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OCR for page 24
Causality of a Given Cancer After Known
Radiation Exposure
VICTOR P. BONO
A person's chief concerns after exposure to low-level radiation are the
probability (risk) of developing a cancer and, to a lesser extent, the risk of the
exposure's causing a genetic defect in a descendant (National Research
Council, 1972, 1980; United Nations Scientific Committee on the Effects of
Atomic Radiation [UNSCEARl, 1982~. This paper deals with carcinogene-
sis, examining the possible causal relationship between carcinogenesis and
a specific exposure to a carcinogenic agent, especially ionizing radiation.
With increasing frequency in personal injury claims, specific cancers in
specific individuals are alleged to have been caused by some specified
radiation exposure, which was sustained while the individual was in the
employ of a given organization (Schaffer, 19841. Questions of liability and
compensation then arise, which may be addressed either within the frame-
work of worker's compensation or by tort litigation. The question of cause
and effect is central; more specifically, what magentas) might have been the
causers) of the harm that, if sufficiently severe, could have resulted in the
quantal response) of cancer. It is possible that more than one form of related
harm, each ineffective alone, could interact in such a way that the combina-
tion initiates a quantal response.
What is at issue would appear to be purely medical matters to be addressed
by a physician trained in toxicology. However, the quantal response of
cancer, particularly that from low-level radiation exposure, is sufficiently
distinctive in its genesis to draw into question the adequacy of the traditional
medical approach to determining causation. In support of this contention,
this paper first discusses the meaning of exposure to hazards and the risk of
~4
OCR for page 25
CLACK C~US~LI~ ~ KNOWN EDITION EXPOSURE
~5
accidental harm in the context of public health and its subdisciplines of
epidemiology and accident statistics. This discussion is followed by consid-
eration of the infrequent casualties that result from such exposure. In partic-
ular, the question of whether causality and the kinds of harm can be
addressed adequately only by one with medical knowledge and experience is
examined. Finally, the single-cell origin of many cancers and of genetic
defects is discussed, as well as the probabilistic nature of the induction of
many types of cancer. It is concluded that, for these diseases, the traditional
medical approach must be replaced by a probabilistic approach to address
adequately the questions of causality.
ACCIDENTAL HARM IN POPULATIONS
OF EXPOSED PERSONS
Randomly induced (accidental) harm is dealt with in the discipline of
public health, which is concerned primarily with the health and well-being
of populations. The common characteristic of such populations, which are
usually constituted on geographical or occupational bases, is that they are or
may be exposed directly to infectious or chemical agents present in the
environment or to carriers or vehicles for such agents. They may also be
exposed to the common agent, energy, present as an integral property of
energy carriers, which are physical objects in the environment potentially in
motion relative to the individual. An exposure results in random encounters
or collisions of agents or energy carriers with individuals, which produce
direct transfers ofthe agent. As a consequence ofthese transfers, a small and
usually more or less constant percentage of exposed individuals may become
ill or injured during any equivalent exposure period.
The concern of the professional public health officer must be for the
population as a whole, without regard to the identity of any individual. Thus
the public health officer, who often has an M.D. degree, must be knowl-
edgeable in epidemiology and statistics and must be aware of trends in
disease incidence, accident statistics, changes in exposure conditions, and
possible unusual susceptibilities in segments of the population (see
gingham, in this volume). Whereas a person who becomes a casualty imme-
diately becomes an identified patient of a physician, the casualty is impor-
tant to the public health officer primarily as a statistic (if the person dies, as a
death statistic).
Should the question of single versus multiple causation arise with respect
to any casualty, the public health professional might be asked about the
exposure conditions under which the accidental encounter and agent transfer
occurred, causing the harm and its consequent probability of a quantal
response. However, he or she would probably be unable to provide an
OCR for page 26
26
VICTOR ~ BOND
authoritative judgment as to the amount of harm caused in any single indi-
vidual or the risk of quantal response to such harm in that individual.
The public health official is trained to estimate the actual or statistically
expected excess incidence of a given illness or traumatic condition in a
population of otherwise normal individuals (see Table 14. This fractional
number is equal to the risk of the given condition for the average individual
in a normal population. In other words, one can never determine the actual
risk to any one person; only average values can be obtained. The risk dealt
with by the public health officer is, in principle, purely physical: it is the
probability not only that an accidental event will bring together two objects,
the agent source and the biological target, but also that a resulting transfer of
agent will occur. Public health officers usually do not attempt to estimate the
subsequent purely biological probability that a particular above-threshold
amount of harm will cause a quantal response.
