From inequitable to sustainable e-waste processing for reduction of impact on human health and the environment.

Recycling of electric and electronic waste products (e-waste) which amounted to more than 50 million metric tonnes per year worldwide is a massive and global operation. Unfortunately, an estimated 70-80% of this waste has not been properly managed because the waste went from developed to low-income countries to be dumped into landfills or informally recycled. Such recycling has been carried out either directly on landfill sites or in small, often family-run recycling shops without much regulations or oversights. The process traditionally involved manual dismantling, cleaning with hazardous solvents, burning and melting on open fires, etc., which would generate a variety of toxic substances and exposure/hazards to applicators, family members, proximate residents and the environment. The situation clearly calls for global responsibility to reduce the impact on human health and the environment, especially in developing countries where poor residents have been shouldering the hazardous burden. On the other hand, formal e-waste recycling has been mainly conducted in small scales in industrialized countries. Whether the latter process would impose less risk to populations and environment has not been determined yet. Therefore, the main objectives of this review are: 1. to address current trends and emerging threats of not only informal but also formal e-waste management practices, and 2. to propose adequate measures and interventions. A major recommendation is to conduct independent surveillance of compliance with e-waste trading and processing according to the Basel Ban Amendment. The recycling industry needs to be carefully evaluated by joint effort from international agencies, producing industries and other stakeholders to develop better processes. Subsequent transition to more sustainable and equitable e-waste management solutions should result in more effective use of natural resources, and in prevention of adverse effects on health and the environment.

Protocol for a systematic review and meta-analysis of human exposure to pesticide residues in honey and other bees' products.

BACKGROUND: The presence of pesticides in honey and related products is an increasing concern for consumers and producers, although there is lack of data on the current burden of exposure of the general human population through these products. We present a protocol for a systematic review and meta-analysis of contamination to insecticides, herbicides and fungicides of products from honeybees, and an estimation of how much the consumption of these products contributes to the ADI (Acceptable Daily Intake) of selected substances. OBJECTIVES: We aim to systematically review and meta-analyse studies on the contamination to plant protection products in honey, royal jelly, beeswax and propolis, applying the Navigation Guide and WHO-ILO systematic review methodology as an organizing framework. DATA SOURCES: We will search electronic academic databases for potentially relevant records from PubMed, TOXNET and EMBASE. We will include quantitative studies analysing the contamination from insecticides, herbicides and fungicides in honey, propolis, royal jelly and beeswax. In particular, we will evaluate the presence of the following substances and classes of pesticides: Glyphosate, Chlorpyrifos, pyrethroid and neonicotinoid pesticides, fungicides and acaricides. STUDY APPRAISAL AND SYNTHESIS METHODS: At least two authors will independently screen titles and abstracts at a first stage of review, and full texts at a second stage, of potentially eligible records against the eligibility criteria; data extraction of included studies will then be performed by at least two authors, in blind. At least two authors will assess risk of bias and the quality of evidence, using the most suited tools currently available. The data on prevalence of contaminated samples and concentration of pesticides in the products will be combined using meta-analysis: when more than three studies reporting the necessary measures to fit the models are available, meta-analysis will be performed separately by product and by exposure; otherwise, weighted descriptive analysis will be performed. We will report the results using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA).

Sensitising effects of genetically modified enzymes used in flavour, fragrance, detergence and pharmaceutical production: cross-sectional study.

