Dose-response curves for chronic leukemia in A-bomb survivors and liver tumors in patients given Thorotrast (colloidal thorium dioxide) show large threshold effects. The existence of these threshold effects can be explained by the following hypothesis. A high dose of radiation causes a persistent wound in a cellrenewable tissue. Disorder of the injured cell society partly frees the component cells from territorial restraints on their proliferation, enabling them to continue development of their cellular functions toward advanced autonomy. This progression might be achieved by continued epigenetic and genetic changes as a result of occasional errors in the otherwise concerted healing action of various endogenous factors recruited for tissue repair.
Carcinogenesis is not simply a single-cell problem but a cell-society problem. Therefore, it is not warranted to estimate risk at low doses by linear extrapolation from cancer data at high doses without knowledge of the mechanism of radiation carcinogenesis.

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Characteristic features of the leukemia among atomic bomb survivors were studied. Dose estimates of atomic bomb radiation were based on T65D, but the new dosimetry system DS86 was used for some analyses. The ratio of a single leukemia type to all leukemias was highest for CML in Hiroshima, and the occurrence of CML was thought to be most characteristic to atomic bomb radiation induced leukemia. The threshold of CML occurrence in Hiroshima is likely to be between 0.5 ?? 0.09 Gy. However, the threshold of acute leukemia appears to be nearly 1 Gy. In the distribution of AML subtypes by FAB classification, there was no M3 case in 1 Gy or more group, although several atypical AML cases of survivors were observed. Although aplastic anemia has not increased as a late effect of the atomic bomb radiation exposure, many atypical leukemia or other myeloproliferative diseases who had been diagnosed as aplastic anemia or its related diseases have been experienced among atomic bomb survivors. Chromosome study was conducted using colony forming cells induced by hemopoietic stem cells of peripheral blood of proximal survivors. Same chromosome aberrations were observed in colony forming cells and peripheral T-cells in several atomic bomb survivors.

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The intravascular injection of the formerly used contrast medium Thorotrast —a colloidal suspension of thoriumdioxide— causes a chronic exposure to α-particles especially in the organs of the reticuloendothelial system. The German Thorotrast Study comprises 2326 Thorotrast patients and 1890 contemporary matched patients in the control group to be evaluated. 899 Thorotrast patients and 662 controls had clinical and biophysical follow-up examinations every two years since 1969. The recent most important results of the study are: A high excess rate of primary liver cancer (410/2) was observed beginning after the 15th year of exposure. 31% of the tumors are combined with cirrhosis and 6% with other neoplastic diseases. A clear (mean) dose rate effect relationship exists. The tumor frequency depends on the time of exposure or the cumulative dose to the liver respectively and not primarily on the age at injection. The lowest cumulative doses at 10 years before diagnosis of liver cancer were about 2 Gy. Risk estimates for liver cancer after 40 years of exposure are 500 malignant tumors per 10⁴ person-Gy for men and 300 for women.
A high excess rate exists also for leukaemias (excluding CLL) starting already 5 years after Thorotrast injection (39/4). The lowest cumulative doses to the red bone marrow at time of death were about 0.5 Gy. According to the present result, an excess rate can be expected for carcinomas of the extrahepatic bile ducts, pancreas, oesophagus, larynx, as well as Non-Hodgkin''s lymphomas, bone sarcomas, plasmacytomas and mesotheliomas.

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In Japan, several thousand people, three-quarters of whom were war-wounded, have been administered Thorotrast. An epidemiological follow-up study on Thorotrast-administered war-wounded veterans was initiated in 1963. The 7th survey of the study was conducted on 286 veterans at the end of 1986, of whom 262 had received Thorotrast intravascularly and 24 by other routes.
Of those who had received Thorotrast intravascularly, 58 were alive, 197 had died and 7 could not be traced. The main causes of death were 56 malignant liver tumors, 18 cirrhoses of the liver, 6 blood diseases and 5 cancers of the extrahepatic bile duct. Statistical analysis showed that the incidences of these disorders were signficantly higher in the Thorotrast cases than in the controls. The lifespans of Thorotrast administered persons decreased with the amount of Thorotrast injected when compared with those of the controls.
Between 1945 and 1990, 357 persons who had been administered Thorotrast intravascularly were autopsied, and 240 malignant liver tumors and 4 malignant peritoneal tumors were found. The incidences of the liver and peritoneal tumors in the Thorotrast autopsies were significantly higher than those in the control autopsies, respectively. Histological examination of the Thorotrast-induced malignant liver tumors revealed a chronological change in the incidences of the histological patterns, especially in those of combined malignant tumors. Dosimetry of Thorotrast autopsy materials revealed the following mean dose rates; 26.1 cGy/year in the liver, 91.2 cGy/year in the spleen and 8.5 cGy/year in the bone marrow.

