Medical Aspects of Chemical Warfare (2008) - The Black Vault

Long-Term Health Effects of Chemical Threat Agents• chronic respiratory diseases (asthma, chronicbronchitis, emphysema, chronic obstructivepulmonary disease, chronic laryngitis);• respiratory cancers (nasopharyngeal, laryngeal,and lung);• pigmentation abnormalities of the skin;• chronic skin ulceration and scar formation;• skin cancer;• chronic conjunctivitis;• recurrent corneal ulcerative disease;• delayed recurrent keratitis;• leukemia (nitrogen mustard);• bone marrow depression and (resulting) immunosuppression;• psychological disorders (mood disorders,anxiety disorders, and traumatic stress disorders);and• sexual dysfunction as a result of scrotal andpenile scarring.Although laboratory evidence suggests that all ofthese might occur, there is no data in humans to indicatethat all have occurred. The study report recognizedthis by stating, “It is also possible that skin cancersdid not occur in the studied populations…” 19 and“…underrepresented in human studies is informationon chronic or delayed effects [on the bone marrow andimmune system].” 19 The report also pointed out thatthe psychological disorders were from the stress of theexposure and not from the agent, and there seemed tobe no data on sexual dysfunction. Moreover, it is notclear from the report whether these effects follow oneor multiple mustard exposures.All human studies dealing with chronic mustarddisease processes are retrospective and fraught withthe problems inherent in retrospective studies. Theseproblems include bias in the sampling populations;lack of epidemiological controls for the effects ofsmoking, lifestyle, race, gender, age, or exposure toother chemicals; differential quality of available healthcare; and incorrect diagnosis. 6 These limitations makeabsolute interpretation of the studies difficult.Over the past several years, Iranian investigatorshave provided a number of papers that study the latetoxic effects of mustard exposure in patients 16 to20 years after the Iran-Iraq conflicts of the 1980s. 20–26Balali-Mood and Hefazi 27 have summarized most ofthese data in a comparative review of early and latetoxic effects of mustard.CarcinogenesisMustard is an alkylating agent similar to drugsthat have been used in cancer chemotherapy, suchas nitrogen mustard, Cytoxan (Bristol-Myers SquibbOncology Division, Princeton, NJ), and methotrexate.Since DNA is one of mustard’s most sensitive targets, itis not surprising that carcinogenesis and radiomimeticeffects are seen.In studies 18,28,29 conducted from 1949 through 1953by WE Heston with mustard and strain-A mice (immunocompromised),the occurrence of pulmonarytumors was easily demonstrated. Studies conducted atEdgewood Arsenal, Maryland, examined the carcinogeniceffects on rats in whole-body chamber exposures.Mustard readily produced skin malignancies in rats,but no excess tumors at other sites. 30 Subcutaneousinjections totaling about 6 mg/kg of mustard producedsarcomas and other malignancies at injection sites inC3H, C3Hf, and strain-A mice, but did not result in anincrease of malignancies at other sites. 29Human data on the carcinogenicity of mustard arefrom (a) battlefield exposures, (b) accidents, and (c)workers in chemical factories. Both British and Americanstudies have investigated the increased incidenceof pulmonary carcinoma arising from World War Ibattlefield exposure. All are difficult to interpret, owingto the lack of controls for age, chronic pulmonarydisease, cigarette smoking, and other factors that mighthave affected the outcome. 31–33In contrast to battlefield exposures, studies of factoryworkers involved in the production of mustardhave shown a definite link between prolonged exposureto low doses of mustard and cancer. 6 Severalstudies 17,34–38 have provided evidence of an increasedrisk of respiratory tract cancers in factory workers.Easton et al 35 found a 45% increase in deaths due tolung cancer, a 170% increase in death from cancer ofthe larynx, and a 450% increase in deaths from cancerof the pharynx, compared with expected deaths in thegeneral population. The risks for cancer of the pharynxand lung were significantly related to the duration ofemployment at the factory. For reasons analyzed morefully elsewhere, 39 the association between a singleexposure to mustard and airway cancer is not as wellestablished.Japanese studies suggest a greater potential risk ofcancer from mustard than do the British studies. Eastonet al 35 and Manning et al 17 suggest that the difference isrelated to the design of the Japanese studies and to thelower industrial hygiene standards in Japan at the timeof the studies. 6 The weight of the evidence—cellular,epidemiological, and toxicological—indicates a causalassociation between mustard exposure and the occurrenceof excess respiratory cancer, skin cancer, andpossibly leukemia. Inadequate exposure informationlimits accurate estimation of the cancer excesses thatmay be expected. 19313