Carcinogenesis by Radioactive Substances*

JACOB FURTH AND JOHN L. TULLIS

(Children's Cancer Research Foundation and Cancer Research Institute of the New England Deaconess Hospital, Boston, Mass.)

Knowledge of the potential dangers of exposure mary tumors, and leukemias), and (c) by co-car- to radioactive substances and the institution of cinogenic action. In the last instance isotopes are proper safety precautions have helped to reduce presumed to condition another force or be condi- accidental exposures to radioactive substances. tioned by one (as aseptic or microbial inflamma- However, the carcinogenic hazard from them has tion, fractures, carcinogenic hydrocarbons). by no means been eliminated, and, in spite of the Radioisotopes may induce neoplasms by a pre- exercise of reasonable care and the use of improved dominantly local action without exerting a sys- technics, accidents in the laboratory and industry temic effect. This may be explained in part by the may still occur. Because of the vastly increased tendency of certain isotopes to concentrate in scientific usage and the projected expansion of specific loci in the body, and in part by the general atomic power in industry, the potential hazard protection afforded by relatively undamaged tis- will increase in the future. sues. On the other hand, some isotopes, such as In the following we shall review briefly car- p32, that are widely distributed in the body can cinogenesis in man by naturally occurring and ar- produce leukemia in susceptible animals. Also, tificially produced radioactive substances, the destruction or depression of one organ may initiate lung cancer problem in miners, the development of changes in another organ. For example, radiothy- bone tumors in luminous dial painters and in pa- roidectomy in mice leads to the development of tients treated with radium-containing nostrums, pituitary tumors. This is the consequence of sus- and the development of cancers in patients who tained stimulation of thyrotropes which continue received thorotrast (ThO~) as a diagnostic proce- to proliferate in the absence of the thyroid. Like- dure several decades ago. We shall also review wise, ovarian depression by irradiation leads to some of the experimental work which indicates the stimulation of gonadotropes which in turn cause extensiveness, the limitations, the problems, and tumorous changes in the irradiated ovaries. The the prospects associated with the use of radioiso- precise role of ionizing irradiation in this type of topes as carcinogenic agents. Finally, brief con- carcinogenesis is controversial. It is now widely sideration will be given to the external use of radio- accepted that, in the induction of tumors of endo- isotopes and to the "fall out" problem. crine glands, a direct mutagenic radiation effect plays little if any role, and that an indirect specific GENERALITIES hormonal imbalance is essential for their develop- Tumor induction by ionizing irradiation can be ment. brought about (a) by direct action (as in skin, Tumor induction is influenced by mitotic ac- bone), (b) by indirect action 1 (as ovarian and roam- tivity only in a limited sense. A rapid rate of re- * The work in our laboratories has been supported by the placement of injured cells does not necessarily in- Atomic Energy Commission Contracts AT(30-1) 901 and dicate likelihood of tumor formation. For instance, AT(80-1) 1739 and the United States Public Health Service the replacement rate of epithelial cells of the cor- Grants C-~547 and C-~59. nea and of the small intestine is high, yet they do This is one of three papers presented in a Symposium on Radioactive Isotopes and Cancer at the 46th Annual Meeting not give rise to tumors. On the other hand, grow- of the American Association for Cancer Research, Inc., in ing human bone is more radiosensitive than resting San Francisco on April 16, 1955. The first paper, by David bone. If the cell in mitosis is an end-cell, injury to M. Greenberg, was published in the August, 1955, issue of it will not cause a cancer; if it is a reserve cell, it Cancer Research. The third paper, by John H. Lawrence, .will appear in the March issue. may. Some other basic factors determining the induc- 1For such indirect effects, Mole (67) introduced the word "abscopal" effect, meaning away from the target, at a distance tion of cancer are: (a) the half-life of the isotope, from the irradiated volume, to contrast this effect from that of (b) the amount retained in the body, (c) the char- oxidizing radicals which act in their immediate proximity. acter and dose of irradiation emitted, (d) the char-

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1956 American Association for Cancer Research. Cancer Research acter of decay products, (e) the individual sensitiv- One explanation offered for the extraordinary ities of cells and tissues, (f) degree of protection frequency of lung tumors in the uranium miners of afforded by nonirradiated cells in the irradiated Schneeberg and J~chymov was that of Lorenz host, and (g) a variety of other known and un- (61), who believed that the Rn concentration in known co-carcinogenic factors. the air was not great enough to be carcinogenic The belief that long-continued and repeated and postulated the essentiality of some contribu- application of radiation is essential for carcino- tory factors, such as chronic respiratory disease, genicity is fallacious, as the effects of instantane- inhaled ore dust, or heredity. Evans maintained ous exposures to atomic bombs indicate. When ex- that the Rn concentration in the air of the mines posures are repeated, the dose rate, the interval (averaged 3 X 10 -~2 curies/cc; tumor dose about between doses, and the total dose all are impor- 3000 rem [roentgen equivalent mammal]) was the tant, and the response will vary with different chief factor in the production of lung cancers in types of cells. There can be additivity or syner- these miners (~-e4). gism, or apparent antagonism. Evidence is accu- While the greatest potential radiation hazard mulating in favor of the theory that carcinogenesis comes from Rn and two of its alpha-emitting is a multistage process. Small doses of a carcinogen daughters, dust particles also may contain and col- may cause hidden changes which become manifest lect radioactive material, be inhaled, and become when the cells are exposed to a second stimulus. fixed in the lungs. Solid daughters of Rn become The carcinogenic response varies so widely with attached to the bronchial epithelium as well as to species and strains that the liability of man to de- dust, and thus ventilation and dust control are velop certain neoplasms will be learned only from basic safeguards. observations on man. Animal experiments help in In a consideration of carcinogenesis by particu- the understanding of the underlying basic mech- late matter, there is the problem of lack of unifor- anisms and in obtaining leads on possible events mity in distribution. For bone-seeking metals, a in man, but direct extrapolation of data among tenfold difference in concentration is used in cal- species is not permissible. culations. From the distribution of anthracotic material in the lungs, it is apparent that minute URANIUM MINING AND MILLING AND THE foreign particles have a tendency to pile up in cer- LUNG TUMORPROBLEM tain loci. It is highly probable that the pulmonary Mining and processing uranium ores in the cancers produced by radioisotopes result from a United States is a recent, rapidly expanding ven- local action of radioisotopes fixed in such loci. The ture. The median Rn concentration found in the lung cancers in the miners, like lung cancers in unventilated mines of Colorado Plateau is higher man in general, arise mainly in the bronchi. Ac- than the median concentration reported in the U cording to Evans "the tissue dose of alpha-radia- ore mines of Bohemia and Saxony (s where tion delivered to the bronchial epithelium is great- pitchblende has been mined for centuries. Suffi- est in the larger bronchi" (e3). It should now be cient time has not elapsed to allow lung cancer to possible to quantitate, by autoradiographs of become a problem in the American mines, but it lungs of uranium miners, the amount of radio- has long been a controversial problem in the Euro- activity in different loci of the respiratory tract, pean pitchblende mines (7S, 74, 83). This contro- as was done with bone tumors induced by Ra (60). versy is due in part to inadequacy of the available Experimentally, this problem has not been studied records. According to one of the last available re- adequately. This is owing in part to lack of an ex- ports, 180 miners in Jhchymov (Joachimsthal), perimental animal susceptible to lung tumors simi- Bohemia, received compensation for lung cancer lar to those of man. during the 4 years between 1939-43 (83). That Although the reported isolated instances of lung is more than half the number of miners employed tumor among workers in radium laboratories in there 10 years earlier. Of thirteen Jhchymov min- Europe (Neizel, see Lorenz [61]) are of little sta- ers examined at autopsy in 19~9-39, nine had pul- tistical significance, the four cases of squamous- monary cancers and only four were cancer-free cell carcinoma of paranasal sinuses among the dial (73). The time spent in mines by patients with painters are probably due to Rn and are somewhat cancer range from 13 to e3 years. Two were work- analogous to the lung tumors of the miners. The ing until shortly before death, and seven had been dose of Rn is small but inflammation of the sinuses out of work for periods of from 1 to ~7 years. Evi- may have facilitated fixation of Rn or acted as a dence of anthraeosis and silicosis were minimal. co-carcinogen. This relationship, first indicated by Later, Sikl (83) stated that, of 5~ deaths, twenty Lacassagne and associates, has been discussed were caused by carcinoma of the lung. elsewhere (30).

