Search

CXC chemokine receptor 2 (CXCR2) is a key receptor in the chemotaxis of neutrophils to sites of inflammation. The studies reported here describe the pharmacological characterization of danirixin, a CXCR2 antagonist in the diaryl urea chemical class. Danirixin has high affinity for CXCR2, with a negative log of the 50% inhibitory concentration (pIC 50 ) of 7.9 for binding to Chinese hamster ovary cell (CHO)-expressed human CXCR2, and 78-fold selectivity over binding to CHO-expressed CXCR1. Danirixin is a competitive antagonist against CXCL8 in Ca 2+ -mobilization assays, with a K B (the concentration of antagonist that binds 50% of the receptor population) of 6.5 nM and antagonist potency (pA 2 ) of 8.44, and is fully reversible in washout experiments over 180 minutes. In rat and human whole-blood studies assessing neutrophil activation by surface CD11b expression following CXCL2 (rat) or CXCL1 (human) challenge, danirixin blocks the CD11b upregulation with pIC 50 s of 6.05 and 6.3, respectively. Danirixin dosed orally also blocked the influx of neutrophils into the lung in vivo in rats following aerosol lipopolysaccharide or ozone challenge, with median effective doses (ED 50 s) of 1.4 and 16 mg/kg respectively. Thus, danirixin would be expected to block chemotaxis in disease states in which neutrophils are increased in response to inflammation, such as pulmonary diseases. In comparison with navarixin, a CXCR2 antagonist from a different chemical class, the binding characterization of danirixin is distinct. These observations may offer insight into the previously observed clinical differences in induction of neutropenia between these compounds., (Copyright © 2017 by The Author(s).)

Six cytogenetics laboratories joined in a collaborative study of rat chromosome aberrations to measure interlaboratory variation in results of standardized procedures and to devise methods to minimize interlaboratory differences. A preliminary workshop was held to resolve scoring differences, to develop a joint protocol and common glossary, and to reach agreement on uniform reporting methods. Osborne-Mendel rats from a common source were sent to each laboratory. Triethylenemelamine (TEM) was used at doses of 100, 200, 300 and 400 microgram/kg to induce clastogenic effects; results were compared to those of a control group of untreated animals. Femoral bone marrow cells were evaluated with the scorers unaware of the dosage. Final results showed highly significant dose effects with the test compound, and most laboratories showed a similar pattern of dose response. This study illustrates that rat cytogenetic analysis can be an effective test system for evaluation of a compound for mutagenic potential, particularly for the index reflecting the proportion of abnormal cells, but that results should be interpreted cautiously when arbitrary values are assigned for some of the categories being analyzed, as was done in this project for the category of severely damaged cells.

Cytogenetics data resulting from one laboratory in a multiple-laboratory study were analyzed to determine if 5 well-trained scorers produced significantly different results using metaphase scoring procedures. Although the scorers reached the same general conclusion, results show that scorer differences exists (p less than 0.01). Consequently, all participating scorers in a laboratory should be used equally in all treatment groups and the results should be analyzed accordingly to account for scorer variations. This is easily accomplished in controlled prospective experiments; however, it is often difficult in retrospective studies using data which exists. In such studies, every effort should be made to analyze and interpret the data so that scorer differences are taken into account. For severely damaged cells not only were there scorer differences but the difference were greater at higher doses. This phenomenon may be related to the operational definition of a severely damaged cell, since scorers who identify more damage than other scorers would logically tend to classify more cells as severely damaged both overall and at lower doses.

Low-back pain is a major occupational health problem. Risk factors predisposing to the development of low-back pain are discussed. These include individual risk factors such as age, sex, anthropometry, musculoskeletal abnormalities, muscle strength and physical fitness, psychological factors, and previous attacks of low-back pain and workplace factors such as heavy work, lifting, bending, and slipping. Various programs for prevention are evaluated. These include selection of workers, education and training regarding lifting methods, design of lifting jobs, and fitness training. Limitations of the various studies of these programs are discussed. Preemployment strength testing and ergonomic job design together appear to offer the greatest promise.

