Search

Health and exposure criteria have not been established for lewisite [dichloro(2-chlorovinyl) arsine], a potent toxic vesicant that reacts with the sulfhydryl groups of proteins through its arsenic group. Sixty Sprague-Dawley rats of each sex, 6-7 wk old, were divided into 6 groups (10/group/sex) and gavaged with either 0, 0.01, 0.1, 0.5, 1.0, or 2.0 m g/kg of lewisite in sesame oil 5 d/wk for 13 wk. No significant dose-related change in body weight was observed. At the high dose, serum protein, creatinine, SGOT, and SGPT were decreased in males; lymphocytes and platelets were increased in females. A treatment related lesion was detected in the forestomach of both sexes at 2.0 m g/kg. These lesions were characterized by necrosis of the stratified squamous epithelium accompanied by infiltration of neutrophils and macrophages, proliferation of neocapillaries, hemorrhage, edema, and fibroblast proliferation. Mild acute inflammation of the glandular stomach was also observed in some cases at 1.0 and 2.0 mg/kg. Early deaths were attributed to severe inflammation of the upper and/or lower respiratory tract, possibly from deposition or reflux of test material into the pharynx. Estimated dose range for NOEL appears to be >0.5 and <1.0 m g/kg when administered orally. [ABSTRACT FROM AUTHOR]

Subacute and Chronic Toxicity Studies of Trinitroglycerin in Dogs, Rats, and Mice. ELLIS, H. V., III, HONG, C. B., LEE, C. C., DACRE, J. C., AND GLENNON, J. P. (1984). . 4, 248–260. Subacute and chronic oral toxicities of trinitroglycerin (TNG) were studied in beagle dogs, CD rats, and CD-1 mice. No adverse effects were seen in dogs given up to 1 mg/kg/day of TNG for 4 weeks, then 5 mg/kg/day for 9 more weeks. Dogs given 25 to 200 mg/kg/ day for 5 days had transient and dose-related severe methemoglobinemia, while 200 mg/kg/day produced depression; dogs given 1, 5, or 25 mg/kg/day for 12 months had transient and dose-related mild methemoglobinemia. Rats fed 0.1% TNG for 5 weeks, then 0.5% (230–234 mg/kg/day) for 8 more weeks had decreases in feed consumption and weight gain after the increase in dosage; rats fed 2.5% TNG (1406 or 1416 mg/kg/day for males and females, respectively) for 13 weeks suffered adverse effects, including weight loss, compensated anemia, and testicular degeneration, but they resumed gaining weight as feeding continued. Rats fed 1% TNG (363 or 434 mg/kg/day for males and females, respectively) for 2 years had decreased weight gain, decreased grooming, methemoglobinemia and its sequelae, cholangiofibrosis, hepatocellular carcinoma, and interstitial cell tumors of the testis. A decrease in the naturally occurring pituitary chromophobe adenoma and mammary tumors increased the life span of the females. Some rats fed 0.1% TNG (31.5 or 38.1 mg/kg/day for males and females, respectively) had mild hepatic lesions similar to those seen in rats fed the larger doses. No adverse effects were seen in mice fed up to 0.1% TNG for 3 weeks, then 0.5% for 10 more weeks. Mice fed 1% TNG (1022 or 1058 mg/kg/day for males and females, respectively) for 2 years had decreased weight gain, decreased grooming, and methemoglobinemia and its sequelae, but no obvious cellular changes as found in the rats. [ABSTRACT FROM PUBLISHER]

