Background The risk of malignant mesothelioma (MM) increases in proportion to the cumulative exposure and the third or fourth power of time since the first exposure to asbestos. However, little is known about the risk of MM after more than 40 years since the first exposure, as most epidemiological studies are not followed for sufficient time.
Methods Data from six cohort studies of exposed workers and two cohorts of residential exposure were pooled. A nested case control design combines cases and controls for time and age. Conditional logistic regression modeled the relationship between the time elapsed since first exposure and the risk of MM.
Results The combined data included 22,048 asbestos-exposed individuals (5,769 women), 707 pleural MM (165 women), and 155 peritoneal MM cases (32 female). The median time since first exposure for MM pleural cases was 38.4 years (IQR 31.3-45.3). The median duration of exposure for pleural MM cases was 3.75 years (IQR 0.7-18.2). The rate and risk of pleural MM increased to 45 years after the first exposure, and then appeared to increase more slowly since the first exposure. The rate of increase in peritoneal MM over the 10 to 50 years since the first exposure has continued to increase
Conclusions Exposure to asbestos poses a long-term risk of developing pleural and peritoneal mesothelioma, which increases after the end of exposure. While the rate of increase seems to begin to stabilize after 40 to 50 years, no one survives long enough for the excess risk to disappear.
Uncommon rates of pleural and peritoneal MM for the 5-year categories since the first exposure and duration of exposure were created by dividing the number of cases by the number of person-years in each 5-year category since the first exposure and duration of exposure and multiplying by 10,000.
Conditional logistic regression examined the relationship between time elapsed since first exposure and pleural and peritoneal MM. A clearance term (used in Berry 20126) was included in the models to examine changes in the temporal exponent (power of elapsed time since first exposure). The temporal exponent was also examined as a function of exposure time. The models have been adjusted for sex. The source of asbestos exposure (mines and factories, asbestos cement plant, amosite plant, environmental and railway exposure) and the type of asbestos exposure (crocidolite, amosite and mixture (chrysotile and crocidolite) also examined which variables were included in the final model based on its statistical significance (p <0.05) after its inclusion in the model All statistical analyzes and data manipulation were performed in Stata V .12.20
In this study, data from six occupational cohort studies and two residential cohort studies were pooled to examine MM rates after more than 40 years of first exposure to asbestos. For the pleural MM, the graph of the relationship of rates with the time elapsed since the first exposure begins to flatten approximately 45 years after the first exposure, suggesting that the MM rate does not continue to increase as rapidly as the power of the time elapsed since the first exposure. Crocidolite conferred the greatest risk of pleural MM compared to amosite and mixed fibers. For peritoneal MM, the rate continued to increase proportionately with the time elapsed since the first exposure and shows no sign of flattening.
Together, the Wittenoom cohorts contributed more cases of pleural MM than the other cohorts combined. The duration of exposure was shorter among the Wittenoom cohorts than among the Italian cohorts. Cohorts also differed in the intensity of their exposure. Workers at the Wittenoom, Eternit and Amosite factories have experienced a significant number of deaths from asbestosis and other respiratory causes, but this is not the case for Wittenoom residents, Eternit's wives or railwaymen. An increased risk of mesothelioma occurs when the load of lung fibers is greater and the cumulative dose is higher, as it may have been in cohort members with an excess of asbestos-related diseases. Asbestos fibers migrate into the pleural space as a result of interstitial fluid, a process exacerbated by chronic inflammation, which is also related to the amount of fiber retained in the lungs22.
