High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients.

The physiological role of phosphodiesterase (PDE)11 is unknown and its biochemical characteristics are poorly understood. We have expressed human His-tagged PDE11A4 and purified the enzyme to apparent homogeneity. PDE11A4 displays K(m) values of 0.97 microM for cGMP and 2.4 microM for cAMP, and maximal velocities were 4- to 10-fold higher for cAMP than for cGMP. Given the homology between PDE11 and PDE5, we have compared the biochemical potencies of tadalafil (Cialis, Lilly-ICOS), vardenafil (Levitra, Bayer-GSK), and sildenafil (Viagra, Pfizer Inc.) for PDE11A4 and PDE5A1. PDE5A1/PDE11A4 selectivities are 40-, 9300-, and 1000-fold for tadalafil, vardenafil, and sildenafil, respectively. This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients.

Cancer mortality patterns among hairdressers and barbers in 24 US states, 1984 to 1995.

We evaluated cancer mortality patterns among hairdressers and barbers, according to occupation, coded on 7.2 million death certificates in 24 states from 1984 to 1995. Of the 38,721 deaths among white and black hairdressers and barbers of both sexes, 9495 were from all malignant neoplasms. Mortality odds ratios were significantly elevated for all malignant neoplasms, lung cancer, and all lymphatic and hemopoietic cancers among black and white female hairdressers. White female hairdressers had significant excess mortality from cancers of the stomach, colon, pancreas, breast, and bladder and from non-Hodgkin's lymphoma and lymphoid leukemia; mortality from these cancers was also elevated among black female hairdressers. White male hairdressers had significantly elevated mortality from non-melanoma skin cancer and non-Hodgkin's lymphoma. Mortality from all malignant neoplasms, although significantly elevated among both white and black female hairdressers, was significantly below the null for white male hairdressers. Black and white male barbers had significantly elevated mortality from stomach and pharyngeal cancer, respectively. A significant deficit in mortality from all neoplasms and cancers of the pancreas, lung, and prostate was noted for white male barbers. This large study of cancer mortality among hairdressers and barbers showed some differences in mortality patterns by gender and race. Further studies are required to determine if specific occupational exposures may explain some of the elevated cancer rates.

Characterization of the binding site for a novel class of noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonists.

The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor is an ionotropic glutamate receptor that mediates fast excitatory synaptic transmission throughout the central nervous system. In addition to the glutamate binding site, allosteric modulatory sites on the receptor are inferred from the ability of synthetic compounds to affect channel function without interaction with the glutamate binding site. We have identified a novel class of potent, noncompetitive AMPA receptor antagonists typified by CP-465, 022 and CP-526,427. The latter compound was radiolabeled and used to elucidate the pharmacology of one allosteric modulatory site. [(3)H]CP-526,427 labels a single binding site in rat forebrain membranes with a K(d) value of 3.3 nM and a B(max) of 7.0 pmol/mg of protein. The [(3)H]CP-526,427 binding site does not seem to interact directly with the glutamate binding site but overlaps with that for another class of AMPA receptor antagonists, the 2,3-benzodiazepines. This binding site is distinct from that for the antagonist Evans blue and for several classes of compounds that modulate AMPA receptor desensitization. These results indicate the existence of at least two physically distinct allosteric sites on the AMPA receptor through which channel activity or desensitization is modulated.

Occupational medicine in Canada in 1996.

Occupational medicine in Canada presents many paradoxes and anomalies. This paper outlines the history, status, and current direction of occupational medicine in the country, with an emphasis on the unusual features of the Canadian experience.

Fatalities in the construction industry in the United States, 1992 and 1993.

To improve the estimates of occupational fatality rates for persons employed in the construction industry, several sources of data on the number of fatalities (the numerator) and the number of persons engaged in construction work (the denominator) were examined. Based on this examination, the Census of Fatal Occupational Injuries (CFOI), complied by the Bureau of Labor Statistics (BLS), was used to obtain numerators and the Current Population Survey, conducted by the Bureau of the census for the BLS, was used to obtain denominators. Adjustments were made in the numerator to include only occupations that were included in the denominator. Occupations were divided into two groups-those in the construction trades and those in other occupations within construction (e.g., clerical, sales). The analysis found fatality rates of 14.2 and 13.3 per 100,000 person-years, respectively, for 1992 and 1993, with wide variation in rates among the different trades. There were also major differences among the trades in the types of fatal injuries. Self-employed workers had much lower death rates overall than wage workers, but this is largely due to much lower proportions of high hazard trades among the self-employed. There have been wide variations in the occupational fatality rates reported for construction workers each year due to the differing methods of estimating the number of fatalities by the different data sources. This study provides a baseline of fatality rates using the best available current data. It compares the results from these data sources with those from other sources that have been used and discusses some of the problems inherent in the data from other sources. This study provides a significantly improved protocol for the calculation of fatality rates against which later rates can be compared consistently. Nevertheless, many deficiencies in the data sources used are identified. There remains ample room for continued improvement.

Why construction is different.

Construction differs markedly from many other types of manufacturing in that the nature of the work exacerbates the safety and health risks faced by workers. Even for workers who have health care coverage, the authors point out, the transient nature of the industry makes it difficult to trace an individual's exposure to health hazards.

Controlling injury hazards in construction.

Using information from the U.S. government and the scientific literature, the authors identify preventive strategies for specific types of injuries and categorize features of employers and workers that are associated with low injury rates. They conclude that safe working conditions are possible and are related to the attitudes of workers and management.

Controlling occupational health hazards in construction.

This chapter describes, evaluates, and illustrates generic and conventional industrial hygiene methods for controlling occupational hazards affecting construction workers. Case studies that identify and control exposure to asbestos, lead, crystalline silica, and additives to cement are discussed.

