E., New York University Medical
Center, New York, N.Y.—Chairman
Bair, Dr. William J., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Casarett, Dr. George W., University of Rochester
Medical Center, Rochester, N.Y.
Epp, Dr. Edward R., Massachusetts General Hos-
pital, Boston, Mass.
Goldman, Dr. Marvin, University of California,
Davis, Calif.
Gregg, Dr. Earle C., University Hospital, Cleveland,
Ohio
Lewis, Dr. Edward B., California Institute of Tech-
nology, Pasadena, Calif.
McClellan, Dr. Roger O., Lovelace Foundation,
Albuquerque, New Mexico
Radford, Dr. Edward P., Johns Hopkins University,
Baltimore, Maryland
Guests
Alexander, Mr. R. E., Nuclear Regulatory Comis-
sion, Washington, D.C.
Hobbs, Dr. Charles H., Lovelace Foundation,
Albuquerque, New Mexico
Nelson, Dr. Neal S., Environmental Protection
Agency, Washington, D.C.
Park, Dr. James F., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Sanders, Dr. Charles L., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Wachholz, Dr. Bruce W., Atomic Energy Commis-
sion, Washington, D.C.
National Academy of Sciences—Assembly of Life
Sciences—Divison of Medical Sciences
Hilberg, Dr. Albert W., Senior Staff Officer
McConnaughey, Dr. David A., Senior Staff Officer
C.1
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January 30 - 31, 1975 - (Jan. 31)
Committee Members
Albert, Dr. Roy E., New York University Medical
Center, New York, N.Y.—Chairman
Bair, Dr. William }., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Casarett, Dr. George W., University of Rochester
Medical Center, Rochester, N.Y.
Epp, Dr. Edward R., Massachusetts General Hos-
pital, Boston, Mass.
Goldman, Dr. Marvin, University of California,
Davis, Calif.
Gregg, Dr. Earle C, University Hospital, Cleveland,
Ohio
Lewis, Dr. Edward B., California Institute of Tech-
nology, Pasadena, Calif.
Radford, Dr. Edward P., Johns Hopkins University,
Baltimore, Maryland
Guests
Alexander, Mr. R. E., Nuclear Regulatory Commis-
sion, Washington, D.C.
Hobbs, Dr. Charles H., Lovelace Foundation,
Albuquerque, New Mexico
Nelson, Dr. Neal S., Environmental Protection
Agency, Washington, D.C.
Park, Dr. James F., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Sanders, Dr. Charles L., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Wachholz, Dr. Bruce W., Atomic Energy Commis-
sion, Washington, D.C.
National Academy of Sciences—Assembly of Life
Sciences—Division of Medical Sceiences
Hilberg, Dr. Albert W., Senior Staff Officer
March 13 - 14,1975 - (Mar. 13)
Committee Members
Albert, Dr. Roy E., New York University Medical
Center, New York, N.Y.—Chairman
Bair, Dr. William J., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Casarett, Dr. George W., University of Rochester
Medical Center, Rochester, N.Y.
Epp, Dr. Edward R., Massachusetts General Hos-
pital, Boston, Mass.
Goldman, Dr. Marvin, University of California,
Davis, Calif.
Gregg, Dr. Earle C., University Hospital, Cleveland,
Ohio
McClellan, Dr. Roger O., Lovelace Foundation,
Albuquerque, New Mexico
Radford, Dr. Edward P., Johns Hopkins University,
Baltimore, Maryland
National Academy of Sciences—Assembly of Life
Sciences—Divison of Medical Sciences
Hilberg, Dr. Albert W., Senior Staff Officer
Kennedy, Dr. Thomas J., Jr., Executive Director,
Assembly of Life Sciences
Vosburg, Dr. Albert C., Associate Executive Direc-
tor, Assembly of Life Sciences
March 13 - 14,1975 - (Mar. 14)
Committee Members
Albert, Dr. Roy E., New York University Medical
Center, New York, N.Y.—Chairman
Bair, Dr. William J., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Casarett, Dr. George W., University of Rochester
Medical Center, Rochester, N.Y.
Epp, Dr. Edward R., Massachusetts General Hos-
pital, Boston, Mass.
Goldman, Dr. Marvin, University of California,
Davis, Calif.
Gregg, Dr. Earle C., University Hospital, Cleveland,
Ohio
Lewis, Dr. Edward B., California Institute of Tech-
nology, Pasadena, Calif.
McClellan, Dr. Roger O., Lovelace Foundation,
Albuquerque, New Mexico
Radford, Dr. Edward P., Johns Hopkins University,
Baltimore, Maryland
National Academy of Sciences—Assembly of Life
Sciences—Division of Medical Sciences
Hilberg, Dr. Albert W., Senior Staff Officer
C.2
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May 21 - 22,1975 - (May 21)
Committee Members
Albert, Dr. Roy E., New York University Medical
Center, New York, N.Y.—Chairman
Alpen, Dr. Edward L, Battelle Pacific Northwest
Laboratory, Richland, Wash.
Bair, Dr. William J., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Casarett, Dr. George W., University of Rochester
Medical Center, Rochester, N.Y.
Epp, Dr. Edward R., Massachusetts General Hos-
pital, Boston, Mass.