NEOPLASMS CAUSED BY RADIUM AND serious interference with health, while tumors de- MESOTHORIUM IN MAN veloped in other patients with a Ra burden of but M:artland's description of osteogenic sarcoma in 1 #g. Individual differences in sensitivity, or per- the radium dial painters (19~5) served as a warn- haps the relative concentrations of MsTh and Th ing to curtail the industrial and therapeutic use of admixed with Ra, account for these remarkable radium (66). The technic of dial painting was differences. There is some uncertainty about the changed, and the use of radium water orally and doses because of absorption of Rn on glass surfaces injection of radium chloride for treatment of vari- and errors in technics. ous diseases were discontinued. However, in all of From the physical standpoint, Evans (~3) and, those who had been exposed previously, the haz- more recently, Spiers (84) made a thorough study ards of late effects persist. of these cases, and much of our present knowledge Aub et al. (5) reviewed 30 cases of radium poi- of energy levels of bone-seeking isotopes that are soning in which they estimated the radium con- carcinogenic is based on their calculations. Some tent. There had been ten deaths in this group at of the essential data in relation to tumor induction the time of this report; eight were caused by malignant tumors. Data on these cases are shown in TABLE 1 Table I. TUMORS IN MAN FROM RA POISONING (58) The radium paints for luminous watch dials and Ra Death the medicinal radium waters contain variable Type of tumor (~g.) Exposure type (Years)* Osteosarcoma, humerus 8-9 Therapeutic injection ~3 amounts of mesothorium (MsTh), an isotope of " , tibia 6 5 Dial painting 27 radium with the same chemical but different decay " , finger 0 8 Therapeutic injection 28 characteristics. The decay products of the two are Giant-cell sarcoma, jaw 1.5 Dial painting 15 Fibrosarcoma, knee joint 5-6 Therapeutic, oral 17 somewhat differently distributed in the body, and Squamous carcinoma, 10 Dial painting 19 this may explain in part the great variation in sinus tumorigenesis in relation to quantity of radioac- Squamous carcinoma, f~-9 " " 34 sinus tivity found in the body. Squamous carcinoma, 1.0 " " 34 Looney reviewed 36 patients who were treated SINUS with radium chloride and fourteen luminous dial Osteosarcoma, femur 3.8 " " 3~ " , elbow O . 5 " " Living workers (59). All patients who have 1 ug. or more " , ischium 1.3 " " 30 of Ra in their bones have roentgenographic evi- Fibrosarcoma, foot 1.3 Therapeutic injection ~ dence of changes in bone density. Thus far, four Osteosarcoma, tibia 0.8 " " 24 ? " , vertebrae 6.8 " " ? malignant bone tumors have developed in the 36 " , tibia 3.6 " " 24 patients given Ra medically and three malignant * After exposure. bone tumors in the fourteen luminous dial workers (Table 1). by Ra in man are stated by Aub et al. (5). Ra, Autoradiographs (60) show a random distribu- much like Ca, is semipermanently deposited in tion of radium in trabecular bones and concentra- bone. tion of radium in the cementing lines and Haver- According to Aub et al. (5) and Evans (2~) the daily rate sian systems of compact bone (Fig. 1). The radium of Ra excretion is estimated at about 0.005 per cent of the seems to be deposited in areas that were metaboli- total present in the body. The total Ra content in fatal cally active at the time of administration or re- cases was 1-5 #g. The average Ra content of dry bone was distribution of Ra. The areas of more uniform and 1.5 X 109 gin. Fifty-five per cent of Rn and its decay prod- nets (RaA, RaC) were retained in bones. Two to 10 rep less dense deposition were probably the result of (roentgen equivalent physical) of alpha/day for 10-15 years inorganic ion exchange (80). The areas of micro- is estimated to cause cancer in one-half to one-tenth of scopic bone destruction do not always correspond the exposed people; this delivers a total of about 7000 rep = with those of radium deposition. 35,000 rem. The Ra burden of one-fifth of these produced cancer in man. In general, the tumor incidence (~0 per cent) and average latent period (19.5-31 years) in per- The maximum permissible burden of a bone- sons with Ra and MsTh poisoning varied but little seeking alpha-emitter, expressed as Ra, was re- with different degrees of radioactivity (> 1 to < 10 considered by Spiers (84) in the light of the calcu- #g.). The problem of radium storage in relation to lated dose rates to osteocytes and of the relative tumor incidence is interesting but involved. Pa- biological efficiency of alpha radiation, for which tients vary in their ability to store radium and in a factor of ~0 is proposed by the International their response to it. Aub et al. (5) cited cases of Committee of Radiation Protection. Difficulties of three patients in whom radium contents of 10-~3 calculation result in part from lack of uniformity t~g. were stored for from s to ~25 years without of radiation. The radiation dose to osteocytes

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1956 American Association for Cancer Research. Cancer Research was calculated by Hoecker and Roofe (44), utiliz- kidneys, but these cells do not seem to proliferate ing alpha track radiographs made on preserved (Hollcraft et al. [45] and Casarett [1S]) (Fig. 2). bones of dial painters who had died 20 years This change is analogous to that seen in thyroids earlier. The maximum concentration in their damaged by I TM and other sites of radiation in that samples was 7 times more than the average for the they possess hyperchromatic, large, often bizarre- skeleton as a whole. If osteocytes are regarded as shaped nuclei (cf. 64, 65) (Figs. $ and 4). The ab- a "limited volume of tissue" to which the higher normal cells resemble neoplastic cells, but are not permissible dose rate of 1.5 r/week is allowed, the known to give rise to tumors. It is possible that permissible Ra burden may be 0.1 #g. (Spiers they are permanently altered cells (radiation [84]). This burden in the skeleton will deliver to mutants) but do not possess the intrinsic growth osteocytes 1.6 rem per week -0.08 rep). An esti- power of fully autonomous cells, or are restrained mated 0.4 rem/week will be delivered to bone from proliferation by the desmoplastic reaction marrow and 0.03 rem/week to blood. caused by irradiation. (The latter could be tested The relative efficiency of a-rays for carcinogenic experimentally by transplantations in normal action is not precisely known, nor is the mecha- hosts.) Similar, but reversible, chromatin abnor- nism by which radiation induces malignant malities can, however, also be induced by folic changes, and therefore all estimates are crude. Ion- acid deficiency. izing radiations are known to produce gene muta- In the experiments of Casarett (13), the nephro- tions and structural damage to chromosomes. sis caused by the alpha-emitting Po terminated in According to Lea (56), a-rays may be one-third as nephrosclerosis, with formation of adenomas. Did effective as x- or "/-rays in the production of mu- these adenomas result from attempted regenera- tations, but, according to Gray (41), they are more tion of injured tubules or from radioactivity? effective in causing chromosome damage. They remind us of the renal tumors induced in Similarly, little is known about the morpho- hamsters by estrogens and of adenomas in sclerotic genesis of bone tumor development. Since bone human kidneys. The character of these renal tu- tumors induced by radioisotopes are autonomous, mors and those in the adrenal medulla, described the basic change is to be sought in an irreversible by Casarett (13) as late effects of Po damage, re- change in osteocytes. Modifications in osteocytes quire elucidation. as a consequence of irradiation have, to our knowledge, not been investigated, and the known radia- THORIUM DIOXIDE (T~oaoTaAST) tion-induced non-neoplastic changes in bones may Introduced in 1928 as a contrast medium in be merely incidental. The latter may be caused by radiography, Th02 became the most widely used damage to nutrient vessels. One such lesion is radioactive substance before artificial radioiso- aseptic necrosis of bone. The other, so-called "radi- topes were available. When injected into the blood ation osteitis," is a diffuse fibrosis of the marrow stream, it is phagocytosed by the reticulo-endo- with disorganization of hemopoietic structures, in- thelial (RE) system, chiefly of liver and spleen. filtration of inflammatory cells, resorption of bone Very recently, Looney et al. (58, 59) reviewed the by osteoclasts, and some atypical bone formation. status of 35 people who received 8-15 gm. of thoro- Neither of these lesions is localized entirely to re- trast intravenously for diagnostic purposes. With gions of greatest alpha activity. increasing time, larger and larger aggregates of Experimentally, numerous investigators have thorotrast were demonstrated in the RE cells. demonstrated the ability of Ra and MsTh to cause These aggregates were usually 10-100 microns in osteosarcoma by intravenous administration in diameter, but some were as large as 1-2 mm. Be- rabbits (see 30) and by oral administration in rats cause of the short range of the alpha tracks, aggre- (see 30). In these animals tumors appeared as gation of thorotrast particles is accompanied by early as 1 year after administration of the car- marked reduction of biologic efficiency. Evans (23) cinogen, while in man tumor formation required calculated the liver dose of alpha radiation after 10 years. intravenous injection of thorotrast to be 1.5-5 Implantation of Ra- or Rn-filled sealed tubes rem/day. Tissue containing 1 per cent thorotrast caused fibrosarcoma and carcinoma but not bone would then receive 3000 rep or 15,000 rem in 10 sarcoma. Bone sarcoma is favored only by inti- years, an amount comparable with the carcino- mate contact of "bone seekers" with osteoblasts. genic dose in chronic radium poisoning. While Ra is essentially a bone-seeker, some de- MacMahon et al. (65) described a patient with cay products of Rn, notably Po, cause severe, endothelial-cell sarcoma of the liver in the vicinity often fatal, kidney damage. Hyperchromatic cells, of thorium deposits, who died 12 years after re- many with bizarre giant nuclei, are present in these ceiving thorotrast. This was the first well docu-

