The Challenging Issue of High Background Radiation Areas SMJ Mortazavi Prof. of Medical Physics Shiraz University of Medical Sciences 1 Mortazavi SMJ, Ph.D

Paracelsus ( ) "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison…." Mortazavi SMJ, Ph.D 2

Hormesis All chemical substances will exhibit a toxic effect given a large enough dose. If the dose is low enough even a highly toxic substance will cease to cause a harmful effect. The toxic potency of a chemical is thus ultimately defined by the dose (the amount) of the chemical that will produce a specific response in a specific biological system. Source: Mortazavi SMJ, Ph.D 3

LNT & Radiation Hormesis The radiation hormesis model, unlike the LNT model, assumes that adaptive/protective mechanisms can be stimulated by low-dose radiation and that they can prevent both spontaneous and toxicant-related cancers as well as other adverse health effects (Calabrese et al. 2007). Mortazavi SMJ, Ph.D 4

Natural radiation deficiency symptoms  It has been long known that protozoa and bacteria exposed to artificially lowered levels of natural radiation demonstrate deficiency symptoms expressed as dramatically decreased proliferation. Mortazavi SMJ, Ph.D 5

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Radon & Lung Cancer in Ramsar, Iran  Radon levels in some dwellings are up to 3700 Bq/m3 (over 100 pCi/L).   The people and their ancestors exposed to abnormally high radiation levels over many generations.  If a radiation dose of a few hundred mSv per year is detrimental to health causing genetic abnormalities or an increased risk of cancer, it should be evident in these people. Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to high levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of Natural Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara, M. Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp , Elsevier, Amsterdam,

HBRAs Around the World Mortazavi SMJ, Ph.D 11

Mortazavi SMJ, Ph.D Study Design Ramsar was divided into eight health districts and a health center provided primary health services in each health district. Indoor radon concentration levels were previously measured in each dwelling by the Iranian Nuclear Regulatory Authority experts. Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to high levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of Natural Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara, M. Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp , Elsevier, Amsterdam,

Mortazavi SMJ, Ph.D Cancer Mortality The overall cancer mortality, lung cancer mortality and neonatal death rate of different districts in the years from 2000 to 2001 were collected. The radon prone houses were located in a district named Ramak. Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to high levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of Natural Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara, M. Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp , Elsevier, Amsterdam,

Mortazavi SMJ, Ph.D Surprising Results Our study showed that the highest lung cancer mortality rate was in Galesh Mahaleeh, where the radon levels were normal. On the other hand, the lowest lung cancer mortality rate was in Ramak, where the highest concentrations of radon in the dwellings were found Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to high levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of Natural Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara, M. Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp , Elsevier, Amsterdam,

Mortazavi SMJ, Ph.D Crude Lung Cancer Rate Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to high levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of Natural Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara, M. Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp , Elsevier, Amsterdam,

Mortazavi SMJ, Ph.D Adjusted Lung Cancer Rate Mortazavi SMJ, M. Ghiassi-Nejad and M. Rezaiean. Cancer risk due to exposure to high levels of natural radon in the inhabitants of Ramsar, Iran in: High Levels of Natural Radiation and Radon Areas: Radiation Dose and Health Effects, T. Sugahara, M. Morishima, M. Sohrabi, Y Sasaki, I. Hayata, and S. Akiba Eds, pp , Elsevier, Amsterdam,

Mortazavi SMJ, Ph.D 17 The Study of Tumor Markers in High Background Radiation Areas Source: S Taeb, SMJ Mortazavi, A Ghaderi, H Mozdarani, MR Kardan, SAR Mortazavi, A Soleimani, I Nikokar, M Haghani, A Soofi. Alterations of PSA, CA15.3, CA125, Cyfra21- 1, CEA, CA19.9, AFP and Tag72 tumor markers in human blood serum due to long term exposure to high levels of natural background radiation in Ramsar, Iran. International Journal of Radiation Research. in press.

