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Background: Ambulatory Advanced Heart Failure (AAHF) is characterized by recurrent HF hospitalizations, escalating diuretic requirements, intolerance to neurohormonal antagonists, end-organ dysfunction, short-term reduced life expectancy despite optimal medical management (OMM). The role of intermittent inotropes in AAHF is unclear. The RELEVANT-HF registry was designed to obtain insight on the effectiveness and safety of compassionate scheduled repetitive 24-hour levosimendan infusions (LEVO) in AAHF patients., Methods: 185 AAHF NYHA class III-IV patients, with ≥2 HF hospitalizations/emergency visits in the previous 6 months and systolic dysfunction, were treated with LEVO at tailored doses (0.05-0.2 μg/kg/min) without prior bolus every 3-4 weeks. We compared data on HF hospitalizations (percent days spent in hospital, DIH) in the 6 months before and after treatment start., Results: Infusion-related adverse events occurred in 23 (12.4%) patients the commonest being ventricular arrhythmias (16, 8.6%). During follow-up, 37 patients (20%) required for clinical instability treatment adjustments (decreases in infusion dose, rate of infusion or interval). From the 6 months before to the 6 months after treatment start we found lower DIH (9.4 (8.2) % vs 2.8 (6.6) %, p < 0.0001), cumulative number (1.3 (0.6) vs 1.8 (0.8), p = 0.0001) and length of HF admissions (17.4 (15.6) vs 21.6 (13.4) days, p = 0.0001). One-year survival was 86% overall and 78% free from death/LVAD/urgent transplant., Conclusions: In AAHF patients, who remain symptomatic despite OMM, LEVO is well tolerated and associated with lower overall length of hospital stay during six months. This multicentre clinical experience underscores the need for a randomized controlled trial of LEVO impact on outcomes in AAHF patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The progressive improvement of lymphoma therapies has led to a significant prolongation of patient survival and life expectancy. However, lymphoma survivors are at high risk of experiencing a range of early and late adverse effects associated with the extent of treatment exposure. Among these, second malignancies and cardiopulmonary diseases can be fatal, and neurocognitive dysfunction, endocrinopathy, muscle atrophy, and persistent fatigue can affect patients' quality of life for decades after treatment. Early recognition and reduction of risk factors and proper monitoring and treatment of these complications require well-defined follow-up criteria, close coordination among specialists of different disciplines, and a tailored model of survivorship care. We have summarized the major aspects of therapy-related effects in lymphoma patients, reviewed the current recommendations for follow-up protocols, and described a new hospital-based model of survivorship care provision from a recent multicenter Italian experience., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Exposure to inorganic Arsenic (iAs) through drinking water is a major public health problem affecting most countries. iAs has been classified by the International Agency for Research on Cancer as Group 1: "Carcinogenic to humans". Although numerous studies have shown the related adverse effects of iAs, sensitive appropriate biomarkers for studies of environmental epidemiology are still required. The present work aims at investigate the role of microRNAs (miRNAs), powerful negative regulators of gene expression, playing a key role in many physiological and pathological cellular processes, in iAs exposure. To this end, we analyzed miRNA changes in expression profile triggered by iAs exposure in Jurkat cell line. We used microarray technology to profile the expression of miRNAs following 2 μmol/L sodium arsenite treatment at different time points. Moreover, we performed phenotypic analysis of iAs treated cells. Real Time Polymerase Chain Reaction (RT-PCR) was used to validate miRNA microarray data and to assay expression modulation of selected relevant mRNAs. Finally, bioinformatics techniques were applied to reconstruct iAs-relevant molecular pathways and miRNA regulatory networks from the expression data. We report miRNAs modulated after iAs treatment in Jurkat cells. In particular, we highlight 36 miRNAs exhibiting consistent dysregulation and particularly a panel of 8 miRNAs which we also validated by RT-PCR analysis. Computational analysis of lists of putative target genes for these 8 miRNAs points to an involvement in arsenic-response pathways, for a subset of them, that were analyzed by RT-PCR. Furthermore, iAs exposure reveals induction of cell cycle progression and the failure of apoptosis, supporting the idea of iAs carcinogenic activity. Our study provides a list of miRNAs whose expression levels are affected by iAs treatment, corroborating the importance of proceeding with the hunt for specific subset of miRNAs, which can serve as potential biomarkers of iAs effects with useful diagnostic value., (Copyright © 2013 Elsevier B.V. All rights reserved.)

