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Introduction: SARS-CoV-2 pandemic evolved in 2 consecutive waves during 2020. Improvements in the management of COVID-19 led to a reduction in mortality rates among hospitalized patients during the second wave. Whether this progress benefited kidney transplant recipients (KTRs), a population particularly vulnerable to severe COVID-19, remained unclear., Methods: In France, 957 KTRs were hospitalized for COVID-19 in 2020 and their data were prospectively collected into the French Solid Organ Transplant (SOT) COVID registry. The presentation, management, and outcomes of the 359 KTRs diagnosed during the first wave were compared to those of the 598 of the second wave., Results: Baseline comorbidities were similar between KTRs of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs. 58.4%, P  < 0.001) or calcineurin inhibitor (32.1% vs. 16.6%, P  < 0.001) was less frequent during the second wave. Hydroxychloroquine and azithromycin that were commonly used during the first wave (21.7% and 30.9%, respectively) but were almost abandoned during the second wave. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, P  < 0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, P  = 0.48) and COVID-19 hospitalization period was not associated with death due to COVID-19 in multivariate analysis (Hazard ratio 0.89, 95% confidence interval 0.67-1.17, P  = 0.4)., Conclusion: We conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality among KTRs. Our data indirectly support the importance of vaccination and neutralizing monoclonal anti-SARS-CoV-2 antibodies to protect KTRS from severe COVID-19., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Kidney transplant recipients (KTRs) are prone to develop severe COVID-19 and are less well protected by vaccine than immunocompetent subjects. Thus, the use of neutralizing anti-SARS-CoV-2 monoclonal antibody (MoAb) to confer a passive immunity appears attractive in KTRs., Methods: We performed a French nationwide study to compare COVID-19-related hospitalization, 30-day admission to intensive care unit (ICU), and 30-day death between KTRs who received an early infusion of MoAb (MoAb group) and KTRs who did not (control group). Controls were identified from the COVID-SFT registry (NCT04360707) using a propensity score matching with the following covariates: age, sex, delay between transplantation and infection, induction and maintenance immunosuppressive therapy, initial symptoms, and comorbidities., Results: A total of 80 KTRs received MoAb between February 2021 and June 2021. They were matched to 155 controls. COVID-19-related hospitalization, 30-day admission to ICU, and 30-day death were less frequently observed in the MoAb group (35.0% vs. 49.7%, P  = 0.032; 2.5% vs. 15.5%, P  = 0.002; 1.25% vs. 11.6%, P  = 0.005, respectively). No patient required mechanical ventilation in the MoAb group. The number of patients to treat to prevent 1 death was 9.7., Conclusion: The early use of MoAb in KTRs with a mild form of COVID-19 largely improved outcomes in KTRs., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Glyphosate (G) is the active ingredient of the most widely used herbicide products. It targets the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), which lacks in humans, suggesting to confer a low mammalian toxicity to G-based herbicides (GBHs). Despite this, the use of G is currently under intense debate. Many studies indicating its hazard and toxicity on non-target organisms are emerging, and associations between GBHs and immune-endocrine disturbances have been described. This review aims to investigate, based on recent epidemiological studies and studies performed in vitro and in vivo in animals, the possible association between GBHs and immune-endocrine alterations. Published data suggest that GBHs have endocrine disrupting potentiality targeting sex and thyroid hormones, although its relevance for humans will require further investigations. Evidence of immunotoxicity are limited compared to those on endocrine effects, but overall highlight possible noxious effects, including lung inflammation and rhinitis. An attractive hypothesis could be the one that connects microbiota dysbiosis with possible immune-endocrine outcomes. Indeed, several intestinal microorganisms express the enzyme EPSPS and, studies are emerging that highlight a possible G-induced dysbiosis. Considering the wide use of GBHs in agriculture, further studies investigating their noxious effects at levels relevant for human exposure should be performed. A critical analysis of emerging evidence of G toxicity is required to better characterize its safety profile. In addition, attention should be paid to the differences between G alone and its formulations, which, containing substances able to increase G absorption, may present a different toxicity profile., (Copyright © 2021 Elsevier B.V. All rights reserved.)