Why Tumor Markers? Recently, as no excess cancer rate was reported in these areas by epidemiological studies, we studied the tumor markers in the inhabitants of these areas to shed some light on the impact of high levels of background radiation on cancer induction. Mortazavi SMJ, Ph.D 18

Methods The level of background gamma radiation as well as indoor radon was determined using RDS-110 and CR dosimeters. Thirty five individuals from a high background radiation area (HBRA) and 35 individuals from a normal background radiation area (NBRA) were randomly selected to participate in the study. Commercial ELISA kits (sandwich type ELISA tests) were used to measure the serum levels of PSA, CA15.3, CA125, Cyfra21-1, CEA, CA19.9, AFP and Tag72 tumor markers. Mortazavi SMJ, Ph.D 19

Results Among the eight biomarkers investigated, the means of PSA, CA15.3, CA125, CA19.9 and AFP concentrations between the HBRAs and NBRAs were not different. However, Cyfra21, CEA and Tag72 in HBRA group revealed significant increases compared to those of NBRA group (P<0.05). Statistically significant correlation between the external gamma dose as well as indoor radon level and the concentration of CEA (P<0.001), Cyfra- 21(P<0.001) and TAG 72 (P<0.001 and 0.01 respectively) biomarkers were also observed. Mortazavi SMJ, Ph.D 20

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What is Adaptive Response ? Is it different from Radiation Hormesis ? Mortazavi SMJ, Ph.D 23

Adaptive Response When large radiation exposure is preceded by a small “tickle” dose, the effect of the large dose is sometimes diminished Mortazavi SMJ, Ph.D 24

Adaptive Response Observed Expected Shadley and Wolff 1987 Aberrations Dose cGy When a small dose of radiation is given before a larger one, it would be expected there would be more chromosome aberrations than when just the large dose was given. But that is not what happens. With a small “tickle” dose before the larger dose, there were only about half as many aberrations than with just a large dose! Intervention Mortazavi SMJ, Ph.D

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Adaptive Response Mechanisms Small doses of radiation appear to:  Stimulate protective responses  Triggering DNA repair mechanisms  Elimination of severely damaged cells Mortazavi SMJ, Ph.D 27

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Adaptive response is specific There seems to be a genetic basis for adaptive response, since it is demonstrated only in specific cell lines, tissues, animal lines and individuals. It is demonstrated only for specific biological changes. Mortazavi SMJ, Ph.D 29

Genetic Basis? Mortazavi SMJ, Ph.D Mortazavi SMJ, Ikushima T, and Mozdarani H. Variability of chromosomal radioadaptive response in human lymphocytes. Iran. J. Radat. Res., 1(1): ,

Genetic Basis? Mortazavi SMJ, Ph.D 31

Natural Radiation & Adaptive Response High levels of natural radiation can induce adaptive responses Mortazavi SMJ, Ph.D 32

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Mortazavi SMJ, Ph.D 115 citations recorded by Web of Science The 1 st report on the induction of adaptive response in the residents of High Background Radiation Areas (HBRAs) 34

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Implications of Ramsar Findings and RF-Induced Adaptive Response in Space Research Mortazavi SMJ, Ph.D 39

From HBRAs to Space  Our findings on the induction of adaptive response in the residents of HBRAs helped us to hypothesize that adaptive response studies may help choose astronauts for long-term space travel.  This hypothesis was based on our results on:  The variability of adaptive response in different individuals (some people are non-responsive).  The space environment:  Galactic Cosmic Radiation  Adapting Dose  Solar Particle Events  Challenging Dose Mortazavi SMJ, Ph.D 40

Adaptive Response in Space Research  In a report entitled “Adaptive response studies may help choose astronauts for long-term space travel”, which published in "Advances in Space Research" (Mortazavi et al., 2003), it was previously hypothesized that screening of the candidates of deep space missions by Ground-based in vitro adaptive response tests before any mission can be used to identify the individuals who respond well to low levels of ionizing radiation and reveal high magnitudes of radioadaptive response (Mortazavi et al., 2005). Mortazavi SMJ, Ph.D 41

Mortazavi SMJ, Ph.D Citations in the Web of Science (ISI)

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Two years after Mortazavi et al 2003 report, NASA agrees that lightweight solar protons stimulate repair processes to help reduce the effects of the heavy cosmic ray ions 2005-Cancer specialist Dr. John Dicello “Cells often react in unexpected ways to radiation, notes Dicello. For example, there's a puzzling phenomenon known as adaptive response. Sometimes, when tissue is exposed to damaging radiation, it not only repairs itself, but also learns to repair itself better next time. How that works is still being investigated” “The damage could be less than the two kinds added together -- or it could be more! There could, perhaps, be an adaptive response in which lightweight solar protons stimulate repair processes to help reduce the effects of the heavy cosmic ray ions. Or something totally unexpected could happen”. Mysterious Cancer Mortazavi SMJ, Ph.D 44

