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OCR for page 415
APPENDIX ~{
Cellular Radiobiology
INTRODUCTION
Cellular radiobiology is a well-developed discipline, dating to almost
90 yr ago, when it was first recognized that exposure to ionizing radiation
had biological consequences. Much information has since been accumulated
from studies with irradiated animals and plants and, over the last 50 yr
in particular, from studies of effects at the cellular, physical, and chemical
levels. Molecular and cellular radiobiology have contributed greatly both
to our understanding of the physical and chemical processes involved in
the induction of radiation effects and to our understanding of the responses
observed in whole organisms. Mom the vast store of radiobiological in-
formation, it is possible to draw a number of general principles.26 28~35~36
These principles sometune constitute our only rational basis for making
human risk assessments, for example, when direct empirical observations
on which to base such assessments are not available.
DOS~RESPONSE CURVES
Many models have been developed to describe radiabiological re-
sponses, but one broad generalization is that empirical dose-response
curves for cellular radiobiological effects, whether in viva or in vitro,
take the general form:
Y = (a + ID + ABODE) expt—ID—,B2D2), (II-1)
where Y is the response observed in a population, a is the spontaneous
incidence, axe and ,6~ are the coefficients for the induction of the observed
415
OCR for page 416
416
HEALTH RISKS OF RADON AND OTHER ALPHA fITTERS
effect, D is the dose, and the exponential is a term expressing the loss
of observed response due to competing effects, such as cell killing, with
2 and p2 as the coefficients for cell kiBing. For doses well below that
at which competing effects are important, the simpler expression, Y =
a + cad + pD2, suffices. The relationship is often referred to as mixed
quadratic or linear-quadratic, although the expression is simply quadratic.
Such an expression adequately describes the dose-response relationship at
low to moderate doses of low linear energy transfer (LET) radiation for
a wide variety of cellular radiobiological endpoints, including induction of
mutations and induction of the various classes of chromosomal aberrations.
As described in more detail below, the quadratic expression also describes
adequately the responses of such systems to high-LET radiation.
Cell killing is often analyzed according to the following expression for
survival:
S = 1—(1—e ),
(II-2)
where k is the coefficient for killing, and n is an exponent often called the
hit number or extrapolation number. The survival fraction can also be
expressed by an c'D + pD2 model of the form:
S = expt—aD—,BD2),
(II-3)
the same as the last term in the complete quadratic with saturation model
given above in Equation II-1.
Although the quadratic model can be derived entirely empirically from
response data, there appears to be a rational biophysical basis. What such
dose-effect curves imply is that some of the effects of radiation of any given
class are induced by single ionizing events (i.e., the passage of a single
photon or of a single particle), whereas others result from the interaction
of two or more statistically independent ionizing events. The dose-squared
term can be understood in another way: If P is the probability of hitting
a target and causing a sublethal amount of damage, then the probability
that target will be hit twice (or more), to give an effective hit, is (P)(P),
or p2. The quadratic expression can yield curves ranging from linear (or
nearly linear), in the case where l] is so small in relation to ax that the aD
dominates, to essentially dose-squared, in the case where ~ is negligibly
small in relation to ,0. Mutation induction in simple prokaryotic cells is an
example of linear response, and the induction of two-break chromosomal
aberrations of the exchange type in higher eukaryotic cells exposed to acute
doses of low-LET radiation is an example of quadratic response. Many
dose-response curves, however, are somewhere in between.