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The respective average annual doses are about 330 and 110 mR/yr, in the high background radiation areas (HBRA) in Yangjiang County and the control areas (CA) in Enping and Taishan Counties. Both the HBRA and CA are in Guangdong Province which borders the South China Sea. The frequencies of chromosome aberration in circulating lymphocytes were examined for persons residing in the HBRA and CA. Those in the HBRA had increased frequencies of detectable abnormalities in stable aberrations (translocations and inversions) and unstable aberrations (dicentrics and rings). Previous reports have shown that when samples of circulating lymphocytes taken from inhabitants were tested in vitro for mitotic responses to phytohemagglutinin (PHA) and for the degree of unscheduled DNA synthesis (UDS) induced by UV-irradiation, there were higher responsiveness and UDS rates for those in the HBRA than in the CA. In contrast, mortality from all cancers and those from leukemia, breast and lung cancers that are inducible by radiation was not higher in the HBRA. Although the differences in the cancer mortality rates for the HBRA and CA are not significant, the findings are compatible with the assumption that the lower mortality from cancer in the HBRA is the result of the hormetic effects of the three-fold higher dose rate of background radiation in that areas. This assumption requires further study.

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This report describes the risk of cancer and in particular cancers other than leukemia among the survivors of the atomic bombing of Hiroshima and Nagasaki. Attention focuses primarily on the risk of death from cancer among individuals in the Life Span Study sample of the Radiation Effect Research Foundation in the period 1950-1985 based on the recently revised dosimetry, termed the DS86 doses.
Mortality from malignant tumors is increased among A-bomb survivors as a late effect of A-bomb radiation. Besides the well-known increase of leukemia, there also has been demonstrated increase of cancer of the lung, breast, esophagus, stomach, colon, ovary, urinary bladder, thyroid, and of multiple myeloma, but no increase has yet been observed in mortality from cancer of the rectum, gallbladder, pancreas, prostate and uterus, and of malignant lymphoma.
The pattern of appearance over time of radiation-induced cancer other than leukemia differs from that of leukemia. In general, radiation-induced solid cancer begins to appear after attaining the age at which the cancer is normally prone to develop (so-called cancer age), and continues to increase proportionately with the increase in mortality of the control group as it ages.
Sensitivity to radiation, in terms of cancer induction, is higher for persons who were young at the time of the bomb (ATB) in general than for those who were older ATB. Furthermore, susceptibility to radiationinduced cancer tends to be higher in pre than in post-natally exposed survivors (at least those exposed as adults).
Other radiation effect modifiers and the shape of the dose response curve will also be discussed.

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Parental exposure to radiation could induce various kinds of tumors in the next generation. In ICR mice, a large and significant increase of adult types tumor was observed in the F₁ offspring after X-ray exposure at spermatozoa and spermatid stages, and less clear increase was observed after spermatogonial exposure. Mature oocytes were resistant upto 1 Gy, but very sensitive to tumor induction at higher doses. While there was no difference in the tumor incidence between acute and fractionated (0.36 Gy at 2 hr intervals) irradiation at post-gonial stages, a large reduction of tumor incidence was observed after spermatogonial and mature oocyte exposure, suggesting some repairs of X-ray damages in these germ cells.
Acute lymphocytic leukemia was not induced in ICR and LT mice after spermatogonial exposure, while a large increase of adult type cancers was observed in F₁ offspring. However, 1.9-3.2 fold and 4.5-7.4 fold increases of leukemia incidence were observed in ICR and LT mice, when spermatozoa stage was treated with the X-ray doses of 0.36-5.04 Gy and 3.6-5.04 Gy, respectively, indicating the large difference in the sensitivity of developing germ cells to leukemia induction by radiation in the F₁ offspring. In contrast to ICR and LT mice, N5 strain developed about 10 or 18 times higher incidence of leukemia in the offspring after spermatogonial or spermatozoa exposure to 5.04 Gy of X-rays, respectively, showing a marked difference in the sensitivity to the leukemia induction by radiation between mouse strains.
These differential sensitivities between germ cell stages and also between mouse strains reconcile the difference between two population studies in Hiroshima/Nagasaki and Sellafield. However, there were large diffirences in the doubling doses for leukemia induction between the mouse experiments and Sellafield study in human.

