No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Long‐term effect of arsenic exposure: Results from an occupational cohort study
Abstract
Background
In 1976 in Manfredonia (Italy), arsenic was released into the atmosphere due to an accident in a petrochemical plant. We aimed to analyze the mortality of workers involved in the factory for the site cleaning activities.
Methods
The cohort consisted of 1467 workers grouped into contract, fertilizer, and plastic workers. The outcome of interest was mortality for specific causes. Standardized mortality ratios (SMR) and 95% confidence intervals (95%CI) were computed.
Results
For all workers and all causes of death combined, the SMR was less than 1.0. Mortality ratios were increased for malignant neoplasms of the pleura, bone and melanoma of the skin. Contract workers, the group mostly exposed to arsenic, showed statistically significant SMRs for several malignancies, in particular for lung cancer (SMR = 1.26; 95%CI: 1.05‐1.54).
Conclusions
Overall, the results reported here on mortality among persons occupationally exposed to arsenic are consistent with the literature and biologically plausible.
... Using this inclusion criterion, more than 300 of workers who took part in clean-up activities following the accident and were included in an epidemiological surveillance program, were excluded from the study. In 2016, there was an updated follow-up of the two sub-cohorts as originally enumerated (Gianicolo, 2021;Gianicolo et al., 2019;Gianicolo et al., 2019). ...
... Using this inclusion criterion, more than 300 of workers who took part in clean-up activities following the accident and were included in an epidemiological surveillance program, were excluded from the study. In 2016, there was an updated follow-up of the two sub-cohorts as originally enumerated (Gianicolo, 2021;Gianicolo et al., 2019;Gianicolo et al., 2019). ...
... Since a measure of exposure to arsenic or concentrations of arsenic in urine were not available for the analysis, as done in previous studies, the area of work combined with the type of contract was used as a surrogate of exposure. Contract workers are assumed to be the most exposed, followed by fertilizer workers and plastic workers as the least exposed (Casciani and Attias, 1999;Gianicolo et al., 2019). This assumption is based on legal documents that reported concentrations of arsenic in soil in the range 0.22-4.50 ...
Background
On September 1976, due to the explosion of an ammonia-washing column at the petrochemical plant in Manfredonia (Italy), 39 tonnes of arsenic were released into the atmosphere, contaminating the plants and the neighbourhoods close to it. The aim of this study is to present the results of a 45-year follow up of exposed workers with a focus on residential exposure.
Methods
We contacted Italian General Registries Offices and updated the vital status of persons involved in the clean-up activities following the disaster. The outcome of interest was the overall and cause-specific mortality. An accelerated failure time (AFT) approach was used when appropriate to model the risk of mortality.
Results
1772 workers contributing 67,743 person years were considered in the analysis. For overall mortality, results of the age-adjusted AFT model show an accelerator factor of 0.89 (95%CI 0.80–0.99) among contract workers, which means a shortening of survival in comparison to the reference category (plastic area workers). When accounting for latency greater than 20 years, higher mortality rates for lung cancer were observed among workers residing in Manfredonia.
Discussion
An increased risk of mortality among workers who were more exposed to arsenic during the clean-up activities has been observed. In fact, a loss of 5 years of life among more exposed workers was calculated. Furthermore, the mortality rates of residents in Manfredonia were higher than those of workers residing elsewhere.
... Questo eccesso aumenta (+40%; dato non riportato in tabella) con periodi di latenza compresi tra i 15 e i 20 anni dall'incidente. 29 Il confronto interno alla coorte ha messo in evidenza in-R A S S E G N E E A R T I C O L I www.epiprev.it Tabella 1. Persone in studio, numero di decessi e anni-persona, per caratteristiche delle persone in studio. ...
... Nell'impianto di Manfredonia è stata, infatti, accertata la presenza di amianto 53 e sono stati riportati in letteratura eccessi di mesoteliomi tra i lavoratori della coorte. 16,29,54 Per quanto concerne il confronto interno, questo è limitato dalla bassa numerosità dei lavoratori della categoria di riferimento, che ha reso incerte le stime degli hazard ratio. ...
Introduction:
in 1976, a major chemical accident occurred in Manfredonia (Apulia Region, Southern Italy) due to an explosion in the fertilizer area. More than 10 tons of arsenic were released into the atmosphere, contaminating the plant and the surrounding areas. At the end of the 90s, criminal proceedings were initiated and a cohort study was conducted within the trial.
Objectives:
to update the vital status of workers enrolled within the trial; some relevant results are also given.
Methods:
two different approaches were used to update the vital status depending on the residence of the individuals in the cohort. We computed cause-specific standardised mortality ratios (SMRs), stratified according to the type of employment (urea sector, caprolactam sector, and contract workers), with 95% confidence intervals (95%CI). For internal comparison purpose, Cox regression models were used and hazard ratios (HRs) were calculated, considering workers from the caprolactam area as a reference category.
Results:
the cohort consisted of 1,467 workers; 114 were dead at the end of the previous follow-up. Among 728 workers residing in Manfredonia, we identified 619 people still alive and 93 deceased. Among 625 not-residents, 508 were alive and 93 deceased. For 285 cases out of 306, cause of death was ascertained. Contract workers show a statistically significant SMR for lung cancer (SMR: 1.26; 95%CI 1.05-1.54) and an increased risk for overall mortality (HR: 2.3; 95%CI 1.1-4.9). Workers residing in Manfredonia show a higher risk of lung cancer mortality in comparison to not-residents (HR: 2.3; 95%CI 1.1-4.9).
Conclusions:
workers who were most exposed to arsenic during the site cleaning show an increased risk of overall mortality compared to the least exposed and an increased risk of lung cancer compared to the general population.
... 35 Also, in Italy and in 1976, a major chemical accident Table 1 Absolute and relative frequencies of each type of technological disaster by year of occurrence as well as the average rates of mortality, affected individuals, and injuries per million inhabitants, and the standard deviations for each of the average rates. occurred that released large quantities of arsenic into the atmosphere, in the study by Gianicolo et al., 36 carried out years later, on the causes of mortality of the plant workers at the time of the accident showed a statistically significant excess mortality for the workers most exposed to arsenic. ...
This study examine the epidemiological profile of technological disasters that occurred in Europe between 2000 and 2021 in terms of morbidity-mortality and to analyse their temporal trends. A decreasing trend was found for the total number of technological disasters, as well as for each of the types (transport accident, industrial accident, and miscellaneous accident). However, no upward, or downward trends were found for the average mortality rate, for the average of affected people rate and for the average of injury rate per year. The most frequent type of technological disaster in Europe between 2000 and 2021 was the transport accident followed by miscellaneous accidents. The type of technological disaster with the highest average mortality rate is also the transport accident. Research on disasters is hampered by the lack of common inclusion criteria for existing databases. It would be important to establish common inclusion criteria to improve the analytical capacity and comparability of disaster research results.
... A calcareous bedrock and historical sources of arsenic contamination in the aquifer characterize Site 2 (Ciampi et al., 2023). Arsenic oxides accumulated in the fractured aquifer as a result of the 1976 explosion of an industrial plant (Liberti and Polemio, 1981;Gianicolo et al., 2019;Mangia et al., 2018). Both sites feature decades of P&T efforts to mitigate groundwater pollution. ...
