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,

Chemical warfare agents: estimating oral reference doses.

Health risk assessments for sites contaminated with chemical warfare agents require a comparison of the potential levels of exposure with a characterization of the toxic potency of each chemical. For noncancer health effects, toxic potency is expressed in terms of Reference Doses (RfD). A RfD is a daily exposure level or dose (usually expressed in units of milligrams of chemical per kilogram body weight per day) for the human population, including sensitive subpopulations, that is likely to be without an appreciable risk of deleterious effects. A daily exposure at or below the RfD is not likely to be associated with health risks, but as the amount of chemical that an individual is exposed to increases above the RfD, the probability that an adverse effect will occur also increases. A RfD is derived by first examining the available human or animal toxicity data to identify a dose or exposure that corresponds to a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL). The NOAEL is the exposure level at which there are no statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Effects may be produced at this level, but they are not considered to be adverse if they do not result in functional impairment or pathological lesions that affect the performance of the whole organism or which reduce an organism's ability to cope with additional challenge. The LOAEL is the lowest exposure level at which there are statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. If only a LOAEL is identified by the toxicity data, a NOAEL is estimated by dividing the LOAEL by a factor no greater than 10. This extrapolation factor of 10 or less is termed the LOAEL-to-NOAEL Uncertainty Factor (UFL). The NOAEL is also adjusted by the application of other Uncertainty Factors, including (1) a UFH < or = 10 to ensure that the resulting RfD protects segments of the human population that may be more sensitive to the chemical than the average person; (2) a UFA < or = 10 to extrapolate from the experimental animal species to humans; (3) a UFS < or = 10 to extrapolate from an experimental subchronic exposure study to a potential chronic exposure; and (4) a UFD < or = 10 to ensure that the resulting RfD is protective for all possible adverse effects, particularly those that may not have been adequately evaluated in the available studies. A Modifying Factor (MF), based on a qualitative professional assessment of the data, may also be used to account for other factors (e.g., deficiencies in the critical study) that are not adequately covered by the standard Uncertainty Factors. 1. Agent HD (Sulfur Mustard). RfDe = 7 x 10(-6) mg kg-1 d-1. A LOAEL was identified in a two-generation reproductive toxicity study conducted in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), and extrapolation from a subchronic to chronic exposure (10). A LOAEL-to-NOAEL UF of 3, instead of the default value of 10, was used because the critical effect (stomach lesions) was considered to be "mild" in severity and may have been enhanced by the vehicle used (sesame oil in which sulfur mustard is fully soluble) and the route of administration (gavage), which is more likely to result in localized irritant effects. The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level.

[Lung parenchymatous changes following mustard gas poisoning]. / Lungenparenchymveränderungen nach Schwefellostvergiftung.

The authors present a late sequel of poisoning with dichlorodiethyl sulphide, also known as mustard gas or Ypérite, in a patient of 22 years of age--a late sequel not described in the literature to date. After the poisoning, a severe pulmonary fibrosis with pulmonary artery hypertension developed. A mediastinal emphysema that had so far been observed only during the acute intoxication phase, was evident even two years after the intoxication. Perivascular collections of air in the left lung communicating via the left hilus with the mediastinal air point to the existence of bronchus or lung parenchyma fistulas.

Concentrations of mustard gas [bis(2-chloroethyl)sulfide] in the tissues of a victim of a vesicant exposure.

An Iranian soldier died at a toxicological intensive care unit at Munich seven days after a vesicant exposure. At the autopsy the typical symptoms of mustard gas intoxication were found. The vesicant was detected qualitatively by gas chromatography-mass spectrometry (GC-MS) in the abdominal fat and quantified in the tissues and in the body fluids by the following method: (1) extraction by dichloromethane, (2) cleanup of the extracts by thin-layer chromatography (TLC) on silica plates, (3) extractive derivatization with gold-chloride, and (4) quantitative determination by electrothermal atomic absorption spectrometry (ET-AAS). The equal extracts, after heating, served for blanks. The following concentrations were found (milligrams of mustard gas/kilograms of tissue wet weight): brain 10.7, cerebrospinal fluid 1.9, liver 2.4, kidney 5.6; spleen 1.5, lung 0.8, muscle 3.9, fat 15.1, skin 8.4, skin with subcutaneous fatty tissue 11.8, liquid from a skin blister: below detection limit, blood 1.1, and urine: below detection limit.

[Early cancer and related changes in the bronchial epithelium of former mustard gas workers].

The bronchial epithelium taken in stepwise transverse sections was examined histologically in 66 autopsy cases, composed of groups consisting 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. An additional 5 surgical lung cancer specimens removed from MG ex-workers were also examined. From these groups, foci of moderate or severe atypia including cellular atypia, dysplasia and carcinoma in situ (CIS), detected in the total number of slides for each autopsy group, were counted as 146 out of 3,485, 72 out of 2,226, 70 out of 3,797, and 18 out of 4,611, respectively. Seven CIS lesions were detected from among all MG-exposed cases and 1 CIS lesion was found in a non-MG lung cancer case. Six of these occurred with dysplasia and 4 were associated with early invasion. Among 62 autopsy cases with known smoking histories, multivariate analysis revealed a significant correlation between the incidence rate of atypia and MG exposure only in non-lung cancer cases: the incidence rate of atypia was also influenced significantly by smoking and age. Among lung cancer cases, the incidence rate of atypia was significantly higher (p less than 0.01) in cases of squamous cell carcinoma than those of small cell carcinoma.

[Cancer of the respiratory tract observed in workers having retired from a poison gas factory].

Okunojima, a small island in the Inland Sea of Japan, off the shore of Takehara city was notorious for the production of poison gases from 1927 to 1945. Of the gases produced there, yperite and lewisite were the most poisonous and caused severe residual damage. It has been ascertained by studies conducted to date that the retired workers of this poison gas factory have a high risk of various types of malignant tumors including cancers of the respiratory tract. Such cancers observed in the retired workers from the poison gas factory are characterized by the following clinical features. Cancers are mainly central-type tumors with the site of development distributed from the airway to the hilar region and histologically, squamous and undifferentiated cell carcinoma predominate. Recently, the occurrence of malignant tumors has been discussed in relation to suppressed immune competence. Such disturbance of the immunological surveillance system seems to induce malignant changes of normal cells. On the other hand, we have demonstrated that the retired workers often showed impaired immunity. Therefore we considered that potentiation of immunity might possibly prevent the occurrence of malignant tumors and we took steps to enhance the immune competence of the retired workers with N-CWS. Its effect in preventing carcinogenesis will be shown in the near future.

[Skin damage caused by the effect of nitrogen mustard gas]. / Hautschäden durch Einwirkung von Stickstofflost.

The skin lesions seen in patients exposed to toxic war gases (dichlorethyl sulfide) are described. Histologic and electron microscopic findings are presented. The clinical course of the lesions is discussed.

[Morpho-toxicologic findings following war gas effect (S-Lost)]. / Morpho-toxikologische Befunde nach Kampfgaseinwirkung (S-Lost).

Mustard gas or Yperite, an old and formerly well known chemical warfare agent was recently used against human beings in the Middle east. Some of the victims were transferred to European University Hospitals for intensive treatment. They all showed vesication of the skin and also the typical symptoms of severe damage of the respiratory mucosa. The macroscopical and microscopical observations after war gas exposure and the detection of mustard gas in biological material are reported.