Comprehensive data are not available to evaluate the potential risk to reproduction from exposure to sulfur mustard (HD), [bis(2-chloroethyl) sulfide]; thus, the reproductive effects of HD were evaluated in Sprague-Dawley rats. Groups, of rats (27 females and 20 males/group/generation) were gavaged with 0, 0.03, 0.1, or 0.4 mg/kg HD 5 d/week for 13 weeks prior to mating and throughout gestation, parturition, and lactation in a 42-week, 2-generation study. Growth of adult F1 rats of both sexes was reduced by the 0.4 mg/kg exposure. There were no significant effects on reproductive function or pregnancy outcome in either generation, except for an altered sex ratio in the 0.4 mg/kg group. Although not different at birth, growth of the 0.4 mg/kg F1 and F2 offspring was depressed during lactation. A dose-related lesion of the squamous epithelium of the forestomach was observed in adults of both sexes and both the F1 and F2 generation. For a given treatment, the incidence was approximately the same for each sex at each generation. When animals were pooled by sex and generation, approximately 70% (66 out of 94) of the low dose group had only mild microscopic lesions, 72% (68 out of 94) of the intermediate dose group had moderate lesions, and 81% (76 out of 94) of the high group had marked lesions. The lesion, acanthosis, was characterized by thickening of the squamous musoca with varying degrees of hyperkeratosis. Benign neoplasms of the forestomach were found in about 10% of the intermediate and high dose groups in both F0 and F1 generations. Based on these results, the No-Observable-Adverse-Effect-Level (NOAEL) is 0.1 mg/kg/d.

There have been reports of chemical attacks in which sulfur mustard might have been used (a) on Iranian soldiers and civilians during the Gulf War in 1984 and 1985 and (b) in an Iraqi chemical attack on the Iranian-occupied village of Halbja in 1988, resulting in many civilian casualties. Heavy use of chemical warfare in Afghanistan by the Soviet military is a recent innovation in military tactics that has been highly successful and may ensure further use of chemical agents in future military conflicts and terrorist attacks as a profitable adjunct to conventional military arms. Mustard is a poisonous chemical agent that exerts a local action on the eyes, skin, and respiratory tissue, with subsequent systemic action on the nervous, cardiac, and digestive systems in humans and laboratory animals, causing lacrimation, malaise, anorexia, salivation, respiratory distress, vomiting, hyperexcitability, and cardiac distress. Under extreme circumstances, dependent upon the dose and length of exposure to the agent, necrosis of the skin and mucous membranes of the respiratory system, bronchitis, bronchopneumonia, intestinal lesions, hemoconcentration, leucopenia, convulsions with systemic distress, and death occur. Severe mustard poisoning in humans is associated with systemic injury, which is manifested as headache, epigastric distresses, anorexia, diarrhea, and cachexia and is usually observed at mustard doses of 1000 mg/min/m3 with damage to hematopoietic tissues and progressive leucopenia. Sulfur mustard is a cell poison that causes disruption and impairment of a variety of cellular activities that are dependent upon a very specific integral relationship. These cytotoxic effects are manifested in widespread metabolic disturbances whose variable characteristics are observed in enzymatic deficiencies, vesicant action, abnormal mitotic activity and cell division, bone marrow disruption, disturbances in hematopoietic activity, and systemic poisoning. Indeed, mustard gas readily combines with various components of the cell such as amino acids, amines, and proteins. Although evidence of an association between lung cancer and mustard gas encountered on the battlefields of World War I is at best suggestive if not problematical (Case and Lea, 1955; Beebe, 1960; Norman, 1975), the epidemiological data accumulated from the poison gas factories in Japan (Yamada et al., 1953; Wada et al., 1968; Inada et al., 1978; Shigenobu, 1980; Nishimoto et al., 1983; Hirono et al., 1984; Takuoka et al., 1986), in Germany (Weiss, 1958; Hellmann, 1970a; Weiss and Weiss, 1975; Klehr, 1984) and in England (Manning et al., 1981; Easton et al., 1988) are substantial (International Agency for Research on Cancer, 1975). Unfortunately, attempts to seek confirmatory and substantial evidence in laboratory animals such as mice (Boyland and Horning, 1949; Heston, 1950; Heston, 1953a; McNamara et al., 1975) and rats (Griffin et al., 1951; McNamara et al., 1975; Sasser et al., 1996) have not been consistent. Sulfur mustard has been shown to be mutagenic in a variety of different species using many different laboratory techniques from fruit flies, microorganisms and mammalian cell cultures (Fox and Scott, 1980). Evidence is slowly accumulating from human data (Hellmann, 1970a; Lohs, 1975; Wulf et al., 1985). Evidence for the teratogenicity of mustard has been negative in assessment of fetotoxicity and adverse effects of mustard on the reproductive potential of both human and animal studies. Indeed, investigations of women adversely affected by mustard are minimal because most of the studies have been performed on former men employees of poison gas factories and have been negative or questionable. We have recently emphasized the need to assess the affect of a suspected teratogen on maternal toxicity in laboratory animals before any conclusions can be made.(ABSTRACT TRUNCATED)

