A 20 Year Cancer-Related Mortality Follow-up Study of Mustard Gas Exposed Iranian Veterans

by
Farahnaz Falahati, Mohammad Reza Soroush,
Amir Ali Salamat,Shahriar Khateri, Ali Reza Hosseini
Janbazan Medical and Enginearing Research Center JMERC
19615/616 Tehran – Iran

Abstract
           Chemical warfare agents were frequently used by Iraqi forces during Iraq-Iran war (1980-1988). It has been estimated that about 100,000 Iranian military and civilians have been exposed to this chemical agent during the 80's and at present about 45,000 individuals are suffering from long term health effects of mustard gas which is an alkylating agent with highly cytotoxic properties even at low dose levels. The International Agency for Research on Cancer (IARC) has classified mustard gas as a carcinogen.
          In this Investigation a Retrospective mortality Follow-up study was conducted among those CW victims who died between 1984-2004, because of a confirmed malignancy.
          We considered two main inclusion criteria:

I. Confirmed wartime exposure to mustard gas.
II. At least 6 months interval between exposure and pathologic diagnosis of cancer.

           Among 45,000 Iranian C.W Victims who are receiving medical services by Janbazan Organization 124 of them are known to have died of cancer during the period between (1984-2004) we reviewed all medical documents of these cases as well as their follow-up medical files.
           It has been elicited from the results of our study that hematopoetic cancers are the most common malignancies in our subjects. This study has been carried out of an ongoing nation wide project.

Introduction
           Sulfur Mustard [bis (2-chloro ethyl) sulfide] is one of a class of chemical warfare (CW) agents known as vesicants or blistering agents. Also known by mustard gas and the military designation of HD, sulfur mustard has been by far the most widely used CW agent in chemical attacks from its first use in 1917 to the latest reports of its possible employment against military personnel who served in the Persian Gulf in 1991 during operation Desert storm.(1) Mustard also was used extensively by Iraqi forces during the Iraq--Iran war of the 1980s against Iranian military and civilians. (2)
          The primary routes of potential human wartime exposure include sulfur mustard inhalation and cutaneous exposure. The use of protective mask and clothing may reduce some deleterious effects of these agents, but exposure times and concentrations are also important.
          Unprotected exposure to mustard gas among military personnel and civilians has resulted in erythema, edema, skin lesions, conjunctivitis. Following severe exposure, death occurred 2--3 days after exposure, often from respiratory damage. Survivors often develop long term health effects resulting from this exposure.(3,5,6) The acute and long-term effects of mustard on Iranian veterans have been described in literature but little or no work has been conducted to assess its human carcinogenicity on these casualties.
          Sulfur mustard is a DNA alkylating agent and has previously been suspected of causing increased cancer risks among exposed military and occupational workers; it is classified as a human carcinogen (group 1) by International Agency of Research on Cancer (IARC).(4) A series of experiments on lab animals have indicated that sulfur mustard is extremely cytotoxic at low doses and a limited number of human studies examining occupational exposure to sulfur mustard have also reported an increased risk of some cancers like respiratory cancers associated with exposure. (12-13)
          During the Iraq-Iran war, sulfur mustard was employed on numerous occasions between 1984-1988. Estimates are that about 100,000 Iranian military and civilians were exposed to mustard during this period and at present 45,000 individuals are suffering from its long-term health effects.(14) Until now, no study has been conducted on the cancer related mortality among Iranian exposed veterans. In this study we conducted a retrospective 20 year mortality in persons who had received nonlethal exposures of sulfur mustard 1984-2004 and eventually died with a confirmed malignancy.

Materials And Methods

Subjects
          Subjects for this study were recruited from Janbazan Organization (Veterans Affair) who had been exposed to sulfur mustard in Iraqi attacks between 1984-1988 and died between1984-2004 with a confirmed malignancy.
          Documents were gathered from military and civil files, as well as from hospital and death files, and reviewed for early manifestations after exposure, subsequent medical complications, and the date of exposure, to distinguish sulfur mustard from other agents.
          Demographic data of all subjects were reviewed in the Janbazan Organization database of medical records. All subjects with confirmed exposure to sulfur mustard were followed from their exposure time to the date of their death.
          In all subjects we also considered some data about their age at the time of exposure and the long term sequelae of sulfur mustard exposure in their lung, skin, eyes and so on.

Inclusion criteria
           We considered three inclusion criteria for our subjects. First, confirmed wartime exposure to sulfur mustard, according to records of early clinical manifestations after exposure as seen in their military and medical records. Second, an interval of at least six months between exposure time and pathologic diagnosis of cancer, in order to rule out prior malignancy. Third, death caused by cancer, as confirmed by pathology, which also determined the type of cancer. On the basis of these inclusion criteria we entered 129 subjects to our study.

