A R T I C L E  I N F O		ABSTRACT
REVIEW ARTICLE		Introduction : Radon (Rn)  is a chemically inert gas with no odor, color, and taste. It is created from the decay of uranium in the soil and can penetrate the building through the interiors. As a result, Rn can enter the human body with the release of alpha radiation along with airborne dust and cause chronic illnesses such as lung cancer and multiple sclerosis. The Multiple Sclerosis disease, as a complex multifactor disease, is the most common widespread neurotic disorder among the young people. The purpose of this study was to collect and review the past studies published in this field since 1996. Materials and Methods: In this review, the related articles were searched and studied using key words such as "Radon, Action, Thoron, MS, MS Disseminated, and Sclerosis" using the PRISMA statement. Results: After reviewing the studies, several effective factors in the prevalence of MS were identified. Some of these factors were a result of the exposure to high levels of radon gas. Penetrations from the building cracks of floor, soil bed, and dwelling materials as well as the water resources are among the most important sources of Rn. Conclusion: According to the results, the amount of Rn and it’s daughters in the environment are recognized as the risk factors for the MS prevalence.
Article History: Received: 16 August 2019 Accepted: 20 October 2019
*Corresponding Author: Ali Asghar Ebrahimi Email: ebrahimi20007@gmail.com Tel: +983531492273
Keywords: Radon Gas, Alpha Radiation, Multiple Sclerosis, Myelin, Environmental Pollutant.

In addition to some positive aspects, the growth of human societies and human development in various fields also had some side effects, such as human diseases ¹. Multiple Sclerosis (MS) is a complex multi-factor disease and the most common neurotic disorder among the young adults ². In this disease, the immune system attacks myelin (fat shells), protector of the cell of central nervous system, brain, and the spinal cord, and damages them. Consequently, the destruction of myelin nervous cells leads to disorders in the transmission of nerve signals from the brain and the spinal cord to other parts of the body, which leads to the emergence of the special MS symptoms ³(Koriem, 2016 #14). In fact, MS is recognized as a chronic disease of self-immunity and inflammation that is fully cost-effective. The treatment of MS includes disease symptom management. Moreover, MS is a highly debilitating chronic illness with social and economic consequences and is recognized as the second most common cause of young people's disability ^{4, 5}.
The most important symptoms of MS are having optical disorders, fingersand toes' fading, a momentum electric shock in the body, cold and warm sensation in some parts of the body, incoordination in body organs (especially feet in walking), impatience, too muchsleep, body blemishes, laziness and numbness, early fatigue, general weakness of the body, muscle spasm, lack of coordination between words in the speech, headache, excessive urinary excretion, longer digestion, sensitive and early suffering, constipation, nightmare, and interest to eat the acidity foods with cold nature (such as dairy products, especially yogurt and ice cream). In the case of disease progress, MS leads to the lack of control in the urine discharge, hot/cold weather intolerance, decreased sexual desire, severe weakness in making intimate relationships with spouse, and experiencing premature ejaculation in men, depression and low self-esteem, isolation, and imbalance, as well as having muscle vibrations while moving and walking ⁵.
The MS is more common among women than men and usually strikes at the age of 24 up to 40 years ⁶. According to the International Federation of MS, the average outbreak of the disease was 30 in 100000 in 2008, which rose to 33 in 100000 in 2013. The highest prevalence rate was in the North America (140 in 100000) and Europe (108 in 100000); wheres, the lowest was in the south of African desert (1.2 in 1000000) and East Asia (2.2 in 100000).  In Iran, the prevalence rate of MS is 15-30 in 1000000 ⁷. According to the WHO classification in the Atlas of MS in 2008, Iran belongs to the medium-range regions ⁵. Based on a study of the geographical distribution of MS, Iran is located in an area with a low MS prevalence rate ⁸.
The conducted research is partly in agreement with the first category, but violates the second ⁵. However, according to recent studies, it has become clear that Iran is now located in the area with medium to high prevalence ⁹.
