Antifibrotic treatment response and prognostic predictors in patients with idiopathic pulmonary fibrosis and exposed to occupational dust.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is an aggressive interstitial lung disease with an unpredictable course. Occupational dust exposure may contribute to IPF onset, but its impact on antifibrotic treatment and disease prognosis is still unknown. We evaluated clinical characteristics, respiratory function and prognostic predictors at diagnosis and at 12 month treatment of pirfenidone or nintedanib in IPF patients according to occupational dust exposure. METHODS: A total of 115 IPF patients were recruited. At diagnosis, we collected demographic, clinical characteristics, occupational history. Pulmonary function tests were performed and two prognostic indices [Gender, Age, Physiology (GAP) and Composite Physiologic Index (CPI)] calculated, both at diagnosis and after the 12 month treatment. The date of long-term oxygen therapy (LTOT) initiation was recorded during the entire follow-up (mean = 37.85, range 12-60 months). RESULTS: At baseline, patients exposed to occupational dust [≥ 10 years (n = 62)] showed a lower percentage of graduates (19.3% vs 54.7%; p = 0.04) and a higher percentage of asbestos exposure (46.8% vs 18.9%; p 0.002) than patients not exposed [< 10 years (n = 53)]. Both at diagnosis and after 12 months of antifibrotics, no significant differences for respiratory function and prognostic predictors were found. The multivariate analysis confirmed that occupational dust exposure did not affect neither FVC and DLCO after 12 month therapy nor the timing of LTOT initiation. CONCLUSION: Occupational dust exposure lasting 10 years or more does not seem to influence the therapeutic effects of antifibrotics and the prognostic predictors in patients with IPF.

Position Paper on Asbestos of the Italian Society of Occupational Medicine.

The Position Paper (PP) on asbestos of the Italian Society of Occupational Medicine (SIML) aims at providing a tool to the occupational physician to address current diagnostic criteria and results of epidemiological studies, and their consequences in terms of preventive and evaluation actions for insurance, compensation and litigation. The PP was based on an extensive review of the scientific literature and was compiled by a Working Group comprising researchers who have contributed to the international literature on asbestos-related diseases, as well as occupational physicians with extensive experience in the evaluation of risks and the medical surveillance of workers currently and formerly exposed to asbestos. The PP was drafted and reviewed between 2017 and 2018; its final version was prepared according to the guidelines of AGREE Reporting Checklist. All the members of the Working Group subscribed to the document, which was eventually approved by SIML's Executive Committee. The first section addresses industrial hygiene issues, such as methods for environmental monitoring, advantages and limitations of different microscopy techniques, the potential role of microfibers and approaches for retrospective assessment of exposure, in particular in epidemiological studies. The second section reviews the biological effects of asbestos with particular attention to the diagnostic aspects of asbestosis, pleural changes, mesothelioma and lung cancer. In the following section the criteria of causal attribution are discussed, together with different hypotheses on the form of the risk functions, with a comparison of the opinions prevalent in the literature. In particular, the models of the risk function for mesothelioma were examined, in the light of the hypothesis of an acceleration or anticipation of the events in relation to the dose. The last section discusses topics of immediate relevance for the occupational physician, such as health surveillance of former exposed and of workers currently exposed in remediation activities.

Silica, silicosis and lung cancer: what level of exposure is acceptable?

Silica, silicosis and lung cancer: what level of exposure is acceptable?

Biological monitoring of cobalt in hard metal factory workers.

PURPOSE: The main aim of this study was to investigate the cobalt (Co) concentrations in urine along 4 months and their relationship with Co concentrations in blood and haemoglobin (adducts) in 34 workers from a hard metal manufacturing plant where metallic Co and Co oxide were used. Furthermore, the excretion kinetics of Co was investigated and the half-lives of Co in blood, plasma and urine were calculated along 18 days of non-exposure in the same workers. METHODS: Co was analysed, in all biological samples, by ICP/MS. RESULTS: Wide fluctuations in the urinary Co concentration were observed throughout the work shift and during the work week. A highly significant linear correlation was found between Co concentration (geometrical mean) in urine samples provided each Thursday (end shift) during 16 subsequent weeks and levels of Co-haemoglobin adducts or blood Co concentrations at the end of the same period. The Co elimination kinetics in globin calculated along 18 days without Co exposure was slow, being related to the physiological metabolism of haemoglobin, while in blood, plasma and urine Co half-lives were 12.3, 9.1 and 5.3 days, respectively. CONCLUSION: Co concentrations in haemoglobin or blood are highly related to the geometrical mean concentration of urinary Co when samples are collected weekly for several subsequent weeks. The biological monitoring of occupational exposure to Co in hard metal facilities provides reliable results by using the Co concentrations in haemoglobin or in whole blood. The urinary findings, though, do not show the same reliability because of their wide daily and weekly fluctuations.