OCR for page 417
CELLULAR RADIOBIOLOGY
EFFECT OF DOSE RATE AND FRACTIONATION
417
The expressions presented above apply specifically to low-LET radi-
ation, such as x or gamma rays, delivered at a high (acute) rate. It was
noticed early, however, that when low-LET doses were protracted or appre-
ciable periods passed between successive dose fractions, the effectiveness
of the total dose was likely to diminish. In fact, as dose rate decreased,
the radiobiological endpoints that at higher dose rates had response curves
with an appreciable ,BD2 term began to lose that term. Eventually, little
was left of the pD2 term, and the dose-response curve was essentially
linear, represented simply by aD. With increasing interfraction time, much
the same thing happened, with the ,BD2 term for the total dose decreasing
until, instead of what is often called complete interaction ti.e., p(D, +
D2 + D3 . . .121, one observed the sum of pD2 terms for the individual
fractions (i.e., ,CD,2 + ~BD22 + ,BD32 . . A. This implied that somehow
the subeffective partial lesions left at the end of the first dose fraction were
becoming unavailable, or repaired, with time; thus, if enough time elapsed
between fractions (a few hours), none were left from the first dose fraction
to interact with those from the second. Loss of subeffective partial lesions
also accounts for the sunple dose-rate effect. Lea35 understood this early
and created a correction factor that he called the G factor to correct for
dose-rate effects:
G = 2~/T)2(T/r—1 + e-/,
(II-4)
where ~ Is the average time between breakage and restitution, and T is
the duration of treatment.
EFFECT OF LET
As the LET of radiation (usually calculated as track-average LET)
increases, two things happen. First, for radiobiological endpoints that have
a substantial ,BD2 term with acute doses of low-LET radiation, the curves
begin to straighten, losing the D2 component and tending toward linearity.
Second, the effectiveness of the c'D component also increases, indicating
that this is not the same phenomenon as that observed for dose rate or
fractionation with low-LET radiation. In sum, the higher-LET radiation
seems to be capable, if it deposits energy in a target at all, of causing
fully effective events. In other words, the production of subeffective lesions
becomes less and less likely, while the production of fully effective lesions
becomes more likely as LET increases. This makes sense, because as the
ionization per unit track length increases, a target becomes more likely to
suffer substantial damage, if it is affected at all. In fact, one might expect
that if the LET of radiation becomes high enough, the effectiveness with
OCR for page 418
418
HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
increasing LET would saturate at some point and then fall off as the LET
continued to increase. That is what is observed, particularly in prokaryotic
systems. For the induction of radiobiological effects in mammalian cells,
the target volume appears to be large enough for the effect to occur at a
higher LET, with the maximally eRective LET being around 100 keV/,um.
MICROSCOPIC DOSE DISTRIBUTION
With energetic photon irradiation, the quantity dose, used in calcu-
lating a dose-effect model, has an easily understood meaning and is easy
to measure empirically. However, the situation often is not so simple for
particle irradiation from internally deposited radionuclides, particularly
when the mean path length of the charged particle is small in relation to
the diameter of the average cell or subcellular structure of interest and
when the distribution of the radionuclide is very nonuniform. The problem
is particularly acute when, as in the case of tritium incorporated into the
DNA of a cell in the form of tritiated purines or pyrimidines, only parts
of cells have incorporated the radionuclide and only some of the potential
target cells have incorporated any radionuclide at all. In such cases, dose
expressed in the usual terms of the average amount of energy deposited
per unit of tissue mass over the mass of the organs (or parts of organs)
becomes meaningless, if not actually misleading. Here it is important to
consider the microscopic distribution of dose and the doses accumulated
by individual targets (usually taken to be individual cell nuclei).
In the case of the alpha-emitting radionuclides of interest here, we must
consider the problem presented by the inadequacy of simply measuring
body or even organ burdens of a radionuclide, and try instead to identify
the target cells at risk for a particular possible health impact and then to
determine the average dose to the nuclei of all these cells. The distribution
factor will otherwise be confounded with the relative biological effectiveness
(RBE) factor, and that can lead to large uncertainties and ambiguities. In
fact, if the RBE for a given particle seems to be reasonably well established,
deviations from that RBE can be used to infer the magnitude that must
be attributed to the microscopic dose-distribution factor.
