Aggregate Exposure and Cumulative Risk Assessment--Integrating Occupational and Non-occupational Risk Factors.

Occupational exposure limits have traditionally focused on preventing morbidity and mortality arising from inhalation exposures to individual chemical stressors in the workplace. While central to occupational risk assessment, occupational exposure limits have limited application as a refined disease prevention tool because they do not account for all of the complexities of the work and non-occupational environments and are based on varying health endpoints. To be of greater utility, occupational exposure limits and other risk management tools could integrate broader consideration of risks from multiple exposure pathways and routes (aggregate risk) as well as the combined risk from exposure to both chemical and non-chemical stressors, within and beyond the workplace, including the possibility that such exposures may cause interactions or modify the toxic effects observed (cumulative risk). Although still at a rudimentary stage in many cases, a variety of methods and tools have been developed or are being used in allied risk assessment fields to incorporate such considerations in the risk assessment process. These approaches, which are collectively referred to as cumulative risk assessment, have potential to be adapted or modified for occupational scenarios and provide a tangible path forward for occupational risk assessment. Accounting for complex exposures in the workplace and the broader risks faced by the individual also requires a more complete consideration of the composite effects of occupational and non-occupational risk factors to fully assess and manage worker health problems. Barriers to integrating these different factors remain, but new and ongoing community-based and worker health-related initiatives may provide mechanisms for identifying and integrating risk from aggregate exposures and cumulative risks from all relevant sources, be they occupational or non-occupational.

Workplace monitoring of occupational exposure to refractory ceramic fiber--a 17-year retrospective.

This article presents a 17-year (1990-2006) retrospective summary of ongoing studies of occupational exposure to refractory ceramic fiber (RCF) in the United States. Beginning in 1990, RCF producers integrated and harmonized individual workplace monitoring programs to provide data useful for various longitudinal and cross-sectional analyses, benchmarking, and various technical analyses. For 10 of these 17 years, the program has been conducted in partnership with government agencies, first a 5-year (1993-1998) program with the U.S. Environmental Protection Agency and later another 5-year (2002-2006) program with the Occupational Safety and Health Administration and the National Institute for Occupational Safety and Health. This article updates earlier published studies and provides lessons to be learned in the design of industrial hygiene monitoring and control programs.

[Benefit of pharmaceutical anti-oedematous treatment in acute adult epiglottitis]. / Intérêt du traitement médicamenteux anti-oedémateux au cours de l'épiglottite aiguë de l'adulte.

Acute adult epiglottitis is a potentially life threatening infectious and respiratory emergency as it may result in airway obstruction. Endotracheal intubation, if needed, is a highly risky option in this situation and responsible for important morbidity and mortality rate. The option of a pharmaceutical anti-oedematous treatment, in order to avoid the risks involved in the endotracheal route has rarely been described. We here report the case of a 50-year-old man with a serious acute infectious epiglottitis who was treated at home by a Mobile Intensive Care Unit where a treatment of nebulized epinephrine and intravenous steroids was undoubtedly a successful option to the endotracheal route. So that, for adult patients and in the absence of any risk of an imminent respiratory arrest, this anti-oedematous treatment should be considered in order to avoid endotracheal route, an option which should be undertaken in case of complications. Nevertheless, this isolated case study concerning an adult is not transposable to children for which airway obstruction tolerance is lower.

Knowledge management in occupational hygiene: the United States example.

Knowledge management is an emerging field focusing on assessing the creation, transfer, and utilization of knowledge to address specific challenges. Generally, knowledge management has described efforts within and between companies to consider knowledge as a manageable asset. In this paper, we suggest that occupational hygiene knowledge can be considered a manageable asset by businesses and that the entire field of occupational hygiene in the USA can be appraised in terms of knowledge management. The knowledge cycle creates a foundation for knowledge management. Knowledge creation (research, recognition and evaluation), transfer (distribution, dissemination and diffusion), and utilization (risk management and control) make up the key elements of the knowledge cycle. Defining and understanding the roles of knowledge cycle elements facilitate the application of knowledge management to problems, systems, and situations in individual companies and in the field of occupational hygiene in general. Examples of current, effective knowledge management practices within occupational hygiene in the USA are described, and recommendations for further utilization of knowledge management principles are also presented.

Electron microscopy study of refractory ceramic fibers.