Pump-and-treat (P&T) is commonly used to remediate contaminated groundwater sites. The scientific community is currently engaged in a debate regarding the long-term effectiveness and sustainability of P&T for groundwater remediation. This work aims to provide a quantitative comparative analysis of the performance of an alternative system to traditional P&T, to support the development of sustainable groundwater remediation plans. Two industrial sites with unique geological frameworks and contamination with dense non-aqueous phase liquid (DNAPL) and arsenic (As) respectively, were selected for the study. At both locations, attempts were made for decades to clean up groundwater contamination by pump-and-treat. In response to persistently high levels of pollutants, groundwater circulation wells (GCWs) were installed to explore the possibility of accelerating the remediation process in unconsolidated and rock deposits. This comparative evaluation focuses on the different mobilization patterns observed, resulting variations in contaminant concentration, mass discharge, and volume of extracted groundwater. To facilitate the fusion of multi-source data, including geological, hydrological, hydraulic, and chemical information, and enable the continuous extraction of time-sensitive information, a geodatabase-supported conceptual site model (CSM) is utilized as a dynamic and interactive interface. This approach is used to assess the performance of GCW and P&T at the investigated sites. At Site 1, the GCW stimulated microbiological reductive dichlorination and mobilized significantly higher 1,2-DCE concentrations than P&T, despite recirculating a smaller volume of groundwater. At Site 2, As removal rate by GCW resulted generally higher than pumping wells. One conventional well mobilized higher masses of As in the early stages of P&T. This reflected the P&T's impact on accessible contaminant pools in early operational periods. P&T withdrew a significantly larger volume of groundwater than the GCW. The outcomes unveil the diverse contaminant removal behavior characterizing two distinct remediation strategies in different geological environments, revealing the dynamics and decontamination mechanisms that feature GCWs and P&T and emphasizing the limitations of traditional groundwater extraction systems in targeting aged pollution sources. GCWs have been shown to reduce remediation time, increase mass removal, and minimize the significant water consumption associated with P&T. These benefits pave the way for more sustainable groundwater remediation approaches in various hydrogeochemical scenarios.
... The literature on arsenic in drinking water and lung cancer has focused mainly on areas contaminated with high arsenic concentrations [46] and, only in the last years, on low arsenic exposures [47,48]; moreover, the type of interaction with cigarette smoke has not always been evaluated. In addition, less attention has been focused on occupational exposure to arsenic, although the risk of developing lung cancer among miners and workers in metallurgical and petrochemical industries has increased [49,50]. ...
Although a higher lung cancer risk has been already associated with arsenic exposure, the contribution of arsenic and its compounds to the carcinogenic effects of other agents, such as tobacco smoke, is not well characterized. This systematic review examined the relationship between occupational and non-occupational arsenic exposure and tobacco smoking on lung cancer risk using papers published from 2010 to 2022. Two databases, PUBMED and Scifinder, were used for the searches. Among the sixteen human studies included, four were about occupational exposure, and the others were about arsenic in drinking water. Furthermore, only three case-control studies and two cohort studies evaluated an additive or multiplicative interaction. The interaction between arsenic exposure and tobacco smoke seems to be negligible at low arsenic concentrations (<100 μg/L), while there is a synergistic effect at higher concentrations. Finally, it is not yet possible to assess whether a linear no-threshold (LNT) model for lung cancer risk can be applied to the co-exposure to arsenic and tobacco smoke. Although the methodological quality of the included studies is good, these findings suggest that rigorous and accurate prospective studies on this topic are highly needed.
... 18 The results showed a positive link. An Italian cohort study including 1467 fertilizer and plastic workers showed that the arsenic exposure was associated with cancer of pleura, bone and melanoma 19 . The study from Bengladesh showed that the arsenic toxic well water consumption put the population at high risk of cancer. ...
... It is suggested that there is a significant association between cutaneous melanoma and exposure to arsenical pesticides (Dennis et al., 2010). It is also found that the mortality rate of melanoma is significantly increased in the population that was occupationally exposed to arsenic (Gianicolo et al., 2019). Moreover, the increased mortality of skin cancer, including melanoma is higher than the predicted rate resulting from aging suggesting that the increased mortality results from environmental exposure such as arsenic exposure ( Alonso et al., 2010). ...
Background
Melanoma is a highly malignant tumor. Moreover, its prevalence is increasing at a rapid rate year after year. Currently, UV light is the leading cause of melanoma, although numerous other risk factors exist, including arsenic. The link between arsenic and the likelihood of developing melanoma has long been debated. As a result, we conducted a meta‐analysis of the available data to investigate the association between arsenic exposure and melanoma.
Methods
We identified seven non‐randomized controlled studies with 41,949 participants by searching the Chinese CNKI, Embase, PubMed, and Cochrane Library databases. We then used random‐effects or fixed‐effects models to evaluate the pooled odds ratios (OR) and their 95% confidence intervals (CI). Subgroup analyses were also carried out with different included regions.
Results
Participants in the study who were exposed to arsenic had a somewhat higher chance of developing melanoma than those who were not (OR = 1.47, 95% CI 1.01–2.13). A subgroup analysis was also carried out for the US region, and the findings were not statistically significant (OR = 1.40, 95% CI 0.94–2.07).
Conclusion
This meta‐analysis shows that arsenic exposure relates to an increased risk of melanoma.
High-profile RNA epigenetic modification N⁶-methyladenosine (m⁶A), as a double-edged sword for cancer, can either promote or inhibit arsenic-induced skin carcinogenesis. However, the core m⁶A-target gene determining the duality of m⁶A and the regulatory mechanism of m⁶A on the core gene are still poorly understood. Based on m⁶A microarray detection, integrated multi-omics analysis, and further experiments in vitro and in vivo, we explored the molecular basis for the dual role of m⁶A in cancer induced by environmental pollutants using models in different stages of arsenic carcinogenesis, including As-treated, As-transformed, and As-tumorigenic cell models. We found that the key proliferative signaling node AKT1 is in the center of the m⁶A-regulatory network in arsenic carcinogenicity. The m⁶A level on AKT1 mRNA (3’UTR, CDS, and 5’UTR) dynamically changed in different stages of arsenic carcinogenesis. The m⁶A writer METTL3-catalyzed upregulation of m⁶A promotes AKT1 expression by elevating m⁶A reader YTHDF1-mediated AKT1 mRNA stability in As-treated and As-transformed cells, while the m⁶A eraser FTO-catalyzed downregulation of m⁶A promotes AKT1 expression mainly by inhibiting m⁶A reader YTHDF2-mediated AKT1 mRNA degradation in As-tumorigenic cells. Furthermore, upregulation of m⁶A inhibits the expression of AKT1 negative regulator PHLPP2 and promotes the expression of AKT1 positive regulator PDK1. These changes in AKT1 regulators result in AKT1 activation by upregulating AKT1 phosphorylation at S473 and T308. Interestingly, the FTO-catalyzed decrease in m⁶A prevents AKT upregulation in As-treated cells but promotes AKT upregulation in As-tumorigenic cells. Both inhibitors targeting the m⁶A writer and eraser can inhibit the AKT1-mediated proliferation of As-tumorigenic cells by breaking the balance of m⁶A regulators. Our results demonstrated that AKT1 is the core hub determining m⁶A as a double-edged sword. Changed m⁶A dynamically upregulates the expression and activity of AKT1 in different stages of arsenic carcinogenesis. This study can advance our understanding of the dual role and precise time-specific mechanism of RNA epigenetics involved in the carcinogenesis of hazardous materials.
Persistent arsenic (As) pollution sources from anthropogenic activities pose a serious threat to groundwater quality. This work aims to illustrate the application of an innovative remediation technology to remove As from a heavily contaminated fractured aquifer at a historically polluted industrial site. Groundwater circulation well (GCW) technology was tested to significantly increase and accelerate the mobilization and removal of As in the source area. The GCW extracts and re-injects groundwater at different depths of a vertical circulation well. By pumping out and reinjecting in different screen sections of the well, the resulting vertical hydraulic gradients create recirculation cells and affect and mobilize trapped contaminants that cannot be influenced by traditional pumping systems. The first 45-m deep IEG-GCW® system was installed in 2020, equipped with 4 screen sections at different depths and with an above-ground As removal system by oxidation and filtration on Macrolite (Enki). A geomodeling approach supports both remediation and multi-source data interpretation. The first months of operation demonstrate the hydraulic effectiveness of the IEG-GCW® system in the fractured rock aquifer and the ability to significantly enhance As removal compared to conventional pumping wells currently feeding a centralized treatment system. The recirculation flow rate amounts to about 2 m³/h. Water pumped and treated by the GCW system is reintroduced with As concentrations reduced by an average of 20%–60%. During the pilot test, the recirculating system removed 23 kg As whilst the entire central pump-and-treat (P&T) system removed 129 kg, although it treated 100 times more water volume. The P&T plant removed 259 mg As per m³ of pumped and treated groundwater while the GCW removed 4814 mg As per m³ of the treated groundwater. The results offer the opportunity for a more environmentally sustainable remediation approach by actively attacking the contamination source rather than containing the plume.