MODELS OTHER THAN THE QUADRATIC
Models designed to describe and, thus, to permit prediction of the
response of cell populations to radiation with different LETs can be di-
vided broadly into two categories: those derived empirically from observed
cellular dose-response curves (observation obviates assumptions about or
dependence on underlying molecular or subcellular biological ejects or
mechanisms), and those built on assumptions about underlying subcellular
OCR for page 419
CELLULAR RADIOBIOLOGY
419
mechanisms (which might or might not be shown to be applicable). A1-
though the two approaches must ultimately converge, there can be little
confidence that this will occur soon.
The first category includes two models that are related to the original
target theory:35 the quadratic model and the model of Bond et al.8 As
noted above, the former is applicable to a wide variety of endpoints in many
systems, particularly with low-level exposure to radiation ti.e., either small
doses at any dose rate or larger doses at very low dose rates). It also
adequately accommodates dose-rate and protraction effects and accurately
describes most responses as a function of LET in tissue in terms of an
increasing ED component and a decreasing ,BD2 contribution as the LET
increases.
Thus, with very low doses, the mean absorbed dose to the population of
cells increases only because the fraction of cells hit increases; the mean dose
(specific energy) delivered stochastically to the hit cells remains constant.
However, as the fraction of cells hit approaches unity, the absorbed dose
to the cell population can increase only if the number of hits per cell
increases.8 At high doses and high dose rates, where each cell has received
many hits, the variance of the mean decreases; so the dose to each cell, the
mean dose to the cell population, and the mean dose to the organ or other
medium approach equality.
The other model that belongs in this category and that combines some
elements of hit theory with those of microdosimetry is under development.8
The unique addition is an empirically derived hit size effectiveness factor.
This factor gives the probability that a cell with a certain amount of energy
deposited within it will respond as a function of the energy deposited. Ad-
ditional testing with different endpoints and biological systems is necessary
before the degree of applicability of the model can be ascertained.
The second category includes several models that cover a wide vari-
ety of assumptions, some of which are commented on below. The early
dual-action model33 combines microdosimetry with assumptions about the
stochastic interactions of microdosimetric events to derive the basic for-
mulation:
E = K(§D + D2),
(II-5)
where S. is a physical quantity equal to the average specific energy (dose
to a subcellular target volume in single events), and K is the sensitivity
coefficient. This expression is equivalent to the more general aD ~ ,BD2
formulation, with K: equivalent to ~ and K equivalent to §.
A recently developed thesis is the lethal and potentially lethal model,24
which, with the earlier repair-nonrepair model of cell survival46 and other
models, is built on the added assumptions of irreparable lethal lesions,
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420
HEALTH RISKS OF RADON AND OTHER ALPHA-EMITS
repairable potentially lethal lesions, first-order kinetics for correct repair,
and second-order kinetics for misrepair. Although the models have been
applied only to cell lethality in plateau-phase tstationary-phase) cells in
culture, they do take LET and dose rate into account. The principal
mathematical formulation is complex and embraces a power expansion,
but the first two terms also yield the aD + ,BD2 expression. Such models
constitute valuable contributions in attempting to unify the most attractive
features of a number of others; the extent of their universality remains to
be determined.
Other models have also been developed, for example, the molecular
theory of Chadwick and Leenhouts,2t the kinetic model of Dienes,25 the
cybernetic model of Kappos and Pohlit,32 the incomplete-repair model
of Thames,45 and the repair model of Braby and Roesch.~9 Many are
limited, in that they deal either with only a small fraction of the many
radiobiological factors that must be taken into account (e.g., some are
limited to high dose rates and others to the question of repair, possible
misrepair, and dose rate), or in encompassing only particular endpoints
(e.g., some deal only with cell lethality, and others exclude it).
There is evidence that the various models can be reconciled, but it
seems unlikely that there will be general agreement or that the mechanistic
assumptions behind any of them will soon be proved.