Malignant mesothelioma has always been difficult to diagnose and has often been misclassified as lung cancer. Given the relatively small number of mesothelioma cases, any potential misclassification could have a significant impact on our results. Therefore, controls were periodically performed among all incident cases to confirm the diagnosis. Cases of cohort incidents of Wittenoom workers and WA residents were pathologically and histologically verified by the WA Mesothelioma Registry and a group of anatomopathology experts for cases residing outside the WA. Cases of mesothelioma in the Casale Monferrato region of Italy have been pathologically evaluated and confirmed in two studies23, 24. More recent studies of Eternit cohorts of workers and wives on the review of the diagnosis undertaken by the mesothelioma registry, in which pathology and immunohistochemistry.8 No systematic effort of this type was made for cases reported by death certificate, with the exception of an effort to collect clinical records: however, the results of these earlier studies suggest a reassuring level of diagnostic accuracy. In the region of Veneto (Italy), where the vast majority of railway workers live, every effort has been made to verify any new diagnosis of mesothelioma with clinical information since 1984.
This study shows that women tend to have a longer latency period than men for mesothelioma. Most of the women in this study had exposure to asbestos from residential or domestic sources, which was generally lower than that observed in the workplace. It has been shown elsewhere that exposure to asbestos is associated with a longer latency period25. Among Wittenoom women, those who worked for the asbestos company had a shorter latency period than those with similar cumulative exposure during their stay in Wittenoom, 26 although Wittenoom workers' latency was shown to be independent of degree of exposure.6
Amphibole fiber clearance was observed from lung tissue in animal experiments and post-mortem pulmonary fiber counts in occupationally exposed workers. Rats exposed to crocidolite by inhalation for 6 months showed that 73% of the fibers had been removed 18 months after the last exposure. The amount of chrysotile in the lungs has not increased with continued inhalation exposure, suggesting a high kill rate for chrysotile.27 Among crocidolite miners in South Africa, a half-life of 6 years was estimated, 28 corresponding to an elimination rate of 12% per year.29 The rate of elimination of lung burden in women assemblers of gas masks of the Second World War, exposed to large quantities of crocidolite over a short period of time it was estimated at 7.5% per year.30 The annual release of about 9% is estimated to be Wittenoom21 workers. The elimination of asbestos fibers can explain the flattening profile of pleural mesothelioma, the rate of which does not increase as rapidly as the production time. In contrast, for peritoneal mesothelioma, the risk increases more rapidly than the time spent at maximum power, suggesting that the removal of asbestos fibers from the lungs over a long period may be less important, perhaps at because of the temporal pattern of fiber migration to the peritoneum in the most exposed individuals in whom the majority of peritoneal mesotheliomas occur. In this study, we found no significant effect on clearance in the peritoneal mesothelioma model.
Reductions in the rate of malignant mesothelioma have been reported in several countries in recent years31-33. In Norway, the rate of mesothelioma among men increased from 1.6 per 100,000 in 2000-2004 to 1.5 per 100,000 in 2005-2009. The rate among women was much lower at 0.3 per 100,000 but had not declined31. Similarly, in the United States, mesothelioma rates decreased from 2005, but no change was observed in women. These declining rates may reflect the reduced use of asbestos-based products in these countries beginning in the 1970s, 32, 33. These decreases are consistent with what is observed in this study. We found that the rate of increase in pleural mesothelioma decreased when there was no such reduction for peritoneal mesothelioma, confirming that these two neoplasms should be examined separately.
Previous work indicated a lower mesothelioma rate in children exposed for the first time to Wittenoom at the age of 15 (47 years out of 100,000) compared to those exposed at age 15 (112 years on 100,000) .7 More recent work has shown that the mesothelioma rate of the pleura decreased to 34 per 100,000 among people exposed to asbestos aged less than 15 years for the first time34. However, those exposed as children have more time to live after exposure and their lifetime risk, according to this study, could therefore not be lower than those exposed to advanced ages. An increased risk reduction in patients with long latency indicates that the effect of asbestos does not occur in the early stages of carcinogenesis.
Exposure to asbestos poses a long-term risk of developing pleural and peritoneal mesothelioma, which increases after cessation of exposure despite a slight release of fibers. Although the rate of increase seems to stabilize for pleural mesothelioma after 40 to 50 years, no one survives long enough for the risk to go away.