Asbestos burden in lungs of mesothelioma patients with pleural plaques, lung fibrosis and/or ferruginous bodies at histology: a postmortem SEM-EDS study.

The causal attribution of asbestos-related diseases to past asbestos exposures is of crucial importance in clinical and legal contexts. Often this evaluation is made based on the history of exposure, but this method presents important limitations. To assess past asbestos exposure, pleural plaques (PP), lung fibrosis and histological evidence of ferruginous bodies (FB) can be used in combination with anamnestic data. However, such markers have never been associated with a threshold value of inhaled asbestos. With this study we attempted to shed light on the dose-response relationship of PP, lung fibrosis and FBs, investigating if their prevalence in exposed individuals who died from malignant mesothelioma (MM) is related to the concentration of asbestos in lungs assessed using scanning electron microscopy equipped with energy dispersive spectroscopy. Moreover, we estimated the values of asbestos concentration in lungs associated with PP, lung fibrosis and FB. Lung fibrosis showed a significant positive relationship with asbestos lung content, whereas PP and FB did not. We identified, for the first time, critical lung concentrations of asbestos related to the presence of PP, lung fibrosis and FB at histology (respectively, 19 800, 26 400 and 27 400 fibers per gram of dry weight), that were all well-below the background levels of asbestos identified in our laboratory. Such data suggest that PP, lung fibrosis and FB at histology should be used with caution in the causal attribution of MM to past asbestos exposures, while evaluation of amphibole lung content using analytical electron microscopy should be preferred.

A postmortem case control study of asbestos burden in lungs of malignant mesothelioma cases.

BACKGROUND: Asbestos lung content is regarded as the most reliable tool for causal attribution of malignant mesothelioma (MM) to previous asbestos exposures. However, there is a lack of studies on asbestos burden in lungs of MM patients in comparison with healthy individuals. This study aims to provide such a comparison, investigating, as well, differences in asbestos lung burden with sex and time trends. METHODS: Asbestos lung content has been assessed on formalin-fixed lung fragments using scanning electron microscopy coupled with energy dispersion spectroscopy (SEM-EDS) on individuals deceased from MM (cases) and healthy subjects without any lung disease who died from violent causes (controls) between 2005 and 2023. RESULTS: Asbestos and asbestos bodies (ABs) were found, respectively, in 73.7% and 43.2% of cases and in 28 and 22% of controls; in MM cases the most represented asbestos types were crocidolite and amosite, whereas in controls it was tremolite-actinolite asbestos. The concentration of both asbestos fibers and ABs was statistically significantly higher in MM cases compared to controls. The mean asbestos fibers width was also significantly higher in cases than controls. Males and females with MM showed similar asbestos and ABs concentrations, but females had higher concentrations of chrysotile, and significantly lower fibers width compared to males. Time trends show that MM lung asbestos concentrations decreased starting in 2011. DISCUSSION: The results suggest a correlation between asbestos burden in lungs and MM risk. The different concentration of chrysotile, as well as the different width of asbestos fibers in MM males and females might reflect a sex difference in response of the lung microenvironment to inhaled asbestos. Finally, this study provides the first pathological evidence of the effect of the ban of asbestos use, demonstrating a significant decrease of asbestos lung content after 2011.

Reconstructing historical exposure to asbestos: the validation of 'educated guesses'.