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Female B6C3F₁ mice were irradiated on day 17 prenatal age, or day 0, 7, 35, 105, 240 or 365 postnatal age with 0.95, 1.9, 2.85, 3.8 or 5.7 Gy of γ-rays from ¹³⁷Cs. They were allowed to live out their entire life spans under specific pathogen free conditions. All the mice were given autopsies at death and were examined histologically for neoplastic and non-neoplastic diseases. The mice in the early postnatal period were most sensitive to the life-shortening effect of radiation. The shortening effect of irradiation given during the late fetal period was almost the same as that given during the young adult period. Incidences of lung, liver, pituitary, ovarian and bone tumors and malignant lymphoma of the lymphocytic type increased after irradiation of mice in the late fetal period. Mice in the early postnatal period are more susceptible to the induction of liver and ovarian tumors and malignant lymphoma of the lymphocytic type than are fetal mice. Myeloid leukemia and Harderian gland tumor did not develop in excess when mice were irradiated in fetal or in neonatal period; whereas, these neoplasms were induced by irradiation during the adult period.

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To evaluate the lifetime hazards of ionizing radiation exposure, 1680 beagles received whole-body, 60-Cobalt gamma exposures or sham-exposures during development. Eight groups of 120 dogs each received mean doses of 16 or 83 cGy at 8 (preimplantation), 28 (embryonic), or 55 (late fetal) days postcoitus (dpc), or 2 (neonatal) days postpartum (dpp). One group of 120 dogs received 83 cGy at 70 dpp (juvenile), and one group of 240 dogs received 83 cGy at 365 dpp (young adult). Sham-irradiations were delivered to 360 controls. Sexes were equally represented. Young dogs, up to 4 years of age, had an increase in benign and malignant neoplasms after irradiation in the perinatal period at 55 dpc or 2 dpp. Among these, 4 fatal cancers were observed. No malignancies occurred in comparably-aged controls. The increase in both fatal neoplasms and all neoplasms in the perinatally-exposed groups were statistically significant. Over the full lifetime, dogs irradiated in the perinatal period also had the strongest evidence for an increased risk for fatal malignancies of all types. Though not as strong, there was a trend for increased risk for fatal cancer in dogs irradiated at all other ages. The risk of fatal malignancy after irradiation was greater in females than in males. Dogs exposed at 55 dpc had a significant increase in lymphoid neoplasia and dogs exposed at 8 and 55 dpc had increased risk for hemangiosarcoma. There was no evidence for an increased risk for mammary carcinoma in irradiated females. Dogs exposed as juveniles at 70 dpp had a significant increase in all benign and malignant thyroid neoplasms, including fatal thyroid carcinoma.

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This paper presents a review of several studies conducted in our laboratory to examine the carcinogenic effects in mice of high-LET radiation and, for comparison, of low-LET reference radiation. For some specific end-points the following conclusions can be formulated: i) the dose-response curves for myeloid leukemia and malignant lymphoma can be interpreted in terms of induction and inactivation; in particular, the data confirmed that a linear dependence of the induction on dose is adequate to describe the response to fission neutrons, while a pure quadratic dependence is consistent with the experimental data for low-LET radiation; ii) in the liver, a marked age-dependence was demonstrated for radiation-induced tumors with a much higher susceptibility in young than in old mice; also for these tumors the dose-effect curves can be described by a linear and a quadratic relationships for high and low-LET radiation, respectively; iii) data on ovarian tumor induction suggested threshold-like dose responses: these peculiar shapes as well as the absence of a clear radiation quality dependence of the curves are difficult findings to explain using a simple model of radiation action, and they might better be related to a non-stochastic effect of hormonal imbalance following irradiation.