In epidemiological studies designed to identify potential health risks of exposures to synthetic vitreous fibers, the characterization of airborne fiber dimensions may be essential for assessing mechanisms of fiber toxicity. Toward this end, air sampling was conducted as part of an industry-wide study of workers potentially exposed to airborne fibrous dusts during the manufacture of refractory ceramic fibers (RCF) and RCF products. Analyses of a subset of samples obtained on the sample filter as well as on the conductive sampling cowl were performed using both scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to characterize dimensions of airborne fibers. Comparison was made of bivariate fiber size distributions (length and diameter) from air samples analyzed by SEM and by TEM techniques. Results of the analyses indicate that RCF size distributions include fibers small enough in diameter (< 0.25 microm) to be unresolved by SEM. However, longer fibers (> 60 microm) may go undetected by TEM, as evidenced by the proportion of fibers in this category for TEM and SEM analyses (1% and 5%, respectively). Limitations of the microscopic techniques and differences in fiber-sizing rules for each method are believed to have contributed to the variation among fiber-sizing results. It was concluded from these data that further attempts to characterize RCF exposure in manufacturing and related operations should include analysis by TEM and SEM, since the smallest diameter fibers are not resolved with SEM and the fibers of longer length are not sized by TEM.

Identifying high-risk small business industries for occupational safety and health interventions.

BACKGROUND: Approximately one-third (32%) of U.S. workers are employed in small business industries (those with 80% of workers in establishments with fewer than 100 employees), and approximately 53 million persons in private industry work in small business establishments. This study was performed to identify small business industries at high risk for occupational injuries, illnesses, and fatalities. METHODS: Small business industries were identified from among all three- and four-digit Standard Industrial Classification (SIC) codes and ranked using Bureau of Labor Statistics (BLS) data by rates and numbers of occupational injuries, illnesses, and fatalities. Both incidence rates and number of injury, illness, and fatality cases were evaluated. RESULTS: The 253 small business industries identified accounted for 1,568 work-related fatalities (34% of all private industry). Transportation incidents and violent acts were the leading causes of these fatalities. Detailed injury and illness data were available for 105 small business industries, that accounted for 1,476,400 work-related injuries, and 55,850 occupational illnesses. Many of the small business industries had morbidity and mortality rates exceeding the average rates for all private industry. The highest risk small business industries, based on a combined morbidity and mortality index, included logging, cut stone and stone products, truck terminals, and roofing, siding, and sheet metal work. CONCLUSIONS: Identification of high-risk small business industries indicates priorities for those interested in developing targeted prevention programs.

Rabies virus entry at the neuromuscular junction in nerve-muscle cocultures.

Early events in rabies virus entry into neurons were investigated in chick spinal cord-muscle cocultures. Rabies virus (CVS strain) was adsorbed to the surface of cells in the cold. At times up to 10 min of warming to 37 degrees C, virus was most intensely localized to dense swellings on the myotube surface. Texas Red-labeled alpha-bungarotoxin, which binds to nicotinic acetylcholine receptors, colocalized precisely with virus at the densities identifying these regions as neuromuscular junctions. Rabies virus also colocalized in the junctions with synapsin I, a marker for synaptic vesicles. The endosome tracers Lucifer Yellow, Texan Red-dextran, and rhodamine-wheat germ agglutinin were added to the cultures at the end of the virus adsorption period and the cultures were warmed. At 10 min, rabies virus and tracers colocalized at neuromuscular junctions and nerve terminals. At 30 min, rabies virus and tracers showed more intense fluorescence over nerve fibers and nerve cell bodies. At 60 min, nerve terminals, nerve fibers, and nerve cell bodies showed intense fluorescence and colocalization for rabies virus and tracers. LysoTracker Red, a marker for acidic compartments, colocalized with rabies virus at nerve-muscle contacts. These findings show that in nerve-muscle cocultures, the neuromuscular junction is the major site of entry into neurons. Colocalization of virus and endosome tracers within nerve terminals indicates that virus resides in an early endosome compartment, some of which are acidified. The progressive increase of virus and tracers in nerve fibers and nerve cell bodies over time is consistent with retrograde transport of endocytosed virus from the motor nerve terminal.

Nicotine binding to native and substituted peptides comprising residues 188-207 of nicotinic acetylcholine receptor alpha1, alpha2, alpha3, alpha4, alpha5, and alpha7 subunits.

Structural determinants of L-[(3)H]nicotine binding to synthetic peptides comprising residues 188-207 of nicotinic acetylcholine receptor alpha subunits were invesitigated by equilibrium binding analysis. Two binding components were detected, one of low affinity (K(d) approximately 1.5 microM) that did not differ significantly among peptides and another of high affinity. The high affinity binding component was higher for the neuronal peptides (K(d) = 14-23 nM) than the muscle alpha1 peptides (K(d) = 52 nM). The following nonconservative substitutions in the alpha4 peptide resulted in a significant decrease in nicotine affinity for the peptide: Y190A, Y190D, C192G, E195A, E195-, P199A, P199-, and Y203A. Substitution of alpha4P199 with a leucine which is present in the alpha1 sequence decreased the affinity of the alpha4 peptide for nicotine and substitution of alpha1L199 with a proline (alpha4) or a glutamine (alpha3) increased the affinity of the alpha1 peptide. It is concluded that aromatic residues contribute to the binding site for nicotine on the alpha4 subunit and that the residue present at position 199 partly determines differences in nicotine affinity for different alpha subunits.