A sensitive, selective, accurate and precise method for simultaneous quantification of doxorubicin (DOX) and doxorubicinol (DOXol) in human plasma of patients diagnosed as having intermediate stage unresectable hepatocellular carcinoma (HCC) was developed. The method was based on electrospray tandem mass spectrometry in selected reaction monitoring mode. DOX, DOXol and trofosfamide, an internal standard, were extracted from plasma by using a simple solid phase extraction (SPE) procedure after the addition of 0.1 M hydrochloric acid. A 200-μL aliquot of the extracted sample reconstituted in mobile phase was analyzed on a Zorbax SB-C18 UHPLC column (50 mm × 2.1 mm, 1.8 μm particle size) in 8 min. The mobile phase consisted of acetonitrile and 0.1% formic acid pH 4.5 (95:05 v/v). Good accuracy and precision of this method were demonstrated by determination of spiked plasma QC samples in four consecutive days. The SPE extraction recoveries ranged from 72.3 to 77.3% and 75.5 to 98.4% for doxorubicin and doxorubicinol, respectively. The intra-day and inter-day precisions were less than 11.4%. The limit of quantitation was 1.0 ng/mL for both compounds. The calibration curves of DOX and DOXol were analyzed by weighted linear regression with 1/x as a weighting factor. They were linear over the concentration range of 1.0-100.0 ng/mL with R(2) greater than 0.99. This developed method was successfully applied to study plasma pharmacokinetics in patients affected by HCC and treated with transarterial chemoemolization practices (TACEs) using HepaSphere™ pre-loaded with DOX in a standardized procedure., (Copyright © 2012 Elsevier B.V. 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.)

Exposure assessment of health care workers to antineoplastic drugs (ADs) is still an open issue since new, critical, and emerging factors may put pharmacists who prepare hazardous drugs or nurses who administer anti cancer agents to an increased risk of developing adverse health effects. Overall, eight pharmacies and nine patient areas have been surveyed in this study. Wipe and pad samples were experienced during the surveillance program in four Italian health care settings. Urine samples were collected from workers handling ADs. Cyclophosphamide (CP), ifosfamide (IF), and gemcitabine (GEM) were detected in all the work environments by using a LC-MS/MS method-based capable of analysing all the three drugs simultaneously. In total, 54% of wipe samples were positive for at least one drug and 19% of pad samples were shown to be contaminated by cyclophosphamide. Pharmacies were generally more contaminated than patient areas with the exception of one site where a nurse had an acute exposure during the cleaning-up of an hazardous drug solution spill. In total, 22 urine samples collected from pharmacists and 78 urine samples from nurses had no detectable concentrations of any antineoplastic drugs. Despite the adherence to the recommended safety practices residue contamination on surfaces and floors has continued to be assessed in all the investigated sites., (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.)

The use of antineoplastic agents for the treatment of cancer and other non-neoplastic diseases is an increasingly common practice in hospitals. As a result, workers involved with handling antineoplastic drugs may be accidentally exposed to these agents, placing them at potential risk for long term adverse effects. To date, the challenge of protecting workers' health is persisting and expanding, with an increasing number of publications demonstrating that contamination of antineoplastic drugs (ADs) is still present on work surfaces after cleaning procedures are concluded. In this paper, five workplaces were selected for surveillance of professional exposure to ADs. Hospital pharmacies involved in the study were set in the North (Units A1 and B2), Center (Units C3 and D4) and South (Unit E5) of Italy. Contamination levels on a number of work surfaces and trends over a 10-year period are presented. Environmental and biological levels were obtained by high performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (MS/MS). A strong reduction of surface contamination was evidenced since 2003, when the recommended procedures for the safe handling of antineoplastic drugs started to be followed by health care workers. Employers' adherence to these recommendations allowed risk characterisation to achieve other important goals. The percentage of positive urine samples was found to be around 30% in the 1990s and 2% in the 2000s. Moreover, no positive samples were detected in 2006 or 2007. In conclusion, our study emphasized that one helpful strategy to reduce risk to all potentially exposed workers is also provided by a data-storage system that allows potential risks of working to be rapidly identified and controlled., (Copyright © 2010 Elsevier B.V. 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.)

