Are children more vulnerable to mesothelioma than adults? A comparison of mesothelioma risk among children and adults exposed non-occupationally to blue asbestos at Wittenoom.

OBJECTIVES: The presence of asbestos in public buildings is a legacy of past asbestos use in many developed countries. Of particular concern is the amount and current condition in schools and the vulnerability of children to mesothelioma. Our aim was to compare the risk of mesothelioma between those exposed to blue asbestos as children and as adults at Wittenoom. METHODS: Public sources were used to establish the Wittenoom residents' cohort. Mesothelioma incidence rates per 100 000 person-years at risk were derived for those first exposed to asbestos at Wittenoom as children (<15 years) or adults separately. Proportional hazards survival models examined the slope of the exposure-response relationship between asbestos exposure and incidence of mesothelioma in different sex and age groups. RESULTS: The mesothelioma rate was lower among those first exposed as children (76.8 per 100 000) than those first exposed as adults (121.3 per 100 000). Adjusting for cumulative exposure to asbestos and sex, those exposed as adults had a greater risk of mesothelioma (adjusted HR 2.5, 95% CI 1.7 to 3.7). The slope of the exposure-response relationship did not differ between those exposed as children and those exposed as adults. CONCLUSION: We found no greater susceptibility to mesothelioma among those first exposed to asbestos as children than those first exposed as adults. However, given the long latency of mesothelioma, and the greater years of life yet to be lived by the Wittenoom children, it is likely that there will be more cases of mesothelioma in the future among those first exposed as children.

Familial aggregation of malignant mesothelioma in former workers and residents of Wittenoom, Western Australia.

Clustering of cases of malignant mesothelioma within families has often been observed, but disentangling genetic and exposure effects has not been done. Former workers and residents exposed to crocidolite at Wittenoom, Western Australia, where many families shared exposure to asbestos, have had high rates of mesothelioma. Our study aimed to estimate the additional risk of mesothelioma in relatives, after allowance for common exposure to crocidolite. More than 11,000 former asbestos workers and residents from Wittenoom have been followed up in cancer and death registries. Levels of exposure for all members of the Wittenoom cohorts have been estimated previously. Relationships between family members of all mesothelioma cases were established from questionnaires, birth and death certificates. Expected numbers of cases of mesothelioma were estimated by fitting a Weibull survival model to all data, based on time from first asbestos exposure, duration and intensity of exposure and age. For each family group, the earliest case was considered the index case. Predicted risk was estimated for each subject from the time of diagnosis of the index case. Familial risk ratios were estimated by dividing observed cases by the sum of risks of all same degree relatives of index cases. There were 369 family groups with at least one case of mesothelioma and a further 25 cases of mesothelioma among relatives in the same families, with 12.9 expected. The risk ratio for blood relatives was 1.9 (95% confidence interval [CI] = 1.3-2.9, p = 0.002). These findings suggest an important, but not large, genetic component in mesothelioma, similar to many other cancers.

Retinol supplementation and mesothelioma incidence in workers earlier exposed to blue asbestos (Crocidolite) at Wittenoom, Western Australia.

Owing to the high rates of malignant mesothelioma in workers exposed to crocidolite earlier at Wittenoom and evidence of protection against cancer by vitamin A, a population-based cancer prevention programme providing retinol supplements (25 000 IU/day) was commenced in 1990. The former workers at Wittenoom known to be alive and living in Western Australia in June 1990 constitute the study population. The participants were classified into two groups: those who received supplemental retinol (intervention group) and those who received none (comparison group). The relative rate of mesothelioma for those receiving retinol was estimated using Cox regression, adjusting for cumulative asbestos exposure and age at first exposure to asbestos. Nine hundred and twenty-eight former Wittenoom workers received retinol at some stage of the programme, whereas 1471 workers never received retinol (comparison group). Those who received retinol were younger, had a greater exposure to asbestos and smoked less than the comparison group. There were 65 cases of mesothelioma in the retinol group and 88 in the comparison group. After adjustment, the hazard ratio was 0.99 (95% confidence interval=0.70-1.41). This result did not alter when the participants who received only retinol once or those who received beta-carotene earlier were excluded from the analysis. In conclusion, this study provides little support for possible preventive effects of retinol against mesothelioma in workers exposed to blue asbestos.

Prediction of mesothelioma and lung cancer in a cohort of asbestos exposed workers.