QUANTAL RESPONSE IN A POPULATION
OF HARMED PERSONS
An individual is brought to the attention of a physician because of illness
or injury and therefore has presumably been harmed by some agent or
process. Then begins the process of collecting medical information from the
patient's history, a physical examination, or specialized diagnostic proce-
dures. This information permits the physician to diagnose the kind, amount,
and probable cause of harm sustained; to prescribe therapy; and usually to
forecast the prospect of recovery based on the prescribed regimen of treat-
ment. In particular, the physician assesses whether the amount of harm is
near the threshold for a quantal response, either in the form of lethality or in a
permanent functional incapacitation. If the patient dies, an autopsy may be
performed to obtain further diagnostic information about the injury and its
causes.
If the illness or injury is associated with exposure to a presumably exces-
sive amount of a specific agent or agents, then an estimate of the amount (or
dose)2 of each agent involved would be.helpful, but not necessarily decisive
to the overall evaluation. That is to say, the physician is always mindful of
agent-amount-effect relationships in two contexts: (1) the amount of a
potentially harmful agent received by the patient and (2) the amount (dose)
of a therapeutic agent that could be prescribed to destroy or control the
causative agent but at the same time cause only minimal damage to the
normal tissues.
The amount of harm due to a specific agent is determined principally by
the dose. Even though the severity of harm caused by a given dose varies
among individuals (see gingham, in this volume), severity and dose are
OCR for page 27
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27
OCR for page 28
28
VICTOR ~ BOND
sometimes used interchangeably to indicate the severity of biological dam-
age (for example, the severity of harm may be used as a "biological dosime-
ter"~. Thus, the probability of a quantal response may be estimated in terms
of either dose or severity of harm (see Table 1) .
When the physician evaluates the risk of a quantal response as a function
of dose or severity of organ harm, the reference population used is quite
different from that used in the public health subdisciplines (see Table 11. For
the physician, the individuals in the population of reference all have the
common characteristic that they have been harmed, and all manifest the
particular illness or injury in varying degrees. If this population is divided
into groups, each having nominally the same dose or severity of harm, one
can evaluate the probability of a quantal response as a function of the dose or
severity of harm. From this relationship can be seen the distribution of
sensitivities and the amount of harm required to cause a quantal response in
the average individual. If the illness is due to a particular harmful agent, then
the population could be regarded as having been assaulted by that agent and
could be subdivided into groups having received nominally the same amount
of agent. Thus, the physician's assessment of the probability (risk) that any
given individual will show a quantal response is based upon knowledge of
the response to harm for the average individual in a population, modified by
such considerations as age and sex, which may affect an individual's sensi-
tivity.
RADIOTHERAPY OR ACCIDENTAL HIGH-LEVEL
RADIATION EXPOSURE
Knowing the circumstances under which exposure to radiation may occur
is critical to understanding the associated quantal responsefs). Thus, for
each circumstance, it is necessary to look at the steps that lead from exposure
to a possible quantal response.
Consider the circumstance in which organ harm is clearly present, which
can occur only in cases of high-level exposure. Although such harm is seen
almost exclusively in the radiotherapy of malignant tumors, it has been
observed in accidents. Radiotherapy may involve large amounts of radia-
tion, frequently thousands of reds delivered over relatively brief intervals
(hours to weeks) to limited regions ofthe body. Because some normal tissues
must be included in a radiotherapy beam, quantal responses may appear
within days, weeks, or months, in the form of function-impairing lesions of
the skin or deeper tissues. Although a few such responses are expected and
unavoidable, questions about cause and effect remain, particularly if the
observed response may have been aggravated or even caused by factors
other then radiation, such as medication orinjury from bums and other forms
of trauma.
OCR for page 29
CATCH C~US~LI~ ~ KNOWN EDIT ION EXPOSURE
29
Under these circumstances, there is rarely any question that harm to
normal tissues from radiation exposure has occurred. Even if no quantal
response has appeared, agents other than radiation may be suspected to have
aggravated the lesion. Physicians make this determination on the basis of
information gathered from the patient history, physical findings, laboratory
tests, and histopathological examination of tissues obtained by biopsy or
autopsy. Thus, it is clear that judgments on the type and amount of harm, the
probability of a quantal response, and the evaluation of cause and effect must
lie in the province of the physician.
A physician is also uniquely qualified to render an authoritative opinion on
the separate roles of multiple suspected causative agents. The opinion would
be stated as best professional judgment, although some quantitative assess-
ment of the evidence may be presented in probabilistic terms (for example,
"It is more probable than not," or "It is beyond reasonable doubt" that the
expressed opinion is in fact correct).
