Cancer Incidence in Volcanic Areas: A Systematic Review

Background: There are more than 1,000 active volcanoes worldwide with inhabitants within 100 km of them. Volcanoes spill several toxic metals and spew pollution through gasses, causing soil and water contamination. The dangerously active volcanoes place the nearby population at risk for volcanic hazards. This review aimed to determine whether people living in these volcanic areas have higher risk of cancer and more attention should be given to this danger. Methods: A systematic literature search was conducted of PUBMED, Science Direct, SCOPUS, Proquest, and Google Scholar, and from citation searching. We assessed the quality of the studies and extracted the incidence rate of cancer in the volcanic areas compared to non-volcanic areas. Results: The search identified 360 articles, with 11 studies meeting our selection criteria. The results reported the incidence of cancer in children was predominantly in volcanic areas with girls suffering as much as 1.4 per 100,000 per year. The highest cancer age standardized incidence rates for females, males, and overall calculation in volcanic areas were reported as 31.7/100,000/year in Catania, 10.34/100,000/year in Furnas, and 38.3/100,000/year in Catania-Messina-Enna for thyroid cancer. We observed the increasing incidence of carcinoma for some types of cancer in volcanic areas. Conclusion: Cancer incidence in volcanic areas was higher than non-volcanic areas and it is caused by multifactorial conditions. The concentrations of hazardous elements of volcanic products vary among volcanoes and are related to the harmful risk for the inhabitants. The negative effects of volcanic products to human health should be given more consideration.


Introduction
There are approximately 1,550 active volcanoes in the world and most of them are on the seafloor. These volcanoes particularly exist in tectonic plate boundaries. In the Pacific Ocean, the so-called 'Ring of Fire' forms a horseshoe from South America to North America, reaching to Indonesia. Alongside, there are 452 volcanoes, of which 75% are in active status. Archipelago nations host the highest population within 100 km of active volcanoes and also many inhabitants live within areas of high volcanic hazards and risks (Cottrell, 2015;Hariyono and Liliasari, 2018). Areas close to volcanic activity are characterized by non-anthropogenic pollution involving the atmosphere, soil and water. Previous research informed that some metal spills from the earth's crust cannot be easily degraded. Therefore, they have a negative impact on the ecosystems of plants, animals and humans around these volcanic areas (Yamamoto et al., 1995). A study conducted by Pellegriti in 2009 reported findings of boron (B), iron (Fe), manganese (Mg), vanadium (V), and radon (222Ra) higher than maximum permissible concentrations in drinking and irrigation water sources on the plain of Mt. Etna, which is the source of water for most of the population in the province of Catania (Pellegriti et al., 2009). In another similar study, some cancer incidence rates were reported higher in volcanic areas, such as the increasing incidence of gastric cancer in Iran and Japan (Amani et al., 2015). In some studies, incidence rates of various cancer types were increased in volcanic areas. This was possibly caused by chronic exposure to various toxic ground gas emissions. The component elements of these emissions are iron (Fe), zinc (Zn), copper (Cu), selenium (Se), nickel (Ni), cobalt (Co), cadmium (Cd) radon (Rn), mercury (Hg), arsenic (As), lead (Pb), hydrogen sulphide (H2S), and carbon dioxide (CO 2 ) (Kristbjornsdottir and Rafnsson, 2013). Although some of these metals, such as trace metals including iron (Fe), zinc (Zn), copper (Cu), and selenium (Se), are essential micronutrients for the body, however, the presence of these metals and gases in the volcanic load are considered to be closely related to the incidence of cancer. In addition, some of these metals and gases are carcinogenic (Malandrino et al., 2020). Increased exposure to these elements in either inorganic or organic form through inhalation, skin contact and digestion can initiate the growth of cancer (Russo et al., 2015;Malandrino et al., 2020).
One well-known example of carcinogenic action is the presence of high concentrations of the toxic metal, arsenic (As) in drinking water and food, which is associated with several types of cancer such as thyroid cancer through the metalation processes of arsenic (As) into dimethyl arsenic acid (DMA), also known as cacodylic acid, which is a carcinogenic substance (Hariyono and Liliasari, 2018). Another dangerous volcanic compound is cadmium (Cd), which is a carcinogenic substance that can induce oxidative stress by inhibiting antioxidant enzymes, activating PI3K (phosphoinositide 3-kinase) and extracellular signal-regulated kinase (ERK) signaling pathways, deregulating cell proliferation, damaging DNA repair mechanisms and promoting tumor progression and invasiveness (Prozialeck et al., 2003;Malandrino et al., 2020). This study aimed to determine whether populations in volcanic areas have higher incidence of cancer so the people and the responsible governments should give more attention to this danger.

