Toxic Effects Of Sulfur Mustard Research Articles

Prooxidant-antioxidant balance in Iranian veterans exposed to mustard gas and its correlation with biochemical and hematological parameters

The present study aimed to evaluate serum prooxidant -antioxidant balance (PAB) in an Iranian population exposed to sulfur mustard (SM) more than 20 years ago. In this study, 42 SM-exposed subjects and 30 unexposed subjects (as controls) were recruited. Serum PAB, biochemical, and hematological parameters were measured in all subjects. Correlation of PAB with biochemical and hematological parameters was determined. The mean PAB values in the SM-exposed group (82.5 ± 34.8 HK) were significantly higher than that in the control group [47.5 ± 17.8 HK] (p < 0.001). The results demonstrated that serum PAB values were positively correlated with alkaline phosphatase activities in the SM-exposed group. Furthermore, PAB values showed a significant negative correlation with hepatic enzymes (AST, ALT), triglycerides, total bilirubin, and mean corpuscular hemoglobin concentrations. PAB values showed a borderline significant negative correlation with uric acid. The present results suggest that late oxidative stress and alterations in biochemical and hematological parameters may be a consequence of the frequent respiratory infections rather than direct toxic effects of SM.

An evidence-based review of the genotoxic and reproductive effects of sulfur mustard.

Sulfur mustard (SM) is a chemical warfare agent which is cytotoxic in nature, and at the molecular level, SM acts as DNA alkylating agent leading to genotoxic and reproductive effects. Mostly, the exposed areas of the body are the main targets for SM; however, it also adversely affects various tissues of the body and ultimately exhibits long-term complications including genotoxic and reproductive effects, even in thenext generations. The effect of SM on reproductive system is the reason behind male infertility. The chronic genotoxic and reproductive complications of SM have been observed in thenext generation, such as reproductive hormones disturbances, testicular atrophy, deficiency of spermcells, retarded growth of sperm and male infertility. SM exerts toxic effects through various mechanisms causing reproductive dysfunction. The key mechanisms include DNA alkylation, production of reactive oxygen species(ROS) and nicotinamide adenine dinucleotide(NAD) depletion. However, the exact molecular mechanism of such long-term effects of SM is still unclear. In general, DNA damage, cell death and defects in the cell membrane are frequently observed in SM-exposed individuals. SM can activate various cellular and molecular mechanisms related to oxidative stress(OS) and inflammatory responses throughout the reproductive system, which can cause decreased spermatogenesis and impaired sperm quality via damage to tissue function and structure. Moreover, the toxic effects of SM on the reproductive system as well as the occurrence of male infertility among exposed war troopers in the late exposure phase is still uncertain. The chronic effects of SM exposure in parents can cause congenital defects in their children. In this review, we aimed to investigate chronic genotoxic and reproductive effects of SM and their molecular mechanisms in the next generations.

Commentary on: a review on delayed toxic effects of sulfur mustard in Iranian veterans