OBJECTIVES: The use of genetically engineered enzymes in the synthesis of flavourings, fragrances and other applications has increased tremendously. There is, however, a paucity of data on sensitisation and/or allergy to the finished products. We aimed to review the use of genetically modified enzymes and the enormous challenges in human biomonitoring studies with suitable assays of specific IgE to a variety of modified enzyme proteins in occupational settings and measure specific IgE to modified enzymes in exposed workers. METHODS: Specific IgE antibodies against workplace-specific individual enzymes were measured by the specific fluorescence enzyme-labelled immunoassay in 813 exposed workers seen in cross-sectional surveys. RESULTS: Twenty-three per cent of all exposed workers showed type I sensitisation with IgE antibodies directed against respective workplace-specific enzymes. The highest sensitisation frequencies observed were for workers exposed enzymes derived from α-amylase (44%), followed by stainzyme (41%), pancreatinin (35%), savinase (31%), papain (31%), ovozyme (28%), phytase (16%), trypsin (15%) and lipase (4%). The highest individual antibody levels (up to 110 kU/L) were detected in workers exposed to phytase, xylanase and glucanase. In a subgroup comprising 134 workers, detailed clinical diagnostics confirmed work-related symptoms. There was a strong correlation (r=0.75, p<0.0001) between the symptoms and antibody levels. Workers with work-related respiratory symptoms showed a higher prevalence for the presence of specific IgE antibodies against workplace-specific enzymes than asymptomatic exposed workers (likelihood ratio 2.32, sensitivity 0.92, specificity 0.6). CONCLUSIONS: Our data confirm the previous findings showing that genetically engineered enzymes are potent allergens eliciting immediate-type sensitisation. Owing to lack of commercial diagnostic tests, few of those exposed receive regular surveillance including biomonitoring with relevant specific IgE assays.

Prostate cancer and toxicity from critical use exemptions of methyl bromide: environmental protection helps protect against human health risks.

BACKGROUND: Although ozone-depleting methyl bromide was destined for phase-out by 2005, it is still widely applied as a consequence of various critical-use-exemptions and mandatory international regulations aiming to restrict the spread of pests and alien species (e.g. in globalized transport and storage). The withdrawal of methyl bromide because of its environmental risk could fortuitously help in the containment of its human toxicity. METHODS: We performed a systematic review of the literature, including in vitro toxicological and epidemiological studies of occupational and community exposure to the halogenated hydrocarbon pesticide methyl bromide. We focused on toxic (especially chronic) or carcinogenic effects from the use of methyl bromide, on biomonitoring data and reference values. Eligible epidemiological studies were subjected to meta-analysis. RESULTS: Out of the 542 peer reviewed publications between 1990-2011, we found only 91 referring to toxicity of methyl bromide and 29 using the term "carcinogenic", "neoplastic" or "mutagenic". Several studies provide new additional data pertaining to the mechanistic aspects of methyl bromide toxicity. Few studies have performed a detailed exposure assessment including biomonitoring. Three evaluated epidemiological studies assessed a possible association between cancer and methyl bromide. Overall, exposure to methyl bromide is associated with an increased risk of prostate cancer OR, 1.21; 95% CI (0,98-1.49), P = 0.076. Two epidemiological studies have analyzed environmental, non-occupational exposure to methyl bromide providing evidence for its health risk to the general public. None of the epidemiological studies addressed its use as a fumigant in freight containers, although recent field and case reports do refer to its toxic effects associated with its use in shipping and storage. CONCLUSIONS: Both the epidemiological evidence and toxicological data suggest a possible link between methyl bromide exposure and serious health problems, including prostate cancer risk from occupational and community exposure. The environmental risks of methyl bromide are not in doubt, but also its health risks, especially for genetically predisposed subjects, should not be underestimated.

Halogenated hydrocarbon pesticides and other volatile organic contaminants provide analytical challenges in global trading.

Protection against infestation of a container cargo by alien species is achieved by mandatory fumigation with pesticides. Most of the effective fumigants are methyl and ethyl halide gases that are highly toxic and are a risk to both human health and the environment. There is a worldwide need for a reliable and robust analytical screening procedure for these volatile chemicals in a multitude of health and environmental scenarios. We have established a highly sensitive broad spectrum mass spectrometry method combined with thermal desorption gas chromatography to detect, identify and quantify volatile pesticide residues. Using this method, 1201 random ambient air samples taken from freight containers arriving at the biggest European ports of Hamburg and Rotterdam were analyzed over a period of two and a half years. This analytical procedure is a valuable strategy to measure air pollution from these hazardous chemicals, to help in the identification of pesticides in the new mixtures/formulations that are being adopted globally and to analyze expired breath samples after suspected intoxication in biomonitoring.

