Longitudinal study of respiratory function and symptoms in a non-smoking group of long-term officially-acknowledged victims of pollution-related illness

Background Air pollution is known to be a leading cause of respiratory symptoms. Many cross-sectional studies reported that air pollution caused respiratory disease in Japanese individuals in the 1960s. Japan has laws regulating air pollution levels and providing compensation for victims of pollution-related respiratory disease. However, long-term changes in respiratory function and symptoms in individuals who were exposed to air pollution in the 1960s have not been well studied. This study aimed to investigate longitudinal respiratory function and symptoms in older, non-smoking, long-term officially-acknowledged victims of pollution-related illness. Methods The study included 563 officially-acknowledged victims of pollution-related illness living in Kurashiki, Okayama who were aged ≥ 65 years in 2009. Data were retrospectively collected from yearly respiratory symptom questionnaires and spirometry examinations conducted from 2000 to 2009. Results Respiratory function declined significantly from 2000 to 2009 (p < 0.01), but the mean annual changes were relatively small. The change in mean vital capacity was −40.5 ml/year in males and −32.7 ml/year in females, and the change in mean forced expiratory volume in 1 second was −27.6 ml/year in males and −23.9 ml/year in females. Dyspnea was the only symptom that worsened significantly from 2000 to 2009 in both sexes (males: p < 0.05, females: p < 0.01). Conclusions Our results suggest that the high concentrations of air pollutants around 1970 resulted in a decrease in respiratory function and an increase in respiratory symptoms in the study population. From 2000 to 2009, the mean annual changes in respiratory function were within the normal range, even though the severity of dyspnea worsened. The changes in respiratory function and symptoms over the study period were probably due to aging. The laws governing air pollution levels and providing compensation for officially-acknowledged victims of pollution-related illness in Japan may be effective for respiratory disease cause by pollution.


Background
Air pollution is a serious problem throughout the world. Epidemiological studies have reported that air pollution is associated with adverse respiratory effects [1][2][3][4][5][6][7] and increased mortality [8][9][10]. Some areas of Japan experienced high levels of air pollution during the period of rapid economic growth after World War II and many people who lived in these areas complained about respiratory symptoms. In response, the Japanese government implemented air pollution laws. The Basic Law for Environmental Pollution Control was implemented in 1967, and air pollution has decreased since then. The Pollution-Related Health Damage Special Measures Law was implemented in 1969. Japanese citizens who experience health impairment caused by air pollution are certified by prefectural government committees. These officially-acknowledged victims of pollution-related illness qualify for treatment and compensation.
The air in Kurashiki, Okayama had a high sulfur dioxide (SO 2 ) concentration in the 1960s because of the high concentration of industrial areas. The number of officially-acknowledged victims of pollution-related illness in Kurashiki peaked at 3,838 in 1988, which was equivalent to 0.9% of the population of the city. An assessment in 2009 revealed that this number had fallen to 1,392. Of the 1,807 individuals (1,118 males, 689 females) who died from 1988 to 2009, the cause of death was available for 501. These 501 individuals were 326 males (65.1%) and 175 females (34.9%) with a mean age at death of 75.3 years (range 15-90 years); the mean age at death was 72.3 years in males and 76.3 years in females. The causes of death were respiratory disease (n = 216, 43.1%), malignant neoplasm (n = 151, 30.1%), circulatory disease (n = 77, 15.4%), and other (n = 57, 14.4%). The percentage of people aged ≥ 65 years in Japan increased to 23% in 2009, and a similar pattern of aging occurred in Kurashiki. Of the 1,392 victims of pollution-related illness who were still alive in 2009, 774 (55.6%) were aged ≥ 65 years. The mean age of officiallyacknowledged victims of pollution-related illnesses in Kurashiki is increasing, and these individuals are now beginning to develop respiratory illnesses and complications due to aging. These combined health challenges are of major economic and social concern [11].
Many cross-sectional studies have examined the effects of air pollution on respiratory function based on the concentrations or types of pollutants. The Seattle Panel Study [12] reported that the concentration of particulate pollutants was associated with the magnitude of impairment in respiratory function in adults. Almost all studies to date have been cross-sectional, and few longitudinal studies have included measurements of respiratory function. In particular, there is a lack of studies reporting the respiratory symptoms and function of officially-acknowledged victims of pollution-related illness who have received compensation. Furthermore, the effects on respiratory function and symptoms of living in a city that initially had unacceptably high levels of pollution, and later had lower levels of pollution, have not been investigated.
The aim of this study was to conduct a longitudinal assessment of respiratory symptoms and function in older long-term officially-acknowledged victims of pollutionrelated illness in Japan.