None of the models in this category has the simplicity or the generality
of application of the quadratic model, and none is at the point of applica-
bility to the problems of predicting either genetic or carcinogenic responses
in mammalian systems. Thus, although they contribute to our general
understanding and appreciation of problems remaining to be solved, they
cannot yet be applied in practical exercises that require the prediction of
risk associated with exposure to principally low-level radiation. Therefore,
it appears reasonable that the quadratic model be used.
APPLICATION TO RISK ESTIMATION FOR
INCORPORATED ALPHA-EMITTING RADIONUCLIDES
With some notable exceptions such as Thorotrast-exposed patients,
radium-dial painters, or uranium miners there is generally little direct
information on the human health effects of the internally incorporated
alpha-emitting radionuclides. However, we can derive several generaliza-
tions that can be applied to the problem of extrapolating available empirical
evidence of the induction of human health effects by low-LET radiation.
First, even though the question of whether the low-LET effects best fit
a simple linear dose-response model or a dose-squared model is unsettled, as
far as the epidemiological data on radiation carcinogenesis are concerned
(see Committee on the Biological Effects of Ionizing Radiations WEIR
OCR for page 421
C~.rr.l~AR RADIOBIOLOGY
421
IIIi38), we can be reasonably sure that the dose-effect curves of alpha
particles are linear (or essentially linear), at least for the low to moderate
doses of interest, for which saturation effects can be ignored. Second, the
evidence is that there are no dose-rate effects for high-LET alpha particles
(with the one possible exception of in vitro cell transformation as discussed
below). Third, we can be sure that the yields of effects per unit dose of
alpha particles are greater than those per unit dose for low-LET x or
gamma rays, that is, that the RBE for alpha particles is greater than
unity. Although the appropriate RBE for a given alpha particle might
not have been empirically measured in an appropriate target-cell system,
generalizations on the basis of LET seem reasonable, provided that they
are based on RBEs determined in cells likely to have similar cell nucleus
and target volumes and based on doses that produce similar hit fractions
per red. Thus, in considering the hazard of induction of a malignancy of,
say, the liver by deposition of plutonium, it seems reasonable to multiply
the low-dose risk coefficients for low-LET radiation available in the BEIR
III report38 by an appropriate RBE factor to derive a new estimate that
can be useful in the absence of empirical information on the overall risk
associated with the radionuclide of interest.
We present below the empirical evidence from cellular Idiobiology on
RBE for alpha particles, with necessary background information, on which
to base estimates of expected effects of exposure of human populations to
alpha-emitting radionuclides.
MAMMALIAN CELL SURVIVAL
Although much work had been done earlier with prokaryotes and
unicellular eukaryotes, mammalian cell survival studies became possible
only with the development by Puck et al.39 of a practical clonal assay for
the survival of single mammalian cells in culture. The general principles
already discussed in this appendix were elucidated mainly with low-LET
x and gamma rays and have been reviewed elsewhere. Much work has
been done with high-LET irradiation, particularly with neutrons, protons,
and beams of heavy ions, largely because of interest in their potential
application to radiation oncology. Much less has been done on cell killing
by alpha particles from the radionuclides of interest here. Therefore, it
is necessary to consider the larger body of data from other high-LET
radiation.
Extensive studies with fast neutrons of various energies have been
done by Broerse et al.,20 Be~Ty,6 and by the Radiological Research Labora-
tory group at Columbia University.30~34 The last studies are of particular
interest because of the essentially monoenergetic neutron beams that the
group at Columbia University was able to use. Survival curves for Chinese
OCR for page 422
422
HEALTH RISKS OF RADON AND OTHER ALPNA-EMITTERS
hamster cells irradiated with neutrons of 0.1-50 MeV have been obtained.
As expected, neutron energies below a few million electron volts produced
exponential survival curves without the shoulder characteristic of low-LET
survival curves. At energies above a few million electron volts, the LET is
lower and a small shoulder becomes evident.