Exposure to fumigants in containers: a questionnaire assessment on 125 French dockers.

BACKGROUND: Cases of intoxications to gas from container's atmosphere have been described. For diagnosis, Fum Ex 2 questionnaire has been developed by the European Society for Environmental and Occupational Medicine. The aim of this study was to enhance knowledge on health effects of toxic substances in containers and to validate this questionnaire in medical follow-up and diagnosis. MATERIALS AND METHODS: In 2014, 125 French dockers answered the questionnaire in a face-to-face interview. RESULTS: 83.5% declared no exposure to fumigants or pesticides. Most frequently declared symptoms were fatigue and neurological disorders for dockers and respiratory irritation for refrigeration technicians. Only 28 workers wore regularly individual protection equipment. CONCLUSIONS: A "healthy worker" effect could explain low level of symptoms. Fum Ex 2 questionnaire is relevant for diagnosis. Workers in all steps of the logistic transport chain and consumers are exposed to containers' atmosphere.

Influence of fumigants on sunflower seeds: Characteristics of fumigant desorption and changes in volatile profiles.

Fumigation of transport containers is common practice to protect stored products from pests. Yet little is known about the desorption times and effects of the highly toxic gases used in this process. To shed light on the behavior of fumigants in real food, we treated sunflower seeds (Helianthus annuus L.) with 100ppm phosphine (PH3), methyl bromide (MeBr) or 1,2-dichloroethane (DCE) for 72h. The compound concentrations in the air were then analyzed by thermal desorption/2D gas chromatography coupled to mass spectrometry and flame photometric detection (TD-2D-GC-MS/FPD). A desorption time of several months was observed for DCE, whereas PH3 and MeBr were outgassed in a matter of days. To investigate possible interactions between gases and constituents of the seeds, non-fumigated, fumigated and outgassed samples were analyzed by headspace solid-phase microextraction GC-MS. We observed significantly different volatile profiles in fumigated and subsequently outgassed seeds compared to non-fumigated seeds. Whereas PH3-treated seeds released far more terpenoids, the volatile pattern of seeds exposed to DCE revealed significantly fewer terpenoids but more aldehydes. These changes are likely to affect food aroma characteristics.

Homologous and lysophosphatidic acid-induced desensitization of the atrial natriuretic peptide receptor, guanylyl cyclase-A, in MA-10 leydig cells.

The cardiac hormone atrial natriuretic peptide (ANP) signals via interaction with a plasma membrane receptor, which has guanylyl cyclase (GC) activity and is referred to as GC-A. Desensitization of GC-A is thought to represent a physiologically important regulatory mechanism, but the signaling pathways implicated and cell type-specific effects are still poorly understood. Here we demonstrate that sustained exposure to either ANP itself or the bioactive lipid lysophosphatidic acid (LPA) elicits GC-A desensitization in MA-10 Leydig cells. Both reactions show similar kinetics and evoke equal decreases (by 40%) in GC-A hormone responsiveness. Homologous (ANP induced) desensitization, in which cGMP is generated as second messenger, is blocked by distinct cAMP-dependent protein kinase [protein kinase A (PKA)] inhibitors, H 89, and Rp-8-CPT-cAMPs, providing evidence that PKA mediates the reaction. Accordingly, the ANP/cGMP-elicited effects are mimicked by a cAMP analog, 8-bromo-cAMP. The LPA-induced (heterologous) desensitization is not blocked by PKA inhibition, indicating a different signaling pathway. LPA, but not ANP, enhances ERK phosphorylation and induces cell rounding together with a dramatic reorganization of actin filaments. Consistent with the identification of LPA receptor (LPA2 and LPA3) gene expression, the findings are indicative of LPA receptor-mediated reactions. This study demonstrates for the first time coexistence of homologous and heterologous desensitization of GC-A in the same cell type, reveals that these reactions are mediated by different pathways, and identifies a novel cross talk between phospholipid and natriuretic peptide signaling. The morphoregulatory activities exerted by LPA suggest a crucial role for Leydig cell physiology.