Although many studies have been conducted on MS, the cause of  this disease is still unknown¹⁰. Yet, it is reported that a set of environmental causes, infections, genetic problems, immune system, viruses, toxins, and metabolic problems as well as materials such as nitric oxide are involved in it’s occurrence¹¹. Rn, as an external factor, was found to be effective on MS occurrence and aggravation. Radon is a gas that is chemically inert or ineffective and does not have any odor, color, and taste. It also decays naturally from ²³⁸U, ²³⁵U, and ²³²Th in many types of soil, rock, and water produced in the earth. The ²²²Rn is produced from the decay of ²³⁸U, as the most important source of internal radiation. Humans are generally exposed to it throughout their lives.  Three radon isotopes (²¹⁹Rn, ²²⁰Rn, ²²²Rn) are in the form of gas and are released from the earth, stone, construction materials, and short-lived decay products gathered in closed spaces, especially in the building. ²¹⁹Rn and ²²⁰Rn are not as important as ²²²Rn due to their short lives. The most important sources of radon are soil, construction materials (e.g. rock, cement, etc.), water resources, and natural energy sources (such as gas, coal, etc.) ¹².
Radon density in the buildings is also widely related to the geological structure, structure of the building, and the ventilation system. Therefore, radon density depends on many different factors. Although soil, rock, and foundation structure around the building is the most important source of radon, radon caused by building materials may increase it’s density in the indoor environment ¹³. The half-life of ²²²Rn is 3.83 days that is enough to enter the indoor space of the building ¹². Based on the WHO report, the effects of Rn on health are divided into two categories: the lung cancer and other diseases. Radon is known to be the second leading cause of lung cancer after cigarette smoking. Radon also causes other diseases such as leukemia, liver cancer, cardiovascular disease, and MS ^{14, 15}. Different studies are undertaken in this regard. As an example, MS has a significant positive correlation (p < 0.01) with Rn contents in indoor air. Based on these data, this hypothesis is proposed that the content of Rn in inhaled air is a risk factor in MS ¹⁶. Nevertheless, to the best of our knowledge, no review study has been ever conducted in recent years aiming to do a synthesis review on the literature in this regard. Thus, this study aimed to conclude the findings by reviewing the recent studies published since 1996.
Materials and Methods
In this review, keywords were selected using mesh, thoron, radon, action, MS, disseminated sclerosis, and multiple sclerosis. The search was conducted among the english sources and databases such as Science Direct, Google Scholar, Pub Med, Scopus, and ISI. The PRISMA statement was employed to select the articles (See Figure 1 for the flowchart).
As Figure1 represents, 249 articles were found from the general search results. Then, the duplicates and unrelated articles were removed, so that 235 articles remained as the final database of the study, including 6 ecological studies, 1 review, 3 pilot, 1 guidelines, and 3 case-control studies. All the articles were published from 1996 to 2019. The criteria for selecting articles included the type of study, subject relevance, and the articles availability.

Results
 Radon gas has not only positive functional effects, but also negative harmful effects¹⁷. In this review, the harmful effects of Rn on the development of the MS disease were addressed. Radon gas has an important role in the development of various diseases including lung cancer, leukemia, skin cancer ¹⁸, gastric cancer ¹⁷ , and MS ¹⁴.
Numerous studies have been conducted on the relationship between Rn and MS in the countries with high risk of MS. These countries included the United States ^18-20 , England ²¹ , Ireland ^{22, 23}, Norway ²⁴, and Sweden ²⁵ The relationship between the occurrence of MS and Rn has been proven statistically and inferentially in the studied countries by measuring the density of Rn. In other words, if the area had a high Rn density, the rate of MS prevalence was also high. Neuberger et al. carried out a research in the city of Kansas, the United States. Their results showed that the adjusted odds-ratio for MS prevalence increased by 1.98 (95% CI = 0.98 to 3.98, p = 0.06) for each unit increase in the time-weighted average of the natural log of radon exposure. Although not statistically significant, a trend of increase was observed in the probability of MS prevalence with each unit increase in the time-weighted average of the natural log of radon exposure ²⁶. Furthermore, the study carried out in Wales, England, by Groves et al. showed that although a trend of increasing MS incidence was identified with increased radon concentration, the correlation was not statistically significant ²⁷.