Gregg, Dr. Earle C, University Hospital, Cleveland,
Ohio
Lewis, Dr. Edward B., California Institute of Tech-
nology, Pasadena, Calif.
McClellan, Dr. Roger O., Lovelace Foundation,
Albuquerque, New Mexico
Radford, Dr. Edward P., Johns Hopkins University,
Baltimore, Maryland
National Academy of Sciences—Assembly of Life
Sciences—Division of Medical Sciences
Hilberg, Dr. Albert W., Senior Staff Officer
May 21 22, 1975 - (May 22)
Committee Members
Albert, Dr. Roy E., New York University Medical
Center, New York, N.Y.—Chairman
Alpen, Dr. Edward L., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Bair, Dr. William J., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Casarett, Dr. George W., University of Rochester
Medical Center, Rochester, N.Y.
Epp, Dr. Edward R., Massachusetts General Hos-
pital, Boston, Mass.
Gregg, Dr. Earle C., University Hospital, Cleveland,
Ohio
Lewis, Dr. Edward B., California Institute of Tech-
nology, Pasadena, Calif.
McClellan, Dr. Roger O., Lovelace Foundation,
Albuquerque, New Mexico
Radford, Dr. Edward P., Johns Hopkins University,
Baltimore, Maryland
National Academy of Sciences—Assembly of Life
Sciences—Division of Medical Sciences
Hilberg, Dr. Albert W., Senior Staff Officer
Kennedy, Dr. Thomas J., Jr., Executive Director,
Assembly of Life Sciences
Sitton, Mr. Paul L., Special Assistant to the NAS
President
July 8-9, 1975 - (July 8)
Committee Members
Albert, Dr. Roy E., New York University Medical
Center, New York, N.Y.—Chairman
Alpen, Dr. Edward L., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Bair, Dr. William J., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Casarett, Dr. George W., University of Rochester
Medical Center, Rochester, N.Y.
Epp, Dr. Edward R., Massachusetts General Hos-
pital, Boston, Mass.
Goldman, Dr. Marivn, University of California,
Davis, Calif.
Gregg, Dr. Earle C., University Hospital, Cleveland,
Ohio
Lewis, Dr. Edward B., California Institute of Tech-
nology, Pasadena, Calif.
McClellan, Dr. Roger O., Lovelace Foundation,
Albuquerque, New Mexico
Radford, Dr. Edward P., Johns Hopkins University,
Baltimore, Maryland
Guests
Cochran, Dr. Thomas B., Natural Resources Defense
Council, Washington, D.C.
Ellett, Dr. William H., Environmental Protection
Agency, Washington, D.C.
Tamplin, Dr. Arthur R., Natural Resources Defense
Council, Washington, D.C.
National Academy of Sciences—Assembly of Life
Sciences—Division of Medical Sciences
Hilberg, Dr. Albert W., Senior Staff Officer
Kennedy, Dr. Thomas J., Jr., Executive Director,
Assembly of Life Sciences
C.3
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July 8 - 9,1975 - (July 9)
Committee Members
Albert, Dr. Roy E., New York University Medical
Center, New York, N.Y.—Chairman
Alpen, Dr. Edward L, Battelle Pacific Northwest
Laboratory, Richland, Wash.
Bair, Dr. William J., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Casarett, Dr. George W., University of Rochester
Medical Center, Rochester, N.Y.
Epp, Dr. Edward R., Massachusetts General Hos-
pital, Boston, Mass.
Goldman, Dr. Marvin, University of California,
Davis, Calif.
Gregg, Dr. Earle C.,-University Hospital, Cleveland,
Ohio
Lewis, Dr. Edward B., California Institute of Tech-
nology, Pasadena, Calif.
Radford, Dr. Edward P., Johns Hopkins University,
Baltimore, Maryland
Guest
Ellett, Dr. William H., Environmental Protection
Agency, Washington, D.C.
National Academy of Sciences—Assembly of Life
Sciences—Division of Medical Sciences
Hilberg, Dr. Albert W., Senior Staff Officer
November 21, 1975
Committee Members
Albert, Dr. Roy E., New York University Medical
Center, New York, N.Y.—Chairman
Alpen, Dr. Edward L., Donner Laboratory, Univer-
sity of California, Berkeley, Calif.
Bair, Dr. William J., Battelle Pacific Northwest
Laboratory, Richland, Wash.
Casarett, Dr. George W., University of Rochester
Medical Center, Rochester, N.Y.
Epp, Dr. Edward R., Massachusetts General Hos-
pital, Boston, Mass.
Goldman, Dr. Marvin, University of California,
Davis, Calif.
Gregg, Dr. Earle C, University Hospital, Cleveland,
Ohio
Lewis, Dr. Edward B., California Institute of Tech-
nology, Pasadena, Calif.
McClellan, Dr. Roger O., Lovelace Foundation,
Albuquerque, New Mexico
Guest
Counts, Ms. Leila, Battelle Pacific Northwest
Laboratory, Richland, Washington
National Academy of Sciences—Assembly of Life
Sciences—Division of Medical Sciences
Hilberg, Dr. Albert W., Senior Staff Officer
C.4
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