Mustard gas exposure and carcinogenesis of lung

Abstract

Sulfur mustard (SM), also known as mustard gas, is an alkylating compound used as a chemical weapon in World War I and by Iraqi forces against Iranians and indigenous Iraqi Kurds during the Iran-Iraq War of the 1980s. Although SM is a proven carcinogen there are conflicting views regarding the carcinogenicity of a single exposure. The present study characterizes lung cancers formed in mustard gas victims from the Iran-Iraq War.Methods and Materials-Demographic information and tumor specimens were collected from 20 Iranian male lung cancer patients with single high-dose SM exposures during the Iran-Iraq war. Formalin fixed, paraffin-embedded lung cancers were analyzed by immunohistochemistry for p53 protein. In addition, DNA was extracted from the tissues, PCR amplified and sequenced to identify mutations in the p53 and KRAS genes associated with SM exposure.Results-A relatively early age of lung cancer onset (ranging from 28 to 73 with a mean of 48) in mustard gas victims, particularly those in the non-smoking population (mean age of 40.7), may be an indication of a unique etiology for these cancers. Seven of the 20 patients developed lung cancer Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript before the age of 40. Five of 16 cancers from which DNA sequence data was obtainable provided information on eight p53 mutations (within exons 5-8). These mutations were predominately G to A transitions; a mutation consistent with the DNA lesion caused by SM. Two of the lung cancers had multiple p53 point mutations, similar to results obtained from factory workers chronically exposed to mustard agent. No mutations were detected in the KRAS gene.Discussion-The distinguishing characteristics of lung carcinogenesis in these mustard gas victims suggest that a single exposure may increase the risk of lung cancer development in some individuals.

Bronchial leiomyoma in a chemical warfare victim—a causative agent or an incidental finding: A case report

“…Now near 8500 Iranian veterans with well-documented exposures to mustard gas are under investigation for confirming the long term carcinogenicity of this agent. 10 Lung, nasopharynx, thyroid gastrointestinal and skin cancers and also different types of leukemia are among the malignancies which were reported in these cohort but urogenital cancers was not increased in these patients. 10 Deaths from respiratory cancer occurred in 2.5% of those American veterans who exposed to sulfur mustard in World War I.…”

“…10 Lung, nasopharynx, thyroid gastrointestinal and skin cancers and also different types of leukemia are among the malignancies which were reported in these cohort but urogenital cancers was not increased in these patients. 10 Deaths from respiratory cancer occurred in 2.5% of those American veterans who exposed to sulfur mustard in World War I. In the study of Japanese factory workers, respiratory tract tumors accounted for 58% of all reported malignant tumors (16% of all deaths).…”

“…7 Also, association between chemical warfare and lung cancer was not well understood but many reports in the literature have confirmed that sulfur mustard may decreased the age at which people were at risk of developing lung cancer and also increase the rate of lung cancer in the victims. [8][9][10][11] In the acute phase, sulfur mustard which is an alkylating agent, may be rapidly results in bronchiolitis obliterans or "mustard lung" but the chronic effects of this type of chemical warfare poisoning in the victims remained to be depicted. 11 Only a few seconds of exposure to this relatively odorless gas is enough for developing the symptoms.…”

“…Chronic respiratory symptoms such as asthma, bronchiectasis, bronchitis, bronchiolitis, sinusitis, and bronchial stenosis are among the common symptoms in the survivors. 10 Chronic complications are due to the adverse effect of this agent on immunoregulatory pathways and also mutations in important oncogenes or tumor suppressor genes such as p53 or KRAS with a known increase in lung cancer risk. 13,14 Unfortunately, long term epidemiological studies are required for confirming the association of this type of poisoning with lung cancer.…”

Sulfur mustard and respiratory diseases: Revisit with special reference to the “Comments on ‘Sulfur Mustard and Respiratory Diseases’, Tang and Loke () and a prepared Integrated Mechanism for Chronic Pulmonary Disease from Exposure to Sulfur Mustard” by Saburi and Ghanei ()

“…Hosseini-khalili et al (2009) recently suggested that a single HD exposure may increase the risk of lung cancer development. Combined with many other reports mentioned in our publication (Tang & Loke, 2012), a comprehensive genomic study will certainly reveal more mutated gene and provide evidence for better understanding of the mechanism of HD-induced respiratory diseases.…”