Per anni l’interazione tra scienza e politica è stata rappresentata come una relazione di tipo unidirezionale, nella quale gli scienziati fornirebbero ai politici una conoscenza neutrale, obiettiva e affidabile a supporto del processo decisionale. La complessità delle sfide attuali in cui “i fatti sono incerti, i valori in discussione, gli interessi elevati e le decisioni urgenti”, ha reso questa narrazione inadeguata sul piano della conoscenza e della sua condivisione pubblica. Questo volume racconta il cambiamento di tale interazione a partire dall’approccio della “scienza post-normale” (PNS), proposto negli anni ‘90 da Jerome Ravetz e Silvio Funtowicz. Esso ospita le riflessioni dei due ideatori sull’attualità e sul futuro della PNS e raccoglie i contributi di oltre 50 autrici e autori che esplorano le sfide che la PNS rappresenta sul piano teorico e su quello delle pratiche di ricerca partecipativa e di public engagement diffuse in Italia.
Il libro è il primo della Collana Editoriale SCIENZIATI IN AFFANNO? che affronta i cambiamenti in atto nella ricerca in un contesto in cui le relazioni scienza, società e politica sono oggetto di discussione e ridefinizione pubblica.
Die Beteiligung der Öffentlichkeit ist essenziell bei der Gewinnung neuen Wissens. Ein solcher partizipativer Ansatz ist bei umweltepidemiologischen Studien von besonderer Relevanz. Dies wurde in einer Studie umgesetzt, deren Ziel es war, die Auswirkungen der Industriekatastrophe einer petrochemischen Fabrik zu untersuchen.
Starch, and silver nitrate were used for one pot facile synthesis of starch capped silver nanoparticles. Transmission electron microscopy (TEM), dynamic light scattering (DLS), iodometry titration, and UV-visible spectroscopy were used for the characterization and encapsulation of silver nanoparticles into the helix of amylose. TEM images confirm that morphology of nanoparticles changed entirely (from spherical and chain-like aggregated to only chain like beautiful silver) in excess of starch concentration. Starch capped nanoparticles were used for detection of hydrogen peroxide. The results reveal that sensing rate of hydrogen peroxide depend on the nature of the scavenger (H2O2 > isopropyl alcohol, benzoquinone > tertiary butyl alcohol > potassium iodide). The activation energy = 31 kJ/mol, enthalpy = 28 kJ/mol and entropy = -201 J/K/mol of activation were calculated for the H2O2 sensing. Thermogravimetric analysis shows two step thermal degradation of three kind of amylose. KI-I2 colorimetric method was used to determine of amylose content in potato extract. The antibacterial activity of starch-Ag NPs were estimated against two human pathogens such as Gram positive Staphylococcus aureus MTCC-3160 (S. aureus) and Gram negative Escherichia coli MTCC-450 (E. coli) by using disks diffusion method. Ag NPs have excellent antibacterial activity towards both human strains.
This study determined the heavy metals (HM) contamination in soil and food of Zhob and Loralai valleys of Sulaiman fold belt, Baluchistan province, Pakistan. For this purpose, soil and food (food crops and fruits) sample were collected and analyzed for the HM using atomic absorption spectrometry (Perkin Elmer, AAS-PEA-700)
Among HM, the iron (Fe) showed highest concentration in soil and food, followed by manganese (Mn), nickel (Ni) and chromium (Cr), while lowest for cadmium (Cd). Results revealed multifold higher contamination facto(CF), pollution load index (PLI) and ecological risk index (ERI) values for soil in the Zhob valley as compared
to Loralai valley. Plant enrichment factor (PEF) for Cr, Ni, Fe and Cu were 18.3, 13.6, 12.7 and 11.4. Elevated PEF values led to higher plant bioaccumulation factor (PBF) and resulted in the potential health risk. The HM contaminations were evaluated for daily intake of metal (DIM) and hazard quotient (HQ). Results showed that HQ values >1 for Cd and Ni to the exposed population through food consumption in the Zhob valley. Higher risk in the Zhob valley was due to higher contamination that could be attributed to denudation of ophiolites.
One of the main aim of the participate research carried out in Manfredonia (Apulia Region, Southern Italy) was to evaluate the exposure to the arsenic released during the industrial accident occurred in 1976, by reconstructing the event and the extent of contamination through an analysis of all the collected environmental data, the information issued from the participated research group, and the execution of meteo-dispersive simulation. The emission form the blown-out column consisted of two fractions. The first fraction was a mix of liquid and solid material fallen in the area of the plant, with peaks of deposition exceeded 1,500 mg/kg of arsenic, to which mainly workers are exposed. The second fraction was a cloud which was dispersed and carried by the wind beyond the plant area, towards the town. This second fraction was calculated using meteorological simulations and short-term dispersion simulations (a few hours). The map of ground deposition is in accordance with the maps created out of the first deposition measurement of the ground (correlation index: 0.67), although this map identifies a larger area of contamination. Both measured and modelled depositions show a maximum deposition 2 km away from the outburst site. The reconstructed deposition map gives a contamination value with a gradient in the populated area, that is a relevant instrument to evaluate citizens' exposition.
On 26 September 1976 in Manfredonia (Italy), a mixture containing arsenic (As) compounds was released into the atmosphere due to an accident in a petrochemical plant. The aim of this work is reconstructing the extent of As contamination within the framework of an epidemiological study including both workers of the plant and residents in Manfredonia. Emission consisted of two fractions. One was a liquid solution mixed together with a solid material that hits the area of the plant and mainly affected the workers. The second fraction consisted of a cloud that was dispersed and transported by the wind beyond the plant area. Contamination within the plant has been accounted for using deposition data collected after the accident. Contamination outside the plant has been determined using a dispersion model. A comparison between predictions and measurements confirms that maximum contamination occurred 1.7 km away from the plant, but the area affected by the fallout was larger than it was supposed to be in the days following the accident. Providing a gradient in the contamination, predicted deposition maps are a relevant tool in the population exposure assessment, even if some uncertainty remains regarding establishing possible exposure routes via the food chain.
Background:
Region II in northern Chile (population 442 570) experienced a sudden major increase in arsenic water concentrations in 1958 in the main city of Antofagasta, followed by a major reduction in exposure when an arsenic removal plant was installed in 1970. It provides a unique opportunity to study latency effects of exposure to arsenic, and this is the first study with mortality data up to 40 years after exposure reduction.
Methods:
We previously identified high mortality rates in Region II up to the year 2000. Here we present rate ratios (RRs) for Region II compared with all the rest of Chile from 2001 to 2010, and with unexposed Region V (population 1 539 852) for all years from 1950 to 2010. All statistical tests were one-sided.
Results:
From 2001 to 2010, comparing Region II with the rest of Chile, lung and bladder mortality were still greatly elevated (RR = 3.38, 95% confidence interval [CI] = 3.19 to 3.58, P < .001 for lung cancer in men; RR = 2.41, 95% CI = 2.20 to 2.64, P < .001 for lung cancer in women; RR = 4.79, 95% CI = 4.20 to 5.46, P < .001 for bladder cancer in men; RR = 6.43, 95% CI = 5.49 to 7.54, P < .001 for bladder cancer in women). Kidney cancer mortality was also elevated (RR = 1.75, 95% CI = 1.49 to 2.05, P < .001 for men; RR = 2.09, 95% CI = 1.69 to 2.57, P < .001 for women). Earlier short latency acute myocardial infarction mortality increases had subsided.
