**Author details**

Ruhi Cakir

Second, expert scientists in free radicals ought to distinguish the chronic intracellular oxidative stress typical of several pathologies by the transitory (5 min) calculated oxidative stress occurring when a precise volume of blood is exposed ex vivo to an equal volume of gas (O2\_/ O3) with well-defined ozone concentrations ranging from 20 up to 40 mg/ml per ml of blood. It needs to be emphasized that the exogenous oxidative stress caused by ozone in blood is due to the fact that ozone, once dissolved in the plasmatic water, instantaneously reacts with biomolecules and disappears but generates ROS, among which are H2O2 and LOPs. These are the effective ozone messengers that interact with a variety of cells and elicit the now-termed 'therapeutic shock' due to the multiform biological responses. That ozone acts as a real chemical drug is proved by the fact that the ozone messengers, to be effective, must reach a threshold because otherwise there are no biological effects and the therapeutic results, if any, are due to a placebo effect. Although we have proven that ozone therapy is not a nebulous approach and has been shown amenable to a precise scientific scrutiny, it is probable that much

Everyone knows that plasma and blood cells contain an almost redundant antioxidant system made up of hydro-liposoluble compounds and antioxidant enzymes. During aging or patho‐ logic conditions, this is not sufficient to correct the intracellular oxidative stress, but normally it is adequate to tame ozone toxicity while allowing the generation of ROS and LOPs. Thus all data emphasizing ozone toxicity can be easily dismissed because the following is now well

**1.** Blood is a much more ozone-resistant 'tissue' than the respiratory tract that, for anatomic, biochemical and metabolic reasons, is always at a loss when exposed to ozone, and therefore it is wrong to extrapolate ozone toxicity for the pulmonary system to blood. **2.** Washed and saline-resuspended erythrocytes, fully depleted of the plasmatic antioxi‐ dants, are obviously very sensitive to ozonation, and all of these unnatural data have

**3.** The same occurs for cells cultured in antioxidant-poor media and exposed continuously for days to ozone. Surprisingly, cell biologists reported only the ozone concentration but have neither calculated nor taken into account the cumulative dose of ozone that after a

**4.** The conclusion is that, although ozone is potentially mutagenic, so far all experimental data performed in physiological conditions and clinical evidence have neithershown any cell damage nor adverse effects in patients. As a matter of fact, blood is exposed to ozone concentrations (0.21\_/1.68 mM) lower than the mutagenic ones (1.5\_/5.6 mM). The question of whether ozone is genotoxic and mutagenic is a critical one and has been extensively discussed elsewhere. (3) What has never been entirely appreciated is the fact that we can only use an ozone dose that does not overwhelm the antioxidant capacity of

Hopefully this discussion should put an end to the confusion between the endogenously constant oxidative stress due to the oxygen and the transitory and occasional therapeutic 'shock' due to precise blood ozonation. A point that should not be overlooked is that ozone

neither physiological nor practical significance.

long exposure kills the cells.

still remains to be uncovered.

172 Pharmacology and Nutritional Intervention in the Treatment of Disease

proven:

blood.

Mediozon Clinics, Istanbul, Turkey