There are no studies which have compared the risk of severe COVID-19 and related mortality between transplant recipients and nontransplant patients. We enrolled two groups of patients hospitalized for COVID-19, that is, kidney transplant recipients (KTR) from the French Registry of Solid Organ Transplant (n = 306) and a single-center cohort of nontransplant patients (n = 795). An analysis was performed among subgroups matched for age and risk factors for severe COVID-19 or mortality. Severe COVID-19 was defined as admission (or transfer) to an intensive care unit, need for mechanical ventilation, or death. Transplant recipients were younger and had more comorbidities compared to nontransplant patients. They presented with higher creatinine levels and developed more episodes of acute kidney injury. After matching, the 30-day cumulative incidence of severe COVID-19 did not differ between KTR and nontransplant patients; however, 30-day COVID-19-related mortality was significantly higher in KTR (17.9% vs 11.4%, respectively, p = .038). Age >60 years, cardiovascular disease, dyspnea, fever, lymphopenia, and C-reactive protein (CRP) were associated with severe COVID-19 in univariate analysis, whereas transplant status and serum creatinine levels were not. Age >60 years, hypertension, cardiovascular disease, diabetes, CRP >60 mg/L, lymphopenia, kidney transplant status (HR = 1.55), and creatinine level >115 µmol/L (HR = 2.32) were associated with COVID-19-related mortality in univariate analysis. In multivariable analysis, cardiovascular disease, dyspnea, and fever were associated with severe disease, whereas age >60 years, cardiovascular disease, dyspnea, fever, and creatinine level>115 µmol/L retained their independent associations with mortality. KTR had a higher COVID-19-related mortality compared to nontransplant hospitalized patients., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in recipients of a kidney transplant remain scanty. The aim of this registry-based observational study was to explore characteristics and clinical outcomes of recipients of kidney transplants included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. Covid-19 was diagnosed in symptomatic patients who had a positive PCR assay for SARS-CoV-2 or having typical lung lesions on imaging. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. Risk factors for severe disease or death were determined. Of the 279 patients, 243 were admitted to hospital and 36 were managed at home. The median age of hospitalized patients was 61.6 years; most had comorbidities (hypertension, 90.1%; overweight, 63.8%; diabetes, 41.3%; cardiovascular disease, 36.2%). Fever, cough, dyspnea, and diarrhea were the most common symptoms on admission. Laboratory findings revealed mild inflammation frequently accompanied by lymphopenia. Immunosuppressive drugs were generally withdrawn (calcineurin inhibitors: 28.7%; antimetabolites: 70.8%). Treatment was mainly based on hydroxychloroquine (24.7%), antiviral drugs (7.8%), and tocilizumab (5.3%). Severe Covid-19 occurred in 106 patients (46%). Forty-three hospitalized patients died (30-day mortality 22.8%). Multivariable analysis identified overweight, fever, and dyspnea as independent risk factors for severe disease, whereas age over 60 years, cardiovascular disease, and dyspnea were independently associated with mortality. Thus, Covid-19 in recipients of kidney transplants portends a high mortality rate. Proper management of immunosuppression and tailored treatment of this population remain challenging., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

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 "patch" and "hand-wash" 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 μg, leading to a median absorbed dose of 0.9 μg/kg. The median post-exposure ETU excretion was 3.7 μg. The modeled EBEL for mancozeb was 148 μg of free ETU or 697 μg 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This paper presents an analysis of risk mitigation measures taken by countries around the world facing the current COVID-19 outbreak. In light of the current pandemic the authors collated and clustered (using harmonised terminology) the risk mitigation measures taken around the globe in the combat to contain, and since March 11, 2020, to limit the spread of the SARS-CoV-2 virus known to cause the Coronavirus disease 2019 (COVID-19). This overview gathers lessons learnt, providing an update on the current knowledge for authorities, sectors and first responders on the effectiveness of said measures, and may allow enhanced prevention, preparedness and response for future outbreaks. Various measures such as mobility restrictions, physical distancing, hygienic measures, socio-economic restrictions, communication and international support mechanisms have been clustered and are reviewed in terms of the nature of the actions taken and their qualitative early-perceived impact. At the time of writing, it is still too premature to express the quantitative effectiveness of each risk mitigation cluster, but it seems that the best mitigation results are reported when applying a combination of voluntary and enforceable measures., (© 2020 The Authors.)

