The challenging issue of low dose radiation hormesis and adaptive response- findings from earth to space (Nov 17 2014)

Debate:

Non-Linear Dose Response

SMJ MortazaviProf. of Medical Physics

Shiraz University of Medical Sciences

[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. 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


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

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 radiation and that they can prevent both

spontaneous and toxicant-related cancers as

well as other adverse health effects (Calabrese

et al. 2007).


Natural radiation deficiency

symptoms

It has been long known that protozoaand bacteria exposed to artificially lowered levels of natural levels of natural radiation demonstrate deficiency symptoms expressed as dramatically decreased proliferation.





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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.

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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

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� Indoor radon concentration levels were

previously measured in each dwelling by the

Iranian Nuclear Regulatory Authority experts.


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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.

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collected.

� The radon prone houses were located in a district

named Ramak.


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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

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mortality rate was in Ramak, where the highest

concentrations of radon in the dwellings were

found


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Crude Lung

Cancer Rate

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Adjusted

Lung Cancer

Rate

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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

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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.

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

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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.

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

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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.

What is Adaptive

Response?

Radiation Is it different from Radiation

Hormesis?


Adaptive Response

When large radiation

exposure is preceded by

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exposure is preceded by

a small �tickle� dose, the

effect of the large dose is

sometimes diminished

Adaptive Response

708090

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

09/01

0102030405060

0 0.5 150 0.5 + 150

ObservedExpected

Shadley and Wolff 1987

Dose cGy

Intervention


Adaptive Response Mechanisms

Small doses of radiation appear to:

Stimulate protective responses

Triggering DNA repair mechanisms

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Triggering DNA repair mechanisms

Elimination of severely damaged

cells

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Adaptive response is specific

There seems to be a genetic basis foradaptive response, since it is

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adaptive response, since it isdemonstrated only in specific cell lines, tissues, animal lines and individuals.

It is demonstrated only for specificbiological changes.

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Genetic Basis? Mortazavi SMJ, Ph.D

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Mortazavi SMJ, Ikushima T, and Mozdarani H. Variability of chromosomal radioadaptiveresponse in human lymphocytes. Iran. J. Radat. Res., 1(1): 55 - 61, 2003.

Genetic Basis? Mortazavi SMJ, Ph.D

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Natural Radiation &

Adaptive Response

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

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115 citations recorded by Web of Science

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Radiofrequency-Induced

Adaptive Response

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Radiofrequency-Induced Adaptive

Response

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� In 2009, it was found 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).

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).

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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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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

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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).


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

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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).


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-

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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).


� 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

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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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Window Theory

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Mortazavi SMJ, Ph.D

RE Mitchel:

�the adaptive response in

mammalian cells and mammals operates within a certain window that can be defined by

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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.

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efficacy against various tumors.

� Like many other chemotherapeutic drugs,

administration of DOX has toxic effects on

hematopoietic cells

Jin et al. 2012

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

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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.

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

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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 ìW/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 ìW/cm2 and 1200 ìW/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.

Non-responsiveness Phenomenon

Lack of AR in Some Individuals


Reported by:�Ikushima, T., and Mortazavi SMJ. Radioadaptive response: itsvariability in cultured human lymphocytes, In: Biological effectsof low dose radiation, Yamada T, Mothersil C, Mich BD andPotten CS (eds), pp 81-86, 2000.�Mortazavi SMJ, Ikushima T, and Mozdarani H. Variability ofchromosomal radioadaptive response in human lymphocytes. Iran.J. Radat. Res., 1(1): 55 - 61, 2003.

Immunological Implications

of

RF-Induced Adaptive

Response

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Response

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).

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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).

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

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radiation emitted from a GSM mobile phone

increases their resistance to a subsequent

bacterial infection (E. coli infection) (Mortazavi

et al. , 2012b).

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

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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.

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

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resistance against solar particle events or

infections caused by life-threatening

microorganisms.

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

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(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

23 citations according to Scopus

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2003

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.

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� �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/

http://science.nasa.gov/

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Four years after Mortazavi et al 2003

George et al. 2007:�This study of adaptive response is very interesting and it is important that the phenomenon be investigated further.

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

RF-Induced

Adaptive

Response in

Space

Research

� Different

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

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radioresistance to lethal doses of gamma rays after exposure to microwave radiation and

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� Mortazavi, S.M., Cameron, J.R., Niroomand-rad, A. Adaptive response studies may help

choose astronauts for long-term space travel. Adv Space Res 31, 1543-51, 2003.

� Mortazavi, S.M.J. Window Theory in Non-Ionizing Radiation-Induced Adaptive

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Lethal Doses of Gamma Rays in Mice and Rats after Exposure to Microwave Radiation

Emitted by a GSM Mobile Phone Simulator. Dose Response in press, 2012a.

� 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.

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The challenging issue of low dose radiation hormesis and adaptive response- findings from earth to space (Nov 17 2014)