Occupational exposure to genotoxic agents.

Millions of workers in the United States are potentially exposed each year to hazardous chemicals, dusts, or fibers in occupational settings. Some of these agents are genotoxic and may cause genetic alterations in the somatic or germ cells of exposed workers. Such alterations, if they occur in proto-oncogenes or tumor suppressor genes, which are involved in controlling cell growth or differentiation, may lead to the development of cancer. Genetic alterations in germ cells may also lead to reproductive failure or genetic disorders in subsequent generations. It has been estimated that occupational exposure accounts for 4% of all human cancers and up to 30% of cancer among blue-collar workers. Approximately 20,000 cancer deaths each year are attributable to occupational exposure in the United States. Occupational cancer and reproductive abnormalities have been listed on the National Occupational Research Agenda master list of research priorities as major occupational diseases and injuries.     

Legislative aspects: an evaluation of the impact of COSHH schedule 9 for assessing biological risks

Exposure to biological agents in the workplace can cause infection, allergy or toxicosis. Health effects caused by biological agents in the workplace are related both to incidental exposure and to deliberate work with microorganisms. A small but significant percentage of occupational allergy is associated with biological agents in organic dusts, and a new reporting scheme recorded more than 1000 new cases of occupational infection in its first year. Assessing risks from workplace biological agents in the UK forms part of the Control of Substances Hazardous to Health (COSHH) regulations. Legislation (Schedule 9) and guidance which deals with biological agents were added to implement EC Biological Agents Directives and to emphasise the position of biological agents in COSHH.We evaluated the impact of COSHH Schedule 9 by interviewing representatives of workers in laboratories deliberately handling microorganisms and discussing in a Focus Group format with representatives from industries where incidental exposure to microorganisms could occur. This paper describes the outcome of that evaluation and examines the tools available to assess risks from exposure to workplace microorganisms.     

Chemical safety in animal care,use, and research

Chemical safety is an essential element of an effective occupational health and safety program. Controlling exposures to chemical agents requires a careful process of hazard recognition, risk assessment, development of control measures, communication of the risks and control measures, and training to ensure that the indicated controls will be utilized. Managing chemical safety in animal care and use presents a unique challenge, in part because research is frequently conducted in two very different environments--the research laboratory and the animal care facility. The chemical agents specific to each of these environments are typically well understood by the employees working there; however, the extent of understanding may not be adequate when these individuals, or chemicals, cross over into the other environment. In addition, many chemicals utilized in animal research are not typically used in the research laboratory, and therefore the level of employee knowledge and proficiency may be less compared with more routinely used materials. Finally, the research protocol may involve the exposure of laboratory animals to either toxic chemicals or chemicals with unknown hazards. Such animal protocols require careful review to minimize the potential for unanticipated exposures of the research staff or animal care personnel. Numerous guidelines and regulations are cited, which define the standard of practice for the safe use of chemicals. Key chemical safety issues relevant to personnel involved in the care and use of research animals are discussed.     

Reduction,refinement and replacement: putting the immune system to work

Many chemicals are known to be, or have been implicated as, contact allergens, and allergic contact dermatitis is an important occupational and environmental health issue. It is the responsibility of toxicologists to identify those chemicals that have the potential to induce skin sensitisation, and to assess the conditions under which there will exist a risk to human health. This article describes progress that has been made in the development of new approaches to the toxicological evaluation of skin sensitisation, and the benefits to animal welfare that such developments have already produced, and are likely to produce in the future. In this context, the local lymph node assay is described with regard to hazard identification and risk assessment, and possible strategies for the development of in vitro approaches to safety assessment are discussed.     

Role of Nitric Oxide in the Progression of Pneumoconiosis

Conflicting evidence has been reported as to whether nitric oxide (NO) possesses anti-inflammatory or inflammatory properties. Data are presented indicating that in vitro or in vivo exposure to selected occupational dusts, i.e., crystalline silica, organic dust contaminated with endotoxin, or asbestos, results in upregulation of inducible nitric oxide synthase (iNOS) and the production of NO by alveolar macrophages and pulmonary epithelial cells. Nitric oxide production is associated temporally and anatomically with pulmonary damage, inflammation, and disease progression in response to occupational dusts. Blockage of inducible nitric oxide synthase by administration of NOS inhibitors or in iNOS knockout mice decreases the magnitude of injury and inflammation following in vivo exposure to silica, endotoxin, or asbestos. Therefore, NO may play an important role in the initiation and progression of pneumoconiosis.     