mented instance of tumor induction by this iso- marion on tumor production in relation to dose, tope3 dose rate, type of radiation, on biologic effective- Because the greatest concentration of ThO2 is ness, and on synergistic, antagonistic, and other in the spleen, it might be expected that neoplasms factors which modify the biologic effectiveness of would occur most frequently in this organ, as radiation. Looney et al. remarked (59), but no tumors have Table 3 shows the quantity and kind of isotopes been reported in the spleen; nor have they been shipped by the AEC for medical and industrial noted about the dense granulomas which formed uses since 1946 and their reported carcinogenicity. at sites of extravasations at sites of injections (59). With the exception of Co 6~ which is used only On the other hand, five neoplasms have been re- in sealed containers for external irradiation, all ported about ducts or sinuses into which thorotrast those detailed have been tested for carcinogenici- was injected: two in the lacrimal duct, one in the ty. C 14 is not carcinogenic and Au 19s colloid causes maxillary sinus, one in the renal pelvis, and one in only adenomas of the liver. the mammary duct. In the liver, five tumors were observed (Table ~). TABLE The long latency of carcinogenesis by ThO2 is MALIGNANT TUMORS AT SITES OF evident from all reports. Cancers are still appear- INJECTION OF THOROTRAST* ing in scattered regions of the body three decades Tumor No. after use of the isotope. The tumor induction rate type Site years 1" is low, for, considering the large number of people Sarcoma Kidney pelvis 16 Carcinoma Lacrimal duct ? who have received ThO2, the total number developing tumors is small. Squamous-cell carcinoma de- " Maxillary sinus 10 veloped on the eyelid of a man 35 years after in- " Mammary gland 10 " Liver ? jection of ThO2 in the lacrimal duct. The excised Cholangioma " 10 tissue was estimated to have delivered 1.5 r/day Carcinoma " 10 or e0,000 r in ~5 years (Rudolphi [80]). A similar Sarcoma " 1 Carcinoma " 19 tumor was found in the maxillary antrum of an- Hemangio- other man who had retained ThO2 injected there endothelioma " 28 10 years earlier (Hofer [43]); a carcinoma of the * Abbreviated from Looney et al. (59). lung was noted 18 years after bronchography with t After administration of thorotrast. ThO2 (1). These and other cases have been well reviewed by Looney et al. (59), who have also dis- Phosphorus-32.--P 32 is one of the radioisotopes cussed the uncertainty of the causal relation be- most frequently used clinically. Will it increase the tween leukemia and administered thorotrast in the leukemia incidence in man? Leukemias developed few reported cases. in four (3 per cent) of 148 polycythemic patients ThO2 administered to man for visualization of treated with pn2 and observed by Stroebel and vessels caused vascular changes that are likened to Pease (85) over a 10-year period, one of chronic thromboangiitis obliterans and arteriosclerosis. and three of acute myeloid type. This is not a con- The vascular changes may, to some extent, have vincing figure, for polycythemia sometimes termi- counteracted the tumor-producing properties of nates in myeloid leukemia as if the latter were a the ThO~. natural developmental phase of polycythemia. Before the discovery of the carcinogenic hydro- There are not enough data to know how often this carbons, ThO~ was perhaps the best available occurs: (a) without any treatment, (b) after use of carcinogen. Carcinomas and sarcomas, including an erythrolytic agent, (c) after total or partial osteosarcomas, were induced with it in rats, guinea body x-radiation, and (d) after use of PaL pigs, and rabbits. This early work (see 30) demon- The fact that all four leukemias observed by strated the relative responsiveness of different Stroebel and Pease were myeloid could relate these adult tissues to this radiocarcinogen. The basic to either polycythemia, a disease of the marrow, findings were duplicated later with hydrocarbons or to irradiation. Most leukemias among the and more recently with artificial radioisotopes. Japanese exposed to atomic bomb were myeloid, and most of them were acute (54, 68). ARTIFICIAL I~ADIOISOTOPES Life-span studies in animals on the carcinoge- While the old observations were empirical, and nicity of internally administered p2 were conduct- mainly qualitative, research in the post-nuclear 2The remarkable ability of ThO2 to produce hemangio- fission era has become more quantitative. Present- endothelioma is indicated by the recent article of Tesluk and day projects are apt to be designed to yield infor- Nordin (Arch. Path., 60:493-501, 1955).

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1956 American Association for Cancer Research. 10 Cancer Research ed in two laboratories, one by Koletsky et al. (51) was a distinct reduction of the latent period when in rats, the other by Brues et al. (12) in mice. the dose was increased. The threshold was sharp, 1 Brues et al. (12) showed that, with respect to izc/gm causing tumors in 32 per cent of the rats, leukemogenic effects in mice, p32 is a carcinogenic and 0.5 and 0.25 izc/gm producing none. All squa- stimulus comparable with x-rays. It is effective mous-cell carcinomas occurred in rats receiving the whether given in single or in fractionated doses. largest dose and, with one exception, originated Increasing doses are more effective until a satura- about the nasopharynx. It is noteworthy that in tion value is reached. There is also evidence for a the rat 1TM caused the development of bone tumors, threshold dose and dose rate below which tumors to which the strain used shows some susceptibility,

TABLE 3 RADIOACTIVE ISOTOPE DISTRIBUTION DATA (August 2, 1946 to May 31, 1955) Mostly from the Eighteenth Semiannual Report of the AEC (4) RAD~TION MEV CumEs DISo SHIP- Average TRIBUTED MEI~I'TS EXPERIMENTAL Isozors HALF-rIFE B energy 7 energy X 10 X 100 CARCINOGENICITY Iodine-131 8.0 days 0.205 0.3-0.7 285 259 Thyroid, pituitary Phosphorus-32 14.3 days 0.695 86 156 Bone, skin, leukemia Carbon-14 5740 years 0.050 3 20 None Sodium-24 14.9 hours 0.540 1.38-2.75 3 25 Gold-198 2.69 days 0.320 0.411 164 25 Liver (adenoma) Tritium-3 12.4 years 0.006 64 2 Strontium-89 53 days 0.500\ Bone Strontium-90 25 years 0.220J 31 8 Bone Cobalt-60 5.2 years 0.099 1.17-1.33 5963 10 (External) Cesium-137 37 years 0.170 219 5 Iridium-192 70 days 0.225 0.13-0.65 236 1 Polonium-210 138.3 days * 0.8 113 1 Bone Others 73 182 t Total: 7240 694 * 5.$, 4.5a. ? Bone tumors were also produced with ygl, Ce1% pu~sg, U2=, U23a, and Ca4S; epidermoid carcinomas of the oral and nasal cavities with SrSg; harderian gland, adrenal, kidney, and other tumors with Po~t0. (M. P. Finkel, personal communication to the authors.)

