CMPH Journal

Introduction

Even though asbestos as mining dusty crushed product has been banned by law from industrial processes in many Western countries since the nineties, the prevention and early detection of AsbestosRelated Diseases (ARD) in ex-exposed workers is still a pertinent goal of occupational medicine. Occasions of asbestos exposure still might occur for various jobs in workplaces worldwide, in the contemporary time [1]. ARD and its symptoms negatively affect the quality of life of workers and cause work discontinuation, work disability, and death. The diagnosis procedure is complex because of overlapping of signs/symptoms with other nonasbestos lung diseases. This is a restraint for the early detection, management, and right to compensation for occupational diseases. Former asbestos-exposed workers appear healthy during most of their lives and, thereof, are careless of their health condition unless suffering from physical dysfunction or symptoms. ARD mortality has been declining in countries where asbestos ban regulation was applied, such as in Italy and other European countries. Even in these protected working populations, there are identifiable groups at higher prevalence of ARD. For instance, individuals processing asbestos-containing materials are filed at risk of contracting ARD in a lifetime by the national worker’s protection agencies, such as INAIL in Italy. More difficulty for medical and compensative aims is to distinguish between workplace exposure and/or exposure to naturally occurring asbestos (NOA). The ARD long latency makes unfeasible for the occupational health professionals to follow up with workers. Effect modifiers of asbestos toxicity such as sex, age [2], smoke status [3], workplace-, homeplace distance- presence of friable manufactures (ruined dwellings, canopies) [4], are more factors for risk assessment and public health preventive measures, too. Non-irrelevant levels of risk of work-related ARD have been shown for various contemporary workers’ groups [5] (Table S1). Besides malignant mesothelioma, low-to-intermediate intensity of exposure, (i.e. <0.5 f/cc/0.1 ff/l, per year) has been associated to increased risk of lung cancer and (non-pleural) related death [6]. The risk of exposure to free asbestos cannot be excluded in the surrounding areas where are ACM (asbestos-containing materials), such as cement products [7]. Studies conducted on smokers have shown that asbestos is a multiplicative risk factor of lung cancer [8]. Epidemiological data showed that there is not a safe exposure limit and that the risk of ARD is proportional to the number of inhaled fibres. Hence, a higher relative risk of asbestos exposure is assumed for the workers, compared to the general population. Nowadays, (relatively) low amounts of breathable free fibres, not innocuous, could be released in the workplace from asbestoscontaining materials (ACMs). For instance, detachment of free fibres can occur for tangential forces during the transformation processes, manoeuvres on friable materials, or moisture infiltration. Waste ACMs are given all over the national territory and still undisposed in the industry and in the living environment. Such current public harm needs to be secured by specialized workers. Asbestos is still found in industry plants in oven and pipes being potential exposure source for non-ACM workers, too [9]. It is of utmost importance to improve our knowledge of what impact non-dusty asbestos might have on health and whether other risk factors play a multiplicative/exacerbating role in the pathogenesis of ARD. Conversely, whether asbestos might influence the nonARD pathologic outcome triggered by other chemical risk factors in the workplace. To elucidate the health status after 20 years (at admission and post-retirement) observation in the former workers of several firms of two automotive businesses, we conducted a health surveillance protocol to show ARD promptly in a cohort of former asbestos workers of the Abruzzi region of Italy. All the enrolled subjects lived in Abruzzi, a small rural region of central Italy where environmental exposure to Naturally Occurring Asbestos (NOA) is minimal [10]. We characterized this cohort thoroughly also to detect disabling/enabling conditions, known to affect productivity and potentially compensable. Furthermore, the data were analysed for the task, residential asbestos, and smoke to catch the predictivity of associated features.

Subjects and Methods

We performed a retrospective cohort analysis of the association between occupational exposure to asbestos and incident diseases, either pulmonary (ARD/respiratory) and extra-pulmonary (ARD or non-ARD). The study cohort consisted of ex-workers of the automotive sector of two different businesses, manufacturing and production. Description of the occupational groups and specific tasks and their numerosity of the Manufacturing and the Production sectors of employment are detailed in Table S2. Comparative analyses were performed between different pairs of complementing sub-cohorts of workers anthropometrically alike. Our population of ex-workers showed homogenous relevant characteristics of interest for this study (Table 1). Besides, the contribution of extra-occupational asbestos and smoke to disease risk were analyzed.

Table 1: Health surveillance relevant clinical findings of the former asbestos Abruzzi workers are shown with the etiopathogenetic role of asbestos, the occurrence among several Italian national and regional reference populations, and the statistic results.