Potential significance of airborne fiber dimensions measured in the U.S. refractory ceramic fiber manufacturing industry.

BACKGROUND: To determine dimensions of airborne fibers in the U.S. refractory ceramic fiber (RCF) manufacturing industry, fibers collected through personal air sampling for employees at RCF manufacturing and processing operations have been measured. METHODS: Data were derived from transmission electron microscopy analyses of 118 air samples collected over a 20-year period. RESULTS: Characteristics of sized fibers include: diameter measurements of <60; 0.19 to 1.0 micron, m of which 75% are less than 0.6 micron and length ranging from < 0.6 to > 20 micron, with 68% of fibers between 2.4 and 20 micron. CONCLUSIONS: Exposures in RCF manufacturing include airborne fibers with dimensions (diameter < 0.1-0.4 micron, length < 10 micron) historically associated with biological effects in pleural tissues. Air sampling data and a review of studies relating fiber size to pleural effects in animals and humans support the belief that information on fiber dimensions is essential for studies with synthetic vitreous fibers.

Waglerin-1 selectively blocks the epsilon form of the muscle nicotinic acetylcholine receptor.

Neonatal mice resist the lethal effect of Waglerin-1. Because Waglerin-1 blocks the nicotinic acetylcholine receptor of mature end-plates, the appearance of lethality may result from the epsilon- for gamma-subunit substitution. In support of this hypothesis, adult knockout (KO) mice lacking the gene coding for the epsilon-subunit resist the lethal effect of Waglerin-1. In contrast, heterozygous litter mates respond to Waglerin-1 like adult wild-type mice. In vitro application of 1 microM Waglerin-1 inhibited spontaneous miniature end-plate potentials and evoked end-plate potentials of adult wild-type and heterozygous KO mice. Both miniature end-plate potentials and end-plate potentials of neonatal wild-type and adult homozygous KO mice resisted Waglerin-1. Waglerin-1 decreased the end-plate response of adult wild-type mice to iontophoretically applied acetylcholine (ACh) with an IC50 value of 50 nM; 1 microM Waglerin-1 decreased the ACh response to 4 +/- 1% of control for adult heterozygous KO mice. In contrast, 1 microM Waglerin-1 decreased the ACh response to 73 +/- 2% of control for wild-type mice less than 11 days old and had no effect on the ACh response of adult homozygous KO mice. Between 11 and 12 days after birth, the suppressant effect of Waglerin-1 on wild-type end-plate responses to ACh dramatically increased. Waglerin-1 reduced binding of alpha-bungarotoxin to end-plates of adult but not neonatal wild-type mice. These data demonstrate that Waglerin-1 selectively blocks the mouse muscle nicotinic acetylcholine receptor containing the epsilon-subunit.

Rabies virus entry into endosomes in IMR-32 human neuroblastoma cells.

Early events in rabies virus entry into cultured IMR-32 human neuroblastoma cells were investigated. After adsorption of rabies virus to the cell surface in the cold and warming to 37 degrees C in the presence of tracers for early endosomes, rabies virus and tracers were localized by immunofluorescence microscopy. After 5 min, rabies virus colocalized with Lucifer Yellow, Texas Red-dextran, rhodamine-wheat germ agglutinin, and transferrin receptor in puncta in the cell body, neurites, and nerve terminals. Rabies virus did not colocalize with lysosomal glycoprotein. An acidotropic probe revealed that some of the virus-containing puncta were acidified. Rabies virus also colocalized with synapsin I, a synaptic vesicle marker, in swellings along processes, indicating some virus enters nerve terminals. Electron microscopy revealed the presence of rabies virus within irregular membrane compartments located near the cell surface in the cell body and neurites. The membrane of the virus particle was often continuous with that of the vacuole. It is concluded that rabies virus enters IMR-32 neuroblastoma cells by adsorptive endocytosis and that, shortly after entry, rabies virus is located within and fuses with acidic endosomes.

Amino acids within residues 181-200 of the nicotinic acetylcholine receptor alpha1 subunit involved in nicotine binding.