BACKGROUND: In both the epidemiological and legal context, the causal attribution of asbestos-related lung diseases requires retrospective exposure assessment (REA). AIMS: To assess the correlation between the retrospective assessment of occupational and anthropogenic environmental exposure to asbestos and its content in the lung tissue. METHODS: Based on the available exposure information, a team of occupational physicians retrospectively assessed cumulative exposure to asbestos in 24 subjects who died of asbestos-related diseases. The asbestos lung content was analysed using analytical scanning electron microscope (SEM-EDS). The Log10 asbestos fibre count in the autoptic samples was predicted as a function of the Log10 estimated cumulative exposure using univariate regression analysis. RESULTS: The median count of asbestos fibres by grams of dry weight (ff/gdw) in the lung tissue was 81 339 (range 0-2 135 849.06); it was 287 144 (range 0-2 135 849.06) among the occupationally exposed, and 29 671 (range 0-116 891) among the subjects who only had anthropogenic environmental and/or household exposure. Amphiboles, and particularly amosite (52%) and crocidolite (43%), were detected in all the study subjects. Chrysotile was not detected in any of the samples. Overall, the retrospective estimate of lifetime cumulative exposure to asbestos showed a moderate correlation with the total asbestos fibre count in the autoptic lung, with the regression model explaining 38-55% of the total variance. CONCLUSIONS: Detailed information on occupational, environmental and household exposure circumstances would be indispensable for experienced industrial hygienists and/or occupational physicians to reliably assess past exposure to amphiboles or mixed types of asbestos.

Source and symptoms of COVID-19 among hospital workers in Milan.

BACKGROUND: Healthcare workers (HCWs) are commonly infected by SARS-CoV-2 and represent one of the most vulnerable groups. Adequate prevention strategies are necessary to guarantee HCWs' safety, as well as to prevent dissemination of the infection among patients. AIMS: To describe a case series of SARS-CoV-2-positive HCWs in a large public healthcare organization in Milan (Italy) during the most devastating weeks of the epidemic and analyse the sources, symptoms and duration of SARS-CoV-2 infection. METHODS: This study included 172 SARS-CoV-2-positive HCWs who were infected between the 25th of February and the 7th of April 2020. A nasopharyngeal swab (NPS) and RT-PCR were used to indicate. RESULTS: Initially, the most common sources of infection were other positive HCWs (49%). Medical doctors and nursing assistants were most frequently infected, with infection rates of 53/1000 and 50/1000, respectively. COVID-19 departments were less affected than internal medicine, surgery, intensive care, or emergency room. The most commonly reported symptom was mild cough, while loss of smell (anosmia) and loss of taste (ageusia) were reported as moderate and severe by 30-40% of HCWs. The time necessary for 50% of workers to recover from the infection was 23 days, while it took 41 days for 95% of HCWs to become virus-free. CONCLUSIONS: HCWs are commonly infected due to close contacts with other positive HCWs, and non-COVID departments were most affected. Most HCWs were asymptomatic or subclinical but contact tracing and testing of asymptomatic HCWs help identify and isolate infected workers.

Reduction of Extended-Release Tacrolimus Dose in Low-Immunological-Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor-Specific Antibodies: A Randomized Study.

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0 ) >3 µg/L; group B had no change in TacER dose (TacER C0 7-12 µg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 µg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 µg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 µg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.

Workers' health surveillance: implementation of the Directive 89/391/EEC in Europe.

BACKGROUND: European Union (EU) Directive 89/391 addressed occupational health surveillance, which recommends to provide workers with 'access to health surveillance at regular intervals', aiming to prevent work-related and occupational diseases. AIMS: To investigate how EU countries adopted this Directive. METHODS: We invited one selected representative per member state to complete a questionnaire. RESULTS: All 28 EU countries implemented the Directive in some form. Workers' health surveillance (WHS) is available to all workers in 15 countries, while in 12, only specific subgroups have access. In 21 countries, workers' participation is mandatory, and in 22, the employer covers the cost. In 13 countries, access to WHS is not available to all workers but depends on exposure to specific risk factors, size of the enterprise or belonging to vulnerable groups. In 26 countries, the employer appoints and revokes the physician in charge of WHS. Twelve countries have no recent figures, reports or cost-benefit analyses of their WHS programmes. In 15 countries where reports exist, they are often in the native language. CONCLUSIONS: Coverage and quality of occupational health surveillance should be evaluated to facilitate learning from good practice and from scientific studies. We propose a serious debate in the EU with the aim of protecting workers more effectively, including the use of evidence-based WHS programmes.

Long-Term Clinical Impact of Adaptation of Initial Tacrolimus Dosing to CYP3A5 Genotype.

Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5 genotype is associated with improved achievement of target trough concentration (C0 ), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5 genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0 was within target range (10-15 ng/mL) at day 10. Our results indicate that the incidence of biopsy-proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0 target ranges earlier. Patients' death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes.

Kidney transplant recipients carrying the CYP3A4*22 allelic variant have reduced tacrolimus clearance and often reach supratherapeutic tacrolimus concentrations.

CYP3A4*22 is an allelic variant of the cytochrome P450 3A4 associated with a decreased activity. Carriers of this polymorphism may require reduced tacrolimus (Tac) doses to reach the target residual concentrations (Co). We tested this hypothesis in a population of kidney transplant recipients extracted from a multicenter, prospective and randomized study. Among the 186 kidney transplant recipients included, 9.3% (18 patients) were heterozygous for the CYP3A4*22 genotype and none were homozygous (allele frequency of 4.8%). Ten days after transplantation (3 days after starting treatment with Tac), 11% of the CYP3A4*22 carriers were within the target range of Tac Co (10-15 ng/mL), whereas among the CYP3A4*1/*1 carriers, 40% were within the target range (p = 0.02, OR = 0.19 [0.03; 0.69]). The mean Tac Co at day 10 in the CYP3A4*1/*22 group was 23.5 ng/mL (16.6-30.9) compared with 15.1 ng/mL (14-16.3) in the CYP3A4*1/*1 group, p < 0.001. The Tac Co/dose significantly depended on the CYP3A4 genotype during the follow-up (random effects model, p < 0.001) with the corresponding equivalent dose for patients heterozygous for CYP3A4*22 being 0.67 [0.54; 0.84] times the dose for CYP3A4*1/*1 carriers. In conclusion, the CYP3A4*22 allelic variant is associated with a significantly altered Tac metabolism and carriers of this polymorphism often reach supratherapeutic concentrations.

Hepatitis E virus infection: an emerging occupational risk?

BACKGROUND: Hepatitis E virus (HEV) infection is endemic in many developing countries, causing substantial morbidity. Transmission is primarily faeco-oral and is associated with both sporadic infections and epidemics in areas where poor sanitation and weak public health infrastructures exist. Recently, it has become clear that HEV is also an endemic disease in industrialized countries. Moreover, a porcine reservoir and growing evidence of zoonotic transmission have been reported in these countries, suggesting the possibility of occupational transmission to man. AIMS: To summarize the current knowledge on the epidemiology and prevention of transmission of HEV infection in occupational settings. METHODS: The following key words were used to explore PubMed: hepatitis E, disease, epidemiology, profession(al), occupation(al). RESULTS: After screening of the results, 107 publications were retained. In non-endemic regions, seroprevalence varied from a few per cent (2-7.8%) in Europe, Japan and South America to 18.2-20.6% in the USA, Russia, UK, southern France and Asia. A meta-analysis of 12 cross-sectional studies evaluating HEV immunoglobulin G (IgG) seroprevalence in individuals occupationally exposed to swine showed greater odds of seropositivity in the exposed group but also a high degree of heterogeneity. A funnel plot suggested publication bias. CONCLUSIONS: There was a significant association between occupational exposure to swine and HEV IgG seroprevalence, but the level of prevalence detected depended also on the type of HEV IgG kits used. Further research, including on mechanisms and risk factors for infection, as well as the development of better serological tests for identification of infection, is required.

[Biological agents in animal breeding: an ancient but still relevant risk]. / Agenti biologici in allevamento: un rischio antico e sempre attuale.

Agricultural activities expose workers to biological risk, due to the close contact that could occur with pathogens' reservoirs, such as soil, animals, manure and animal products. The paper describes factors that have contributed on the reduction or eradication of zoonoses, such as brucellosis, salmonellosis and bovine tuberculosis (monitoring and prevention of animal infectious diseases, industrialization and mechanization of agricultural activities), and on the other hand the emergence of new risks and new diseases (adaptability of microorganisms, generation of new strains, antibiotic resistance, dissemination of vectors). The role of Occupational Medicine in the prevention of zoonoses is discussed.

