Establishing health-based biological exposure limits for pesticides : A proof of principle study using mancozeb

Pesticides represent an economical, labor-saving, and efficient tool for pest management, but their intrinsic toxic properties may endanger workers and the general population. Risk assessment is necessary, and biological monitoring represents a potentially valuable tool. Several international agencies propose biological exposure indices (BEI), especially for substances which are commonly absorbed through the skin. Biological monitoring for pesticide exposure and risk assessment seems a natural choice, but biological exposure limits (BEL) for pesticides are lacking. This study aims at establishing equivalent biological exposure limits (EBEL) for pesticides using real-life field data and the Acceptable Operator Exposure Level (AOEL) of mancozeb as the reference. This study included a group of 16 vineyard pesticide applicators from Northern Italy, a subgroup of a more extensive study of 28 applicators. Their exposure was estimated using \u201cpatch\u201d and \u201chand-wash\u201d methodologies, together with biological monitoring of free ethylene-bis-thiourea (ETU) excretion in 24-h pre- and post-exposure urine samples. Modeling was done using univariate linear regression with ETU excretion as the dependent variable and the estimated absorbed dose as the independent variable. The median skin deposition of mancozeb in our study population was 125 \u3bcg, leading to a median absorbed dose of 0.9 \u3bcg/kg. The median post-exposure ETU excretion was 3.7 \u3bcg. The modeled EBEL for mancozeb was 148 \u3bcg of free ETU or 697 \u3bcg of total ETU, accounting for around 75% of the maximum theoretical excretion based on a mass balance model. Although preliminary and based on a small population of low-exposed workers, our results demonstrate a procedure to develop strongly needed biological exposure limits for pesticides

Developing approaches to control SARS-CoV-2 in a public hospital

The Territorial Public Health Care Company (in Italian, ASST) of the Saints Paolo e Carlo of Milano includes two large public hospitals, and several outpatients and territorial healthcare services. It employs 5642 workers. The outbreak of novel coronavirus disease 2019 (COVID-19) reached our ASST in the last week of February when a doctor in the Intensive Care Unit of the San Paolo Hospital was diagnosed with COVID-19. Our Occupational Health Unit immediately introduced measures to control the epidemic. Our approach was based on contact tracing and isolation of asymptomatic infected workers. A \u2018close contact\u2019 was defined as a person who had face-to-face contact or spent at least 15 min in an indoor environment with a positive subject (patient, colleague or relative) without any protective equipment (surgical mask). From 27 February to 23 April we tested 2907 workers (51% of the total workforce) with nasopharyngeal swabs (NPS) using rtPCR for SARS-CoV-2 detection [1,2], with positive results in 152 hospital and 33 territorial workers (3% of the total workforce). All the infected workers were asked to fill in a daily electronic data collection form for the duration of the infection. About 50% remained substantially asymptomatic for the quarantine period, which ended when the workers underwent two NPS on two consecutive days with a negative result. The time to recovery took from 12\u201347 days, with a median duration of about 30 days, which is longer than normally expected. Symptomatic workers showed only very mild symptoms; mainly loss/change of smell and taste. Four were hospitalized but none had severe or life-threatening infection. The data suggest that the \u2018active search approach\u2019 is more effective in closed communities such as groups of healthcare workers than generalized testing. We have started a retrospective survey of 100 positive workers studying symptoms, source of exposure and co-morbidities using a modified version of the \u2018WHO novel coronavirus acute respiratory infection clinical characterization data tool\u2019, administered by telephone interview. Finally, in order to prepare for future outbreaks, we are testing a novel telemedicine approach enabling us to follow quarantined workers with a digital platform with a mobile phone app that provides remote video examinations and online symptoms and health parameter checking (body temperature, oxygen saturation, etc.). The platform facilitates rapid intervention. Using this approach, we can follow a large cohort of workers with continuous monitoring. The tool may also be able to reduce the rate of patients\u2019 hospitalization. We are also comparing those with positive and negative swabs using a rapid immunochromatographic assay for the detection of IgG and IgM antibodies to SARS-CoV-2 virus in whole blood to assess potential immunity. Preliminary results are promising for IgG, even though the protective capacity of this immunoglobulin is still unknown