Health-care personnel handling antineoplastic drugs could be at risk for adverse health effects. We aimed to evaluate genotoxic and cytotoxic effects of antineoplastic drug exposure of personnel preparing and administering such drugs in three Oncology Hospitals in Italy enrolling 42 exposed subjects and 53 controls. Furthermore, we aimed to study the possible influence of XRCC1 and hOGG1 DNA repair genes polymorphisms on genotoxicity induced on buccal cells. We performed workplace and personal monitoring of some drugs and used exposure diary informations to characterize the exposure. Urinary 5-FU metabolite (α-fluoro-β-alanine) was measured. Buccal Micronucleus Cytome (BMCyt) assay was used to evaluate DNA damage and other cellular anomalies. GEM and 5-FU contamination was found in 68% and 42% of wipe/swab samples respectively. GEM deposition was found on workers' pads while no α-fluoro-β-alanine was found. BMCyt-assay showed higher genotoxicity and cytotoxicity on nurses administering antineoplastics than on preparators and controls. Among micronucleus (MN) positive (with MN frequency higher than 1.5‰) exposed subjects, the percentage of those carrying XRCC1 mut/het genotype was higher than in MN positive-controls. Using the sensitive BMCyt assay, we demonstrated that handling antineoplastics still represents a potential occupational health risk for workers that should be better trained/informed regarding such risks., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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 h 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 3356µg and from 21 to 111 µg, respectively. Urinary monohydroxyl-derivative PEN-OH was the most abundant metabolite; its excretion rate peaked within 24 h 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 µg/L and from 2.5 to 10.2 µg/L, respectively. The concentration of PEN-OH during the work shift, in the 24 h after and in the 25-48 h 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 h post-exposure urine is a promising candidate for biomonitoring PEN exposure in agricultural workers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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 (C 0 ) >3 μg/L; group B had no change in TacER dose (TacER C 0 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 C 0 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 C 0 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., (© 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Hemolytic-uremic syndrome due to enterohemorrhagic Escherichia coli, belonging to serogroup O91 has rarely been described. We report here a case of post-diarrheal HUS due to EHEC O91 in an elderly patient for whom diagnosis was delayed given a previously diagnosed C. difficile infection. This case highlights the usefulness of Shiga-toxin detection., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Parkinsons' disease (PD) is the most common neurodegenerative movement disorder that is a consequence of premature death of dopamine-containing neurons in the substantia nigra. A number of observations have led to the hypothesis that environmental factors, including pesticides, play a significant role in the development of PD. Among pesticides, most commonly herbicides (paraquat in particular) and insecticides have been considered. The aim of this study is to address the uncertainties provided by epidemiological studies on the role of pesticide exposures in the development of PD, with the help of experimental toxicological data. Animal models that reproduce all clinical and pathological features of human PD are not available. In addition, the fundamental questions relate to the extrapolation from experimental to actual human exposure, taking also into account the role of genetic factors. Available measurements or estimates of human exposure levels that are significantly lower than those used in animal experimentation provide little support for a causal correlation between pesticide exposure and development of PD in humans. A possible role of acute poisonings or episodes of excessive exposure, and/or of combined exposures especially at early age and/or in the presence of certain genetic variants can be hypothesised. Follow up of survivors of acute poisonings by pesticides would provide information useful in this respect. According to the available data, from a public health point of view, prevention of "high" exposures, even asymptomatic ones, especially in utero and during early age is a priority., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