Drug Eluting Microsphere-Transarterial Chemoembolization (DEM-TACE) is a new delivery system to administrate drugs in a controlled manner useful for application in the chemoembolization of colorectal cancer metastases to the liver. DEM-TACE is focused to obtain higher concentrations of the drug to the tumor with lower systemic concentrations than traditional cancer chemotherapy. Therefore a specific, precise and sensitive LC-ESI-MS/MS assay procedure was properly designed to detect and quantify epirubicin at the concentrations expected from a transarterial chemoembolization with microspheres. Serum samples were kept acidic (pH approximately of 3.5) and sample preparation consisted of a solid phase extraction (SPE) procedure with HLB OASIS cartridges using a methylene chloride/2-propanol/methanol mixture solution to recover epirubicin. The analyses consisted of reversed-phase high-performance liquid chromatography (rp-HPLC) coupled with tandem mass spectrometry (MS/MS). Accuracy, precision and matrix effect of this procedure were carried out by analyzing four quality control samples (QCs) on five separate days. The validation parameters were assessed by recovery studies of spiked serum samples. Recoveries were found to vary between 92 and 98% at the QC levels (5, 40, 80 and 150 microg/L) with relative standard deviation (RSD) always less than 3.7%. The limit of detection (LOD) was set at 1 microg/L. The developed procedure has been also applied to investigate the different capability of two types of commercially available microspheres to release epirubicin into the human circulatory system.

The long-established observation that some rheumatologic disorders (RDs) are associated with--or precede--the clinical manifestations of a variety of solid and hematological tumors represents an important clue for the early diagnosis and effective treatment of the cancers. Inflammatory myopathies, seronegative rheumatoid arthritis and some atypical vasculitides are the most frequently reported paraneoplastic RDs, although paraneoplastic scleroderma- and lupus-like syndromes, erythema nodosum, and Raynaud's syndrome have also been observed. Generally, the clinical course of a paraneoplastic RD parallels that of the cancer, and surgical removal of the tumor or its medical treatment usually results in a marked regression of the clinical manifestations of the RD. Most paraneoplastic RDs are difficultly distinguishable from idiopathic RDs. Even so, some atypical features of the clinical presentation raise the suspicion of an underlying tumor. This review summarizes current hypotheses for the pathogenesis that leads a tumor to present as an RD and discusses the clinical features that help distinguish paraneoplastic from idiopathic RDs.

Occupational exposure to antineoplastic cytostatic drugs has been recognized as a potential health hazard since the seventies. Safety guidelines and recommendations have been published in several countries in order to improve operating procedures and keep exposure levels as low as possible. Nevertheless, contamination still occurs. With a view to preventing exposure, standardized authorized methods and a mandatory monitoring system appear to be an essential prerequisite. First of all, reliable analytical methods are necessary, and a wide number of drugs should be monitored, on the basis of the continual change in the treatment protocols. In fact, most of the methods available in the literature were not properly validated, and a lack of details concerning quality assurance is clearly observed. When assessing analytical methods applied for routine testing, validation studies are of utmost importance. Not only performance parameters, such as sensitivity, specificity, LOD and LLQ, should therefore be determined, but also the uncertainty of measurement, which gives a measure of the confidence that can be placed on the results.

