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At least 127 records · Page 7Linked to original sources
PubMed1986

Induction of DNA repair in rat spermatocytes and hepatocytes by 1,2-dibromoethane: the role of glutathione conjugation.

1,2-Dibromoethane (EDB) is a widely used industrial chemical, and a well-known mutagen and carcinogen. EDB is biotransformed either by cytochrome P450-dependent oxidation, leading to the formation of bromoacetaldehyde, or by enzyme-catalyzed conjugation with glutathione, giving rise to reactive half-sulfur mustard compounds and their derivatives. In vitro mutagenicity and DNA binding studies suggest that the latter pathway is the primary source of genotoxic metabolites from EDB. In this study we have examined EDB-induced unscheduled DNA synthesis (UDS) in F-344 rat pachytene spermatocytes and hepatocytes. EDB (10-100 microM) induced UDS in both hepatocytes and spermatocytes in vitro. In contrast, only hepatocytes exhibited UDS when isolated from rats given EDB (100 mg/kg) 2 h earlier, and only then if the compound was given i.p. rather than orally. Preincubation of hepatocytes or spermatocytes with inhibitors of cytochrome P450-mediated oxidation had no effect on EDB induction of UDS in vitro. In contrast, depletion of cellular glutathione strongly inhibited EDB-induced UDS in both cell types in vitro. Treatment of rats with 175 mg metyrapone/kg (an inhibitor of hepatic mixed-function oxidases) 1 h prior to administration of EDB in vivo had no effect on EDB-induced UDS in hepatocytes, but led to a positive UDS response to EDB in spermatocytes in vivo. This suggests that the mixed-function oxidase pathway of metabolism is the primary route of clearance of EDB and that inhibition of cytochrome P450-mediated oxidation led to a more extensive tissue distribution of the parent compound. These data also suggest that the pathway which produces genotoxic metabolites from EDB in hepatocytes and spermatocytes, in vitro and in vivo, involves the conjugation of EDB to glutathione and its subsequent metabolism.

Animals↗
PubMed1975

Lung cancer mortality in World War I veterans with mustard-gas injury: 1919-1965.

A study of the mortality experience of three samples of World War I veterans totaling 7,151 U.S. white males was extended from 1956 through 1965 to learn whether a single exposure to mustard gas with respiratory injury was associated with increased risk of lung cancer in later life. Rosters of men born between 1889 and 1893 [2,718 exposed to mustard gas, 1,855 hospitalized with pneumonia in 1918, and 2,578 with wounds of the extremities (controls)] were traced via the Veterans Administration's death records. The 4,136 deaths reported were 95% of that expected. The conclusions of the original study were not altered by the additional 10 years of follow-up. Observed deaths from lung cancer numbered 69, or 2.5% for the mustard-gas group as compared to 33, or 1.8%, for the pneumonia group and 50, or 1.9%, for the controls. The risk of death from lung cancer among men gassed relative to that for the controls was estimated as 1.3, with 95% confidence limits of 0.9-1.9. These figures failed to make a strong case for a carcinogenic effect, apparently because a suffcient dose of mustard gas was not received,

Adult↗
PubMed1977

Acute corneal injury by mustard gas.

Described is an acute ocular injury caused by mustard gas. The clinical course was similar to what has been established by laboratory research. Some of the histopathologic events have been discussed in theory since no tissue sample from this reported case was available for examination.

Acute Disease↗
PubMed1990

Full-thickness human skin explants for testing the toxicity of topically applied chemicals.

This report describes a model organ-culture system for testing the toxicity of chemical substances that are topically applied to human skin. In this system, the viable keratinocytes in the full-thickness skin explants are protected by the same keratinized layer as skin remaining on the donor, and toxicity can be assessed microscopically and/or biochemically. The human skin specimens were discards from a variety of surgical procedures. They were cut into full-thickness 1.0-cm2 explants, and briefly exposed to the military vesicant sulfur mustard (SM), which was used as a model toxicant. The explants were then organ cultured in small Petri dishes for 24 h at 36 degrees C. In the 0.03-1.0% dosage range, a straight-line dose-response relationship occurred between the concentration of SM applied and the number of paranuclear vacuoles seen histologically in the epidermis. Within the same SM dosage range, there was also a proportional decrease in 14C-leucine incorporation by the explants. Thus, the number of paranuclear vacuoles reflected decreases in protein synthesis by the injured epidermal cells. The epidermis of full-thickness untreated (control) human skin explants usually remained viable for 7 d when stored at 4 degrees C in culture medium. During storage, a relatively small number of paranuclear vacuoles developed within the epidermis, but the explants were still quite satisfactory for testing SM toxicity. Incubation (for 4 or 24 h at 36 degrees C) of such control skin explants reduced (often by 50%) the small number of paranuclear vacuoles produced during 4-7 d of storage. This reduction was probably caused by autolysis of many of the vacuolated cells. Two types of paranuclear vacuoles could be identified by both light and electron microscopy: a storage type and a toxicant type. The storage type seemed to be caused by autolysis of cell components. The toxicant type seemed to be caused by an invagination of the plasma membrane. Only toxicant-type vacuoles increased appreciably in number when skin explants were exposed to mustard, and to other toxicants.

