Radijacija i rizik od karcinoma

Volim ovakve tekstove. Kako je pun podataka, uglavnom će ga većina preskočiti. Kasnije ću da ga dajem kao odgovor svima koji i dalje ne žele da razumeju radijaciju, efekte radijacije, načine odbrane i nastanak karcinoma. Na kraju će biti gomila referenci, tek da nerviram one koji o radijaciji uče iz apokaliptičnih filmova.

Prosta činjenica je da život postoji u pravom moru radijacije, kao i hemijskih komponenti i činjenica je da sve stupa u neprekidne interakcije svake milisekunde naših života. U takvom okruženju prosečni život jedinke je već oko 75 godina.

Jednoćelijski organizmi postoje već oko 3.5 milijardi godina, dok višećelijski postoje oko 600 miliona. Sve vreme život je izložen svim formama radijacije pa i jonizujućem. Da bi život postojao i opstao u takvom okruženju morali su da se razviju adaptivni i zaštitni mehanizmi. To je jednostavno evolucija.

Tu počinjemo da se razilazimo. Ljubitelji straha od radijacije nikako da razumeju šta je evolucija. Nikako ne žele da prihvate činjenicu da nam je benefit evolucije upravo zaštita od radijacije. Mogu da prihvate svaku činjenicu, osim radijacije. To je ono kada strah pomuti pamet ili kada su interesi druge vrste preveliki.

Neki autori kao C.I.Sanders tvrde da niske doze radijacije godišnje spašavaju veliki broj života.

Nimalo nije sporno, niti iko to tvrdi, da su visoke doze radijacije opasne, ali, manje poznata činjenica, odsustvo radijacije ima sličan efekat.

Kancerogeneza je prilično složen mehanizam koji se ne može posmatrati kao prosto mutacije jedne ćelije. Da bi karcinom mogao da poraste ćelije moraju pravazići mehanizme i signale domaćina i postati samo dovoljne. Studije su pokazale da je to uveliko vezano sa starošću domaćina, što je stariji organizam veća je verovatnoća da ćelije neće slušati centar već će tražiti svoje načine za rast. Postoji tu još bitnih elemenata kao što su signali iz stomalnih ćelija i fibroblasta koji mogu da ubrzaju ili uspore rast.

Po teoriji lobista i radiofoba, svaki pojedinačni pogodak radijacije može da izazove karcinom. Ako znamo da svako od nas ima između 10.000 i 20.000 radioaktivnih raspada unutar tela (10.000 do 20.000 Bekerela) i ako svakoga od nas pogodi 15.000 gama zraka i to sve u jednoj jedinoj sekundi i svake sekunde a da je kada je nastajao život ta doza bila i do 50 puta veća, onda se postavlja pitanje kako je uopšte život moguć. Po LNT modelu život nije moguć. Dokazi u prilog LNT modela su bazirani na političkim ili finansijskim motivima a istraživanja koja ih potkrepljuju na traljavom nenaučnom radu.

Kada organizam dobije signal kancerogenog rasta neke ćelije aktivira se mehanizam apoptoze. Karcinomi mogu da ga zaobiđu, inače ne bi ni bilo karcinoma. Po G.Bauveru i njegovim istraživanjima, niske doze radijacije pomažu apoptozu malignih ćelija, sasvim suprotno od LNT modela. Bukvalno tamo gde je prisutna radijacija (u granicama niskih doza) mogućnost uništavanja malignih ćelija je veća. Da nije toga ne bi ni postojao Ramsar paradoks i slični (mesto sa jako velikom radijacijom koja je i više od sto puta veća od one normalne kod nas, ali sa procentualno značajno nižom  incidencom karcinoma).

Pretpostavka je da karcinomi rastu iz jedne ćelije koja se deli, ali broj deoba jedne ćelije je ograničen. Broj telomera se smanjuje nakon svake replikacije DNK (DNA) i nakon izvesnog broja replikacija više se ne replicira. Karcinomske ćelije imaju dva mehanizma za izbegavanje prestanka replikacije, jedan je reaktivacija telomera a drugi je ALT mehanizam koji ne uključuje telomere.

Nekontrolisani rast karcinoma i invazija tkiva, kao i pojava metastaza izazivaju smrt organizma. Za metastaze se svatra da prvo invadiraju krvne ili limfne sudove i nakon toga se krvotokom ili limfotokom prenose u udaljena tkiva.

Evoluciono organizmi su razvili prirodnu zaštitu (APN) koja može biti molekularna, ćelijska, tkivna ili na nivou čitavog organizma.

Molekularna zaštita se odnosi pre svega na visoke doze radijacije gde jonizujuće zračenje cepa molekule vode i stvara hidrogen koji oštećuje ćelije u celosti ili njihov DNK što može dovesti do razvijanja karcinoma. Međutiv evolutivno smo razvili mehanizme koji to sprečavaju, tako imamo enzimske mehanizme kao što su superoksid dismutaza, katalaza, glutation peroksidaza, ali i neenzimske koji uključuju vitamin C i E, glutation, tioredoksin-1 koji je posebno bitan jer redukuje oba mehanizma i stara balans (redox). 

Kataoka je u istraživanjima dokazao da doze od 200 mGy razvijaju mehanizme dok doze od 4Gy (visoke doze) te mehanizme ne razvijaju. Dokazano je da doze od 500mGy momentalno stvaraju molekularnu zaštitu. Paradoksalno, dokazano je da niske doza radona koje su inhalirane povećavaju odbranu organizma, ali i smanjuju inflamaciju i bol. Podsetimo da se do skora smatralo da je radon jedan od glavnih izazivača karcinoma pluća.

Ispitivanjima Comptonovog elektrona dolazimo do podatka da se u jednom milisekundi nakon ozračenja aktivira čak 200 mehanizama zaštite. 

Postoji još niz mehanizama kao su signalni enzimi koji šalju signale ćelijama o mogućem oštećenju.

Veoma važno je istraživanje koje su obavili Koana i saradnici na vinskim mušicama. Posebnu važnost mu daje jer je upravo istraživanje na vinskim mušicama iz 1926. godine bila preteča LNT modela. Ozraniči su reproduktivne ćelije niskim dozama i visokim dozama radijacije. Kod niskih doza bilo je manje mutacija nego kod kontrolne grupe, dok je kod visokih bilo značajno više. Sasvim suprotno LNT modelu.

Istraživanjima dolazimo do brojke od 10.000 prirodnih događaja koji mogu da oštete DNK u jednom satu. Od tog broja svega 10 otpada na radijaciju. To uopšte ne ide u prilog tome da jedan pogodak radijacije izaziva kancerogenezu, šta ćemo sa ostalih 9990 događaja? Oni nisu važni?

Ćelijski mehanizmi odbrane. Ćelije neprekidno bivaju izložene stresu, trumama i oštećenjima. Prirodni automatski mehanizam odgovora na oštećenje je stanje prestanka replikacije ćelije. nema replikacije, nema tumora. Kod kontinuiranog izlaganja traume kao što je visoka doza radijacije ili kontinuirano izlaganje hemijskim toksinima dovodi do stanja povećane inflamacije koja veliki broj ćelija dovodi u stanje nerepliciranja, što u tom slučaju ima negativni efekat. Kod niskuh doza radijacije dolazi do smanjenja inflamacije.

Po R.B.Skotu umereno izlaganje radonu smanjuje mogućnost razvijanja karcinoma pluća kod pušača. 

Apoptoza, nekroza i autofagija su takođe celularni mehanizmi odbrane. Apoptoza je kontrolisani mehanizam uništavanja oštećenih i kancerogenih ćelija, nekroza je nekontrolisani mehanizam uništavanja ćelija i nastupa kod velikih trauma (kao što je visoka radijacija), dok je  autofagija mehanizam gde se uništavaju ćelije ili delovi ćelija kod stresa.

Ono što je od krucijalne važnosti, niske doze radijacije povećavaju apoptozu, znači kontrolisano i programirano uništavanje oštećenih ćelija. Istraživanja su pokazala da izlaganje germ ćelija (koje su najostljivije) niskim dozama radijacije dovodi do toga da su zaštićenije od oštećenja od onih ćelija koje nisu bile izložene radijaciji.

