Extrapolation of the Relative Risk of Radiogenic Neoplasms across Mouse Strains and to Man

Abstract

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.

On cancer risk estimation of urban air pollution

“…The validity of the multiplicative model agrees with results of experimental studies of radiogenic cancer where an additive model could be rejected in most cases in favor of the multiplicative model (12). For these reasons, the National Research Council (13) has adopted the multiplicative model.…”

“…c) The question whether the life-time dose or the dose per day (i.e., a dose rate) determines the risk creates an uncertainty by a factor 35 corresponding to the human-to-rodent longevity ratio (17). Due to the irreversibility of genotoxic events, the lifetime dose is expected to have a decisive influence, as has been found for ionizing radiation (12) and recently for alkylating chemotherapeutics (18). Therefore, the extrapolation on the basis of daily dose, as done by the U.S. EPA (16), may lead to considerable underestimation.…”

Common fragile sites are conserved features of human and mouse chromosomes and relate to large active genes

“…Following APC induction, we found an elevated overall CFS expression in BALB/c compared to C57BL/6 mice. This might bear a relation to the high postirradiation breast cancer risk of BALB/c animals (Storer et al 1988) that is due to strain-specific polymorphisms in the coding region of Prkdc, causing chromatid-type aberrations (Ponnaiya et al 1997;Yu et al 2001). The Prkdc gene encodes the DNA-dependent protein kinase catalytic subunit, which is known to be involved in DNA double-stranded break repair and post-IR signal transduction (Yu et al 2001).…”

Effect of Low Doses of Low-Let Radiation on the Innate Anti-Tumor Reactions in Radioresistant and Radiosensitive Mice

“…Based on their post-irradiation survival rate and incidence of radiogenic neoplasms BALB/c and C57BL/6 mice are regarded as radiosensitive or radioresistant, respectively (Storer et al 1988). Indeed, Ponnaiya et al (1997) demonstrated that primary mammary epithelial cells collected from BALB/c mice and exposed in vitro to 3.0 Gy of 137 Cs γ-rays at 0.74 Gy/min.…”