Assessment of penconazole exposure in winegrowers using urinary biomarkers

Penconazole (PEN) is a fungicide used in agriculture. The aim of this work was to evaluate the exposure to PEN in vineyard workers focusing on urinary biomarkers. Twenty-two agricultural workers were involved in the study; they were investigated during PEN applications and re-entry work, performed for 1-4 consecutive working days, for a total of 42 mixing and applications and 12 re-entries. Potential and actual dermal exposure, including hand exposure, were measured using pads and hand washes. Urine samples were collected starting before the first application, continuing during the work shift, and ending 48\u202fh after the last shift. The determination of PEN in dermal samples and PEN metabolites in urine was performed by liquid chromatography tandem mass spectrometry. Dermal potential body exposure and actual total exposure showed median levels ranging from 18 to 3356\ub5g and from 21 to 111\u202f\ub5g, respectively. Urinary monohydroxyl-derivative PEN-OH was the most abundant metabolite; its excretion rate peaked within 24\u202fh after the work shift. In this period, median concentrations of PEN-OH and the carboxyl-derivative PEN-COOH ranged from 15.6 to 27.6\u202f\ub5g/L and from 2.5 to 10.2\u202f\ub5g/L, respectively. The concentration of PEN-OH during the work shift, in the 24\u202fh after and in the 25-48\u202fh after the work shift were correlated with actual body and total dermal exposure (Pearson's r from 0.279 to 0.562). Our results suggest that PEN-OH in the 24\u202fh post-exposure urine is a promising candidate for biomonitoring PEN exposure in agricultural workers

Environmental and biological monitoring for the identification of main exposure determinants in vineyard mancozeb applicators

Grapevine is a vulnerable crop to several fungal diseases often requiring the use of ethylenebisdithiocarbamate (EBDC) fungicides, such as mancozeb. This fungicide has been reported to have goitrogenic, endocrine disrupting, and possibly immunotoxic effects. The aim of this study was to assess workers' exposure in two scenarios of mancozeb application and analyse the main determinants of exposure in order to better understand their mechanism of influence. Environmental monitoring was performed using a modified Organisation for Economic Co-operation and Development (OECD) "patch" methodology and by hand-wash collection, while mancozeb's metabolite, ethylenethiourea (ETU), was measured in 24-h preexposure and postexposure urine samples. Liquid chromatography-mass spectrometry was used for determination of mancozeb and ETU in different kinds of samples. Closed tractor use resulted in 40 times lower potential exposure compared with open tractor. Coveralls reduced skin exposure 4 and 10 times in case of open and closed tractors, respectively. Gloves used during application resulted in 10 times lower hand exposure in open but increased exposure in closed tractors. This study has demonstrated that exposure to mancozeb is low if safe occupational hygiene procedures are adopted. ETU is confirmed as suitable biological marker of occupational exposure to mancozeb, but the absence of biological exposure limits significantly reduces the possibility to interpret biological monitoring results in occupationally exposed workers

Sorveglianza sanitaria in agricoltura : l\u2019esperienza del Centro Internazionale per la Salute Rurale dell\u2019Azienda Ospedaliera San Paolo di Milano

OCCUPATIONAL HEALTH SURVEILLANCE IN AGRICULTURE: THE EXPERIENCE OF THE INTERNATIONAL CENTRE FOR RURAL HEALTH. 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

A Mumps Outbreak in Vojvodina, Serbia, in 2012 Underlines the Need for Additional Vaccination Opportunities for Young Adults

In 2012, mumps was introduced from Bosnia and Herzegovina to Vojvodina, causing an outbreak with 335 reported cases. The present manuscript analyses the epidemiological and laboratory characteristics of this outbreak, identifies its main causes and suggests potential future preventive measures. Sera of 133 patients were tested for mumps-specific antibodies by ELISA and 15 nose/throat swabs were investigated for mumps virus RNA by RT-PCR. IgG antibodies were found in 127 patients (95.5%). Mumps infection was laboratory-confirmed in 53 patients, including 44 IgM and 9 PCR positive cases. All other 282 cases were classified as epidemiologically-confirmed. More than half of the patients (n = 181, 54%) were 20-29 years old, followed by the 15-19 age bracket (n = 95, 28.4%). Twice as many males as females were affected (67% versus 33%). Disease complications were reported in 13 cases (3.9%), including 9 patients with orchitis and 4 with pancreatitis. According to medical records or anamnestic data, 190 patients (56.7%) were immunized with two doses and 35 (10.4%) with one dose of mumps-containing vaccine. The Serbian sequences corresponded to a minor genotype G variant detected during the 2011/2012 mumps outbreak in Bosnia and Herzegovina. Vaccine failures, the initial one-dose immunization policy and a vaccine shortage between 1999 and 2002 contributed to the outbreak. Additional vaccination opportunities should be offered to young adults during transition periods in their life trajectories

Protein alterations associated with temozolomide resistance in subclones of human glioblastoma cell lines

Temozolomide (TMZ) is the standard chemotherapeutic agent for human malignant glioma, but intrinsic or acquired chemoresistance represents a major obstacle to successful treatment of this highly lethal group of tumours. Obtaining better understanding of the molecular mechanisms underlying TMZ resistance in malignant glioma is important for the development of better treatment strategies. We have successfully established a passage control line (D54-C10) and resistant variants (D54-P5 and D54-P10) from the parental TMZ-sensitive malignant glioma cell line D54-C0. The resistant sub-cell lines showed alterations in cell morphology, enhanced cell adhesion, increased migration capacities, and cell cycle arrests. Proteomic analysis identified a set of proteins that showed gradual changes in expression according to their 50% inhibitory concentration (IC50). Successful validation was provided by transcript profiling in another malignant glioma cell line U87-MG and its resistant counterparts. Moreover, three of the identified proteins (vimentin, cathepsin D and prolyl 4-hydroxylase, beta polypeptide) were confirmed to be upregulated in high-grade glioma. Our data suggest that acquired TMZ resistance in human malignant glioma is associated with promotion of malignant phenotypes, and our reported molecular candidates may serve not only as markers of chemoresistance but also as potential therapeutic targets in the treatment of TMZ-resistant human malignant glioma, providing a platform for future investigations

Interstitial fluid: the overlooked component of the tumor microenvironment?