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Under select radiological conditions, chronic radiation exposure elicits a high incidence of myeloproliferative disease, principally myeloid leukemia (ML), in beagles. Previously we demonstrated that for full ML expression, a four-stage preclinical sequence is required, namely (I) suppression, (II) recovery, (III) accommodation, and (IV) preleukemic transition. Within this pathological sequence, a critical early event has been identified as the acquisition of radioresistence by hematopoietic progenitors that serves to mediate a newfound regenerative hematopoietic capacity. As such, this event “sets the stage” for preleukemic progression by initiating progression from preclinical phase I to II. Due to the nature of target cell suppression, the induction of crisis, and the outgrowth of progenitors with altered phenotypes, this preleukemic event resembles the “immortalization” step of the in vitro transformation sequence following induction with either physical and chemical carcinogens. The radiological, temporal, and biological dictages governing this event have been extensively evaluated and will be discussed in light of their role in the induction and progression of chronic radiation leukemia

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A series of experiments was carried out using female (C57BL/6N×C3H/He)F₁ mice (BCF₁) to assess the carcinogenic effect of tritiated water (HTO) following a preliminary experiment in which the acute effect of HTO was studied in young female mice of C57BL/6L strain in an attempt to gain basic information on the long-term experiment, and the results were compared with those of fission spectrum neutrons and gammarays. The obtained findings are summarized as follows. 1) C57BL/6N mice receiving a single intraperitoneal (i.p.) injection of HTO, 7.4 × 10⁸ Bq (20 mCi) or more, died of bone marrow failure within 20 days. 2) In long-term experiment, BCF₁ mice given 1.4 × 10⁸ Bq to 5.6 × 10⁸ Bq developed solid tumors in a variety of tissues but with no obvious dose dependency. 3) The fractionated exposure of 7.4 × 10⁸ Bq (1.9 ×: 10⁸ each, at 7-day intervals) was highly effective in induction of malignant T-cell lymphomas (85%) with a shorter latency than that of a single exposure (15%). 4) A protracted irradiation of 0.27 Gy of ¹³⁷Cs, designed to simulate the decreasing absorption rate with time after a single i.p. injection of an equivalent dose of HTO resulted in a drastic reduction in induction rate of ovarian tumors as compared with that of an acute ⁶⁰Co gamma irradiation. 5) The carcinogenic potential of HTO, given as a single i.p. injection, was quite similar to that of acute ⁶⁰Co gamma ray irradiation at both 2.7 Gy and 0.27 Gy levels. On the other hand, the effect of HTO was slightly higher than that of protracted gamma-ray irradiation. 6) ²⁵²Cf fission neutrons was found to be more potent in tumor induction than gamma-rays or HTO beta-rays under the present experimental conditions.

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We have presented evidence that the functional thyroid follicles (follicular units, FU) which are formed in grafts of monodispersed rat thyroid cells, and hence the thyroid tumors which later develop in such grafts, are clonal in origin. Transplantation assays indicate that the clonogens comprise ?? 1% of the cells in monodispersed suspensions of normal thyroid tissue. Carcinogenesis studies show that neoplastic initiation of thyroid clonogens by radiation is a common event. Promotion-progression to cancer from radiation initiated clonogens has, however, been shown to be inversely related to the total grafted thyroid cell number; i.e. more tumors develop per irradiated clonogen in grafts of small cell numbers than of large cell numbers. Recent studies have been designed to investigate: a) whether the cell number-dependent inhibition of promotion-progression is mediated by remote hormonal feed-back, local cell-cell interactions, or both; b) the cell population kinetics of the clonogen subpopulation during goitrogenesis and goiter involution; and c) the effect of prolonged exposure to high levels of TSH (thyrotropin) on the capacity of the clonogens to give rise to functional FU. The results indicate that local cell-cell interactions play an important role in the cell numberdependent suppression of neoplastic promotion-progression. They also show that if sufficient thyroid cells are grafted, the thyroid-pituitary axis can be reestablished in thyroidectomized rats fed normal diets. In such animals given iodine deficient diets, the FU that develop in the thyroid grafts shift their secretory pattern to increase the ratio of T3 (triiodothyronine) to T4 (thyroxine), and thus conserve the available iodine. Finally, the clonogenic subpopulation is conserved during both goitrogenesis and goiter involution. When they are transplanted to thyroidectomized recipients, clonogens from two types of goiters form FU that are morphologically indistinguishable from those that develop in grafts of normal thyroid clonogens. Furthermore, the secretion of T3 and T4 by such grafts is dependent on the grafted clonogen number, and hence FU formation, and not on the total number of thyroid cells transplanted. We conclude that the thyroid clonogens, the presumptive cancer progenitor cells, have many of the characteristics of stem cells.