Study population

A representative sub-cohort of the retired past-asbestos exposed workers of Abruzzi, a low populous region in Central Italy, was enrolled in 2019. They were 64-65 years old and had worked for a period of 20 years without discontinuation, from 1971 till 1998, in automotive production and induced plants settled in the same region. A data set was gathered for each ex-worker through interviews, specific questionnaires, and risk-oriented clinical assessments. The subjects, all males, were considered eligible if seemingly healthy, not affected by chronic disease (except diabetes) nor recent acute seasonal disease, not employed in other jobs at risk of occupational exposure to asbestos. Questionnaires were compiled by the occupational physician during workers’ interview to assess anthropometric values, occupational title, job duration, first year of employment, year of retirement, plant, plant location, home location, business sector, homeplace location, smoking habits, and extra-occupational sources of exposures to asbestos. Female workers were not included in this study. Our study population was evaluated against demographic groups of reference, which were selected for geographic proximity, wok exposure, age, sex, and year of survey from published data (Google, PubMed) (Table 1) (Figure 1).

Figure 1: Study design.

Exposure attribution

All automotive employees in Abruzzi, including the one hundredeight consecutive ex-workers who voluntarily joined the active health surveillance program of our O.U. of Occupational Medicine, had been previously classified at high Relative Risk of asbestos exposure for their business’s groups and occupational titles by the regional workers’ insurance institute INAIL and reviewed by us according to OSHA guidelines (OSHA, 2012). Two sub-cohorts of them were classified based on the smoking status as current/past smokers since at least 10 years (smoker), and never smokers (nonsmokers). Other two categories were formed by one-sub-cohort declaring potential exposure to non-occupational asbestos sources, being resident in proximity of roof, chimney, garage, tank, and canopy (confirm), and the complementary sub-cohort denied (deny).

Pulmonary and extra-pulmonary disease outcomes

A data set was gathered for each ex-worker through interviews, questionnaires, and risk-oriented clinical assessments. The subjects were considered eligible if seemingly healthy, not affected by chronic disease nor acute seasonal disease within the month preceding the recruitment, not employed in other jobs at risk of occupational exposure to asbestos. Conclusive diagnosis and medical reports of diseases were made by specialized physicians based on the results of routine laboratory exams, lung function spirometry, echography, standard radiological examinations and/ or HR-CT scans of the thorax performed on each recruited exworker. Diagnostic findings were blind checked by OM physicians of our group who categorized them as pulmonary disease or extrapulmonary disease. Dysplastic lesions without evidence of active ARD were considered pre-malignant ARD lesions. Digital images of all clinical items were stored in the OM online repository (https://www.myqnapcloud.com/home?lang=it). The occurrence of each disease in the whole cohort of ex-workers was evaluated for incidence rate and plausibility against the occurrence of each of the diseases among demographic groups of reference considered for geographic proximity/correspondence and year of our survey, found by extensive search of published data (Google, PubMed) (Table 1 and Figure 1). Categorical/numerical databases were built up from the row clinical data for further statistical analysis of matched occupational-clinical aggregated datasets.

Statistical analysis

Descriptive analysis was carried out using median and interquartile range (IQR) for quantitative variables or using frequencies and percentages to describe the qualitative variables. Normality distribution was tested by the Shapiro-Wilk test. To evaluate relationships between qualitative variables a Pearson chi square test e/o Fisher test was assessed. For quantitative variables, the Wilcoxon rank-sum (Mann-Whitney) test was used to find the differences between median values among the two different subcohorts of workers with three different exposure risk factors for the outcomes of interest, which are the exposure to residential asbestos, tabagism and processing modality of the asbestoscontaining materials at workplace. Crude odds ratio (ORs) and corresponding 95% CI were calculated to quantify the risk associated with residential asbestos, or tabagism, or task/business features and clinical findings (disease, dysfunction) using the Wald test. Relative Risk (RR), and corresponding 95% CI, of occurrence of disease (ARD, or respiratory, or metabolic) between two sub-cohorts of workers (Manufacturing and Production) were calculated. Statistical significance was set at the p<0.05 level. All analyses were performed using 2024 MedCalc Software Ltd.