Chest ultrasonography in health surveillance of asbestos-related lung diseases.

OBJECTIVES: Exposure to asbestos fibers can lead to different lung diseases, such as pleural thickening and effusion, asbestosis, mesothelioma, and lung cancer. These diseases are expected to peak in the next few years. The aim of the study was to validate ultrasonography (US) as a diagnostic tool in the management of lung diseases in subjects with a history of occupational exposure to asbestos. METHODS: Fifty-nine retired male workers previously exposed to asbestos were enrolled in the study. Chest US was performed in all the subjects. The US operator was blinded to earlier performed computed tomography (CT) scan reports and images. The sonographic pathological findings were pleural thickening (with or without calcifications), peripheral lung consolidation, and focal sonographic interstitial syndrome and diffuse pneumogenic sonographic interstitial syndrome (pulmonary asbestosis). Significant US findings were recorded, stored, and subsequently compared with CT scans. RESULTS: With some patients falling into more than one category, on CT scan, pleural thickening was reported in 33 cases (56%, 26 with calcifications), focal interstitial peripheral alterations in 23 (39%), asbestosis in 6 (10%), and peripheral lung consolidation in 13 cases (22%). Comparing each pathological condition to CT scan reports, US findings had high levels of sensitivity, specificity, positive, and negative predictive values. US did not prove effective for the detection of central lung nodules or diaphragmatic pleural thickenings. Chest US was considered to be the best technique to detect minimal pleural effusions (six subjects, 10%). CONCLUSIONS: Chest US might be considered an additional tool to follow up subjects occupationally exposed to asbestos who have already undergone CT scan examination and whose pathology is detectable by US as well.

[Relevance and role of guideline values for chemical risk assessment.] / Significato e ruolo dei valori guida nella valutazione del rischio chimico.

OBJECTIVES: Guideline values have been defined by the ad hoc S.I.M.L.I.I. Working Group as "the level of a risk factor, previously established for an environmental or biological context, to which the levels actually measured for/in the workers should be compared, in order to assess their degree of exposure". METHODS: Guideline values include limit values, action levels and reference values, and may refer to an environmental or biological matrix. RESULTS: The present paper aims to discuss the methodologies currently used for the definition of the most relevant guideline and limit values at the national and international level, with a particular attention to those used in the European Union (OEL). CONCLUSIONS: It is concluded that a correct use of guideline values represents a fundamental tool for both the assessment and the management of chemical risk in workers exposed to toxic and/or carcinogenic substances.

ICOH International Code of Ethics for Occupational Health Professionals: Historical fortune and future perspectives in Italy. / I1 Codice Internazionale di Etica ICOH per gli operatori di Medicina del Lvoro: fortuna storica e prospettive future in Italia.

The Working Group responsible for the Italian translation of the third edition of the International Code of Ethics, appointed by the President of the International Commission on Occupational Health (ICOH), Dr. Jukka Takala, completed last April the revision work. The final text, already available on the ICOH website, has been printed and distributed by the Italian National Institute for Insurance against Accidents at Work (INAIL) at the 79th National Congress of the Italian Society of Occupational Medicine and Industrial Hygiene (SIMLII), in Rome. The curators of this third Italian edition have accomplished the delicate task of adaptation in Italian, taking into account the specificities of the practice of medicine in the Italian work environment. It involves many professionals with diverse roles and responsibilities in the public and private sectors for safety, hygiene, health and environment in relation to work. More than twenty years after the first Italian edition, we trace the evolution of the ICOH International Code of Ethics, in order to focus its birth, national and international distribution, and continuous improvement as well as its ability to direct the stakeholders towards a participatory prevention model, in a legislative framework that has seen over the past two decades a radical change in the Italian world of work.

[The teaching of occupational medicine in the Master of Science in Medicine in the twenty years since the introduction of Table XVIII]. / L'insegnamento della Medicina del lavoro nel corso di laurea magistrale in Medicina e Chirurgia a vent'anni dall'introduzione della Tabella XVIII.