Mehanizmi na nivou tkiva. Interakcija između ćelija jednog tkiva je presudna za sprečavanje rasta karcinoma. Niske doze radijacije povećavaju sposobnost ćelija u tkivu da spreče širenje malignog tkiva i pomažu uništenje prekanceroznih ćelija. 

Jedan od razloga pojave karcinoma kod pušača je benzopiren koji se transformiše u kancerogen BaP diol epoksid (BPDE). BPDE menja mikrookruženje, pre svega stomalne ćelije i stvara uslov za razvitak malignih ćelija, pre svega prekomernom aktivacijom IL6 koji izaziva inflamaciju. Dokazano je da niske doze radijacije sprečavaju razvijanje IL6.

Mehanizmi na nivou tela. Kao što postoje mehanizmi na nivou molekula, ćelija i tkiva, tako postoje mehanizmi koji uključuju odgovor čitavog tela. Karcinomi imaju mogućnost da zaobiđu mehanizme.

Ispitivanjem mesta sa značajno povećanom radijacijom (sem pomenutog Rasmsara - Kerala, Misasa, Guangdong, neka mesta u Brazilu i USA) dovela su do zaključka da imunisistem ljudi koji žive u tim područjima radi brže i efikasnije u uništavanju malignih ćelija. 

Niske doze radijacije aktiviraju NK ćelije (natural killer), ADCC kod splenocita, onda CD2, CD25, CD28, CD48, CD71, signalne molekula c-GMP i p38MAPK.

Jedno od ključnih pitanja je dejstvo radijacije na plod. Ne postoje jasni dokazi da doze ispod 100mGy mogu izazvati oštećenja. Visoke doze izazivaju promene, to je nesporno. Da li će doći do oštećenja zavisi od faze razvoja ploda, u ranijim fazama povećava se verovatnoća. 

Decenijama se pogrešno smatra da je radijacija maltene osnovni uzrok nastanka karcinoma. To je provučeno kroz sramni LNT model. Evidentno je da niske doze radijacije deluju povoljno na već prisutne adaptivne mehanizme koji su nastali tokom evolucije. Moramo reći i da su nastali zbog radijacije. Niko ne govori da su visoke doze radijacije zdrave ili korisne, ali nikako se niske doze ne smeju satanizovati jer to dovodi do potpuno pogrešnih zaključaka i pravaca u lečenju karcinoma. Satanizacija radijacije je dovela do besmislenog straha koji se naziva radiofobija i koji prosto koči razum kod ljudi koji se bave naukom i trebalo bi da razmišljaju o dokazima a ne o emocijama.

Tekst je nastao na osnovu rada "The LNT model for cancer induction is not supported by radiobiological data" Bobija Skota iz Univerziteta u Albukerkiju i Sujentar Tarmalingama iz Univerziteta u Ontariju.

Reference

[1] R.O. McClellan, Radiation toxicity, in: A.W. Hayes, C.L. Kruger (Eds.), Hayes'

Principals and Methods of Toxicology, 6 ed., CRC Press, Inc., Boca Raton (FL),

2014, pp. 883–955.

[2] M. Tubiana, A. Aurengo, D. Averbeck, R. Masse, Recent reports on the effect of low

doses of ionizing radiation and its dose-effect relationship, Radiat. Environ.

Biophys. 44 (4) (2006) 245–251.

[3] C.L. Sanders, Radiobiology and Radiation Hormesis: New Evidence and its

Implications for Medicine and Society, Springer International Publishing, 2017.

[4] L.R. Dartnell, Ionizing radiation and life, Astrobiology 11 (6) (2011) 551–582.

[5] G.F. Atkinson, Report upon some preliminary experiments with the rontgen rays

on plants, Science 7 (158) (1898) 7–13.

[6] E.I. Azzam, N.W. Colangelo, J.D. Domogauer, N. Sharma, S.M. de Toledo, Is io-

nizing radiation harmful at any exposure? An echo that continues to vibrate,

Health Phys. 110 (3) (2016) 249–251.

[7] T.D. Luckey, Hormesis with Ionizing Radiation, CRC Press, Inc, Boca Raton (FL),

1980.

[8] T.D. Luckey, Radiation Hormesis, CRC Press, Inc, Boca Raton (FL), 1991.

[9] H. Castillo, G.B. Smith, Below-background ionizing radiation as an environmental

cue for bacteria, Front. Microbiol. 8 (2017) 1–7, https://doi.org/10.3389/fmicb.

2017.00177.

[10] H. Castillo, X. Li, F. Schilkey, G.B. Smith, Transcriptome analysis reveals a stress

response of Shewanella oneidensis deprived of background levels of ionizing ra-

diation, PLoS One 13 (5) (2018) e0196472https://doi.org/10.1371/journal.pone.

0196472.

[11] H. Castillo, D. Schoderbek, S. Dulal, G. Escobar, J. Wood, R. Nelson, G. Smith,

Stress induction in the bacteria Shewanella oneidensis and Deinococcus radiodurans

in response to below-background ionizing radiation, Int. J. Radiat. Biol. 1 (2015)

33, https://doi.org/10.3109/09553002.2015.1062571.

[12] H. Sies, L.E. Feinendegen, Radiation hormesis: the link to nanomolar hydrogen

peroxide, Antioxidants Redox Signal. 27 (9) (2017) 596–598.

[13] H. Planel, J.P. Soleilhavoup, R. Tixador, G. Richoilley, A. Conter, F. Croute,

C. Caratero, Y. Gaubin, Influence on cell proliferation of background radiation or

exposure to very low, chronic gamma radiation, Health Phys. 52 (5) (1987)

571–578.

[14] L. Cai, S.Z. Liu, Induction of cytogenetic adaptive response of somatic and germ

cells in vivo and in vitro by low-dose X-irradiation, Int. J. Radiat. Biol. 58 (1)

(1990) 187–194.

[15] L.E. Feinendegen, J.M. Cuttler, Biological effects from low doses and dose rates of

ionizing radiation: science in the service of protecting humans, a synopsis, Health

Phys. 114 (6) (2018) 623–626.

[16] L.E. Feinendegen, M. Pollycove, R.D. Neumann, Whole-body responses to low-

level radiation exposure: new concepts in mammalian radiobiology, Exp. Hematol.

35 (4 Suppl 1) (2007) 37–46.

[17] R.E. Mitchel, E.I. Azzam, S.M. de Toledo, Adaptation to ionizing radiation in

mammalian cells, in: T.M. Kovals (Ed.), Stress-Inducible Processes in Higher

Eukaryotic Cells, Plenum Press, New York, 1997, pp. 221–243.

[18] K.I. Seong, S. Seo, D. Lee, M.J. Kim, S.S. Lee, S. Park, Y.W. Jin, Is the linear no-

threshold dose-response paradigm still necessary for the assessment of health ef-

fects of low dose radiation? J. Kor. Med. Sci. 31 (Suppl 1) (2016) S10–S23.

[19] J.F. Ward, The complexity of DNA damage: relevance to biological consequences,

Int. J. Radiat. Biol. 66 (5) (1994) 427–432.

[20] B.R. Scott, It's time for a new low-dose-radiation risk assessment paradigm–one

that acknowledges hormesis, Dose Response 6 (4) (2008) 333–351.

[21] B.R. Scott, Low-dose-radiation stimulated natural chemical and biological pro-

tection against lung cancer, Dose Response 6 (3) (2008) 299–318.

[22] B.R. Scott, Low-dose radiation risk extrapolation fallacy associated with the linear-

no-threshold model, Hum. Exp. Toxicol. 27 (2) (2008) 163–168.

[23] B.R. Scott, Small radiation doses enhance natural barriers to cancer, J Am

Physicians Surg 22 (4) (2017) 105–110.

[24] K. Sakai, Y. Hoshi, T. Nomura, T. Oda, T. Iwasaki, K. Fujita, T. Yamada, Tanooka,

Suppression of carcinogenic processes in mice by chronic low dose rate gamma-

irradiation, Int. J. Low Radiat. 1 (1) (2003) 142‒146.

[25] B.R. Scott, J. Di Palma, Sparsely ionizing diagnostic and natural background ra-

diations are likely preventing cancer and other genomic-instability-associated

diseases, Dose-Response 5 (3) (2006) 230–255.

