This was a population-based nested case-control study to evaluate the risk of mesothelioma death associated with neighborhood asbestos exposure due to a large-scale AC plant in Amagasaki, Japan. The results demonstrated that ORs in the top quintile were 21.4 for all, 23.7 for males, and 26.0 for females compared to the bottom quintile, suggesting that there were no substantial gender differences in relationship to the magnitude of risk.
In our previous studies, SMRs associated with neighborhood exposure showed a substantial sex difference because the effect of occupational exposure was higher in males than females and not controlled appropriately. We reported SMRs of 6.75 for males and 14.99 for females  because the effect of occupational exposure was included in the national mortality rates used as reference rates, which resulted in lower SMR for males than females. In the study by Kurumatani and Kumagai (2008), SMRs were estimated further by excluding mesothelioma cases that had possible occupational exposure from the numerator only and not excluding occupational exposure from the denominator. As a result, SMR was 2.6 for males and 9.9 for females, showing a much greater difference. Such sex differences were variable, depending on the attributable proportion of occupational exposure. Thus, we adopted a nested case-control design, by adequately taking into account the large effect of occupational asbestos exposure on the evaluation for neighborhood asbestos exposure, collecting enough data related to an individual’s occupational and non-occupational exposure within the whole cohort population.
A recent pooled analysis of 21 AC worker cohorts in Italy  showed a similar tendency in relation to gender difference, with significant increases in mortality from all causes (SMR: men 1.2; women 1.3) and from asbestos-related diseases such as malignant neoplasm of the peritoneum (SMR: men 14.2; women 15.1) and the lung (SMR: 1.7 and 1.7), except for pleura (SMR: 22.4 and 48.1). It also showed that the rate ratio (RR) by Poisson regression analyses for pleural and peritoneal malignant neoplasms increased with cumulative exposure (fiber-type weighted index), while with the time since first exposure it showed an increase in the first four decades, followed by a plateau in both genders for pleural malignant neoplasm. A population-based case-control study in France  demonstrated that ORs for the highest occupational exposure were 13.2 for males and 18.2 for females compared to those never exposed, also indicating no substantial gender differences. Regarding the association with non-occupational exposure, ORs for the highest probability of exposure were 4.6 for males and 7.5 for females compared to those never exposed. Furthermore, the population attributable risk (ARp) for those non-occupational subjects was 20.0% in males and 38.7% in females, suggesting that the overall population-attributable risk of asbestos exposure in females was largely driven by non-occupational exposure, considering the difficulty in assessing domestic or environmental exposure.
In order to adjust properly for occupational exposure, we adopted two independent steps, an exclusion of direct occupational exposure and a rating for the reliability of exposure, and consequently 32 cases and 61 controls were excluded from our analyses. There was no doubt that the experience of directly handling asbestos products could have a significant impact on the evaluation for non-occupational exposure, however, it could not be used for proper assessment of occupational exposure due to lack of information on exposure intensity. The remaining cases and controls after exclusion were classified into three mutually exclusive tiers that were based on the reliability of exposure and contributed to adequate adjustments by using a conditional logistic regression model. We observed that the risk magnitude of occupational asbestos exposure was comparably higher than that of non-occupational exposure, demonstrating that ORs of “Convincing” compared to “None” were 25.4 for all, 40.0 for males, and 6.9 for females to suggest that the sex differences seemed to be fair.
To assess neighborhood exposure, we used cumulative indices of individuals’ residence-specific asbestos exposures, calculated by the relative concentration of airborne asbestos fibers multiplied by the duration at each residence during the potential exposure period (1957–1975). Many studies have evaluated neighborhood asbestos exposure by distance or by the simulated relative concentration of airborne asbestos fibers based on the nearest residence from the emission point. In order to clarify the effect of distance on the contribution to our cumulative indices, we chose only one residence, which addressed the maximum (highest) value of residence-specific exposure and compared characteristics of the cases and controls. Table 5 shows the distribution by stratified levels of the cumulative dose of neighborhood exposure (Levels 1 to 5) and indicates that approximately 90% of both cases and controls in Level 5 were classified to the same Level 5 of residence-specific exposure. Similarly, in Level 4 of the cumulative dose of residence-specific exposures, over 80% of both cases and controls were classified to the same Level 4 of residence-specific exposure. These findings suggested that just a single residence could contribute to the evaluation of cumulative neighborhood exposure in most subjects (approximately 80–90%). For the relative concentration and duration, there were no substantial differences in distribution between cases and controls in the same exposure levels. However, in relationship to the nearest residence in which a subject lived for at least one year, we did not observe an obvious association with cumulative exposure levels. Moreover, we observed that 26.5% of cases and 22.1% of controls had lived within 500 m of the AC plant for over a year, and 4.1% of cases and 2.9% of controls had lived more than 2 km from the AC plant for over a year in Level 5, which is supposedly the highest risk group.