LOW-LEVEL EXPOSURE OF NORMAL POPULATIONS
Low-level radiation exposure includes that from background radiation,
medical diagnostic procedures (averaging perhaps 0.1 reds per year), and
occupational exposures (averaging one-tenth or less of the maximum annual
exposure limit of 5 rems). In this range, quantal responses are not encoun-
tered. In fact, any possible harm at the time of exposure is so slight as to be
undetectable by the physician. Even if an excess of chromosome abnormali-
ties in the blood should be found (unlikely with low-level exposure), this has
not been shown to signify any radiation-induced disease or to presage a
malignancy in that individual (Awe, 1975~.
The only quantal effects of consequence resulting from low-level expo-
sure are the possibility of cancer in the person exposed or genetic defects in
descendants of the exposed person. Of these two responses, the genetic
defects are certainly caused by harm to a "target" in a single reproductive
cell. If severe enough, this injury can cause a transformation (mutation) in
the cell that otherwise continues to function apparently normally. If a cell so
transformed becomes one of the two cells that unite to form a new individ-
ual, then one or more organs may show abnormalities.
The hypothesis that many, if not most, types of cancer also can be initiated
by alteration of a single cell is strongly supported, but not proved, by
available evidence (Fialkow et al., 1967; Nowell, 1967; Fialkow et al.,
1977; Gould et al., 1978; Land et al., 1983; Gould, 1984; Vogelstein et al.,
19851. The monoclonal nature of a number of human tumors has been
demonstrated that is, all cells in the tumor have been found to have identi-
cal genetic characteristics. This does not necessarily mean that only one cell
was malignantly transformed. However, it is strong evidence that the tumor
OCR for page 30
30
VICTOR ~ BOND
does represent the successful proliferation of only one cell or at most a few
cells to the point that the tumor can grow by competing with normal cell
populations and tissues. In other words, the carcinogenic alteration of a cell
transforms it from a cooperative unit in a population of cells (an organ)
devoted to a particular function, to an alien unit capable of independent and
parasitic organlike growth.
Although it is assumed here that both cancer and genetic defects are of
single-cell origin, it is well known that an initiated cancer cell may require an
extracellular promoter (for example, a hormone or other chemical) before
manifesting itself as a cancer, or that it may be prevented from expression by
inhibitors such as immune mechanisms (Bond, 19841. However, most such
promoters are normally present within the body, and the amount of any
specific promoter is unlikely to be affected by low-level radiation exposure.
The fact that such promoters may be present and may play a role in tumor
expression must therefore generally be considered normal and not a phe-
nomenon inducible by low-level radiation. Although theoretically possible,
the probability of exposure to an external promoter in the workplace, for
example, in conjunction with exposure to an initiator, appears small indeed
(UNSCEAR, 19821.
Thus, as indicated in Table 1, medical training alone provides no basis for
judging whether a specific exposure to low-level radiation was or was not the
cause of a specified tumor. Considering the single-cell origin of a tumor, the
harm is undetectable at the time of exposure and potential initiation of a
tumor, and diagnosis or prediction of malignancy is not possible. A similar
situation exists for any tumor putatively associated with a radiation exposure
(see Table 11. Clinical information relates only to the presence of a tumor, its
type, and the prognosis with respect to a quantal effect. None of the informa-
tion relates to a single-cell origin or the causes of the cellular transformation
that may have initiated the process.
RADIOBIOLOGICAL RESPONSE FUNCTIONS
A single-cell response to low-level exposure can be initiated by a random
interaction (accidental collision or event) between a single charged particle
and one or more sites in the DNA of a cell. Evidence for this is the initial
"linear, no-threshold" relation between the excess incidence of a quantal
response seen in an exposed population of cells (animals) and the absorbed
dose to the organ or other medium in which the cells are supported. Figures
1, 2, and 3 show such responses for, respectively, mutations, cancer in
animals, and chromosome abnormalities. The initial proportionality is evi-
dence that a single-hit interaction between a charged particle and an appro-
priate DNA target in the single cell can, to the virtual exclusion of any other
OCR for page 31
CONCH C~US~LI~ All KNOWN EDITION EXPOSURE
1.0
0 01
no
(J
to
- 0 001
0 0001
- ~ ~ ~ Allele I ~ IT 1llll ~ ~ lillll I I ~ TIlTr
CONSTANT HIGH DOSE RATE,-
VARYING DOSE~
_ X RAYS ·/. · · ~
Hi/
_ Y~
i'
LID a,O+0D2
~ _-
1 1 1 1 1 11~1 1 1 1 1 1 1111 1 1 1 1 1 1111 1 1 1 1 1 1 11
0~l 10° 101
ABSORBED DOSE ( rod )
1o2 103
FIGURE 1 Radiation-induced mutations in the stamen hair cells of the
plant Tradescantia. Note the double log plot, on which a slope of 45 °
corresponds to a linear response on arithmetic coordinates. The single-
hit region extends to about 10 reds, above which the multihit region is
dominant. It is in this high-dose region that the chance of cooperative
interaction between two or more separate subeffective radiation events,
or one such radiation and similar chemical event, may in principle occur
(Underbrink and Sparrow, 1974; Emmerling-Thompson and
Nawrocky, 1980).