Dear Editor-in-Chief I read with interest the recent nice article published by Dr Razavi titled “A review on delayed toxic effects of sulfur mustard in Iranian veterans” [1]. Sulfur mustards (SM), commonly known as mustard gas are alkylating agents capable of causing short and long term morbidity [2]. The author stated in Table three that ophthalmic complications in Khateri et al. studies are 93.3% but there is a typesetting problem over there and the correct number is 39.3% [3]. The eyes are the most sensitive organ to SM exposure. Nearly 90% of eye injuries after SM exposure may cause later some kind of ocular disorders [4]. Also, in the paper of Razavi et al. [1], they have highlighted that SM can remain in the battlefields (for example beside the moats in World War I) and can be found in the amount of 1–25 mg/m3 in 6–12 inch depth of the soil. In moderate temperatures with mild winds, SM can remain stable for more than a week but some forms of SM can be stored in the soil for up to 10 years [1]. Natural degradation of SM in soil is a result of chemical hydrolysis and biodegradation. The major product of chemical hydrolysis is thiodiglycol. Chemical hydrolysis of SM and its chlorine derivatives in soil depends on soil type and moisture content, degree of contamination, and temperature. If the moisture content of soil is lower than 50% of its moisture capacity, then chemical hydrolysis in soil does not occur [5]. With higher temperatures and moisture content, the extent of hydrolysis of SM increases, but never to 100% completion. The SM is known to degrade faster in alkaline soils. If SM droplets are considerably below the soil surface, then SM can persist for several years [6,7]. The process of biodegradation of thiodiglycol is still longer [8]. Elimination, hydrolysis and sulfoxide products were also detected in extracts of soil samples from the Iran–Iraq war [9]. SM can be absorbed following inhalation [10] and dermal [10,11] exposure from air and soil. Therefore, although SM is a very reactive substance which hydrolyzing rapidly on contact with water, it may persist in the environment for many years, even decades, longer than expected [12]. Considering all the above facts, the correct assessment of the amount of agent in the air, in nearby water, on equipment, and on the ground (substrates such as soil, grass, concrete and asphalt) is critical to making correct decisions about the need for decontamination. Therefore, testing methods that detect both the SM and its degradation products, some of which may be toxic, since the war zones in our country now are major tourist areas where every year a large number of people travel there, are essential. Again, I would like to thank authors for collecting those valuable data using mostly domestic data and writhing such a nice review.

A review on delayed toxic effects of sulfur mustard in Iranian veterans.

Iranian soldiers were attacked with chemical bombs, rockets and artillery shells 387 times during the 8-years war by Iraq (1980–1988). More than 1,000 tons of sulfur mustard gas was used in the battlefields by the Iraqis against Iranian people. A high rate of morbidities occurred as the result of these attacks. This study aimed to evaluate the delayed toxic effects of sulfur mustard gas on Iranian victims. During a systematic search, a total of 193 (109 more relevant to the main aim) articles on sulfur mustard gas were reviewed using known international and national databases. No special evaluation was conducted on the quality of the articles and their publication in accredited journals was considered sufficient. High rate of morbidities as the result of chemical attacks by sulfur mustard among Iranian people occurred. Iranian researchers found a numerous late complications among the victims which we be listed as wide range of respiratory, ocular, dermatological, psychological, hematological, immunological, gastrointestinal and endocrine complications, all influenced the quality of life of exposed victims. The mortality rate due to this agent was 3%. Although, mortality rate induced by sulfur mustard among Iranian people was low, variety and chronicity of toxic effects and complications of this chemical agent were dramatic.

Delayed toxic effects of sulfur mustard on respiratory tract of Iranian veterans

To investigate late toxic effects of sulfur mustard (SM) on the upper and lower respiratory tracts of Iranian veterans, 43 male veterans with more than 25% disability due to SM poisoning in 20-25 years after exposure, were studied. Direct laryngoscopy, pulmonary function tests, arterial blood gasses and pH, computed tomography of sinuses and lungs were investigated. The patients were aged 50.6 (8.9 SD) years with body mass index (BMI) of 26.6 (4.0) and disability of 53.2 (17.0%). The common findings of the upper respiratory tract were dysphonia (79.1%), post-nasal discharge (PND; 41.9%), lower larynx position (30.2%), limitation of vocal cords (25.6%) and mucosal inflammation of larynx (14.8%). The common lower respiratory diseases were diagnosed as chronic obstructive respiratory disease (84%), bronchiectasis (44.1%) and lung fibrosis (7.7%). Severity of disability was negatively correlated with BMI (p = 0.032), spirometric parameters (p < 0.001) and oxygen saturation (p < 0.001), but positively correlated with low-density lipoproteins (LDL <0.010), blood pressure (p = 0.008), diabetes mellitus (p < 0.001), wheezing (p = 0.0043) and bronchiectasis (p < 0.001). Delayed toxic effects of SM in upper and lower respiratory tracts were mostly inflammatory and infectious complications, SM-induced disabilities were significantly correlated with risk factors such as diabetes mellitus, hypertension, LDL and lower-respiratory complications.

