Editing Radiation hormesis (section)

== Proposed mechanism and ongoing debate ==
[[Image:Hormesis dose response graph.svg|220px|thumb|left|A very low dose of a chemical agent may trigger from an [[organism]] the opposite response to a very high dose.]]
Radiation hormesis proposes that radiation exposure comparable to and just above the natural [[background radiation|background level of radiation]] is not harmful but beneficial, while accepting that much higher levels of radiation are hazardous. Proponents of radiation hormesis typically claim that radio-protective responses in cells and the immune system not only counter the harmful effects of radiation but additionally act to inhibit spontaneous cancer not related to radiation exposure. Radiation hormesis stands in stark contrast to the more generally accepted [[linear no-threshold model]] (LNT), which states that the radiation dose-risk relationship is linear across all doses, so that small doses are still damaging, albeit less so than higher ones. Opinion pieces on chemical and radiobiological hormesis appeared in the journals [[Nature (journal)|Nature]]<ref name="Calabrese"/> and [[Science (journal)|Science]]<ref name ="Kaiser"/> in 2003.

Assessing the risk of radiation at low doses (<100 [[Sievert|mSv]]) and low dose rates (<0.1 [[Sievert|mSv]].min<sup>−1</sup>) is highly problematic and controversial.<ref name=Mullenders>{{cite journal |doi=10.1038/nrc2677 |title=Assessing cancer risks of low-dose radiation |year=2009 |last1=Mullenders |first1=Leon |last2=Atkinson |first2=Mike |last3=Paretzke |first3=Herwig |last4=Sabatier |first4=Laure |last5=Bouffler |first5=Simon |journal=Nature Reviews Cancer |volume=9 |issue=8 |pages=596–604 |pmid=19629073|s2cid=10610131 }}</ref><ref name=Tubiana>{{cite journal |doi=10.1148/radiol.2511080671 |title=The Linear No-Threshold Relationship is Inconsistent with Radiation Biologic and Experimental Data1 |year=2009 |last1=Tubiana |first1=M. |last2=Feinendegen |first2=L. E. |last3=Yang |first3=C. |last4=Kaminski |first4=J. M. |journal=Radiology |volume=251 |pages=13–22 |pmid=19332842 |issue=1 |pmc=2663584}}</ref> While [[epidemiological]] studies on populations of people exposed to an acute dose of high level radiation such as [[Hibakusha|Japanese atomic bomb survivors]] ({{nihongo|hibakusha|被爆者}}) have robustly upheld the [[linear no-threshold model|LNT]] (mean dose ~210 mSv),<ref name=Samartzis>{{cite journal |doi=10.2106/JBJS.J.00256 |title=Exposure to Ionizing Radiation and Development of Bone Sarcoma: New Insights Based on Atomic-Bomb Survivors of Hiroshima and Nagasaki |year=2011 |last1=Samartzis |first1=Dino |journal=The Journal of Bone and Joint Surgery. American Volume |volume=93 |issue=11 |pages=1008–15 |pmid=21984980 |last2=Nishi |first2=N |last3=Hayashi |first3=M |last4=Cologne |first4=J |last5=Cullings |first5=HM |last6=Kodama |first6=K |last7=Miles |first7=EF |last8=Funamoto |first8=S |last9=Suyama |first9=A|last10=Soda |first10=M |last11=Kasagi |first11=F |display-authors=8 |citeseerx=10.1.1.1004.393 }}</ref> studies involving low doses and low dose rates have failed to detect any increased cancer rate.<ref name="Tubiana"/> This is because the baseline cancer rate is already very high (~42 of 100 people will be diagnosed in their lifetime) and it fluctuates ~40% because of lifestyle and environmental effects,<ref name="parkin2011"/><ref name=Boice2012>{{cite journal |doi=10.1088/0952-4746/32/1/N33 |title=Radiation epidemiology: A perspective on Fukushima |year=2012 |last1=Boice Jr |first1=John D |journal=Journal of Radiological Protection |volume=32 |pages=N33–40 |pmid=22395193 |issue=1|s2cid=250881575 }}</ref> obscuring the subtle effects of low level radiation. Epidemiological studies may be capable of detecting elevated cancer rates as low as 1.2 to 1.3 ''i.e.'' 20% to 30% increase. But for low doses (1–100 mSv) the predicted elevated risks are only 1.001 to 1.04 and excess cancer cases, if present, cannot be detected due to confounding factors, errors and biases.<ref name=Boice2012/><ref name=Boice>{{cite journal |bibcode=2010JRP....30..115B |title=Invited Editorial: Uncertainties in studies of low statistical power Uncertainties in studies of low statistical power |last1=Boice |first1=John D. |volume=30 |year=2010 |pages=115–20 |journal=Journal of Radiological Protection |doi=10.1088/0952-4746/30/2/E02 |pmid=20548136 |issue=2|s2cid=36270712 |doi-access=free }}</ref><ref>{{cite journal | doi = 10.2203/dose-response.09-019.Fornalski | pmid=20585442 | title = The Healthy Worker Effect and Nuclear Industry Workers | journal = Dose-Response| volume = 8| issue = 2| pages = 125–47| year = 2010 | last1 = Fornalski | first1 = K. W. | last2 = Dobrzyński | first2 = L. | pmc=2889508}}</ref>