BACKGROUND: Several papers have reported state-wide projections of mesothelioma deaths, but few have computed these predictions in selected exposed groups. OBJECTIVE: To predict the future deaths attributable to asbestos in a cohort of railway rolling stock workers. METHODS: The future mortality of the 1,146 living workers has been computed in term of individual probability of dying for three different risks: baseline mortality, lung cancer excess, mesothelioma mortality. Lung cancer mortality attributable to asbestos was calculated assuming the excess risk as stable or with a decrease after a period of time since first exposure. Mesothelioma mortality was based on cumulative exposure and time since first exposure, with the inclusion of a term for clearance of asbestos fibres from the lung. RESULTS: The most likely range of the number of deaths attributable to asbestos in the period 2005-2050 was 15-30 for excess of lung cancer, and 23-35 for mesothelioma. CONCLUSION: This study provides predictions of asbestos-related mortality even in a selected cohort of exposed subjects, using previous knowledge about exposure-response relationship. The inclusion of individual information in the projection model helps reduce misclassification and improves the results. The method could be extended in other selected cohorts.

Mesothelioma and asbestos.

The current state of knowledge concerning mesothelioma risk estimates is reviewed. Estimates of the risk of mesothelioma exist for the commercial asbestos fiber types chrysotile, amosite and crocidolite. Data also exist on which to assess risks for winchite (sodic tremolite) and anthophyllite asbestos. Uncertainty in estimates is primarily related to limitations in measurements of exposure. Differences in the dimensions of the various fiber types and of the same fiber types at different stages of processing add a further complication. Never-the-less, in practical terms, crocidolite presents the highest asbestos related mesothelioma risk. The risk associated with sodic tremolite (winchite) appears to be similar. In chrysotile miners and millers, the mesothelioma risk has been linked with exposure to asbestiform tremolite. Exposure to chrysotile in a pure form seems likely to present a very low if any risk of mesothelioma. While the majority of mesothelial tumors result from exposure to the asbestos minerals, there are other well established and suspected etiological agents. While a practical threshold seems to exist for exposure to chrysotile, it is unlikely to exist for the amphibole asbestos minerals, especially for crocidolite. To date there is no indication of an increased risk of mesothelioma resulting from non-commercial fiber exposure in the taconite industry.

An overview of the risk of lung cancer in relation to exposure to asbestos and of taconite miners.

Exposure-response relationships between the relative risk of lung cancer and quantitative measures of exposure to asbestos are available from a number of epidemiological studies. Meta-analyses of these relationships have been published by Lash et al. (1997) [Lash, T.L., Crouch, E.A.C., Green, L.C., 1997. A meta-analysis of the relation between cumulative exposure to asbestos and relative risk of lung cancer. Occup. Environ. Med. 54, 254-263] and Hodgson and Darnton (2000) [Hodgson, J.T., Darnton, A., 2000. The quantitative risks of mesothelioma and lung cancer in relation to asbestos exposure. Ann. Occup. Hyg. 44, 565-601]. In this paper, the risks derived in these meta-analyses have been compared. Lash et al., concentrated on process and found that the risk of lung cancer increased as the asbestos is refined by processing. Hodgson and Darnton concentrated on fibre type and found that the risk was highest for exposure to amphibole asbestos (crocidolite and amosite), lowest for chrysotile and intermediate for mixed exposure. Some of the differences between the conclusions from the two meta-analyses are a consequence of the choice of studies included. The range of asbestos types included in the studies in the analysis of Hodgson and Darnton was wider than that in Lash et al., enabling differences between fibre types to be analyzed more readily. There are situations where occupational exposure to chrysotile asbestos has shown no detectable increase in risk of lung cancer. Taconite miners have shown no increased risk of mortality due to lung cancer.

Projected mesothelioma incidence in men in New South Wales.

OBJECTIVES: Based on observed numbers of incident mesotheliomas since 1972, to predict future numbers in men in New South Wales. METHODS: The incidence of mesothelioma was modelled in two ways. First by using an age/birth cohort model, and second by using a model based on potential exposure to asbestos in terms of age and calendar year. The latter model included a term for clearance of asbestos fibres from the lungs, and a term for diagnostic fraction. The age and calendar year model was based on the model introduced by Hodgson and colleagues but replaced piecewise effects by smooth functions represented by cubic splines. RESULTS: The number of mesotheliomas between 2004 and 2060 was predicted as 6690 with the age-cohort model and as 6779 by the age and calendar year model, with peak annual numbers of 187 in the year 2021 and 196 in the year 2014 with the two models respectively. CONCLUSIONS: The pattern of parameter estimates in the two models was in accord with the known use of amphibole asbestos in Australia. The predicted peak year of 2014-21 is 30-35 years after the phasing out of amphibole use, and this period is in accord with predictions for the UK and the US; in the latter country the peak was 10-15 years earlier corresponding to a marked decline of amphibole use in and following the 1960s.

