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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

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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

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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

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slot, ED En In o a Ct Can o . ~ 5: 2 Cal Cal Cal o ._ 'Dig Cal An lo: Ct OF O = ,3 - V if - ~ O m ~ a< = o ,,, ~ Cal Ct _ 50 ~ ~ U. ._ ~ ._ U' ._ ~ en - C5 Ct o Cal ._ C) o o . _ 0 Z Do Ct ._ 0 Ct ~4 C) 0 ._ _ t _ ~._ .^ a,) .= ~.^ ~C) ._ _ ._ IS g ~ 0 it ~c) ~. ~. c) c,, ~ ~ ~D or AD ;^ _ Ct Ct C,) Ct C-, o o C ~ O =0 >, I,_ ~ Hi, ~ ~u ~ Dct Ce ~ ~ =, ~ ~C., ~it> O ~ ~ ~ ~ O ~= o ~ 3 . , ~ 9 O ~ ~O ~ c~:t ~L) ~ O~ C) ~ ~ ~,D_ - ~ I:: ~- ~C) ~C) ~ o ~ Cal ~ C)o C: ~ ~='=Z .= =.= ~ - - o ~ ~ =.= ED ~ ct o _ C) Ct Ct a' c' ~.. .. I: Id ~0 e C e c c' Ct ~ ~C) ~ 0 ~ 0 ~ Ct C) & ~ ~V V 27

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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.

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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

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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

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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,

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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).

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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

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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

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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).

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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

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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

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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

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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.

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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. REFERENCES Awa, A. A. 1975. A review ofthirty years of Hiroshima and Nagasaki atomic bomb survivors, II. Biologic effects, chromosome aberrations in somatic cells. (Japanese) Journal of Radia- tion Research, Supplement 16: 122-131. Bond, V. P. 1959. The medical effects of radiation. Pp. 1 17, 126, and 127 in Proceedings ofthe

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42 VICTOR ~ BOND National Association of Claimants' Compensation Attorneys (NACCA), 13th Annual Conv., Miami Beach, Florida. Cincinnati, Ohio: W. H. Anderson. Bond, V. P. 1981a. The cancer risk attributable to radiation exposure: Some practical prob- lems. Health Physics 40: 108. Bond, V. P. 1981b. Testimony before the Senate Committee on Labor and Human Resources concerning the Radiation Exposure Compensation Act of 1981. 27 October. Bond, V. P. 1982a. The conceptual basis for evaluating risk from low-level radiation exposure. In Proceedings, 17th Annual Meeting of the National Council on Radiation Protection and Measurements. Issues in Setting Radiation Standards; Proceedings No.3,25-65. Bethesda, Md.: National Council on Radiation Protection. Bond, V. P. 1982b. Testimony before the Joins Hearings ofthe Senate Committee on Labor and Human Resources and the Committee on the Judiciary concerning the Atomic Bomb Fallout Compensation Act of 1982. Subcommittee on Agency Administration, 12 March. Bond, V. P. 1984. Stochastic basis for dose-response curves, RBE and temporal dependence. Pp.387-402 in Radiation Carcinogenesis, Epidemiology and Biological Significance, J. D. Boice and J. F. Fraumeni, eds. New York: Raven Press. Bond, V. P., and L. F. Feinendegen. 1966. Intranuclear 3H thymidine: Dosimetric, radiobio- logical and radiation protection aspects. Health Physics 12: 1007-1014. Bond, V. P., and M. N. Varma. 1983. A stochastic, weighted hit size theory of cellular radiobiological action. Pp.423-438 in Radiation Protection, 8th Symposium on Microdosi- met~y, Julich, Federal Republic of Germany, 27 September- 1 October 1982, J. Booz and H. G. Ebert, eds. Luxembourg: Commission of European Communities. Bond, V. P., L. A. Schairer, and M. N. Varma. 1984a. The effect of combined chemical and radiation exposures on Tradescantia flower color mutation frequency. Environmental Mutagenesis 6:416-417. Abstract, Environmental Mutagen Society, 15th Annual Meeting, Montreal, 1984. Bond, V. P., L. A. Schairer, and M. N. Varma. 1984b. Somatic response of Tradescantia stamen hairs to combined chemical radiation exposure. Abstract, Radiation Research Soci- ety Meeting, Orlando, Florida, 1984. Cox, L. A. 1984. Probability of causation and the attributable proportion of risk. Risk Analysis 4:224-240. Emmerling-Thompson, M., and M. M. Nawrocky. 1980. Genetic basis for using Tradescan- tia clone 4430 as an environmental monitor of mutagens. Journal of Heredity 71:261. Fialkow, P., S. Gartler, and A. Yoshida. 1967. Clonal origin of chronic myelocytic leukemia in man. Proceedings of the National Academy of Sciences 58: 1468. Fialkow, P. J., R. Jacobson, and T. Papyannopoulou. 1977. Chronic myelocytic leukemia: Clonal origin in a stem cell common to the granulocyte, e~throcyte, platelet and moncite/ macrophage. American Journal of Medicine 63: 125. Finney, D. J. 1964. Probit Analysis. 2d ed. New York: Cambridge University Press. Fry, R. J. M., P. Powers-Risius, E. L. Alpen, E. J. Ainsworth, R. L. Ullrich.1983. High-LET radiation carcinogenesis. Advances in Space Research 3(8):241-248. Gould, M. N. 1984. Radiation initiation of carcinogensis in vivo: A rare or common cellular event. P.347 in Radiation Carcinogenesis, Epidemiology and Biological Significance, J. D. Boice and J. F. Fraumeni, eds. New York: Raven Press. Gould, M. N., R. Jintle, J. Crowley, andK. Clifton. 1978. Reevaluationofthenumberofcells involved in neutron induction of mammary neoplasms. Cancer Research 38: 189-192. Jablon, S. 1985. Testimony before the Senate Committee on Labor and Human Resources concerning the Radiation Exposure Compensation Act of 1981. Kellerer, A. M. 1976. Microdosimetry and its implicati~ons for the primary processes in radiation carcinogenesis. In Biology of Radiation Carcinogenesis, J. M. Yuhas, R. W. Tennant, and D. J. Regan, eds. New York: Raven Press.