In particular, variations in smoking prevalence or even accuracy in reporting smoking cause wide variation in excess cancer and measurement error bias. Thus, even a large study of many thousands of subjects with imperfect smoking prevalence information will fail to detect the effects of low level radiation than a smaller study that properly compensates for smoking prevalence.<ref>{{cite journal |doi=10.1097/00004032-199012000-00004 |title=Design Issues in Epidemiologic Studies of Indoor Exposure to Rn and Risk of Lung Cancer |year=1990 |last1=Lubin |first1=Jay H. |last2=Samet |first2=Jonathan M. |last3=Weinberg |first3=Clarice|author3-link=Clarice Weinberg |journal=Health Physics |volume=59 |issue=6 |pages=807–17 |pmid=2228608}}</ref> Given the absence of direct epidemiological evidence, there is considerable debate as to whether the dose-response relationship <100 mSv is supralinear, linear (LNT), has a threshold, is ''sub-linear'', or whether the coefficient is negative with a sign change, i.e. a hormetic response.

The radiation [[adaptive response]] seems to be a main origin of the potential hormetic effect. The theoretical studies indicate that the adaptive response is responsible for the shape of dose-response curve and can transform the linear relationship (LNT) into the hormetic one.<ref>{{cite journal | doi = 10.1667/RR14302.1 |pmid=27588596 | title = Modeling of Irradiated Cell Transformation: Dose- and Time-Dependent Effects | journal = Radiation Research | volume = 186| issue = 4| pages = 396–406| year = 2016 | last1 = Dobrzyński | first1 = L. | last2 = Fornalski | first2 = K. W. | last3 = Socol | first3 = Y. | last4 = Reszczyńska | first4 = J. M.| bibcode = 2016RadR..186..396D |s2cid=41033441 }}</ref><ref>{{cite journal |doi=10.1103/PhysRevE.99.022139 | vauthors = Fornalski KW |title=Radiation adaptive response and cancer: from the statistical physics point of view |volume=99 |issue=2 |journal=Physical Review E |date=2019| page = 022139 | pmid = 30934317 | bibcode = 2019PhRvE..99b2139F | s2cid = 91187501 }}</ref>

While most major consensus reports and government bodies currently adhere to LNT,<ref>{{cite journal |doi=10.1097/00004032-199810000-00001 |title=From Chimney Sweeps to Astronauts |year=1998 |last1=Hall |first1=Eric J. |journal=Health Physics |volume=75 |issue=4 |pages=357–66 |pmid=9753358|s2cid=30056597 }}</ref> the 2005 [[French Academy of Sciences]]-[[Académie Nationale de Médecine|National Academy of Medicine]]'s report concerning the effects of low-level radiation rejected LNT as a scientific model of [[carcinogenic]] risk at low doses.<ref name="Aurengo"/>

<blockquote>Using LNT to estimate the carcinogenic effect at doses of less than 20 mSv is not justified in the light of current radiobiologic knowledge.</blockquote>

They consider there to be several dose-effect relationships rather than only one, and that these relationships have many variables such as target tissue, radiation dose, dose rate and individual sensitivity factors. They request that further study is required on low doses (less than 100 [[Sievert|mSv]]) and very low doses (less than 10 [[Sievert|mSv]]) as well as the impact of tissue type and age. The Academy considers the LNT model is only useful for regulatory purposes as it simplifies the administrative task. Quoting results from literature research,<ref name="Calabrese2"/><ref name="Duport"/> they furthermore claim that approximately 40% of laboratory studies on cell cultures and animals indicate some degree of chemical or radiobiological hormesis, and state:

<blockquote>...its existence in the laboratory is beyond question and its mechanism of action appears well understood.</blockquote>