Delayed toxic effects of sulfur mustard on upper and lower respiratory tracts in Iranian veterans

Delayed toxic effects of sulfur mustard on upper and lower respiratory tracts in Iranian veterans

Systemic and ocular complications of sulfur mustard: A panoramic review

This review describes the evaluation of acute and chronic systemic and ocular toxic effects of sulfur mustard (SM) on exposed humans. It is intended to increase the awareness of extensive and dangerous environmental hazards of this agent and describe different treatment modalities for systemic and ocular involvement. Historical information and current events were accessed through the internal and external military field manuals and Internet searches. We reviewed the history, mechanism of action, and clinical and treatment modalities relating to ocular involvement of SM poisoning, by accident, terrorism, or war exposure. SM is the most dangerous organochlorine vesicant agent, which alkylates DNA. In liquid or gas form, its main targets are the eyes, skin, and lungs. Clinical effects are like burns accompanied by loss of immunity, respiratory failure, and ophthalmic, gastrointestinal, and hematological signs. Ocular effects of SM differ in acute and chronic toxicity. There are no specific antidotes for SM poisoning; hence, preventive medicine and modalities are paramount. So the first and most efficient treatment is to remove and decontaminate the victims. Most of the acute ocular problems heal during a few weeks after exposure, but rare regression of the signs and symptoms can occur up to more than 20 years after exposure, the so-called delayed keratitis that may lead to an uncontrolled penetrating keratoplasty and blindness.

Comparison of Early and Late Toxic Effects of Sulfur Mustard in Iranian Veterans

Sulfur mustard is an alkylating agent that reacts with ocular, respiratory, cutaneous, and bone marrow tissues, resulting in early and late toxic effects. We compare these effects based on the experience in Iranian veterans exposed to the agent during the Iran-Iraq conflict (1983-88). The first clinical manifestations of sulfur mustard poisoning occurred in the eyes with a sensation of grittiness, lacrimation, photophobia, blepharospasm, and corneal ulceration. Respiratory effects appeared as rhinorhea, laryngitis, tracheobronchitis, and dyspnoea. Skin lesions varied from erythema to bullous necrotization. Initial leukocytosis and lymphopenia returned to normal within four weeks in recovered patients, but marked cytopenia with bone marrow failure occurred in fatal cases. Late toxic effects of sulfur mustard were most commonly found in lungs, skin and eyes. Main respiratory complications were chronic obstructive pulmonary disease, bronchiectasis, asthma, large airway narrowing, and pulmonary fibrosis. Late skin lesions were hyperpigmentation, dry skin, atrophy, and hypopigmentation. Fifteen of the severely intoxicated patients were diagnosed with delayed keratitis, having corneal vascularization, thinning, and epithelial defect. Respiratory complications exacerbated over time, while cutaneous and ocular lesions decreased or remained constant. Both the severity and frequency of bronchiectatic lesions increased during long-term follow-up. The only deteriorating cutaneous complication was dry skin. The maximum incidence of delayed kaeratitis was observed 15 to 20 years after initial exposure. Being suggested as the main cause ofassociated with malignancies and recurrent infections, natural killer cells were significantly lower 16 to 20 years after intoxication.

Late Respiratory Complications of Mustard Gas Poisoning in Iranian Veterans

Mustard gas or sulfur mustard (SM) is an alkylating chemical warfare agent that was widely used during the World War I and in the Iran-Iraq conflict. We aimed to study late toxic effects of SM on the respiratory system of severely intoxicated Iranian veterans. Respiratory examination, spirometry, arterial blood gas (ABG) analysis, and high resolution computed tomograpghy (HRCT) of the chest were performed on all severely SM-poisoned veterans in the province of Khorasan, Iran. HRCT abnormalities were classified into four grades based on the number of lung lobes involved. ABG and spirometric results were compared with each other, as well as, with the severity grades of HRCT abnormalities, using Spearman's rank correlation test. Forty male subjects with confirmed SM poisoning 16 to 20 years ago, were studied. Main respiratory complications were diagnosed as chronic obstructive pulmonary disease (COPD) (35%), bronchiectasis (32.5%), asthma (25%), large airway narrowing (15%), pulmonary fibrosis (7.5%), and simple chronic bronchitis (5%) patients. While there was a significant correlation (p<0.05) between ABG and spirometric results, the severity grades of HRCT abnormalities revealed a significant correlation (p<0.05) only with PaO2. We concluded that SM-induced respiratory complications tend to progress over the years. While spirometry is a valuable diagnostic tool for evaluation of pulmonary impairment during regular follow-ups, ABG and HRCT are more objective and should be more considered for evaluation of the severity and for diagnosis of the respiratory complications.