Lysophosphatidic acid signals through mitogen-activated protein kinase-extracellular signal regulated kinase in ovarian theca cells expressing the LPA1/edg2-receptor: involvement of a nonclassical pathway?

We investigated the mechanism of lysophosphatidic acid (LPA) signaling in ovarian theca cells and observed that stimulation with this bioactive lipid markedly enhanced Thr/Tyr phosphorylation of the MAPK ERK1/2. Activation of ERK was transient, showing a peak at 5 min that declined thereafter, and was not associated with a concomitant nuclear translocation of the enzyme, suggesting that a cytosolic tyrosine phosphatase may be responsible for switching off the signal. Epidermal growth factor (EGF)-induced activation of the enzyme in the same cell system was more rapid (peaking at 1 min), sustainable for at least 60 min, and could be suppressed by prior treatment with either pertussis toxin or a noncompetitive inhibitor of Ras acceptor protein, manumycin A. This functional inhibition of either Gi or Ras failed, however, to affect the LPA-induced ERK-phosphorylation. Surprisingly, functional inhibition of Rho-GTPase, in C3-exotoxin-lipofected cells, markedly reduced LPA-stimulated phosphorylation of ERK, without affecting the EGF-induced stimulation of MAPK. Theca cells labeled with anti-LPA1/edg2-type antibody showed a distinct cell surface labeling, which is reflected in the expression of (LPA1)-type LPA receptors at both mRNA and protein levels. The findings indicate that LPA transiently stimulates MAPK ERK in LPA1/edg2-expressing theca cells and suggest an alternative mechanism regulating the activation of ERK that differs from the canonical EGF-Ras-MAPK kinase pathway.

Spotlight on the diagnosis of extrinsic allergic alveolitis (hypersensitivity pneumonitis).

Repeated inhalative exposures to antigenic material from a variety of sources, mainly from moulds, thermophilic Actinomycetes, and avians, respectively, can induce immune responses with the clinical picture of extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis. Delays of years or even decades till the diagnosis is made are not uncommon; frequent misdiagnoses include allergic asthma, COPD, recurrent flue and other infections. We provide here the state of the art references, a detailed case description and recommend a current diagnostics schema.

Is the analysis of histamine and/or interleukin-4 release after isocyanate challenge useful in the identification of patients with IgE-mediated isocyanate asthma?

Isocyanates are a well-known and frequent cause of occupational asthma. The implementation of specific inhalation challenges (SICs) is the gold standard in asthma diagnosis supporting occupational case history, lung function testing, specific skin prick tests and the detection of specific IgE. However, the diagnosis is not always definitive. An interesting new approach, analyses of individual genetic susceptibilities, requires discrimination between a positive SIC reaction arising from IgE-mediated immune responses and one from other pathophysiological mechanisms. Hence, additional refinement tools would be helpful in defining sub-classes of occupational asthma and diagnosis. We used total IgE levels, specific IgE and SIC results for sub-classification of 27 symptomatic isocyanate workers studied. Some mutations in glutathione S-transferases (GSTs) are suspected either to enhance or to decrease the individual risk in the development of isocyanate asthma. Our patient groups were assessed for the point mutations GSTP1*I105V and GSTP1*A114V as well as deletions (null mutations) of GSTM1 and GSTT1. There seems to be a higher risk in developing IgE-mediated reactions when GSTM1 is deleted, while GSTT1 deletions were found more frequently in the SIC positive group. Blood samples taken before SIC, 30-60 min and 24h after SIC, were analyzed for histamine and IL-4, classical markers for the IgE-mediated antigen-specific activation of basophils or mast cells. We suggest that the utility of histamine measurements might provide an additional useful marker reflecting isocyanate-induced cellular reactions (although the sampling times require optimization). The promising measurement of IL-4 is not feasible at present due to the lack of a reliable, validated assay.