Because it is difficult to evaluate various asbestos exposures independently, most studies report risks associated with several combined non-occupational exposures such as neighborhood, domestic, and household. Although few studies of neighborhood exposure have been reported, and there is large heterogeneity among results from those studies, a recent meta-analysis reported an increased risk of mesothelioma death by exposure types, with a summary relative risk estimate (SRRE) of 5.33 (95% CI: 2.53–11.23) from neighborhood exposure, 4.31 (95% CI: 2.58–7.20) from domestic exposure, and 2.41 (95% CI: 1.30–4.48) from household exposure . Other researchers reported a clear increasing trend in relationship to the cumulative exposure index, demonstrating that the highest OR was 23.3 (95% CI: 2.9-186.9), but they did not assess the exclusive estimates that could be associated with neighborhood, domestic, and household exposures . Magnani and colleagues conducted a case-control study in Casale, Italy, and showed a significant increased risk of mesothelioma in a population that had only lived in the city, with an OR of 20.6 (95% CI: 6.2–68.6) . In the same city, another study estimated OR in relationship to distance from an AC plant, however, the results were thought to be due to combined exposure of the neighborhood and household . In another study that looked at distance from an AC plant in Bari, Italy, the highest OR (5.29 [95% CI: 1.18–23.73]) was for people living within a range up to 500 m from the center of the plant . A population-based case-control study conducted in six areas in Italy, Spain, and Switzerland estimated that the OR for high probability of environmental exposure (living within 2000 m of asbestos mines, AC plants, asbestos textiles, shipyards, or brakes factories) was 11.5 (95% CI: 3.5–38.2), while the OR for moderate or high probability of domestic exposure was 4.81 (95% CI: 1.8–13.1) . Classification of non-occupational exposure in existing literature is considerably heterogeneous. For example, different or combined definitions of environmental asbestos exposure have been used in various published studies . However, regardless of the different indicators and the range of categories in those studies, the magnitude of association indicated by OR seems to be fairly consistent with our results.
There were some limitations to our study. First, we observed differences in the types of respondents between cases and controls (Table 1). The highest proportion of respondents among controls was the exposed subject, while the highest proportion of respondents among cases was a spouse or child of the exposed subject. Case interviews were thought to contain critically important information for the Ministry of Environment to make decisions about compensation certification, hence, the bereaved families had detailed information about the cases’ occupational histories and any other possibilities related to asbestos exposure at that time. In contrast, most families of the controls, even though they were spouses and children, were not well informed about details of the indexed subjects’ occupational and residential histories throughout their lifetime. We therefore needed to interview control subjects as well as their families to collect data with the same accuracy as that for the cases.
A second limitation was that the consent rate for interviews of the bereaved families of cases seemed to be low (62.1%). However, the psychological effects on bereaved families due to the miserable epidemic of mesothelioma deaths within a small area in Amagasaki City would also have to be considered. In the municipal administrative reports, there were various reasons for non-consent: 1) unwilling to look back on the past, 2) not well informed about history of the indexed subject, 3) recognized as an industrial compensation, 4) no bereaved families in the city, and 5) other reasons. Although the consent rate was 64.9% among controls when Amagasaki City Government first asked about contact availability, after we sent advance questionnaires to the controls, the consent rate dropped to 39.5%, which is more indicative of a consent rate likely to be observed in a survey of the general population.
Third, we obtained the list of mesothelioma deaths from Japanese vital statistics, which began to record the primary cause of death according to ICD-10 in 1995, and the cause of death was posted from a death certificate. Although the mesothelioma diagnosis was not histologically confirmed, the frequency of misclassifications on the cause of mesothelioma deaths qualified by a specialist was thought to be negligible. Fourth, the simulated asbestos concentrations were determined from several assumptions, and the relative numbers ranged from 1 to 107 (unit, 1/m3), based on a 10 m x 10 m grid resolution.
The final limitation was that we used cumulative indices of residence-specific exposures to evaluate neighborhood exposure, however, It might be necessary to consider more specific working area of daily living, such as walking to school, gardening, and agricultural working.
A recent world-wide trend assessment for excess risk of mesothelioma deaths using a period analysis from 1996 to 2005 demonstrated a significant increasing rate in Japan of 3.9% annual percent change, with overall quite large disparities between countries . Similarly, our previous studies in Amagasaki City demonstrated that mesothelioma deaths increased significantly in long-term resident cohorts both in males and females from 2002 to 2015, with consistent trends in the three periods from 2002–2006, 2007–2011, and 2012–2015. A recent paper suggested that non-occupational exposure mainly contributed to the overall population attributable risk, especially for females . Although it was only a municipal administrative report in Amagasaki City, a gradual increase in mesothelioma deaths from non-occupational exposures was observed for males (19% during 2002–2007, 35% during 2008–2015) and females (39% during 2002–2007, 73% during 2008–2015). One possible consideration might be an age-cohort effect, in which the risk of mesothelioma remains and never diminishes for the people who were exposed in early life, even after removal of the AC plant. Therefore, we should continue to pay close attention to trends in the risk of mesothelioma death associated with low-dose asbestos exposures including neighborhood exposure.