Tracheobronchial Stenosis Following Sulfur Mustard Inhalation

Sulfur mustard inhalation leads to different respiratory complications. In this article, we describe late stenotic effects of mustard gas inhalation on major airways. About 15 yr after exposure, suspect cases suffering from severe respiratory disorders underwent complete workup for central airway stenosis. Patients were evaluated with bronchoscopy and tracheal computerized tomography scan. The mean age of patients was 43 ± 8 yr. The mean exposure time was 16 ± 0.7 yr. The mean time between injury and diagnosis of tracheobronchial stenosis was 11.7 ± 4.8 yr. Among the 33 referred cases with no other risk factor of stenosis, 8 cases had significant stenosis in their major airways, confirmed by tracheal computerized tomography scan and bronchoscopy. We conclude that direct toxic effects of sulfur mustard can lead to tracheobronchial stenosis with different degrees of involvement ranging from diffuse tracheal stenosis to stenosis of the isolated left main bronchus or glottic and subglottic stenosis.

Release of sulfur mustard-modified DNA bases by Escherichia coli 3-methyladenine DNA glycosylase II.

The toxic effects of sulfur mustard have been attributed to DNA modification with the formation of 7-hydroxyethylthioethyl guanine, 3-hydroxyethylthioethyl adenine and the cross-link, di-(2-guanin-7-yl-ethyl)sulfide. To investigate the action of bacterial 3-methyladenine DNA glycosylase II (Gly II) on these adducts, calf thymus DNA was modified with [14C]sulfur mustard and used as a substrate for Gly II. Gly II releases both 3-hydroxyethylthioethyl adenine and 7-hydroxyethylthioethyl guanine from this substrate. In comparison with the activity of Gly II towards methylated DNA, 3-hydroxyethylthioethyl adenine is released somewhat more slowly than 3-methyladenine, while 7-hydroxyethylthioethyl guanine is released much more readily than 7-methylguanine. Glycosylase action may play a role in protecting cells from the toxic effects of sulfur mustard.

Toxic effects of sulfur mustard on respiratory epithelial cells in culture.

Sulfur mustard (SM) is known to induce cutaneous injury and to cause acute damage to the respiratory tract. Although skin vesication has been demonstrated on human epidermal keratinocytes in culture, no study has been carried out to analyze the effects of SM on the ultrastructural and functional activity of surface respiratory epithelial cells. To evaluate this SM toxicity, we developed an in vitro model of respiratory epithelial cells in primary culture. The study was performed on surface epithelial cells from rabbit trachea cultured according to the explant-outgrowth technique. The functional activity of the cultures was evaluated by measuring the ciliary beating frequency (CBF) of the ciliated cells with a videomicroscopic method. The morphological aspects of the cells were analyzed by light and electron microscopy. Addition of 0.1 mM SM directly into the culture medium produced a sudden and irreversible CBF inhibition, first observed after 2 hr on the ciliated cells of the outgrowth periphery. The arrest of the ciliary beating progressively reached the whole surface of the outgrowth and was simultaneously observed with a detachment of the outgrowth cells. It began at the outgrowth border, leading to the exfoliation of cell sheets, and then to the whole culture after 48 hr. Morphological damage was expressed by intense vacuolisation and disorganization of cytoplasmic and nuclear structures. These findings suggest that the detachment of the respiratory epithelial cells from the matrix represents a major toxic effect of 0.1 mM SM. SM dramatically affects the viability of respiratory epithelial cells in culture. Moreover, the sudden CBF inhibition is more likely due to the death of the ciliated cells than to a specific ciliotoxic effect of SM.