In 1991, the implementation of the new programme for education and training in Medicine and Surgery has introduced the teaching of Occupational Medicine (OM) as a compulsory subject for all medical students. After two decades from that event and in conjunction with the implementation of the new academic departments introduced by the law 240/2010, the aim of the present study was to address the current status and the main characteristics of education and training, including clinical activities, in OM in Italian Universities and to update the information on the related academic human resources available. A questionnaire was developed to investigate the different features of the academic staff belonging to the area of OM (SSD MED/44), and to evaluate the organization of teaching and the clinical activities performed by the Occupational Medicine sections. The results showed that among the 40 Italian universities with a degree course in Medicine and Surgery, 67% of them have at least one full professor, 72% one associate professor and 78% one assistant professor belonging to the area of OM. Nevertheless, a steady decrease in the number of academic staff is observed with time, which caused a lack of presence of the discipline in some universities. In most degree courses in Medicine and Surgery the teaching of OM is usually included in an integrated course together with other disciplines such as General and Applied Hygiene and/or Forensic and Legal Medicine. Within the integrated course the number of University Education & Training Credits (CFU, corresponding to approx. 25 hrs of teaching overall) assigned to OM is generally between 2 and 3 (61% of cases). The teaching of OM is also present in eight different master degree courses (MSc) and in 33 different triennial degree courses (BSc). To support the teaching clinical activities, such as workers' health surveillance, laboratories, ambulatories, and DH or inpatient activities are performed, in one or more of these forms, by almost all of the OM institutions. The findings of this study, despite being subject to change rapidly with time, still provide an invaluable set of information and should represent, therefore, a rational basis for planning the future recruitment of academic staff and for updating the contents and methodologies of graduate education and training in Occupational Medicine in Italian universities.

[Update on benzene: from industrial toxicant to environmental carcinogen]. / Il benzene oggi: da tossico industriale a cancerogeno ambientale.

Benzene, an industrial chemical myelotoxic at high doses in workers, is now an almost ubiquitous pollutant. It is also a no-threshold genotoxic carcinogen causing acute leukemia and other lymphoaematological tumours. Although its mechanism of action has not been fully clarified, benzene toxicity and carcinogenicity depend on metabolic activation. Polymorphism of activating and detoxifying enzymes (CYP, GST, NQO1) may be critical, therefore, in modulating individual susceptibility to benzene. Further uncertainty factors in assessing low level benzene exposure are the limited sensitivity and specificity of most exposure biomarkers, the frequent coexposure to other volatile organic chemicals (VOC), and the presence of non occupational sources of exposure, such as cigarette smoke and veicular traffic. The aim of this presentation is to introduce the main current critical issues in the risk assessment and the biological monitoring of occupational exposure to benzene at low doses.

[Considerations on the limit values for benzene]. / Considerazioni sui valori limite per il benzene.

Occupational exposure limits and guideline values for the general population proposed for benzene by several international bodies are discussed and compared with the Italian and EU occupational limit values, taking also into account the criteria used for their derivation. Benzene is an environmental pollutant, and the EU guideline value for ambient air is 5 microg/m3, based on carcinogenic risk. Presently, occupational exposures are greatly reduced, and in many instances close to those of the general population. Consequently, it does not seem to be appropriate to maintain the Italian and the EU occupational exposure limits of 1 ppm (3.2 mg/m3), which are inconsistent with the ALARA principle and not justified by technological constraints. It should be pointed out that, in any case, preventive interventions should be carried out, beyond the compliance with the established limit values, in order to ensure the lowest exposure and by carrying out biological monitoring as a tool to verify the appropriateness of risk management measures.

[Biomarkers of effect and susceptibility to low doses of benzene]. / Indicatori di effetto e di suscettibilità alle basse dosi di benzene.

Current occupational exposure levels to benzene are reduced by three orders of magnitudo (from ppm to ppb) as compared to the past. As benzene toxicity is related to its biotransformation and bioactivation pathways seem to be more active at lower exposure levels, observed effects could be higher than expected. Although the genetic polymorphisms of relevant and functional metabolic enzymes are implied in the modulation of either the risk of adverse effects [myeloperoxidase and NAD(P)H:quinone oxidoreductase] or of the biomarkers of internal dose (glutathione S-transferases M1-1, T1-1, A1-1), they are not appliable as biomarkers of susceptibility. Among biomarkers of early effect, only the longitudinal monitoring of blood cell count seems suitable to be applied in health surveillance protocols, whereas the use of biomarkers of genotoxic effect at current exposure levels is at the present not supported by literature data.