The main goal of this study is to establish the reference values of individual Polychlorinated biphenyl (PCB) congeners in non-occupationally exposed subjects. Since the PCB pattern in human serum is related to the living area, two different population groups from North and Central Italy, were compared. Serum concentrations of both coplanar and non-coplanar PCB congeners were measured by using gas chromatography coupled with low-resolution mass spectrometry (HRGC-LRMS). A fast and reliable method for the determination of 60 congeners had been previously validated. Its reliability was further verified by using high-resolution mass spectrometry. Thirty-one congeners out of 60 were found at detectable concentrations in at least one sample. The mean value for total PCBs was found to be 2.48 and 3.93 microg/L for the two population groups. Eight dioxin-like PCBs were detected. In accordance with the findings from the literature, the most abundant congeners were found to be 153, 138, 180, and 170. Both univariate and multivariate analysis showed that age is a significant determinant of PCB concentrations. The correlation increased with increasing chlorination. Slight differences in the PCB pattern were observed in the two population groups.

Twenty-four hour personal exposures (both occupational and environmental) to benzo(a)pyrene (BaP) of 15 taxi drivers working in Genoa, Italy, were monitored in May-July 1998 (15 samplings), February 1999 (7 samplings) and June 1999 (7 samplings). The mean BaP exposures measured at these different times were 1.4 ng/m3, 1.23 ng/m3 and 1.22 ng/m3, respectively, values were significantly greater than the levels found in controls (0.16+/-0.2 ng/m3). Mean daily personal BaP exposures of taxi drivers were not statistically different from the mean daily airborne BaP concentrations measured by fixed samplers during the same sampling periods.

Background: Exposure to indoor allergens has already been shown to occur in many public places, including workplaces, in several countries. Aim of this study was to measure the levels of house dust mites, cat and cockroach allergens in indoor workplaces (offices and archives) in Italy and to evaluate the possible relationships between allergen levels and building characteristics, type of ventilation, indoor relative humidity and temperature., Methods: Der f 1 and Der p 1, Fel d 1, Bla g 2 were measured by ELISA in dust samples collected from floors or upholstered seats of 160 workplaces., Results: Detectable Der p 1 levels were found in 86 (54%) workplaces Der f 1 in 87 (55%), Fel d 1 in 86 (54%) and Bla g 2 in 3 (1.9%). Der p 1 allergen concentrations expressed per weight were higher than the proposed sensitization thresholds in 7 samples, Der f 1 in 5, Fel d 1 in 6 and Bla g 2 in 3. The highest allergen levels were detected in samples from upholstered seats. A significant correlation was found between Der f 1 level on floors, expressed per surface, and indoor temperature (r = 0.39; P < 0.01)., Conclusions: In our study we found that upholstered seats in workplaces in Italy may constitute a significant reservoir both of house dust mites and cat allergens. Exposure to these allergens in workplaces may represent a risk factor for elicitation of symptoms and/or induction/maintenance of inflammation in allergic individuals and might also constitute a risk factor for sensitization., (Copyright 2004 Elsevier B.V.)

In order to assess occupational exposure of hospital personnel involved in the preparation and administration of antineoplastic drugs, biological and environmental monitoring are essential to identify the main exposure routes and to quantify potential health risks. If workplace contamination cannot be completely avoided, it is of utmost importance to reduce exposure to the lowest possible levels. To this aim, not only do education and training of the exposed subjects play an important role, but accurate standardized sampling techniques and analytical methods are also required. A critical overview of the most significant methods available in the literature is presented and their value is discussed, especially with respect to their sensitivity and specificity. In addition, attention is given to validation procedures and, consequently, to their reliability. The results from the most important surveys carried out at hospital departments are also discussed, with a view to improving both monitoring strategies and moreover working conditions.

To detect trace amounts of urinary cyclophosphamide (CP), ifosfamide (IF) and methotrexate (MTX), sensitive and specific high-performance liquid chromatography/ tandem mass spectrometry (HPLC-MS/MS) procedures, incorporating either liquid-liquid (for CP and IF), or solid-phase, extraction (for MTX) have been developed. Urinary platinum (Pt) was also detected using inductively coupled plasma-mass spectrometry (ICP-MS). These methods showed acceptable imprecision and inaccuracy. The limit of detection (LOD) was 50 ng/l for CP and IF, 200 ng/l for MTX and 1 ng/l for Pt. Biomonitoring was performed on two consecutive days on nine subjects preparing, and seven administering, antineoplastic drugs. Urine was collected at the beginning, at the end and during the work shift. Eighteen urine samples were positive for CP (range: 50-10031 ng/l), whereas IF was detected in one subject only (153 ng/l). LOD was never exceeded for MTX. In urine samples from nurses and pharmacy technicians, Pt was detected in three subjects (range 920-1300 ng/l). These findings were compared with the results from a previous survey carried out in the same hospital when different work practices were in use. The proposed methods are simple, fast and reliable and can be used to identify exposure of hospital personnel handling antineoplastic drugs.