Conclusions:
Lung, bladder, and kidney cancer mortality due to arsenic exposure have very long latencies, with increased risks manifesting 40 years after exposure reduction. Our findings suggest that arsenic in drinking water may involve one of the longest cancer latencies for a human carcinogen.
Introduction: This paper reports the
experience of a participatory project in
environmental epidemiology, formally
initiated in 2015 and still underway, in
Manfredonia, southern Italy. We provide some
background information and justification
for our choice of a participatory model of
investigation, and summarize the antecedents
to our involvement, from the siting of
a petrochemical plant in the area in 1971
to a series of events which triggered public
discontent, concern and unrest.
Methods: We proceed by providing
a description and discussion of the various
steps of our study, focusing mainly on the
dynamics of public engagement.
Results: The initial disappointment and
mistrust of concerned citizens have been
reduced. The consequent dialogue led to
a shared research protocol. Each step of
the research has been made public and
accessible.
Conclusion: We conclude with some remarks
on our experience and the lessons we are
drawing from it, including the challenges for
its possible replication. The participatory
project contributed to promoting public
engagement and restoring some trust in
scientific research.
The non-equivalence of statistical significance and clinical importance has long been recognised, but this error of interpretation remains common. Although a significant result in a large study may sometimes not be clinically important, a far greater problem arises from misinterpretation of non-significant findings. By convention a P value greater than 5% (P>0.05) is called “not significant.” Randomised controlled clinical trials that do not show a significant difference between the treatments being compared are often called “negative.” This term wrongly implies that the study has shown that there is no difference, whereas usually all that has been shown is an absence of evidence of a difference. These are quite different statements.The sample size of controlled trials is generally inadequate, with a consequent lack of power to detect real, and clinically worthwhile, differences in treatment. Freiman et al1 found that only 30% of a sample of 71 trials published in the New England Journal of Medicine in 1978-9 with P>0.1 were large enough to have a 90% chance of detecting even a 50% difference in the effectiveness of the treatments being compared, and they found no improvement in a similar sample of trials published in 1988. To interpret all these “negative” trials as providing evidence of the ineffectiveness of new treatments is clearly wrong and foolhardy. The term “negative” should not be used in this context.2A recent example is given by a trial comparing octreotide and sclerotherapy in patients with variceal bleeding.3 The study was carried out on a sample of only 100 despite a reported calculation that suggested that 1800 patients were needed. This trial had only a 5% chance of getting a statistically significant result if the stated clinically worthwhile treatment difference truly existed. One consequence of such low statistical power was a wide confidence interval for the treatment difference. The authors concluded that the two treatments were equally effective despite a 95% confidence interval that included differences between the cure rates of the two treatments of up to 20 percentage points.Similar evidence of the dangers of misinterpretation of non-significant results is found in numerous metaanalyses (overviews) of published trials, when few or none of the individual trials were statistically large enough. A dramatic example is provided by the overview of clinical trials evaluating fibrinolytic treatment (mostly streptokinase) for preventing reinfarction after acute myocardial infarction. The overview of randomised controlled trials found a modest but clinically worthwhile (and highly significant) reduction in mortality of 22%,4 but only five of the 24 trials had shown a statistically significant effect with P<0.05. The lack of statistical significance of most of the individual trials led to a long delay before the true value of streptokinase was appreciated.While it is usually reasonable not to accept a new treatment unless there is positive evidence in its favour, when issues of public health are concerned we must question whether the absence of evidence is a valid enough justification for inaction. A recent publicised example is the suggested link between some sudden infant deaths and antimony in cot mattresses. Statements about the absence of evidence are common—for example, in relation to the possible link between violent behaviour and exposure to violence on television and video, the possible harmful effects of pesticide residues in drinking water, the possible link between electromagnetic fields and leukaemia, and the possible transmission of bovine spongiform encephalopathy from cows. Can we be comfortable that the absence of clear evidence in such cases means that there is no risk or only a negligible one?When we are told that “there is no evidence that A causes B” we should first ask whether absence of evidence means simply that there is no information at all. If there are data we should look for quantification of the association rather than just a P value. Where risks are small P values may well mislead: confidence intervals are likely to be wide, indicating considerable uncertainty. While we can never prove the absence of a relation, when necessary we should seek evidence against the link between A and B—for example, from case-control studies. The importance of carrying out such studies will relate to the seriousness of the postulated effect and how widespread is the exposure in the population.References↵Bailar JC, Mosteller FFreiman JA, Chalmers TC, Smith H, Kuebler RR.The importance of beta, the type II error, and sample size in the design and interpretation of the randomized controlled trial: survey of two sets of “negative” trials. In: Bailar JC, Mosteller F eds.Medical uses of statistics.2nd ed. Boston, MA: NEJM Books,1992: 357–73.↵Chalmers I.Proposal to outlaw the term “negative trial.”BMJ1985;290: 1002.↵Sung JJY, Chung SCS, Lai C-W, Chan FKL, Leung JWC, Yung M-L, Kassianides C, et al.Octreotide infusion or emergency sclerotherapy for variceal haemorrhage.Lancet1993;342:637–41.OpenUrlCrossRefMedlineWeb of Science↵Yusuf S, Collins R, Peto R, Furberg C, Stampfer MJ, Goldhaber SZ, et al.Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials.Eur Heart J1985;6:556–85.OpenUrlFREE Full Text
Background: Diabetes affects an estimated 346 million persons globally, and total deaths from diabetes are projected to increase > 50% in the next decade. Understanding the role of environmental chemicals in the development or progression of diabetes is an emerging issue in environmental health. In 2011, the National Toxicology Program (NTP) organized a workshop to assess the literature for evidence of associations between certain chemicals, including inorganic arsenic, and diabetes and/or obesity to help develop a focused research agenda. This review is derived from discussions at that workshop.
Objectives: Our objectives were to assess the consistency, strength/weaknesses, and biological plausibility of findings in the scientific literature regarding arsenic and diabetes and to identify data gaps and areas for future evaluation or research. The extent of the existing literature was insufficient to consider obesity as an outcome.
Data Sources, Extraction, and Synthesis: Studies related to arsenic and diabetes or obesity were identified through PubMed and supplemented with relevant studies identified by reviewing the reference lists in the primary literature or review articles.
Conclusions: Existing human data provide limited to sufficient support for an association between arsenic and diabetes in populations with relatively high exposure levels (≥ 150 µg arsenic/L in drinking water). The evidence is insufficient to conclude that arsenic is associated with diabetes in lower exposure (< 150 µg arsenic/L drinking water), although recent studies with better measures of outcome and exposure support an association. The animal literature as a whole was inconclusive; however, studies using better measures of diabetes-relevant end points support a link between arsenic and diabetes.
Cohort mortality studies, which compare the observed mortality of a historically exposed cohort to an expected mortality based on figures from a national population, are among the most common and useful types of studies done in occupational epidemiology. Such studies are primarily based on records which lack data on smoking. Hence it is often difficult to determine whether an observed excess of a given smoking-related disease is the result of occupational exposures, an excess consumption of cigarettes among the exposed, or an interaction between the two. The purpose of this paper is to outline the different types of control which may be exercised in cohort mortality studies to control for the effects of smoking. Indirect control, which uses only existing data, may be exercised through (i) analysis of other smoking-related causes of death besides the cause-of-death of primary interest, (ii) use of an internal reference group instead of the national population, (iii) adjustment of the excess risk based on hypothetical smoking habits, or (iv) analysis for a dose-response relationship between occupational exposure and disease. Direct control, which requires interviews, may be exercised through (i) a survey of the smoking habits of currently employed cohort members, (ii) a survey of all cohort members, or (iii) a "nested" case-referent study within the cohort. The choice of which method to use depends on the cost and the degree of accuracy required by the investigator.