Results

Health surveillance findings

The ex-workers participating to the study (N=108) were free of mesothelioma and lung cancer at surveillance visit, in 2019. Compared to the (closest) age- and year-matched reference groups, pleural plaques (N=8) (IRR=3.7; 95% CI: 1.4899-8.343; p=0.0037), asbestosis (N=3) (IRR=1462.0; 95% CI: 277.094966.5; p<0.0001), colorectal carcinoma (N=3) (IRR= 61.7; 95% CI: 12.271-192.29; p<0.0001) and prostate cancer (IRR=17.470; 95% CI: 3.5649-51.989; p<0.0008 and IRR=7.3714; 95% CI: 1.5179-21.598; p=0.0092) occurred at significantly higher rates in our cohort (Table 1). Pulmonary nodules (N=11) incidence rate was slightly higher in our cohort (IRR=0.7275, 95% CI:

0.2989-1.7250) or seemingly much higher for larynx carcinoma (N=1) (IRR=10.404) and thyroid nodules (N=1) (IRR=46.2964 95% CI: 0.7847-889.31; p=0.031) (Table 1). Haematological disorders/malignancies such as MGUS (N=4), at an incidence rate slightly higher (IRR=1.2348-2.4; 95% CI: 0.3359 to 3.168), and MDS (N=1) (IRR=3.0864; 95% CI: 0.05879-38.439). Former asbestos workers were affected by one or more dysmetabolic signs including hypertension (N=50), hypercholesterolemia (N=25), hyperglycaemia (N=1), hypertriglyceridemia (N=2) hyperuricemia (N=10), glaucoma (N=4). Type-2 diabetes (N=18) and cardiovascular diseases as ischemic diseases (N=2), OSAS (N=2), venous thrombosis (N=1), all promoted by the abovementioned conditions, were accordingly diagnosed, too. Overall, metabolic syndrome (N=72) was detected at significantly higher rate in our cohort (IRR=3.1746; 95% CI: 1.9299-5.4360; p<0.0001 vs. Italians; IR=2.6667; 95% CI: 1.6711-4.3879; p<0.0001, vs. over-70 patients). Hypertension (IRR=4.6296; 95% CI: 2.320410.239, p<0.0001). T2D incidence was significantly higher

(IRR=2.6907; 95% CI: 1.4883-3.9689, p=0.0006, vs. Abruzzi/ Tuscany residents). Gastric dysplasia (N=1) and multiple polyps of the colon (N=1), arthritis (N=1), thrombocytopenia (N=1) affected single workers at higher, but not significant, incidence rate (Table S1). Ex-workers were affected by various lung diseases (N=35) (Table S1). Of these, COPD (N=6) and asthma (N=4) rates approximated the national and regional incidence, respectively. Notably, COPD was significantly lower whether compared to elderly smokers (IRR=0.100, 95% CI: 0.03893-0.2593, p<0.0001). Even, dyspnoea after exertion (N=17) was statistically underrepresented in our cohort, compared to other European populations (Table S1). Benign prostate hyperplasia (N=22) was seemingly more prevalent our workers than Italians (RR= 6.2304, CI 4.2848 to 9.0595, P<0.0001). The main results described in this paragraph are shown in Table 1, unless otherwise indicated. Anthropometric and job and health anamnestic data were not significantly different between the two sub-cohorts (Table S2).

Residential asbestos and smoking status

Residential asbestos: The whole original cohort of former asbestos workers included one sub-cohort of them living near non-occupational asbestos sources (N=50), and the other one not (N=58), accounting 96% and 89% of total disease cases, respectively (Table 2). Residential asbestos was not associated (OR<1) with higher occurrence of restrictive respiratory diseases, nor metabolic syndrome and T2D, nor BPH which were, conversely, all significantly associated (p<0.05) with occupational exposure alone (Table 2). Seemingly, although not significantly associated (OR>1; p>0.05), pulmonary nodules, asbestosis, colon carcinoma, and prostate cancer, and obstructive/inflammatory pulmonary conditions mostly gained in the cohort of workers exclusively exposed to occupational asbestos (Table 2). Residential asbestos resulted by a small margin and not significantly associated with pleural plaques (OR<1; p>0.05) (Table 2). Smoke. One sub-cohort of the asbestos workers’ whole cohort included (past/current) smokers (N=66), and non-smokers (N=42). No statistically significant differences resulted (p>0.05), for each pathology. Yet, non-smoking (asbestos-exposed) workers were those more often affected by pleural plaques (OR=1.6316; 95% CI: 0.3852-6.9109), pulmonary nodules (OR=1.3541; 95% CI: 0.3850-4.7430), prostate cancer (OR=3.2500; 95% CI: 0.2854-37.0125), and benign prostate hyperplasia (OR=1.7742; 95% CI: 0.6899-4.5628). Asbestosis occurred at a slightly higher rate among smokers of the asbestos cohort (OR=0.8125; 95% CI: 0.0713-9.2531), compared to the non-smokers. Larynx carcinoma, colorectal cancer, multiple colon polyps, and MDS were only diagnosed in (current) smokers, who were also more affected by T2D, glaucoma and other metabolic conditions, compared to the non-smokers. Smokers of our cohort were not affected by gastric dysplasia, thyroid nodules, and thrombocytopenia, and were less affected by asthma (Table 3).