31
radiation particle or increment of another transforming agent, initiate a
cancer or a genetic defect.
In discussing the reason why so-called dose-effect curves such as those
shown in Figures 1 through 3 are initially linear, no-threshold in form, it
must be recognized that the use of the word dose on the abscissa is conceptu-
ally inappropriate and misleading (Bond and Feinendegen, 1966; Kellerer,
1976; Bond, 1982a). The quantity is the average amount of energy per unit
mass of organ or medium, which conveys little or no information about what
happens at the cellular level as a result of a low-level exposure. The risk that
any particular cell will be randomly assaulted at the appropriate site depends
on the number of charged particles in the vicinity of the target cell during an
exposure, whereas the chance that any cell actually hit during the exposure
will then be transformed depends on the size of each physical event. That is,
OCR for page 32
32
70
60 _
50 _
o
~ 40
z 30
20
VICTOR ~ BOND
IdARDERIAN GLAND TUMORS
.
, , ~
/
/
- I/
.~
40ARGoN
570 MeV/amu
I/
at 0 - 20 rod
if/ LINEAR FIT 1.35~0.04P >.80
SQUARE ROOT OF DOSE 3 9 + 0 9 P << 001
20 40 6080 100
DOSE (pad)
120 140 160
FIGURE 2 An initially "linear, no-threshold" response for a tumor of the Harder~an gland (a
retro-orbital gland of the eye) of the mouse. The initial linearity is relatively easy to demon-
strate with the high linear energy transfer (LET) radiation used because such radiations are
much more effective per unit dose than are low-LET radiations. The bending over of the curve
at higher closes is due largely to competing effects such as killing of "induced?' cells (Fry et al.,
1983).
the risk of a cellular transformation or mutation depends first on the average
number of charged particles traversing the environment of the cell per unit
time (fluence rate), multiplied by the exposure time; this value gives the total
exposure in terms of fluence (Bond, 1982a). Second, it depends on how
many of these events, or hits, will be large enough to have a nonzero chance
of transforming the affected cells (Bond, 1982a, 1984; Bond and Varma,
1983; Varma and Bond, 1983~. Accordingly, the abscissas in Figures 1 and
2, at least in the low-exposure range, should more properly denote exposure
measured by the fluence rather than the dose to either the organ or the cell.
The ordinate on both curves is the (excess) incidence of transformed or
mutated cells, equal to the probability (risk) that the average exposed normal
cell will be hit and transformed or mutated (beyond the small spontaneous
rate that is always present, even without the exposure).
OCR for page 33
CANCER CAUSALITY AFTER KIIO{YN RAlDI'ION EXPOSURE
33
80
USA
~ 70 _
Lo
o
° 60 _
Go:
Lo
~ 50
LL
<( 40 _
X 30 _
50
Lo
~ 20
To
I
10
x X- RAYS
+ HELIUM
LITHIUM - 58 MEV
LITHIUM - 30 MEV
BORON
CARBON
OXYGEN
I, ~:
, ,\~\~/ T
T //
~ /
if/~
A
///~ _ ~W~ i___
. _-
_
_-~ -
100 200 300 lo
DOSE (mad)
FIGURE 3 Absorbed dose-cell quantal response curves for an induced chromosome abnor-
mality, covering the full range of linear energy transfer (LET). Because the abnormality is
detectable in moribund cells, the linear response can be observed well into the higher dose
region. The curves marked "alpha He" and "alpha X" indicate that the curvilinear responses
of low-LET radiation at high exposure rates, where intracellular repair is precluded because of
the close temporal juxtaposition of successive hits, become linear when the exposure rate
becomes vely low (Skarsgard et al., 1967).