Structural determinants of L-[3H]nicotine binding to the sequence flanking Cys 192 and Cys 193 of the Torpedo acetylcholine receptor alpha1 subunit were investigated using synthetic peptides (residues 181-200) and fusion proteins (residues 166-211). Nicotine binding at a single concentration (30 nM) was compared with 71 peptides and fusion proteins in which individual amino acids at positions 181-200 were substituted. Substitution of Lys 185, Tyr 190, Cys 192, Cys 193, Thr 196, and Tyr 198 resulted in the greatest reduction in nicotine binding. Equilibrium binding of [3H]nicotine to peptide 181-200 revealed a binding component with an apparent KD of 1.2 microM. Substitution of Lys 185 (with Glu), His 186, Tyr 190, Cys 192, Cys 193, and Tyr 198 resulted in a significant reduction in affinity. Affinity was not affected significantly by substitution of Arg 182, Lys 185 (with Gly or Arg), Val 188, Tyr 189, Pro 194, Asp 195, Thr 196, and Asp 200. It is concluded that Lys 185, His 186, Tyr 190, Cys 192, Cys 193, and Tyr 198 play the greatest role in nicotine binding to residues 181-200 of the alpha1 subunit. Previous studies have implicated Tyr 190, Cys 192, Cys 193, and Tyr 198 in agonist binding to the acetylcholine receptor. These results confirm a role for these residues and also demonstrate a function for Lys 185 and His 186 in nicotine binding.

Rabies virus entry into cultured rat hippocampal neurons.

Rabies virus entry into cultured hippocampal neurons was investigated by immunofluorescence and electron microscopy. Hippocampal neurons were susceptible to rabies virus infection and became filled with viral antigen 1 day after infection. Infection was inhibited by the lysosomotropic agents chloroquine and ammonium chloride. To study entry, neurons were adsorbed with rabies virus at 4 degrees C and warmed to 37 degrees C for short periods of time prior to fixation and localization of viral antigen by immunofluorescence microscopy By 5 min at 37 degrees C, viral antigen was localized to puncta in the cell body and dendrites and in synapses along dendrites. Little viral antigen was present in axons. Cells adsorbed with rabies virus were incubated with tracers for early endosomes. The endocytic tracers or markers Lucifer Yellow, transferrin receptor, dextran, and wheat germ agglutinin co-localized with rabies virus, indicating that rabies virus enters an endosome compartment shortly after uptake. Rabies virus also co-localized with LysoTracker Red, an acidotropic probe, indicating that some of the virus-containing endosomes are acidified. Rabies virus also co-localized with synapsin I, a synaptic vesicle marker, in nerve terminals but did not co-localize with lysosomal glycoprotein. By electron microscopy, after adsorption of virus and warming for 10 min, virus particles were present in coated pits, coated vesicles, and vacuolar membrane compartments in processes and axon terminals. It is concluded that rabies virus enters the somatodendritic domain and axon terminals of cultured hippocampal neurons by adsorptive endocytosis and is located in endosomes shortly after uptake.

Rabies virus infection of IMR-32 human neuroblastoma cells and effect of neurochemical and other agents.

IMR-32 human neuroblastoma cells are a continuous nerve cell line expressing neuronal nicotinic acetylcholine receptors. These cells were found to be susceptible to infection by rabies virus (CVS strain). After infection, viral antigen accumulated in the cell body in puncta and larger masses and spread out into the processes until at 3-4 days the entire cell was filled with antigen and lysed. A variety of chemical agents including cholinergic agonists and antagonists were tested for ability to inhibit infection of IMR-32 cells in a fluorescent focus assay. Agents found to inhibit infection were antibodies against the viral glycoprotein, gangliosides, a synthetic peptide of the neurotoxin-binding site of Torpedo acetylcholine receptor alpha1 subunit, alpha-bungarotoxin, and lysosomotropic agents. All other agents tested including other cholinergic ligands and synthetic peptides were not effective. Except for lysosomotropic agents, the agents which inhibited infection also inhibited attachment of virus to the cell surface. These results indicate that IMR-32 cells are a useful model in studying the interaction of a neurotropic virus with human neurons. The ability of alpha-bungarotoxin to inhibit infection suggests that neuronal alpha-bungarotoxin-binding receptors might serve as central nervous system receptors for rabies virus.

Rabies virus binding to the nicotinic acetylcholine receptor alpha subunit demonstrated by virus overlay protein binding assay.

A virus overlay protein binding assay was used to study binding of 125I-labelled rabies virus to the acetylcholine receptor (AChR) from Torpedo californica electric organ membranes. After gel electrophoresis of electric organ membranes and transfer of proteins to nitrocellulose, 125I-labelled alpha-bungarotoxin, a curaremimetic neurotoxin, bound to a 40 kDa band and 125I-labelled rabies virus bound to 51 kDa and 40 kDa bands. Binding of rabies virus to the 40 kDa band was inhibited by unlabelled alpha-bungarotoxin. In blots of affinity-purified AChR, labelled virus bound to the 40 kDa alpha subunit and was competed by alpha-bungarotoxin. Based on binding of rabies virus to the alpha subunit and the ability of alpha-bungarotoxin to compete for binding, rabies virus appears to bind to the neurotoxin-binding site of the nicotinic AChR alpha subunit.