Biomimicry of volatile‐based microbial control for managing emerging fungal pathogens

Volatile organic compounds (VOCs) are known to be produced by a wide range of micro‐organisms and for a number of purposes. Volatile‐based microbial inhibition in environments such as soil is well‐founded, with numerous antimicrobial VOCs having been identified. Inhibitory VOCs are of interest as microbial control agents, as low concentrations of gaseous VOCs can elicit significant antimicrobial effects. Volatile organic compounds are organic chemicals typically characterized as having low molecular weight, low solubility in water, and high vapour pressure. Consequently, VOCs readily evaporate to the gaseous phase at standard temperature and pressure. This contact‐independent antagonism presents unique advantages over traditional, contact‐dependent microbial control methods, including increased surface exposure and reduced environmental persistence. This approach has been the focus of our recent research, with positive results suggesting it may be particularly promising for the management of emerging fungal pathogens, such as the causative agents of white‐nose syndrome of bats and snake fungal disease, which are difficult or impossible to treat using traditional approaches. Here, we review the history of volatile‐based microbial control, discuss recent progress in formulations that mimic naturally antagonistic VOCs, outline the development of a novel treatment device, and highlight areas where further work is needed to successfully deploy VOCs against existing and emerging fungal pathogens.     

A review of allergic respiratory disease in laboratory animal workers.

There is increased recognition of hypersensitivity lung disease among workers with laboratory animals as an occupational disease. Symptoms of asthma in 44 of 78 workers with laboratory animal dander allergy reflected the serious consequences of this occupational ailment. Affected employee profiles induced family history of atopy; immediate (Type I) allergic reaction; symptoms of rhinitis, asthma, and cough; hypersensitivity to one or more species, most often rats, mice, and rabbits. Diagnosis depends on history and physical, radiologic, and laboratory examinations, including skin tests with relevant antigens. Control and treatment depend on environmental change (reemployment or reduction of antigen contact); mechanical devices (masks and filters); chemotherapy (bronchodilators, steroids), prophylaxis and immunotherapy (hyposensitization). Standardization of medico-legal criteria covering occupational asthma is needed.     

Noise-Induced Hearing Loss in Korean Workers: Co-Exposure to Organic Solvents and Heavy Metals in Nationwide Industries

Background

Noise exposure is a well-known contributor to work-related hearing loss. Recent biological evidence suggests that exposure to ototoxic chemicals such as organic solvents and heavy metals may be additional contributors to hearing loss. However, in industrial settings, it is difficult to determine the risks of hearing loss due to these chemicals in workplaces accompanied by excessive noise exposure. A few studies suggest that the effect of noise may be enhanced by ototoxic chemicals. Therefore, this study investigated whether co-exposure to organic solvents and/or heavy metals in the workplace modifies the risk of noise exposure on hearing loss in a background of excessive noise.

Methods

We examined 30,072 workers nationwide in a wide range of industries from the Korea National Occupational Health Surveillance 2009. Data on industry-based exposure (e.g., occupational noise, heavy metals, and organic solvents) and subject-specific health outcomes (e.g., audiometric examination) were collected. Noise was measured as the daily 8-h time-weighted average level. Air conduction hearing thresholds were measured from 0.5 to 6 kHz, and pure-tone averages (PTA) (i.e., means of 2, 3, and 4 kHz) were computed.

Results

In the multivariate linear model, PTA increment with occupational noise were 1.64-fold and 2.15-fold higher in individuals exposed to heavy metals and organic solvents than in unexposed individuals, respectively.

Conclusion

This study provides nationwide evidence that co-exposure to heavy metals and/or organic solvents may exacerbate the effect of noise exposure on hearing loss in workplaces. These findings suggest that workers in industries dealing with heavy metals or organic solvents are susceptible to such risks.     

Zoonoses of occupational health importance in contemporary laboratory animal research

In contemporary laboratory animal facilities, workplace exposure to zoonotic pathogens, agents transmitted to humans from vertebrate animals or their tissues, is an occupational hazard. The primary (e.g., macaques, pigs, dogs, rabbits, mice, and rats) and secondary species (e.g., sheep, goats, cats, ferrets, and pigeons) of animals commonly used in biomedical research, as classified by the American College of Laboratory Animal Medicine, are established or potential hosts for a large number of zoonotic agents. Diseases included in this review are principally those wherein a risk to biomedical facility personnel has been documented by published reports of human cases in laboratory animal research settings, or under reasonably similar circumstances. Diseases are listed alphabetically, and each section includes information about clinical disease, transmission, occurrence, and prevention in animal reservoir species and humans. Our goal is to provide a resource for veterinarians, health-care professionals, technical staff, and administrators that will assist in the design and on-going evaluation of institutional occupational health and safety programs.     