Study design and setting
This study was embedded in a longitudinal study of officially-acknowledged victims of pollution-related illness in Kurashiki from 2000 to 2009. The study protocol was approved by the Ethical Committee of Nagasaki University Graduate School of Biomedical Sciences. The study subjects were drawn from the register of officiallyacknowledged victims of pollution-related illness in Kurashiki. Registered victims all met the following conditions as determined by the Public Relief System of Kurashiki City, in accordance with the Pollution-Related Health Damage Special Measures Law (1969) and the Pol lution-Related Health Damage Compensation Law (1973): (1) resided or spent time on activities in an area specified as having significant air pollution (Table 1), and (2) were diagnosed with chronic bronchitis, asthma, or emphysema by a doctor. Registered victims were entitled to various forms of compensation including monthly consultation with a doctor, prescriptions for expectorants and bronchodilators, yearly assessment of respiratory symptoms using a detailed questionnaire, and yearly spirometry, in accordance with the Public Nuisance Countermeasures Law. At the time that certification of pollution-related illness ceased in 1988, the population of Kurashiki was 419,203 (204,958 males, 214,245 females), of which 3,838 were officially-acknowledged victims of pollution-related illness (0.9% of the total population). In 2009, the records of these 3,838 victims were reviewed with the authorization of the Kurashiki City Public Office (Figure 1). At that time there were 1,392 registered survivors (634 males and 758 females). The 774 survivors (55.6%) who were aged ≥ 65 years in 2009 (284 males and 490 females) were screened for inclusion in the study. The majority of these victims were diagnosed with chronic bronchitis (n = 528, 68.2%), asthma (n = 242, 31.3%), or emphysema (n = 4, 0.5%) based on their symptom as described in interviews by authorized doctors. Chronic bronchitis was diagnosed if individuals complained of chronic copious sputum production or persistent coughing, asthma was diagnosed if they complained of recurrent episodes of dyspnea and wheezing, and emphysema was diagnosed if the symptoms did not match the criteria for either bronchitis or asthma. Complete spirometry data for the preceding 10 years were available for most victims. To avoid uneven data distribution and selection bias, 44 victims who did not have complete spirometry data for at least 7 of the years from 2000 to 2009 were excluded. A further 167 victims (116 males, 51 females) were excluded

Air pollution monitoring
The mean daily concentrations of air pollutants were obtained from instruments installed at 21 points in Kurashiki. Measurement of SO 2 concentration was started in 1965, and measurement of nitrogen dioxide (NO 2 ) concentration was started in 1971.

Spirometry measurements
Spirometry was performed by trained staff at Mizushima-Kyodo Hospital using an electronic spirometer (FUDAC ≥ Figure 1 Flow chart showing selection of the study subjects. The study included officially-acknowledged victims of pollution-related illness in Kurashiki who were aged 65 years or older in 2009, and for whom the required data for statistical analysis were available. 70, Fukuda Sangyo Inc., Chiba, Japan). Tests were performed in the sitting position, and were repeated until at least three reproducible forced expiratory curves had been obtained. Forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), and vital capacity (VC) were measured, and the FEV 1 /FVC (%) was calculated. Predicted FEV 1 was calculated using the equation developed by Berglund et al. [13], predicted FVC was calculated using the equation recommended by the Special Committee of Pulmonary Physiology (Japan Respiratory Society, 1993), and predicted VC was calculated using the equation reported by Baldwin et al. [14].

Respiratory symptoms
Respiratory symptoms (dyspnea, wheeze, cough, and sputum production) were assessed by physicians during the same season each year, using the respiratory symptoms questionnaire provided by the government of Japan. Each symptom was graded using a standardized 5-point scale, as follows.

Statistical analysis
The regression coefficients for annual mean changes in FEV 1 , FEV 1 % predicted, FVC, VC, VC % predicted, and FEV 1 /FVC (%) were calculated using simple linear regression analysis. The means and standard deviations were calculated for continuous variables, and a crosstabulation was constructed for categorical variables. The Kolmogorov-Smirnov test was used to examine the distribution of data. Non-normally distributed data were analyzed using nonparametric tests. Data from the time of certification were compared between males and females using the Mann-Whitney U test and the Kruskal-Wallis test. Data were compared between 2000 and 2009 using the Wilcoxon signed-rank test. Mean annual changes in respiratory function were compared between subjects with and without worsening of dyspnea using the Mann-Whitney U test. All analyses were performed using the PASW software package, version 18. A 2tailed value of p < 0.05 was considered statistically significant.   Table 3 shows spirometry findings in 2000 and 2009 by sex. All measurements of respiratory function declined significantly over time (p < 0.01), except for FEV 1 /FVC (%) in both sexes, FEV 1 % predicted in males, and FVC % predicted in females. Table 4 shows comparison of the mean annual changes in spirometry data between results in males and females from 2000 to 2009. Only the mean annual change in VC was significantly greater in males than in females (p < 0.05). Table 5 shows respiratory symptoms in 2000 and 2009 by sex. There was a significant worsening of dyspnea over this time period (males: p < 0.05, females: p < 0.01). In females, there was also a significant worsening of wheeze over this time period (p < 0.01). There was no significant difference between 2000 and 2009 in cough and sputum production. We examined the relationships between worsening of dyspnea and mean annual changes in spirometry measurements (Table 6). In males, the mean annual changes in spirometry measurements were greater in those with worsening dyspnea than those without worsening dyspnea, but the differences were not significant. In females, however, the mean annual changes in all spirometry measurements except FEV 1 /FVC (%) were significantly greater in those with worsening dyspnea than those without worsening dyspnea (all p < 0.05). For the group overall, the mean annual changes in all spirometry measurements, including FEV 1 /FVC (%), were significantly greater in subjects with worsening dyspnea than those without worsening dyspnea (all p < 0.05, data not shown).