[26] B.R. Scott, Residential radon appears to prevent lung cancer, Dose Response 9 (4)

(2011) 444–464.

[27] M. Tubiana, Dose-effect relationship and estimation of the carcinogenic effects of

low doses of ionizing radiation: the joint report of the Academie des Sciences

(Paris) and of the Academie Nationale de Medecine, Int. J. Radiat. Oncol. Biol.

Phys. 63 (2) (2005) 317–319.

[28] M. Tubiana, The 2007 Marie Curie prize: the linear no threshold relationship and

advances in our understanding of carcinogenesis, Int. J. Low Radiat. 5 (3) (2008)

173–204.

[29] M. Tubiana, A. Aurengo, D. Averbeck, A. Bonnin, B. Le Guen, R. Masse, R. Monier,

A.J. Valleron, F. de Vathaire, Dose-effect Relationships and Estimation of the

Carcinogenic Effects of Low Doses of Ionizing Radiation, French Academy of

Sciences – French National Academy of Medicine, Paris, 2005.

[30] W.C. Hahn, R.A. Weinberg, Modelling the molecular circuitry of cancer, Nat. Rev.

Canc. 2 (5) (2002) 331–341.

[31] W.C. Hahn, R.A. Weinberg, Rules for making human tumor cells, N. Engl. J. Med.

347 (20) (2002) 1593–1603.

[32] P. Armitage, R. Doll, The age distribution of cancer and a multi-stage theory of

carcinogenesis, Br. J. Canc. 8 (1) (1954) 1–12.

[33] D. Hanahan, R.A. Weinberg, The hallmarks of cancer, Cell 100 (1) (2000) 57–70.

[34] A. Beheshti, R.K. Sachs, M. Peluso, E. Rietman, P. Hahnfeldt, L. Hlatky, Age and

space irradiation modulate tumor progression: implications for carcinogenesis

risk, Radiat. Res. 179 (2) (2013) 208–220.

[35] A. Beheshti, S. Benzekry, J.T. McDonald, L. Ma, M. Peluso, P. Hahnfeldt, L. Hlatky,

Host age is a systemic regulator of gene expression impacting cancer progression,

Cancer Res. 75 (6) (2015) 1134–1143.

[36] A. Beheshti, J. Wage, J.T. McDonald, C. Lamont, M. Peluso, P. Hahnfeldt,

L. Hlatky, Tumor-host signaling interaction reveals a systemic, age-dependent

splenic immune influence on tumor development, Oncotarget 6 (34) (2015)

35419–35432.

[37] C.J. Tape, S. Ling, M. Dimitriadi, K.M. McMahon, J.D. Worboys, H.S. Leong,

I.C. Norrie, C.J. Miller, G. Poulogiannis, D.A. Lauffenburger, et al., Oncogenic

KRAS regulates tumor cell signaling via stromal reciprocation, Cell 165 (7) (2016)

1818.

[38] NRC (National Research Council), Health Risks from Exposure to Low Levels of

Ionizing Radiation, The National Academies Press; Report BEIR-V, 1990.

[39] NRC (National Research Council), Health Risks from Exposure to Low Levels of

Ionizing Radiation, The National Academies Press, 2006 Report BEIR-VII, Phase 2.

[40] G. Bauer, Low dose radiation and intercellular induction of apoptosis: potential

implications for the control of oncogenesis, Int. J. Radiat. Biol. 83 (11–12) (2007)

873–888.

[41] G. Bauer, Low dose gamma irradiation enhances defined signaling components of

intercellular reactive oxygen-mediated apoptosis induction, J Phys Conf Ser 261

(012001) (2011) 1–15.

[42] J.L. Redpath, D. Liang, T.H. Taylor, C. Christie, E. Elmore, The shape of the dose-

response curve for radiation-induced neoplastic transformation in vitro: evidence

for an adaptive response against neoplastic transformation at low doses of low-LET

radiation, Radiat. Res. 156 (6) (2001) 700–707.

[43] E. Elmore, X.Y. Lao, R. Kapadia, E. Giedzinski, C. Limoli, J.L. Redpath, Low doses

of very low-dose-rate low-LET radiation suppress radiation-induced neoplastic

transformation in vitro and induce an adaptive response, Radiat. Res. 169 (3)

(2008) 311–318.

[44] K.K. Tsai, J. Stuart, Y.Y. Chuang, J.B. Little, Z.M. Yuan, Low-dose radiation-in-

duced senescent stromal fibroblasts render nearby breast cancer cells radio-

resistant, Radiat. Res. 172 (3) (2009) 306–313.

[45] M.K. Boss, R. Bristow, M.W. Dewhirst, Linking the history of radiation biology to

the hallmarks of cancer, Radiat. Res. 181 (6) (2014) 561–577.

[46] R. Sullivan, C.H. Graham, Hypoxia-driven selection of the metastatic phenotype,

B.R. Scott and S. Tharmalingam Chemico-Biological Interactions 301 (2019) 34–53

50

Cancer Metastasis Rev. 26 (2) (2007) 319–331.

[47] B. Krishnamachary, D. Zagzag, H. Nagasawa, K. Rainey, H. Okuyama, J.H. Baek,

G.L. Semenza, Hypoxia-inducible factor-1-dependent repression of E-cadherin in

von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3,

ZFHX1A, and ZFHX1B, Cancer Res. 66 (5) (2006) 2725–2731.

[48] S. Kuphal, A.K. Bosserhoff, Influence of the cytoplasmic domain of E-cadherin on

endogenous N-cadherin expression in malignant melanoma, Oncogene 25 (2)

(2006) 248–259.

[49] C.H. Graham, T.E. Fitzpatrick, K.R. McCrae, Hypoxia stimulates urokinase re-

ceptor expression through a heme protein-dependent pathway, Blood 91 (9)

(1998) 3300–3307.

[50] S. Koochekpour, M. Jeffers, P.H. Wang, C. Gong, G.A. Taylor, L.M. Roessler,

R. Stearman, J.R. Vasselli, W.G. Stetler-Stevenson, W.G. Kaelin Jr.et al., The von

Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth factor/scatter

factor-induced invasion and branching morphogenesis in renal carcinoma cells,

Mol. Cell Biol. 19 (9) (1999) 5902–5912.

[51] R.R. Oh, J.Y. Park, J.H. Lee, M.S. Shin, H.S. Kim, S.K. Lee, Y.S. Kim, S.H. Lee,

S.N. Lee, Y.M. Yang, et al., Expression of HGF/SF and Met protein is associated

with genetic alterations of VHL gene in primary renal cell carcinomas, APMIS 110

(3) (2002) 229–238.

[52] D. Shweiki, A. Itin, D. Soffer, E. Keshet, Vascular endothelial growth factor in-

duced by hypoxia may mediate hypoxia-initiated angiogenesis, Nature 359 (6398)

(1992) 843–845.

[53] A. Cheda, J. Wrembel-Wargocka, E. Lisiak, M. Marciniak, E.M. Nowosielska,

M.K. Janiak, Inhibition of the development of pulmonary tumor nodules and sti-

mulation of the activity of NK cells and macrophages in mice by single low doses

of low-LET radiation, Int. J. Low Radiat. 1 (2) (2004) 171–179.

[54] A. Cheda, J. Wrembel-Wargocka, E. Lisiak, E.M. Nowosielska, M. Marciniak,

M.K. Janiak, Single low doses of X rays inhibit the development of experimental

tumor metastases and trigger the activities of NK cells in mice, Radiat. Res. 161 (3)

(2004) 335–340.

[55] S. Hashimoto, H. Shirato, M. Hosokawa, T. Nishioka, Y. Kuramitsu, K. Matushita,

M. Kobayashi, K. Miyasaka, The suppression of metastases and the change in host

immune response after low-dose total-body irradiation in tumor-bearing rats,

Radiat. Res. 151 (6) (1999) 717–724.

[56] Y. Hosoi, K. Sakamoto, Suppressive effect of low dose total body irradiation on

lung metastasis: dose dependency and effective period, Radiother. Oncol. 26 (2)

(1993) 177–179.