Exclusion criteria:
           Veterans with a positive history of, or a suspicious sign or symptom of, a malignancy before exposure in their medical records and veterans under treatment for any of the major signs and symptoms of any cancer were excluded.
          We also considered occupational exposure to known carcinogens as an exclusion criterion. We decided not to consider smoking history as an exclusion criterion; rather we decided to consider smoking as a variable. (Table3)

Vital Status follow-up:
          For each subject vital status follow-up began from their documented exposure time to mustard to their date or death.

Classification:
           Pathologic finding of each cancer was the main criterion for classification. And according to prevalence of cancers in the victims we considered 7 main classes of cancer. Other less frequently observed cancers were all classified in one group. The 8 main classes are: Hodgkins lymphoma, Non-Hodgkin lymphoma, acute myelocytic leukemia (AML), chronic myelocytic leukemia (CML), lung squamous cell carcinoma (LSCC), laryngeal carcinoma and acute lymphocytic leukemia (ALL) and esophageal squamous cell carcinoma.

Statistical Analysis:
          Statistical analysis of the data was conducted in two stages. The first stage was a descriptive study regarding demographic data, including age at the time of exposure. The second stage was done on each class of cancers according to the pathologic classification. All data were analyzed using the SPSS for windows statistical package. (SPSS 10).

Results And Discussions:
          In this study more than 2000 files were evaluated for the cause of death between 1984-2004. As the preliminary phase of our evaluation 230 cases were assessed for documented war time exposure to sulfur mustard based on their exposure time and early clinical manifestations after exposure. Finally 129 deceased veterans were entered to our study because of confirmed exposure to mustard gas and confirmed cancer- related death in them. Other often observed CW agents included organophosphates and so on.
          Subjects were all male and about 6% of them had history of multiple exposures. The average age at the time of exposure was 29.7 _+12.7, and the average length of follow-up was 8/3 years in each case. (Table2) The average age at the time of death was only 38.6 (14.6 SD) and the average of their survival after diagnosis was 1.4 years (2.8 SD) for the 129 mustard – exposed subjects. Five cases were excluded because of the signs and symptoms of malignancy before their exposures. Most were exposed in the period between 1986 and 1987. All of the deceased veterans died with end stage cancers or secondary complications that related to malignancy. None of the subjects had positive history of occupational exposure to known carcinogens. The most common malignancy in the deceased veterans was AML (19.4%) (Table1). 67.7% (84 persons) had long-term effects of mustard gas in respiratory system, 10.5% had suffered from long-term effects of mustard gas in eyes and 7.3% (9 persons) had been suffering from long-term skin lesions of mustard exposure.
          According to analysis of pathologic finding and classified age of exposure, the most common malignancy in the youngest age group of the exposed veterans (under 30) was AML (37.2%) followed by Hodgkin disease (16.3%) and Non Hodgkin Lymphoma (11.6%). In the second age group of the exposed veterans AML (15.2%) was again found to be the most common malignancy followed by ALL and CML. Finally, in the oldest group the subjects (over 50) other cancers were the most common, which was followed by lung squamous cell carcinoma (26.5%).
          We also determined the types of cancer in the upper and lower range of exposure age. The result suggested that at the age of exposure was related to the type of cancer: the younger veterans (mean age of exposure 19.7 years, 3.7SD) died mostly with Hodgkin Lymphoma, while in the group of oldest patients (average age at exposure 42.8 years, 11.7 SD) lung squamous cell carcinoma was more prevalent.
          We also examined the time of diagnosis of every cancer after exposure. (See Table1) Hodgkin Lymphoma often manifested itself in 4.7 years (4.8SD) following exposure, while AML was (4.7 years, 3.4 SD) and lung SCC (9 years) appeared to be diagnosed later.
           The study was a retrospective follow-up among a deceased population of veterans exposed to sulfur mustard (an alkylating agent, known to be a human carcinogen) used extensively in the Iraq – Iran war of the 1980s.(7)
          Prior studies of mustard gas exposure examined the mortality of veterans exposed to sulfur mustard under battlefield condition during World War I and amongst factory workers involved in the manufacturing of mustard gas over a period of years. These studies reported an increased risk of respiratory cancers.(12,13) A 50 year mortality follow-up study of low level exposure to Mustard gas among Navy servicemen demonstrated that laryngeal cancer, lung and skin cancers were the underlying cause of 125 malignancy induced deaths in the exposed group.(15) The last study failed to exclude some confounding factors such as the consumption of alcohol and occupational exposure to carcinogens and the fact that all exposed were equipped with protective gear. However in our study a small number of subjects protected themselves at the time of exposure, although none had complete protection, they all lacked a history of exposure to other carcinogens except for smoking.
          The reason behind the contradictory findings regarding the type of cancer involved as the underlying cause of death may be due to the unavailability of proper treatment modalities such as bone marrow transplantation during the course of the disease. Studies comparing the cause of death as written on death certificates with that reported on autopsies indicated that certain cancers are under reported on death certificates(16). And, some specific cancers are at times reported as nonspecific cancers on death certificates(17)
          An additional limitation of our study was, the lack of data regarding dose and duration of exposure. To increase the reliability of data collection we also reviewed all official documents of deceased veterans including hospital, military and other documents, but we believe that this study failed to include some veterans without primary manifestations of exposure owing to a lack of documentation regarding their exposure to mustard gas.
          It is important to demonstrate that the short average interval between the pathologic diagnosis of malignancy and death suggests that diagnosis of cancer among the Iranian veterans was often regrettably delayed. Thus adjustment of the screening programs for early detection of common cancers among mustard gas exposed victims is a priority.
          To conclude, despite all limitations of this study, we believe that this study can serve as a gateway for future studies about the prevalence and incidence of each cancer in all mustard gas exposed victims. It can also help us devise more precise screening protocols, which can lead to an earlier detection of some cancers, longer survival and the improvement of health care.