TABLE 4 while in mice it caused leukemias, to which the CARCINOGENICITY OF p32 IN RATS* strain used was susceptible. In assaying a radio- Squa- active substance for carcinogenicity, it may be mou8 worth using many strains of animals of different Dose No. positive Per cent carci- Osteo- Latency species with different liabilities. Not the specific gc/gm wt. /No. inj. Positive noma sarcoma (months) t 4.5~ 9/19 47 3 6 9.5 isotope, but the quantity incorporated per cell, the 3.5; 3.0 12/34 36 5 9 10 type of cell, and the stage at which it is affected ~z.o 4/13 31 o 4 14 are the determining factors in the host response. 1.0 6/19 32 1 5 19 o. 5; o. 25 0/43 The 0.5-gc. dose (that is, one-half of a strongly car- 1.5X7 4/15 27 0 10 5 cinogenic dose in rats) approaches the average * From Koletsky et al. (52), abbreviated. therapeutic dose in man. If the calculations indi- t Shortest latency, 7.5; longest, 25+ months. 12,500 Pep ~ LD60 for mice; 20)< therapeutic dose in man. cating that man is more sensitive to bone tumor induction than small laboratory animals are ac- are not induced. More recently, Finkel 3 noted that cepted, the therapeutic dose for man may well be p32 also causes a few osteogenic sarcomas in mice. within the carcinogenic range. The use of different In rats, on the contrary, p32 readily produces strains and species may disclose an even broader osteogenic sarcomas and squamous carcinomas but spectrum of carcinogenicity of p32. no leukemias (Table 4). Koletsky and Christie (52) Moore et al. (70) attempted to produce adeno- found that single doses of 1)32 in the LDs0 range carcinomas by instilling p32 into the stomach of (4.5 ~zc/gm body weight) and smaller doses pro- mice in thin latex balloons. All five tumors produced osteogenic sarcomas or squamous-cell car- duced were squamous carcinomas, arising from the cinomas, or both, in more than one-third of the forestomach. The only consistent change provoked animals tested. The threshold tumorigenic dose in the mucosa of the glandular stomach was that was about one-fifth of the LDs0 (0.5-1 gc.). There of degeneration and radionecrosis. Adenocarcino- a M. P. Finkel, personal communication to the authors. mas of the stomach are yet to be produced by any

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1956 American Association for Cancer Research. FURTH AND TuLLm--Carcinogenesis by Radioactive Substances 11 means. The use of ps~ incorporated in bakelite lated for cutaneous carcinogenesis by different plaques will be surveyed below. agents by several investigators (Rous and Kidd Gold-198.--When colloids of relatively large [76], Rusch [78], Tannenbaum [86], Berenblum [7], particle size gain entry into the blood stream, they etc.). readily disappear from it and are deposited in the Iodine-131.--The widespread use of I TM in treat- liver and spleen. Those of smaller particle size dis- ment of carcinoma of the thyroid and depression appear much more slowly and are deposited pri- of thyroidal function in hyperthyroidism and hy- marily in the bone marrow and spleen, and to a pertensive heart disease raises the question lesser degree in the liver. Colloids of Au 19s and of whether cancer of the thyroid or of adjacent organs other radioactive elements are being used in ex- might result from the therapeutic use of D n. Thus perimental therapy. They are introduced by dif- far it has not, but the possibility of such a change ferent routes chosen to provide greater concentra- in man is recognized. tion of radioactivity at desired sites. The possibili- There are numerous reports of the effects of I TM ty of producing neoplasms of Kupffer cells by sub- alone, in rats, mice, and other species, but only one lethal doses of colloidal Au ~gs has been explored on the development of carcinoma of the thyroid. without success (88), with a strain of mice in which Therefore, the report by Goldberg and Chaikoff reticulum-cell sarcoma is common. Cirrhosis was (35, 36) is worth closer scrutiny. In seven of 25 produced (53), as was done earlier in the dog by young rats of the Long-Evans strain that received Hahn et al. (4e). Benign liver cell tumors devel- a single injection of 400 gc. of I TM, carcinomas de- oped in 10-~8 per cent of the mice in the series of veloped, some with metastases, 1.5 years to Upton et al. (88), but there were no carcinomas. years after injection. Adenomas occurred in two Cirrhosis and adenomas of the liver are precan- others. In contrast, larger numbers of rats that cerous lesions, and it is still possible that, by re- were given radioiodine by other investigators and peated administration of Au ~gs colloid with the observed for adequate periods of time had many proper host, dose rates, and stimulating co-factors thyroid adenomas but no carcinomas. It is pos- well chosen, liver carcinomas and reticulum-cell sible that the thyroid of Long-Evans strain is es- sarcomas could be induced. pecially sensitive to ionizing radiation, or that The cells in which the radioactive substances some undetected co-carcinogenic force was at localize must receive a tremendous amount of ra- play. The work of others has amply shown the diation. If the dose is large, these cells die, the synergistic effect of goitrogens. The dose of I TM was radioactive substance is released, recirculated, and well chosen by Goldberg and Chaikoff (35). It is taken up again by similar cells. This sequence of one that causes profound damage but also leaves events has been demonstrated by Gabrieli and some thyroid tissue apparently unchanged. These Cutler with colloidal Crp3204 (33). It is remark- conditions are also fufilled in the treatment of able that, in spite of the heavy exposure of RE patients with I TM for hyperthyroidism or heart cells to varied quantities of radioactive substances, disease. Some thyroid epithelial cells are killed, but neoplasms of these cells have not been induced. others are not harmed. Those receiving in-between While Au 19s colloid by itself has little carcino- doses are most likely to undergo a malignant genic power for the liver, when combined with an change. azo-dye carcinogen it enhances the carcinogenicity Are the carcinomas induced in rats by a direct of the latter (Williams et al. [90]). The situation is mutagenic effect of I TM, or do excessive amounts of remarkably similar to the carcinogenic activity of thyrotropin (TSH) play a significant role in their I TM in the thyroid. I TM given alone is only mildly genesis as they do in cancers arising in goiters? carcinogenic, but when combined with goitrogen Most residual cells are atypical. A few cells appear it becomes highly carcinogenic to the thyroid. stimulated, and a high blood level of thyrotropin The tentative generalization may be worth con- is known to follow thyroidectomy. The lack of sidering that carcinogenesis by ionizing irradiation high TSH levels in patients with autonomous thy- is a multi-stage process. Ionizing irradiation may roid carcinomas is not surprising, since malignant produce a chromosomal alteration allied to muta- cells often free themselves from the forces control- tion, and some cells so altered may be potential ling normal growth and secrete less hormone than cancer cells. Without further stimulation they re- do their normal precursors. On the other hand, this main in situ, may produce a few abnormal cells, finding does not exclude some role of TSH excess but ultimately die without producing a cancer. in their genesis. Regenerated functioning thyroid When, however, such cells are subjected to a follicles would inhibit TSH production, and thus growth stimulant of the respective cell, a cancer normal and abnormal thyroid cells could co-exist. eventuates. This concept is similar to that postu- In partially radiothyroidectomized animals, ab-