Mortazavi SMJ, Ph.D 45 George et al. 2007: “This study of adaptive response is very interesting and it is important that the phenomenon be investigated further. Four years after Mortazavi et al 2003 report, in 2007:

Durante and Manti 2008: “Another possibility is that an adaptive response to the space environment takes place after the first exposure, which may confer the exposed individual an increased radioresistance. Such a response would be similar to that hypothesized to explain the apparent lack of adverse health effects in VHBRA and HBRA residents. As pointed out by Mortazavi et al. (2003), radiobiological studies on these areas may lead to the identification of the cellular and molecular mechanisms by which susceptibility to genetic damage and cancer is decreased by chronic radiation exposure, hence helping the astronaut selection process.” Mortazavi SMJ, Ph.D 46

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Mortazavi SMJ, Ph.D Mortazavi et al., Advances in Space Research, Vol 31, No. 6, ,

RF-Induced Adaptive Response in Space Research Different methods that can be used for reducing the risk of radiation during deep space missions Mortazavi SMJ, Ph.D 49

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Implications of RF-Induced Adaptive Response  Although there is a report by Plews et al. that indicates the induction of adaptive response induced by low-dose whole-body radiation treatments prolonged the survival of prion-infected mice by reducing oxidative stress (Plews et al., 2010), to the best of our knowledge our study was the first study which showed the induction of adaptive response as prolonged survival of Escherichia coli-infected BALB/c mice by pre-exposure to radiofrequency radiation (non-ionizing radiation). Mortazavi SMJ, Ph.D 53

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Mortazavi SMJ, Ph.D 57 Source: Mortazavi SMJ, Motamedifar M, Mehdizadeh AR, Namdari G, Taheri M. The Effect of Pre-exposure to Radiofrequency Radiations Emitted from a GSM Mobile Phone on the Suseptibility of BALB/c Mice to Escherichia coli. Journal of Biomedical Physics and Engineering. 2012; 2(4):

Adaptive Response in Space Research Concluding Remark: Exposure of astronauts to continuous isotropic galactic cosmic radiation or low levels of radiofrequency radiation can increase their resistance against solar particle events or infections caused by life-threatening microorganisms. Mortazavi SMJ, Ph.D 58

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Mortazavi, S.M.J., Motamedifar, M., Namdari, G., Taheri, M. Pre-exposure to Radiofrequency Radiations Emitted from a GSM Mobile Phone Increases Resistance to a Bacterial Infection in BALB/c Mice. Journal of Biomedical Physics and Engineering in press, 2012b. Mortazavi, S.M.J., Motamedifar, M., Namdari, G., Taheri, M., Mortazavi, A.R. Counterbalancing immunosuppression-induced infections during long-term stay of humans in space. Journal of Medical Hypotheses and Ideas 7, 8–10, Mortazavi SMJ. Space radiobiology and the new era of induced radioresistance: Should traditional concepts be moved to science history museums? Technology and Health Care in press. Murray, D., Allalunis-Turner, M., Weinfeld, M. VIIIth International Workshop on Radiation Damage to DNA. Int J Radiat Biol 81, , Olivieri, G., Bodycote, J., Wolff, S. Adaptive response of human lymphocytes to low concentrations of radioactive thymidine. Science 223, 594-7, Ozgur, E., Guler, G., Seyhan, N. Mobile phone radiation-induced free radical damage in the liver is inhibited by the antioxidants N-acetyl cysteine and epigallocatechin-gallate. Int J Radiat Biol 86, , Plews, M., Simon, S.L., Boreham, D.R., et al. A radiation-induced adaptive response prolongs the survival of prion-infected mice. Free Radic Biol Med 49, , Samson, L., Cairns, J. A new pathway for DNA repair in Escherichia coli Sannino, A., Sarti, M., Reddy, S.B., Prihoda, T.J., Scarfì, M.R. Induction of adaptive response in human blood lymphocytes exposed to radiofrequency radiation. Radiation research 171, , 2009a. Sannino, A., Sarti, M., Reddy, S.B., Prihoda, T.J., Vijayalaxmi, Scarfi, M.R. Induction of adaptive response in human blood lymphocytes exposed to radiofrequency radiation. Radiat Res 171, , 2009b. Mortazavi SMJ, Ph.D 62

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Thank you! Mortazavi SMJ, Ph.D 64