From these remarks on the origins of cancer, genetic quantal responses,
and their radiobiological initiation, it is evident that the "individual" to be
considered under these circumstances is neither the organ nor the person, but
rather the individual cell (see Table 1~. Further, both mutational and trans-
formational changes that are manifested as cancers or heritable diseases in
descendants are truly rare events so rare that, even with exposures well
above the low-level range, only a small fraction of the exposed population of
persons develops them. This means that the cell population that must be
considered is much larger than that of any organ or individual.
Thus, just as the public health officer must be professionally blind to the
identity of individuals, so the epidemiologist must be blind to which individ-
ual is exposed and may develop a cancer. In principle, it is only the expected
OCR for page 34
34
VICTOR ~ BOND
excess incidence of transformations in the entire cell population that must be
considered. In fact, one cannot do otherwise. In view of the long latent
period between initiation and full expression of cancers and heritable dis-
eases, it is not possible to link with certainty any specific cancer or genetic
defect with any specific exposure, either before or after the development of a
tumor or a genetic defect.
Although the allegation that the specific exposure and the specified cancer
are causally related implies that a single cell must have been stochastically
(accidentally) hit, harmed, and transformed at the time of the exposure,
there is no way to show that such a microaccident involving the specific
radiation did in fact take place. The fact that approximately one out of five
deaths per year in the United States is due to cancer of unknown origin and
that about twice that number of persons per year develop cancers of
unknown origin indicates how precarious such an allegation would be. If
there is no way of knowing even whether a given cancer patient is in fact a
casualty of the implied microaccident, then clearly it is not possible to
evaluate the harm to any single cell and the chance of its transforming. A
causal connection will probably remain impossible to establish and may thus
represent one of the true trans-scientific problems, as so aptly termed by
Alvin Weinberg (in this volume), because it is not amenable to resolution by
scientific means.
Since there is no causally relevant harm to evaluate either before or after a
single-cell response, the special training and experience of the physician are
of little or no value beyond certifying the presence or absence of a cancer or
genetic defect and its type. In particular, it is not possible to establish cause
and effect by the usual medical means of harm assessment. Therefore, the
question of causation can be addressed only on a probabilistic basis.
PROBABILITY OF CAUSATION IN CANCER CASES
The probabilistic approach termed the probability of causation (Bond,
1981a; National Institutes of Health, 1984), although suggested some time
ago (Bond, 1959; Oftedal et al., 1968), has only recently received wide
attention. The recent increase in interest is due to the growing number of
situations in which a causal relation between a cancer in either an exposed
individual ore group has been claimed (Schaffer, 19841. Because the proba-
bility of causation (PC) method and its advantages and possible drawbacks
have been described in detail elsewhere (Bond, 1982b; Cox, 1984; National
InstitutesofHealth,1984;NationalResearchCouncil,1984;Jablon,1985),
only the relatively simple principles involved will be presented here.
Because risk coefficients are required for the PC method, these, and the
risk of cancer for a given dose, are discussed first. This is followed by a
OCR for page 35
CONCH C~US~LI~ ~ KNOWN ~DIf ION EXPOSURE
35
presentation of the PC method. In particular, this section discusses the
circumstances under which the PC method provides a true probability that
the single agent, radiation, was causally related to the observed effect, and
the circumstances under which the possibility of multiple causation and thus
of shared responsibility must be considered.
The risk coefficient RC, derived from a population exposed to known
amounts of radiation, is the expected excess incidence of a specified cancer
per unit dose of radiation. The numerical value of RC is also termed the
"nsk" of cancer per unit dose for the "statistically average" individual in
that or a similar population. An RC can be expressed either as a function of
time, usually in years (for example, excess cases per 106 persons per year per
red) or as the total excess cases over a lifetime (for example, excess cases per
106 persons per red). Table 2 contains examples of absolute risk coefficients
for several cancers. The actual values for absolute risk are rough average
values selected from the extensive data published by the National Institutes
of Health (1984, Table VI-1-A, p. 761. The NIH document also provides
values for relative risk. The total excess incidence, or average risk, for any
given dose is simply the RC multiplied by the given dose.
However, the use of human studies to derive RCs for "low-level expo-
sure" involves extrapolation to the low-exposure region where statistical
limitations preclude direct observation of an excess incidence, if it exists.
Such extrapolations for low-LET radiations are conservative in the sense
that values for the probability of causation so derived are upper limits. Thus,
the consequent error in the PC is in the direction of favoring the individual
plaintiff (see Whipple, in this volume).
