Ionizing and Non-Ionizing Radiation-Induced Adaptive Response: Findings From E arth to S pace

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Ionizing and Non-Ionizing Radiation-Induced Adaptive Response: Findings From Earth to Space SMJ Mortazavi Prof. of Medical Physics Shiraz University of Medical Sciences [email protected] 1

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Ionizing and Non-Ionizing Radiation-Induced Adaptive Response: Findings From E arth to S pace. SMJ Mortazavi Prof. of Medical Physics Shiraz University of Medical Sciences [email protected]. Paracelsus (1493-1541). "All substances are poisons; there is none which is not a poison. - PowerPoint PPT Presentation

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Ionizing and Non-Ionizing Radiation-Induced Adaptive

Response: Findings From Earth to Space

SMJ MortazaviProf. of Medical Physics

Shiraz University of Medical [email protected]

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Paracelsus (1493-1541)

•"All substances are poisons; there is none which is not a poison.

•The right dose differentiates a poison…."

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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: http://learn.caim.yale.edu/chemsafe/references/dose.html

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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).

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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.

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Mortazavi SMJ, Ph.D 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. 436-437, Elsevier, Amsterdam, 2005.

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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. 436-437, Elsevier, Amsterdam, 2005.

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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. 436-437, Elsevier, Amsterdam, 2005.

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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. 436-437, Elsevier, Amsterdam, 2005.

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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. 436-437, Elsevier, Amsterdam, 2005.

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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. 436-437, Elsevier, Amsterdam, 2005.

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The Study of Tumor Markersin 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.

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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.

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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.

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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.

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What is Adaptive Response?Is it different from

Radiation Hormesis?

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Adaptive Response

When large radiation exposure is preceded by a small “tickle” dose, the effect of the large dose is sometimes diminished

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Adaptive Response Mechanisms

Small doses of radiation appear to:Stimulate protective responsesTriggering DNA repair mechanisms

Elimination of severely damaged cells

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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.

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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): 55 - 61, 2003.

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Genetic Basis? Mortazavi SMJ, Ph.D

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Natural Radiation & Adaptive Response

High levels of natural radiation can induce adaptive responses

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Two survey meters show dose rates of 142 and 143 µSv/h on contact with a bedroom wall

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105 citations recorded by Web of Science

The 1st report on the induction of adaptive response in the residents of High Background Radiation Areas (HBRAs)

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Radiofrequency-Induced Adaptive Response

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Radiofrequency-Induced Adaptive Response

• In 2009, it was found for the 1st time that pre-exposure of cultured cells to radiofrequency radiation induced an adaptive response which increased the resistance of these cells to mytomycin C (Sannino et al. , 2009a).

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Radiofrequency-Induced Adaptive Response

Mortazavi et al. also found that laboratory animals pre-irradiated with radiofrequency radiation were less susceptible to subsequent lethal effects of high doses of ionizing radiation (Mortazavi et al. , 2011a, Mortazavi et al. , 2012a).

These findings later confirmed by our subsequent reports (Mortazavi et al. , 2011b, Mortazavi et al, 2012a) as well as the very limited published reports that investigated the induction of adaptive response after pre-treatment with microwave radiation (Cao et al. , 2011, Jiang et al. , 2012, Sannino et al. , 2009b, Sannino et al. , 2011, Zeni et al. , 2012).

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Radiofrequency-Induced Adaptive Response As indicated before, Sannino et al. had

previously reported that pre-exposure of peripheral blood lymphocytes collected from human volunteers to non-ionizing RF radiation (900 MHz, at a peak specific absorption rate of 10 W/kg for 20 h) increases their resistance to a challenge dose of mitomycin C (100 ng/ml at 48 h) (Sannino, Sarti, 2009b).

Later, they confirmed their previous results and showed that the timing of adapting dose exposure of radiofrequency plays an important role in the process of adaptive response induction (Sannino, Zeni, 2011). 2012).

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Radiofrequency-Induced Adaptive Response

On the other hand, Chinese researchers have recently shown that pre-exposure of mice to non-ionizing 900 MHz RF induced adaptive response and thus reduced the hematopoietic tissue damage from a subsequent challenge dose of ionizing radiation (Cao, Xu, 2011).

Zeni et al. also showed that when lymphocytes were pre-exposed to RF at 0.3W/kg SAR and then treated with mitomycin C, these cells showed a significant reduction in the frequency of micronuclei, compared with the cells treated with MMC alone (Zeni, Sannino, 2012).

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Radiofrequency-Induced Adaptive Response Jiang et al. also recently used a relatively similar

method as we did previously (using the gamma radiation as the challenge dose) and indicated that mice pre-exposed to RF for 3, 5, 7 and 14 days showed progressively decreased damage and were significantly different from those exposed to gamma-radiation alone (Jiang, Nie, 2012).