They go on to outline a growing body of research that illustrates that the human body is not a passive accumulator of [[ionizing radiation|radiation]] damage but it actively repairs the damage caused via a number of different processes, including:<ref name="Aurengo"/><ref name="Tubiana"/>

* Mechanisms that mitigate [[reactive oxygen]] species generated by ionizing radiation and [[oxidative stress]].
* [[Apoptosis]] of radiation damaged cells that may undergo [[tumorigenesis]] is initiated at only few mSv.
* Cell death during [[meiosis]] of radiation damaged cells that were unsuccessfully repaired.
* The existence of a [[cellular signaling]] system that alerts neighboring cells of cellular damage.
* The activation of [[Enzyme|enzymatic]] [[DNA repair]] mechanisms around 10 mSv.
* Modern [[DNA microarray]] studies which show that numerous [[genes]] are activated at [[Ionizing radiation|radiation]] doses well below the level that [[mutagenesis]] is detected.
* [[Ionizing radiation|Radiation]]-induced [[tumorigenesis]] may have a threshold related to damage density, as revealed by experiments that employ blocking grids to thinly distribute [[Ionizing radiation|radiation]].
* A large increase in tumours in [[immunosuppressed]] individuals illustrates that the immune system efficiently destroys aberrant cells and nascent tumors.

Furthermore, increased sensitivity to radiation induced cancer in the inherited condition [[Ataxia-telangiectasia#Differential Diagnosis|Ataxia-telangiectasia like disorder]], illustrates the damaging effects of loss of the repair gene [[HMre11|Mre11h]] resulting in the inability to fix DNA double-strand breaks.<ref name=Stewart1>{{cite journal |doi=10.1016/S0092-8674(00)81547-0 |title=The DNA Double-Strand Break Repair Gene hMRE11 is Mutated in Individuals with an Ataxia-Telangiectasia-like Disorder |year=1999 |last1=Stewart |first1=G |journal=Cell |volume=99 |issue=6 |pages=577–87 |pmid=10612394 |last2=Maser |first2=RS |last3=Stankovic |first3=T |last4=Bressan |first4=DA |last5=Kaplan |first5=MI |last6=Jaspers |first6=NG |last7=Raams |first7=A |last8=Byrd |first8=PJ |last9=Petrini |first9=JH|last10=Taylor |first10=A. M. |display-authors=8 |doi-access=free }}</ref>

The BEIR-VII report argued that, "the presence of a true dose threshold demands totally error-free DNA damage response and repair." The specific damage they worry about is double strand breaks (DSBs) and they continue, "error-prone nonhomologous end joining (NHEJ) repair in postirradiation cellular response, argues strongly against a DNA repair-mediated low-dose threshold for cancer initiation".<ref>{{harvnb|BEIR VII Phase 2|2006|p=245}}</ref> Recent research observed that DSBs caused by [[CAT scans]] are repaired within 24 hours and DSBs may be more efficiently repaired at low doses, suggesting that the risk of ionizing radiation at low doses may not be directly proportional to the dose.<ref name="Löbrich2005">{{cite journal |bibcode=2005PNAS..102.8984L |title=In vivo formation and repair of DNA double-strand breaks after computed tomography examinations |last1=Löbrich |first1=Markus |last2=Rief |first2=Nicole |last3=Kühne |first3=Martin |last4=Heckmann |first4=Martina |last5=Fleckenstein |first5=Jochen |last6=Rübe |first6=Christian |last7=Uder |first7=Michael |volume=102 |year=2005 |pages=8984–89 |journal=Proceedings of the National Academy of Sciences |doi=10.1073/pnas.0501895102 |issue=25 |pmid=15956203 |pmc=1150277|doi-access=free }}</ref><ref name=Neumaier2011>{{cite journal |bibcode=2012PNAS..109..443N |title=Evidence for formation of DNA repair centers and dose-response nonlinearity in human cells |last1=Neumaier |first1=T. |last2=Swenson |first2=J. |last3=Pham |first3=C. |last4=Polyzos |first4=A. |last5=Lo |first5=A. T. |last6=Yang |first6=P. |last7=Dyball |first7=J. |last8=Asaithamby |first8=A. |last9=Chen |first9=D. J. |last10=Bissell |first10=M. J. |last11=Thalhammer |first11=S. |last12=Costes |first12=S. V. |volume=109 |year=2012 |pages=443–48 |journal=Proceedings of the National Academy of Sciences |doi=10.1073/pnas.1117849108 |issue=2 |pmid=22184222 |pmc=3258602|display-authors=8 |doi-access=free }}</ref> However, it is not known if low-dose ionizing radiation stimulates the repair of DSBs not caused by ionizing radiation ''i.e.'' a hormetic response. 
 