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CONCH C~US~LI~ ~ KNOWN ~Dl~ION EXPOSURE 43 Land, L., L. F. Parada, and R. A. Weinberg. 1983. Cellular oncogenes and multistage carcinogenesis. Science222:771-778. National Institutes of Health. 1984. Report of the National Institutes of Health (NIH) Ad Hoc Working Group to Develop Radioepidemiological Tables. U. S. Department of Health. National Research Council. 1972. The Effects on Populations of Exposure to Low Levels of Ionizing Radiation. Advisory Committee on the Biological Effects of Ionizing Radiations. Washington, D.C.: National Academy of Sciences. National Research Council. 1980. The Effects on Populations of Exposure to Low Levels of Ionizing Radiation: 1980. Committee on the Biological Effects of Ionizing Radiations. Washington, D.C.: National Academy Press. National Research Council. 1984. Assigned Share for Radiation as a Cause for Cancer. Review of Radioepidemiological Tables Assigning Probabilities of Causation. Oversight Committee on Radioepidemiology Tables. Washington, D. C.: National Academy Press. Nowell, P. C. 1967. The clonalevaluationof tumor cellpopulations. Science 194:23. Oftedal, P., M. Knut, and H. Torlief. 1968. On the probability of radiation being the cause of leukemia. British Journal of Radiology 41:711-712. Schaffer, W. G. 1984. Claims forinjuries from occupational radiation exposures in the United States: Recent developments. Health Physics Society's Newsletter, Vol. 12, No. 12. Skarsgard, L. D., B. A. Kihlman, L. Parker, C. M. Puiara, and S. Richardson. 1967. Survival, chromosome abnormalities, and recovery in heavy ion- and x-irradiated mamma- lian cells. Radiation Research Development 7:208. Underbrink, A. G., and A. H. Sparrow. 1974. The influence of experimental endpoints, dose, dose rate, neutron energy, nitrogen ions, hypoxia, chromosome volume and ploidy level on RBE in Tradescantia stamen hairs and pollen. P. 185 in Proceedings of International Atomic Energy Agency Symposium, Biological Effects of Neutrons, Vienna. United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). 1982. Ionizing Radiation: Sources and Biological Effects. Report to the General Assem- bly, United Nations, New York. Varma, M. N., and V. P. Bond. 1983. Empirical evaluation of cell critical volume dose vs. cell response function forpink mutations in Tradescantia. Pp. 439-540 in Radiation Protection, 8th Symposium on Microdosimetry, Julich, Federal Republic of Germany, 27 September- 1 October 1982, J. Booz and H. G. Ebert, eds. Luxembourg: Commission of European Communities. Vogelstein, B., E. R. Fearon, S. R. Hamilton, and A. P. Feinberg. 1985. Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors. Science 727:642-645.