$Q[PQQIGSYXSYPKQVPV XVQJPXVJQJQVVPG +6K QEJ 5'6Z E 5(-0K QG:+IPQQ G a National Institute for Public ealth and the Environment (IVM), P Box 1, 3720 BA Bilthoven, The Netherlands, helmut.schollnberger@rivm.nl, also: helmut.schoellnberger@sbg.ac.at b Purdue niversity School of ealth Sciences, 550 Stadium Mall rive, est afayette, IN 47907-2051, SA, trebor@purdue.edu c adiation Biology and ealth Physics Branch, Atomic Energy of Canada imited, Chalk iver aboratories, Chalk iver, ntario K0J 1J0, Canada, mitchelr@aecl.ca d Institute of Physics and Biophysics, niversity of Salzburg, ellbrunnerstr. 34, A-5020 Salzburg, Austria, werner.hofmann@sbg.ac.at $EV A multi-stage cancer model that describes the putative rate-limiting steps in carcinogenesis was developed and used to investigate the potential impact on lung cancer incidence of the hormesis mechanisms suggested by einendegen and Pollycove. In this deterministic cancer model, radiation and endogenous processes damage the NA of target cells in the lung. Some fraction of the misrepaired or unrepaired NA damage induces genomic instability and, ultimately, leads to the accumulation of malignant cells. The model accounts for cell birth and death processes. It also includes a rate of malignant transformation and a lag period for tumour formation. Cellular defence mechanisms are incorporated into the model by postulating dose and dose rate dependent radical scavenging. The accuracy of NA damage repair also depends on dose and dose rate. Sensitivity studies were conducted to identify critical model inputs and to help define the shapes of the cumulative lung cancer incidence curves that may arise when dose and dose rate dependent cellular defence mechanisms are incorporated into a multi-stage cancer model. or lung cancer, both linear no-threshold (NT) and non-nt shaped responses can be obtained. The reported studies clearly show that it is critical to know whether or not and to what extent multiply damaged NA sites are formed by endogenous processes. Model inputs that give rise to -shaped responses are consistent with an effective cumulative lung cancer incidence threshold that may be as high as 300 mgy (4 mgy per year for 75 years). 1
,QGXQ The linear no-threshold (NT) model is used within the radiation protection community to establish guidelines to protect workers and the public from the potential human health risks of ionising radiation. The NT model, as illustrated in igure 1a, is premised on the idea that the smallest possible dose of radiation can cause cancer. owever, there are biological responses to a variety of chemical and radiological agents that may be -shaped (igure 1b) rather than NT (e.g., see [1]). This phenomenon is called hormesis, the stimulating effect of sub-inhibitory concentrations of any toxic substance on any organism [2]. Calabrese and Baldwin [3] uncovered thousands of studies that demonstrate hormesis effects across the whole plant and animal kingdom and for a wide variety of biological endpoints. V Q X \ E I J % V Q X \ E I J % $EVEGGVE\XQV $EVEGGVE\XQV )JX+\SKXYVGSQJQQKVKGE8VKSGGVVSQVV In 1996, Azzam and co-workers demonstrated that low doses (1-100 mgy) of g -rays, when delivered at low dose rates (2.4 mgy/min), GXG the neoplastic transformation frequency in C3 10T1/2 cells (mouse embryo fibroblasts) to a rate three- to four-fold EZ the spontaneous transformation frequency [4]. This has been confirmed in human-hybrid cell systems [5-8]. These results demonstrate that low-dose-rate radiation exposures may induce processes, such as error-free NA double strand break repair, that can reduce the overall rate of cell transformation (see also [9-11] and www.magma.ca/~mitchel/). The aim of this study is to examine the potential impact that cellular adaptations in NA damage repair and enzymatic radical scavengers may have on the cumulative incidence of lung cancer under low dose and dose rate exposure conditions. 0VQG0KGV e have developed a multi-stage lung cancer model (igure 2) that describes the crucial biological events in the processes of carcinogenesis. In the model, radiation and endogenous processes damage the NA of target cells in the lung. Some fraction of the misrepaired or unrepaired NA damage induces genomic instability and leads to the accumulation of initiated and malignant cells. The model explicitly accounts for the formation of initiated cells via rate constant k, cell birth (via mitotic rates k M1 and k M2 ) and death processes (constant rates k d1 and k d2 that comprise necrosis, apoptosis and cell differentiation), malignant transformation (k mt ), and a lag period (t 0 ) for tumour formation. To examine the potential significance of radioprotective mechanisms, dose and dose rate dependent NA repair and radical scavenging phenomena are incorporated into the model. Changes in NA repair and radical scavenging with dose rate (and hence dose) are modelled using a dimensionless scale-functions (igure 3), denoted * and ) respectively. or values of * and ) greater than one, radiation is less effective at inducing genomic instability and cell transformation (i.e., reduces the rate constant N in igure 2). 2