This investigation sought to examine whether methods proposed to control the healthy worker survivor effect would influence the shape or magnitude of the dose-response curve for respiratory cancer induced by arsenic.
Results from an unadjusted analysis are compared with results obtained by applying four different methods for control of the healthy worker survivor effect to data on arsenic exposure and respiratory cancer. The four methods are: exposure lag, adjustment for work status, cohort restriction, and the G null test.
Cohort restriction gave erratic results depending upon the minimum years of follow up used. Exposure lag substantially increased the rate ratios and a non-linear shape (decreasing slope) compared with an unlagged analysis. Adjusting for work status (currently employed upsilon retired or otherwise not employed) yielded slightly higher rate ratios than an unadjusted analysis, with an overall shape similar to the baseline analysis. Results from the G null test procedure of Robins (1986), although not directly comparable with the baseline analysis, did show an adverse effect of exposure that seemed to reach a maximum when exposure was lagged between 10 and 20 years.
All results confirm an adverse effect of arsenic exposure on respiratory cancer. In these data, it seems that the healthy worker survivor effect was not strong enough to mask the strong effect of arsenic exposure on respiratory cancer. Nevertheless, several methods show a stronger association between arsenic exposure and respiratory cancer after adjustment for the healthy worker survivor effect, suggesting that for weaker causal associations, studies not controlling for this source of bias will have low power to detect results. Although the G methods are theoretically the most unbiased, further work elucidating the validity of the assumptions underlying lagging, adjustment for work status, and the G methods are needed before clear recommendations can be made.
Arsenic exposure is a likely cause of blackfoot disease and a potential risk factor for atherosclerosis. The authors performed a systematic review of the epidemiologic evidence on the association between arsenic and cardiovascular outcomes. The search period was January 1966 through April 2005. Thirteen studies conducted in general populations (eight in high-arsenic areas in Taiwan, five in other countries) and 16 studies conducted in occupational populations were identified. Exposure was assessed ecologically in most studies. In Taiwan, relative risks comparing the highest arsenic exposure category with the lowest ranged from 1.59 to 4.90 for coronary disease, from 1.19 to 2.69 for stroke, and from 1.66 to 4.28 for peripheral arterial disease. In other general populations, relative risks ranged from 0.84 to 1.54 for coronary disease, from 0.69 to 1.53 for stroke, and from 0.61 to 1.58 for peripheral arterial disease. In occupational populations, relative risks ranged from 0.40 to 2.14 for coronary disease mortality and from 0.30 to 1.33 for stroke mortality. Methodologic limitations, however, limited interpretation of the moderate-to-strong associations between high arsenic exposure and cardiovascular outcomes in Taiwan. In other populations or in occupational settings, the evidence was inconclusive. Because of the high prevalence of arsenic exposure, carefully performed studies of arsenic and cardiovascular outcomes should be a research priority.
Chronic arsenic exposure has been suggested to contribute to diabetes development. We performed a systematic review of the experimental and epidemiologic evidence on the association of arsenic and type 2 diabetes. We identified 19 in vitro studies of arsenic and glucose metabolism. Five studies reported that arsenic interfered with transcription factors involved in insulin-related gene expression: upstream factor 1 in pancreatic beta-cells and peroxisome proliferative-activated receptor gamma in preadipocytes. Other in vitro studies assessed the effect of arsenic on glucose uptake, typically using very high concentrations of arsenite or arsenate. These studies provide limited insight on potential mechanisms. We identified 10 in vivo studies in animals. These studies showed inconsistent effects of arsenic on glucose metabolism. Finally, we identified 19 epidemiologic studies (6 in high-arsenic areas in Taiwan and Bangladesh, 9 in occupational populations, and 4 in other populations). In studies from Taiwan and Bangladesh, the pooled relative risk estimate for diabetes comparing extreme arsenic exposure categories was 2.52 (95% confidence interval, 1.69-3.75), although methodologic problems limit the interpretation of the association. The evidence from occupational studies and from general populations other than Taiwan or Bangladesh was inconsistent. In summary, the current available evidence is inadequate to establish a causal role of arsenic in diabetes. Because arsenic exposure is widespread and diabetes prevalence is reaching epidemic proportions, experimental studies using arsenic concentrations relevant to human exposure and prospective epidemiologic studies measuring arsenic biomarkers and appropriately assessing diabetes should be a research priority.
Region II of Chile (the second most northerly administrative region) experienced dramatic increases in average arsenic water concentrations beginning in 1958, followed by marked declines in the 1970s when water treatment plants were installed. This history provides a unique opportunity to study time trends in the development of arsenic-related cancers, including lung and bladder cancers.
We investigated lung and bladder cancer mortality from 1950 to 2000 for region II compared with region V, where drinking water was not contaminated with arsenic. Mortality data were obtained from 218,174 death certificates for the two regions for 1950-1970 and from mortality data tapes that identified 307,541 deaths in the two regions for 1971-2000. Poisson regression models were used to identify time trends in rate ratios (RRs) of mortality from lung and bladder cancers comparing region II with region V.
Lung and bladder cancer mortality rate ratios for region II compared with region V started to increase about 10 years after high arsenic exposures commenced and continued to rise until peaking in 1986-1997. The peak lung cancer mortality RRs were 3.61 (95% confidence interval [CI] = 3.13 to 4.16) for men and 3.26 (95% CI = 2.50 to 4.23) for women. The peak bladder cancer RRs were 6.10 (95% CI = 3.97 to 9.39) for men and 13.8 (95% CI = 7.74 to 24.5) for women. Combined lung and bladder cancer mortality rates in region II were highest in the period 1992-1994, with mortality rates of 153 and 50 per 100,000 men and women, respectively, in region II compared with 54 and 19 per 100,000 in region V.
Such large increases in total population cancer mortality rates have, to our knowledge, not been documented for any other environmental exposure. The long latency pattern is noteworthy, with mortality from lung and bladder cancers continuing to be high until the late 1990s, even though major decreases in arsenic exposure occurred more than 25 years earlier.
Dieses Werk ist nicht nur ein umfassendes Lehrbuch der Statistik im klassischen Sinn, sondern zugleich ein Handbuch für jeden, der statistische Probleme im Zusammenhang mit Experiment und Erhebung zu lösen hat. Hier dient es fächerübergreifend dem Mediziner, dem Ingenieur sowie dem Betriebswirt. Die 15. Auflage wurde um das Kapitel "Meta-Analyse zur Kombination von Studien, Experimenten und Prognosen" erweitert, in dem erstmalig auch Time-To-Event-Studien, inhomogene Wirtschaftsprognosen, kreuz-korrelierte Zeitreihen sowie konkurrierende Labore kombiniert werden.
This book provides an overview to researchers, graduate, and undergraduate students, as well as academicians who are interested in arsenic. It covers human health risks and established cases of human ailments and sheds light on prospective control measures, both biological and physico-chemical. Arsenic (As) is a widely distributed element in the environment having no known useful physiological function in plants or animals. Historically, this metalloid has been known to be used widely as a poison. Effects of arsenic have come to light in the past few decades due to its increasing contamination in several parts of world, with the worst situation being in Bangladesh and West Bengal, India. The worrying issue is the ingestion of arsenic through water and food and associated health risks due to its carcinogenic and neurotoxic nature. The impact of the problem is widespread, and it has led to extensive research on finding both the causes and solutions. These attempts have allowed us to understand the various probable causes of arsenic contamination in the environment, and at the same time, have provided a number of possible solutions. It is reported that more than 200 mineral species contain As. Generally, As binds with iron and sulfur to form arsenopyrite. According to one estimate from the World Health Organization (WHO), contextual levels of As in soil ranges from 1 to 40 mg kg-1. Arsenic toxicity is related to its oxidation state which is present in the medium. As is a protoplastic toxin, due to its consequence on sulphydryl group it interferes in cell enzymes, cell respiration and in mitosis. Exposure of As may occur to humans via several industries, such as refining or smelting of metal ores, microelectronics, wood preservation, battery manufacturing, and also to those who work in power plants that burn arsenic-rich coal. © Springer International Publishing AG 2017. All rights reserved.