The risk coefficients and the risk from any given dose are prospective in
that they permit the estimation, for a given exposed population or the aver-
age individual in that population, of the expected excess incidence and thus
the risk. They do not address directly the retrospective situation in which a
TABLE 2 Absolute Risk Coefficient for Selected
Cancers: Approximate Values for Young to
Middle-Aged Adults
Type of Cancer
Risk Coefficient
(cases per 106 exposed,
per year, per red)
Leukemia
(excluding chronic lymphocytic)
Esophageal
Stomach
Thyroid
Colon
0.1
0.4
0.25
SOURCE: National Institutes of Health (1984, Table VI-1-A, p. 76).
OCR for page 36
36
VICTOR ~ BOND
specific cancer is alleged to have been caused by a specified earlier expo-
sure.
The retrospective situation is addressed by the probability of causation
method. In simplest form, the approach is described by the ratio
PC= RR
RB + RR + RO + RC
(1)
where PC is the probability of causation, and RR is the expected excess
incidence of cancer due to a radiation exposure of a population (equal to the
risk to the average person); RB is the baseline normal or spontaneous inci-
dence of cancer of a given type in that population; RO is the risk from other
kinds of exposure (including that due to any additional radiation exposure
other than that claimed to be causative); and Rc is the risk from chemical
carcinogens. The expected excess incidence RR is simply the absorbed dose
in reds to the organ in which the specified tumor is presumed to have
originated, multiplied by the risk coefficient for that tumor type. Although
the PC formulation denotes absolute risk, the relative risk can be used
instead without altering the principles involved (National Institutes of
Health, 19841.
Uncertainties with respect to radiation exposure exist in the dose, the
baseline incidence, and the risk coefficients used to calculate a PC. Signifi-
cant improvement in the first two measures is possible in principle, given the
required expenditure of time and effort. Although better data in the third
area, risk coefficients, are becoming available as current epidemiologic
studies on exposed human populations progress and as the doses are refined,
there is a limit to the extent that uncertainty can be reduced considering the
hoped-for decline in the number of new, excessively exposed populations.
Thus, Equation 1 will yield a fraction representing the probability that a
specific exposure was causative. For instance, suppose that a 50-year-old
male has developed a myelocytic leukemia, and that the exposure sustained
at age 30 and claimed to be causative was 2 reds of X rays. The risk
coefficient is approximately 1 x 10-6 per person, per red, per year (Table
2), and the baseline leukemia incidence for en individual of age 50 is approx-
imately 10 x 10-6 per year (Table 31. The probability of causation, assum-
ing RO and RC are negligible, is then
2 x 1 x 10-6
PC = = 0.03, or3.0 percent.
70x 10-6+2x 10-6
Consider first the low-level exposure regions. Here the linearity of the
absorbed dose-quanta! response function indicates independent action by
each event involving a target, and thus complete genetic or carcinogenic
OCR for page 37
CONCH C~US~LI~ ~ KNOWN EDITION EXPOSURE
TABLE 3 Approximate Baseline Incidence of Selected
Cancers in Young to Middle-Aged Adults
Type of Cancer
Risk Coefficient
(cases per 106 exposed,
per year, per red)
Leukemia
(excluding chronic lymphocytic)
Esophageal
Stomach
Thyroid
Colon
70
40
100
40
350
SOURCE: National Institutes of Health ( 1984, Table VII- 1, pp. 103-104).
37
transformation ofthe cell as the result of a single event. That is to say, there is
no measurable contribution from multihit action (the action of smaller hits
from the same carcinogen, radiation, each ineffective in itself, combining to
cause a quantal cell transformation). It is therefore particularly unlikely that
a hit from a different carcinogen could have played a role in the initiation of
any of these radiation-associated cellular transformations. Such results
effectively rule out multiple causes for the initiation of a single cancer. In
other words. the evidence is strong that, for low-level exposures, radiation
and other possible causes of cancer are mutually exclusive.
This deduction is supported by the results of~studies on the combined
effects of radiation and chemicals at low and high exposures. The results of
one such investigation are shown in Figure 4 (Bond et al., 1984a), where
there is a lack of synergistic action in the linear, low-level exposure region.
The PC in this region can thus be taken to be a true probability that radiation
alone is causally related.
When cancer arises from low-level exposure, then, one logical approach
to dealing with causation and liability is to assign responsibility for the
cancer to the party under whose aegis the radiation exposure was experi-
enced, but only if the PC exceeds 50 percent. An alternative might be to
award compensation incrementally between a certain minimum level of
probability perhaps 20 percent and 50 percent. Several other graduated
schemes could be worked out. An upper-limit amount of compensation
could be included for the highest PC, together with a "sole remedy" clause
limiting adjudication to this solution. In any event, this approach lends itself
to an administrative solution according to an agreed-upon plan, rather than
the alternative of litigating each claim separately, in either a workmen's
compensation or a tort claims forum.