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1956 American Association for Cancer Research. Cancer Research sence of thyroid hyperplasia in spite of TSH excess this connection that most tumors induced by endo- appears to be the rule. The rudimentary and ab- crine imbalance are dependent neoplasms. This normal thyroid follicles are usually embedded in points to a probably basic difference in the char- excessive connective tissue, and the nutrient ar- acter of thyroid tumors induced by goitrogens teries are markedly stenosed. These changes may and those induced by ionizing irradiation. The in part be responsible for lack of adequate com- former are probably dependent and are induced by pensatory hyperplasia. M:aloof et al. (64, 65) found an abscopal mechanism, while the latter are that these thyroids fail to enlarge in response to autonomous and are probably induced by a direct the administration of thiouracil in spite of persist- mutagenic effect. ent hypertrophy of some cells. They found only Doniach estimated that the 8,000-10,000 rep one adenoma of the thyroid in 500 rats studied, in- dose required to cause remission in Graves' disease dicating that radioiodine lowers the proliferative in man is in the carcinogenic range, and the possi- capacity of thyroid cells. bility of late development of thyroid carcinoma in Bizarre thyroid cells in I131-treated animals were patients given thyroid-depressing doses of 1 Ial noted by all investigators. Thiouracil accentuates must be reckoned with. Nevertheless, this hazard atypicity (Doniach [19]). Some cells appear to be alone should be no more of a deterrent to the use somewhat functionally active and capable of un- of I TM than is the rare occurrence of carcinomas dergoing hypertrophy but seldom hyperplasia, so and sarcomas at sites of irradiation following that the compensated thyroid will be small with therapeutic use of x-rays. However, treatment large cells. with thiouracil combined with radiation appears Following subtotal surgical resection, remnants highly hazardous. of the thyroid fail to regenerate into a normal- It is remarkable that in mice I TM does not pro- sized gland. The compensating organ is small with duce carcinoma of the thyroid. The number of ani- hyperfunctioning cells, usually in adenomatoid mals exposed by different investigators within the arrangements. The bizarre hyperchromatic cells of theoretically effective dose range and observed for the irradiated thyroid are lacking. 1-2 years probably amounts to several hundred. The induction of carcinoma in thyroid after ad- The most likely carcinogenic dose in mice is about ministration of I TM is not a simple matter of direct 10-50 pc. In our experience small adenomas are carcinogenesis by ionizing irradiation. Maloof et common, but not carcinomas. Although the abnor- al. (65) and Doniach (19) estimated that in rats mal cells morphologically resemble cancer cells, 50 gc. delivers a total dose of 80,000 rep, and 100 they do not seem to possess the intrinsic power to gc. 60,000-197,000 rep. Were direct radiation alone proliferate as cancer cells. Their functional in- responsible for the induction of malignant thyroid adequacy is indicated by failure to capture I TM. tumors, they would have occurred in many rats The carcinogenic hazard of radioiodine therapy and mice receiving doses larger than 50/~c. appears to be due in part to direct neoplastic trans- Administration of I TM is often combined with an formation of thyroid epithelium and to the produc- antithyroidal drug. Doniach (19) tested the car- tion of some irreversible change of thyroid epi- cinogenic potency of 5, 30, and 100 pc. of I TM on thelium which renders it sensitive to excessive the thyroid of rats, alone and in combination with stimulation. Interference with thyroxin synthesis a subsequent course of methylthiouracil. Thioura- or mere lack of I TM (6) causes increased output of cil itself produced adenomas only. I TM increased the TSH, which is a specific growth stimulus to the formation of adenomas in the 5- and 30-~c. but not thyroid. in the 100-pc. group. In five of the twenty rats that Once a chromosomal alteration is introduced in had been given 80 gc. of I TM and methylthiouracil, a cell, time is needed for that cell to unfold all the carcinomas developed. The radiation dose range to potentialities conferred upon it. In the mouse, the the thyroid in the 30-pc. group was ~,~70-16,~00 life span is about ~ years, but for theoretical pur- rep. The 9,000 rep usually given to patients with poses the period of exposure can be prolonged by Graves' disease is within this range. Apparently, grafting the exposed thyroids on new hosts simi- ionizing radiation causes an irreversible pre-neo- larly stimulated. By this technic, the changes plastic alteration in the thyroid cells which be- which occur in one generation can be simulated in comes evident when these cells are brought to pro- a host with longer life expectancy. Making use of liferation by a second agent which is a powerful this method, Morris et al. (71) were able to produce growth-stimulant but has, in itself, only minimal malignant tumors in mice with thiouracil alone. carcinogenic capacity. But even these tumors were conditioned neo- Carcinomas originating in I181-treated rats are plasms at the start. In man, there are decades likewise dependent tumors. It is noteworthy in available for disclosure of malignant features in

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1956 American Association for Cancer Research. FURTH AND TuLLIs--Carcinogenesis by Radioactive Substances 13 the original host. Several decades will be required radiothyroidectomized C57BL mice, which are before it will be known whether radiothyroidecto- highly susceptible to leukemogenesis by ionizing my is carcinogenic in man. radiations. In the meantime the principles for I m treatment enumerated It should be recalled that x-ray therapy of the by Doniach (19) are worth citing: (a) treat patients under 45 thyroid is also not without carcinogenic hazard. only if other methods have failed or when life expectancy is Sarcoma developed in the thyroid region in a under 20 years; (b) minimal dose of I m should be administered; woman 30 years after radiotherapy for thyrotoxi- and (c) thyroxine medication should be instituted after the thyrotoxie symptoms are relieved in cases of Graves' disease, cosis, squamous-cell carcinoma of the hypophar- or after all responsive cells are destroyed in cases of cancer. It ynx and larynx in another patient, and a fibro- should be remembered that thyroxine counteracts and TSH sarcoma of the esophagus in a third (see 30, 31). promotes this type of carcinogenesis. Pituitary tumor induction by Im.--Although Structures adjacent to the thyroid also receive I TM fails to induce thyroid tumors in mice, it regu- near-carcinogenic quantities of irradiation. Cancer larly produces pituitary tumors (Figs. 5, 6) when of the larynx was described occurring 8 weeks and given in doses causing complete or nearly complete 11 months after treatment with 180 and 51 gc. of destruction of the thyroid (37, 38). The relation of I TM, respectively (87). The latency period of tumor dose of I TM to tumor induction is shown in Table 5. development was too short in these cases to accept Thyroid implants or adequate thyroxin treatment

TABLE 5 RELATION BETWEEN DOSE OF I zal AND SEX TO INDUCTION OF PITUITARY TUMORS IN MICE (29)