Radon gas in homes is the largest source of radiation dose for most individuals and it is generally advised that the concentration be kept below 150 Bq/m³ (4 pCi/L).<ref>{{cite web |url=http://www.surgeongeneral.gov/pressreleases/sg01132005.html |title=Surgeon General Releases National Health Advisory On Radon |access-date=28 November 2008 |publisher=US HHS Office of the Surgeon General |date=January 12, 2005  |archive-url=https://web.archive.org/web/20080516195401/http://www.surgeongeneral.gov/pressreleases/sg01132005.html |archive-date=16 May 2008 }}</ref> A recent retrospective case-control study of lung cancer risk showed substantial cancer rate reduction between 50 and 123 Bq per cubic meter relative to a group at zero to 25 Bq per cubic meter.<ref>{{cite journal |doi=10.1097/01.HP.0000288561.53790.5f |title=Case-Control Study of Lung Cancer Risk from Residential Radon Exposure in Worcester County, Massachusetts |year=2008 |last1=Thompson |first1=Richard E. |last2=Nelson |first2=Donald F. |last3=Popkin |first3=Joel H. |last4=Popkin |first4=Zenaida |journal=Health Physics |volume=94 |issue=3 |pages=228–41 |pmid=18301096|s2cid=21134066 }}</ref> This study is cited as evidence for hormesis, but a single study all by itself cannot be regarded as definitive. Other studies into the effects of domestic [[radon]] exposure have not reported a hormetic effect; including for example the respected "Iowa Radon Lung Cancer Study" of Field et al. (2000), which also used sophisticated radon exposure [[dosimetry]].<ref>{{cite journal |doi=10.1093/oxfordjournals.aje.a010153 |title=Residential Radon Gas Exposure and Lung Cancer: The Iowa Radon Lung Cancer Study |year=2000 |last1=Field |first1=R. W. |last2=Steck |first2=D. J. |last3=Smith |first3=B. J. |last4=Brus |first4=C. P. |last5=Fisher |first5=E. L. |last6=Neuberger |first6=J. S. |last7=Platz |first7=C. E. |last8=Robinson |first8=R. A. |last9=Woolson |first9=R. F. |last10=Lynch |first10=C. F. |journal=American Journal of Epidemiology |volume=151 |issue=11 |pages=1091–102 |pmid=10873134|display-authors=8 |doi-access=free }}</ref> In addition, Darby et al. (2005) argue that radon exposure is negatively correlated with the tendency to smoke and environmental studies need to accurately control for this; people living in urban areas where smoking rates are higher usually have lower levels of radon exposure due to the increased prevalence of multi-story dwellings.<ref name=Darby>{{cite journal |doi=10.1136/bmj.38308.477650.63 |title=Radon in homes and risk of lung cancer: Collaborative analysis of individual data from 13 European case-control studies |year=2005 |last1=Darby |first1=S |journal=BMJ |volume=330 |issue=7485 |page=223 |pmid=15613366 |last2=Hill |first2=D |last3=Auvinen |first3=A |last4=Barros-Dios |first4=JM |last5=Baysson |first5=H |last6=Bochicchio |first6=F |last7=Deo |first7=H |last8=Falk |first8=R |last9=Forastiere |first9=F |last10=Hakama |first10=M |last11=Heid |first11=I |last12=Kreienbrock |first12=L |last13=Kreuzer |first13=M |last14=Lagarde |first14=F |last15=Mäkeläinen |first15=I |last16=Muirhead |first16=C |last17=Oberaigner |first17=W |last18=Pershagen |first18=G |last19=Ruano-Ravina |first19=A |last20=Ruosteenoja |first20=E |last21=Rosario |first21=A. S. |last22=Tirmarche |first22=M |last23=Tomásek |first23=L |last24=Whitley |first24=E |last25=Wichmann |first25=H. E. |last26=Doll |first26=R |pmc=546066|display-authors=8 }}</ref>  When doing so, they found a significant increase in lung cancer amongst smokers exposed to radon at doses as low as 100 to 199 Bq m<sup>−3</sup> and warned that smoking greatly increases the risk posed by radon exposure ''i.e.'' reducing the prevalence of smoking would decrease deaths caused by radon.<ref name=Darby/><ref name=Mendez>{{cite journal |doi=10.2105/AJPH.2009.189225 |title=The Impact of Declining Smoking on Radon-Related Lung Cancer in the United States |year=2011 |last1=Méndez |first1=David |last2=Alshanqeety |first2=Omar |last3=Warner |first3=Kenneth E. |last4=Lantz |first4=Paula M. |last5=Courant |first5=Paul N. |journal=American Journal of Public Health |volume=101 |issue=2 |pages=310–14 |pmid=21228294 |pmc=3020207}}</ref> However, the discussion about the opposite experimental results is still going on,<ref>{{cite journal |last=Fornalski |first=K. W. |author2=Adams, R. |author3=Allison, W. |author4=Corrice, L. E. |author5=Cuttler, J. M. |author6=Davey, Ch. |author7=Dobrzyński, L. |author8=Esposito, V. J. |author9=Feinendegen, L. E. |author10=Gomez, L. S. |author11=Lewis, P. |author12=Mahn, J. |author13=Miller, M. L. |author14=Pennington, Ch. W. |author15=Sacks, B. |author16=Sutou, S. |author17=Welsh, J. S. |pmid=26223888 |title=The assumption of radon-induced cancer risk |year=2015 |journal=Cancer Causes & Control |doi=10.1007/s10552-015-0638-9 |issue=26 |volume=10 |pages=1517–18|s2cid=15952263 }}</ref> especially the popular US and German studies have found some hormetic effects.<ref>{{cite journal |author=Cohen BL |title=Test of the linear-no threshold theory of radiation carcinogenesis for inhaled radon decay products |journal=Health Phys |volume=68 |issue=2|year=1995 |pmid=7814250 |url=http://www.phyast.pitt.edu/%7Eblc/LNT-1995.PDF |doi=10.1097/00004032-199502000-00002 |pages=157–74|s2cid=41388715 }}</ref><ref>{{cite journal |last=Becker |first=K. |pmid=19330110 |pmc=2651614 |title=Health Effects of High Radon Environments in Central Europe: Another Test for the LNT Hypothesis? |year=2003 |journal=Nonlinearity Biol Toxicol Med |issue=1 |volume=1 |pages=3–35|doi=10.1080/15401420390844447 }}</ref>