Mechanism and epidemiology of laboratory animal allergy

Laboratory animal allergy (LAA) is a form of occupational allergic disease. The development of laboratory animal allergy is due to the presence of IgE antibodies directed against animal proteins. The process of sensitization (development of IgE antibodies) is a complex process which involves interaction of antigen presenting cells and lymphocytes of the Th-2 cell type. These cells generate a host of cytokines and other factors which lead to immediate hypersensitivity reactions and other factors which lead to immediate hypersensitivity reactions and the generation of allergic inflammation. Typical symptoms of laboratory animal allergy include nasal symptoms, such as sneezing, watery discharge, and congestion. Skin rashes are also common. Asthma, which produces symptoms of cough, wheezing, and shortness of breath, may affect 20-38% of workers who are sensitized to laboratory animal allergens. Rarely a generalized, life-threatening allergic reaction (anaphylaxis) may occur. The estimated prevalence of laboratory animal allergy is variable depending on the method used for diagnosis, but nonetheless may affect up to 46% of exposed workers. The presence of pre-existing allergies to non-work place allergens (e.g., dust mite, pollens, molds), exposure to laboratory animal allergens, and possibly tobacco smoking are risk factors for the development of laboratory animal allergy. Progress in the understanding of the mechanism and epidemiology of laboratory animal allergy will lead to improved methods for its prevention.     

Occupational Dermatoses in Ontario, 1955 to 1962

In Ontario in 1962, with a compensationeligible labour force of 1,814,000, 10 out of each 1000 workers received compensation for some occupational dermatosis, as defined here; 36 out of each 1000 workers received compensation for some cause. Contact dermatitides made up 5042 of 7448 cases of occupational disease for which compensation and/or medical aid was paid in 1955 and 1956. In eight years, 1955 to 1962 (inclusive), of a total of 534,557 “compensation only” cases, 7023 received payment for contact dermatitis. The average yearly cost of compensation of a worker with a contact dermatitis was estimated at $1113; the annual total cost, at $900,000. The average cost of an occupational dermatosis was $368; the annual total cost, $10 million. Occupational dermatoses account for almost one-third of all compensation costs. The cost of “medical aid only” is excluded from all of these estimates. In contact dermatitis, primary irritants (chemicals) are still the main causative agents. Skin sensitizers, the epoxy resins particularly, have become more prominent in recent years. There is no all-purpose barrier cream or protective clothing. Proper personal hygiene remains the most effective preventive agent in industry.     

Parameters of immunity acute phase reaction in men in relation to exposure duration to mercury vapours.

The study was carried out in 89 men aged 21 to 57 years with a history of exposure to mercury vapour from 2 to 26 years during occupational work involving chlorine production by the method of mercury electrolysis. The workers were divided into three groups depending on the duration of occupational exposure: 1) 32 workers with a short history of exposure 2-10 years, 2) 37 workers with medium-long exposure - 11-20 years, and 3) 20 workers with a history of long exposure - 21-26 years. The urinary concentrations of mercury in these individuals was 73 +/- 60 microliters x 1(-1), and in blood this concentration was not exceeding 50 microliters x 1(-1). The control group comprised 40 men aged 17 to 52 years. They had not had any occupational exposure to chemicals, or harmful physical factors. On the basis of clinical, haematological and biochemical studies 89 workers with occupational exposure to mercury vapour were regarded as clinically healthy. None of them had any symptoms and signs of the complete neurasthenic syndrome or organic brain injury. Increased nervous excitability was the complaint of 24 workers, 9 had headaches, sleep disturbances were reported by 5, and a feeling of tiredness and apathy was mentioned by 5 men. EEG recording demonstrated 81 normal tracings, and moderately pathological records in 8 men. The parameters of immunity and proteins acute phase reaction were determined, measuring the concentration of immunoglobulins, lysozyme, C3c, C4, alpha 1-acid glycoprotein, haptoglobin and ceruloplasmin in serum. A lower level of IgA, IgG and lysozyme was only noted in individuals with occupational exposure exceeding 20 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epidemiology in protection and prevention against environmental mutagens/carcinogens Examples from occupational medicine