[57] A.X. Jin, S.Y. Wang, D.Y. Wei, Mechanism of low level ionizing radiation in in-

hibiting B16 melanoma blood-born pulmonary metastasis, Chin J Radiol Med Prot

17 (1997) 236–239.

[58] M. Takahashi, S. Kojima, Suppression of atopic dermatitis and tumor metastasis in

mice by small amounts of radon, Radiat. Res. 165 (3) (2006) 337–342.

[59] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144 (5)

(2011) 646–674.

[60] Z. Jaworowski, Radiation risk and ethics, Phys. Today 52 (9) (1999) 24–29.

[61] H.S. Ducoff, Radiation hormesis: incredible or inevitable? Kor. J. Biol. Sci. 6 (3)

(2002) 187–193.

[62] A.L. Bhatia, Radiation exposure and evolutionary perspectives with special re-

ferences to neutral theory, Int. J. Low Radiat. 5 (2) (2008) 113–122.

[63] Z. Jaworowski, The paradigm that failed, Int. J. Low Radiat. 5 (2) (2008) 151–155.

[64] P.A. Karam, S.A. Leslie, Calculations of background beta-gamma radiation dose

through geologic time, Health Phys. 77 (6) (1999) 662–667.

[65] L.E. Feinendegen, 2010 Marie Curie prize lecture: low-dose induced protection

invalidates the linear-no-threshold model in mammalian bodies – a system-biology

approach, Int. J. Low Radiat. 8 (2) (2011) 78–95.

[66] L.E. Feinendegen, M. Pollycove, C.A. Sondhaus, Responses to low doses of ionizing

radiation in biological systems, Nonlinearity Biol. Toxicol. Med. 2 (3) (2004)

143–171.

[67] A. Petkau, W.S. Chelack, Radioprotective effect of superoxide dismutase on model

phospholipid membranes, Biochim. Biophys. Acta 433 (3) (1976) 445–456.

[68] M. Quintiliani, The oxygen effect in radiation inactivation of DNA and enzymes,

Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 50 (4) (1986) 573–594.

[69] S. Kojima, E. Takai, M. Tsukimoto, ATP released from low-dose gamma ray-irra-

diated cells activates intracellular antioxidant systems via purine receptors, J. Anti

Aging Med. 8 (7) (2011) 108–113.

[70] F. Zoccarato, L. Cavallini, A. Alexandre, Respiration-dependent removal of exo-

genous H2O2 in brain mitochondria: inhibition by Ca2+, J. Biol. Chem. 279 (6)

(2004) 4166–4174.

[71] E.V. Kalinina, N.N. Chernov, A.N. Saprin, Involvement of thio-, peroxi-, and glu-

taredoxins in cellular redox-dependent processes, Biochemistry (Mosc.) 73 (13)

(2008) 1493–1510.

[72] T. Kataoka, Study of antioxidative effects and anti-inflammatory effects in mice

due to low-dose X-irradiation or radon inhalation, J. Radiat. Res. 54 (4) (2013)

587–596.

[73] S. Kojima, H. Ishida, M. Takahashi, K. Yamaoka, Elevation of glutathione induced

by low-dose gamma rays and its involvement in increased natural killer activity,

Radiat. Res. 157 (3) (2002) 275–280.

[74] S. Kojima, O. Matsuki, T. Nomura, A. Kubodera, Y. Honda, S. Honda, H. Tanooka,

H. Wakasugi, K. Yamaoka, Induction of mRNAs for glutathione synthesis-related

proteins in mouse liver by low doses of gamma-rays, Biochim. Biophys. Acta 1381

(3) (1998) 312–318.

[75] S. Kojima, O. Matsuki, T. Nomura, N. Shimura, A. Kubodera, K. Yamaoka,

H. Tanooka, H. Wakasugi, Y. Honda, S. Honda, et al., Localization of glutathione

and induction of glutathione synthesis-related proteins in mouse brain by low

doses of gamma-rays, Brain Res. 808 (2) (1998) 262–269.

[76] K. Yamaoka, S. Kojima, M. Takahashi, T. Nomura, K. Iriyama, Change of glu-

tathione peroxidase synthesis along with that of superoxide dismutase synthesis in

mice spleens after low-dose X-ray irradiation, Biochim. Biophys. Acta 1381 (2)

(1998) 265–270.

[77] Y. Kawakita, M. Ikekita, R. Kurozumi, S. Kojima, Increase of intracellular glu-

tathione by low-dose gamma-ray irradiation is mediated by transcription factor

AP-1 in RAW 264.7 cells, Biol. Pharm. Bull. 26 (1) (2003) 19–23.

[78] B.R. Scott, S.A. Belinsky, S. Leng, Y. Lin, J.A. Wilder, L.A. Damiani, Radiation-

stimulated epigenetic reprogramming of adaptive-response genes in the lung: an

evolutionary gift for mounting adaptive protection against lung cancer, Dose-

Response 7 (2) (2009) 104–131.

[79] R. Katz, M.P.R. Waligórski, On the linear extrapolation to low doses, Radiat.

Protect. Dosim. 52 (1994) 197–199.

[80] B.E. Erickson, The therapeutic use of radon: a biomedical treatment in Europe; an

"alternative" remedy in the United States, Dose Response 5 (1) (2006) 48–62.

[81] S. Kojima, Y. Ohshima, H. Nakatsukasa, M. Tsukimoto, Role of ATP as a key sig-

naling molecule mediating radiation-induced biological effects, Dose-Response 15

(1) (2017), https://doi.org/10.1177/1559325817690638 15 Feb 2017.

[82] S. Kojima, M. Tsukimoto, N. Shimura, H. Koga, A. Murata, T. Takara, Treatment of

cancer and inflammation with low-dose ionizing radiation: three case reports,

Dose-Response 15 (1) (2017), https://doi.org/10.1177/1559325817697531 [23

Mar 2017].

[83] D. Einor, A. Bonisoli-Alquati, D. Costantini, T.A. Mousseau, A.P. Moller, Ionizing

radiation, antioxidant response and oxidative damage: a meta-analysis, Sci. Total

Environ. 548–549 (2016) 463–471.

[84] L.E. Feinendegen, Reactive oxygen species in cell responses to toxic agents, Hum.

Exp. Toxicol. 21 (2) (2002) 85–90.

[85] L.T. Dauer, A.L. Brooks, D.G. Hoel, W.F. Morgan, D. Stram, P. Tran, Review and

evaluation of updated research on the health effects associated with low-dose

ionising radiation, Radiat. Protect. Dosim. 140 (2) (2010) 103–136.

[86] B.R. Scott, Modeling DNA double-strand break repair kinetics as an epiregulated

cell-community-wide (epicellcom) response to radiation stress, Dose Response 9

(4) (2011) 579–601.

[87] A.M. Vaiserman, Hormesis, adaptive epigenetic reorganization, and implications

for human health and longevity, Dose-Response 8 (1) (2010) 16–21.

[88] K. Donohue, The epigenetics of adaptation: focusing on epigenetic stability as an

evolving trait, Evolution 68 (3) (2014) 617–619.

[89] A.P. Feinberg, R.A. Irizarry, Evolution in health and medicine Sackler colloquium:

stochastic epigenetic variation as a driving force of development, evolutionary

adaptation, and disease, Proc. Natl. Acad. Sci. U. S. A. 107 (Suppl 1) (2010)

1757–1764.

[90] I. Mendizabal, T.E. Keller, J. Zeng, S.V. Yi, Epigenetics and evolution, Integr.

Comp. Biol. 54 (1) (2014) 31–42.

[91] O.J. Rando, K.J. Verstrepen, Timescales of genetic and epigenetic inheritance, Cell

128 (4) (2007) 655–668.

[92] A. Vojta, V. Zoldos, Adaptation or malignant transformation: the two faces of

epigenetically mediated response to stress, BioMed Res. Int. (2013), https://doi.

org/10.1155/2013/954060 [26 Sep 2013].

[93] S. Tharmalingam, S. Sreetharan, A.V. Kulesza, D.R. Boreham, T.C. Tai, Low-dose

ionizing radiation exposure, oxidative stress and epigenetic programing of health

and disease, Radiat. Res. 188 (4.2) (2017) 525–538.