The results of a polycentric study to assess the reference values of urinary mercury (U-Hg) in four Italian cities are presented. A total of 383 subjects were selected on the basis of standardised criteria by a questionnaire on personal habits, lifestyle, occupational or non-occupational exposure to Hg, medical history, number and area of dental amalgams. U-Hg was determined by hydride generation atomic absorption method (HG-AAS), with a detection limit of 0.5 microg/l and by flow injection (FI) inductively coupled plasma mass spectrometry (ICP-MS), with a detection limit of 0.03 microg/l. The median value of U-Hg, determined by HG-AAS, was 0.78 microg/g creatinine (0.75 for males and 0.83 for females), with 5 degrees and 95 degrees percentiles, respectively, of 0.17 and 3.66 microg/g creatinine. When determined by FI ICP-MS, the median value was 0.79 microg/g creatinine (0.77 for males and 0.79 for females) with 5 degrees and 95 degrees percentiles of, respectively, 0.12 and 5.02 microg/g creatinine. Among the independent variables, city of origin, area of dental amalgams, fish intake and tobacco smoking significantly influenced the U-Hg levels. The U-Hg reference values from this survey are lower than those from other recent investigations, probably due to characteristics and selection of the examined individuals and to the strict control of pre-analytical and analytical factors of variability.

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.

This paper presents the results of a polycentric study carried out in seven different areas, organized by the Italian Society of Reference Values (SIVR) for assessing reference values of lead in blood (B-Pb) at the current doses of the metal to general population. The estimated arithmetic mean for B-Pb in males was of 45.1 microg/l and 30.6 microg/l in females; the 95th centile was 100 and 60 for males and females, respectively. The main variables influencing B-Pb levels were gender, age, BMI, outside sport practice, alcohol consumption and smoking habits, while the geographic area and the urban residence did not affect the metal concentration in blood.

5-Fluorouracil (5-FU) is one of the most widely used antineoplastic drugs. It can be therefore considered to be a model compound for the identification of exposure routes during preparation and administration of cytostatic agents, especially for nucleoside analogue drugs. In this study, an HPLC-UV method was validated for determination of 5-FU in wipe samples by direct analysis of the aqueous solutions and in air samples by using solid-phase extraction (SPE). When samples were pre-treated on styrene-divinylbenzene resin SPE columns, a 20-fold preconcentration of the analyte was achieved. As regards air samples, correlation coefficients were always higher than 0.998 and the limit of detection was assessed at 15 ng on filter. In order to verify the reliability of these procedures, 5-chlorouracil was used as internal standard. The procedure presented here has been applied to the environmental monitoring of occupational exposed subjects. The amount of 5-FU ranged from 0.043 to 0.23 microg/m3 in air samples and from 0.2 to 470.1 microg/dm2 in wipe samples. 5-FU was also detected on the internal side of the gloves (0.07 to 3.77 microg/pair of gloves).