Let us consider next exposures well above the low-level exposure region
but well short of the large-exposure region characterized by radiotherapy
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38
VICTOR ~ BOND
SYNERGISTIC EFFECT OF COMBINED EMS AND T-RAY EXPOSURE
INFLORESCENCE IMMERSION IN 10-2 M EMS FOR 4hCS
FOLLOWED BY ACUTE IRRADIATION
8
_ ~
~ Al
I "= 6
4
~ _4
c
. _
o
-
-6
-8
1 1 1 1 1 1 1 1
1 or _
hi_
TPOdeSCOntiO Clone 4430
· Data from 1983
· DQTQ from 1984
1 1 1 1 1 1
SYI)er9;Sm
Additive
AlOtO9OI1;Sm
1 1 1
0 10 20 30 40 50 60 70 80 90 100
ACUTE 137-CESIUM GAMMA EXPOSURE (POd)
FIGURE 4 Synergism between the effects of radiation and those of a chemical mutagen,
demonstrable in Tradescantia Cody in the larger-dose multihit region. Note that in the low-dose
single-hit region, the combined response is no more than simply additive and may be antago-
~iistic or mutually protective.
(for an example see Figure 1, where exposures in the range of 100 reds were
delivered in a time much shorter than that required for repair processes).
Here the increasing nonlinearity of the dose-response curve indicates coop-
erative action between radiation hits that are too small separately to cause a
mutation or carcinogenic transformation. Because of this multihit character-
istic, one such hit could conceivably be contributed by a chemical mutagen
or carcinogen that may be present.
That such combined-effect action is possible is also shown in Figure 4, for
the case in which the Tradescantia cells were exposed both to radiation and
to the chemical mutagen ethylmethanesulfonate (EMS), an alkylating agent
(Bond et al., 1984a, 1984b). Note that synergistic action is apparent in that
the response to the combined action of the radiation and the chemical muta-
gen clearly exceeded the sum of the responses to the agents administered
separately. When PC is calculated for this high-level region, one cannot
exclude the probable contribution of the combined action of both agents in
the shared mode. It is reasonable to infer further that there was multiple
OCR for page 39
CANCER C~US~LI~ ~ KNOWN EDITION EXPOSURE
39
responsibility for the cancer. This interpretation could be important, espe-
cially if additional and simultaneous exposure to a chemical carcinogen or
mutagen could be demonstrated.
Here also, harm that is detectable in an organ at such relatively high
exposures could be relevant only to assessing the severity of the acute organ
damage in the individual who was dosed by an agent or agents, and not to the
evaluation of possible cellular transformations that might be relevant to
cancer. Only the statistical approach is adequate to deduce either a true
probability of causation or an indication of the relative contribution of two or
more agents. Current evidence is that, for low-level exposures, multiple
causative agents for a given tumor are most unlikely. This indicates that the
PC in this low-level exposure region is a true probability that a single agent
(radiation) was causative, and that it does not represent an assignable share
of the causation.
As with considerations of cancer alleged to be caused by a single agent,
medical knowledge alone does not equip one to deal quantitatively with
questions of multiple causation. Medical training and experience are invalu-
able when dealing with the causers) of a quantal response in the context of
demonstrable harm or competing injuries. However, such training is of little
or no value in determining the causative role of a particular risk or of
competing risks.
It should not be inferred from the above, however, that multiple, essen-
tially simultaneous exposures to carcinogens or mutagens occur frequently,
nor that synergism is frequent. Of two mutagenic and carcinogenic com-
pounds tested recently (Bond, 1984), one (EMS) was found to be synergistic
with radiation. Even that compound showed a cooperative effect only with
large exposures, and the factor was no more than about 2.
A 1982 report of UNSCEAR indicates strongly that, although further
experimental study of possible synergistic effects is needed, there is at
present little evidence that combined effects will emerge as a serious prob-
lem. To quote directly from the report:
For humans in environmental circumstances the Committee has been unable to
document any clear case of synergistic interaction between radiation and other
agents, which could lead to substantial modifications of the risk estimates for
significant sections of the populations. Presumably this is due to the fact that most
of the agents likely to act synergistically with radiation, as judged by the results of
animal expenments, are not found in sufficient concentration in nature. A specific
exception is the case of tobacco smoke, which raises essentially problems of
industrial hygiene in some working environments [UNSCEAR, 1982, p. 762~.