[94] P. Fei, W.S. El-Deiry, P53 and radiation responses, Oncogene 22 (37) (2003)

5774–5783.

[95] H. Mirzaie-Joniani, D. Eriksson, A. Sheikholvaezin, A. Johansson, P.O. Lofroth,

L. Johansson, T. Stigbrand, Apoptosis induced by low-dose and low-dose-rate ra-

diation, Cancer 94 (4 Suppl) (2002) 1210–1214.

[96] R.D. Wood, M. Mitchell, J. Sgouros, T. Lindahl, Human DNA repair genes, Science

291 (5507) (2001) 1284–1289.

[97] D. Pan, Y. Du, B. Hu, The role of epigenetic modulation in the cellular response to

ionizing radiation, Internet J. Radiol. 2 (1) (2015) 7–14.

[98] C. Furusawa, K. Kaneko, Epigenetic feedback regulation accelerates adaptation

and evolution, PLoS One 8 (5) (2013) e61251.

[99] A.J. Bernal, D.C. Dolinoy, D. Huang, D.A. Skaar, C. Weinhouse, R.L. Jirtle,

Adaptive radiation-induced epigenetic alterations mitigated by antioxidants,

FASEB J. 27 (2) (2013) 665–671.

[100] D.M. Duhl, H. Vrieling, K.A. Miller, G.L. Wolff, G.S. Barsh, Neomorphic agouti

mutations in obese yellow mice, Nat. Genet. 8 (1) (1994) 59–65.

[101] R. Petkova, S. Chakarov, The final checkpoint. Cancer as an adaptive evolutionary

mechanism, Biotechnol. Biotechnol. Equip. 30 (3) (2016) 434–442.

[102] D.E. Barnes, T. Lindahl, Repair and genetic consequences of endogenous DNA base

damage in mammalian cells, Annu. Rev. Genet. 38 (2004) 445–476.

[103] T. Lindahl, Instability and decay of the primary structure of DNA, Nature 362

(6422) (1993) 709–715.

[104] J.W. Drake, B. Charlesworth, D. Charlesworth, J.F. Crow, Rates of spontaneous

mutation, Genetics 148 (4) (1998) 1667–1686.

[105] NCRP (National Council on Radiation Protection and Measurement), Potential

Impact of Individual Genetic Susceptibility and Previous Radiation Exposure on

Radiation Risk for Astronaut, U.S. Government Printing Office, Washington, DC,

2010.

[106] F.R. Tang, W.K. Loke, Molecular mechanisms of low dose ionizing radiation-in-

duced hormesis, adaptive responses, radioresistance, bystander effects, and

genomic instability, Int. J. Radiat. Biol. 91 (1) (2015) 13–27.

[107] B.R. Scott, Radiation-hormesis phenotypes, the related mechanisms and implica-

tions for disease prevention and therapy, J Cell Commun Signal 8 (4) (2014)

341–352.

[108] K. Komatsu, NBS1 and multiple regulations of DNA damage response, J. Radiat.

B.R. Scott and S. Tharmalingam Chemico-Biological Interactions 301 (2019) 34–53

51

Res. 57 (Suppl 1) (2016) i11–i17.

[109] T. Koana, M.O. Okada, K. Ogura, H. Tsujimura, K. Sakai, Reduction of background

mutations by low-dose X irradiation of Drosophila spermatocytes at a low dose

rate, Radiat. Res. 167 (2) (2007) 217–221.

[110] T. Koana, T. Takahashi, H. Tsujimura, Reduction of spontaneous somatic mutation

frequency by a low-dose X irradiation of Drosophila larvae and possible involve-

ment of DNA single-strand damage repair, Radiat. Res. 177 (3) (2012) 265–271.

[111] P.F. Wilson, Magnification of inter-individual variation in biological responses

after low doses and dose-rates of ionizing radiation, Health Phys. 110 (3) (2016)

296–298.

[112] V. Jain, P.R. Kumar, P.K. Koya, G. Jaikrishan, B. Das, Lack of increased DNA

double-strand breaks in peripheral blood mononuclear cells of individuals from

high level natural radiation areas of Kerala coast in India, Mutat. Res. 788 (2016)

50–57.

[113] D. Billen, Spontaneous DNA damage and its significance for the "negligible dose"

controversy in radiation protection, Radiat. Res. 124 (2) (1990) 242–245.

[114] R.L. Saul, B.N. Ames, Background levels of DNA damage in the population, Basic

Life Sci. 38 (1986) 529–535.

[115] R.B. Setlow, DNA repair, aging, and cancer, Natl. Canc. Inst. Monogr. 60 (1982)

249–255.

[116] H.J. Muller, Artificial transmutation of the gene, Science 66 (1699) (1927) 84–87.

[117] K. Ogura, J. Magae, Y. Kawakami, T. Koana, Reduction in mutation frequency by

very low-dose gamma irradiation of Drosophila melanogaster germ cells, Radiat.

Res. 171 (1) (2009) 1–8.

[118] E.J. Calabrese, On the origins of the linear no-threshold (LNT) dogma by means of

untruths, artful dodges and blind faith, Environ. Res. 142 (2015) 432–442.

[119] K. Rothkamm, M. Lobrich, Evidence for a lack of DNA double-strand break repair

in human cells exposed to very low x-ray doses, Proc. Natl. Acad. Sci. U. S. A. 100

(9) (2003) 5057–5062.

[120] H.J. Muller, L.S. Altenburg, H.U. Meyer, M. Edmonson, E. Altenburg, The lack of

proportionality between mutation rate and ultraviolet dose in Drosophila,

Heredity 8 (2) (1954) 153–185.

[121] S.A. Amundson, R.A. Lee, C.A. Koch-Paiz, M.L. Bittner, P. Meltzer, J.M. Trent,

A.J. Fornace Jr., Differential responses of stress genes to low dose-rate gamma

irradiation, Mol. Canc. Res. 1 (6) (2003) 445–452.

[122] L. Ackermann, M. Schell, W. Pokrzywa, E. Kevei, A. Gartner, B. Schumacher,

T. Hoppe, E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-

break repair and apoptosis, Nat. Struct. Mol. Biol. 23 (11) (2016) 995–1002.

[123] S. Gasser, D.H. Raulet, The DNA damage response arouses the immune system,

Cancer Res. 66 (8) (2006) 3959–3962.

[124] R. Nakad, B. Schumacher, DNA damage response and immune defense: links and

mechanisms, Front. Genet. 7 (2016) 147, https://doi.org/10.3389/fgene.2016.

00147 [9 Aug 2016].

[125] I.S. Pateras, S. Havaki, X. Nikitopoulou, K. Vougas, P.A. Townsend,

M.I. Panayiotidis, A.G. Georgakilas, V.G. Gorgoulis, The DNA damage response

and immune signaling alliance: is it good or bad? Nature decides when and where,

Pharmacol. Ther. 154 (2015) 36–56.

[126] S.P. Jackson, J. Bartek, The DNA-damage response in human biology and disease,

Nature 461 (7267) (2009) 1071–1078.

[127] M. Sokolov, R. Neumann, Global gene expression alterations as a crucial con-

stituent of human cell response to low doses of ionizing radiation exposure, Int. J.

Mol. Sci. 17 (1) (2015), https://doi.org/10.3390/ijms17010055 [31 Dec 2015].

[128] R.C.C. Penha, S.C.S. Limab, L.F.R. Pintoc, A. Fuscod, Radiation-induced senes-

cence and thyroid cancer: a barrier or a driving force, Pajar 3 (1) (2015) 29–35.

[129] I. Ben-Porath, R.A. Weinberg, The signals and pathways activating cellular se-

nescence, Int. J. Biochem. Cell Biol. 37 (5) (2005) 961–976.

[130] J. Campisi, Cellular senescence as a tumor-suppressor mechanism, Trends Cell

Biol. 11 (11) (2001) S27–S31.

[131] W.E. Wright, J.W. Shay, Cellular senescence as a tumor-protection mechanism: the

essential role of counting, Curr. Opin. Genet. Dev. 11 (1) (2001) 98–103.