In a large multilaboratory cytogenetic study of interlaboratory variations using 4 dose levels of triethylenemelamine and a control, a severely damaged cell was operationally defined as a cell which contained at least 10 aberrations of any type. A review of this study suggested that the use of this definition introduced a bias in the measurement and interpretation of results for the other cytogenetic categories studied. As a result, the original severely damaged cells were carefully reanalyzed to investigate the characteristics of this bias and to seek procedures to minimize or eliminate it. Results characterize this bias and demonstrate that when a severely damaged cell is defined as one containing at least 20 aberrations and those aberrations in the remaining non-severely damaged cells are classified by specific type, the bias is significantly reduced and chromosome analysis can be improved as a test system.

Four groups of 4 domestic pigs were exposed to 0, 20, 100, and 500 ppm benzene vapor 6 h/d, 5 d/wk, for 3 wk. Two groups of 10 rats were exposed to 0 and 500 ppm: the exposed rats for 6 h/d, 5 d/wk, for 3 wk, the nonexposed rats for 6 h/d, 5 d. Rats were killed within 72 h after exposure; values for pigs were obtained shortly after exposure and on final examination at 4-16 wk after exposure. Pigs were evaluated for changes in white and red blood cell counts, hemoglobin level, lymphocyte count, proportion of E-rosette-forming lymphocytes, myeloid-erythroid ratio, and presence of multinucleate erythroblasts. With the exception of the E-rosette test, the same parameters were measured in the rat. Statistically significant (p less than 0.05) depression of white cell counts, total lymphocytes, and proportion of E-rosette-forming lymphocytes was observed in pigs exposed to 500 ppm; recovery to values not significantly different from control values was observed on final examination. Fewer postexposure effects were seen at 100 ppm, and there were no significant differences from control values at 20 ppm. Both pigs and rats exposed to 500 ppm showed a significant decrease in the mean myeloid-erythroid ratio within 72 h. These values returned to normal in the pig 4-16 wk after exposure; recovery in the rat was not evaluated. An increased number of bone marrow erythroblasts with more than 2 nuclei was found on final examination of pigs exposed to 500 and 100 ppm, but the difference was significant only at the 100-ppm level because of the variability at the higher level. A significant increase (p less than 0.004) in multinucleate cells was seen in the rats exposed to 500 ppm.

As a result of recent interest in the carcinogenic effect of dioxane, a mortality study was conducted on employees exposed to this compound at a major chemical company plant. Standard follow-up techniques were used to ascertain the vital status of a total of 165 employees ever exposed to dioxane since 1954. Observed deaths from overall cancer were not significantly different from the expected number of deaths. The observations were based on small numbers of deaths of employees who were apparently exposed at low levels and for relatively short exposures.

Industrial epidemiology is a specialized discipline concerned with the study of disease occurrence in specific subgroups of the general population, i.e., of relatively healthy members of the work force for whom adequate records are available. Although the ultimate purpose of industrial epidemiology--the prevention of disease--is a logical extension of programs of industrial medicine and occupational and community health, epidemiologic methods must draw on interdisciplinary skills. The existence of centralized records kept in the course of business may make it easier to collect information about industrial populations than to gather data relative to other population subgroups. Many deficiencies in epidemiologic studies of worker groups, however, can be related to poor methods of data-gathering, inadequate record keeping, and an incomplete data base. Sources of information for epidemiologic studies of worker groups may include personnel and medical records, government reports, insurance files, production records, industrial hygiene measurements, surveys and questionnaires, and an organized follow-up program. In some cases, the ready availability of multiple sources of information may lead to differential information bias, and this should be avoided.

This report presents cytogenetic findings from a group of 209 workers employed for up to 28 years in the manufacture of vinyl chloride monomer at the Texas Division of Dow Chemical U.S.A. Cytogenetic evaluation results from this group were compared to results found in examination of individuals being considered for employment. Statistical analyses were performed on a group basis for chromatid aberrations, chromosome aberrations and proportion of abnormal cells; no statistical difference of significance was found between the two groups. Comparison of these results with reported studies suggests that the level of cytogenetic aberrations in vinyl chloride workers is probably related to the length and level of exposure, and that risk of adverse genetic effect can be avoided in controlled, minimal-exposure environments.