There has been a steep increase in the prevalence of dementia in recent decades, which has roughly followed an increase in pesticide use some decades earlier, a time when it is probable that current dementia patients could have been exposed to pesticides. This raises the question whether pesticides contribute to dementia pathogenesis. Indeed, many studies have found increased prevalence of cognitive, behavioral and psychomotor dysfunction in individuals chronically exposed to pesticides. Furthermore, evidence from recent studies shows a possible association between chronic pesticide exposure and an increased prevalence of dementia, including Alzheimer's disease (AD) dementia. At the cellular and molecular level, the mechanism of action of many classes of pesticides suggests that these compounds could be, at least partly, accountable for the neurodegeneration accompanying AD and other dementias. For example, organophosphates, which inhibit acetylcholinesterase as do the drugs used in treating AD symptoms, have also been shown to lead to microtubule derangements and tau hyperphosphorylation, a hallmark of AD. This emerging association is of considerable public health importance, given the increasing dementia prevalence and pesticide use. Here we review the epidemiological links between dementia and pesticide exposure and discuss the possible pathophysiological mechanisms and clinical implications of this association., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Persistent organic pollutants comprised of organic chemicals like polychlorinated biphenyls, dibenzo-p-dioxins, dibenzofurans and organochlorinated pesticides which have many characteristics in common. Once released in the environment they resist physical, biological, chemical and photochemical breakdown processes and thus persist in the environment. They are subject to long transboundary air pollution transport. They accumulate in the food chain due to their lipophilicity, bioaccumulation and biomagnification properties. Human exposure occurs through inhalation of air, ingestion of food and skin contact. Because most of them bioaccumulate and remain preferentially in fat, their long-term effects are still a matter of public health concern. They are condemned for health adverse effects such as cancer, reproductive defects, neurobehavioral abnormalities, endocrine and immunological toxicity. These effects can be elicited via a number of mechanisms among others include disruption of endocrine system, oxidation stress and epigenetic. However most of the mechanisms are not clear thus a number of studies are ongoing trying to elucidate them. In this review, the underlying possible mechanisms of action and their possible roles in adverse developmental and reproductive processes are discussed and where possible a linkage is made to some existing epidemiological data. Both genomic and nongenomic pathways are used to describe these effects. Understanding of these mechanisms will enable development of strategies to protect the public by reducing these adverse effects. This review is limited to persistent organochlorinated pesticides (OCPs) such as dichlorodiphenyltrichloroethane (DDT) and its metabolites, hexachlorobenzene (HCB), beta-hexachlorocyclohexane (β-HCH) and endosulfan., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The immune system can be the target of many chemicals, with potentially severe adverse effects on the host's health. In Western countries pesticides, together with new and modified patterns of exposure to chemicals, have been implicated in the increasing prevalence of diseases associated with alterations of the immune response, such as hypersensitivity reactions, certain autoimmune diseases and cancers. Xenobiotics may initiate, facilitate or exacerbate pathological immune processes, resulting in immunotoxicity by induction of mutations in genes coding for immunoregulatory factors, modifying immune tolerance and activation pathways. The purpose of this article is to update the evidence of pesticide immunotoxicity. Even if experimental data as well as sporadic human studies indicate that some pesticides can affect the immune system, overall, existing epidemiological studies are inadequate to raise conclusions on the immunotoxic risk associated to pesticide exposure. The available studies on the effects of pesticides on human immune system have several limitations including poor indication on exposure levels, multiple chemical exposures, heterogeneity of the approach, and difficulty in giving a prognostic significance to the slight changes often observed. Further studies are necessary, and they should be preferably carried out through comparison of pre and post-exposure findings in the same group of subjects with a matched control group. Attempt should be made to define the prognostic significance of slight changes often observed. Animal and in vitro studies are also important and necessary to scientifically support epidemiological evidences on pesticide-induced immunotoxicity., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Open field, variability of climatic and working conditions, and the use of complex mixtures of pesticides makes biological and environmental monitoring in agriculture, and therefore risk assessment and management, very complicated. A need of pointing out alternative risk assessment approaches, not necessarily based on measures, but simple, user-friendly and reliable, feasible also in the less advanced situations and in particular in small size enterprises, arises. This aim can be reached through a combination of environmental monitoring, biological monitoring and computational modelling. We have used this combination of methods for the creation of "exposure and risk profiles" to be applied in specific exposure scenarios, and we have tested this approach on a sample of Italian rice and maize herbicide applicators. We have given specific "toxicity scores" to the different products used and we have identified, for each of the major working phases, that is mixing and loading, spraying, maintenance and cleaning of equipment, the main variables affecting exposure and inserted