Enrico Pira

Neurotoxic effects of aluminium among foundry workers and Alzheimer's disease.

BACKGROUND In a cross-sectional case-control study conducted in northern Italy, 64 former aluminium dust-exposed workers were compared with 32 unexposed controls from other companies matched for age, professional training, economic status, educational and clinical features. The findings lead the authors to suggest a possible role of the inhalation of aluminium dust in pre-clinical mild cognitive disorder which might prelude Alzheimers disease (AD) or AD-like neurological deterioration. METHODS The investigation involved a standardised occupational and medical history with particular attention to exposure and symptoms, assessments of neurotoxic metals in serum: aluminium (Al-s), copper (Cu-s) and zinc (Zn-s), and in blood: manganese (Mn-b), lead (Pb-b) and iron (Fe-b). Cognitive functions were assessed by the Mini Mental State Examination (MMSE), the Clock Drawing Test (CDT) and auditory evoked Event-Related Potential (ERP-P300). To detect early signs of mild cognitive impairment (MCI), the time required to solve the MMSE (MMSE-time) and CDT (CDT-time) was also measured. RESULTS Significantly higher internal doses of Al-s and Fe-b were found in the ex-employees compared to the control group. The neuropsychological tests showed a significant difference in the latency of P300, MMSE score, MMSE-time, CDT score and CDT-time between the exposed and the control population. P300 latency was found to correlate positively with Al-s and MMSE-time. Al-s has significant effects on all tests: a negative relationship was observed between internal Al concentrations, MMSE score and CDT score; a positive relationship was found between internal Al concentrations, MMSE-time and CDT-time. All the potential confounders such as age, height, weight, blood pressure, schooling years, alcohol, coffee consumption and smoking habit were taken into account. CONCLUSIONS These findings suggest a role of aluminium in early neurotoxic effects that can be detected at a pre-clinical stage by P300, MMSE, MMSE-time, CDT-time and CDT score, considering a 10 micrograms/l cut-off level of serum aluminium, in aluminium foundry workers with concomitant high blood levels of iron. The authors raise the question whether pre-clinical detection of aluminium neurotoxicity and consequent early treatment might help to prevent or retard the onset of AD or AD-like pathologies.

Effective treatment of manganese-induced occupational Parkinsonism with p-aminosalicylic acid: a case of 17-year follow-up study.

Objective: Chronic manganese (Mn) intoxication induces syndromes resembling Parkinson disease. The clinical intervention has largely been unsuccessful. We report a 17-year follow-up study of effective treatment of occupational Mn parkinsonism with sodium para-aminosalicylic acid (PAS). Methods: The patient, female and aged 50 at the time of treatment, was exposed to airborne Mn for 21 years (1963–1984). The patient had palpitations, hand tremor, lower limb myalgia, hypermyotonia, and a distinct festinating gait. She received 6 g PAS per day through an intravenous drip infusion for 4 days and rested for 3 days as one therapeutic course. Fifteen such courses were carried out between March and June 1987. Results: At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal. Recent follow-up examination at age 67 years (in 2004) showed a general normal presentation in clinical, neurologic, brain magnetic resonance imaging, and handwriting examinations with a minor yet passable gait. Conclusions: This case study suggests that PAS appears to be an effective drug for treatment of severe chronic Mn poisoning with a promising prognosis.

Cancer mortality in a cohort of asbestos textile workers

A cohort of 889 men and 1077 women employed for at least 1 month between 1946 and 1984 by a former Italian leading asbestos (mainly textile) company, characterised by extremely heavy exposures often for short durations, was followed up to 1996, for a total of 53 024 person-years of observation. Employment data were obtained from factory personnel records, while vital status and causes of death were ascertained through municipality registers and local health units. We observed 222 cancer deaths compared with 116.4 expected (standardized mortality ratio, SMR=191). The highest ratios were found for pleural (SMR=4105), peritoneal (SMR=1817) and lung (SMR=282) cancers. We observed direct relationships with duration of employment for lung and peritoneal cancer, and with time since first employment for lung cancer and mesothelioma. Pleural cancer risk was independent from duration (SMR=3428 for employment <1 year, 7659 for 1–4 years, 2979 for 5–9 years and 2130 for ⩾10 years). Corresponding SMRs for lung cancer were 139, 251, 233 and 531. Nonsignificantly increased ratios were found for ovarian (SMR=261), laryngeal (SMR=238) and oro-pharyngeal (SMR=226) cancers. This study confirms and further quantifies the central role of latency in pleural mesothelioma and of cumulative exposure in lung cancer.