Age and sex differences in malignant mesothelioma after residential exposure to blue asbestos (crocidolite).

BACKGROUND: Blue asbestos was mined and milled at Wittenoom, Western Australia, from 1943 until 1966. Various public records were used to establish a cohort of residents of the nearby township. Mine tailings were distributed throughout the town. AIMS: To report the incident number of malignant mesotheliomas that have occurred in residents of the town who did not work at the mine or mill; and to determine if female subjects are more susceptible to asbestos exposure than male subjects, and if children are more susceptible than adults. SUBJECTS AND METHODS: A total of 4,768 residents of the town of Wittenoom have been followed up in cancer and death registries. RESULTS: There were 67 cases of mesothelioma, and 64 deaths with mesothelioma to the end of 2002. The mortality rate with mesothelioma increased with increasing residence duration, time since first exposure, and estimated cumulative exposure. The mesothelioma mortality rate was consistently lower for female subjects when compared with male subjects, but the dose-response curve was steeper for female subjects. The rate was lower in those first exposed as children compared with those first exposed at > or = 15 years of age. The dose-response slope for asbestos exposure and mortality from mesothelioma was not different between those who were first exposed as children than those who were first exposed at > or = 15 years of age. CONCLUSIONS: Former residents of a crocidolite mining town have a high rate of mesothelioma. The rate is higher in male subjects and those > or = 15 years of age at first exposure, but women have a steeper dose-response curve.

Relative risk and acceleration in lung cancer.

For a substance that increases the relative risk of disease, it does not necessarily follow that the proportion of cases due to exposure to the substance is the same as the attributable fraction in the exposed. An alternative explanation is that the substance has accelerated the occurrence of disease and, therefore, played a role in all cases. When the incidence of disease with time follows the Weibull distribution, it is well known that the proportional hazards model and the accelerated failure time model are equivalent. The purpose of this paper is to provide a numerical illustration of the relationship between the relative risk and the acceleration time of occurrence of cases. A Weibull distribution is a good approximation for lung cancer death rates up to the age of 80 years. The numerical relationship between the relative risk and the time by which cases are accelerated is given for lung cancer deaths occurring at ages of 40-75 years with relative risks of 1.01-3. As an example, for a death due to lung cancer at age 60 years in a smoker, relative risks of 2 and 1.1 due to occupational exposure to a substance correspond to accelerations of 5.2 years and 8 months, respectively.

Comparing the part with the whole: should overlap be ignored in public health measures?

BACKGROUND: In public health, health outcomes such as cancer incidence or mortality of subgroups are often compared with health outcomes of the whole population. Our objective was to explore the effect of overlap that occurs in such comparisons and to develop a correction factor to adjust the test statistics and confidence intervals to allow for the effect in situations where the full data are not available. METHOD: The standard error of a difference between a statistic calculated for a subgroup and for the whole population was derived theoretically both ignoring and allowing for overlap. The ratio of these standard errors was defined as the correction factor. Cancer incidence and death data (1997-2001) for the Australian state of New South Wales (NSW) were examined to demonstrate the utility of the correction factor. RESULTS: If the overlap is ignored, significance tests are conservative and confidence intervals too wide. In an example with an overlap of 12%, the correction factor was 1.13 and the significance level of 0.08 was corrected to 0.05 by taking the overlap into account. CONCLUSIONS: The overlap may not be of concern if the result is significant or if the subgroup is <10% of the whole population, but if the overlap is greater than 10% it should not be ignored. The easiest way of allowing for overlap is to use a correction factor, calculated from the amount of overlap, to adjust analyses that ignore overlap.

Nonuniform risk of bloodstream infection with increasing central venous catheter-days.

