The Influence of Dose and Dose Rate on the Incidence of Neoplastic Disease in RFM Mice after Neutron Irradiation

Ullrich, Robert L.; Jernigan, M. C.; Cosgrove, G. E.; Satterfield, L C; Bowles, N. D.; Storer, John B.

doi:10.2307/3574539

Cited by 93 publications

(26 citation statements)

References 9 publications

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“…Both neutron and gamma irradiation are potential carcinogens, as demonstrated by the fact that both can transform cells in vitro (14)(15)(16) and induce tumors, including thymic lymphomas, in animals (17,18). One goal of this study was to determine whether the differences in qualities of these different forms of radiation might result in tumors with a different pattern of ras gene mutations.…”

Section: Comparison Between Different Forms Of Ionizing Radiation Intmentioning

confidence: 99%

ras activation in human tumors and in animal model systems.

Corominas

Sloan

León

et al. 1991

Environ Health Perspect

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Environmental agents such as radiation and chemicals are known to cause genetic damage. Alterations in a limited set of cellular genes called proto-oncogenes lead to unregulated proliferation and differentiation. We have studied the role of the ras gene family in carcinogenesis using two different animal models. In one case, thymic lymphomas were induced in mice by either gamma or neutron radiation, and in the other, keratoacanthomas were induced in rabbit skin with dimethylbezanthracene. Human keratoacanthomas similar to the ones induced in rabbits were also analyzed. We found that different types of radiation such as gamma rays and neutrons, induced different point mutations in ras genes. A novel Kras mutation in codon 146 has been found in thymic lymphomas induced by neutrons. Keratoacanthomas induced in rabbit skin by dimethylbenzanthracene show a high frequency of H-ras-activated genes carrying a mutation in codon 61. The same is observed in human keratoacanthomas, although mutations are in both the 12th and the 61st codons of the H-ras gene. H-ras activation is less frequent in human squamous cell carcinomas than in keratoacanthomas, suggesting that ras genes could play a role in vivo in differentiation as well as in proliferation.

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Section: Comparison Between Different Forms Of Ionizing Radiation Intmentioning

confidence: 99%

ras activation in human tumors and in animal model systems.

Corominas

Sloan

León

et al. 1991

Environ Health Perspect

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“…In view of the multistage nature of the cancer process and our uncertainty as to the mechanism(s) of carcinogenesis at low doses, the actual shape(s) of the doseresponse curve(s) for low-level radiation carcinogenesis remain(s) to be defined. Also complicating extrapolation into the low dose domain is evidence, for certain types of neoplasms, that the incidence per unit dose of high-LET radiation may increase with decreasing dose and dose rate, giving a dose-effect curve that is convex upward (20)(21)(22) (Fig. 4) (23).…”

Section: Carcinogenic Effectsmentioning

confidence: 99%

Environmental Standards for Ionizing Radiation: Theoretical Basis for Dose-Response Curves

Upton¹

1983

Environmental Health Perspectives

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The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells.For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about doseresponse relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell.

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“…We have been studying ras oncogene activation in murine thymic lymphomas induced either by the chemical carcinogen N-nitroso-N-methylurea or by gamma radiation and have found activated K-and N-ras genes in a significant proportion of the tumors (7,20). In this study, we wanted to determine the extent of ras oncogene activation in neutroninduced thymic lymphomas in RF/J mice and compare it with our previous analysis of gamma ray-induced thymic lymphomas in the same strain of mouse.Gamma and neutron radiation are two types of ionizing radiation that deliver energy to target molecules in very different ways (13 (23,24). As yet, however, activation of specific oncogenes in neutron-induced tumors or cell transformants has not been described.…”

mentioning

confidence: 99%

Neutron radiation can activate K-ras via a point mutation in codon 146 and induces a different spectrum of ras mutations than does gamma radiation.

1990

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Neutron radiation is known to produce tumors in animals and cause ceH transformation. We Animal model systems have provided a means by which oncogene activation can be studied in tumors in which the inducing agent and genetic background are well controlled (8,16,21). We have been studying ras oncogene activation in murine thymic lymphomas induced either by the chemical carcinogen N-nitroso-N-methylurea or by gamma radiation and have found activated K-and N-ras genes in a significant proportion of the tumors (7,20). In this study, we wanted to determine the extent of ras oncogene activation in neutroninduced thymic lymphomas in RF/J mice and compare it with our previous analysis of gamma ray-induced thymic lymphomas in the same strain of mouse.Gamma and neutron radiation are two types of ionizing radiation that deliver energy to target molecules in very different ways (13 (23,24). As yet, however, activation of specific oncogenes in neutron-induced tumors or cell transformants has not been described. Biologically significant consequences of the different actions of neutron and gamma radiation can be studied by comparing the activating point mutations of ras oncogenes that result from tumors induced by the different radiation treatments.To determine an optimal dose of neutron radiation that would induce thymic lymphomas with high frequency, we irradiated female RF/J mice (The Jackson Laboratory, Bar Harbor, Maine) between 4 and 7 weeks old with a single dose of 0.8, 1.0, 2.0, or 3.0 Gy of whole-body 0.44-MeV neutron radiation. Neutrons were produced from a Van de Graaff particle accelerator. Uniform whole-body neutron irradiation was delivered to mice restrained in Plexiglas cylinders and rotated around the neutron source. To correct for possible fluctuations, after one-half of the dose was administered, the tubes were rotated by 1800. The complete dose was administered in a period of 2 to 6 h. Mice were sacrificed when they appeared visibly ill and had palpable lymph nodes. The only effective dose was 1.0 Gy. All of the mice given 2.0 and 3.0 Gy of neutrons died within 2 weeks from radiation sickness.

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The Influence of Dose and Dose Rate on the Incidence of Neoplastic Disease in RFM Mice after Neutron Irradiation

Cited by 93 publications

References 9 publications

ras activation in human tumors and in animal model systems.

ras activation in human tumors and in animal model systems.

Environmental Standards for Ionizing Radiation: Theoretical Basis for Dose-Response Curves

Neutron radiation can activate K-ras via a point mutation in codon 146 and induces a different spectrum of ras mutations than does gamma radiation.

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