Objectives: To define the maximum tolerated dose (MTD), the toxicity and pharmacokinetic profile of BBR3464, a novel triplatinum complex., Patients and Methods: Fourteen patients with advanced solid tumors not responsive to previous antitumor treatments received BBR 3464 on a daily x 5 schedule every twenty-eighth day. The drug was given as a one-hour infusion with pre-and post-treatment hydration (500 ml in one hour) and no antiemetic prophylaxis. The starting dose was 0.03 mg/m2/day. A modified accelerated titration escalation design was used. Total and free platinum (Pt) concentrations in plasma and urine were assessed by ICP-MS on days 1 and 5 of the first cycle., Results: Dose was escalated four times up to 0.17 mg/m2/day. Short-lasting neutropenia and diarrhea of late onset were dose-limiting and defined the MTD at 0.12 mg/m2. Nausea and vomiting were rare, neither neuro- nor renal toxic effects were observed. BBR3464 showed a rapid distribution phase of 1 hour and a terminal half-life of several days. At 0.17 mg/m2 plasma Cmax and AUC on day 5 were higher than on day 1, indicating drug accumulation. Approximately 10% of the equivalent dose of BBR3464 (2.2%-13.4%) was recovered in a 24-hour urine collection., Conclusions: The higher than expected incidence of neutropenia and GI toxicity might be related to the prolonged half-life and accumulation of total and free Pt after daily administrations. Lack of nephrotoxicity and the low urinary excretion support the use of the drug without hydration. The single intermittent schedule has been selected for clinical development.

Background: The oral bis (acetate) ammine dichloro cyclohexylamine platinum (IV) analogue (BMS-182751) was brought into clinical development because it was shown to be cytotoxic against some human tumour cell lines and to have an antitumor activity in murine tumours at least comparable to that of parenteral cisplatin and carboplatin. In early clinical studies in which the optimal schedule of treatment was daily for five consecutive days, dose-dependent nausea and vomiting occurred in about two-thirds of patients., Patients and Methods: To evaluate if the use of lower daily doses for longer periods of time could result in a better tolerability, JM216 was given once daily for 14 consecutive days every four to five weeks to adult patients with solid tumors. Oral antiemetics were given prophylactically only at the highest doses. The pharmacokinetics of total and ultrafiltrable platinum were studied on days 1 and 14 of the first cycle by Inductively Coupled-Mass-Spectrometry (ICP-MS)., Results: Forty-six patients were treated at doses ranging from 10 mg/m2/d to 50 mg/m2/d and 39 were evaluable for hematologic toxicity over 74 cycles. MTDs were reached at 45 mg/m2/d and 50 mg/m2/d x 14 repeated every five weeks in patients with extensive, or limited/no prior treatment, respectively. The dose-limiting toxicity was neutropenia which was delayed and variable among patients. Other non-hematological toxicities were severe vomiting (22% of cycles), diarrhea (28% of cycles) and drug-associated fever (32% of patients), controlled with paracetamol. Subjective improvement with disappearance of tumour-related pain was observed in one patient with chemotherapy-resistant metastatic prostate cancer and in one previously untreated patient with malignant mesothelioma. Cmax and AUC values of both total and ultrafiltrable platinum on days 1 and 14 were highly variable among patients. Only Cmax on day 1 was linearly related to the dose. Total and ultrafiltrable platinum were still detectable two weeks after the last dose. No relationship could be established between AUC values and toxicities., Conclusions: Daily doses of JM216 of 40 mg/m2 and 45 mg/m2 for 14 consecutive days every five weeks with oral antiemetic prophylaxis are selected for phase II evaluation of single agent in patients with extensive or limited/no prior treatment, respectively. The administration of JM216 on a day x 14 schedule produced nausea and vomiting comparable to that observed with the day x 5 regimen but of longer duration. The variability of pharmacokinetics and pharmacodynamics, even though limited at the doses proposed for phase II evaluation of JM216 as single agent, recommend a careful monitoring of the patients.

Background: The most striking of carboplatin's advantages (CBDCA) over cisplatin (CDDP) is its markedly reduced rate of neurotoxic effects. However, the use of CBDCA higher-intensity schedules and the association with other neurotoxic drugs in polychemotherapy may cause some concern about its safety with respect to peripheral nervous system damage., Materials and Methods: Two different schedules of CBDCA administration (10 mg/kg and 15 mg/kg i.p. twice a week for nine times) were evaluated in Wistar rats. Neurotoxicity was assessed for behavioral (tail-flick test), neurophysiological (nerve conduction velocity in the tail nerve), morphological, morphometrical and analytical effects., Results: CBDCA administration induced dose-dependent peripheral neurotoxicity. Pain perception and nerve conduction velocity in the tail were significantly impaired, particularly after the high-dose treatment. The dorsal root ganglia sensory neurons and, to a lesser extent, satellite cells showed the same changes as those induced by CDDP, mainly affecting the nucleus and nucleolus of ganglionic sensory neurons. Moreover, significant amounts of platinum were detected in the dorsal root ganglia and kidney after CBDCA treatment., Conclusions: CBDCA is neurotoxic in our model, and the type of pathological changes it induces are so closely similar to those caused by CDDP that it is probable that neurotoxicity is induced in the two drugs by the same mechanism. This model can be used alone or in combination with other drugs to explore the effect of CBDCA on the peripheral nervous system.