Materials and Methods
This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher et al., 2009).

Information sources and search strategy
Database searching was conducted of PUBMED, Science Direct, SCOPUS, Proquest, and Google Scholar. Citation searching of reference lists was also performed. Databases were searched on May 15, 2021 without limitation on date, country, patients race, age, and gender. Keywords related to the incidence of cancer in volcanic areas are provided in Table 1. Duplicate references were removed manually.

Inclusion and exclusion criteria
Articles in English were selected without time restriction and the inclusion criteria of this review were studies in human populations and studies reporting comparison of incidence of cancer in volcanic and non-volcanic areas. The exclusion criteria were brief communications, letters, reviews, editorials, and articles that could not be accessed.

Study selection
The process of selection consisted of two steps. In the first step, we checked the titles and abstracts of all studies using predefined criteria for screening. All reviewers were involved in making the final decisions. The inclusion and exclusion criteria provided the guidance. In the second step, the selection was repeated by reading the whole paper and the final decision was made by all reviewers after discussion in case of any disagreement.

Data collection process
The collection process involved the collection of important relevant material from the articles. The data inputted into tabular form in this study included author's name, title of study, duration of study, study region, age-standardised incidence rate (ASR)/100,000, event of cancer, total population, incidence rate (IR), and p value. Data related to the metal components of the air, soil and water in the volcanic area were also collected.

Quality assessment of studies
The quality of each study was assessed by the two authors using the Joanna Briggs Institute (JBI) critical appraisal checklist for cohort studies with the scale as percentages (Goplen et al., 2019;Moola et al., 2020). Any disagreements were resolved by discussion between the authors who assessed the article. The primary outcome was the incidence of cancer in volcanic areas compared to non-volcanic areas.

Study selection
The total number of the articles that we recorded from the keywords was 360 articles. After removing the duplication, a total of 246 articles were selected for the screening process. We reviewed the titles and types of articles using the inclusion and exclusion criteria. From the 246 studies, 218 were excluded and 28 studies were selected. In the next data selection, from the 28 studies, 19 were removed after the full text was read thoroughly. There were two additional included articles identified from the citation searching. At the end of selection process, the total number of studies was 11. A flowchart of the selection process is shown in Figure 1.

Risk of Bias
According to the JBI Critical Appraisal Checklist for Cohort studies, all of the studies were considered to have low risk of bias. Some studies did not identify the confounding factors and how to deal with them (Table 3).