Circulating mitochondrial DNA as biomarker linking environmental chemical exposure to early preclinical lesions elevation of mtDNA in human serum after exposure to carcinogenic halo-alkane-based pesticides.

There is a need for a panel of suitable biomarkers for detection of environmental chemical exposure leading to the initiation or progression of degenerative diseases or potentially, to cancer. As the peripheral blood may contain increased levels of circulating cell-free DNA in diseased individuals, we aimed to evaluate this DNA as effect biomarker recognizing vulnerability after exposure to environmental chemicals. We recruited 164 individuals presumably exposed to halo-alkane-based pesticides. Exposure evaluation was based on human biomonitoring analysis; as biomarker of exposure parent halo-methanes, -ethanes and their metabolites, as well as the hemoglobin-adducts methyl valine and hydroxyl ethyl valine in blood were used, complemented by expert evaluation of exposure and clinical intoxication symptoms as well as a questionnaire. Assessment showed exposures to halo alkanes in the concentration range being higher than non-cancer reference doses (RfD) but (mostly) lower than the occupational exposure limits. We quantified circulating DNA in serum from 86 individuals with confirmed exposure to off-gassing halo-alkane pesticides (in storage facilities or in home environment) and 30 non-exposed controls, and found that exposure was significantly associated with elevated serum levels of circulating mitochondrial DNA (in size of 79 bp, mtDNA-79, p = 0.0001). The decreased integrity of mtDNA (mtDNA-230/mtDNA-79) in exposed individuals implicates apoptotic processes (p = 0.015). The relative amounts of mtDNA-79 in serum were positively associated with the lag-time after intoxication to these chemicals (r = 0.99, p<0.0001). Several months of post-exposure the specificity of this biomarker increased from 30% to 97% in patients with intoxication symptoms. Our findings indicate that mitochondrial DNA has a potential to serve as a biomarker recognizing vulnerable risk groups after exposure to toxic/carcinogenic chemicals.

Health effects due to fumigated freight containers and goods: how to detect, how to act.

Headache, concentration and memory disorders, dizziness and nausea, skin irritation, respiratory distress, and muscle cramps - isolated or in various combinations - may be the result of acute or chronic intoxication by fumigants. The occurrence of these symptoms in workers who are engaged in the opening and unloading of containers, unpacking of imported goods, ventilating of containers, or working on bulk carriers are urgent indications of intoxication by fumigants or other toxic chemical residues in the transported goods. The severity of the disorder depends on the concentration and duration of exposure, distribution and release of the fumigant, its kinetics, the individual susceptibility of the person, as well as any simultaneous exposure to other toxic substances. Physical symptoms, acute and chronic health effects due to contact with fumigants, are complex and difficult to discover. In this article we explain how to identify the guiding symptoms and describe the appropriate diagnostic steps and the prevention of such events on cargo vessels as well as in the logistics and the handling of imported goods.

Surprises perilous: toxic health hazards for employees unloading fumigated shipping containers.

The fumigation of freight containers to protect transported goods from fungal and pest infestation has increased worldwide in the last five years due to international regulations requiring fumigation or heat treatment of wooden packaging material and dunnage. We have found in 2008 that every sixth container and its contents do retain harmful concentrations of various fumigants and chemicals, representing a significant health risk for port and transport workers, customs officials, warehousemen, store employees and consumers. The shipping documents of these containers did not provide any information about the fumigation procedure or the used fumigant. We report here the cases of 26 patients introduced to our outpatient clinic with presumed intoxication to fumigants, or with symptoms due to inhaling the air out of fumigated containers. All patients were examined from 2007 to 2010 according to a standardized comprehensive diagnostic program. We were able to confirm the diagnosis based on typical symptoms and extensive clinical examination; by laboratory analysis we identified ethylene dichloride, methyl bromide, phosphine and methylene chloride. The predominant symptoms were headaches, concentration and memory problems, dizziness and nausea, irritation of the skin and mucous membranes and a reduced ability to do exercise. In addition to the neurological and neuropsychological impairments our analyses verified the development of reactive airways dysfunction syndrome (RADS) in 14 of 26 patients with long lasting symptoms due to their contact with fumigants. Intoxications with fumigants are serious and could be avoided. These systematical explored cases show the sustainable impact for health and socio-economic wellbeing. These findings also emphasize the necessity for international standards on permitted fumigants, appropriate labeling in the shipping documents and handling of fumigated containers.