Discussion
This paper presents the first longitudinal study of respiratory function and symptoms in officially-acknowledged victims of pollution-related illness who were exposed to air pollution at least 40 years previously, and continued to receive various forms of compensation from the government. Spirometry data at the time of certification, revealed low FEV 1 , FEV 1 % predicted, and FEV 1 /FVC (%). In addition, a high proportion of victims complained of respiratory symptoms. Many victims were diagnosed with chronic bronchitis or asthma. We consider that the respiratory disease in this group was caused mainly by the high environmental levels of SO 2 and NO 2 during 1965 to 1974, because approximately 60% of the victims were first registered during the 1970s. Our results are consistent with those of past reports indicating that high environmental levels of SO 2 (40-60 ppb) and NO 2 (17.4 ppb) can affect the bronchi and bronchioles, resulting in respiratory symptoms such as a cough, sputum, wheeze, and breathlessness [1][2][3][4][5][6][7][15][16][17]. Our results show significant differences in respiratory function between males and females at the time of certification, with FEV 1 % predicted, FVC % predicted, VC % predicted, and FEV 1 /FVC (%) significantly lower in males than in females. These differences are thought to result from the anatomical differences between the sexes. Many studies have shown that lung volumes are smaller in females than in age-matched males [18,19]. Although, FEV 1 % predicted, FVC % predicted, VC % predicted, and FEV 1 /FVC (%) were significantly lower in males than in females, respiratory symptoms were not significantly different between males and females. This differs from previous reports that females appear to be more significantly affected by air pollution than males [20][21][22]. It is unknown whether sex affects the defense mechanisms and responses to air pollution in this study. In the current study, most of the males were working or had worked in a factory, whereas about 40% of females were housewives during the 1960s and 1970s [23,24]. The level of exposure therefore differed by sex, with males exposed to more air pollution than females, which would be expected to result in greater impairment of lung function in males [11]. However, we could not definitively determine the reasons for the differences between males and females observed in this study.
Our longitudinal analysis showed a significant decline in respiratory function from 2000 to 2009. The mean annual change in FEV 1 in this study was −27.6 ml/year in male and −23.9 ml/year in females. The mean annual change in FEV 1 reported for healthy, non-smoking males and females aged > 65 years is −31 to −22 ml/year [25][26][27].
The results of the current study were within this range. Furthermore, a previous study [28] reported that patients with chronic obstructive pulmonary disease had a mean annual change in FEV 1 of 30-80 ml/year, which is 2 or 3 times the mean annual change in of healthy subjects, and higher than the mean annual change of the subjects in this study. The mean annual change in FVC in this study was −33.4 ml/year. The mean annual change in FVC reported for healthy, non-smoking males and females aged > 65 years is −38 to −11 ml/year [25][26][27][29][30][31]. The mean annual change in VC in this study was −40.6 ml/ year in males and −32.7 ml/year in females. The mean annual change in VC reported for healthy, non-smoking males and females aged > 65 years is −35 to -10 ml/year [25][26][27]29,31,32]. The mean annual changes in FVC and VC in this study were therefore within the previously reported ranges for healthy, non-smoking males and females aged > 65 years. We considered that aging is the main cause of the decline in respiratory function observed from 2000 to 2009, with almost no additional effect cause by exposure to air pollutions. There are several possible reasons for the preservation of respiratory function in our study population. The level of air pollution in Kurashiki exceeded environmental standards until 1973, after which it declined as a result of the establishment of environmental standards and the introduction of antipollution laws. The NO 2 level did not exceed the environmental standard from 2000 to 2009, and continued to decrease during this time. The SO 2 level also did not exceed the environmental standard from 2000 to 2009. Downs et al. [33] reported that a reduction in air pollution may slow the annual rate of decline of respiratory function in adults. Another study showed that pollutant related delay in lung development in children can be attenuated if the children move to cleaner geographic areas [34]. In Switzerland, residence in more polluted areas has been associated with reduced respiratory function in adults [35]. We therefore consider that the study population may not have had a significant pollution-related decline in respiratory function from 2000 to 2009 because the concentrations of air pollutants continued to decrease. Another possible explanation is that medical treatment may have prevented deterioration of symptoms in officially-acknowledged victims of pollutionrelated illness. Reduced decline in respiratory function has been reported following treatment with bronchodilators such as inhaled corticosteroids, long-acting bronchial anticholinergic agents, and long-acting β2 agonists [30,[36][37][38]. It is possible that non-smoking individuals with pollutionrelated illness also sought medical treatment at other healthcare institutions, because continuous medical care is guaranteed by the national government. However, this study did not collect detailed data regarding treatment regimen, and we were therefore unable to evaluate the effects of treatment on respiratory function. Dyspnea worsened significantly in both sexes during from 200 to 2009. The mean annual changes in respiratory function measurements were greater in subjects with worsening dyspnea than in those whose symptoms remained unchanged. However, the mean annual changes in respiratory function measurements in subjects with worsening dyspnea were within the range reported for healthy, nonsmoking males and females aged > 65 years. We therefore think that these changes were due to aging. Previous studies [39,40] reported that exacerbation of dyspnea is associated with age-related decline in respiratory function in normal elderly people. In this study, the mean annual changes in respiratory function measurements were greater in those with worsening dyspnea than those without worsening dyspnea in females but not in males. A previous study showed a stronger association between exposure to air pollution and decline in respiratory function in young   females than young males [20]. Several studies have also shown that females are more likely to notice a worsening of respiratory function than males [41][42][43][44]. This may be because males have a greater tolerance to change in respiratory function [44] In addition, dyspnea which is the subjective perception of respiratory discomfort, is a result of complex and multifocal mechanisms [45]. These include abnormalities in the respiratory control system, neurochemical receptors, ventilation, respiratory muscles, gas exchange, and so on [45]. Therefore, we were not able to determine the reasons for the different relationships between worsening dyspnea and mean annual changes in spirometry findings males and females in this study. Appropriate medical treatment may have prevented the worsening of wheezing (in males) and cough and sputum (in both sexes), but the effects of medical treatment on these symptoms could not be determined in the current study. In our population of officially-acknowledged victims of pollution-related illness who were living in an area where the level of air pollutants did not exceed the environmental standards and were receiving compensation set by the Air Pollution Control Law and the revised Public Nuisance Countermeasures Law of Japan, treatment measures were considered to be effective, and decreases in respiratory function over time were mild. However, dyspnea worsened significantly in both sexes from 2000 to 2009, and further intervention for dyspnea is required.
This study has some limitations. First, we evaluated only non-smoking officially-acknowledged victims of pollutionrelated illness, and did not include a control group of subjects who lived in the same area. Second, our study population included more females than males. This may be partly explained by a higher death rate in males, as 65% of the deceased individuals for whom records were available were male. The population of Kurashiki also had a higher proportion of females than males, and more males than females were excluded because they were smokers. Third, spirometry testing was conducted during various seasons. Fourth, differences in social background, employment and lifestyle, which could have resulted in differences in exposure to environmental pollutants, and differences in treatment were not taken into account.