[Plant protection products: new tools for exposure and risk assessment in agriculture]. / Antiparassitari: nuovi strumenti per la valutazione dell'esposizione del rischio in ambito agricolo.

Our experience in assessment and management of chemical risk in agriculture consists of three lines: i) definition and modeling of the relationships between different exposure determinants to create the possibility of doing risk assessment without measurements ii) identification, from the Acceptable Operator Exposure Levels (AOEL), of provisional biological exposure indices for pesticides; iii) identification of analytical approaches adequate for the production of the measures needed to support the above mentioned activities starting from the use of multi-residue methods, allowing the determination in one run of several active ingredients and metabolites.

[Time course of excretion of tebuconazole and its metabolites in vineyard workers]. / Cinetica di escrezione del tebuconazolo e dei suoi metaboliti in viticoltori.

Tebuconazole (TEB) is a fungicide widely used in vineyards. This work aimed at the identification of urinary metabolites of TEB for the biological monitoring of exposure, and to study their kinetics of excretion. Major urinary metabolites of TEB in rats are t-butyl-hydroxy-and-carboxy-tebuconazole (TEB-OH and TEB-COOH). TEB and these metabolites were determined in urine samples of 5 wine growers who collected each void before (24 hours), during and after (48 hours) TEB application. These chemicals were found in 95%, 100% and 100% of the samples with levels of < 1.5-13.4 microg/L for TEB, 5.2-749 microg/L for TEB-OH e 2.8-234 microg/l for TEB-COOH. TEB-OH is the major metabolite of TEB, its concentration increases at the end of exposure and peaks after 16-24 hours. TEB-COOH has similar pattern. TEB-OH and TEB -COOH are promising candidates for biological monitoring of TEB exposure; preliminary results suggest the day after the application as the best sampling time.

[Physically-based model of pesticide application for risk assessment of agricultural workers]. / Valutazione del rischio nell'applicazione in campo di prodotti fitosanitari attraverso modelli a base fisica per la stima dell'esposizione.

Due to their unavoidable toxicity to non-target organisms, including man, the not of Plant Protection Products requires a thorough risk assessment to rationally advise safe use procedures and protection equipment by farmers. Most information on active substances and formulations, such as dermal absorption rates and exposure limits are available in the large body of regulatory data. Physically-based computational models can be used to forecast risk in real-life conditions (preventive assessment by 'exposure profiles'), to drive the cost-effective use of products and equipment and to understand the sources of unexpected exposure.

[Possible use of microRNAs as biomarkers for monitoring of workers exposed to asbestos]. / Possibile impiego di microRNA come biomarcatori nel monitoraggio dei lavoratori professionalmente esposti ad amianto.

Exposure to asbestos is the predominant cause of pleural mesothelioma (PM). The PM is a tumor difficult to diagnose, chemoresistant, and with rising Incidence. The long latency periods and the lack of preventive and therapeutic strategies for the MP, suggest that asbestos will be a social and health issue in the near future. Therefore, this overview focuses on current knowledge of epigenetic alterations and on the key role of microRNAs, small RNAs that negatively regulate gene expression, as biomarkers in PM development. Dysregulated microRNA expression pattern is specific for different cancers, including MP. MicroRNA expression analysis is a promising tool for diagnosis, typing of MP than normal tissue and other lung tumors and monitoring of new therapies. However, a better knowledge of miRNA signatures in PM is still necessary to verify the contribution of specific miRNAs as diagnostic biomarkers, also compared to different asbestos forms, exposure and subject work history.

[Evaluation of experimental data for developmental neurotoxicity of pesticides]. / Valutazione dei dati sperimentali per la neurotossicità dello sviluppo dei pesticidi.

Epidemiological studies on neurodevelopmental effects of pesticides are inconclusive. Experimental developmental neurotoxicity studies, sometimes show effects on pups given doses lower than adults; most of the times these effects were transient, aspecific, with scattered biochemical, molecular or neurobehavioural changes, generally associated with high bolus doses. At repeated low doses, effects in pups did not occur at doses lower than in adults. Since the effects of high bolus doses are possible, preventive interventions should aim at reducing these exposures.