Subjects occupationally exposed to potential mutagens/carcinogens represent the most suitable groups for epidemiological studies aimed at assessing the risk for the individual or the offspring. Several cancer risks to humans have been detected by epidemiological studies performed in occupational settings. Cancer epidemiology studies have been able (a) to identify specific occupations or agents associated with the risk; (b) to verify the results of experimental studies; (c) to test the effectiveness of changes in production or preventive measures in decreasing risks. Reproductive epidemiology has suggested a risk of spontaneous abortions or of malformation in the offspring of workers exposed to some chemicals or occupations, but data are often conflicting due to methodological problems. With the aim of early assessment of risk in mind, the epidemiological use of indicators of exposure or of the early effect of exposure to genotoxic agents is increasingly applied to occupational groups. Cytological monitoring of subjects at risk of occupational cancer of lung or bladder is carried out mainly to diagnose precancerous lesions of target tissues. Cytogenetic methods (chromosome aberrations, SCE, micronuclei) in somatic cells provide a means for detecting early effects of occupational exposure to known or potential mutagens/carcinogens in selected groups of individuals, but their significance is widely debated. Monitoring of urinary mutagenicity, as applied in nurses handling cytostatic drugs, is an example of how an indicator of exposure to genotoxins can be used to evaluate the impact of preventive measures. Among the perspectives, biochemical epidemiology seems to be promising in detecting individuals genetically susceptible to cancer.     

Cytokine fingerprinting: characterization of chemical allergens.

Chemical allergy is a common and important occupational health issue. Allergic sensitization induced by chemicals may take a variety of forms, including allergic contact dermatitis (skin sensitization) and allergic asthma and rhinitis (sensitization of the respiratory tract). There is a need to identify and characterize chemicals that have the potential to cause such sensitization reactions. Although a number of methods are available for the prospective analysis of skin sensitizing activity, there are currently no widely accepted tests for the identification of chemical respiratory allergens. We here describe a novel approach, cytokine fingerprinting, that has the potential to distinguish between chemical contact and respiratory allergens. The pattern of cytokine production by draining lymph node cells (LNCs) is evaluated following repeated topical exposure of mice to test chemicals. Experience to date reveals that contact allergens stimulate the selective development of type 1 immune responses associated with the secretion by draining LNCs of interferon gamma (IFN-gamma), but little interleukin-4 (IL-4) or interleukin-10 (IL-10). In contrast, chemical respiratory allergens are found to induce the appearance of preferential type 2 immune responses characterized by IL-4 and IL-10 production, but comparatively low levels of IFN-gamma. It is proposed that cytokine fingerprinting may permit the simultaneous identification and characterization of those chemicals that have the potential to cause allergic sensitization.     

The molecular biology of hepatitis C virus

Hepatitis C virus (HCV) is one of the main causative agents for transfusion associated- and sporadic cases of non-A, non-B hepatitis throughout the world. HCV has a positive strand RNA of about 9400 nucleotides, as its genome, whose organization is similar to those of animal pestiviruses or human flaviviruses. In spite of the lack of the effective replication system in tissue culture cells, parts of the viral genome were expressed under the control of foreign promoters and the synthesized viral protein has been used for diagnostic assays.     

The relationship between CD86/CD54 expression and THP-1 cell viability in an in vitro skin sensitization test – human cell line activation test (h-CLAT)

Recent regulations for cosmetics in Europe prohibit animal testing for evaluating the sensitization potential of chemicals to improve animal welfare. Yet, there is not an acceptable Organization for Economic Co-operation and Development non-animal skin sensitization test method. Several in vitro skin sensitization methods that focus on the activation of Langerhans cells, including human cell lines, are being evaluated as possible alternatives. In our previous study, we optimized our human cell line activation test (h-CLAT) using THP-1 cells (monocytic leukemia cell line) and conducted an inter-laboratory study. We found that measuring CD86/CD54 expression may be useful for predicting skin sensitization. The aim of this study was to confirm the relationship between CD86/CD54 expression and THP-1 cell viability in the h-CLAT. In this study, 21 allergens (e.g., dinitrochlorobenzene, p-phenylenediamine, Ni) and 8 non-allergens (e.g., SLS, lactic acid) were evaluated. For each chemical, more than 10 concentrations that gave a predicted cell viability range of 20–95% were used. The data showed that expression patterns of CD86/CD54 differed depending on chemical. For most allergens, cytotoxicity (65–90% cell viability) was needed for enhancement of CD86/CD54 expression. The criteria of “CD86 ≥ 150 or CD54 ≥ 200” resulted in an accuracy of 93%, which confirms appropriate cut-off criteria for h-CLAT. Furthermore, a good correlation was observed between EC3 of local lymph node assay and EC150(CD86) or EC200(CD54) of h-CLAT (12 or 16 chemicals, respectively), which would provide a useful estimate of allergic potency. These findings suggest that h-CLAT would be a good robust in vitro skin sensitization test.     

