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.