Introduction
On September 26th 1976, in Manfredonia, Italy, a mixture containing arsenic compounds was released into the atmosphere due to an accident in a fertilizer production plant. 40 years later, the municipality promoted an epidemiological programme to investigate possible long-term health effects in the population.
Aim of this work is to estimate population exposure to arsenic, taking into account uncertainties on the accident dynamics by using a dispersion model with different setup initial conditions.
Methods
Contaminant dispersion was estimated with the CALPUFF model initialized with a meteorological model. Meteorological data were not available at the plant location but only at two Air Force weather stations, a few kilometers away. Evaluation of the meteorological model was performed with data available on the same day and with data available in later years in similar synoptic conditions. Different hypothesis on puff vertical release, puff status and composition were assumed from direct testimonies, documental and literature information. We used measured arsenic deposition in soils around the town to test the model inputs.
Results
Meteorological model during the accident evidences complex mountain/sea breeze circulations under high-pressure synoptic conditions. It matches the nearby meteorological station records. Results indicate that the model is capable to reproduce the mean flow and dispersion with some uncertainties due to the hypothesis on the release characterization.
Conclusions
For the first time an up-to-date dispersion model was used and integrated with environmental data, testimonies and proxies to assess the population exposure during the Manfredonia accident. Uncertainties of results should be taken into account in the epidemiological study. The case study confirms the need to collect data on concentration and dispersion of released chemicals during the early phase of an accident, considering the difficulties in collecting them in a late phase.
In observational cohort mortality studies with prolonged periods of exposure to the agent under study, it is not uncommon for risk factors for death to be determinants of subsequent exposure. For instance, in occupational mortality studies date of termination of employment is both a determinant of future exposure (since terminated individuals receive no further exposure) and an independent risk factor for death (since disabled individuals tend to leave employment). When current risk factor status determines subsequent exposure and is determined by previous exposure, standard analyses that estimate age-specific mortality rates as a function of cumulative exposure may underestimate the true effect of exposure on mortality whether or not one adjusts for the risk factor in the analysis. This observation raises the question, which if any population parameters can be given a causal interpretation in observational mortality studies?In answer, we offer a graphical approach to the identification and computation of causal parameters in mortality studies with sustained exposure periods. This approach is shown to be equivalent to an approach in which the observational study is identified with a hypothetical double-blind randomized trial in which data on each subject's assigned treatment protocol has been erased from the data file. Causal inferences can then be made by comparing mortality as a function of treatment protocol, since, in a double-blind randomized trial missing data on treatment protocol, the association of mortality with treatment protocol can still be estimated.We reanalyze the mortality experience of a cohort of arsenic-exposed copper smelter workers with our method and compare our results with those obtained using standard methods. We find an adverse effect of arsenic exposure on all-cause and lung cancer mortality which standard methods fail to detect.
An aerosol mixture containing approximately 12 t of K3AsO3 and H3AsO3 escaped from the NH3 washing column of the ANIC chemical factory near Manfredonia, Southern Italy, in September 26th, 1976, and contaminated about 15 km of the surrounding area, largely cultivated.Among the various measures established to face the aceident, this report describes particularly the soil decontamination strategy. The latter, based on an oxidation‐precipitation treatment using CaOCl2 to oxidize As(III) to As(V) and FeSO4 to form highly insoluble arsenate, integrated the sequestering character of the soil, so that complete inertization of As throughout the accident area was readily attained.
In observational cohort mortality studies with prolonged periods of exposure to the agent under study, it is not uncommon for risk factors for death to be determinants of subsequent exposure. For instance, in occupational mortality studies date of termination of employment is both a determinant of future exposure (since terminated individuals receive no further exposure) and an independent risk factor for death (since disabled individuals tend to leave employment). When current risk factor status determines subsequent exposure and is determined by previous exposure, standard analyses that estimate age-specific mortality rates as a function of cumulative exposure may underestimate the true effect of exposure on mortality whether or not one adjusts for the risk factor in the analysis. This observation raises the question, which if any population parameters can be given a causal interpretation in observational mortality studies? In answer, we offer a graphical approach to the identification and computation of causal parameters in mortality studies with sustained exposure periods. This approach is shown to be equivalent to an approach in which the observational study is identified with a hypothetical double-blind randomized trial in which data on each subject's assigned treatment protocol has been erased from the data file. Causal inferences can then be made by comparing mortality as a function of treatment protocol, since, in a double-blind randomized trial missing data on treatment protocol, the association of mortality with treatment protocol can still be estimated. We reanalyze the mortality experience of a cohort of arsenic-exposed copper smelter workers with our method and compare our results with those obtained using standard methods. We find an adverse effect of arsenic exposure on all-cause and lung cancer mortality which standard methods fail to detect.
This text provides a critical summary of research approaches applied in epidemiologic studies on workplace hazards. It describes the historical development of occupational epidemiology, methods for characterizing exposures, and techniques for designing and implementing studies. The relative strengths and limitations of various study designs for investigating specific health outcomes are emphasized. Also included are presentations of basic and relatively advanced statistical analysis methods, exposure and dose modeling, and subsequent applications of data derived from epidemiologic research, such as in meta-analysis and risk assessment. Throughout, the book illustrates methodological concepts with examples drawn from the peer-reviewed epidemiologic literature. This second edition is an update to the first edition in several notable respects. This text contains descriptions of more recent methodological developments, including the design features of case-cohort and case-crossover studies, and methods for repeated measures analyses. There is also a new chapter on occupational health surveillance. The book concentrates on exposure assessment, describes applications of quantitative exposure data in dose-response modeling, and examines the recognition that improvements in workplace risk identification and quantification requires careful integration of these approaches.
Mortality was updated through 1982 for 611 arsenic-exposed employees originally studied through 1973. In the earlier report, total mortality was observed to have been below the comparable U.S. population; however, mortality was significantly elevated for respiratory cancer. The focus of the update was on respiratory cancer and of special interest was whether the risk of respiratory cancer remained in excess for individuals alive as of the end of the last study. In the update, 9 additional respiratory cancers were observed subsequent to 1973, the end of the follow-up in the original study, versus 7.8 expected. The risk ratio for the time-interval 1974–1982 (standardized mortality ratio SMR = 116) was diminished compared to that reported in the original study (SMR = 330). When the entire study period was analyzed, the risk of respiratory cancer did not appear to decline with interval since exposure cessation. Analyses by duration of arsenic exposure and interval since first exposure did not reveal any obvious dose-response relationships.
When more than one statistical test is performed in analysing the data from a clinical study, some statisticians and journal editors demand that a more stringent criterion be used for “statistical significance” than the conventional P<0.05.1 Many well meaning researchers, eager for methodological rigour, comply without fully grasping what is at stake. Recently, adjustments for multiple tests (or Bonferroni adjustments) have found their way into introductory texts on medical statistics, which has increased their apparent legitimacy. This paper advances the view, widely held by epidemiologists, that Bonferroni adjustments are, at best, unnecessary and, at worst, deleterious to sound statistical inference.