RBE varied with neutron energy, exhibiting a rather broad peak at
approximately 0.4 MeV. Because of the difference in survival-curve shapes,
RBE was a function of the survival fraction at which the comparison was
made with the reference curve, in this case for 25~kV x rays, peaking at
about 9 for 80% survival and falling to approximately 3 at 0.001% survival.
Blakely et al.7 recently reviewed extensive mammalian cell-survival
studies with heavy ions, t2C to 40Ar, which used a variety of tissue-culture
cell types. RBE was found to increase from about 1.0 at a track-average
LET of 10 keV/pm to about 2.5 at a track-average LET of around 100
keV/pm. Survival curves lost their shoulders as LET increased, becoming
simple exponentials for a higher LET. Thus, the results of both the fast-
neutron and the heavy-ion experiments are in general agreement as to the
modification of curve shape and increase in RBE with increasing LET.
The maximal RBE observed in the neutron experiments, about 5 for 5%o
survival, is somewhat higher than the maximum observed in the heavy-ion
experiments, probably because the heavy ions, with their high velocities,
deposit a larger fraction of their energy via lower-LET secondary electrons
and are thus less monochromatic with respect to LET.43 The results of the
heavy-ion experiments clearly demonstrate the falloff in efficiency (dose
wastage) at average LETs greater than approximately 100 keV/,um.
Barendsen and coworkersi-4 have studied mammalian cell-survival
curves for cyclotron-accelerated alpha particles (and deuterons) and for
Echo alpha particles. Polonium-210 alpha particles induced simple expo-
nential survival curves with an RBE ranging from 2.5 (at high acute doses)
to around 6.0 (at low doses). With cyclotron-accelerated alpha particles at
LETs of 25-86 keV/pm, survival curves for the higher-LET alpha particles
were again simple exponentials, although that for 25-keV/,um, alpha parti-
cles did show some evidence of a shoulder. The RBE, in comparison with
the curve for 200-kV x rays, was dose dependent but was in the range of
3-5 for survival below about 20%, with the peak for any degree of survival
at about 100 keV/,um.
Lloyd et al.36 also determined mammalian cell-survival curves for
accelerator-produced alpha particles. Essentially exponential survival
curves were found for alpha particles with LETs of about 85 keV/,um; the
slope agreed well with that determined by Barendsen and coworkers.~~4
Barnhart and Cox5 and Thacker et al.43 have determined survival
curves for Chinese hamster cells in tissue culture exposed to alpha parti-
cles from 238 Pu. Again, the survival curves were exponential. With the
OCR for page 423
C.h~l T. ULAR RADIOBIOLOGY
423
irradiation geometry used, the ranges of LET through the cells were 127-
165 keV/,um and 10~135 keV/pm, respectively, in the two studies. RBE
values of 7-10 were observed for high survival fractions.
Thus, there Is general agreement that cell-survival curves for alpha
particles, as well as other high-LET irradiation, are exponential with high
RBE, peaking at around 100 keV/,um; are dose dependent; and reach
maximal calculated values of about 5-10 at low doses. Low-dose-rate, low-
LET ionizing radiation seems appropriate for comparison for the purposes
of this report (i.e., comparison of the a terms of the quadratic relationship
seems appropriate). Therefore, the lowest dose and, consequently, the
highest RBE observed seem appropriate as a basis for extrapolating from
the BEIR III report38 and similar risk estimates to alpha-particle estimates
when direct human data are not available.
MUTATION IN VITRO
Mutation induction at the hypoxanthine-guanine phosphoribosyl
transferase (HGPRT) locus can be studied in vitro in Chinese hamster
or human cells by using selection in a thioguanine-containing medium.
Dose-effect curves have been determined in this way for both high- and
low-LET radiations. Thacker et al.43 and Cox and Masson22 determined
HGPRT mutation by henry ions in Chinese hamster cells and human
diploid fibroblasts, respectively. Helium, nitrogen, and boron ions with
LETs of 28-470 keV/pm in the irradiated cells were used. Mutation-
induction curves were essentially linear, giving maximal RBEs of about 6
at 9~200 keV/pm when calculated in terms of mutants per survivor and
compared with the initial slope of the curve for gamma rays.