[132] A.R. Davalos, J.P. Coppe, J. Campisi, P.Y. Desprez, Senescent cells as a source of

inflammatory factors for tumor progression, Cancer Metastasis Rev. 29 (2) (2010)

273–283.

[133] K.S. Kulju, J.M. Lehman, Increased p53 protein associated with aging in human

diploid fibroblasts, Exp. Cell Res. 217 (2) (1995) 336–345.

[134] M. Narita, S. Nunez, E. Heard, M. Narita, A.W. Lin, S.A. Hearn, D.L. Spector,

G.J. Hannon, S.W. Lowe, Rb-mediated heterochromatin formation and silencing of

E2F target genes during cellular senescence, Cell 113 (6) (2003) 703–716.

[135] M.V. Blagosklonny, Cell senescence and hypermitogenic arrest, EMBO Rep. 4 (4)

(2003) 358–362.

[136] I.S. Mehta, M. Figgitt, C.S. Clements, I.R. Kill, J.M. Bridger, Alterations to nuclear

architecture and genome behavior in senescent cells, Ann. N. Y. Acad. Sci. 1100

(2007) 250–263.

[137] R.J. Sabin, R.M. Anderson, Cellular Senescence - its role in cancer and the response

to ionizing radiation, Genome Integr. 2 (1) (2011), https://doi.org/10.1186/2041-

9414-2-7 [11 Aug 2011].

[138] J.R. Smith, O.M. Pereira-Smith, Replicative senescence: implications for in vivo

aging and tumor suppression, Science 273 (5271) (1996) 63–67.

[139] M. Collado, M. Serrano, Senescence in tumours: evidence from mice and humans,

Nat. Rev. Canc. 10 (1) (2010) 51–57.

[140] B. Frey, S. Hehlgans, F. Rodel, U.S. Gaipl, Modulation of inflammation by low and

high doses of ionizing radiation: implications for benign and malign diseases,

Cancer Lett. 368 (2) (2015) 230–237.

[141] G. Bauer, Reactive oxygen and nitrogen species: efficient, selective, and interactive

signals during intercellular induction of apoptosis, Anticancer Res. 20 (6B) (2000)

4115–4139.

[142] M. Herdener, S. Heigold, M. Saran, G. Bauer, Target cell-derived superoxide anions

cause efficiency and selectivity of intercellular induction of apoptosis, Free Radic.

Biol. Med. 29 (12) (2000) 1260–1271.

[143] M.L. Hipp, G. Bauer, Intercellular induction of apoptosis in transformed cells does

not depend on p53, Oncogene 15 (7) (1997) 791–797.

[144] P. Kundrat, G. Bauer, P. Jacob, W. Friedland, Mechanistic modelling suggests that

the size of preneoplastic lesions is limited by intercellular induction of apoptosis in

oncogenically transformed cells, Carcinogenesis 33 (2) (2012) 253–259.

[145] P. Kundrat, W. Friedland, Impact of intercellular induction of apoptosis on low-

dose radiation carcinogenesis, Radiat. Protect. Dosim. 166 (1–4) (2015) 170–173.

[146] J. Panse, M.L. Hipp, G. Bauer, Fibroblasts transformed by chemical carcinogens

are sensitive to intercellular induction of apoptosis: implications for the control of

oncogenesis, Carcinogenesis 18 (2) (1997) 259–264.

[147] A. Shigematsu, Y. Adachi, N. Koike-Kiriyama, Y. Suzuki, M. Iwasaki, Y. Koike,

K. Nakano, H. Mukaide, M. Imamura, S. Ikehara, Effects of low-dose irradiation on

enhancement of immunity by dendritic cells, J. Radiat. Res. 48 (1) (2007) 51–55.

[148] T. Chittenden, E.A. Harrington, R. O'Connor, C. Flemington, R.J. Lutz, G.I. Evan,

B.C. Guild, Induction of apoptosis by the Bcl-2 homologue Bak, Nature 374 (6524)

(1995) 733–736.

[149] A.B. Abdelrazzak, D.L. Stevens, G. Bauer, P. O'Neill, M.A. Hill, The role of radia-

tion quality in the stimulation of intercellular induction of apoptosis in trans-

formed cells at very low doses, Radiat. Res. 176 (3) (2011) 346–355.

[150] K. Degenhardt, R. Mathew, B. Beaudoin, K. Bray, D. Anderson, G. Chen,

C. Mukherjee, Y. Shi, C. Gelinas, Y. Fan, et al., Autophagy promotes tumor cell

survival and restricts necrosis, inflammation, and tumorigenesis, Cancer Cell 10

(1) (2006) 51–64.

[151] S. Elmore, Apoptosis: a review of programmed cell death, Toxicol. Pathol. 35 (4)

(2007) 495–516.

[152] G. Liu, P. Gong, L.R. Bernstein, Y. Bi, S. Gong, L. Cai, Apoptotic cell death induced

by low-dose radiation in male germ cells: hormesis and adaptation, Crit. Rev.

Toxicol. 37 (7) (2007) 587–605.

[153] S.Z. Liu, On radiation hormesis expressed in the immune system, Crit. Rev.

Toxicol. 33 (3–4) (2003) 431–441.

[154] D.I. Portess, G. Bauer, M.A. Hill, P. O'Neill, Low-dose irradiation of non-

transformed cells stimulates the selective removal of precancerous cells via in-

tercellular induction of apoptosis, Cancer Res. 67 (3) (2007) 1246–1253.

[155] J. Temme, G. Bauer, Low-dose gamma irradiation enhances superoxide anion

production by nonirradiated cells through TGF-beta1-dependent bystander sig-

naling, Radiat. Res. 179 (4) (2013) 422–432.

[156] G. Bauer, Resistance to tgf-beta-induced elimination of transformed-cells is re-

quired during tumor progression (review-hypothesis), Int. J. Oncol. 6 (6) (1995)

1227–1229.

[157] G. Bauer, Elimination of transformed cells by normal cells: a novel concept for the

control of carcinogenesis, Histol. Histopathol. 11 (1) (1996) 237–255.

[158] E.I. Azzam, S.M. de Toledo, G.P. Raaphorst, R.E. Mitchel, Low-dose ionizing ra-

diation decreases the frequency of neoplastic transformation to a level below the

spontaneous rate in C3H 10T1/2 cells, Radiat. Res. 146 (4) (1996) 369–373.

[159] J.L. Redpath, R.J. Antoniono, Induction of an adaptive response against sponta-

neous neoplastic transformation in vitro by low-dose gamma radiation, Radiat.

Res. 149 (5) (1998) 517–520.

[160] J.L. Redpath, S.C. Short, M. Woodcock, P.J. Johnston, Low-dose reduction in

transformation frequency compared to unirradiated controls: the role of hyper-

radiosensitivity to cell death, Radiat. Res. 159 (3) (2003) 433–436.

[161] F. Rodel, B. Frey, U. Gaipl, L. Keilholz, C. Fournier, K. Manda, H. Schollnberger,

G. Hildebrandt, C. Rodel, Modulation of inflammatory immune reactions by low-

dose ionizing radiation: molecular mechanisms and clinical application, Curr.

Med. Chem. 19 (12) (2012) 1741–1750.

[162] V.R. Bruce, S.A. Belinsky, K. Gott, Y. Liu, T. March, B. Scott, J. Wilder, Low-dose

gamma-radiation inhibits benzo[a]pyrene-induced lung adenoma development in

a/j mice, Dose-Response 10 (4) (2012) 516–526.

[163] R.E. Thompson, Epidemiological evidence for possible radiation hormesis from

radon exposure: a case-control study conducted in Worcester, MA, Dose-Response

9 (1) (2010) 59–75.

[164] R.E. Thompson, D.F. Nelson, J.H. Popkin, Z. Popkin, Case-control study of lung

cancer risk from residential radon exposure in Worcester county, Massachusetts,

Health Phys. 94 (3) (2008) 228–241.

[165] W. Chen, X. Xu, L. Bai, M.T. Padilla, K.M. Gott, S. Leng, C.S. Tellez, J.A. Wilder,

S.A. Belinsky, B.R. Scott, et al., Low-dose gamma-irradiation inhibits IL-6 secretion

from human lung fibroblasts that promotes bronchial epithelial cell transforma-

tion by cigarette-smoke carcinogen, Carcinogenesis 33 (7) (2012) 1368–1374.