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An intrathymic (i.t.) injection assay on B10.Thy-1 congenic mice was used to demonstrate that thymic prelymphoma cells developed first within mouse thymus 4 to 8 days after split-dose irradiation and were present in more than 63% of the test donor mice thymuses examined 21 and 31 days after irradiation. For the characterization of these thymic prelymphoma cells, thymocytes from B10.Thy-1.1 mice sampled 1 mo after irradiation were stained with J11d mAb and mAb against TL-2 (thymus-leukemia) antigen which is not expressed on normal thymocytes of the B10.Thy 1.2 and B10.Thy 1.1 strains but does appear on thymocytes of split-dose irradiated mice. These cells were sorted into subpopulations, samples of which were injected into recipient thymuses to determine which subpopulations contained thymic prelymphoma cells. Results showed that the prelymphoma cells were located in the J11d⁺TL-2⁺ cells. These prelymphoma cells were further characterized phenotypically as to their expression of the CD4 and CD8 antigens, which demonstrated that the thymic prelymphoma cells were present in the CD4-CD8- and CD4-CD8⁺ thymocyte subpopulations mainly and in the CD4⁺CD8⁺ subpopulation.
The experiments on i.t. injection of a graded quantity of TL-2⁺ thymocytes from individual mice suggest that not all TL-2⁺ cells undergo neoplastic initiation and that prelymphoma cells may develop infrequently from one or more TL-2⁺ cells by genetic or epigenetic changes.

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Bone marrow transplantation (BMT) experiments were conducted using B10.Thy 1 congenic mice to explore the nature of bone marrow-thymus interactions during thymic lymphomagenesis induced by fractionated whole-body X-irradiation (FX). BMT from normal Thy 1 congenic donors into FX-treated recipients one day after FX-treatment resulted in the suppression of tumor development; the suppression being exponentially proportional to the increasing number of bone marrow cells injected. The suppression of tumor development by BMT was shown to be due to prevention of the appearance of prelymphoma cells. BMT from FX-treated donors, which are deficient in pre T cells, into lethally (9 Gy) irradiated Thy 1 congenic recipients resulted in the development of high incidence of thymic lymphomas most of which ( ?? 76%) were host-derived, whereas no lymphomas were recovered from the recipients of normal bone marrow. These results suggest that intrathymic T cell precursors which initially repopulate the depleted thymus are prone to undergo preneoplastic changes in the absence of recruitment of more primitive T cell precursors (pre T cells) from the bone marrow but they undergo normal differentiation when large number of pre T cells are available. It was concluded that primary cause of the FX-induced thymic lymphomagenesis was a shortage in supply of pre T cells from the bone marrow to the depleted thymus, which caused differentiation arrest of the progeny of regenerating intrathymic T cell precursors, followed by development of prelymphoma cells that eventually evolve into autonomous lymphoma cells within the thymus.

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We have developed an in vitro-in vivo transplantation assay for measuring the concentration of clonogenic epithelial cells in cell suspensions of rat mammary tissue. Rat mammary clonogens from organoid cultures are capable of the same degree of PLDR as clonogens in vivo. The growth and differentiation of mammary clonogens to alveolar colonies or ductal colonies is regulated as follows: a) in the presence of E₂ and high prolactin (Prl), cortisol induces mammary clonogens to proliferate and differentiate to form alveolar colonies which secrete milk and begin losing clonogenic potential, b) in cortisol deficient rats, Prl and E₂ synergistically stimulate non-secretory ductal colonies, formation of which retain clonogenic potential, c) E₂ without progesterone stimulates alveolar colony formation in the presence of cortisol and high Prl, d) progesterone inhibits mammary clonogen differentiation to milk-producing cells and induces ductogenesis in a dose responsive fashion in the presence of E₂, cortisol and high Prl. High prolactin levels coupled with glucocorticoid deficiency increases the susceptibility to mammary carcinogenesis following low dose radiation exposure by increasing the number of total mammary clonogens which are the presumptive target cells and by stimulating their proliferation after exposure.