An update of cancer mortality among chrysotile asbestos miners in Balangero, northern Italy.

The mortality experience of a cohort of chrysotile miners employed since 1946 in Balangero, northern Italy was updated to the end of 1987 giving a total of 427 deaths out of 27,010 man-years at risk. A substantial excess mortality for all causes (standardised mortality ratio (SMR) = 149) was found, mainly because of high rates for some alcohol related deaths (hepatic cirrhosis, accidents). For mortality from cancer, however, the number of observed deaths (82) was close to that expected (76.2). The SMR was raised for oral cancer (SMR 231 based on six deaths), cancer of the larynx (SMR 267 based on eight deaths), and pleura (SMR 667 based on two deaths), although the excess only reached statistical significance for cancer of the larynx. Rates were not increased for lung, stomach, or any other type of cancer. No consistent association was seen with duration or cumulative dust exposure (fibre-years) for oral cancer, but the greatest risks for laryngeal and pleural cancer were in the highest category of duration and degree of exposure to fibres. Although part of the excess mortality from laryngeal cancer is probably attributable to high alcohol consumption in this group of workers, the data suggest that exposure to chrysotile asbestos (or to the fibre balangeroite that accounts for 0.2-0.5% of total mass in the mine) is associated with some, however moderate, excess risk of laryngeal cancer and pleural mesothelioma. The absence of excess mortality from lung cancer in this cohort is difficult to interpret.

The carcinogenic effect of aromatic amines: An epidemiological study on the role of o-toluidine and 4,4′-methylene bis (2-methylaniline) in inducing bladder cancer in man

Abstract Cause-specific mortality of 906 workers first employed 1922–1970 in a dyestuff factory in Northern Italy was compared to national figures: a marked excess of bladder cancer was observed (36 observed vs 1.23 expected deaths). The mean latent period was 25 years. The excess was higher among those with longer duration of exposure. Some excess of mortality from lung cancer, laryngeal cancer, and esophageal cancer was also found, but a clear explanation could not be provided regarding the causal role of aromatic amines. Mortality from bladder cancer was very much higher among those exposed in benzidine and naphthylamines manufacture as compared to those only exposed in use or intermittent contact. Excess bladder cancer was also very high among workers in fuchsin manufacture. There is evidence that o-toluidine and 4,4′-methylene bis(2-methylaniline) should be implicated in such excess mortality. Caution in handling these compounds is therefore suggested and the need for further studies to confirm such findings is stressed.

Consensus Report of the 2015 Weinman International Conference on Mesothelioma

ABSTRACT On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the groups efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos‐like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA‐exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin‐3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.

Study of Ethmoidal Mucosa in a Population at Occupational High Risk of Sinonasal Adenocarcinoma

The occurrence of nasal adenocarcinomas was first described in 1965. Since 1988 these tumors have been accepted as an occupational disease for woodworkers in Italy. There are several underlying reasons why there is interest in studying the ways in which sinonasal adenocarcinomas occur. Often diagnosed at advanced stages of development because their symptoms are non-specific, these tumors are associated with a high mortality rate. A multidisciplinary study protocol was developed in this investigation. The aim was to identify the factors and conditions that promote sinonasal tumor growth in a population at risk due to occupational exposure to wood dust. Sixty-eight carpenters with a minimum of 10 years exposure to wood dust were studied. The control group comprised 81 volunteers. The patients underwent the following protocol: completion of a case report form, physical examination, evaluation of nasal cavity patency, clinical laboratory tests and histological study of the nasal mucosa. Our study provides significant evidence of the elevated incidence of pavimentous metaplasia in workers occupationally exposed to wood dust. In addition, it underscores a significant deficit of immunoglobulin A in such workers compared to the controls. However, we did not find, as reported elsewhere in the literature, a statistically significant difference between cases and controls as regards nasal symptoms and hyperemia of the nasal mucosa. Our study showed that, even in the absence of evident sinonasal lesions, it is still possible to determine an increased incidence of morphofunctional changes in subjects occupationally exposed to wood dust. Our findings may lead to the identification of occupational groups prone to elevated risk of the disease.