#### Summary points
Adjusting statistical significance for the number of tests that have been performed on study data—the Bonferroni method—creates more problems than it solves
The Bonferroni method is concerned with the general null hypothesis (that all null hypotheses are true simultaneously), which is rarely of interest or use to researchers
The main weakness is that the interpretation of a finding depends on the number of other tests performed
The likelihood of type II errors is also increased, so that truly important differences are deemed non-significant
Simply describing what tests of significance have been performed, and why, is generally the best way of dealing with multiple comparisons
Bonferroni adjustments are based on the following reasoning.1-3 If a null hypothesis is true (for instance, two treatment groups in a randomised trial do not differ in terms of cure rates), a significant difference (P<0.05) will be observed by chance once in 20 trials. This is the type I error, or α. When 20 independent tests are performed (for example, study groups are compared with regard to 20 unrelated variables) and the null hypothesis holds for all 20 comparisons, the chance of at least one test being significant is no longer 0.05, but 0.64. …
Occupational groups are often described as being relatively healthy because their mortality rates are lower than those of the national average. Although correct this confuses the issue for those who are interested in assessing the effects of exposure to a particular chemical. In a further analysis of data collected in a study of all men ever exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain, three factors have been shown to contribute to the low mortality rates that were observed. The three factors: the selection of a healthy population for employment, the survival in the industry of the healthier men, and the length of time that this population has been pursued, have been quantified. The mortality experience within five years of entering this industry was shown to be as low as 37% of that expected; for circulatory disease and respiratory disease it was as low as 21%. There was a progressive increase in standardized mortality ratio with the length of time since entry so that the effect had almost disappeared 15 years after entry. To avoid confounding the selection effect with the survival effect the latter was measured by separating men who survived 15 years after entering the industry according to whether or not they were still in the industry after this period. Those who had left experienced an overall standardized mortality ratio some 50% higher than those still in the industry. This effect, although consistent in the age groups between 25 and 74 years and for all cause groups studied, was greatest in those aged between 25 and 44 years and for lung cancer and respiratory disease.
Adjustments for making multiple comparisons in large bodies of data are recommended to avoid rejecting the null hypothesis too readily. Unfortunately, reducing the type I error for null associations increases the type II error for those associations that are not null. The theoretical basis for advocating a routine adjustment for multiple comparisons is the "universal null hypothesis" that "chance" serves as the first-order explanation for observed phenomena. This hypothesis undermines the basic premises of empirical research, which holds that nature follows regular laws that may be studied through observations. A policy of not making adjustments for multiple comparisons is preferable because it will lead to fewer errors of interpretation when the data under evaluation are not random numbers but actual observations on nature. Furthermore, scientists should not be so reluctant to explore leads that may turn out to be wrong that they penalize themselves by missing possibly important findings.
The cause-specific mortality was followed through 1981 in a cohort of 3,916 male Swedish smelter workers employed for at least 3 months from 1928 through 1967. Arsenic levels in the air of all workplaces within the smelter were estimated for three different time periods. Using this exposure matrix and detailed information of the work history, cumulative arsenic exposure could be computed for each worker. Standardized mortality ratios (SMRs) were calculated for several dose categories using age-specific mortality rates from the county where the smelter was situated. A positive dose-response relationship was found between cumulative arsenic exposure and lung cancer mortality with an overall SMR of 372 (304-450, 95% confidence interval). The lung cancer mortality was related to the estimated average intensity of exposure to arsenic but not to the duration. No positive dose-response relationship was found between arsenic and ischemic heart disease or cerebrovascular disease. There was also no evident dose-response relationship between estimated exposure to sulfur dioxide and lung cancer.
For various reasons, data on smoking are frequently missing, or only partially available, in retrospective epidemiologic studies of occupational risk factors. In such situations, indirect methods may be used to evaluate the magnitude and direction of the potentially confounding effects of smoking. Such an evaluation can be made quantitatively or qualitatively. Here we describe both approaches. A specific problem relates to case-referent studies, where sampling variation in referent selection may limit the possibility of controlling for confounding by smoking, even when smoking data are available. We present data showing that estimates of risk from occupational exposures which are not controlled for smoking may be as accurate as estimates derived after controlling for smoking, when the number of referents is relatively small. The problem of interaction is also discussed. In the absence of smoking data, the investigator has no indication of how smoking and occupation jointly affect disease risk (eg, additively or multiplicatively). The multiplicative model is usually assumed. However, if exposure and smoking act independently (additively), rate ratios are diminished. In such situations, in the presence of negative confounding by smoking, rate ratios may actually even be less than one--also when exposure and disease are strongly related.
Mortality was updated through 1982 for 611 arsenic-exposed employees originally studied through 1973. In the earlier report, total mortality was observed to have been below the comparable U.S. population; however, mortality was significantly elevated for respiratory cancer. The focus of the update was on respiratory cancer and of special interest was whether the risk of respiratory cancer remained in excess for individuals alive as of the end of the last study. In the update, 9 additional respiratory cancers were observed subsequent to 1973, the end of the follow-up in the original study, versus 7.8 expected. The risk ratio for the time-interval 1974-1982 (standardized mortality ratio SMR = 116) was diminished compared to that reported in the original study (SMR = 330). When the entire study period was analyzed, the risk of respiratory cancer did not appear to decline with interval since exposure cessation. Analyses by duration of arsenic exposure and interval since first exposure did not reveal any obvious dose-response relationships.
Hypotheses about the extent, persistence, and constancy for different causes of the healthy worker effect are evaluated using the data of the Dorn Study of Mortality Among US Veterans. Those data were selected because persons who qualify to serve in the armed forces have health status comparable to that of persons able to seek employment. Mortality rates for 5-year age groups and standardized mortality ratios for younger, older, and all age groups were computed and compared to those of the US population for all causes, all cancers, heart disease, stroke, and selected other causes of death. A healthy worker effect of 20% to 40% reduced mortality was shown to persist over the entire age range for the various causes. The overall effect for all causes is 27%.
The proportionate mortality experience of 173 decedents exposed primarily to lead arsenate and calcium arsenate was compared with that of 1,809 decedents not exposed to those compounds. A significant increase in respiratory cancer was found among the exposed employees. The relation between cumulative arsenic exposure and the ratio of observed to expected respiratory malignancy deaths was estimated by means of a least squares approach. The predicted ratio was 7:1 for individuals exposed for a period of more than eight years to compounds that contained an equivalent level of 1 mg/cu m arsenic. In the more heavily exposed individuals, an excess of respiratory cancer was observed 35+ years after the initial exposure. Observations based on the proportionate study were supported by an analysis of the same target population, employing the prospective study in retrospect approach.
Total As content may be determined in blood and urine by means of an AAS method that involves reduction of As to its volatile hydride and ashing at 600 degrees C with MgO and Mg (NO3)2. Separation of inorganic As (InAs), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMAA) by ion-exchange chromatography, followed by direct AAS analysis, allows the determination of each As species in the urine. In a reference population of 148 subjects with only normal environmental exposure to As, total As concentration in the urine averages 17.2 +/- 11.1 micrograms/l. Urinary As consists of 10% each of InAs, MMAA and DMAA, the remaining 70% consisting of other forms of organic As. Blood As concentration averages 5.1 +/- 6.9 micrograms/l and correlates significantly with the urinary concentration of InAs and the sum of its metabolites (InAs + MMAA + DMAA). Inorganic arsenic undergoes methylation in the organism. After ingestion of high quantities of As2O3, the time course of excretion of its metabolites indicates that As methylation occurs by a saturable mechanism. In workers exposed to As2O3, InAs, MMAA and DMAA are the only chemical forms of As excreted in the urine that are relevant to a study of occupational exposure. Blood As concentration is proportional to exposure and correlates only with urinary DMAA excretion; DMAA seems to be the most appropriate single indicator of exposure. At high levels of exposure (total As excretion above 200 micrograms/l), As accumulates in the organism and DMAA excretion reflects its accumulation. At low levels of exposure (total As excretion below 50 micrograms/l) a short-term accumulation does not occur and the best biological indicator of exposure is InAs excretion. Seafood ingestion brings about a marked increase in urinary excretion of total As that lasts for 24-48 h and is not accompanied by any increase in InAs, MMAA or DMAA excretion. Organic As from seafood does not mix with the pool of inorganic As in the organism and may be separately detected in urine. In the biological monitoring of human exposure to As, particularly in the case of high urinary values, the speciation of the chemical forms of As in urine is necessary in order to establish with certainty the source, industrial or alimentary, of exposure.