Sarin (Agent GB, isopropyl methylphosphonofluoridate) is an organophosphate cholinesterase inhibitor. Sarin (Type I or Type II) was administered by gavage to CD rats on d 6-15 of gestation at dose levels of 0, 100, 240, or 380 micrograms/kg/d and to New Zealand White (NZW) rabbits on d 6-19 of gestation at dose levels of 0, 5, 10, or 15 micrograms/kg/d. Females were weighed on gestational days (GD) 0, 6-16 for rats and 6-20 for rabbits, and immediately prior to termination (GD 20 for rats and GD 29 for rabbits). All animals were monitored daily for clinical signs of toxicity throughout dosing and until sacrifice. At necropsy, gravid uteri were weighed and examined for the number and status of implants (live, resorbed, or dead). Individual fetal body weight, malformations, and variations (external, visceral, and skeletal) were recorded. Rat and rabbit dams in the high-dose groups exhibited significant signs of maternal toxicity and increased maternal mortality. Examination of gravid uteri revealed no statistical differences among treatment groups in the incidence of resorptions or of dead or malformed fetuses, or in average body weight of live fetuses per litter. These results show no evidence or developmental toxicity in the CD rat or NZW rabbit following exposure to either Type I or Type II sarin during embryonic differentiation and major organogenesis, even at a dose that produced maternal toxicity.

Diisopropyl methylphosphonate (DIMP), produced during manufacture of the chemical agent GB (Sarin), is a groundwater contaminant at Rocky Mountain Arsenal, Colorado. DIMP was fed for 90 days to dark brown "Ranch Wild" mink housed under controlled indoor conditions. One-year-old mink, 10 of each sex, were fed 0, 50, 450, 2700, 5400, or 8000 ppm in standard ranch diet. Actual DIMP consumption was 0, 8, 73, 400, 827, and 1136 mg/kg body wt/day, respectively. Two additional groups of 10 served as "pair-fed" controls. Body weight and food intake were recorded weekly. Complete blood count and 15 chemical analytes were measured at Weeks 0, 3, 7, and 13. Necropsy and microscopic examination were performed on all mink. No clinical morbidity or deaths occurred. Both sexes fed 8000 ppm ate approximately 20% less and weighed approximately 20% less than the controls; 5400 ppm females had a 10% weight decrement. Plasma cholinesterase (ChE) decreased in the top three dose groups starting at Week 3. At 13 weeks, decrements were approximately 50% but returned to normal after 1 week without DIMP. Erythrocyte ChE was not reduced. Heinz bodies occurred in 10-15% of RBCs in 50% of 8000 ppm mink at 13 weeks, and 0.1-2.0% of RBCs in 25% at 2700 ppm. There were mild decreases in RBC count, hematocrit, and hemoglobin, and increases in reticulocyte count, at the 5400 and 8000 ppm doses. All recovered within 3 weeks after DIMP was withdrawn. The 8000 ppm group had marginal splenic hematopoiesis, histologically. No other treatment-related changes were noted. The 450 ppm dose was a clear no-effect level (approximately 73 mg DIMP/kg body wt/day). Compared to reports of similar studies of DIMP in rats and dogs, these mink displayed no unique species susceptibility.

Five mutagenicity tests were performed on Agent GA (Tabun, phosphoramidocyanidic acid, dimethyl-, ethyl ester) as part of a program to demilitarize chemical warfare agents. GA was mutagenic in Salmonella spp. assays with S-9 and it was a direct-acting mutagen to mouse lymphoma cells. GA did not promote unscheduled DNA synthesis in rat hepatocytes; it induced sister chromatid exchanges in mouse cells in vitro but in vivo. The conclusion that GA is a weakly acting mutagen is supported by the fact that it was mutagenic in only three of the five assays, and that increases in mutagenicity were often less than 2-fold the controls and occurred near toxic levels.