them into a simple algorithm, able to produce "exposure indices". Based on the combination of toxicity indices and exposure indices it is possible to obtain semiquantitative estimates of the risk levels experienced by the workers in the exposure scenarios considered. Results of operator exposure data collected under real-life conditions can be used to validate and refine the algorithms; moreover, the AOEL derived from pre-marketing studies can be combined to estimate tentative biological exposure limits for pesticides, useful to perform individual risk assessment based on technical surveys and on simple biological monitoring. A proof of principle example of this approach is the subject of this article., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Although rice and corn are two main cash crops in Lombardy (North Italy) and their cultivation involves several thousands of farmers, risk assessment of pesticide exposure is rarely done, especially in small and medium sized enterprises. With the use of pads for environmental monitoring (OECD protocol), of pre- and post-exposure 24h urine collection for biological monitoring and of hand wash for hands' exposure, we measured the exposure of 28 agricultural workers to propanil and terbuthylazine in real-life working conditions. In propanil applicators, median daily exposure on the clothes was 73.5μmol per worker, while the exposure on the skin was 22.4μmol. For terbuthylazine, these exposures were 37.2μmol and 0.86μmol per worker, respectively. Median excretion of the propanil metabolite (3,4-dichloroaniline) after exposure was 84nmol in 24h urine, and 13nmol for the metabolite of terbuthylazine. Risk assessment performed by comparing to the AOELs of the applied active ingredients with an estimated internal dose, obtained based on the measured levels of skin and hand exposure and the percentage of dermal absorption of the active ingredients considered showed that 4 propanil workers, and no terbuthylazine workers, were overexposed. Our study helps define and confirm relationships between different exposure determinants, which can be used in the development of tools for risk assessment of exposure to pesticides in small and medium sized enterprises., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) have been widely used in industry and agriculture. Due to their persistence and bioaccumulation, they were globally spread in the environment and may still be found in environmental and biological media, despite the international restrictions on production and use. The main aim of our study was to develop a simple and fast method suitable for the establishment of the reference values for 15 PCB congeners and 16 OCPs in general population subgroups. A cost- and time-saving screening procedure using gas chromatography coupled with low-resolution mass spectrometry, was improved and validated before application to the analysis of real samples. The overall method was validated including uncertainty measurement. Preliminary field data were collected from 95 volunteers living in two Italian areas. HCB, p,p'-DDE, PCB 153, PCB 138 and PCB 180 were the most frequently detected compounds. Age and residence area were found to be significant variables for the most abundant compounds, while no correlation between serum concentrations and gender was observed. Our results suggest that long-banned substances, including PCBs and the pesticides HCB and DDT's breakdown product, are still detectable in the general population., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Biological monitoring (BM or biomonitoring) deals with the assessment of individual human exposure, effect and susceptibility to occupational risk factors. It is a fundamental tool in occupational health risk assessment (OHRA) and occupational health practice (OHP) and it has become one of the most, if not the most active area in occupational health (OH) research today. From the few hundred BM papers published in the 80s, there are now several tens of thousand papers published in the peer review literature each year, and the trend is still rising exponentially. As a result, BM has become a priority for the Scientific Committee on Occupational Toxicology (SCOT) of the International Commission on Occupational Health (ICOH). Moreover, there has been a long-term interest in biological monitoring by other SCs of ICOH such as the Scientific Committees on Toxicology of Metals (SCTM) and on Rural Health (SCRH). Despite its current popularity, though, BM is not always correctly used or interpreted by those involved in OHRA or OHP. The present review has been prepared to fill this gap and to help preventing misuse and misinterpretation of data. Although the document is meant to be a reference primarily for those involved in OH research and/or practice, it might become of interest for a wider audience within and outside ICOH, including scientists, occupational physicians, industrial hygienists and occupational or public health professionals in general, involved in chemical risk assessment for occupational health. The mission of SCOT and also of other SCs of ICOH, such as SCTM and SCRH, is indeed to promote the advancement and diffusion of knowledge on biological monitoring and other relevant occupational toxicology aspects and to make them available and useful to the entire OH scientific community. All