This evaluation implies that, for exposures to more than one carcinogen,
the PC for each exposure can be evaluated separately. That is to say, RC in
Equation 1 can, in most instances, be brought to the numerator in place of
OCR for page 40
40
VICTOR ~ BOND
RR, and the corresponding PC can be evaluated as for radiation. If there is in
fact synergism between two carcinogens, then an assignment of shared
responsibility must be considered. If radiation is one of the carcinogens,
however, the shared mode would be considered for high-level but not for
low-level exposure.
An estimate of the PC is much more powerful than is the dose alone either
for screening cases or determining more definitive estimates of the likeli-
hood of causality. This follows from the dependence of the PC on additional
variables such as the baseline incidence and the RC, either of which can vary
substantially, both innately and with age and sex. It is clear from Equation 1
that PC is greater with large values for dose and RC and smaller with large
values for the baseline incidence.
As an example of the usefulness of the method with large doses of radia-
tion delivered accidentally, consider the Marshallese exposed to as much as
175 reds of penetrating gamma radiation. Out of a total of about 75 high-dose
individuals, one male exposed in early childhood developed myelocytic
leukemia at age 18. The immediate, and correct, conclusion would be that
one case, particularly in a small population, permits no positive deductions
with respect to the leukemogenic potential of 175 reds of gamma radiation.
Moreover, the product of the dose and the RC yields an annual risk of the
order of 10-3, or 10-2 at most, which might also be construed as a basis for
dismissing a causal relationship. However, the PC calculated from this dose
and from information of the kind provided in Table 1 is about 80 percent.
The figure should be larger because the RC in Table 1, estimated for older
individuals and for lower doses and dose rates, should be increased by a
factor of 3 or more. Thus, few would disagree with a decision to handle
responsibility for the leukemia on the basis that the dose of 175 reds was in
fact causative.
Near the other extreme, consider the worker exposed to radiation under
the controlled conditions of a nuclear power plant or laboratory. From actual
recent experience (UNSCEAR, 1982), the large majority of such individ-
uals will probably not receive more than 5 to 10 reds in a working lifetime If
such a worker should develop cancer of the colon, the probability of causa-
tion would be of the order of 0. 1 percent. Should the cancer be rarer and have
a larger risk coefficient, the PC would be larger (with leukemia, about 8
percent). If the threshold PC for a judgment of causality were near 50
percent, then few people would assume that the radiation was involved
causally with either cancer.
Clearly, in situations where the PC is in the range of 50 percent, the values
used in the calculation of PC would come under closer scrutiny. A graded
rather than a threshold approach to compensation should reduce the pressure
to make fine distinctions.
OCR for page 41
CONCH C~US~LI~ Fry KNOWN ~Dl'ION EXPOSURE
41
In discussion of the PC approach, the term average person is used to
indicate that in no case can one calculate a probability that applies strictly to
the specific cancer and the specific individual. As noted, a probability is a
population-denved statistic that applies strictly to the populations for
which the valuers) was obtained by empirical observation. Thus, the proba-
bility applies only to the nonexistent statistically average individual.
However, this situation is not unique to the PC. It applies to the RC, and to
probabilities in accident statistics, life insurance, and other situations in
which probabilities are estimated by observation of populations. It applies in
many legal situations in which a judge or jury is asked to come to a decision,
on the basis of the "best available" (nonquantitative) evidence, that the
reality of some alleged scenario is, for example, "more probable than not"
or "beyond reasonable doubt."
The PC falls into the same category. Although it cannot be said that a
correct decision has been made in each individual case in which the PC has
been used, it does ( 1) constitute an objective and fair approach, (2) provide a
higher probability of a correct decision than would guesswork or a lottery,
and (3) ensure that, if the PC is used in a large number of cases, fairness and
justice, to the degree possible, will have been served. The PC approach is
particularly fair in light of the fact that, unlike most legal situations in which
some individual or individuals almost always know whether or not the
alleged scenario conforms to reality, this cannot be known by anyone in the
situation for which the PC is used. It cannot because the situation addressed
is truly trans-science.
NOTES
A quantal response, as opposed to harm that increases continuously with the amount of
physical insult, is "all-or-nothing" in nature: it is a functional change or failure that either
occurs or does not occur in a biological system. Such responses are not usually spontane-
ously reversible and can be lethal. The quantal response concept was developed by Finney
(1964).
Use of the word "dose'' appears to be appropriate to describe the amount when the
stochastically delivered harmful agent is a drug or chemical. If the agent is a microorga-
nism or energy in some form, more appropriate and less confusing terms might be the size
of the inoculum or of the physical insult, respectively.
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Representative terms from entire chapter:
radiation exposure