OBJECTIVE: To determine whether the conventional rate for central venous catheter (CVC)-associated bloodstream infection (BSI) accurately reflects risk for patients exposed for a variety of in situ periods. PATIENTS AND METHODS: Intensive care unit patients (n = 1,375) were monitored for 7,467 CVC-days. They were monitored until catheter removal, until diagnosis of CVC-associated BSI, or for 24 hours after discharge. RESULTS: The BSI rate was 3.7 per 1,000 CVC-days. Ninety-three percent of these patients had CVCs in situ for 1-15 days. These patients were exposed to 59.7% of all CVC-days; the remaining 7% were exposed to 40.3% of all CVC-days. BSI rates stratified by exposure periods of 1-5 and 6-15 days were 2.1 and 4.5 per 1,000 CVC-days, respectively. The rates for 16-30 and 31-320 days were 10.2 and 2.1 per 1,000 CVC-days, respectively. The probability of BSI with a CVC in situ was 6 in 100 by day 15, 14 in 100 by day 25, 21 in 100 by day 30, and 53 in 100 by day 320. CONCLUSION: The conventional aggregated rate better reflects the risk for the majority of patients rather than for patients exposed to the majority of CVC-days. It does not reflect the true probability of risk for all exposures, especially beyond 30 days. CVCs in situ from 1 to 15 days had less risk of BSI than CVCs in situ more than 15 days, which may explain why scheduled CVC replacement at days 5 to 7 has not been found beneficial.

A randomized controlled trial of cyclosporine withdrawal in renal-transplant recipients: 15-year results.

BACKGROUND: In renal transplantation, the immunosuppressive efficacy of cyclosporine is counterbalanced by its nephrotoxicity. Although cyclosporine improves short-term graft survival, its long-term effects are unclear. METHODS: Recipients of first cadaver renal transplants were randomized into three groups between 1983 and 1986: azathioprine and prednisolone alone (AP, n = 158), long term cyclosporine alone (Cy, n = 166), and short-term cyclosporine followed by azathioprine and prednisolone (CyAP, n = 165). All groups received methylprednisolone induction. RESULTS: There were no significant differences in patient survival at 15 years (48 vs. 56 vs. 51%, P = 0.14), and 15-year graft survival (censored for death) in those patients in the CyAP group (47 vs. 44 vs. 59%, P = 0.06) was not significantly different statistically. When deaths or graft losses before 12 months were censored, the differences in 15-year graft survival between the groups were significant (58%, 51%, 70%, P = 0.01). The CyAP group also had lower mean serum creatinine at all time points beyond 3 months posttransplant out to 10 years (143 vs. 169 vs. 131 micromoles/L, P = 0.04). Per protocol analysis, after censoring patients at change in therapy, increased the observed differences in 15-year graft survival between the groups (54 vs. 38 vs. 65%, P = 0.01). CONCLUSION: Survival and function of first cadaveric kidney transplants is improved by use of short-term cyclosporine followed by azathioprine and prednisolone. Long-term cyclosporine use reduces long-term graft survival.

Silicosis and lung cancer: a mortality study of compensated men with silicosis in New South Wales, Australia.

BACKGROUND: Lung cancer mortality has been found to be in excess in several groups with silicosis, but allowance for smoking was not always possible. We investigated the lung cancer mortality in men with silicosis in New South Wales, Australia, who were compensated, making allowance for smoking habits. METHODS: A mortality study of 1467 men with silicosis in New South Wales who were compensated was carried out comparing observed mortality with that expected from the New South Wales death rates adjusting for age and period. Their smoking habits were compared with national survey smoking rates and the expected number of lung cancer deaths adjusted for smoking. Cases were coded for occupation and industry. RESULTS: The observed mortality was higher than expected, but the only site of cancer showing a significant excess was the lung. The group with silicosis had smoked more than the national rates. After adjusting for smoking the standardized mortality ratio for lung cancer was 1.9 (95% confidence interval 1.5-2.3). Although there were differences in lung cancer mortality between industries and occupations, these differences were not statistically significant. CONCLUSIONS: The excess lung cancer death rate may not be entirely due to silica exposure because compensation may have been influenced by the presence of chronic obstructive respiratory disease and there is some evidence that the presence of this disease increases lung cancer risk independently of smoking.

Health impacts of pesticide exposure in a cohort of outdoor workers.

