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Miyakejima Island is a volcanic island 8 km in diameter located 180 km southsouthwest of Tokyo. In the last 500 years, Mt. Oyama, the island’s highest peak, has erupted approximately every twenty years. The most recent eruption began in June 2000, and due to continuous eruptions and emissions of lethal/unsafe levels of volcanic gas, the Miyake village government decided to evacuate all citizens from the island in September 2000. At the time of the evacuation, the amount of sulfur dioxide (SO₂) discharged, the main toxic component of volcanic gas, was ca. 50,000 tons/day. Volcanic activity gradually decreased, and has since ceased.

As Tokyo Metropolitan Government and the Cabinet Office of Japan (2003) reported that the volcanic gases from Mt. Oyama contain not only SO₂ but also hydrogen sulfide, hydrogen chloride, carbon dioxide, and suspended particulate matter (SPM). The concentrations of gases other than sulfur dioxide, however, are lower than reference values. For example, hydrogen sulfide was at the threshold limit value of 1 ppm recommended by the American Conference of Industrial Hygienists in 2010. Moreover, while it is highly likely that hydrogen chloride and SPM were also discharged, measured concentrations have been negligible. Therefore, volcanic gases other than SO₂ are unlikely to be the cause of health effects.

In September 2002, the Tokyo Metropolitan Government and the Cabinet Office of the Japanese Government organized a Scientific Committee for Assessment of Health Risk and Volcanic Activity on Miyakejima Island (Miyakejima gas kenntoukai) (2003) to discuss requirements for canceling the evacuation order and allowing residents to return to the island. The committee concluded that, although both an acute and chronic health risk due to volcanic gas inhalation remained, residents could return to the island as long as they understood these health risks and voluntarily returned with self-responsibility. The committee also advised the village government to continuously monitor SO₂ concentrations all around the island and to conduct health checkups to detect the early effects of SO₂.

After residents returned to the island, the village government conducted annual health checkupkes under the Ordinance of Security for Safety and Health against Volcanic Gas promulgated by the Miya Village Government. These findings enabled analysis of the effects of SO₂ at 10 years post eruption on the respiratory systems of child residents of Miyakejima as a prospective cohort study. Beginning in 2008, health checkups on the island incorporated measurement of the fractional exhaled nitric oxide (FeNO) concentration. The present study aimed to investigate the relationship between SO₂ exposure and FeNO by comparing FeNO levels from Miyakejima students and students from a reference island in Japan where SO₂ concentrations are far below the Japanese Environmental Standards (JEStd).

The village government of Miyakejima Island conducts annual health checkups under the Ordinance of Security for Safety and Health against Volcanic Gas promulgated by the Miyake Village Government. According to Japanese ethical guidelines on epidemiological studies, informed consent does not need to be obtained from human subjects of investigations conducted based on legal regulations. Therefore, we did not obtain informed consent from the participants on Miyakejima Island. However, we did obtain written consent from subjects from the reference island based on approval by the Ethics Committee of the School of Medicine of Keio University (approval number: 20100306).

2. 2 Study Population

Eligibility criteria: Subjects were second-year junior high school students aged 13-14 years. The study was conducted on Miyakejima Island from 2008-2014. On the reference island, we conducted in 2016. We have FeNO observation and analyses for all participant (Fig. 1). The criteria for hypersusceptibility in this study were (1) a current or a past history of asthma; and/or (2) symptoms of whistling and wheezing.

Fig. 1. 
The flow chart of participant and analysis.

We previously conducted epidemiological studies on volunteers and residents of Miyake who were exposed to SO₂ from volcanic gas across a 10-year period and reported the presence of a quantitative reaction between SO₂ exposure and subjective symptoms. For example, Ishigami et al. (2008) conducted a follow-up study on 611 healthy volunteers, on a person-hour basis (28,413 person-hours), who visited Miyakejima Island to provide support to residents and stayed anywhere from a few to 15 days from February to July 2005. The hourly incidence of irritative symptoms showed clear exposureresponse relationships with hourly average SO₂ concentrations, and exposure to 20-30 ppb SO₂ or above increased the rate ratio of irritative symptoms such as sore throat. This result was consistent with the acute effect. However, our study differs from this study as respiratory effect of child in Miyakejima.

In addition, Iwasawa et al. (2015) found clear dose-response relationships in child Miyakejima residents. The subjects of that study were residents aged 6-18 years who were enrolled in a Miyake elementary school, middle school, or high school at the time of each medical checkup. Applying a logistic regression model, age-, sex-, and hypersusceptibility-adjusted prevalence odds ratios to the reference population showed clear exposure-dependent increases in some irritative symptoms such as “Irritation and/or pain in throat” and “in eyes”, and approximately 30 ppb seemed to be the threshold concentration. This result was consistent with child in Miyakejima. However, our study differs from this study in the respiratory effect assessed by fractional exhaled nitric oxide concentration.