Elimination kinetics of diisocyanates after specific inhalative challenges in humans: mass spectrometry analysis, as a basis for biomonitoring strategies.

BACKGROUND: Isocyanates are some of the leading occupational causes of respiratory disorders, predominantly asthma. Adequate exposure monitoring may recognize risk factors and help to prevent the onset or aggravation of these aliments. Though, the biomonitoring appears to be most suitable for exposure assessment, the sampling time is critical, however. In order to settle the optimal time point for the sample collection in a practical biomonitoring approach, we aimed to measure the elimination of isocyanate urine metabolites. METHODS: A simple biomonitoring method enabling detection of all major diamine metabolites, from mono-, poly- and diisocyanates in one analytical step, has been established. Urine samples from 121 patients undergoing inhalative challenge tests with diisocyanates for diagnostic reasons were separated by gas chromatography and analyzed with mass spectrometry (GC-MS) at various time points (0-24 h) after the onset of exposure. RESULTS: After controlled exposures to different concentrations of diisocyanates (496 ± 102 ppb-min or 1560 ± 420 ppb-min) the elimination kinetics (of respective isocyanate diamine metabolites) revealed differences between aliphatic and aromatic isocyanates (the latter exhibiting a slower elimination) and a dose-response relationship. No significant differences were observed, however, when the elimination time patterns for individual isocyanates were compared, in respect of either low or high exposure or in relation to the presence or absence of prior immunological sensitization. CONCLUSIONS: The detection of isocyanate metabolites in hydrolyzed urine with the help of gas chromatography combined with mass spectrometric detection system appears to be the most suitable, reliable and sensitive method to monitor possible isocyanate uptake by an individual. Additionally, the information on elimination kinetic patterns must be factored into estimates of isocyanate uptake before it is possible for biomonitoring to provide realistic assessments of isocyanate exposure. The pathophysiological elimination of 1,6-hexamethylene diamine, 2,4-diamine toluene, 2,6-diamine toluene, 1,5-naphthalene diamine, 4,4'-diphenylmethane diamine and isophorone diamines (as respective metabolites of: 1,6-hexamethylene diisocyanate, 2,4-toluene diisocyanate and 2,6 toluene diisocyanate, 1,5-naphthalene diisocyanate, 4,4'-diphenylmethane diisocyanate and isophorone diisocyanates) differs between individual isocyanates' diamines.

The assessment of environmental and occupational exposure to hazardous substances by biomonitoring.

BACKGROUND: Modern biomonitoring has expanded beyond its origins in occupational medicine to cover a wide variety of diagnostic procedures and assessments of environmental pollution, ranging from exposure to heavy metals and chemicals to the effects of pesticides and environmental tobacco smoke. In biomonitoring, the overall pollutant load and hazardous exposure of an organism is quantitatively determined, by monitoring the pollutants themselves, their metabolic products and/or conjugates with protein or DNA, in either serum, urine or other body fluids, as well as tissue samples in exceptional circumstances. METHODS: A selective survey of the current literature is exemplified by our recent scientific and clinical experience. RESULTS: Biomonitoring is an excellent way to monitor potentially hazardous substances, especially for the assessment of systemic uptake from chronic exposure and the evaluation of subsequent health risks. Investigative biomonitoring can highlight incidental/accidental intoxication in individuals and provide new categories of problematic pollutants relevant to the general population. CONCLUSIONS: In combination with diagnostic procedures, biomonitoring provides an important contribution to the rational assessment of currently recorded pollutants and resulting health risks. It is as an evaluation tool available in daily practice as well as in health and environmental research applications. Legislation is already implemented that incorporates biomonitoring within the remit of specified occupational health screening.