Both Barnhart and Cox5 and Thacker et al.43 have reported on the
mutagenicity of alpha particles from 238 Pu in Chinese hamster cells. The
study by Barnhart and Cox,5 however, appears to have suffered from
technical difficulties; as noted by Thacker et al., the latter found an RBE
of about 2 for the alpha particles, which had an LET range of 127-165
keV/pm as they traversed the cells, compared with acute exposure to
25~kV x rays.
TRANSFORMATION IN VITRO
A few types of mammalian cells growing in tissue culture can be
transformed in vitro from the growth patterns that characterize fairly
normal cultured cells to a new phenotype that more closely resembles
that of cancer cells. The basic change is from an orderly growth pattern
exhibiting contact inhibition on the culture vessel surface to a pattern
resulting from the loss of contact inhibition. That loss causes the cells
OCR for page 424
424
HEALl,H RISKS OF RADON AND OTHER ALPHA-EAlITTERS
to pile up and overgrow each other and to produce foci of a distinct and
recognizable morphology. Examples are shown in Figure II-1.
The development of cell-culture systems has made it possible to study
the cellular and molecular mechanisms involved in radiation transformation
under defined conditions devoid of host-mediated homeostatic modulating
factors, and to assess the underlying mechanisms qualitatively and quan-
titatively. These systems afford the opportunity to study dose-related and
time-dependent interactions of radiation with single cells and to identify
factors and conditions that can prevent or increase cellular transformation
by radiation. Because such cells transformed in vitro give rise to tumors
when injected into hamsters, whereas untreated cells show no spontaneous
transformation,~4~5 the system has obvious implications with respect to
in viva carcinogenesis. The details of the system and its utility in cellular
radiation biology were recently reviewed by Bore.
The role of DNA as a target in radiation transformation was suggested
early by the requirement of DNA metabolism for fixation of the transformed
state.~5 The ability of genomic high-molecula~-weight DNA purified from
cells transformed In vitro to transmit the transformed phenotype to normal
cells constitutes an important criterion for the neoplastic state of the cells
transformed after exposure to a carcinogen, ~ 3~7~8~4t indicating that
the transformed phenotype of the cells exposed to the carcinogen in vitro
is encoded in the DNA. This criterion aids in mechanistic studies of
transformation that attempt to analyze the specific transforming genes
activated as a result of exposure to the carcinogen and to elucidate genetic
changes.~7~'~
For both low- and high-LET radiation, transformants are produced as
a function of increasing dose up to approximately 1-S surviving cells/100
exposed cells, at which point the curves saturate. ~ansformants are
produced more efficiently by fission neutrons than by 250-kVp x rays, with
an RBE of approximately 10 in the region below saturations 3i Figure
II-2 shows an example for 43~keV neutrons.
Data on alpha-particle-induced in vitro transformation are sparse
and often incomplete (there are no data on the tumorigenicity of the
transformed cells). The eRect of low-energy alpha particles in transforming
the C3H/lOT-1/2 cells was evaluated by Lloyd et al.37 Transformation
frequency per surviving cell increased as the cube of the dose, peaking
at a fluence of 1.5 x 107-2.5 x 107 alpha particles/cm2 (205-342 red).
Maximal transformation frequency reached 4%. No parallel experiments
were carried out with x rays; thus, no RBE for alpha radiation was
determined. By taking the dose required to reach the peak transformation
region and comparing it with x-ray data determined for the same cell line
by Terzaghi and Little,42 an RBE of approximately 2 is obtained.
A study carried out by Robertson et al.40 evaluated the eRects of 238 Pu
alpha particles in mouse BALB/3T3 cells. The A31-11 mouse BALB/3T3
OCR for page 425
CF~UlAR RADIOBIOLOGY
(A) it:
.