The neuropathic potential of acute and repeated exposures of the phosphoramidates tabun (GA) and isofenphos (IFP), of diisopropyl fluorophosphate (DFP) and paraoxon (PO) were examined in the hen with treatments for up to 90 days via intramuscular injections of the highest tolerated doses with atropine protection. Plasma acetylcholinesterase (AChE), non-specific butyrylcholinesterase (BChE) and creatine kinase (CK) activities were measured in order to monitor whether the compounds were present at biologically active concentrations. Locomotor behavior was observed and tissues from the peripheral and central nervous systems were examined for signs of organophosphate-induced delayed neuropathy (OPIDN). No behavioral or histological evidence of OPIDN was observed after treatments with GA, IFP, PO, saline or atropine sulfate. DFP-treated birds displayed locomotor and neuropathological signs of OPIDN with a no effect level (NOEL) between 25 and 50 micrograms/kg.

Soman (GD; phosphonofluoridic acid, methyl-,1,2,2-trimethylpropyl ester) is an organophosphate compound with potent anticholinesterase activity. To determine developmental toxicity, soman was administered orally to CD rats on days 6 through 15 of gestation at dose levels of 0, 37.5, 75, 150, or 165 micrograms/kg/day and to New Zealand White (NZW) rabbits on days 6 through 19 of gestation at dose levels of 0, 2.5, 5, 10, or 15 micrograms/kg/day. At sacrifice, gravid uteri were weighed and examined for number and status of implants. Individual fetal body weights and external, visceral, and skeletal malformations were recorded. Mean maternal weight changes, fetal implantation status/litter, fetal weight, and fetal malformations/litter were compared between dose groups. Monitors for maternal toxicity were net body weight change, treatment weight change, mortality, and clinical signs of toxicity such as lethargy, ataxia, and tremors. Maternal rats and rabbits in the high-dose groups exhibited statistically significant increases in toxicity and mortality when compared to controls. There were no significant dose-related effects among dose groups in the prevalence of postimplantation loss, malformations, or in average body weight of live fetuses per litter. There was no evidence of increased prenatal mortality or fetal toxicity in the CD rat or NZW rabbit following exposure to soman, even at a dose that produced significant maternal toxicity.

Lewisite is an organic arsenical war gas which is a vesicant with attendant toxicities due to its ability to combine with thiol groups which are essential for activity of a variety of enzymes. Although Lewisite has been designated as a "suspected carcinogen," the indictment is not supported by the available scientific evidence. Indeed, the unwarranted conclusion is based on one specific case history of a former German soldier whose lower right leg was exposed to liquid Lewisite in 1940 with subsequent development of intraepidermal squamous cell carcinoma, and the examination of death certificates of former workers at a Japanese factory that manufactured a variety of war gases including mustard gas, hydrocyanic acid, chloracetophenome, phosgene, diphenylcyanarsine and Lewisite. It is difficult to comprehend why Lewisite was selected out of this group of toxic chemicals as one of those responsible for respiratory cancer in these workers. It would appear to be a difficult task, indeed, to disengage a specific worker from one of the other of several gases at the workplace and assign a specific gas-induced death. The evidence that organic arsenicals are carcinogenic is weak. Although the weight of evidence is such that inorganic arsenical derivatives are considered weak mutagens, the evidence that organic arsenicals are mutagenic is poor. Recent examination of the mutagenic potential of Lewisite using the Ames test has shown that Lewisite is not mutagenic under these circumstances. While oral administration of arsenical compounds, whether inorganic or organic, does not induce teratogenicity except at very high dose levels which are associated with some degree of maternal toxicity, parenteral administration has been associated with teratogenicity but information of maternal toxicity has not always been available. Indeed, maternal toxicity should be considered as an important diagnostic tool in assessing whether a chemical is teratogenic. The significance of parenteral routes for inducing teratogenicity is also problematical. Recently, Lewisite has been shown not to be teratogenic in either rats or rabbits. A monograph on arsenic, succinctly states that "no human epidemiological investigations have been conducted on the carcinogenicity of organic arsenic compounds" (WHO 1981). Indeed, the lack of such evidence eminating from epidemiological sources or from animal studies is resounding. At present, there is no evidence that Lewisite is either carcinogenic, mutagenic or teratogenic. A review of toxicological studies of other organic arsenicals has produced no evidence that they might be carcinogenic, mutagenic or teratogenic.