Furthermore, particle microbeam studies show that passage of even a single alpha particle (e.g. from radon and its progeny) through cell nuclei is highly mutagenic,<ref name="pmid9108052">{{cite journal |bibcode=1997PNAS...94.3765H |title=Mutagenic Effects of a Single and an Exact Number of α Particles in Mammalian Cells |last1=Hei |first1=Tom K. |last2=Wu |first2=Li-Jun |last3=Liu |first3=Su-Xian |last4=Vannais |first4=Diane |last5=Waldren |first5=Charles A. |last6=Randers-Pehrson |first6=Gerhard |volume=94 |year=1997 |pages=3765–70 |journal=Proceedings of the National Academy of Sciences of the United States of America |doi=10.1073/pnas.94.8.3765 |pmid=9108052 |issue=8 |pmc=20515|doi-access=free }}</ref> and that alpha radiation may have a higher mutagenic effect at low doses (even if a small fraction of cells are hit by alpha particles) than predicted by linear no-threshold model, a phenomenon attributed to [[bystander effect (radiobiology)|bystander effect]].<ref>{{Cite journal |bibcode=2000PNAS...97.2099Z |title=Induction of a bystander mutagenic effect of alpha particles in mammalian cells |last1=Zhou |first1=Hongning |last2=Randers-Pehrson |first2=Gerhard |last3=Waldren |first3=Charles A. |last4=Vannais |first4=Diane |last5=Hall |first5=Eric J. |last6=Hei |first6=Tom K. |volume=97 |year=2000 |pages=2099–104 |journal=Proceedings of the National Academy of Sciences |doi=10.1073/pnas.030420797 |issue=5 |pmid=10681418 |pmc=15760|doi-access=free }}</ref> However, there is currently insufficient evidence at hand to suggest that the bystander effect promotes [[carcinogenesis]] in humans at low doses.<ref name=Blyth&Sykes2011>{{cite journal |doi=10.1667/RR2548.1 |title=Radiation-Induced Bystander Effects: What Are They, and How Relevant Are They to Human Radiation Exposures? |year=2011 |last1=Blyth |first1=Benjamin J. |last2=Sykes |first2=Pamela J. |journal=Radiation Research |volume=176 |issue=2 |pages=139–57 |pmid=21631286|bibcode=2011RadR..176..139B |s2cid=38879987 }}</ref>