Effective factors in increasing radon gas
Factors affecting the increasing indoor Rn include the type of building materials used in the building, cracks in the walls and the floor, type of the rock and soil, foundation of the building, and used water resources ^{21, 28}. These factors are the main sources through which Rn enters into the building from the existing cracks and gaps on the floor of the building, so that Rn in the soil gradually accumulates under the building and its pressure rises. Because the air pressure inside the building is usually less than the air pressure in the soil, the Rn can enter the building through the wells, drains, and cracks on the building floors¹⁷. The amount of Rn in the closed environment is different in different days and seasons and depends on the seams and cracks of the floor, walls of the building, amount of ventilation, and air exchange in the building. Besides, concentration of Rn is usually more in the lower floors of the building and the underground level than in the top floors ^{1, 17}.
Methods of measuring Rn concentration
Generally, in some ecological studies, the density of Rn has been measured by the radiation protection organization of the country. As a result, a certain amount is mentioned for each house ^21-23. In some studies, the nuclear track method ²⁴, active Alpha track dosimeter ²⁶, radon gas map ²⁷, charcoal canisters ¹⁸, whole body counter steel, ²⁰ and responding to the questionnaire were conducted based on ionizing radiation ²⁵.
The collected data on MS patients in the examined studies
 Data on MS patients in Norway were collected based on the urban type, the mortality rate in 1951-1977, and cases of men/women disability in 1978 ²⁴. Data on MS patients in Ireland were collected by administering a questionnaire to 67 patients who referred to an MS center (33% of responses). The questionnaire included the heating type, building age, number of building floors, sewage drainage system, and used water source. There spondents responded to these questions in accordance with their childhood experience (before age 15) ^{22, 23}.
The MS 20-65 year old patients in Sweden were selected from a large hospital in the southern and southeastern Sweden. In this case-control study, the control people were selcted randomly from the Sweden Registry Office. The data were collected using questionnaires sent to individuals by email. The questionnaire covered these issues: type of occupation, specific exposures to certain agents or animas at work, treatment or examination by X ray, contact with animals, and prolonged use of medications ²⁵.  
In a pilot study in Kansas, the United States, the MS patients were selected from a clinic. The selected patients were treated for two years, their age was more than 68 years, and lived in the ame building since five years ago. The data were collected by a questionnaire ²⁶. To collect the information about MS patients in Wales, the UK, clinical research database was employed. The study population consisted of all patients who lived in Wales, UK over the last five years ²⁷. Data over death rates from motor neuron disease (MND) in the countries of England and Wales in 1981-1989 were obtained from the office of population, censuses, and surveys (OPCS) ²¹.
Effective factors in increasing the occurrence of MS
In the examined studies, the prevalence of MS increased in North America, which was attributed to the radiological sources emitted by a nuclear fall-out  in Washington State. The original sources noted that the geographical distribution of MS incidence was affected by the potential influence of air-borne radioactive debris from atmospheric nuclear tests. Furthermore,  presence of a major nuclear-material processing facility in that state was a more significant effetive factor in this regard. The areas in these studies included East Washington, Northern Iowa, Norway, and the northern areas of the United States that showed the highest levels of Rn and MS ¹⁹.
Another factor affecting the prevalence of MS is the exposure to high levels of Rn and some environmental factors during childhood, before age15, especially for men ^{22, 23, 29}. Furthermore, it was found that the prevalence rate of MS in arid regions was more than coastal areas¹⁹. Regarding latitude, in the Norwegian and English studies, northern regions located at higher latitudes had the highest prevalence rate of MS ^{24, 29}. The other environmental factors that cause MS include sunshine, carbon monoxide, ultraviolet radiation, temperature, latent virus, ionizing radiation, pets, and toxic chemicals ¹⁹.