NO. IN NUMBER OF DAYS AFTER TREATMENT WITH I Isl Dose PITUIT. GROUP 150--299 $00--399 400--499 500-599 (~e.) TUMOR C Q C 9 o~ 9 o~ C 9 25 -- 18 12 3 1 2 1 3 3 10 7 + o 9 3 6 50 -- 1~ 10 3 4 6 9 -{- 13 13 1 4 2 3 11 5 100 -- 4 9 2 1 9 1 q- 20 15 3 3 13 8 2 6 200 -- 3 s I 3 1 -{- 13 17 2 1 5 3 3 5 3 8 -- = normal or early thyroidectomy changes; -[- = microscopic or gross tumors. Italics indicate the occurrence of gross tumors in the respective group. a causal relationship. However, the recommenda- will prevent the appearance of these tumors. tion of King et al. (50) to remove the thyroid tissue Gorbman (39) believes that ionizing radiation ag- surgically prior to treatment with radioiodine is gravates or synergizes the thyroidectomy in its worth considering. The finding of squamous-cell tumorigenic action on the pituitary gland. carcinoma of the trachea in a radiothyroidecto- Gorbman and Edelmann (~1, 40) reported that mized mouse (37) has not been duplicated. reducing the amount of I TM required to destroy the A limiting factor in the therapeutic use of I TM thyroid by keeping mice on a low-iodine diet will for thyroid carcinoma is the incidental general ir- prevent tumor induction even though the thyroid radiation with severe depression of the bone mar- is ablated and that added x-radiation promotes row. Therapeutic doses are within the leukemo- tumorigenesis. Failure to induce pituitary tumors genic range. Two of fourteen patients described by by I TM in species larger than the mouse could be Seidlin et al. (81, 8~), who received 1,450 and 1,600 explained by the greater distance between the gc. of I TM for thyroid cancer, died with subacute pituitary and thyroid. However, pituitary tumors myeloid leukemia 5 years after initiation of I TM can be induced in mice by the blocking of thyroxin treatment. The cumulative blood radiation dose of synthesis with propylthiouracil (69), iodine defi- one patient was about 600 rep, that of the second ciency (6), and by surgical thyroidectomy (18). In probably greater. The incidence of two cases of our experience, there is an inverse relationship be- myeloid leukemia in a small series of fourteen, tween completeness of thyroid destruction and after a compatible latency period, speaks for a pituitary tumor induction in animals given either possible causal relationship between the I TM thera- small doses of I TM after low-iodine treatment or py and leukemia. On the other hand, an increased large doses after normal diet or after surgical incidence of leukemia has not been reported in thyroidectomy.

Furthermore, the pituitary tumors that have mouse, in response to thyroxin deficiency, is a been induced by total-body ionizing irradiation species characteristic. Experience may reveal alone, and were assayed, were either adrenotropie whether human thyrotropes behave as did those of (three out of nine) or mammary gland-stimulating the rat or of the mouse. However, this riddle may (six of nine), and all were autonomous at the start. never be solved, since thyroxin treatment follow- Only one of nine tumors assayed had some thyro- ing radiothyroidectomy, as it is now practiced, tropic combined with marked somatotropic poten- will adequately prevent development of pituitary cies, and all were autonomous, while all the tumors tumors in man. induced by thyroidectomy which were tested were thyrotropic and of the dependent type. None of :FIssION PRODUCTS more than ten primary pituitary tumors induced The carcinogenic effects of bone seeking and by radiothyroidectomy in four strains of mice some other fission products have been studied ex- grew on normal hosts, but all could be grafted on tensively, notably in A.E.C. laboratories. thyroidectomized mice. Administration of thyroid Strontium-89.--The carcinogenicity of radio- hormone to the latter (substitution therapy) re- strontium has been the subject of a large-scale ex- stored the resistance of these animals (Table 6). periment by Brues (9) and by Finkel et al. (~6, ~7). These observations strongly favor the opinion that Single and monthly intraperitoneal injections in the prime and often sole cause of the induction of the range of 0.01-7.8 #c/gm were given to 3,083

TABLE 6 EFFECT OF THYROID HORMONE ON GROWTH OF DEPENDENT PITUITARY TUMORS (34)

RADIOTHYROIDECTOMIZED HOSTS NORMAL HOSTS Treated* Not treated Not treated No. No. with No. No. with No. No. with grafted tumors grafted tumors grafted tumors Experiment I 7 0 10 10 4 0 Experiment II 7 0 10 10 10 0 Experiment III 10 0 7 7 11 0 Experiment IV 7 ~ 8 8 10 0 Experiment V 10 0 6 6 6 0 * The hormonal treatment began at about the time when the tumor was grafted. thyrotropic pituitary tumors by I TM is the sus- mice. Most tumors induced were osteogenie sarco- tained thyroxin deficiency and that the role of ion- mas; a few were fibrosarcomas and hemangioendo- izing irradiation is minor and not essential. theliomas (3.7 per cent of each). There were strain In considering this controversy it is worth re- and sex differences. Females had 1.5 times as many calling that both hormone imbalance and ionizing tumors as males. The number of tumors per ani- irradiation can produce tumors in diverse organs, mal varied from one to fourteen. but the two together do a better job. The differ- Fractionation of 0.~5 or smaller doses did not ence with respect to autonomy may not be enhance tumor production. The same number of fortuitous. tumors were produced when these quantities were This generalization is offered not as a law but given as a single dose or in fractions of up to five as a provocative thought with implications doses. At higher total doses the number of tumors worthy of special research. For example, a parallel increased with increasing fractionation (~7). The study on the character of ovarian tumors induced latent period was about 6 months and, surprising- by ionizing irradiation and hormonal imbalance ly, was independent of the size of the dose. The alone is long overdue. Ionizing irradiation and hor- number of tumors produced was a function of the monal imbalance can be additive or synergistic. dose (Chart 1) up to a certain level, beyond which Ionizing irradiations themselves can act in a dual there was a decrease of carcinogenicity (Chart e). manner, creating a hormonal imbalance and caus- This apparent inhibition in tumor induction by ing irreversible cellular modifications in the auton- larger doses is similar to that observed by others omous cancer cell. after total-body irradiation. For example, fewer It remains to be analyzed why pituitary tumors myeloid leukemias or ovarian, pituitary, and other do not develop in the rat after radiothyroidecto- tumors were noted in mice exposed to very large my. It is possible that thyroxin deficiency is in- doses than in those exposed to medium doses (3~). complete in thyroidectomized rats kept on a nor- All these neoplasms have a long latency period. mal diet or that proliferation of thyrotropes of the This situation has not been fully analyzed, but two

explanations are plausible; namely, loss of a rela- found to be only one-twentieth as effective as the tively large number of animals during the latency other substances. In comparing ability to reduce period and damage to cells and blood vessels to life expectancy, at dose levels approaching those such an extent as to impair proliferative processes. that produced no effect, the ratios of the various Relative biological effwiency of six heavy radioiso- test substances to radium were 7 for plutonium, 8 topes.--Finkel (~5) studied in mice the relative for polonium, 2 for uranium-23~, and 1 for urani- biological effectiveness of radium and of five other um-~33. alpha emitters (Pu 239, Po ~1~ U ~38, U ~~, Th*28). The relative carcinogenic potential was found to be 7:1 for plutonium and ~ : 1 for uranium-~3~. IO0 k ' I ' I ' I ' I ' I" ' I ' I ' I Uranium-~33 and polonium were less effective 50 Z.~. ~ _~ than radium (Chart 3). In these experiments the F .s.~,?_ X..x..x.-x--x"~ __~ 1.0 m_---- 5.0-- 21 Illl ll]llllli

1.0 ,~ JIJl ~JJJJJJIIJl~ 0.5 : It/ell //".,,::.'..'-:-"""i-_-i .._.o__ :_, t ' l 7 / ./~-7-- r ~ 0.1 ~-Iil Y.~'" , "0 .t tl/l,tIll i.,,t' I! ~oo 200 300 400 SOD sod zoo SOD SOD -e..lt t.i,illlk J,: I DAYS AFTER INJECTION CHART l.--Cumulative incidence of animals dying with bone tumors after a single injection of Sr s9 (gc/gm). (From ,~ ,,k;!J Ilil Finkel et al. [~7].) :,.I /llii.,,tkllII I IiI 5.0 ,oli~176 I,f t 1!!1

1.0 O.I 0.5 I.O ~,.0 IO 50 tO0 DOSE I**c/~0) 0.5 CHART 3.--]?robabi]ity of development of bone tumors in $tr .J mice treated with several radioactive heavy metals, surviving the latency period. (From Finkel [35].) ~ 0.1