Bladder Cancer Mortality of Workers Exposed to Aromatic Amines: A 58-Year Follow-up

We previously investigated bladder cancer risk in a cohort of dyestuff workers who were heavily exposed to aromatic amines from 1922 through 1972. We updated the follow-up by 14 years (through 2003) for 590 exposed workers to include more than 30 years of follow-up since last exposure to aromatic amines. Expected numbers of deaths from bladder cancer and other causes were computed by use of national mortality rates from 1951 to 1980 and regional mortality rates subsequently. There were 394 deaths, compared with 262.7 expected (standardized mortality ratio = 1.50, 95% confidence interval = 1.36 to 1.66). Overall, 56 deaths from bladder cancer were observed, compared with 3.4 expected (standardized mortality ratio = 16.5, 95% confidence interval = 12.4 to 21.4). The standardized mortality ratio for bladder cancer increased with younger age at first exposure and increasing duration of exposure. Although the standardized mortality ratio for bladder cancer steadily decreased with time since exposure stopped, the absolute risk remained approximately constant at 3.5 deaths per 1000 man-years up to 29 years after exposure stopped. Excess risk was apparent 30 years or more after last exposure.

Bladder cancer risk in painters: a review of the epidemiological evidence, 1989-2004*

Epidemiological studies on the potential association between painting and the risk of bladder cancer published after the Monograph of the International Agency for Research on Cancer N. 47 of 1989 have been systematically reviewed. These included four cohort studies on the incidence of bladder cancer among painters, with a pooled relative risk (RR) of 1.10 (95% confidence interval, CI, 1.03–1.18), based on 893 cases observed. The corresponding summary RR from four cohort studies on mortality was 1.23 (95% CI 1.11–1.37), based on 370 deaths. The pooled RR from 14 case-control studies and a pooled-analysis of other 11 case-control studies was 1.35 (95% CI 1.19–1.53), based on 465 cases exposed. Overall, the RR from all epidemiological studies was 1.17 (95% 1.11–1.27). Thus, recent epidemiological evidence indicates a moderate excess risk for bladder cancer in painters. Some studies, however, suggested that any such risk would have been greater for exposures in the distant past. Open issues for interpretation include residual confounding by social class and tobacco smoking, and understanding the time-risk relation. In particular, the potential residual risk related to exposure over the last two to three decades remains to be defined.

First and subsequent asbestos exposures in relation to mesothelioma and lung cancer mortality

We analysed data from a cohort of 1966 subjects (889 men and 1077 women) employed by an Italian asbestos (mainly textile) company in the period 1946–1984, who were followed-up to 2004. A total of 62 025 person-years of observation were recorded. We computed standardised mortality ratios (SMR) for all causes and selected cancer sites using national death rates for each 5-year calendar period and age group. There were 68 deaths from mesothelioma (25 men and 43 women, 39 pleural and 29 peritoneal) vs 1.6 expected (SMR=4159), and 109 from lung cancer vs 35.1 expected (SMR=310). The SMRs of pleural/peritoneal cancer were 6661 for subjects exposed only before 30 years of age, 8019 for those first exposed before 30 and still employed at 30–39 years of age and 5786 for those first exposed before 30 and still employed at 40 or more years of age. The corresponding SMRs for lung cancer were 227, 446 and 562. The SMR of mesothelioma was strongly related to time since first exposure. The SMR of lung cancer, but not of mesothelioma, appeared to be related to subsequent exposures.