[International applications and experiences in biological monitoring: state of the art]. / Applicazioni ed esperienze internazionali in tema di monitoraggio biologico: stato dell'arte.

Biological monitoring (BM) represents one of the most dynamic areas of research in occupational health today. From a few tens of articles published yearly in the 70s and 80s, there are now several thousand papers published in the peer review literature each year and the trend is still growing. BM was originally used to assess exposure, effects and susceptibility to occupational agents, but it has been now extended to environmental chemical risk assessment, as well as to several other biomedical sciences, such as epidemiology, tumor science, molecular biology, to mention just a few. The aim of the present paper is to consider new experiences in the use of BM at the international level and to discuss the contribution that these approaches may provide to develop new diagnostic and preventive tools in occupational and environmental health.

[The new methodology to produce instruments for updating occupational physician proposed by Italian Society of Occupational Medicine and Industrial Hygiene (SIMLII)]. / Gli strumenti di orientamento e aggiornamento del Medico del Lavoro della Società Italiana di Medicina del Lavoro e Igiene Industriale (SIMLII): criteri e metodi di produzione.

Starting from the experience of last five years, during which 24 guide liens about the most important aspects of Occupational Physician activity have been produced, the Italian Society of Occupational Medicine and Industrial Hygiene (SIMLII) delegated a specific working group for updating the methodology to be adopted for guide lines and other instruments for improving and standardizing the current activity in our professional field. SIMLII produced in the context of the specific Education and Accreditation Programme for occupational physicians prepared from 2002 25 guide lines or other informative instruments on the most important and controversial themes in which our discipline is involved. They were considered and treated to meet the need to improve and standardise activities and to modify the current approach of occupational physicians and aimed not only at improving the effectiveness of preventive actions but also at constantly adopting rigorous methodologies based where possible on evidence based or on consensus procedures. The Directive of SIMLII was firmly convinced about the opportunity-necessity to critically evaluate the experience carried out during the last years, at the light of the National Program for Guide Lines edited By Italian National Health Institute since 2002 and which concerns preparation, dissemination, updating, implementation of guide lines in Medicine. The guide lines were defined as rational critical effective aid addressed to professionals and patients for health services organization. Relevant was the new Framework Act for the occupational safety and health (Decreto legislativo 81/08) too signed by the President of the Italian Republic on April 9, 2008, which for the first time includes and defines in a legislative act the different possible instruments (technical normative, good practices, guide lines). In this paper we present the new methodology defined by our Society for producing the different kind of instruments such as guide lines, consensus conference reports, technology assessments, good practices statements guide lines focusing as the main aspects those related to definitions, argument choice, working group and coordinator identification, producing methods, evidence evaluation, grading, quality evaluation using AGREE method, dissemination procedure, the conflict of interest and the possible use for distance formation procedure focusing the recommendations that take a practical-applicative approach.

Glutathione transferases and glutathionylated hemoglobin in workers exposed to low doses of 1,3-butadiene.

We evaluated glutathione transferase (GST) activities and the levels of glutathionylated hemoglobin in the RBC of 42 workers exposed to 1,3-butadiene in a petrochemical plant, using 43 workers not exposed to 1,3-butadiene and 82 foresters as internal and external controls, respectively. Median 1,3-butadiene exposure levels were 1.5, 0.4, and 0.1 microg/m3 in 1,3-butadiene-exposed workers, in workers not directly exposed to 1,3-butadiene, and in foresters, respectively. In addition, we determined in the peripheral blood lymphocytes of the same individuals the presence of GST polymorphic genes GSTT1 and GSTM1 and the distribution of GSTP1 allelic variants. Comparing the mean values observed in petrochemical workers with those of control foresters, we found a marked decrease of GST enzymatic activity and a significant increase of glutathionylated hemoglobin in the petrochemical workers. A weak but significant negative correlation was found between levels of 1,3-butadiene exposure and GST activity, whereas a positive correlation was found between 1,3-butadiene exposure and glutathionylated hemoglobin. A negative correlation was also observed between GST activity and glutathionylated hemoglobin. No influence of confounders was observed. Using a multiple linear regression model, up to 50.6% and 41.9% of the variability observed in glutathionylated hemoglobin and GST activity, respectively, were explained by 1,3-butadiene exposure, working setting, and GSTT1 genotype. These results indicate that occupational exposure to 1,3-butadiene induces an oxidative stress that impairs the GST balance in RBC, and suggest that GST activity and glutathionylated hemoglobin could be recommended as promising biomarkers of effect in petrochemical workers.