"~ 0.0 latent period of tumor development was independent of the dose level but varied with the isotope. This is not true for Ra in man. Multiple tumors ~- o.o,-~~~ were the rule, especially after administration of 0.005~ plutonium. The complexity of the problem is well brought out by this type of experiment. Variations in ef- 0,00~ fective dose levels, disintegration schemes, metab- 0.005 0.01 0.05 0.1 0.5 L0 5.0 10.0 olism of daughter products, latent periods, and host Sr 89 (pclgm.) response all contribute to biological differences. CHART ~.--Malignant bone tumors after single and repeat- The "law" of diminishing returns with excessive ed administration of Sr sg. (From Finkel et al. [37].) doses is also well shown by these data. Of the animals that survived the latent period, tumors de- The criteria used to judge the effectiveness of veloped in 15.4 per cent after a large dose, and 4 the isotope were (a) time required for 50 per cent times as many after a smaller dose. This inhibition mortality, (b) reduction of life expectancy, and of tumor formation is probably brought about by (c) carcinogenic activity. The relative biological destruction of tumor-potential tissue by irradia- effectiveness of an isotope was found to vary with tion. the criterion of effect chosen (~5). With respect to Uranium-232, Uranium-233, Plutonium-239, causing fatality within ~0-100 days, radium was Yttrium-91.--In view of the rapidly increasing

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1956 American Association for Cancer Research. 16 Cancer Research mining and milling of uranium ores, Hueper et al. IRRADrATIO~VnTH S~.Ar~DSO~C~.S OF (46, 48) found it desirable to assay for carcinoge- RADIO~SOTOr~.s nicity metallic uranium deposited in exposed parts The use of sealed radioisotopes as a source of B- of the body. They injected powdered U 23s (50 and "y-rays for therapeutic irradiation is a matter mg.) suspended in lanolin into the bone mar- of convenience. Radiogold seeds (Au 19s) are re- row of rats. In one-third of the rats surviving the placing radon seeds because of their convenient minimal period of 6 months, sarcomas developed short half-life (37 days), and Co 6~ is sometimes at the site of injection. Sarcomas were also pro- more convenient because of its longer life (5.5 duced by intrapleural injection of uranium. Note years). The metal is easier to handle than the gas that these tumors induced by U metal at the site Rn, and its ~ is of lesser E (0.97 Kv) than that of of injection were osteogenic. Hueper et al. (46, 48) Rn (3.17 Kv)--and is consequently easier to filter were uncertain whether the tumors were caused by out. Currently, large amounts of Po ~~ Co 6~ and alpha irradiation of uranium or by the metal itself. Sr 9~ incorporated in well sealed sources, are being Metallic nickel powder injected in the same used for industrial and medical purposes (4). amount and vehicle, at similar sites, produced tu- The few tumors resulting from the use of such mors of the same histologic appearance after com- applicators in man have been repeatedly reviewed. parable latency periods. Hueper re-emphasized the These include: Ca) The development of carcinomas possibility of metallo-carcinogenesis, first shown following destruction of hemangiomas in children by Schinz and ~hlinger (79), who observed malig- 13-16 years after exposure to over 100,000 rep. It nant tumors in rabbits 4-7 years after intramedul- is assumed that infants are more sensitive than lary implantation of small quantities of nonradio- adults, but there is not enough experience to prove active arsenic, chromium, and cobalt in metallic the over-all greater sensitivity of infants to radio- form. carcinogens. (b) Fibrosarcoma occurring in a man Similarly, Lisco and Kisieleski (57) implanted in the area of skin treated with Ra 30 years previ- plutonium metal subcutaneously into rabbits ously for carcinoma of the lip (Stewart and Pen- (670-1,800 #g.) and rats (610-800 gg.). The oxide- dergast [see (31)]). The problem is no different from coated plutonium quickly disintegrated, and the that of cancer induction by therapeutic x-radia- implants became encapsulated and calcified. Only tion reviewed elsewhere (30, 31). These tumors small amounts of plutonium were absorbed. An were mostly carcinomas of the skin and sarcomas osteogenic sarcoma, thought to be due to alpha in internal organs, notably bone sarcomas at sites particles of plutonium, developed in only one rat. of osteomyelitis. It is remarkable that in rabbits no sarcomas de- The carcinogenicity of radioactive applicators veloped at the site of Pu implants. The calcium was demonstrated experimentally decades ago. about the Pu fragments may have blocked most They were at times the carcinogen of choice, and of the alpha particles. were applied to different sites to produce different Adenocarcinoma of the colon has been produced tumors. The recent experimental work differs from in four of 33 rats by the feeding of y91 (30) in the old by better dosimetry and the use of larger single doses of from 1.0 to 6.0 gc. The tumors ap- numbers of animals. peared in from 185 to 506 days. A second group of p32 has proved especially valuable in studies of rats received 78 feedings of 0.46, 0.30, or 0.06 gc. induction of skin tumors. It is a purely beta emit- over a period of 3 months. Almost all these rats ter that can be incorporated in bakelite plaques died from carcinoma of the colon in 1-189years. giving uniform irradiation to desired areas of the Pu 239 and ygl produced sarcomas in a large pro- skin or other surfaces (Raper et al. [75]). Single portion of mice, and the latent period of 300 days total surface doses of 4,000-5,000 rep of p32 led to could not be shortened by increasing the dose as skin tumors in mice and rats. Neoplasms began to much as tenfold (Brues et al. [11]). tIaO and C '4 are appear within 4 months, and, by the end of 1 year, potentially carcinogenic but have not been shown each animal averaged twelve cutaneous tumors, to produce tumors. Tritium oxide (H30) when ad- mostly squamous- and basal-cell carcinomas. ministered to animals behaves like water and can The number and types of tumors produced by deliver a total-body dose of as much as 1,300 rep p3~ correspond roughly to the fractions of /~-ray (Jennings and Brues [49]). energy absorbed in the epithelium and subcutane- Brues and Buchanan (10) concluded that C '4 ous tissues, respectively. The optimal dosages for offers a comparatively small hazard because, in induction of malignant tumors were single doses of spite of its long half-life, there is a fairly rapid 4,000 to 5,000 rep. Tumors began to appear only turnover and loss from the tissue. The quantity after a latent period of about 9 months. Up to 40 retained, chiefly in bones, is small. or more tumors of many histologic types were ob-