The "healthy worker survivor effect" describes a continuing selection process such that those who remain employed tend to be healthier than those who leave employment. In an analysis of exposure-response patterns in an occupational study, the healthy worker survivor effect generally attenuates an adverse effect of exposure. In practical terms, such attenuation will be more problematic when evaluating subtle rather than strong associations. The use of an internal referent does not guarantee elimination of this effect, since by definition, it manifests within an occupational cohort. Although documented over 100 years ago, there is little consensus regarding the most appropriate method to control for the healthy worker survivor effect. Four methods have been proposed for its control: (1) restriction of the cohort to survivors of a fixed number of years of follow-up, (2) lagging the exposure to exclude recent exposure incurred by those who remained on the job, (3) adjusting for employment status as a confounder, and (4) treating the healthy worker survivor effect simultaneously as an intermediate and confounding variable by means of the G-null test or its extension, G-estimation analysis, using structurally nested failure time models. This paper reviews the concept of the healthy worker survivor effect and the four methods to control for it.
The study evaluated the mortality of workers exposed to precursors of N-nitroso compounds in a Russian fertilizer plant.
Workers employed at least two years between 1945 and 1985 in production departments or other services were included in the cohort, which comprised 2039 men and 2957 women followed from 1965 to 1990. The standardized mortality ratios (SMR) were calculated using cause-specific death rates for the Moscow region as reference. An internal comparison was carried out using Poisson regression modeling. Exposure to arsenic, nitrogen oxides, and sulfur dioxide was estimated from an industrial hygiene survey.
The production and other workers had no excess of mortality from all causes or all neoplasms. However the male production workers had excess mortality from all cancers combined (SMR 143) and lung cancer (SMR 186) after a latency period of > or = 20 years. Men with the highest exposure to nitrogen oxides had a twofold increase in mortality from stomach cancer, with a marginally significant increasing trend between stomach cancer and cumulative exposure to nitrogen oxides for both genders. Excess mortality from all cancers and stomach cancer was found for the worker with the highest average exposure to arsenic, and excess lung cancer mortality could be attributed to exposure to arsenic.
The investigation showed a weak association between employment in a fertilizer production plant and increased mortality from cancer. The results somewhat support the hypothesis that occupational exposure to precursors of N-nitroso compounds increases the risk of stomach cancer mortality, as does exposure to arsenic.
Randomized controlled clinical trials are conducted to determine whether differences of clinical importance exist between selected treatment regimens. When statistical analysis of the study data finds a P value greater than 5%, it is convention to deem the assessed difference nonsignificant. Just because convention dictates that such study findings be termed nonsignificant, or negative, however, it does not necessarily follow that the study found nothing of clinical importance. Subject samples used in controlled trials tend to be too small. The studies therefore lack the necessary power to detect real, and clinically worthwhile, differences in treatment. Freiman et al. found that only 30% of a sample of 71 trials published in the New England Journal of Medicine in 1978-79 with a P value greater than 10% were large enough to have a 90% chance of detecting even a 50% difference in the effectiveness of the treatments being compared, and they found no improvement in a similar sample of trials published in 1988. It is therefore wrong and unwise to interpret so many negative trials as providing evidence of the ineffectiveness of new treatments. One must instead seriously question whether the absence of evidence is a valid justification for inaction. Efforts must be made to look for quantification of an association rather than just a P value, especially when the risks under investigation are small. The authors cite a recent trial comparing octreotide and sclerotherapy in patients with variceal bleeding, as well as the overview of clinical trials evaluating fibrinolytic treatment for preventing reinfarction after acute myocardial infarction as examples.
The evaluation of epidemiological follow-up studies is frequently based on a comparison of the number O of deaths observed in the cohort from a specified cause with the expected number E calculated from person years in the cohort and mortality rates from a reference population. The ratio SMR = 100 x O/E is called the standardized mortality ratio (SMR). While person years can easily be calculated from the cohort and reference rates are generally available from the national statistical offices or the World Health Organization (WHO), problems can arise with the accessibility of the causes of death of the deceased study participants. However, the information that a person has died may be available, e.g., from population registers. In this paper, a statistical model for this situation is developed to derive a maximum likelihood (ML) estimator for the true (but unknown) number O* of deaths from a specified cause, which uses the known number O of deaths from this cause and the proportion p of all known causes of death among all decreased participants. It is shown that the standardized mortality ratio SMR* based on this estimated number is just SMR* = SMR/p. Easily computable confidence limits can be obtained by dividing the usual confidence limits of the SMR by the opposite limit of the proportion p. However, the confidence level alpha has to be adjusted appropriately.
L'incidente di Manfredonia: la cronistoria degli avvenimenti
- Ambrosi L
Rilievi su un episodio di intossicazione subacuta da composti arsenicali inorganici
- G Corsi
- A Rossi
- P Maestrelli
- G B Bartolucci
- G Picotti
Corsi G, Rossi A, Maestrelli P, Bartolucci GB, Picotti G. Rilievi su un
episodio di intossicazione subacuta da composti arsenicali inorganici.
La Medicina del lavoro. 1979;70:282-291.
What's wrong with Bonferroni adjustments
- Perneger
Perneger TV. What's wrong with Bonferroni adjustments. BMJ.
1998;316:1236-1238.
Manfredonia: catastrofe continuata, cittadinanza ritrovata e rimozione
- Malavasi G
Malavasi G. Manfredonia: catastrofe continuata, cittadinanza ritrovata
e rimozione. Epidemiologia e prevenzione. 2016;40:389-394.
L'incidente di Manfredonia: l'intervento dell primo momento
- L Soleo
- G Assennato
- G Misciagna
Soleo L, Assennato G, Misciagna G, et al. L'incidente di Manfredonia:
l'intervento dell primo momento. La Medicina del lavoro. 1982;73:
309-323.
Valutazione dell'arsenico urinario totale quale indicatore di esposizione professionale
- P A Bertazzi
- L Metelka
- L Riboldi
- S Guercilena
- V Foa
- M Dompe
Bertazzi PA, Metelka L, Riboldi L, Guercilena S, Foa V, Dompe M.
Valutazione dell'arsenico urinario totale quale indicatore di esposizione professionale. La Medicina del lavoro. 1982;73:353-364.
L'incidente di Manfredonia: l'indagine sanitaria a distanza
- L Soleo
- G Assennato
- G Misciagna
Soleo L, Assennato G, Misciagna G, et al. L'incidente di Manfredonia:
l'indagine sanitaria a distanza. La Medicina del lavoro. 1982;73:324-335.
- Ambrosi L Amicarelli
- V L'incidente Di Manfredonia
Ambrosi L, Amicarelli V. L'incidente di Manfredonia: la cronistoria degli
avvenimenti. La Medicina del lavoro. 1982;73:271-275.
Expert testimony in lawsuit number 8437/96. Foggia: Court of Law
- M Casciani
- L Attias
Casciani M, Attias L. Expert testimony in lawsuit number 8437/96.
Foggia: Court of Law; 1999.
Indagine Epidemiologica di Mortalià dei Lavoratori Presenti nello Stabilimento Enichem di Manfredonia il 26.9.1976 e nel Periodo Successivo
- P Comba
- R Pirastu
Comba P, Pirastu R. Indagine Epidemiologica di Mortalià dei Lavoratori
Presenti nello Stabilimento Enichem di Manfredonia il 26.9.1976 e nel
Periodo Successivo. In Procura della Repubblica di Foggia. 2004.