Administration, Topical↗
PubMed1988

Somatic mutation in peripheral lymphocytes of former workers at the Okunojima poison gas factory.

The former workers at the Okunojima poison gas factory comprise a high risk group for malignant tumors such as respiratory tract cancer. Demonstration of injury to somatic cell genes in this group may provide important data for evaluating the association between mustard gas and malignant tumors. So we measured the frequency of T lymphocytes lacking the hypoxanthine guanine phosphoribosyl transferase (HGPRT) activity, by cloning with interleukin 2 (IL2). In this study, we performed cloning of T lymphocytes lacking the HGPRT activity using recombinant IL2 (rIL2) and observed an increased frequency of somatic mutation in poison gas workers who had had more chances to be exposed to mustard gas and those who had worked for a longer period. This result suggested that inhalation of small amounts of mustard gas damaged somatic cell genes, resulting in carcinogenesis.

Aged↗
PubMed1981

Cancer of the larynx and other occupational hazards of mustard gas workers.

An attempt was made to tract 511 men and women who manufactured mustard gas during the 1939--1945 war. Despite limitations in the identifying data available, 428 (84%) were traced to the end of 1974. The numbers of deaths from all neoplasms combined (45) and from all other causes (136) were slightly greater than those expected from national death rates, but not significantly so. Two deaths were attributed to carcinoma of the larynx and one to carcinoma of the trachea, compared with an expected number of 0.40 (P less than 0.02). Carcinoma of the larynx was also mentioned on the death certificate of another man. Seven subjects are known to have developed cancer of the larynx, compared with 0.75 expected (P less than 0.001). Excess mortality was also observed from cancer of the lung, pneumonia and accidents, but the excesses were small and difficult to interpret.

Adult↗
PubMed1986

Early cancer and related lesions in the bronchial epithelium in former workers of mustard gas factory.

The bronchial epithelium in stepwise transverse sections was examined histologically in 66 male autopsy cases, composed of the groups of 19 mustard gas (MG) ex-workers with lung cancer, 17 MG ex-workers with non-lung cancer, 10 non-MG lung cancer cases, and 20 non-MG non-lung cancer cases. Foci of moderate or severe atypical cellular lesion or dysplasia, or of carcinoma in situ (CIS) in total slides of each group, were counted as 146 in 3,485, 72 in 2,226, 70 in 3,797, and 18 in 4,611, respectively. The relative frequency of moderate or severe dysplasia and CIS in MG exposed non-lung cancer cases resembled that found in lung cancer cases of both MG and non-MG exposed. Seven CIS lesions were detected from among all MG-exposed cases and one CIS was found in a non-MG lung cancer case. Six out of eight CIS examples were adjoined by dysplasia. A multi-variate analysis revealed a significant correlation between the incidence of atypical lesions and MG exposure, though the incidence of atypical lesions was also influenced significantly by age, smoking, and chronic bronchitis. The incidence of atypical lesions was significantly higher in cases of squamous cell lung cancer than those of other histological types, particularly small cell cancer.

Adenocarcinoma↗
PubMed1987

An altered lectin binding to mucus glycoprotein in goblet cells of human tracheobronchial epithelium among former mustard-gas workers.

Lectins, which are well known to have an ability to bind with specific carbohydrate residues of glycoprotein, have been used to examine cellular changes associated with malignant transformation. For the analysis of mucus glycoprotein of goblet cells in the tracheobronchial epithelium, 192 paraffin-embedded sections from 54 autopsy cases including the cases with a history of mustard-gas (MG) exposure were stained with seven plant lectins using PAP method. PNA binding with no neuraminidase treatment as well as BSA-1 binding was observed most frequently in MG-exposed lung cancer cases. The proportion of cases positive for SBA binding in MG-exposed and/or lung cancer cases had a statistical difference from non-MG-exposed non-lung cancer cases. These observations may indicate a large heterogeneity in oligosaccharide chains of mucus glycoprotein and suggest its incomplete or abnormal synthesis, which is most likely to be due to previous exposure to carcinogen, such as MG.

Adult↗
PubMed1988

Cancers of the respiratory tract in mustard gas workers.

In a study of a cohort of 2498 men and 1032 women employed in the manufacture of mustard gas in Cheshire during the second world war 3354 (95%) individuals were successfully traced for mortality to the end of 1984. Large and highly significant excesses were observed as compared with national death rates for deaths from cancer of the larynx (11 deaths observed, 4.04 expected, p = 0.003), pharynx (15 observed, 2.73 expected, p less than 0.001), and all other buccal cavity and upper respiratory sites combined (lip, tongue, salivary gland, mouth, nose) (12 observed, 4.29 expected, p = 0.002). For lung cancer, a highly significant but more moderate excess was observed (200 observed, 138.39 expected, p less than 0.001). Significant excesses were also observed for deaths from acute and chronic non-malignant respiratory disease (131 observed, 91.87 expected and 185 observed, 116.31 expected, respectively). The risks for cancers of the pharynx and lung were significantly related to duration of employment. None of these results is substantially altered when expected numbers are calculated from Cheshire urban areas rather than national rates, although the relative risks for lung cancer and non-malignant respiratory disease are substantially reduced if rates for Merseyside, the nearest large conurbation, are used. The results provide strong evidence that exposure to mustard gas can cause cancers of the upper respiratory tract and some evidence that it can cause lung cancer and non-malignant respiratory disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Cohort Studies↗
PubMed1988

Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug development.