The short-term oral toxicity of 2,4,6-trinitrotoluene (alpha-TNT) was determined in dogs, rats, and mice. Single-dose oral LD50s for alpha-TNT in corn oil were 1320 and 794 mg/kg in male and female rats, respectively, and 660 mg/kg in both male and female mice. For multiple-dose studies, dogs were dosed daily for up to 13 wk with alpha-TNT at 0, 0.2, 2.0, or 20 mg/kg by capsule; rats received 0, 0.002, 0.01, 0.05, or 0.25% and mice received 0, 0.001, 0.005, 0.025, or 0.125% alpha-TNT in their diets over the same period. All species receiving the highest doses exhibited anemia, with reduced erythrocytes, hemoglobin, and hematocrit. Alterations were observed in organ weights, including enlarged spleens (accompanied by hemosiderosis) and livers, and depressed body weight and/or body weight gain (temporary in dogs and mice). Alterations in clinical chemistry values included elevated cholesterol and depressed serum glutamicpyruvic transaminase activity in dogs and rats; no effect on serum glutamic-oxaloacetic transaminase activity was observed. Some effects, such as SGPT depression in rats, appeared after 13 wk, suggesting a cumulative toxicity. Reduced testes size was observed in rats at the highest dose regardless of length of exposure. Most of the toxic effects were reversible, but testicular atrophy was not in rats allowed a 4-wk recovery period after treatment. Signs of anemia were present at intermediate dose levels. "No observable effects" levels for alpha-TNT were: dogs, 0.20; rats, 1.42; and mice, 7.76 mg/kg . d.

The oral toxicity of a mixture of 2,4,6-trinitrotoluene and hexahydro-1,3,5-trinitro-1,3,5-triazine (1:0.62, w/w) compounds typically found in munitions plant effluents, was evaluated in mammalian species. Single-dose oral LD50s of the mixture were 574 and 594 mg/kg in male and female rats and 947 and 1130 mg/kg in male and female mice, respectively. Long dispersion periods during preparation or ultraviolet irradiation of the mixture lowered the LD50s. In repeated-exposure studies, dogs were given 0.50, 5.0 or 50 mg/kg X d by capsule for up to 90 d. Rats and mice were fed the mixture in the diet at 0.005, 0.05, or 0.5% for 90 d; mice were also fed at 0.25%. Mortality resulted at the highest dose level in each species. All three species showed depression of body weight or body weight gain, depressed food intake, moderate to severe anemia, and alterations in the spleen (hemosiderosis), liver (hepatomegaly), and testes (atrophy) at the highest dose levels. Cholesterol was elevated in rats and dogs after 90 d. Several species differences were also noted. Uric acid values were elevated in rats but not in dogs, serum glutamic-pyruvic transaminase (SGPT) activity was low in dogs but unchanged in rats, and rats developed hypoplasia of the uterus but dogs did not. Signs of anemia were present at the intermediate dose levels. The lowest dose level in all three species was designated at a "no observable effects" level, based on the absence of clearly treatment-related effects. In a 4-wk study, the irradiated mixture fed to rats at 0.003, 0.03, or 0.3% in the diet was less toxic than the unirradiated mixture.

Cultured Chinese hamster ovary (CHO) cells were exposed to two neurotoxic organophosphates, either sarin (GBI, GBII) at 1.4 X 10(-3) M or soman (GD) at 1.1 and 2.2 X 10(-3) M for 1 h, grown and their metaphase chromosomes scored for sister-chromatid exchanges (SCE). No cytotoxicity was seen with either agent at any dose level tested. Since histograms of SCE per cell showed that they were non-symmetrically arrayed around the mean, the number of SCEs were analyzed by using the nonparametric tests, Mann-Whitney and Kruskall-Wallis. Agents GBI and GBII did not show any significant increase in SCE over baseline. On the other hand, GD demonstrated a statistically significant increase in SCE with and without metabolic activation. Ethyl methanesulfonate (EMS) alone at 5 X 10(-3) M and cyclophosphamide (CP) at 10(-4) M in the presence of rat microsomes (S9) induced a 3- and 8-fold increase in SCE per cell, respectively.