During the period from 1958-1975 some 6720 soldiers took part in a voluntary test program of 24 chemical agents conducted by the US Army at the Army Chemical Test Center at Edgewood, Maryland. In 1980, the Department of the Army asked the Committee on Toxicology of the National Research Council's Board on Toxicology and Environmental Health Hazards to study possible chronic or delayed adverse long-term health effects incurred by servicemen who took part in these tests. The terms of reference to the panel were:
1. determine whether the data available were sufficient to estimate the likelihood that the test chemicals have long-term health effects or delayed sequelae
2. determine whether the involved chemicals, as tested, are likely to produce long-term adverse health effects or delayed sequelae in the test subjects.
Their findings were presented in three volumes: Volume I covered anticholinesterase and anticholinergic chemicals; Volume II covered cholinesterase reactivators, psychochemicals, mustard gas and several irritating substances; Volume III was a follow-up report on the current (as of 1985) health of the test subjects.
The panel concluded that although no evidence had been developed that any of the anticholinesterase (anti-ChE) test compounds surveyed carries long-range adverse health effects in the doses used, they were unable to unequivocally rule out the possibility that some anti-ChE agents produced long-term adverse health effects in some individuals. While exposures to low doses of organophosphate compounds had been reported in the research literature (but not confirmed) to produce subtle changes in EEGs; sleep patterns, and behavior that persisted for up to a year, such effects were not known or reported for the Edgewood cohorts.
There was no firm evidence that any of the anticholinergic test compounds tested produced long-range adverse human health effects in the doses used in the Edgewood tests. However, the high frequency of uncontrolled test variables made evaluation of behavioral effects difficult. The panel concluded that given the available data, it was unlikely that administration of these anticholinergic compounds will have long-term toxicity effects or delayed sequelae. For both the anti-ChE and anticholinergic test subjects, mortality rates were not significantly higher than those for the US population, categorized by age and calendar year.
There was no evidence of chronic disease associated with single or repeated doses of the cholinesterase reactivators; however, lack of follow-up data on the volunteers and the absence of conclusive studies precluded any conclusions regarding the carcinogenicity, mutagenicity or reproductive anomalies that might be associated with these agents.
Mustard gas has known carcinogenicity and mutagenicity at high, long term dosages, but the effects are unknown for low dose exposures.
A follow-up study in 1985 based on a mailed questionnaire concluded that there were no significant long-term effects of any kind or occurrence of clustering of physiological problems that could distinguish the test group exposed to agents from those not exposed, or from the general population. The conclusions were based on responses by 4085 of the 6720 persons tested. The questionnaire was supplemented by a review of VA hospital admissions records of the test subjects, specifically for malignant neoplasms, for mental disorders, and for diseases of the nervous system and sense organs. Study of admission statistics showed no significant admission for these categories than the unexposed baseline test population.
A more recent study by Sidell and Hurst updates the NRC study and is supported by 124 references. The report summarizes historical data on single or repeated acute doses of nerve agents or mustard. The report implicates nerve agents and mustard as the cause or probable cause of several long-term health effects. Repeated symptomatic exposures to mustard seem we]l established as a causal factor in airway cancer. Delayed keratitis has appeared more than 25 years after acute severe lesion due to mustard; pigment changes and skin cancer also have been observed as delayed sequelae at the site of mustard-induced lesions. While the production of non-airway cancer by mustard has been observed in animals, there is little evidence to implicate mustard as the causal agent for non-airway cancer in humans. Despite unequivocal laboratory evidence of, and its classification as a mutagen, there seem to be no definitive data to implicate mustard as a reproductive toxicant in man.
Regarding nerve agents, Sidell and Hurst make the point that while nerve agents and insecticides are both organophosphates, their effects are distinct and differ in their duration. Cholinergic intoxication due to nerve agents lasts for hours, while that from insecticides may persist for weeks. Some pesticides do not cause polyneuropathy, though others have been shown to do so in animals at sub-lethal doses; nerve agents cause polyneuropathy only at doses many times the LD50, requiring extreme intervention to keep the animal alive to observe the effect. Exposure to insecticides has also been shown to express as an "intermediate syndrome" -- that is, intermediate between acute cholinergic effects and delayed neuropathy. Intermediate syndrome has not been described after exposure to nerve agents. Psychological problems, sleep disturbance, and psychomotor difficulties appear with varying degrees of persistence after insecticide exposure.
In its 1993 report, the Institute of Medicine found a causal relationship between substantial exposure to Mustard or Lewisite and a number of conditions including respiratory and skin cancers, skin pigmentation abnormalities, chronic skin ulceration, chronic respiratory diseases, chronic conjunctivitis, delayed recurrent keratitis of the eye, bone marrow and immunosuppression, psychological disorders, and sexual dysfunction. It reported insufficient information to demonstrate causal relationship between exposure and gastrointestinal, hematological, neurological and cardiovascular diseases.