Although it is generally accepted that reference values can be included among the instruments of modern occupational medicine, problems arise when applying them from clinical chemistry to the needs of occupational medicine. Here some general aspects regarding reference values beginning from their theoretical basis, their significance and importance and their possible use in occupational medicine are reviewed. Furthermore, their relationship with other more familiar 'guideline values', such as action levels and limit values, is demonstrated.

Urinary excretion of ethylenethiourea (ETU) was monitored for 8 days in a group of five male non-smoker volunteers on a diet, the items of which were assayed for ETU and carbon sulphide. Urinary excretion of ETU reflected the consumption of wine, fruit and vegetables. Urinary ETU concentrations ranged from 0.6 to 6.7 micrograms/g creatinine. ETU concentrations in the food eaten by the volunteers were generally below the detection limit whereas in wine 8.8 micrograms/l ETU was detected. Evolution of carbon sulphide by food samples ranged from 0.03 to 0.17 mg/kg. Mean (+/- S.D.) daily intake of ETU in wine was 3.5 +/- 0.2% of the acceptable daily intake (ADI): 0.070 +/- 0.004 micrograms/kg body wt. During the 8 days of the study, an average of 48.3% of the ETU ingested in wine was excreted unmodified by the kidneys. Twenty-four hour urinary excretion of ETU was significantly correlated with daily intake of ETU (r = 0.768) and CS2 evolved by the daily food items (r = 0.414).

Urinary levels of 1-hydroxypyrene in a general adult population group are studied. Experimental data are not normally distributed; statistical analysis required a base 10 logarithmic transformation of data. The concentrations of urinary 1-hydroxypyrene measured were expressed as microgram g-1 urinary creatinine and are comparable with those reported by other authors, both for smoker and non-smoker subgroups. Multiple regression analysis shows that, for smokers, the number of cigarettes smoked per day and the body mass index (BMI) significantly influence the levels of urinary 1-hydroxypyrene expressed as microgram g-1 urinary creatinine, whereas no personal or behavioural variable (age, sex, alcohol consumption, dietary intake of pyrene, BMI) modified the 1-hydroxypyrene levels for non-smokers.

We propose a sampling strategy, using individual dosimetry to measure the daily inhaled quantity of PAHs in urban air. The method was applied to monitor 56 subjects living in an Italian town (Pavia; 80 000 inhabitants) and the Environmental Reference Concentration (E.R.C.) of six PAHs (classified as 'possible' carcinogenic agents for humans) was determined. The individual environmental samplings took place in two different seasons (winter and summer), for persons living in four different urban areas with different traffic density. Subjects were selected using a specific questionnaire designed to collect information on indoor and indoor+outdoor exposure times. The mean +/- S.D. value of Benzo[a]pyrene [BaP] was 0.37 +/- 0.15 ng m-3 in winter and 0.12 +/- 0.07 ng m-3 in summer. Assuming 18 m3 as the daily inhaled quantity the estimate of the BaP inhaled quantity was 6.66 ng/day in winter and 2.16 ng/day in summer.

A study using individual dosimetry to evaluate the daily inhaled dose of sixteen aromatic and aliphatic hydrocarbons in three groups of primary school children, living in three Italian towns with 50,000 inhabitants or less, (Treviglio-Lombardy; Poggibonsi-Tuscany; Valenza-Piedmont) is presented. The simultaneous use of two passive samplers (radial diffusion) for each child, for a 24 h period, determined both the indoor and indoor + outdoor environmental reference concentrations. We measured the urinary levels of benzene, toluene, ethylbenzene and xylenes for each child and hence determined the urinary reference values for BTEX. We also considered the possibility of using benzene in urine as a biomarker of environmental exposure of the general population to this xenobiotic. We evaluated how both the environmental and biological measures were influenced by the presence of smokers in the surveyed children's houses. For the group of children living in Poggibonsi, we considered the influence of the living area and the traffic density on environmental concentrations of benzene (indoor and indoor + outdoor).