[Migrant workers in agriculture and animal husbandry: experiences of health surveillance]. / Lavoratori migranti in agricoltura e zootecnia: esperienze di sorveglianza sanitaria.

In Italy, 5 millions migrants live and work. Among them, the employment rate is much higher in comparison with the Italians' one (75% versus 62%). The well known "healthy migrant effect" is confirmed by statistics from the National Institute for Statistics: according to it, migrants access the National Health System for pregnancy and delivery and for accidents. The chronic pathology is not a major concern. Moreover, their work ability is generally complete, without any limitation. Nevertheless, migrants seem to represent a vulnerable subgroup with regard to the risk of 1) occupational injuries: this is strongly linked with the risk of Tetanus infection; 2) disorders of the metabolism, like hyperglycaemia and hyperlipemia, which is linked to a higher cardiovascular risk. In this light data from health surveillance carried out by the International centre for Rural Health of the San Paolo University Hospital in agricultural setting in the Region of Lombardy and the participation of the Centre itself to the Promovax EC-cofunded project are presented.

[Occupational health surveillance in agriculture: the experience of the International Centre for Rural Health]. / Sorveglianza sanitaria in agricoltura: l'esperienza del Centro Internazionale per la Salute Rurale dell'Azienda Ospedaliera San Paolo di Milano.

The results of the activities of occupational health surveillance in agriculture carried out by the International Centre for Rural Health since 2008 are described. The activities involve 800 workers employed in 260 farms in the Region of Lombardy (Italy). The types of farms reflect the vocation toward agricultural sector of the Po Valley and the most representative tasks are related to animal care and use of agricultural machinery. Based on the specific risks, workers are provided with preventive and periodic examinations, and complementary laboratory and instrumental evaluations (hearing and respiratory functions, electrocardiography), related to the different risk factors present in the enterprises. The occupational health priorities identified are, for the time being, noise-induced hearing loss and insufficient immunization against tetanus.

[Diet as a key element of health promotion at the workplace in scientific research and practice. First results of the EU project FAHRE]. / La dieta come elemento cardine della promozione della salute ne luoghi di lavoro nella ricerca scientifica e nella pratica. Primi risultati del progetto EU FAHRE.

The globalization of markets have led to rapid changes in diet and lifestyle in the developed countries, where living standards have improved, and availability and variety of food has increased while physical activity decreases have led to an augment in chronic diseases (obesity and diabetes mellitus), cardiovascular diseases and some specific cancers. In this context there is a need to develop health promotion activities. Workers represent a very appropriate group for such activities because they are relatively homogeneous, easily reachable because they can be found together in the same place and time and the occupational physician has good knowledge of the of health status of individual worker. In this scenario, a renew interest must be posed to the relationship between diet and health. In this context our Group is participating at the FAHRE project (Food and Health Research in Europe). The project aims to establish the state of the art of research at the interface of nutrition and health in the European Union, identifying its strengths and weaknesses in order to propose strategies to increase coordination and improve its functioning as a European Research Area.

[The occupational health physician and the health surveillance in agriculture]. / Il medico del Lavoro Competente e la Sorveglianza Sanitaria in Agricoltura.

Despite the underreporting of occupational diseases in agriculture, available data clearly show a significant health risk, and therefore the need of health surveillance at the workplace. The implementation of health surveillance programs for agricultural workers relies on the possibility of creating a system able to reach the workers at their workplaces, with the collaboration of employers' associations, able to support enterprises in several issues, including risk assessment and management. The health surveillance program can be organized in a component common for all workers, based on physical examination, chemistry, electrocardiography, hearing and lung functions examinations, and on tests addressing specific risks, if present: vibration, physical overload, chemicals, biological agents, allergens. The frequency of examinations must be decided based on risk assessment and health surveillance outcomes.