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Experiments on the dose-response of tumor development induced by repeated local beta irradiation of the back of mice are summarized. Results indicated a 100% tumor incidence on irradiation at 2.5-11.8 Gy per exposure (dose-saturation effect) and the threshold-like dose response at lower doses. The mechanism underlying these phenomena is discussed on the basis of the tissue-misrepair model, that is misrepair caused by repeated stimulation of cell growth after repeated tissue injury.

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The multistage theory of carcinogenesis specifies that cells progress to cancer through a series of discrete, irreversible genetic alterations, but data on radiation-induced cancer incidence in rat skin suggests that an intermediate repairable alteration may occur. Data are presented on cancer induction in rat skin exposed to the following radiations: 1. an electron beam (LET = 0.34 kev/μ), 2. a neon ion beam (LET = 45 kev/μ) and 3. an argon ion beam (LET = 125 kev/μ). The latter 2 beams were generated by the Bevalac at the Lawrence Berkeley Laboratory, Berkeley, CA. About 6.0 cm² of skin was irradiated per rat. The rats were observed every 6 weeks for at least 78 weeks and tumors were scored at first occurrence. Several histological types of cancer, including squamous and basal cell carcinomas, were induced. The total cancer yield was fitted by the quadratic equation, and the equation parameters were estimated by linear regression for each type of radiation. Analysis of the DNA from the electron-induced carcinomas indicated that K-ras and/or c-myc oncogenes were activated in all tumors tested. In situ hybridization indicated that the cancers contain subpopulations of cells with differing amounts of c-myc and H-ras amplification. The results are consistent with the idea that ionizing radiation produces stable, carcinogenically relevant lesions via 2 repairable events at low LET and via a non-repairable, linked event pathway at high LET; either pathway may advance the cell by 1 stage in the multistage model.

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Of the 66, 276 Nagasaki atomic bomb survivors registered at the Scientific Data Center for the Atomic Bomb Disaster at the Nagasaki University School of Medicine, 140 were identified as having skin cancer from the records of 31 hospitals in Nagasaki City. From the cases of these survivors, a statistical analysis was made of the incidence of skin cancers by age, gender, histology and latency period in Nagasaki atomic bomb survivors. The results showed a high correlation between the incidence of skin cancer and distance from the blast hypocenter, and that the incidence of skin cancer in the Nagasaki survivors appears now to be increasing with exposure distance.

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The process of mouse skin tumor formation is subdivided into three operational stages. These stages include initiation, promotion and progression. Ionizing radiation has been found to be a weak initiating agent in the production of malignant squamous cell carcinomas, a complete carcinogen and an agent effective in causing tumor progression. Four skin tumor histologies have been seen with ionizing radiation: benign papillomas, squamous (SCC) and basal (BCC) cell carcinomas and fibrosarcomas. Distinct non-ras transforming genes have been detected in radiation initiated SCCs. A benign papilloma cell line (308) was used as a model system to study ionizing radiation induced progression. A variant 308 cell line (308 10 Gy 5) derived by irradiation of the parental 308 cell has been characterized. The 308 10 Gy 5 cells unlike the parental 308 cells form malignant tumors in athymic nude mice upon subcutaneous injection. The variant 308 10 Gy 5 cells unlike the parental cells also show by northern analysis high steady state levels of the following gene transcripts: stromelysin, metallothionein II A and the proto-oncogenes c-fos and c-jun. Transient transfection studies with a chimeric mouse stromelysin promoter sequence upstream of a chloramphenicol (CAT) reporter gene into 308 and 308 10 Gy 5 cells indicated that the stromelysin promoter was constitutively active in the 308 10 Gy 5 but not in the 308 cells. The ability to divide the process of carcinogenesis into multiple stages in the mouse skin mode has facilitated mechanistic studies that may elucidate the molecular pathways involved in radiation induced tumor development.

