Low-dose cancer risk modeling must recognize up-regulation of protection

Abstract

IONIZING RADIATION PRIMARILY PERTURBS THE BASIC MOLECULAR LEVEL PROPORTIONAL TO DOSE, WITH POTENTIAL DAMAGE PROPAGATION TO HIGHER LEVELS: cells, tissues, organs, and whole body. There are three types of defenses against damage propagation. These operate deterministically and below a certain impact threshold there is no propagation. Physical-static defenses precede metabolic-dynamic defenses acting immediately: scavenging of toxins; - molecular repair, especially of DNA; - removal of damaged cells either by apoptosis, necrosis, phagocytosis, cell differentiation-senescence, or by immune responses, - followed by replacement of lost elements. Another metabolic-dynamic defense arises delayed by up-regulating immediately operating defense mechanisms. Some of these adaptive protections may last beyond a year and all create temporary protection against renewed potentially toxic impacts also from non-radiogenic endogenous sources. Adaptive protections have a maximum after single tissue absorbed doses around 100 to 200 mSv and disappear with higher doses. Low dose rates initiate maximum protection likely at lower cell doses delivered repetitively at certain time intervals. Adaptive protection preventing only about 2 - 3 % of endogenous life-time cancer risk would fully balance a calculated induced cancer risk at about 100 mSv, in agreement with epidemiological data and concordant with an hormetic effect. Low-dose-risk modeling must recognize up-regulation of protection.

Keywords: Low-dose cancer risk; adaptive protections; hormesis.

FIGURE 1:

Scheme of particle distribution in tissues. Shown are several electrons and an alpha-particle. Clearly, total energy absorbed per unit mass correlates with the number of particles in that mass.

FIGURE 2:

The body may be viewed being organized in hierarchical levels with increasing complexity from bottom up. Intricate signaling within and between the various levels always involves cells. The three principal signaling loops assure functional integrity of the body in the face of abundant threats by toxic impacts from external and internal sources.

FIGURE 3:

Threats at the various organizational levels of the body are met by physical-static and metabolic-dynamic defenses against damaging impact, damage creation and damage propagation. These defenses are successful if they restore homeostasis, from the molecular to the tissue-organ level. Only when the defense barriers are overcome, pathology develops with acute and late health effects, such as cancer. The individual defenses respond with individual probabilities

FIGURE 4:

Damage propagation to successive higher level of organization, from DNA, to cells, to tissue, and the effect of protection at the cell and tissue levels may be expressed schematically by a simple set of equations.

FIGURE 5:

The metabolic defenses also operate against the development of cancer. The various steps to clinical cancer have individual probabilities. About 1 in 10⁹ cancer cells may escape defense barriers and cause clinical tumors and disseminated metastases. In industrialized countries, about 2–3 % of cancer incidence is being attributed to background radiation, as is calculated on the basis of the LNT hypothesis (adapted from Feinendegen et al. 2007a,b).

FIGURE 6:

Schematic representation of the dual responses to single low doses feeding into the “Dual-Probability-Model” in Figure 7: a) Low doses of ionizing radiation can up-regulate physiological defenses with delay and some last beyond a year. The up-regulated defenses are also called adaptive protections and depend on dose D and on he time t_p of their action: the probability of protection ranges from 0 – 1 and is P_ap f (D; t_p). b) The risk of radiation induced cancer assumes constant defenses in the body at every dose D according to the LNT hypothesis and is expressed here by the value of P_ind per unit dose. - There are uncertainties at low dose levels shown by light dotted lines: stemming from detrimental by-stander effects. genomic instability, as well as induction of repair; and adaptive protections (adapted from Feinendegen et al. 2007a,b). Note that the scales of the two probabilities P_ind and P_ap f (D; t_p) are independent of each other.

FIGURE 7:

This Figure illustrates the applicability of the “Dual-Probability-Model” for assessing low-dose cancer risk. - Adaptive protections, as shown in Figure 5 and 6, may also operate against non-radiogenic damage and thus reduce “spontaneous cancer. The product of the probability of protection against spontaneous cancer, from 0 to 1, and the probability of spontaneous cancer gives the probability of cancer prevention The clinically observed cancer risk R, then, is the difference between the probabilities of radiation induced cancer and of prevented cancer, given by the solid line. Assuming here a maximum value of P_ap f(D, t_p) at 100 to 200 mGy, the reduction of cancer risk to and below the spontaneous risk appears as an obvious hormetic effect, despite the low values of P_ap f(D, t_p), see table 2 and 3 (adapted from Feinendegen et al. 2007a,b).

FIGURE 8:

Chronic irradiation conforms to repetitive irradiations of micromasses. Microdoses z occur per micromass over time stochastically with various values, upper part, according to their spectrum depending on radiation quality, lower part for 250 kVp x-rays.

FIGURE 9:

The biological risk of chronic irradiation depends of the values of microdoses and the time interval between consecutive microdose events. Mean values for both may be used for assessing risk. The term “cancer risks” here expresses the probability of cancer induction by the hit cell at the time during exposure, with the added time intervals allowing for repair and protection. Shown schematically are three scenarios: 1. where protection outweighs damage; 2. where protection equals damage; 3. where damage outweighs protection.