[166] S. Vicent, L.C. Sayles, D. Vaka, P. Khatri, O. Gevaert, R. Chen, Y. Zheng,

A.K. Gillespie, N. Clarke, Y. Xu, et al., Cross-species functional analysis of cancer-

associated fibroblasts identifies a critical role for CLCF1 and IL-6 in non-small cell

lung cancer in vivo, Cancer Res. 72 (22) (2012) 5744–5756.

[167] A. Farooque, R. Mathur, A. Verma, V. Kaul, A.N. Bhatt, J.S. Adhikari, F. Afrin,

S. Singh, B.S. Dwarakanath, Low-dose radiation therapy of cancer: role of immune

enhancement, Expert Rev. Anticancer Ther. 11 (5) (2011) 791–802.

[168] H. Ren, J. Shen, C. Tomiyama-Miyaji, M. Watanabe, E. Kainuma, M. Inoue,

Y. Kuwano, T. Abo, Augmentation of innate immunity by low-dose irradiation,

Cell. Immunol. 244 (1) (2006) 50–56.

[169] Y. Zhang, S.Z. Liu, Effect of low dose radiation on immune functions of tumor-

bearing mice, Chin J Radiol Health 5 (1996) 235–237.

[170] M.K. Janiak, M. Wincenciak, A. Cheda, E.M. Nowosielska, E.J. Calabrese, Cancer

immunotherapy: how low-level ionizing radiation can play a key role, Cancer

Immunol. Immunother. 66 (7) (2017) 819–832.

[171] M. Mifune, T. Sobue, H. Arimoto, Y. Komoto, S. Kondo, H. Tanooka, Cancer

B.R. Scott and S. Tharmalingam Chemico-Biological Interactions 301 (2019) 34–53

52

mortality survey in a spa area (Misasa, Japan) with a high radon background, Jpn.

J. Canc. Res. 83 (1) (1992) 1–5.

[172] K.S. Nambi, S.D. Soman, Environmental radiation and cancer in India, Health

Phys. 52 (5) (1987) 653–657.

[173] L.X. Wei, Y.R. Zha, Z.F. Tao, W.H. He, D.Q. Chen, Y.L. Yuan, Epidemiological

investigation of radiological effects in high background radiation areas of

Yangjiang, China, J. Radiat. Res. 31 (1) (1990) 119–136.

[174] S.Z. Liu, G.Z. Xu, X.Y. Li, A restudy of the immune functions of inhabitants in an

area of high natural radioactivity in Guangdong, Chin J Radiol Med Prot 5 (1985)

124–127.

[175] G.M. Kendall, C.R. Muirhead, B.H. MacGibbon, J.A. O'Hagan, A.J. Conquest,

A.A. Goodill, B.K. Butland, T.P. Fell, D.A. Jackson, M.A. Webb, et al., Mortality

and occupational exposure to radiation: first analysis of the National Registry for

Radiation Workers, BMJ 304 (6821) (1992) 220–225.

[176] S.Z. Liu, L. Cai, S.Q. Sun, Induction of a cytogenetic adaptive response by exposure

of rabbits to very low dose-rate gamma-radiation, Int. J. Radiat. Biol. 62 (2)

(1992) 187–190.

[177] A.B. Miller, G.R. Howe, G.J. Sherman, J.P. Lindsay, M.J. Yaffe, P.J. Dinner,

H.A. Risch, D.L. Preston, Mortality from breast cancer after irradiation during

fluoroscopic examinations in patients being treated for tuberculosis, N. Engl. J.

Med. 321 (19) (1989) 1285–1289.

[178] A. Safwat, The role of low-dose total body irradiation in treatment of non-

Hodgkin's lymphoma: a new look at an old method, Radiother. Oncol. 56 (1)

(2000) 1–8.

[179] A. Fourquet, J.L. Teillaud, D. Lando, W.H. Fridman, Effects of low dose total body

irradiation (LDTBI) and recombinant human interleukin-2 in mice, Radiother.

Oncol. 26 (3) (1993) 219–225.

[180] R. Liu, S. Xiong, L. Zhang, Y. Chu, Enhancement of antitumor immunity by low-

dose total body irradiationis associated with selectively decreasing the proportion

and number of T regulatory cells, Cell. Mol. Immunol. 7 (2) (2010) 157–162.

[181] X.Y. Li, Y.B. Chen, F.Q. Xia, Effect of low dose radiation on growth of implanted

tumor and cancer induction in mice, Chin J Radiol Health 5 (1996) 21–23.

[182] S.Z. Liu, Nonlinear dose-response relationship in the immune system following

exposure to ionizing radiation: mechanisms and implications, Nonlinearity Biol.

Toxicol. Med. 1 (1) (2003) 71–92.

[183] S. Kojima, K. Nakayama, H. Ishida, Low dose gamma-rays activate immune

functions via induction of glutathione and delay tumor growth, J. Radiat. Res. 45

(1) (2004) 33–39.

[184] R. Pandey, B.S. Shankar, D. Sharma, K.B. Sainis, Low dose radiation induced im-

munomodulation: effect on macrophages and CD8+ T cells, Int. J. Radiat. Biol. 81

(11) (2005) 801–812.

[185] D.S. Gridley, M.J. Pecaut, A. Rizvi, G.B. Coutrakon, X. Luo-Owen, A.Y. Makinde,

J.M. Slater, Low-dose, low-dose-rate proton radiation modulates CD4(+ ) T cell

gene expression, Int. J. Radiat. Biol. 85 (3) (2009) 250–261.

[186] H. Hayase, Y. Ohshima, M. Takahashi, S. Kojima, The enhancement of Th1 im-

munity and the suppression of tumour growth by low-dose γ-radiation, Int. J. Low

Radiat. 5 (4) (2008) 275–298.

[187] Z.Y. Chen, M. Zhang, J.X. Liu, Effects of low dose irradiation on splenic macro-

phage functions in mice, J. Radiat. Res. 13 (1996) 187–189.

[188] Y.G. Yang, S.Z. Liu, Effect of whole-body x-irradiation on IFNγ production by

splenocytes, J. Norman Bethune Univ. Med. Sci. 15 (Suppl) (1989) 11–13.

[189] Y.M. Sun, S.Z. Liu, Changes in TNFα expression in mouse peritoneal macrophages

after whole body x-ray irradiation, J. Radiat. Res. 18 (2000) 235–239.

[190] F. Klug, H. Prakash, P.E. Huber, T. Seibel, N. Bender, N. Halama, C. Pfirschke,

R.H. Voss, C. Timke, L. Umansky, et al., Low-dose irradiation programs macro-

phage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T

cell immunotherapy, Cancer Cell 24 (5) (2013) 589–602.

[191] E.M. Nowosielska, J. Wrembel-Wargocka, A. Cheda, E. Lisiak, M.K. Janiak,

Enhanced cytotoxic activity of macrophages and suppressed tumor metastases in

mice irradiated with low doses of X- rays, J. Radiat. Res. 47 (3–4) (2006) 229–236.

[192] L. Zhou, X. Zhang, H. Li, C. Niu, D. Yu, G. Yang, X. Liang, X. Wen, M. Li, J. Cui,

Validating the pivotal role of the immune system in low-dose radiation-induced

tumor inhibition in Lewis lung cancer-bearing mice, Cancer Med 7 (4) (2018)

1338–1348.

[193] M. Nenoi, B. Wang, G. Vares, In vivo radioadaptive response: a review of studies

relevant to radiation-induced cancer risk, Hum. Exp. Toxicol. 34 (3) (2015)

272–283.

[194] T.K. Day, G. Zeng, A.M. Hooker, M. Bhat, B.R. Scott, D.R. Turner, P.J. Sykes,

Adaptive response for chromosomal inversions in pKZ1 mouse prostate induced by

low doses of X radiation delivered after a high dose, Radiat. Res. 167 (6) (2007)

682–692.

[195] D. Bhattacharjee, Role of radioadaptation on radiation-induced thymic lymphoma

in mice, Mutat. Res. 358 (2) (1996) 231–235.