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The expression of oncogenes was studied in 12 types of 178 mouse tumors induced by radiations and chemicals. DNA was analyzed in tumors in which the overexpression of oncogenes was noted. Amplification of the myc oncogene was found in chemically induced sarcomas, but not in sarcomas induced by radiation. Activation of oncogenes by small mutations and the inactivation of tumor suppressor genes has to be taken in account in the radiation induction of mouse tumors. We therefore made further analyses of radiogenic thymomas. Loss of heterozygocity was revealed in directly induced thymomas by the deletions of allele specific minisatellite bands. Analysis of a hypervariable minisatellite locus also revealed that these thymoma cells suffered high recombinogenic activity during tumorigenesis. In addition, transfection of cellular DNA to normal Golden hamster cells identified the activated K-ras oncogene in the directly induced radiogenic thymomas. Indirectly induced radiogenic thymomas were tested similarly. Transformed cells from secondary transfection experiment were positive for the mouse-specific repetitious sequences, but devoid of mouse ras oncogenes. Indirectly induced radiogenic thymomas originate from unirradiated normal thymus cells transplanted in irradiated hosts. The spontaneous activation of oncogenes yet to be identified may therefore be involved in the development of this tumor.

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Seventy five radiation-related leukemia patients in Hiroshima including 16 patients exposed to more than one Gray were cytogenetically examined. Statistical analysis of data on the frequencies of chromosomal aberrations in the survivor groups according to bone marrow doses by DS86 estimation revealed that the heavily exposed group tended to have significantly higher aberration rates compared to the non-exposed group. Furthermore, the chromosomal aberrations in the survivors were observed to be of a more complex nature and had the characteristic findings of secondary leukemia. These observations therefore suggest that patients with a history of heavy exposure to atomic bomb radiation had leukemic cells originating from a stem cell which had been damaged by irradiation at the time of the bombing as well as cells involved in complex chromosome abnormalities.
Molecular biologic studies on ras genes in acute and chronic leukemias and the bcr gene in chronic myelocytic leukemia were performed in exposed and non-exposed groups. So far, no distinctive differences have been observed in the frequency and sites of point mutations in N- and K-ras genes or in the rearrangement of the bcr gene. Further, retrospective analysis using DNA from leukemia patients who developed this disease in the early period from atomic bomb radiation exposure would be useful for the elucidation of the mechanisms of radiation-induced leukemia.

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It is generally thought that the germinal mutation of tumor-suppressor genes predisposes the affected children to the development of certain types of hereditary tumors while the somatic mutation of the same genes links to the development of non-hereditary tumors. Retinoblastoma susceptibility gene (RB gene) is a prototype of such genes. We studied the parental origin of new mutation of the RB gene in the sporadic hereditary and non-hereditary retinoblastoma and osteosarcoma. The results showed a preferential involvement of parental genome in the new germinal as well as initial somatic mutations. The male-directed mutagenesis even in the somatic cells has been implicated as a reflection of germinal origin of mutation, even for non-hereditary tumors as a manifestation of mutational mosaicism associated with delayed mutation. The importance of the new mutations occurring as mosaics should be emphasized in the evaluation of cancer risks from parental exposures to radiation and chemicals.

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The role of peptide growth factors in the process of multistage carcinogenesis of rat tracheal epithelial (RTE) cells was assessed by examining growth factor requirements and expression of growth factors and their receptors in normal and transformed RTE cells. Transformed RTE cell lines show decreased requirements for bovine pituitary extract, insulin and epidermal growth factor compared to primary RTE cells in culture. An autocrine role for TGFα in transformed RTE cells is suggested by data showing TGFα production and decreased proliferation in the presence of TGFα antisera and TGFα/EGF receptor kinase inhibitor. Therefore, decreased EGF requirements in transformed RTE cells could be explained by autocrine TGFa regulation. In contrast, no evidence for an insulin/IGF-I autocrine pathway could be detected in transformed RTE cells. These data indicate that multiple alterations in growth factor pathways occur in transformed RTE cells.

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