.
425
:' 5~ ~ ~ 4 ~ I:
~ j . ~ it,:
~ if ~ ~ A:-. ~ f ~ it: ~ :< I: ~
~ ~ -. . ~ ~ .~
-I : : ~ .~
' . ~
. . ~ . _4
;. :..
FIGURE II-1 (A) Normal colony of hamster embryo cells. (B) Colony of x-ray-
transformed hamster embryo cells. (C) Focus of C3H/lOT-1/2 cells transformed by x
rays growing over normal cells. Morphology of transformed cells is the same as that
after exposure to high-LET radiation. SOURCE: Borek.l2
OCR for page 426
426
too
lo
-
·s
10
HEALTH RISKS OF RADON AND OTHER ALPHA-EMITTERS
~ 430 keV neutrons
250kVp x-ra~
i
10
HAMSTER EMBRYO
CELLS
.
, ,~,,,] ~ --,,, , · ....,,, ,, ...—
HAMSTER EMBYRO CELLS
,' O ~
~ 10-2
,>10-3 ..
-2~ 30 keV neutrons \
10 ~o~6
0 2 4 6 8 10 0~3 ~o~2 10-' too i'
(A) D O S E / Gy (B) DOSE/Cy
FIGURE II-2 (A) Pooled data on sur~ri~ral of hamster embryo cells uTadiated with
250-kVp x rays (solid circles) or 43~keV monoenergetic neutrons (open circles). Error
bare show estunated standard deviation. 1 Gy = 100 red. (B) Pooled data for
hamster embryo cells on number of transformants per surprising cell after irradiation
with 25~kVp x rays (solid circles) or 430~keV monoenergetic neutrons (open circles)
at the Radiological Research Accelerator Facility. Error bare show 9596 confidence
intermurals for estimates. SOURCE: Borek et al.l6
1 1 1 1 1 1 1 1
430 keV
neutrons
S_.
He 10
1/ /e
95'. confidence limits
... 1 . , 1 . 1 .
cell system was used, and in vitro transformation was induced by 5.~MeV
alpha particles from a specially constructed 238 Pu source. The biological
effects were compared with those of 22~kVp x rays. The alpha-radiation
survival curve gave an RBE of 3.5 at 50% survival. The transformation
frequency increased exponentially with dose in the range examined (25-250
red); the maximal RBE for the induction of transformation in growing cells
wan approximately 3.
However, the RBE for alpha transformation in nonproliferating cells
appeared to be much higher; the yield of transformants among x-irradiated
cells that were held in the stationary phase of growth for 0220 h after
irradiation declined by a factor of nearly 50, whereas no decrease occurred
in alpha-irradiated cells. The findings suggest that carcinogenic damage
induced by high-LET radiation in mammalian cells is very inefficiently
repaired, compared with that induced by x rays, and that the intracellular
carcinogenic effect of exposures to high-LET radiation can be cumulative.
They also suggest that the eBective RBE for alpha radiation in nonpro-
liferating cell populations in viva might be much higher than one would
predict on the basis of measurements in dividing cells.
Work by Hall and Hei29 with C3H/lOT-1/2 cells compared the trans-
forming action of radiation, from a source of 24tAm, delivered at 10
rad/min with that of gamma rays from a i37Cs source with an absorbed
dose rate of 137 rad/min at equivalent doses. Alpha particles were sum
stantially more cytotoxic and more efficient than gamma rays in inducing
oncogenic transformation. The calculated RBE ranged from 2.3 to 9 for
the transformation frequencies examined.
OCR for page 427
Coil r MAR IDIOBIOLOGY
REFERENCES
427
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ture irradiated with alpha-, beta-, 20-KV.X- and 200-KV. X-radiation. Nature
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2. Barendeen, G. W., and T. L. J. Beusker. 1960. Effects of different ionizing radi-
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Representative terms from entire chapter:
mammalian cells