Further, Kochi et al. (2017) found clear dose-response relationships in adult Miyakejima residents. To assess the exposure-effect and exposure-response relationships between SO₂ exposure and effects on respiratory system in adult Miyakejima residents. In this study, they observed minor health effects on the respiratory system and irritation symptoms. They also observed clear dose-response relationships and determined an apparent threshold concentration of approximately 70 ppb. This result was consistent with adult in Miyakejima. However, our study differs from this study in the respiratory effect assessed by fractional exhaled nitric oxide concentration.

FeNO concentration has attracted attention as a marker of airway inflammation and has been measured on child in Miyakejima as a respiratory effect of SO₂ exposure since 2008.

Although emission rates of SO₂ have been gradually decreasing since the initial eruption, levels remain high (Tokyo Metropolitan Government and the Cabinet Office of Japan, 2003), especially in comparison with current levels around Sakurajima in Japan (Uda et al., 1999), Kilaueu in Hawaii (Mannino et al., 1996), and Stromboli and Etna in Italy (Durand et al., 2001).

A nitrate-rich diet and contamination with nasal NO can increase FeNO values and should therefore be avoided or taken into account when measuring FeNO. In this study, consumption of a nitrate-rich diet (Miyake 4.8%, reference 0%) was not statistically significantly different between the two populations.

Fujisawa (2012) previously reported the GM of FeNO concentration. FeNO was measured using NIOX-MINO for Japanese volunteers of general junior high school students and high school students. The presence or absence of allergic disease in the subjects was classified using the Japanese version ISAAC questionnaire. In the analysis excluding allergic rhinitis, the geometric mean value of 79 male was 21 ppb. On the other hand, including allergic rhinitis, the cut-off value was 40 ppb at male subject. Additionally, FeNO is affected by age. Generally, the FeNO becomes higher as the age increases. This study covers second-year junior high school students aged 13-14 years and is close to the median of Fujisawa’s studies.

In contrast, we found that the concentration was 28.3 ppb among children on Miyakejima and 27.7 ppb among children on the reference island. This discrepancy may be due to the persistent presence of salt particles, which can contribute to airway inflammation.

Airway irritative pollutants other than SO₂ may influence FeNO. Tokyo Metropolitan Government and the Cabinet Office of Japan (2003) measured SPM from November 2002 to February 2003 at three sites in Miyakejima Island and average concentrations were 13 to 20 μg/m³, which were lower than JEStd. In the referent island, PM_2.5 was measured from 2011 to 2014 and was lower than the annual JEStd (Kagoshima prefecture, 2019). Horie et al. (2017) and the Okinawa Prefecture Environment White Paper (2016) reported SO₂, SPM and NO₂ were lower than JEStd in the Southwest Islands area in Japan where the reference island belongs. PM_2.5 has dose dependent health effects even in a very low level. For example, Fan et al. (2018) described that an interquartile range (IQR) change in personal exposure to PM_2.5 (16.4 μg/m³) was positively associated with 12.8% increase in FeNO (95% confidence interval, CI: 5.5-20.7%), while nil association was found for ambient PM_2.5. Therefore, airway irritative pollutants other than SO₂ may confound FeNO in this study.

Rapid changes of temperature and atmospheric pressure may affect airway obstruction in asthmatics and wheezers. In Miyakejima island, difference in mean temperature (°C) on the FeNO measurement day and the previous day was 0 in 2008, 0.5 in 2009, 0.1 in 2010, -5.7 in 2011, -0.9 in 2012, 2.6 in 2013 and -2.9 in 2014. In the referent island, that was 1.6. The maximal difference was -5.7°C in 2011 but we could not observe abnormal FeNO deflection.

Our study has some limitations. First, we did not investigate smoking. According to ATS/ERS recommendations (2005), chronically reduced levels of FeNO have been demonstrated in cigarette smokers in addition to acute effects immediately after cigarette smoking. Despite the depressant effect of smoking, smokers with asthma still have a raised FeNO. Subjects should not smoke in the hour before measurements, and short-and long-term active and passive smoking history should be recorded. Since we target children, there should be no smokers. However, the influence of passive smoking could not be denied.

Second, we have not investigated the length of stay in the target and control island. However, this study targets acute respiratory effects. Presence or absence of exposure at the time of survey is important. These data are unlikely to affect exposure to SO₂.

In conclusion, there was no clear significant difference in GM FeNO concentration between students from Miyakejima and a reference island, when the average concentration of SO₂ over a period of 3 months was 22 ppb or less.