Biological monitoring of low level exposure to benzene in an oil refinery: Effect of modulating factors.

The aim of the study was to investigate the effect of various factors that modulate the metabolism of benzene, including smoking habits, metabolic genotype of GST and co-exposure to toluene, on the levels of three biomarkers, i.e. urinary benzene (UB), S-phenylmercapturic acid (SPMA) and t,t-muconic acid (t,t-MA), in 146 refinery workers exposed to low levels of air benzene (AB) in the range <1.5-529.2 µg/m3 (mean value 32.6 µg/m3). The study confirmed the validity of SPMA as a good biomarker of benzene exposure even at low levels of exposure. It was also confirmed that cigarette smoking is the main confounding factor when assessing biological monitoring data of occupational exposure to AB. Our data indicate that the GSTT1, but not the GSTM1 genotype, significantly increases the urinary levels of SPMA, even at low levels of exposure. It is not known, though, whether subjects with a GSTT1 "null" genotype may be more susceptible to the effects of benzene. Finally, environmental toluene appears to inhibit the metabolism of benzene to SPMA even at low concentrations, also resulting in an underestimation by SPMA levels of the actual exposure of workers to benzene.

Biomonitoring of workers using nuclear magnetic resonance-based metabolomics of exhaled breath condensate: A pilot study.

Exhaled breath condensate (EBC) is a non-invasive biological matrix that allows easy access to the lung epithelial lining fluid. It can provide, for instance, useful biochemical information in workers following inhalatory exposure. Recently, nuclear magnetic resonance (NMR)-based metabolomics has been applied to EBC profiling to identify metabolic phenotypes ("metabotypes") of relevance in respiratory medicine. We aimed at verifying if NMR-based metabolomics of EBC, combined with statistical analysis, could find differences in metabolomic profiles between groups of subjects occupationally exposed to levels of airborne inhalable dust, phenol, formaldehyde and volatile organic compounds (VOCs) below regulatory limits. Samples were collected from 20 blue-collar workers without wearing a mask (therefore "exposed" to ambient air) and after wearing a mask ("not exposed"). This procedure was only allowed after the standard air quality tests had shown levels of airborne xenobiotics below the occupational exposure limit or even below the LOD. Ten white-collar controls were also included. After partial least squares discriminant analysis, the exposed to the controlled plant environment and the not exposed groups were clearly separated, and discrimination was due to alteration of fatty acids and alcohols, whose statistical significance was also evaluated. Our results show that NMR-based metabolomics of EBC is a useful tool that has the potential to be successfully used in occupational health to distinguish between subjects exposed and non-exposed to very low airborne levels of chemicals.

Biomonitoring of toxic metals in incinerator workers: A systematic review.

Exposure to chemicals released during urban waste disposal and treatment is increasingly regarded as a potential occupational health issue. Indeed, several toxic metals emitted by an incinerator, including As, Be, Cd, Cr, Pb, Mn, Hg, Ni and V, have potentially toxic properties and their exposure, therefore, may be of concern for the health of the workers involved. The levels of exposure should therefore be carefully measured. Environmental monitoring, however, may be unable, alone, to assess true exposure, due to its intrinsic limitations mainly concerning its inability to assess oral and dermal absorption. In these cases biological monitoring may represent a fundamental supplementary tool for the definition of the workers' true occupational exposure and for the prevention of the related health effects. There is, therefore, an increasing interest in developing and using, in these workers, sensitive and specific biomarkers for health risk assessment, particularly at low or even very low levels of exposure. Despite the large number of original and review articles present in the literature on the biomonitoring of workers exposed to metals, the data on subjects employed in waste treatment activities are scattered and results are sometimes inconsistent. This is the first systematic review, performed according to PRISMA methodology, of the major studies investigating the levels of different toxic metals measured in the main biological matrices (blood, urine, hair) of incinerator workers. The results show that the levels of metals measured in incinerators' workers are generally low, with some notable exceptions for Cd and Pb. These results, though, can be affected by several confounders related either to non-occupational exposure, including diet, area of residence and others, and/or by a number of methodological limitations, as we found in the reported studies. Future work should focus on an integrated approach, using ideally both biological and environmental monitoring. A particular emphasis should be given to the measurement of the different granulometric fractions of the dust containing metals, i.e. inhalable, thoracic, respirable and ultrafine fractions. Moreover, an accurate description of the work tasks and the characteristics and levels of non-occupational exposure should always be provided.