Perspectives on the future.

There is a growing trend toward new forms of labor-management cooperation, through negotiated agreements involving job-site safety and health, workers' compensation, and preventive medicine (see chapter 14). These developments are likely to change safety and health in the industry. At the same time, they provide opportunities for practitioners and researchers in occupational safety and health. If we can venture to express a professional wish, it would be to find answers to the following: How can we, as the professions concerned with the well being of workers, help preserve the characteristics of construction work that are positive while reducing the aspects of the industry's functioning that are so deleterious to health? How do we preserve the crafts with their fostering of self-esteem: through individual freedom on the job, team work, or empowerment? Meanwhile, how do we reduce the destructive patterns of work, not just on the work site, but also involving the pressures and lifestyle associated with intermittent and uncertain employment? The rewards for safety and health professionals in the construction industry are immediate and striking. Whether through the practice of safety and health or through research, results can be measured in short order. That is a professional benefit afforded by few other industries. To structure occupational safety and health programs for construction workers, the safety and health professions need to engage in the labor-management processes that are changing the industry. In construction, it is not enough to think about what needs to be done in individual workplaces. In construction, we must think industry-wide, because that is how workers are employed.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimating possible fraud in coal mine operators' samples of respirable dust.

Coal mine operators are required to sample miners' exposure to respirable dust on a regular basis. A method has been developed for screening all operator samples for detecting possible instances of fraud. This method relies on the occurrence of very low concentration (VLC = 0.1 mg/m3) samples more frequently than expected. The number of underground mine sections from which 50% or more of all samples for FY 1990 were VLC (VLC-50 sections) was compared to the expected number, which was estimated by assuming that the occurrence of VLC samples could be described with a binomial probability distribution. Out of 1983 continuous mining sections, there were 147 VLC-50 sections vs. 7.3 expected (O/E = 20.1). Moreover, these 147 sections occurred more frequently than expected among small as opposed to large mines. For sections using conventional mining methods, 19 of 175 were VLC-50 vs. 0.9 expected (O/E = 20.8). There was one VLC-50 longwall section vs. 0.003 expected. For 99 bituminous and anthracite hand-loading sections the observed number of VLC-50 sections was 65 vs. 78 expected (O/E = 0.8). It is suggested that, except for hand-loading and longwall sections, sampling programs should be investigated at mines with VLC-50 sections.

Transport injuries in small coal mines: an exploratory analysis.

Mine Safety and Health Administration (MSHA) surveillance data were analyzed to elucidate mine characteristics or injury characteristics that distinguished mines with high rates of transport-related injuries from mines with lower transport injury rates. The results showed that most high-rate mines are small, high-rate mines have a disproportionate number of injuries involving young and less experienced workers, and injuries in high-rate mines are proportionally more severe. Further analyses of the MSHA injury data showed that smaller mines have a greater share of fatal and permanently disabling injuries, whereas larger mines have a greater share of injuries involving no lost time. Based on these results, we explored two explanations for the small mine injury risk: (1) a suggestion that differences in injury reporting between large and small mines may contribute to an apparent small mine injury risk, and (2) identification of factors contributing to a true difference in transport-related injury risk between small and large mines. Whereas it was true that most high injury rate mines were small, most small mines were actually zero-rate, having reported employment but no injuries to MSHA. An analysis employing binomial probability theory showed that a substantial proportion of small mines reported zero injuries when it was statistically probable that injuries would have occurred. This indicated that small mines may underreport injuries relative to larger mines. The possibility that reporting bias affected the associations found in this study was explored by eliminating the least severe injuries from the data set and evaluating changes in associations. This "adjustment" for reporting bias did not change previously observed relationships. Finally, MSHA injury data were analyzed in concert with mining population data collected by the Bureau of Mines. With such denominator information, the results indicated a disproportionately high risk of injury among workers in their first year at a mine and indicated that higher injury risk in small mines might be explained by the fact that workers at small mines have substantially less experience than workers at large mines. An effect of age was not found in these analyses. These results suggest the potential importance of targeted training programs for newly hired miners. Results also point to the need to explore specific factors contributing to the small mine injury risk, and to the necessity for complete and accurate reporting of injury data.

Cancer mortality (1956-1985) among male employees of Atomic Energy of Canada Limited with respect to occupational exposure to external low-linear-energy-transfer ionizing radiation.

The mortality experience between 1956 and 1985 of 8977 males employed by Atomic Energy of Canada Limited is reported. A total of 4260 men, 47% of the cohort, were exposed to low doses of external ionizing radiation at low dose rates, with a mean cumulative equivalent dose of 52.1 mSv. For cancers as a whole the excess relative risk, based on 227 deaths, was 0.36% per 10 mSv (90% confidence bounds -0.46, 2.45). This is quite comparable to the corresponding estimate based on the atomic bomb survivors study. There was a positive association between radiation dose and death from leukemia (excluding chronic lymphatic leukemia) P = 0.058. However, this was based on only four deaths and hence cannot sensibly be compared to estimates based on high-dose studies. The present results suggest that, for cancer as a whole, risk estimates based on high-dose studies are unlikely to underestimate risks substantially for low-dose and low-dose-rate exposures.

From explosions to black lung: a history of efforts to control coal mine dust.

Highlights in the history of efforts to prevent occupational lung disease among coal miners in the United States are reviewed. The Federal Coal Mine Health and Safety Act of 1969 is summarized, and the sources and effects of its provisions to prevent coal workers' pneumoconiosis are examined. Descriptions follow of the identification of coal workers' pneumoconiosis as a disease, identification of respirable coal mine dust as its cause, and establishment and enforcement of an exposure limit. The development of prevention efforts focusing on surveillance of both exposure and outcome and of enforcement of dust control methods is examined.