articles retrieved as of 3 January, 2007 as "Review" with the combined key words "biological monitoring" in PubMed from 2000 to 2007 have been scanned individually. This yielded a total of 1400 articles from a grand total of 2486 (excluding limitation on year of publication). When the title was related to human occupational biological monitoring, the abstract was read and its content was included. Articles outside the 2000-2007 time frame or that are not classified as "Review" in PubMed have also been included, when relevant. The review is in four parts: (a) the introduction, containing the basic principles and definitions of BM and the different types of biomarkers (BMK), their toxicological significance, practical use and limitations, (b) the methodological and analytical aspects of BM in exposed workers, (c) the interpretation and management of BM data, including a number of recommendations to be considered when planning, performing and interpreting BM results and, finally, (d) the ethical aspects of BM. A list of key references to relevant papers or documents has been included. The BM of specific chemicals or groups of chemicals is outside the purpose of the review. The document is aimed to represent the state of the art on biological monitoring in occupational risk assessment. We expect that reference to its content will be made, whenever appropriate, by those involved in occupational health practice and research when dealing with BM issues. The document is not meant, though, to represent a rigid nor a permanent set of rules and it will be periodically updated according to new developments and any significant advance in BM science. Any part of the document, therefore, is open to suggestions by scientifically qualified persons or institutions officially involved in BM and comments should be sent directly to the authors. A preliminary draft of the document has been presented at the 7th International Symposium on Biological Monitoring, Beijing, 10-12 September, 2007., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

This study was carried out to define reference values for urinary ethylenethiourea (ETU) in the Northern Italy population and to identify the sources of exposure. Ninety-five healthy subjects were selected. A spot urine sample was collected in the morning, and analyzed using GC/MS in the EI/SIM mode. Thirty-nine subjects showed urinary ETU concentrations lower than the limit of detection (LOD, 0.4 microg/g creatinine), and the remainders ETU concentrations ranging from 0.5 to 11.6 microg/g creatinine. No correlation was shown between smoke or alcohol intake and urinary ETU concentrations. Based on data on ethylene-bis-dithiocarbamate (EBDC) concentrations in food, we estimated a total EBDCs intake of 31.7-50.1 microg/day. These values are largely below the ADIs, but explain the presence of small amounts of ETU in the urine samples we have analyzed. Finally, it was estimated that the mean ETU in urine in the Italian general population is 0.6-0.8 microg/g creatinine, with a 95th percentile of 4.5-5.0 microg/g creatinine. These values can be used as reference, to compare the results of biological monitoring activities carried out on EBDCs occupationally and environmentally exposed populations.

Ethylenethiourea (ETU) is a major metabolite of ethylenebisdithiocarbamate pesticides: a sensitive and specific assay for its determination in human urine is proposed below. ETU is extracted on a diatomaceous earth column using dichloromethane and derivatized with the mixture of N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide and tert-butyldimethyilsilyl chloride. The derivative is analyzed using GC/MS in the EI/SIM mode. The whole procedure is carried out in the presence of ethylenethiourea-d(4) as internal standard. The analytical features of the method are: high specificity, >90% recovery, range of linearity 0-200 microg/L, within- and between-run precision as coefficient of variation, <17 and <20%, respectively, limit of quantification 2 microg/L. In specimens stored in the dark at -20 degrees C ETU is stable for at least 6 months. The procedure was successfully applied to the biological monitoring of vineyard workers exposed to EBDTC and of a matched group of subjects from the general population.

In the present study, the personal exposure to mancozeb and/or ethilenethiourea (ETU) in 13 Italian vineyard workers and in 13 subjects without occupational exposure to pesticides was investigated. With this aim, the level of ETU in urine and the dermal exposure to mancozeb were determined. Baseline urinary ETU results were lower than the analytical limit of detection for all controls (<0.5 microg/g creatinine) and for ten workers (median <0.5, range <0.5-3.4 microg/g creatinine). In workers, urinary ETU was significantly increased at the end of shift (2.5, <0.5-95.2 microg/g creatinine) compared with baseline levels. End-shift urinary ETU was higher in operators using open tractors (n=7) than in those using closed tractors (n=5) (16.2 vs. 2.4 microg/g creatinine), but the difference was not significant (P=0.073). End-shift urinary ETU was positively correlated with dermal exposure to mancozeb determined both over the clothes and on the skin (Spearman's rho=0.770 and 0.702, P=0.009 and 0.024, respectively). Wine consumption positively influenced the excretion of ETU.