The results of a study in which urinary ethylenethiourea (ETU) was assayed in the general population (167 subjects) of four Regions of Italy (Veneto, Lombardy, Piedmont and Trentino Alto Adige) are reported. The results are compared with those in a population of 97 subjects from Rovescala, a hillside wine-producing town a few kilometers from Pavia, where ethylenebisdithiocarbamates are sprayed by helicopter. It was found that an average of 24% of the populations of the four regions, taken together, had urinary ETU levels above detection limits (1.0 microgram 1(-1)) as compared to 37% of the population of Rovescala. The ranges of concentration were 0.8-8.3 micrograms 1(-1) for the four regions and 0.9-61.4 micrograms 1(-1) for Rovescala. Statistically significant variables for urinary ETU levels were smoking and wine drinking.

Obtaining reliable trace element reference values in tissues and fluids from inhabitants of the European Union relies on the availability of standardized and harmonized protocols for the statistical treatment of the data on trace element levels in general European populations. In this context, cadmium was measured in the blood (BCd) of 514 Italian inhabitants from the Lombardy region and the results statistically treated and presented according to a procedure which includes: simple descriptive statistics and graphical analysis such as stem and leaf and box-plot representations (average BCd levels were 0.62 microgram/l; geometric mean, 0.51 microgram/l; median, 0.50 microgram/l; mode, 0.30 microgram/l; 95th percentile, 1.48 micrograms/l; 5th percentile, 0.20 microgram/l); p-p plot, Shapiro-Wilk and Lilliefors tests for normality (the distribution of the data is closer to the log-normal distribution and inconsistent with the hypothesis of normality); analysis of variance (BCd increases from 20 to about 60 years and then decreases; it is influenced by smoking but not by body mass and alcohol consumption and it is higher in men than in women); and step wise multiple regression analysis (BCd is influenced by the number of cigarettes/day and the total dose of exposure, cigarettes/day multiplied by smoking years). Tentative reference intervals for BCd based on the log transformation of the data are 0.14-1.82 micrograms Cd/l (whole population); 0.16-1.94 micrograms Cd/l (male) and 0.13-1.66 micrograms Cd/l (female); 0.24-2.68 micrograms Cd/l (smokers); and 0.14-1.27 micrograms Cd/l (non-smokers).

In order to establish reference values of thallium in tissues of the general population the element was determined in blood (TlB) and urine (TlU) of 123 healthy inhabitants living in the Marche region, Central Italy. The analysis was carried out by inductively coupled plasma-mass spectrometry (ICP-MS; detection limit in our experimental conditions, 0.001 micrograms Tl/I), which was validated by neutron activation analysis (NAA) and laser induced fluorecence (LIF) spectroscopy. The check of pre-analytical factors indicated a low risk of contamination and loss of Tl during sampling, handling and storage before the instrumental analysis (blank of the entire procedure less than the detection limit). Mean values of TlU and TlB were 0.066 micrograms Tl/l and 0.063 micrograms Tl/l, respectively (median in both cases 0.057 microgram Tl/l). No conclusive evidence concerning the distribution followed by our data set, normal or log-normal, were drawn, although Lilliefors test and Kolmogorov's D-test showed a tendency for TlB to follow both the normal and the log-normal while TlU followed a log-normal distribution. Overall correlations between TlU and TlB are rather weak. A significant, but not high, correlation (P < 0.0004, r = 0.44) was observed in females. Age, sex, smoking habits and alcohol consumption did not seem to play any role on TlU and TlB. Tentatively proposed reference intervals are 0.019-0.17 microgram Tl/l (urine) and 0.014-0.19 microgram Tl/l (blood).