Table 2: Distribution of diagnosed pathologies based on the presence or not of residential extra-occupational sources of asbestos.

Table 3: Distribution of the most diagnosed pathologies, based on the smoking status.

Diseases outcomes among Manufacturing and Production workers

Anthropometric characteristics, job history, allocation of the extra-occupational exposures/smoking status showed no significant differences among the two different sectors of employment (Table S1, Tables 2 and 3). However, smokers were mostly employed in the Production sector (OR=1.47; 95% CI: 0.25-1.83, p=0.448), and non-occupational asbestos was mainly declared by the Manufacturing workers (OR=1.80; 95% CI: 0.19-1.37; p=0.179) (Table 4). Diseases risk was unequally distributed. Manufacturing workers had a higher significant risk of overall ARD (RR=1.9; 95% CI:1.14262-3.1129; p=0.0126) and/or of pulmonary diseases (RR=2.6; 95% CI:1.45274.3393; p=0.0005) (Table 4), and Production workers had a significantly higher risk of developing metabolic syndrome (RR=1.3; 95% CI:1.0788-1.4975, p=0.0232) (Table 4), and displayed lung nodules without overt ARD.

Table 4: Association between disabling/enabling conditions/diseases of three categories and business of employment of the workers (OR) and comparison of the risk of occurrence of these pathological conditions between the two automotive businesses using ACMs with different modalities of processing (RR).