A wide range of studies concerned with analytical methods for biological monitoring of exposure to pesticides is reviewed. All phases of analytical procedures are assessed, including sampling and storage, sample preparation and analysis, and validation of methods. Most of the studies aimed at measuring metabolites or unchanged compounds in urine and/or blood as biological indicators of exposure or dose. Biological indicators of effect, such as cholinesterase, are also evaluated. The principal groups of pesticides are considered: organophosphorus pesticides, carbamate pesticides, organochlorine pesticides, pyrethroid pesticides, herbicides, fungicides and other compounds. Choice of the method for biological monitoring of exposure depends on the study population: a detection limit of 1 microg/l or less is required for the general population; higher values are adequate for occupationally exposed subjects. Interpretation of results is also discussed. Since biological indices of exposure are only available for a few compounds, biological reference values, established for the general population, may be used for comparison with levels of professionally exposed subjects.

Pesticides are used worldwide in agriculture, industry, public health and for domestic applications: as a consequence, a great part of the population may be exposed to these compounds. In spite of this extensive use, knowledge on the health risks associated with prolonged exposure is rather poor, and major uncertainties still exist. Epidemiological observations in man have so far produced little conclusive information, mainly because of weaknesses in exposure assessment. Therefore, information on the type and levels of exposure is fundamental in order to better understand and characterize risk to human health. Exposure assessment can be carried out via measurement of environmental concentrations, as well as via determination of the chemical or its metabolites in body tissues (biological monitoring). Besides indices of internal dose, biological monitoring also includes measurements of early effects attributable to interaction between the chemical agent and the human body. Biological monitoring has the advantage, over environmental monitoring, of determining the dose actually absorbed via any possible route: differences in absorption can be taken into account. whether they are due to biological variability or to use of protective equipment. When, in some cases, a combination of occupational and non-occupational exposure occurs, this also can be taken into consideration by biological monitoring. Few reference documents have been published on biological monitoring of pesticides. For this reason, the Office of Occupational Health of the World Health Organization gave ICPS a mandate to prepare a monograph specifically addressed to reviewing methods for biological monitoring of pesticide exposure. This review is based on more than 300 studies published over the period 1980-1999. For the most representative chemical classes, the available biological exposure indices are reported. Both indices of internal dose and. when available, of early effects are discussed. The reported tests were used to monitor exposure of pesticide applicators in agriculture and public health, manufacturing and formulating workers. subjects poisoned after accidental exposure or attempted suicide, volunteers involved in pharmacokinetic studies, as well as sub-groups of the general population exposed to environmentally persistent pesticides. Single chapters deal with organophosphorus insecticides, carbamate pesticides, dithiocarbamates, phenoxyacids, quaternary ammonium compounds. coumarin rodenticides, synthetic pyrethroids, organochlorine pesticides, chlorotriazines, and pentachlorophenol.

Exposure to pesticides can cause a number of effects on the immune system, varying from a slight modulation of immune functions to the development of clinical immune diseases. The aim of this study has been reviewing published data on immune effects of pesticides in humans, with particular attention for effects observed in absence of any other change, and to the possibility of identifying a dose effect relationship. Some evidence of immunotoxic effects in man involve organophosphorus compounds, some organochlorine insecticides (OC), some carbamates, some phenoxy herbicides, dithiocarbamates, and pentachlorophenol (PCP). The alterations are usually observed in absence of any other change; in some cases, data suggest the presence of a dose effect relationship. The prognostic significance of the observed changes is still unclear. The Authors propose a tier approach to assess immune effects in humans.

Occupational exposure to pesticides in agriculture and public health applications may cause acute and long-term health effects. Prevention of adverse effects in the users requires actions to be undertaken in the pre-marketing and post-marketing phase of these products. The pre-marketing preventive actions are primary responsibility of industry and the public administration. Admission of pesticide use (registration) is carried out by considering the toxicological properties of each pesticide (hazard identification), determining the dose-response relationship (NOEL identification), assessing or predicting the exposure level in the various scenarios of their use, and characterising the risk. The decision about admission takes into consideration the balance between risks and benefits. The post-marketing preventive activities consist of the promotion of a proper risk management at the workplace. Such a management includes the risk assessment of the specific conditions of use, the adoption of proper work practices, and the health surveillance of the workers. Each country should develop an adequate National Plan for Prevention of Pesticide Risk which allocates different roles and tasks at the central, regional and local level.