References

1. World Health Organization. Health Aspects of Chemical and Biological weapons, Geneva, Switzerland: World Health Organization; 1970:23 - 34.
2. Presidential Advisory Committee on Gulf War Veteran's Illnesses. Final Report. Washington, DC: US Government printing office; 1996.
3. Dacre JC and Goldman M: Toxicology and pharmacology of the chemical warfare sulfur mustard, Pharmacol Rev. 48.1996; 289 - 326
4. International Agency for Research On Cancer. Mustard gas. In: IARC monographs on the evaluation of the carcinogenic risks to humans. Overall Evaluations of carcinogenicity: An updating of the IARC monograph volumes 1 - 42 (7). Lyon, IARC, 1987; 259 - 60.
5. Emad A, Rezaian GR: Immunoglobulins and cellular constituents of the BAL fluids of patients with sulfur mustard gas induced pulmonary fibrosis. Chest, 1999. 115; 1346 - 51.
6. Emad A, Rezaian GR: The diversity of the effect of sulfur mustard gas inhalation on Respiratory system 10 years after heavy exposure: analysis of 197 cases, chest. 1997 112 (30): 734 - 8.
7. Heston WE, Levillain WD. Pulmonary tumors in strain a mice exposed to mustard gas. Proc. Soc. Exp Bilo 1953; (82): 457 - 460.
8. Heston WE: Carcinogenic action of the mustard. J Natal Cancer Inst. 1950;(11): 415 - 423.
9. Heston WE: Occurrence of tumor s in mice injected subcutaneously with sulfur mustard and nitrogen mustard. J Natal Cancer Inst1953.14; 131 - 140
10. Ludlum DB: Detection of sulfur mustard – induced DNA modification, Chem- Bio–Interact., 1994.91 (1); 39 - 49
11. Heston WE. Occurrence of tumors in Mice injected sulfur Mustard as a carcinogen: application of relative potency analysis to the chemical warfare agents, H, HD, and HT, Regul.Toxicol.Pharmacol (1989).10(1):1 - 25
12. Nishimoto Y. Yamaikido M. Ishioka S et al: Epidemiological studies of lung cancer in Japanese Mustard gas workers. PrincessTakamatsu Symp. (1987),18:95 - 101
13. Yamakido M: Former poison gas workers and cancers: Incidence and Inhibition of Tumor Farmatio by Treatment with Biological Response Modifier N - CWS, Environ.Health.Perspect. (1996) 104(3):485 - 8
14. Khateri S: Victims of chemical weapons in Iran. First edition Tehran: Aftab - e Graphic, 2003. ISBN 964 - 93602 - 5 - 5:3 - 14
15. Bulman T.Kang H: A Fifty year Mortality Follow-up Study of Veterans Exposed to Low Level Chemical Warfare agent, Mustard Gas, Ann Epidemiol 2000,10(5); 333 - 8
16. Engle LW, Struachen JA, Chiazze L: Accuracy of Death Certificates in an Autopsied Population with specific attention to Malignant Neoplasms and Vascular disease .AM J Epidemiol.1980:111;99 - 112
17. Percy C, Staneke , Gloeskler L. Accuracy of cancer death certificates and its effects on cancer mortality statistics. AM J Public Health. 1981: 71; 242 - 250.

Key words:
          Iraq-Iran war, sulfur mustard, Cancers, Chemical warfare, Veterans