Merits and Pitfalls of Currently Used Diagnostic Tools in Mycetoma

Treatment of mycetoma depends on the causative organism and since many organisms, both actinomycetes (actinomycetoma) and fungi (eumycetoma), are capable of producing mycetoma, an accurate diagnosis is crucial. Currently, multiple diagnostic tools are used to determine the extent of infections and to identify the causative agents of mycetoma. These include various imaging, cytological, histopathological, serological, and culture techniques; phenotypic characterisation; and molecular diagnostics. In this review, we summarize these techniques and identify their merits and pitfalls in the identification of the causative agents of mycetoma and the extent of the disease. We also emphasize the fact that there is no ideal diagnostic tool available to identify the causative agents and that future research should focus on the development of new and reliable diagnostic tools.     

Bispecific monoclonal antibodies mediate binding of dengue virus to erythrocytes in a monkey model of passive viremia

Dengue viruses (DEN), causative agents of dengue fever (DF) and more severe dengue hemorrhagic fever (DHF)/dengue shock syndrome, infect over 100 million people every year. Among those infected, up to one-half million people develop DHF, which requires an extensive hospital stay. Recent reports indicate that there is a significant correlation between virus titer in the bloodstream of infected individuals and the severity of the disease, especially the development of DHF. This suggests that if there is a procedure to reduce viremia in infected subjects, then the severity of the disease may be controlled during the critical early stages of the disease before it progresses to DHF. We have generated bispecific mAb complexes (heteropolymer(s), HP), which contain a mAb specific for the DEN envelope glycoprotein cross-linked with a second mAb specific for the primate E complement receptor 1. These HP facilitate rapid binding of DEN to human and monkey E in vitro, with approximately 90% bound within 5 min. Furthermore, in a passive viremia monkey model established by continuous steady state infusion of DEN, injection of HP during the steady state promoted rapid binding of DEN to the E, followed by subsequent clearance from the vascular system. Moreover, HP previously infused into the circulation is capable of efficiently capturing a subsequent challenge dose of DEN and binding it to E. These data suggest that HP potentially can be useful for alleviating DEN infection-associated symptoms by reducing titers of free virus in the vascular system.     

Airway sizes and proportions in children quantified by a video-bronchoscopic technique

Background

Detecting serum antibody against inhaled antigens is an important diagnostic adjunct for hypersensitivity pneumonitis (HP). We sought to validate a quantitative fluorimetric assay testing serum from bird fanciers.

Methods

Antibody activity was assessed in bird fanciers and control subjects using various avian antigens and serological methods, and the titer was compared with symptoms of HP.

Results

IgG antibody against pigeon serum antigens, quantified by fluorimetry, provided a good discriminator of disease. Levels below 10 mg/L were insignificant, and increasing titers were associated with disease. The assay was unaffected by total IgG, autoantibodies and antibody to dietary hen's egg antigens. Antigens from pigeon serum seem sufficient to recognize immune sensitivity to most common pet avian species. Decreasing antibody titers confirmed antigen avoidance.

Conclusion

Increasing antibody titer reflected the likelihood of HP, and decreasing titers confirmed antigen avoidance. Quantifying antibody was rapid and the increased sensitivity will improve the rate of false-negative reporting and obviate the need for invasive diagnostic procedures. Automated fluorimetry provides a method for the international standardization of HP serology thereby improving quality control and improving its suitability as a diagnostic adjunct.     

Endotoxin and cancer chemo-prevention

Reduced rates of lung cancer have been observed in several occupational groups exposed to high levels of organic dusts contaminated by endotoxin. The underlying anti-neoplastic mechanism of endotoxin may be an increased secretion of endogenous anti-neoplastic mediators and activation of the toll-like receptors (TLR). A detoxified endotoxin derivative, Monophosphoryl Lipid A (MPL^®) is marketed in Europe since 1999 as part of the adjuvant systems in allergy vaccines for treatment of allergic rhino-conjunctivitis and allergic asthma. Over 200,000 patients have used them to date (nearly 70% in Germany). Since detailed exposure (MPL^® dose and timing of administration) and individual data are potentially available, an observational follow-up study could be conducted in Germany to investigate the protective effect of MPL^® against cancer, comparing cancer incidence in two groups of patients with allergic rhinitis: those treated with allergoids plus MPL^® and those treated with a vaccine including the same allergoids but not MPL^®. The protective effect of MPL^® could be quantified in ever and never smokers. If this proposed observational study provides evidence of protective effects, MPL^® could be immediately used as a chemo-preventive agent since it is already in use as adjuvant in human vaccines against cancer.