An Integrated Approach for the Environmental Characterization of a Wide Potentially Contaminated Area in Southern Italy.

This paper deals with the environmental characterization of a large and densely populated area, with a poor reputation for contamination, considering the contribution of environmental features (air, soil, soil hydraulic and groundwater) and the potential effects on human health. The use of Geographic Information System (GIS) has made possible a georeferenced inventory and, by overlaying environmental information, an operational synthesis of comprehensive environmental conditions. The cumulative effects on environmental features were evaluated, taking into account superposition effects, by means of the Spatial MultiCriteria Decision Analysis (S-MCDA). The application of the S-MCDA for converging the combination of heterogeneous factors, related to soil, land and water, deeply studied by heterogeneous groups of experts, constitutes the novelty of the paper. The results confirmed an overall higher potential of exposure to contaminants in the environment and higher mortality rates in the study area for some tumours, but hospital admissions for tumours were generally similar to the regional trend. Besides, mortality data may be strictly dependent on the poor socioeconomic conditions, quality of therapy and a lack of welfare in the area relative to the rest of Italy. Finally, as regards the possible relationship between presence of contaminants in the environment and health conditions of the population no definite conclusions can be drawn, although the present study encourages the use of the new proposed methods, that increase the possibilities for studying the combined effect of more environmental factors.

Occupational toluene exposure induces cytochrome P450 2E1 mRNA expression in peripheral lymphocytes.

Print workers are exposed to organic solvents, of which the systemic toxicant toluene is a main component. Toluene induces expression of cytochrome P450 2E1 (CYP2E1), an enzyme involved in its own metabolism and that of other protoxicants, including some procarcinogens. Therefore, we investigated the association between toluene exposure and the CYP2E1 response, as assessed by mRNA content in peripheral lymphocytes or the 6-hydroxychlorzoxazone (6OH-CHZ)/chlorzoxazone (CHZ) quotient (known as CHZ metabolic ratio) in plasma, and the role of genotype (5 -flanking region RsaI/PstI polymorphic sites) in 97 male print workers. The geometric mean (GM) of toluene concentration in the air was 52.80 ppm (10-760 ppm); 54% of the study participants were exposed to toluene concentrations that exceeded the maximum permissible exposure level (MPEL). The GM of urinary hippuric acid at the end of a work shift (0.041 g/g creatinine) was elevated relative to that before the shift (0.027 g/g creatinine; p < 0.05). The GM of the CHZ metabolic ratio was 0.33 (0-9.3), with 40% of the subjects having ratios below the GM. However, the average CYP2E1 mRNA level in peripheral lymphocytes was 1.07 (0.30-3.08), and CYP2E1 mRNA levels within subjects correlated with the toluene exposure ratio (environmental toluene concentration:urinary hippuric acid concentration) (p = 0.014). Genotype did not alter the association between the toluene exposure ratio and mRNA content. In summary, with further validation, CYP2E1 mRNA content in peripheral lymphocytes could be a sensitive and noninvasive biomarker for the continuous monitoring of toluene effects in exposed persons.

Unique Scopolamine Withdrawal Syndrome After Standard Transdermal Use.

We report the case of a 62-year-old woman who developed a withdrawal syndrome after using a standard 1.5-mg transdermal scopolamine (TDS) patch behind the ear to prevent motion sickness during sailing. The patient, who had used TDS occasionally for years without significant adverse effects, more recently, having worn a patch continuously for 7 days, approximately 24 to 36 hours after removing the patch developed dizziness, nausea, sweating, fatigue, and drowsiness. All symptoms disappeared without therapy in about 2 days. Approximately 1 year after the first episode, though, a very similar, more severe disabling reaction developed on 2 occasions. Drowsiness and malaise were accompanied by severe asthenia, orthostatic sweating, inability to stand, and hypotension. All clinical tests (electrocardiogram; spirometry; blood cell count; plasma levels of cortisol, sodium, and potassium; and liver and kidney function tests) were negative, and symptoms disappeared slowly, after several days. Although we are certain that scopolamine was responsible for the symptoms, we are less clear as to the nature of the disorder. The effects being more severe after a more prolonged use of the TDS patch, the increase in severity each successive time, and the time lag between removing the patch and appearance of symptoms all indicated a withdrawal syndrome for which several mechanisms may be suggested.