Cancer Incidence
One study reported overall cancer crude incidence rate as 453.2 per 100,000 per year in volcanic areas and 435.97 per 100,000 per year in non-volcanic areas, indicating higher cancer incidence reported with ASR in volcanic areas. In addition, the study reported lymphatic leukemia, thyroid cancer, and prostate cancer as cancers 1990), Iceland (N=1) (Arnbjörnsson et al., 1986), Hawaii (N=1) (Goodman et al., 1988), and the Azores (Portugal) (N=1) (Amaral et al., 2006). Studies conducted in Sicily compared Catania as the volcanic area to the rest of Sicily. The study in Iceland compared Iceland to Denmark, Finland, Norway, and Sweden as nonvolcanic areas. The study in the Azores, compared Furnas to Santa Maria. The study in Vanuatu compared that region to Papua New Guinea and Fiji. The study in Hawaii compared that region to San Francisco and New Mexico. Most of the studies investigated about thyroid cancer, indicating that the type of thyroid cancer that had higher incidence was papillary thyroid cancer. Besides thyroid cancer, two studies declared that there were other types of cancer found in residents in volcanic areas, which were cervical cancer, liver cancer, skin cancer, lymphatic leukemia, Hodgkin's lymphoma, stomach cancer, breast cancer,    DOI:10.31557/APJCP.2022.23.6.1817 Cancer Incidence in Volcanic Area  Table 2. Continued NR, data not reported; F, female; M, male; ASR, age-standardized incidence rate that were significantly higher in men in volcanic areas and thyroid cancer, breast cancer, lymphatic leukemia, Hodgkin's lymphoma, and stomach cancer as cancers that occur significantly higher in women (Russo et al., 2015). There was one study that reported the incidence of cancer among children (0-19 y.o) in volcanic and non-volcanic areas. Research by Russo in 2017 reported about the incidence of thyroid cancer in children between 2002-2009. The cancer incidence reported with ASR for females was significantly higher in volcanic areas than non-volcanic areas (ASR = 1.4 and 0.6, respectively, p=0.006) and the ASR for males was significantly higher in volcanic areas than non-volcanic areas (ASR = 0.5 and 0.1, respectively, p=0.03). Mostly, differentiated thyroid cancer was diagnosed in the younger age population (5-14 years old) without differentiation in gender (Russo et al., 2017).
The highest cancer incidence reported with ASR for females in volcanic areas was 31.7/100,000/year in Catania (Pellegriti et al., 2009), while the lowest was 5.9/100,000/year (Malandrino et al., 2013). The highest cancer incidence reported with ASR for females in non-volcanic area was 14.1/100,000/year in the rest of Catania in Sicily (Pellegriti et al., 2009), while the lowest was 2.2/100.000/year in Vanuatu (Paksoy et al., 1990) (Figure 2).
The highest cancer incidence reported with ASR for males in volcanic areas was 10.34/100,000/year in Furnas (Amaral et al., 2006), while the lowest was 1.3/100,000/year in Catania (Malandrino et al., 2013). The highest cancer incidence reported with ASR for males in non-volcanic areas was 13.58/100,000/year in Santa Maria (Amaral et al., 2006), while the lowest was 0.35/100.000/year in Vanuatu (Paksoy et al., 1990) ( Figure 3).
The highest overall cancer incidence reported with ASR in volcanic areas was 38.3/100,000/year in Catania-Messina-Enna for thyroid cancer (Boffetta et al., 2020), and the lowest was 0.07/100,000/year in Catania (Tavarelli et al., 2017). The highest overall cancer incidence reported with ASR in non-volcanic areas was 24.4/100,000/year in Palermo (Boffetta et al., 2020) and the lowest was 0.05/100,000/year in Catania for anaplastic thyroid cancer (Tavarelli et al., 2017) (Figure 4).

