Renal Damage in the Mouse: The Response to Very Small Doses per Fraction

Abstract

Experiments were undertaken to study the effect on the mouse kidney of repeated X-ray doses in the range 0.2 to 1.6 Gy per fraction and neutron doses in the range 0.05 to 0.25 Gy per fraction. A top-up design of experiment was used, so that additional graded doses of d(4)-Be neutrons (EN = 2.3 MeV) were given to bring the subthreshold damage produced by these treatments into the measurable range. This approach avoided the necessity to use a large number of fractions to study low doses per fraction. Renal damage was assessed using three methods: 51Cr-EDTA clearance, urine output, and hematocrit at 16-50 weeks postirradiation. The dose-response curves obtained were resolved best at 29 weeks. However, the results were also examined by fitting second-order polynomials to the data for response versus time postirradiation and using interpolated values from these functions at 29 weeks to construct dose-response curves. This method reduced slightly the variation in the dose-response data, but the interrelationship between the dose-response curves remained the same. The data were used to test the linear-quadratic (LQ) description of the underlying X-ray dose-fractionation relationship. The model fits well down to X-ray doses per fraction of approximately 1 Gy, but lower X-ray doses were more effective per gray than predicted by LQ, as seen previously in skin [M. C. Joiner et al., Int. J. Radiat. Biol. 49, 565-580 (1986)]. This increased X-ray effectiveness and deviation from LQ are reflected directly in a decrease in the RBE of d(4)-Be neutrons relative to X-rays at low doses, since the underlying response to these neutrons is linear in this low-dose region. The RBE decreases from 9.9 to 4.7 as the X-ray dose per fraction is reduced below 0.8 Gy to 0.2 Gy, reflecting an increase in X-ray effectiveness by a factor of 2.1. A model is discussed which attempts to explain this behavior at low doses per fraction.

Treatment modelling: The influence of micro-environmental conditions

“…It also has to be mentioned that the Joiner and Johns model [29], which we will refer to as ''the linear quadratic model with inducible repair'' (LQ/ IR) or simply as ''the inducible repair model'', is virtually identical to the linear quadratic model above 1 Gy and up to several tens of Gy (the dose range where the LQ model has been used with reasonable accuracy) for oxic cells.…”

“…However, a series of experiments initiated in the mid-1980s [28,29] have shown that the LQ model fails to predict the cell response to very small doses of radiation (below 0.5Á1 Gy). This hypersensitivity to low doses has been shown to exist in vivo both in normal tissues [28Á31] and in tumours [32,33] as well as in a wide range of cell lines studied in vitro [34Á42].…”

“…All these models assume different mechanisms for the transition from the sensitive to the resistant state of the cell. Thus, the model proposed by Joiner and Johns [29] is an adaptation of the LQ model which assumes a gradual transition that is consistent with the repair rate being related to the level of damage: the more damage is inflicted, the more efficient the induction of the repair mechanisms. By contrast, the model proposed by Wouters and Skarsgard [36] assumes that the cells need a certain threshold level of damage to activate the repair mechanisms, while the activation has an ''on-off '' characteristic, activation meaning fully resistant response and inactivation fully sensitive response.…”

“…Consequently, several alternative models [29,36,46] have been proposed to replace the LQ model. All these models assume different mechanisms for the transition from the sensitive to the resistant state of the cell.…”

“…Among these three models, the Joiner and Johns model [29] is the most convenient to use, as it is closely related to the LQ model and can therefore use the large database of LQ parameters which have been derived along the many years of use of the latter model. It also has to be mentioned that the Joiner and Johns model [29], which we will refer to as ''the linear quadratic model with inducible repair'' (LQ/ IR) or simply as ''the inducible repair model'', is virtually identical to the linear quadratic model above 1 Gy and up to several tens of Gy (the dose range where the LQ model has been used with reasonable accuracy) for oxic cells.…”