We compared mortality of 1,999 outdoor staff working as part of an insecticide application program during 1935-1996 with that of 1,984 outdoor workers not occupationally exposed to insecticides, and with the Australian population. Surviving subjects also completed a morbidity questionnaire. Mortality was significantly higher in both exposed and control subjects compared with the Australian population. The major cause was mortality from smoking-related diseases. Mortality was also significantly increased in exposed subjects for a number of conditions that do not appear to be the result of smoking patterns. Compared with the general Australian population, mortality over the total study period was increased for asthma [standardized mortality ratio (SMR) = 3.45; 95% confidence interval (CI), 1.39-7.10] and for diabetes (SMR = 3.57; 95% CI, 1.16-8.32 for subjects working < 5 years). Mortality from pancreatic cancer was more frequent in subjects exposed to 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (SMR = 5.27; 95% CI, 1.09-15.40 for subjects working < 3 years). Compared with the control population, mortality from leukemia was increased in subjects working with more modern chemicals (standardized incidence ratio = 20.90; 95% CI, 1.54-284.41 for myeloid leukemia in the highest exposure group). There was also an increase in self-reported chronic illness and asthma, and lower neuropsychologic functioning scores among surviving exposed subjects when compared with controls. Diabetes was reported more commonly by subjects reporting occupational use of herbicides. These findings lend weight to other studies suggesting an association between adverse health effects and exposure to pesticides.

Socio-economic mortality differentials in Sydney over a quarter of a century, 1970-94.

OBJECTIVE: To examine trends in socio-economic differentials in all-cause mortality in Sydney over a 25-year period (1970-94). METHODS: Five measures of single indicators (two for occupation, two for education and one for income) and a composite measure of socio-economic disadvantage based on Census data (the Australian Bureau of Statistics' Index of Relative Socio-Economic Disadvantage) were used as indicators of socio-economic status by local govemment area. The relationship between mortality and socio-economic status was examined using quintiles based on these six measures of socio-economic status. RESULTS: Socio-economic differentials in mortality were evident for males and females for all periods, and over the 25-year period the relative socio-economic differentials did not decline. For males, the socio-economic status differential in mortality widened, irrespective of socio-economic status indicator used, whereas for females it widened only when certain socio-economic indicators were used: occupation (unemployment measure) and income, but was not significant for the other single indicators or for the composite indicator. CONCLUSIONS: Sydney trends of widening inequalities are generally similar to those reported for Britain and for other industrialised countries, suggesting that this is a common phenomenon and that policies to reduce health inequalities over the past quarter of a century have not been effective.

Analytic methods for comparing two dichotomous screening or diagnostic tests applied to two populations of differing disease prevalence when individuals negative on both tests are unverified.

Two dichotomous screening tests may be compared by applying both tests to all members of a sampled population. For individuals with a positive result on either test the disease status may be verified by a reference standard, but for individuals negative on both tests the disease status may be unverified because the probability of disease is so low that further investigation is costly, unacceptable and perhaps unethical. If the tests have been applied to samples from two populations which have different disease prevalences then unbiased estimates of the true positive and false positive rates of each test, the prevalences in the two populations, and two parameters representing dependence between the two tests can be estimated using maximum likelihood methods. The methods are based on the assumption that the sensitivities and specificities of the two tests, and the dependencies between the tests, are independent of prevalence. A test of goodness of fit provides a test of this.

Differences in muscle fiber growth in slow-twitch muscles of the forelimb and hindlimb of the rat: role of the pituitary and food intake.

This investigation tested the hypothesis that differences in the growth of fore- and hindlimb muscles in the rat are regulated by the pituitary and food intake. Using morphometric techniques, the growth of muscle fibers was compared in two slow-twitch muscles, the flexor carpi ulnaris (FCU) of the forelimb, and the soleus of the hindlimb, in male Wistar rats fed ad libitum, food restricted (FR) or hypophysectomized (hypox) from age 60 days. Growth was defined as an increase in fiber diameter and/or type 1 fiber percentage. The soleus had larger diameter fibers than the FCU in controls and FR, but not hypox rats. The growth in diameter, between 60 and 180 days, of both types 1 and 2 fibers in the soleus and type 2 fibers in the FCU was inhibited by hypox and, to a lesser extent, FR. Neither type 1 fiber diameter nor percentage of type 1 fibers in the FCU increased with age nor was it affected by hypox or FR. The percentage of type 1 fibers was higher in the soleus than the FCU and was further increased in the soleus of hypox rats. Food restriction produced a smaller rise than hypox in type 1 fiber percentage in the soleus. Thus, differences in fore- and hindlimb muscle fiber growth are modulated by pituitary hormones and, to a lesser extent, by food intake.