Conclusion
The results of this study suggest that the high concentrations of air pollutants during the 1970s affected respiratory function. However, the mean annual changes in respiratory function in officially-acknowledged victims of pollution-related illness were within the range of healthy, non-smoking males and females aged > 65 years, even though the severity of dyspnea worsened over time. These results suggest that the changes were limited to the effects of aging. The reduction air pollution levels and the laws regarding pollution-related compensation and treatment in Japan may therefore be effective for reducing respiratory disease cause by pollution.

Competing interests
The authors declare that they have no competing interests.
Authors' contributions HS was the principal investigator, contributed to the design of the study, handled funding and supervision, and made critical revisions to the manuscript for important intellectual content. TT designed the study, collected the data, analyzed and interpreted the data, and prepared the manuscript. SH interpreted the data, analyzed the data, handled supervision, and made critical revisions to the manuscript for important intellectual content. RK made critical revisions to the manuscript for important intellectual content. MA collected d and interpreted the data, drafted the manuscript and made critical revisions to the manuscript for important intellectual content. YY, TN, NM, KK, and YY collected, analyzed, and interpreted the data. All authors read and approved the final manuscript.

Acknowledgments
We thank the study participants, technical staff, administrative support team, and our coworkers for their help. In addition, we are grateful to Sue Jenkins, PhD, Associate Professor at the School of Physiotherapy, Curtin University for help in reviewing this manuscript. This study was supported by the Environmental Restoration and Conservation Agency and Mizushima-Kyodo Hospital.