Discussion
This review presents the incidence rates of cancer in volcanic regions compared to non-volcanic regions. The highest cancer incidence reported with ASR in volcanic areas for females was papillary thyroid cancer in Catania compared to the other regions and types of cancer. The incidence was significantly higher in the volcanic areas than non-volcanic areas with p=<0.001. The mechanisms of the volcanic environment that influence the increasing of cancer incidence has not been proven yet, although some studies stated that the thyroid gland is sensitive to radiation. Mount Etna located near Catania, releases radioactive radon gas (Rodrigues et al., 2012;Hariyono and Liliasari, 2018). In these areas, radon can contaminate sources of groundwater with more than the maximum allowed concentrations (Pellegriti et al., 2009). Radon (Rn) is a radioactive compound from volcanic gases that can diffuse through soil substrates. Indoor radon (222Rn) was monitored in high concentrations in some house (>2,000 Bq/m 3 ) near mount Etna and high radon degassing was measured in soil samples (>10,000 Bq/m 3 ) (Neri et al., 2019). One study in Furnas found that indoor radon (222Rn) concentration was positively correlated with the frequency of micronucleated cells in buccal epithelial (Linhares et al., 2018). The presence of radon is strongly associated with several cancers such as thyroid and lung cancer. Radon can decay and release α particles that can penetrate to soft tissue to a lesser degree than gamma-rays and cause damage DNA and tumorigenesis. Radon can also be a gas that can decay and settle in the airways causing radiation exposure to the thyroid (Goyal et al., 2015).
In the collective data in Figure 3, the highest incidence of cancer in males was found in Portugal. The types of cancer with high incidence in Furnas compared to Santa Maria were lip, oral, and pharynx cancer. This pattern may be caused by environmental factors such as pollution from gas particles, trace elements, and radon from volcanic activity. Continuous exposure to elements in volcanic regions is possibly associated to the increasing of cancer incidence through complex mechanisms (Amaral et al., 2006). Furnas is located in soil diffuse degassing areas where fumarolic discharges and the toxic gasses are continuously released. These are carbon dioxide (CO 2 ), hydrogen sulfide (H2S), sulfur dioxide (SO 2 ), hydrogen chloride (HCl), hydrogen fluoride (HFl), and the radioactive gas radon (Rn). One study conducted by Rodrigues et al., (2012)  Water (Pellegriti et al., 2009) Volcanic Ash (Barone et al., 2021) 2