Given that the MS virus is mentioned as one of the causes for developing MS, the related hypothesis is that some types of viruses may remain latent in the body organs for a long time. These viruses can be re-activated due to a variety of factors, among which the most important one is exposure to high doses of ionizing radiation ²⁴. The reason is that Rn is in the group of ionizing radiation derived from radon decay as well as alpha and beta particles. Release of these products have a risk of irradiation in causing MS ^{15, 19, 24}. This gas has a particular dependence on fat, so it is stored in organs rich in fat-like neural systems and narrow bones. It also can cause breast cancer or tissue cancer ²⁰, because the pod myelin sheaths (nerve fibers), made of fatty materials, are attacked in MS patients. Thus, it can be concluded that the pod myelin fat is solved by environmental radon ^{18, 31}. The most convincing scientific studies on MS and ionizing radiation conducted in Norway showed that radon was an effective factor in MS ²⁴.

P value	Domestic radon concentration database	Age (year)	Number population study case of MS	MS potions database	Study Design	Year and country	study
0.096	Radon gas map and utilized data at postcode sector level	15-85	115 case	The Health Improvement Network (THIN) clinical research database	Ecological	2005-2012 in England and Wales	Groves, 2016 21
0.06	Long-term alpha track dosimeters for 5-6 months in the winter	Mean age: 42.35	97 MS patients and 51 non-MS controls	The University of Kansas Medical Center’s Neurology Department clinic	A pilot case-control study	2000-2006 In Kansas, USA	Neuberger, 201114
< 0.05	Whole body counter data, steel room Bi214  background	-	315 female and 179 male	Participating in community-based bioavailability studies over a period of 13 years	Ecological	1988-2004 In Grand Forks, North Dakota	Momcilovic, 2005 29
< 0.01	The nuclear track method for 6-month periods	-	195 case in rural and in urban areas	Based on municipal rates for the sum of deaths in the period from 1951 to 1977 and disability pension cases in 1978 for both sexes	Ecological	1987-1989 in 6 of Norway’s 19 counties	Bolviken, 200324 200131
No	Radiological Protection Institute of Ireland(RPII) by sampling homes in 10-Km grid squares	36.8	671 case	Communications with General Practitioners, Neurologists, County Physicians, Hospital Coding Lists, Local MS Societies, Respite Care Facilities and Interferon Prescription Lists.	Pilot	1992 In Ireland	Carroll, 2005 23
< 0.05 < 0.01	The National Radiological Protection Board(NRPB) by sampling homes in 10-Km grid squares	15 to 85 uper	9220 Deaths	Data for deaths from motor neuron disease (MND)mortality were obtained from the Office of population censuses and Surveys(OPCS)	Ecological	1981-1989 t in England and Wales he counties of England and Wales	Neilson, 1996 28
No	Environmental Protection Agency (Pekmezovic et al.)	All ages	100000 population (cases/100k)	National Multiple Sclerosis Society (NMSS) - Iowa Chapter	Ecological	1993 in 92 of Iowa's 99 counties	Eidbo& Prater, 2004 20
No	9-page questionnaire x-ray examinations, radiological work, cosmic radiation, gamma radiation and treatment with ionizing radiation	20-65	From 83 cases (response rate 89%) and 467 controls (response rate 80%) in these two counties	Cases of MS obtained  in the two largest hospitals in south-central Sweden and controls were randomly drawn from this register of the population in these two counties from where the cases were obtained	Case-control	1981-1985 in the two largest hospitals in south-central Sweden that two counties covered by these hospitals	Axelson, 2001 25
No	9-page questionnaire X-ray examinations, radiological work, cosmic radiation, gamma radiation and treatment with ionizing radiation	20-65	91 Responding cases (response rate 94%) and 348 population controls (response rate 87%)	Cases of MS obtained at the main hospitals in two counties in southeast Sweden and controls were randomly drawn from this register of the population in these two counties from where the cases were obtained	Case-control	1983-1988 in two counties in southeast Sweden	Axelson,2001 25
No	The 222Rn was measured with charcoal canisters	-	15 MS patients and 15 non-diseased controls	The Grand Forks MS Support Group, subjects  with no apparent health problems were recruited locally	Case-control	In Grand Forks, North Dakota	Lykken, 2008 17
No	Radiological Protection Institute of Ireland(RPII)	Befor the age of 15	67 respondents, response rate 33%	Membership of the MS Society in Ireland	Pilot	1971-1981 In Northwest Ireland	Gilmore, 2003 22

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