[196] Y. Ina, H. Tanooka, T. Yamada, K. Sakai, Suppression of thymic lymphoma in-

duction by life-long low-dose-rate irradiation accompanied by immune activation

in C57BL/6 mice, Radiat. Res. 163 (2) (2005) 153–158.

[197] R.E. Mitchel, J.S. Jackson, R.A. McCann, D.R. Boreham, The adaptive response

modifies latency for radiation-induced myeloid leukemia in CBA/H mice, Radiat.

Res. 152 (3) (1999) 273–279.

[198] R.E. Mitchel, J.S. Jackson, D.P. Morrison, S.M. Carlisle, Low doses of radiation

increase the latency of spontaneous lymphomas and spinal osteosarcomas in

cancer-prone, radiation-sensitive Trp53 heterozygous mice, Radiat. Res. 159 (3)

(2003) 320–327.

[199] R.E. Mitchel, Low doses of radiation reduce risk in vivo, Dose Response 5 (1)

(2006) 1–10.

[200] S. Kakinuma, K. Yamauchi, Y. Amasaki, M. Nishimura, Y. Shimada, Low-dose

radiation attenuates chemical mutagenesis in vivo, J. Radiat. Res. 50 (5) (2009)

401–405.

[201] E. Calabrese, The linear no-threshold (LNT) dose response model: a comprehensive

assessment of its historical and scientific foundations, Chem. Biol. Interact. (2019)

(this issue).

[202] D. Costantini, B. Borremans, The linear no-threshold model is less realistic than

threshold or hormesis-based models: an evolutionary perspective, Chem. Biol.

Interact. (2019) (this issue).

[203] P.F. Ricci, S. Tharmalingam, Ionizing radiations epidemiology does not support

the LNT model, Chem. Biol. Interact. (2018) (this issue).

[204] S. Tharmalingam, S. Sreetharan, A.L. Brooks, D.R. Boreham, Re-evaluation of the

linear no-threshold (LNT) model using new paradigms and modern molecular

studies, Chem. Biol. Interact. (2018) (this issue).

[205] A.M. Zarnke, S. Tharmalingam, D.R. Boreham, A.L. Brooks, BEIR VI Radon: the

rest of the story, Chem. Biol. Interact. (2018) (this issue).

[206] V.V. Frolkis, Stress-age syndrome, Mech. Ageing Dev. 69 (1–2) (1993) 93–107.

[207] R. Arking, C. Giroux, Antioxidant genes, hormesis, and demographic longevity, J.

Anti Aging Med. 4 (2) (2001) 125–136.

[208] C. Harding, F. Pompei, E.E. Lee, R. Wilson, Cancer suppression at old age, Cancer

Res. 68 (11) (2008) 4465–4478.

[209] R.R. Langley, I.J. Fidler, Tumor cell-organ microenvironment interactions in the

pathogenesis of cancer metastasis, Endocr. Rev. 28 (3) (2007) 297–321.

[210] C. Lopez-Otin, M.A. Blasco, L. Partridge, M. Serrano, G. Kroemer, The hallmarks of

aging, Cell 153 (6) (2013) 1194–1217.

[211] P. Shaw, A. Duncan, A. Vouyouka, K. Ozsvath, Radiation exposure and pregnancy,

J. Vasc. Surg. 53 (1 Suppl) (2011) 28S–34S.

[212] C.E. Boklage, Survival probability of human conceptions from fertilization to term,

Int. J. Fertil. 35 (2) (1990) 81–94 75, 79-80.

[213] R.L. Brent, The effect of embryonic and fetal exposure to x-ray, microwaves, and

ultrasound: counseling the pregnant and nonpregnant patient about these risks,

Semin. Oncol. 16 (5) (1989) 347–368.

[214] R.L. Brent, Carcinogenic risks of prenatal ionizing radiation, Semin. Fetal Neonatal

Med. 19 (3) (2014) 203–213.

[215] R.L. Brent, Protection of the gametes embryo/fetus from prenatal radiation ex-

posure, Health Phys. 108 (2) (2015) 242–274.

[216] J. Vieira Dias, C. Gloaguen, D. Kereselidze, L. Manens, K. Tack, T.G. Ebrahimian,

Gamma low-dose-rate ionizing radiation stimulates adaptive functional and mo-

lecular response in human aortic endothelial cells in a threshold-, dose-, and dose

rate-dependent manner, Dose-Response 16 (1) (2018), https://doi.org/10.1177/

1559325818755238 [4 Mar 2018].

[217] B.A. Ulsh, Checking the foundation: recent radiobiology and the linear no-

threshold theory, Health Phys. 99 (6) (2010) 747–758.

[218] M.H. Barcellos-Hoff, E.A. Blakely, S. Burma, A.J. Fornace Jr., S. Gerson, L. Hlatky,

D.G. Kirsch, U. Luderer, J. Shay, Y. Wang, et al., Concepts and challenges in cancer

risk prediction for the space radiation environment, Life Sci. Space Res. 6 (2015)

92–103.

[219] C.L. Sanders, B.R. Scott, Smoking and hormesis as confounding factors in radiation

pulmonary carcinogenesis, Dose-Response. 6 (1) (2006) 53–79.

[220] T.K. Day, G. Zeng, A.M. Hooker, M. Bhat, B.R. Scott, D.R. Turner, P.J. Sykes,

Extremely low priming doses of X radiation induce an adaptive response for

chromosomal inversions in pKZ1 mouse prostate, Radiat. Res. 166 (5) (2006)

757–766.

[221] B.R. Scott, Stochastic thresholds: a novel explanation of nonlinear dose-response

relationships for stochastic radiobiological effects, Dose Response 3 (4) (2006)

547–567.

[222] S.H. Moolgavkar, D.J. Venzon, General relative risk regression models for epide-

miologic studies, Am. J. Epidemiol. 126 (5) (1987) 949–961.

[223] S.H. Moolgavkar, A.G. Knudson Jr., Mutation and cancer: a model for human

carcinogenesis, J. Natl. Cancer Inst. 66 (6) (1981) 1037–1052.

[224] M.S. Sasaki, A. Tachibana, S. Takeda, Cancer risk at low doses of ionizing radia-

tion: artificial neural networks inference from atomic bomb survivors, J. Radiat.

Res. 55 (3) (2014) 391–406.

[225] S. Sutou, Rediscovery of an old article reporting that the area around the epicenter

in Hiroshima was heavily contaminated with residual radiation, indicating that

exposure doses of A-bomb survivors were largely underestimated, J. Radiat. Res.

58 (5) (2017) 745–754.

[226] H. Schollnberger, P.M. Eckl, Protective bystander effects simulated with the state-

vector model, Dose Response 5 (3) (2007) 187–203.

[227] H. Schollnberger, R.E. Mitchel, J.L. Redpath, D.J. Crawford-Brown, W. Hofmann,

Detrimental and protective bystander effects: a model approach, Radiat. Res. 168

(5) (2007) 614–626.

[228] L. Fleishman, D. Crawford-Brown, W. Hofmann, A computational model for ra-

diation-induced cellular transformation to in vitro irradiation of cells by acute

doses of X-rays, Math. Biosci. 215 (2) (2008) 186–192.

[229] A.B. Hill, The environment and disease: association or causation? Proc. Roy. Soc.

Med. 58 (1965) 295–300.

[230] B.A. Ulsh, The new radiobiology: returning to our roots, Dose-Response 10 (4)

(2012) 593–609.

[231] M.P. Little, J.H. Hendry, J.S. Puskin, Lack of Correlation between stem-cell pro-

liferation and radiation- or smoking-associated cancer risk, PLoS One 11 (3)

(2016) e0150335, , https://doi.org/10.1371/journal.pone.0150335.

[232] M. Tubiana, L.E. Feinendegen, C. Yang, J.M. Kaminski, The linear no-threshold

relationship is inconsistent with radiation biologic and experimental data,

Radiology 251 (1) (2009) 13–22, https://doi.org/10.1148/radiol.2511080671.

[233] B.R. Scott, Avoiding diagnostic imaging may be the real health risk, not imaging, J

Am Physicians Surg 21 (3) (2016) 74–80.

B.R. Scott and S. Tharmalingam Chemico-Biological Interactions 301 (2019) 34–53

53