served in a single rat. Daily 13-ray treatments of 50 (14), the radiation was administered before the rep produced similar results, but 348 exposure chemical. Conceivably, a synergistic effect of days, or a total of 13,400 rep, were required to pro- greater magnitude might have been found if the duce tumors. After daily administration of the sequence had been reversed and optimally timed. 50-rep dose, tumors developed in the skin or hair follicle without gross premonitory changes. "FALL-OUT" PROBLEMS Passonneau et al. (7~) exposed the skin of rats There are two fall-out problems: that of expo- for 48 hours over a 35 sq. cm. area to/3-irradiation sure to fission products soon after and close to the of Srg~ 9~ In one series the material was distrib- area of detonation of an atomic or hydrogen bomb, uted uniformly over the source, while in others it and that of exposure to increased and accumulated was in the form of point sources (10, e0, or 50 in radioactivity on the surface of the globe resulting number). Papillomas began to appear within 4 from repeated and remote detonations of nuclear months and malignant tumors within 7 months. weapons. The latter were carcinomas and sarcomas in ap- TABLE 7 proximately equal numbers. Formation of skin tumors was greater after exposure to diffusely dis- 1~2 AND METHYLCHOLANTHRENE CARCINO- tributed /~-radiations than after exposure to the GENESIS IN MICE* Methyl- pt~ + same amount of isotope in point sources. Perhaps p32 cholan- Methyl- pa2 one of the most interesting and surprising of their (5,000 threne cholan- 10,000 observations was an up to fivefold increase in the rep) (1.7 rag.) threne rep incidence of benign mammary tumors. Mammary Cumulative per cent 10 17 70 7 with papilloma, at tumor development is believed to be due not to 250 days extrinsic carcinogens but to estrogens. Mammary Days to: tumors developing in mice after total-body irradi- maximal epilation ulceration 22 10 16 2~ ation are frequently associated with estrogen- healing of ulcer 107 24 40 73 secreting granulosa-cell tumors, but they can also early papilloma 82 45 80 69 develop in the presence of atrophic ovaries. * From Cloudman et al. (14), abbreviated. Guinea pigs have also been shown to be sensitive to the induction of breast tumors by ionizing ir- The problems of somatic injury are also linked radiation, and this carcinogenesis is also unrelated to that of genetic hazard. Most neoplastic changes to granulosa-cell tumors (Lorenz [6e]). The use of are allied to mutations caused by exposures of p32 plaques may prove to be a useful tool in the higher intensities. The possible role of "normal" study of the pathogenesis of mammary tumors by background irradiation with photons and radio- ionizing irradiation. active particles, including that steadily created by The effects of combined cutaneous application cosmic rays, has been the subject of some specula- of p32 and y9, and methylcholanthrene were tion and experimentation. There is no evidence studied by Cloudman et al. (14), who found these indicating that it plays a role in causation of spon- agents to be approximately additive in producing taneous tumors of man and animals. most skin tumors, and possibly synergistic in the The effects from internally deposited fission production of papillomas (Table 7). The sequence products are slight compared with the effects of of changes (epilation, ulceration, healing of ulcer, external exposure, because the amount of incorpo- and early papillomas formations) occurred faster rated radioactivity is relatively small and short- in the hydrocarbon-treated animals. lived. However, both external and internal irradia- In studies with combinations of carcinogens, the tion from fall-out are associated with some hazard outcome depends on the concentration of the of carcinogenesis. agents used as well as on the time relationship in The fall-out from both A and H bombs is of their application. A tissue-destructive dose, or one essentially the same composition, both types de- causing marked atrophy and scarring with riving most energy from uranium fission. The de- sclerosed vessels, may counteract a second car- gree of hazard depends on the power of the bomb, cinogenic agent. Administration of a second car- site of detonation, time and duration of exposure, cinogen in a state of heightened mitotic activity and other variables. As Lapp (55) stated, "The may, on the contrary, cause a synergistic effect. bomb (hydrogen) dislodges millions of tons of Tumor induction by hydrocarbons proceeds faster earth churned into the fireball and coated with than by radioactivity, and it is possible that car- prodigious quantities of radioactivity created by cinogenesis by the two agents is due to different the fission process; fission products adhere to the events. In the experiments by Cloudman et al. debris .... The "hot" debris is swept upwards to

Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1956 American Association for Cancer Research. 18 Cancer Research the stratosphere and is dispersed by the wind. The 1954 have been carefully studied (8, 15, 16, 17 and heavy particles fall out first..., the tiny par- personal communication). The total body expo- ticles can be wafted around the world without sure was estimated to range from 14 to 175 r. The descending." general irradiation was intense enough to cause The activity in a fall-out ellipse 50 miles wide nausea and vomiting. The skin exposure from B- and s miles long would be about 500 roentgen/ rays was of sufficient intensity to cause epilation, hour, 1 hour after detonation, dropping rapidly as depigmentation, and ulceration. However, all time passes. This intensity would be subject to these injuries were transient, and 1 year after ex- considerable fluctuation, depending upon mixing posure only a slight depression of lymphoid levels in the bomb cloud, its dispersal in the stratosphere, remained. The internal exposure was considered and the vagaries of meteorology. The radioactive to be well below the carcinogenic level, the highest dust observed at considerable distances from the internal dose being to the thyroid (up to about site of nuclear detonation is chiefly of short life and ~00 rep). of a low order, adding little to the natural radio- As to the C '4 build-up, rough calculations by activity of the earth's surface and atmosphere. In Arnold (5), based on the estimated energy release an editorial in The New England Journal of Medi- of the fusion tests so far, indicate that these tests cine (89, and personal communication) it is con- will change only negligibly the small percentage of cluded that the medical importance of the slight C 14 already present in the atmosphere. Further- increase in the radioactivity of the earth's atmos- more, C TM has not been proved to be carcinogenic. phere has been greatly exaggerated in the current Biophysical aspects of the fall-out from bomb press. The Atomic Energy Commission (4) lends clouds have been well reviewed by Andrews in an support to this conclusion with the statement that article which appeared after completion of this "None of the extensive data collected from all the paper (~). tests shows that residual radioactivity is being There is a vast difference between a carefully concentrated in dangerous amounts anywhere in prepared program for exploding nuclear devices at the world outside the testing areas." places and times chosen to minimize possible in- In those areas where actual exposure to and jury to man and an all-out war where both sides contamination from radioactive fall-out material use such devices in the most damaging ways pos- can take place, a hazard exists. A single instanta- sible. We share the philosophy of Andrews (~) that neous exposure alone can cause a variety of neo- if the first alternative helps to prevent the second, plasms, as the long-term studies in mice exposed we must accept the first, with the uncertainty of at Eniwetok in the 195~ atomic bomb trials (3~) some information not yet known on possible radi- indicate. Some tumors have a very low induction ation injuries to a small number of people. rate; others appear after very long latent periods. Thus far, in men exposed to single doses of exter- CLOSING COMMENTS nal total-body irradiation, only leukemias have Opinions as to future hazard from radioactivity been observed (54, 68). vary widely. A pessimistic picture is seen by Hue- The quantity of inhaled or ingested radioactive per (47), who believes that "Mankind has entered particles, the amount absorbed from injured con- an artificial carcinogenic environment, in which taminated skin, the site of deposition in the body, exposures to ionizing radiations of various types the rapidity of excretion, and the specific radio- and numerous sources will play an increasingly activity characteristics of the material determine important role in the production of cancers." the internal hazard. The fate of these elements in To many optimists, on the contrary, with our the body is expected to be similar to that noted in present control and regulation of safe handling in animals that were given fission products. production and distribution of radioactive iso- In people thus far exposed accidentally, suffi- topes, sealing of sources, safeguarding of disposal, cient time has not elapsed since exposure for neo- etc., the use of radioactive isotopes does not con- plasms to become manifest. Anemia and the pres- stitute an unsurmountable carcinogenic hazard. ence of radioactivity in bone, and tardy removal A realistic view must consider the possibility of of radioactive substances from the skin, may pos- future accidents and incidents involving liberation sibly lead to the development of skin and bone tu- of large quantities of radioactive substances. Fur- mors. The generalized character of irradiation thermore, there is always an element of unpre- makes the development of leukemia a possibility, dictability in the use of any new drug. Only by since leukemia is known to develop after whole- experience shall we learn the threshold carcino- body irradiation in both man and mice. The Mar- genic doses of radioisotopes in man. It is too early shall Islanders accidentally exposed to fall-out in to tell how many persons, if any, have already

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FIG. 1.--Autoradiograph of the humerus of a woman who developed osteosarcoma ~2 years after drinking radium water. (From Looney and Woodruff [60].) FIG. 2.--Photomicrograph of the kidney of a rat treated with polonium, showing several cells with giant, hyperchromatic, bizarre-shaped nuclei. (From Casarett [13].) FIGS. 3 and 4.--Thyroidal remnants of a mouse that had been given 400 gc. of 1131 (Fig. 3) and of another animal that had been given 270 gc. of 1131 (Fig. 4). Both sections show bizarre-shaped epithelial cells with giant hyperchromatic nuclei similar to those seen in Figure 2.

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Downloaded from cancerres.aacrjournals.org on September 26, 2021. © 1956 American Association for Cancer Research. l,'lr, s. 5 ~md 6. Primary pituitary tumor induced in a mouse by ra(liothyr(~i(le('tonly. (Fig. 5) Bulging of the posteri'~l cranium. (Fig. 6) The tumor exposed, showing a bulky m~ss pushil'g the optic (.hi~lsm forward and occupying more than h~df of the erani~ll ('~lvity. (Fr~m Furth [~81.)

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Jacob Furth and John L. Tullis

Cancer Res 1956;16:5-21.

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