Background: The interstitium, situated between the blood and lymph vessels and the cells, consists of a solid or matrix phase and a fluid phase, together constituting the tissue microenvironment. Here we focus on the interstitial fluid phase of tumors, i.e., the fluid bathing the tumor and stromal cells. Novel knowledge on this compartment may provide important insight into how tumors develop and how they respond to therapy. Results: We discuss available techniques for interstitial fluid isolation and implications of recent findings with respect to transcapillary fluid balance and uptake of macromolecular therapeutic agents. By the development of new methods it is emerging that local gradients exist in signaling substances from neoplastic tissue to plasma. Such gradients may provide new insight into the biology of tumors and mechanistic aspects linked to therapy. The emergence of sensitive proteomic technologies has made the interstitial fluid compartment in general and that of tumors in particular a highly valuable source for tissue-specific proteins that may serve as biomarker candidates. Potential biomarkers will appear locally at high concentrations in the tissue of interest and will eventually appear in the plasma, where they are diluted. Conclusions: Access to fluid that reliably reflects the local microenvironment enables us to identify substances that can be used in early detection and monitoring of disease

Biomedical informatics and translational medicine

Biomedical informatics involves a core set of methodologies that can provide a foundation for crossing the "translational barriers" associated with translational medicine. To this end, the fundamental aspects of biomedical informatics (e.g., bioinformatics, imaging informatics, clinical informatics, and public health informatics) may be essential in helping improve the ability to bring basic research findings to the bedside, evaluate the efficacy of interventions across communities, and enable the assessment of the eventual impact of translational medicine innovations on health policies. Here, a brief description is provided for a selection of key biomedical informatics topics (Decision Support, Natural Language Processing, Standards, Information Retrieval, and Electronic Health Records) and their relevance to translational medicine. Based on contributions and advancements in each of these topic areas, the article proposes that biomedical informatics practitioners ("biomedical informaticians") can be essential members of translational medicine teams

EXPLORING NOVEL APPROACHES TO PESTICIDE EXPOSURE AND RISK ASSESSMENT

Introduction. Agrochemicals, short from agricultural chemicals, is a term used for various chemical products which are commonly used in agriculture. The most famous representative example of agrochemicals are pesticides, but it may also include fertilizers, hormones or similar chemical growth agents, as well as raw animal manure. Even as an active substance is authorized in European Union, and products containing this active substance are authorized and marketed, there is still a need for risk assessment to communicate and to manage risk with regard to the different risk groups, workers and the general population as a whole. Overall Goal. The goal of this effort is the creation of Exposure and Risk Profiles, as a reliable, scientifically based way to forecast pesticide exposure and workers\u2019 risk in typical scenarios from a minimum set of available information, aimed at performing a preliminary risk assessment even without the need of \u201cin field\u201d measurements. Methodology. To reach our goal we have conducted a wide published literature search to define the process of pesticide application and the most common exposure determinants. Then we conducted two real-life field studies on exposure to pesticide in different use scenarios in the vineyards of the Region of Lombardy (one study in the framework of the ACROPOLIS project of the European Union, and another financed by INAIL). We collected field information in the form of a structured questionnaire, with a goal to record the variables previously identified as important modifiers of pesticide exposure. Also we collected exposure measurements, using two methodologies: skin pads and whole-body method, following in principle the OECD guidelines. Finally, we used the results from the field to develop a method that allows for a re-use of field data in risk assessment, by creating a Risk Assessment Scheme which can be used to assess risk in the field, without doing any measurements. Results. We report the main phases of pesticide work and variables, together with their influence, as a result of our wide literature search. Also we report the results of two field studies, first on 7 workers applying Tebuconazole on 12 work-days, and second on 28 workers applying Mancozeb on 38 work-days. Finally, we show a proposed approach to using field measurements from our study in the Region of Lombardy to perform future risk-assessment in one defined scenario of closed and filtered tractors. Discussion and Conclusions. Our work has tackled the problem of risk assessment for pesticide exposure in agriculture, which has been unfairly neglected in the past years. Through the use of literature data, field studies and computational modelling, we have managed to analyze and summarize the characteristics of pesticide application in agriculture, explore the real-life field conditions during pesticide application in vineyards in Italy, collect the field measurements necessary to do exposure and risk assessment, and to develop a method to use the data collected to produce a Risk Assessment Scheme. The study results and the above mentioned tool represent a step forward towards rapid, simple and scientifically based risk assessment in real-life conditions of pesticide application in agriculture