We describe events that led to successful testing of melphalan, one of the nitrogen mustard compounds, in children with newly diagnosed, poor-risk rhabdomyosarcoma (RMS). Preclinical studies with xenografts of human RMS, growing in the flanks of immune-deprived mice, had indicated superior oncolytic activity by melphalan compared with other agents commonly used to treat this tumor. However, in a conventional phase II trial, melphalan failed to produce partial responses in 12 of 13 heavily pretreated patients with recurrent tumors. Subsequent comparison of the drug's pharmacokinetics in mice and patients indicated that its poor clinical performance was not the result of interspecies differences in drug disposition. Therefore, we elected to retest melphalan in untreated patients, before they were enrolled in a phase III study. Of 13 children who received the drug for 6 weeks, ten had partial responses, confirming the significant antitumor activity seen in the xenograft system. These findings illustrate the inherent limitations of phase II drug trials in previously treated patients and suggest a useful paradigm for the development of antineoplastic drugs.

Adolescent↗
PubMedDate not supplied

Ultrastructural correlates of the protection afforded by niacinamide against sulfur mustard-induced cytotoxicity of human lymphocytes in vitro.

Sulfur mustard (HD) has been shown to cause a concentration-dependent decrease in viability of human lymphocytes in vitro as measured by dye exclusion; this decrease is preventable by inhibitors of poly(adenosine diphosphatase ribose) polymerase such as niacinamide. The present study investigates the morphologic correlates of the protection afforded by niacinamide through scanning and transmission electron microscopic analysis of human lymphocytes incubated in the presence or absence of 10(3) M niacinamide for 24 h at 37 degrees C and exposed in vitro to 10(-3) M HD. Lymphocytes exposed to HD alone demonstrated 30% to 40% viability and loss of microvilli, large cytoplasmic vacuoles, extensive blebbing of the perinuclear envelope, loss of cytoplasmic organelles, condensation of nuclear chromatin, and multiple perforations of the plasmalemma. In the presence of niacinamide HD-treated lymphocytes had a viability of 87% and, except for blunting of the microvilli, essentially normal ultrastructure. Although the sequence of observed ultrastructural changes was not established, results of this morphologic study suggest that, in addition to the prevention of plasmalemmal defects and dye infusion, the mechanism of niacinamide protection appears to include preservation of the morphologic and functional integrity of cellular organelles.

Cell Membrane↗
PubMed1979

[Glycoproteins in the blood of dogs after administration of beta, beta'-dichlorodiethylsulphide].

The protein spectrum of the dog blood serum was studied after the administration of beta,beta'-dichlorodiethylsulphide. Paper electrophoresis was used for this purpose. Fuchsin-positive substances were determined after previous oxidation with periodic acid, which made it possible to reveal that the glycoproteins detected in this way were represented in serum proteins mostly in the fraction of alpha 2 globulins. After beta, beta'-dichlorodiethylsulphide intoxication the values of these glycoproteins significantly increase. The rise is statistically significant 24 hours after administration (average rise by 141%) and within the time scope it reaches its maximum in the terminal stage (rise by 210%).

Animals↗
PubMed2002

The Department of Defense's Persian Gulf War registry year 2000: an examination of veterans' health status.

This study examined the health status of 46,633 Persian Gulf War theater veterans who received full clinical evaluations in the Department of Defense's Gulf War Comprehensive Clinical Evaluation Program (CCEP) as of spring 2000. Clinical data analyzed included demographic information, 15 health symptoms, 19 wartime exposures, and primary and secondary physician-determined medical diagnoses based on International Classification of Diseases, 9th Revision, Clinical Modification, criteria. Findings and discussions are arrayed, by gender, with comparative 1996 data from the Department of Veterans Affairs Health Examination Registry Program. Many veterans reported fewer physical symptoms now than during the time of the Gulf War. Many endorsed symptoms of joint pain, fatigue, weight change, and sleep disturbances. Most reported exposure to diesel fuel and the nerve agent antidote pyridostigmine bromide; far fewer female veterans reported combat involvement. The most frequent primary or secondary diagnosed medical conditions were musculoskeletal/connective tissue diseases, ill-defined conditions, and mental disorders. Female veterans were diagnosed more frequently with mental disorders. Symptom endorsement and diagnosis rates between the CCEP and the Department of Veterans Affairs registry were not dissimilar. Overall, the self-reported general health of veterans with symptoms was much poorer (females had higher rates of "fair to poor" health than males) than that of veterans with no reported symptoms.

Adult↗