It has also been reported that pre-exposure of Human promyelocytic leukemia HL-60 cells to 900 MHz radiofrequency radiation for 1 hour/day for 3 days had a protective effect in hematopoietic tissue damage induced by doxorubicin, a chemotherapeutic drug (Jin et al. , 2012).

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Radiofrequency-Induced Adaptive Response

•More recently, Jiang et al. used the micronuclei (MN) assay as the endpoint and showed that exposure of mice to both adapting (900MHz RF radiation) and challenge (3Gy gamma-radiation) doses (AD+CD) resulted in a significant decrease in MN indices compared to those exposed to CD alone (Jiang et al. , 2013).

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Radiofrequency-Induced Adaptive Response

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Window Theory

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RE Mitchel:

“the adaptive response in mammalian cells and mammals operates within a certain window that can be defined by upper and lower dose thresholds, typically between about 1 and 100 mGy for a single low dose rate exposure”

(Mitchel 2010)

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Doxorubicin

•Doxorubicin (DOX or adriamycin) is the most commonly used anticancer drug because of its efficacy against various tumors.

•Like many other chemotherapeutic drugs, administration of DOX has toxic effects on hematopoietic cells

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Jin et al. 2012

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Minimum power density•A preliminary experiment was conducted

to determine the minimum power density needed for 900 MHz RF pre-exposure to minimize the damage induced by subsequent exposure to DOX.

•Cells were pre-exposed to 900 MHz RF at 12, 120 and 1200 mW/cm2 power density for 1 hour/day for 3 days.

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Jin et al. 2012

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Jin et al. 2012

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Window Theory in Non-Ionizing Radiation-Induced Adaptive Responses

Dear Editor,

I read with great interest an article by Jin et al. “The Effect of Combined Exposure of 900 MHz Radiofrequency Fields and Doxorubicin in HL-60 Cells", published in the Sep 2012 issue of PLOS ONE Journal (Jin et al. 2012). The authors of the article reported some interesting findings on the induction of adaptive response by pre-exposure of HL-60 Cells to radiofrequency (RF) radiations. As summarized in Table 1, the viability of the cells exposed to DOX alone was 70.2 ± 0.2 while when cells were exposed to 900 MHz RF radiation at 12 μW/cm2 before treatment with DOX, the viability was 82.8 ± 2.1 (P<0.01). RF exposure at higher power densities significantly decreased the viability (60.7 ± 0.5 and 58.6 ± 0.5 for 120 μW/cm2 and 1200 μW/cm2, respectively). On the other hand they reported that they had previously conducted a preliminary experiment to determine the minimum power density for RF pre-exposures to minimize the damage induced by subsequent exposure to DOX.

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Non-responsiveness Phenomenon

Lack of AR in Some Individuals

Reported by:•Ikushima, T., and Mortazavi SMJ. Radioadaptive response: its variability in cultured human lymphocytes, In: Biological effects of low dose radiation, Yamada T, Mothersil C, Mich BD and Potten CS (eds), pp 81-86, 2000.•Mortazavi SMJ, Ikushima T, and Mozdarani H. Variability of chromosomal radioadaptive response in human lymphocytes. Iran. J. Radat. Res., 1(1): 55 - 61, 2003.

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Immunological Implications of

RF-Induced Adaptive Response

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Immune System & Space Research Immune system is highly susceptible to different

stressors exist during space flight (Gridley et al. , 2009).

Dysregulation of the immune system during and immediately following space missions (Crucian et al. , 2011, Crucian et al. , 2008).

Despite the well-known reversible immunological alterations in short-term spaceflights, the bioeffects of long-duration spaceflight on neuroimmune responses have not been completely known so far (Stowe et al. , 2011).

Solar and galactic radiation are associated with increased risk of infection during long term stay of human outside the Earth’s magnetic field (Zhou et al. , 2012).

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Implications of RF-Induced Adaptive Response •Mortazavi et al. have also recently shown

that pre-exposure of BALB/c mice to radiofrequency radiation emitted from a GSM mobile phone increases their resistance to a subsequent bacterial infection (E. coli infection) (Mortazavi et al. , 2012b).

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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).

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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):139-46.

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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.

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Implications of RF-Induced Adaptive

Response in

Space Research

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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).

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2003

25 citations according to Scopus

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2003

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Two years after Mortazavi et al 2003 report, NASA agrees that adaptive response is a puzzling issue in space radiobiology

•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 http://science.nasa.gov/

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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:

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• 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.”

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Mortazavi et al., Advances in Space Research, Vol 31, No. 6, 1543-1552, 2003

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RF-Induced Adaptive Response in Space Research• Different

methods that can be used for reducing the risk of radiation during deep space missions

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References:• Bose Girigoswami, K., Ghosh, R. Response to gamma-irradiation in V79 cells conditioned by

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Thank you

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