On the shape of neutron dose-effect curves for radiogenic cancers and life shortening in mice.

Male and female hybrid BCF1 (C57BL/6 Bd x BALB/c Bd) were exposed to total neutron doses of 0.06, 0.12, 0.24, and 0.48 Gy in fractions over a period of 24 weeks. The fractionation regimens were: 24 weekly fractions of 0.0025 Gy, 12 fractions of 0.01 Gy every 2 weeks, 6 fractions of 0.04 Gy every 4 weeks, and 3 fractions of 0.16 Gy every 8 weeks. In order to detect any change in susceptibility with age over the period of exposures from 16 weeks to 40 weeks of age, mice were exposed to single doses of 0.025, 0.05, 0.10, and 0.2 Gy at 16 and 40 weeks of age. These experiments were designed to test whether the initial parts of the dose-response relationships for life shortening and cancer induction could be determined economically by using fractionated exposures and whether or not the initial slopes were linear. The conclusions were that for life shortening and most radiogenic cancers, the dose-effect curves are linear and that fractionation of the neutron dose has no effect on the magnitude of the response of equal total doses over the range of doses studied. The ratio of such initial slopes and comparable linear initial slopes for a reference radiation should provide maximum and constant relative biological effectiveness values.

Extrapolation of the relative risk of radiogenic neoplasms across mouse strains and to man.

We have examined two interrelated questions: is the susceptibility for radiogenic cancer related to the natural incidence, and are the responses of cancer induction by radiation described better by an absolute or a relative risk model. Also, we have examined whether it is possible to extrapolate relative risk estimates across species, from mice to humans. The answers to these questions were obtained from determinations of risk estimates for nine neoplasms in female and male C3Hf/Bd and C57BL/6 Bd mice and from data obtained from previous experiments with female BALB/c Bd and RFM mice. The mice were exposed to 137Cs gamma rays at 0.4 Gy/min to doses of 0, 0.5, 1.0, or 2.0 Gy. When tumors that were considered the cause of death were examined, both the control and induced mortality rates for the various tumors varied considerably among sexes and strains. The results suggest that in general susceptibility is determined by the control incidence. The relative risk model was significantly superior in five of the tumor types: lung, breast, liver, ovary, and adrenal. Both models appeared to fit myeloid leukemia and Harderian gland tumors, and neither provided good fits for thymic lymphoma and reticulum cell sarcoma. When risk estimates of radiation-induced tumors in humans and mice were compared, it was found that the relative risk estimates for lung, breast, and leukemia were not significantly different between humans and mice. In the case of liver tumors, mice had a higher risk than humans. These results indicate that the relative risk model is the appropriate approach for risk estimation for a number of tumors. The apparent concordance of relative risk estimates between humans and mice for the small number of cancers examined encourages us to undertake further studies.

Ambiguous carcinogens and their regulation.

Examination of five animal and one human studies suggest that certain agents increase the incidence of some cancers but simultaneously reduce the incidence of other cancers. Yellow die #3, for example, sharply increases the incidence of liver tumors but practically eliminates naturally occurring leukemia/lymphoma in F-344 male rates. Such ambiguity in the action of presumed carcinogens suggests that caution must be used by regulatory bodies in proscribing suspected carcinogens, or even in recommending changes in lifestyle or dietary habits as a means of reducing incidence of cancer.

Limiting values for the RBE of fission neutrons at low doses for life shortening in mice.

We have analyzed recently published data on the effects of low doses of fission neutrons on the mean survival times of mice. The analysis for single-dose exposures was confined to doses of 20 rad or less, while for fractionated exposures only total doses of 80 rad or less were considered. We fitted the data to the frequently used power function model: life shortening = beta D lambda, where D is the radiation dose. We show that, at low doses per fraction, either (1) the effects are not additive or (2) the dose-effect curve for single exposures cannot show a greater negative curvature than about the 0.9 power of dose. Analysis of the data for gamma rays showed that an exponent of 1.0 gave an acceptable fit. Taken together, these findings indicate that the RBE for neutrons cannot change more rapidly with neutron dose than about RBEN approximately = k/D0.1N. This conflicts with the more widely accepted relationship, RBEN approximately = k/D0.5N. Because of the inherent implausibility of exponents less than 1.0 for the neutron dose-effect curves at low doses we conclude that at neutron doses of 20 rad or less the RBE for life shortening is constant and ranges from 13 to 22 depending on mouse strain and sex.

Life shortening in BALB/c mice following brief, protracted, or fractionated exposures to neutrons.

The effects of acute, protracted, or fractionated exposures to fission neutrons on survival times of female BALB/c mice were examined and compared. Mice were given single, brief exposures or exposures given in equal fractions at either 1- or 30-day intervals to doses of 0, 2.5, 5, 10, 20, 50, and 200 rad at the Health Physics Research Reactor (HPRR) or protracted exposures at rates ranging from 0.1 to 10 rad/day using a moderated 252Cf source to doses of 0, 2.5, 5, 10, 20, and 40 rad. The 252Cf source was moderated to have a similar spectron to that of the HPRR facility. After single or fractionated exposures the extent of life shortening increased rapidly over the 0-50 rad range and then began the plateau. No simple model adequately described the dose response over this entire dose range. Over the 0-50 rad dose range for exposures at the HPRR and over the 0-40 rad dose range for protracted exposures the dose response could be adequately described by either a linear model or a square root of the dose regression model except when the dose was fractionated using a 30-day interval. In this instance a linear model provided an adequate fit while a square root of the dose model could be rejected. No increase in effectiveness after fractionation or protraction was observed for neutron-induced life shortening at doses below 50 rad, while at 50 and 200 rad an increase in effectiveness was observed in this and in previous studies. These data were interpreted to suggest that in the dose range below 20-40 rad the dose-effect curve for life shortening may be linear and begins to flatten at higher doses rather than continuously bending at low doses.