)JX&QSXYYZIKPXVJQPG 3.5 3.0 imensionless repair factor, * 2.5 2.0 1.5 1.0 0.5 0.0 0 100 200 300 400 500 )JX5SVQY[PSVIKGPQVQVV'1$ S IXQQ* 7K Y GG QVQGK\SGVQJ[SGIPQX\XQJGQVXVP*\ \ 5VXV Simulations were performed with the closed form solution for the cumulative lung cancer incidence model. Estimates of model parameters are derived from data reported in the literature. igure 4 shows the cumulative lung cancer incidence at an age of 75 years versus the total absorbed dose delivered in the same time span. The effects of different levels of cellular adaptations in NA repair with scavenger effects switched off are shown. igure 5 shows the combined effects of cellular adaptations in radical scavenging and NA repair processes. These results suggest that radiation must induce changes in radical scavenging and NA repair greater than about 30 or 40% () and * > 1.3 to 1.4) of the baseline values in order to produce cumulative incidence levels outside the range expected for endogenous processes and background radiation (i.e., the horizontal dotted lines at 3.1 10 4 and 6.4 10 4 ). 3
(75 yr) 10-2 Cumulative cancer incidence at 75 years, 1 10-3 10-4 10-5 100 200 300 400 500 600 700 800 900 1000 )JX 6G Q Q GQ KPVV IIV 'VKG QV VKZ K IIV I X GSQVQ'1$S) QGˆ * ˆ (75 yr) 10-2 Cumulative cancer incidence at 75 years, 1 10-3 10-4 10-5 0 100 200 300 400 500 600 700 800 900 1000 )JX3GGVKSVIKQQGQXYVZKQEKXGIQPKQVPV QXGG Q K PG'VKG Q IIV I G VYQJQJ QG'1$ S ) QG* Q K QJIP'GQPEQGIIVIGVYQJQJQG'1$S)QG*Q KQJIP'VK'GQPEQGIIVIGVYQJQJQG'1$S )QG*QKQJIP 'VXVVQQG&QXVQV Sensitivity studies highlight the importance of including endogenously formed NA damage in estimates of low-dose cancer incidence levels. or doses comparable to background radiation levels, endogenous NA damage accounts for as much as 80 to 95% of the predicted lung cancers. or a 4
lifetime dose of 1 Gy, endogenous processes may still account for as much as 38% of the predicted cancers. or the range of model inputs deemed biologically plausible, both NT and non-nt shaped responses can be obtained. Model inputs that give rise to -shaped responses are consistent with an effective cancer incidence threshold that may be as high as 300 mgy (4 mgy per year for 75 years). $NQZGJPQV ork supported by the Marie Curie Individual ellowship EC Contract No IG-CT-2002-50513 and by the ow ose adiation esearch Program, Biological and Environmental esearch (BE),.S. epartment of Energy, Grant No. E-G02-03E63541. 5IQV 1. Calabrese, E.J., Baldwin,.A. Toxicology rethinks its central belief. Nature, 421(6924): 691-692, (2003). 2. orland. orland s Illustrated Medical ictionary, 25 th edition. Saunders B, Philadelphia, ondon, Toronto (1974). 3. Calabrese, E.J., Baldwin,.A. Crit. ev. Toxicol., 33(3-4): 215-424, (2003). 4. Azzam, E.I., de Toledo, S.M., aaphorst, G.P., Mitchel,.E. ow-dose ionizing radiation decreases the frequency of neoplastic transformation to a level below the spontaneous rate in C3 10T1/2 cells. adiat. es., 146(4): 369-373, (1996). 5. edpath, J.., Antoniono,.J. Induction of an adaptive response against spontaneous neoplastic transformation in vitro by low-dose gamma radiation. adiat. es., 149(5): 517-20, (1998). 6. edpath, J.., iang,., Taylor, T.., Christie, C., Elmore, E. The shape of the dose-response curve for radiation-induced neoplastic transformation in vitro: evidence for an adaptive response against neoplastic transformation at low doses of low-et radiation. adiat. es., 156(6): 700-707, (2001). 7. edpath, J.., u, Q., ao, X., Molloi, S., Elmore, E. ow doses of diagnostic energy X-rays protect against neoplastic transformation in vitro. Int. J. adiat. Biol., 79(4): 235-240, (2003). 8. edpath, J.., Short, S.C., oodcock, M., Johnston, P.J. ow-dose reduction in transformation frequency compared to unirradiated controls: the role of hyper-radiosensitivity to cell death. adiat. es., 159(3): 433-436, (2003). 9. einendegen,.e., Mühlensiepen,., Bond, V.P., Sondhaus, C.A. Intracellular stimulation of biochemical control mechanisms by low-dose, low-et irradiation. ealth Phys., 52(5): 663-669, (1987). 10. Schöllnberger,., Mitchel,.E., Azzam, E.I., Crawford-Brown,.J., ofmann,. Explanation of protective effects of low doses of gamma-radiation with a mechanistic radiobiological model. Int. J. adiat. Biol., 78(12): 1159-1173, (2002). 11. Mitchel,.E., Jackson, J.S., Morrison,.P., Carlisle, S.M. ow doses of radiation increase the latency of spontaneous lymphomas and spinal osteosarcomas in cancer-prone, radiation-sensitive Trp53 heterozygous mice. adiat. es., 159(3): 320-327, (2003). 5