Discussion

Principal finding of our study is that some past workers of the metalworking/construction industry, priory classified at high relative risk of exposure to asbestos - by the regional service of the National Institute against Accidents and professional diseases at Work (INAIL) - had been exposed to pathogenetic asbestos in the workplace. In fact, a variety of known asbestos-related diseases were diagnosed, and others could be related to it, according to recent published reports [24-32] (Figure 2). Pleural plaques, asbestosis and malignant pulmonary nodules, and prostate cancer were detected. Colorectal carcinoma and haematological (pre) malignant MGUS were also diagnosed. The attribution of these diseases to occupational exposure is supported by our finding that residential exposure was irrelevant to the disease outcome. Moreover, the workers lived in Abruzzi, a small region where the environment can be considered NOA-free [10]. Besides, our study shows that respiratory diseases compatible with (underlying) ARD [24,29,31] often affected the workers (Table 5). Unexpectedly, most of the workers were also affected by clinical traits of metabolic syndrome, more often than the community of the same geographic area (Table 5). In our study, cigarette smoke was not an influential factor for pleural plaques and asbestosis. Nevertheless, past workers with a diagnosis of larynx cancer, colorectal cancer, pulmonary nodules, polyps of the colon, and MDS (all potentially triggered and amplified by asbestos) were all smokers. As expected, smoking was associated with respiratory lung diseases, T2D and metabolic syndrome, displayed by our cohort of ex-asbestos workers at a higher incidence than control cohorts. The other relevant finding is that Manufacturing workers developed overall ARD and severe respiratory diseases at the highest rate, compared to the Production workers (Figure 2). Instead, Production workers, more often smokers, were affected by metabolic syndrome and no cases of pleural plaques and asbestosis were diagnosed. Briefly, this study shows that the manufacturing mode of processing of asbestos-containing materials posed the workers a higher risk of inhalation of released free asbestos and is crucially linked to the burden and arrangement of the pathological outline among the workers. Almost thirty years ago, many countries banned the use of massive dusty asbestos in workplaces. This commitment imposed the adoption of stringent hygienic working conditions, which contributed to the reduction of severe ARD cases in our region. Indeed, only two cases of ARD were reported among the Abruzzi workers (2022 protocol, INAIL open data) and, in our cohort, no mesothelioma nor overt lung cancer were diagnosed. In the time to come workers will experience an “emerging” risk of exposure to single free fibres detached from compact ACM. We believe that such exposure regarded our Manufacturing workers for most of their working period. Manufacturing workers were potentially exposed to released free asbestos for the type of jobs carried out that imply handling and modelling (through tangential forces) of materials having asbestos. Instead, the Production workers, dedicated to assembly and mounting and check of components, were at lower/null risk of dispersion of asbestosinhalable fibrous particles. For our cohort of workers, this distinction of jobs corresponds to different relative risks and two different disease profiles showed by our study in the two businesses of employment. In Italy, it is predicted that occupational asbestos to lead to highly incident non-deadly chronic lung diseases and disability, rather than deadly ones [33], affecting workers’ quality of life and health. This new scenario might be challenging for the national/regional medical care systems and the productivity of the companies dealing with ACM. Furthermore, asbestos is still considered a main oncologic risk factor for workers and citizens [34]. Rather, the occurrence of sporadic cases strongly suggests that genetic/epigenetic factors might drive the onset and progression of (multiple and scattered) ARD in these individuals [34-38]. Non-occupational asbestos exposure, expected to increase the risk of ARD, especially for children, women and the elderly [33], will arise from the close operation of object refinement, as for the manufacturing workers. Hence, the findings described here might be of inspiration to promote future research to clarify the non-carcinogenic role of occupational asbestos and inspire proper safety, health surveillance and regulative actions for both occupational and public health protection. In this study, we have shown that the mode of processing the asbestos-containing materials, rather than just permanency itself in the (working) environment, is crucial for the release of inhalable fibres and pathological consequences. This finding has important implications for the management of asbestos waste and the preservation of the natural living environment. The strength of this study consists of the possibility to study a cohort of past workers while alive and in good general health conditions, who were collaborative for interviews, visits and instrumental diagnostics for the characterization of familiar, job and anamnestic data for this study. Altogether, they formed a highly homogeneous cohort of past asbestos workers being males, the same age, with common lifestyles, residences, and absence of natural asbestos near homeplace, except for the features of interest for this study, that is job, smoke and residential asbestos. Furthermore, the study was conducted in 2019, when the maximal incidence of asbestosrelated diseases worldwide was predicted [6, 13-15] to allow the highest enrolment of “healthy” past workers. The weakness of this study is the size of our cohort, which was not sufficiently large to detect the rare mesothelioma cases in Abruzzi and the possible overestimation of the differences with the reference population. Given the rarity and latency of these diseases, investigations of the complex network of crucial molecular factors involved in asbestos pathogenicity would need more subjects and prolonged periods [32]. Various ARD, indolent pre-cancerous and dysmetabolic conditions were reported, also as multiple diseases. This suggests that common and/or overlapping pathogenetic pathways are triggered/worsened by asbestos, reflecting its complex and not fully understood toxicological profile figured out by diverse chemical-physical characteristics as iron content, fluoride content, zeta (ξ) potential of (Nano)fibres and their impingement/ agglomeration [33-39]. Furthermore, our findings suggest that asbestos might act as an endocrine disruptor [40]. Rather, the occurrence of unique cases with lower rates compared to regional/ national residents (gastric dysplasia, colon polyposis, thyroid nodules suggests that genetic/epigenetic predisposing factors might have driven the onset and progression in these individuals [41-44]. Workplace chemical risk factors other than asbestos might have been (co)responsible for the observed non-ARD outcomes [45-59] (Figure 2). Our findings might be of guidance for taking proper safety, health surveillance, and regulative actions. Implications for clinicians would be plant-specific and workertailored risk evaluation and management, focusing on smoke and metabolic syndrome at job placement, and workers at risk to take part in preventive visits and research, as the one reported here, to make latent cases appear prompt and to develop therapies. Implications for policymakers regard the potentially wider noncarcinogenic harm of asbestos highlighted by our study. Among unanswered issues are the non-carcinogenic role of occupational asbestos and other aero-dispersed substances in the workplace. Since the working settings might resemble those described by us, our cohort might stand for a “human model” of exposure to asbestos for further investigations. For instance, the identification of biological markers of exposure to asbestos and early disease would be auspicious. This study means asbestos toxicity might be more multifaced and prompt chronic diseases and lung and nonlung asbestos-related diseases, in occupational and environmental settings where asbestos-containing materials are forged and or disrupted [60].

Figure 2: Infographic on the spectrum of Asbestos-Related Diseases (ARDs) and alterations which are reputed precursor of ARDs (preARDs) and others cumulatively detected in the formerly asbestos-exposed workers by the proper diagnostic means.