Azores, Portugal
Carbon dioxide (CO2), hydrogen sulfide (H2S), sulfur dioxide (SO2), hydrogen chloride (HCl), hydrogen fluoride (HFl), and radon (Rn) Soil (Rodrigues et al., 2012) 3 Iceland argon (Ar), methylene (CH2), carbon monoxide (CO), CO2, carbonyl sulfide (COS), hydrogen (H2),HF, hydrogen chloride (HCl), H2O, H2S, sulfuric acid (H2SO4), ammonium (NH4), disulfur (S2), sulfate (SO4), SiF Gases (Arnbjörnsson et al., 1986)   anomalies (ONA) such as karyolysis, pyknosis, and karyorrhexis were higher in patients from the volcanically active environment than the non-exposed group. Higher ONA and MNC were significantly associated with exposure in the volcanically active environment. This research may be related to the increasing incidence of lip, oral, and pharynx cancers. In our data, the overall highest incidence for cancer was thyroid carcinoma in Catania-Messina-Enna. Also, the types of cancer that appear are lip, oral cavity and thorax cancer in Furnas; and lymphatic leukemia, Hodgkin's lymphoma, stomach, breast cancer, and prostate cancer in Sicily; and liver, cervix, and skin cancer in Vanuatu. The increasing incidence of breast, thyroid, and skin cancer may be related to high radon exposure (Kristbjornsdottir and Rafnsson, 2012;Kristbjornsdottir et al., 2016). One study conducted in mice from volcanic areas showed that concentrations of aluminium (Al), lead (Pb), cadmium (Cd), and zinc (Zn) in the liver and kidneys were higher than those from non-volcanic areas. Additionally, the level of apoptotic nuclei in all organs were increased in inhabitants from volcanic areas. It may be caused by exposure to cadmium (Cd) and lead (Pb) that can degenerate DNA and stimulate the pathogenesis of cancer (Amaral et al., 2007). In addition, the presence of heavy metals such as lead (Pb), arsenic (As), cadmium (Cd), and mercury (Hg), are toxic for humans. Their presence causes genetic alteration that should be considered as an etiology for cancer initiation, for instance, the mutation of BRAF V600E. In Catania, the mutation has been found to increase the risk by 1.7-fold for papillary thyroid cancer than the other regions in Sicily. It could be possible that the radiation and genetic alteration play major roles in the carcinogenic mechanism (Goyal et al., 2015;Joneidi et al., 2019).
Some gas emissions and metal components are around volcanoes presumed dangerous to human health. One study in Catania described that six elements including arsenic (As), boron (B), molybdenum (Mo), antimony (Sb), selenium (Se), and vanadium (V) were significantly increased in drinking water samples. It was emphasized by the higher amount of those elements found in the urine specimens of local inhabitants (Malandrino et al., 2016). The rat experiment proved that rats which consumed boron (B), cadmium (Cd), and molybdenum (Mo) in drinking water presented additional neoplastic features on rat's thyroid after 10 months of goitrogenic diet (Luca et al., 2017). Nickel (Ni) is one of the components of volcanic dust that are released into the environment. In human lung cells, nickel (Ni) compounds are collected and retained in the cytoplasm and nucleus and persist for long periods of time. This retention causes DNA methylation, long-term gene silencing and also causes hypoxia in inducible genes and has been implicated in nickel-related carcinogenesis. The existence of nickel also affects the tumor associated cell migration and invasion, tumor microenvironment and survival, and its increased expression can be found in many types of cancer . Nickel has significant effects on the steroidogenic pathways. It could regulate organs upstream of the endocrine axis to affect the hypothalamus and pituitary gland and can cause abnormal secretion of pituitary hormones. The condition further affects target organs of the endocrine axis, resulting in dysfunction therein and abnormal secretion of related hormones. Studies of the negative effects of nickel in human adrenocortical carcinoma concluded that it could decrease the production of testosterone and progesterone (Lukac et al., 2020;Yang and Ma, 2021). Another dangerous component is cadmium (Cd), which can accumulate in tissues and organs especially in the kidneys. It was stated that cadmium impairs the DNA damage repair mechanism, inhibits apoptosis, induces oxidative stress, and has genotoxic effects. In the colon tumor cell line, cadmium disrupts the intestinal barrier function by decreasing the amount of E-cadherin and occludin. This leads to increased permeability for pathogens and harmful substances. High cadmium levels lead to genomic instability through multifactorial pathways which cause the promotion of cancer by activating proto-oncogenes and inactivating tumor suppressor genes through disruption of cell signaling pathway by epigenetic alteration, besides causing other diseases attributed to genomic instability (Bishak et al., 2015;Luo et al., 2019). Arsenic (As) is a pollutant that comes from many sources, including volcanic activity. It has been identified to be the causal agent of skin, bladder, lung, liver, and prostate cancers through increasing of oxidative stress, increasing inflammation, accumulation of free radical, and altering histone methylation (Filipič, 2012;Brocato and Costa, 2013). Arsenic (As), cadmium (Cd), and chromium (Cr) exposures in children and adolescents are associated with oxidative damage to DNA. They can be excreted in urine and detected as urinary biomarkers (Franken et al., 2017). Another harmful compound in volcanic emissions is sulphur dioxide (SO 2 ). Sulphur dioxide emission rates in Yasur (Vanuatu) vary due to volcanic activity. In PM 2.5, it can penetrate into the lung tissue, other parts of the respiratory system, and has association with mortality from 29 cancer sites. Moreover, it could disturb DNA repair, leading to DNA methylation and genotoxic effects (Bani and Lardy, 2007;Su et al., 2019).

Limitations
Our study was limited to searches of PUBMED, Scopus, Proquest, Science Direct, and Google Scholar databases for related articles in the English. Articles in the other databases and not written in English were not recorded. Most of the articles were based on case studies from Portugal and most of the cancer incidence identified was thyroid cancer. All of the articles that we found are cohort studies.
In conclusion, cancer incidence reported with agestandardised rates in volcanic areas from the data in this systematic review was higher than non-volcanic areas. This pattern is due to multifactorial causes, and one of them is exposure to the hazardous components from volcanic products. The concentration of components of volcanic products is different from one volcano to another and this is related to the harmful risk to its inhabitants. Although it is still debatable, components from volcanic products that are hazardous to human health should