Subchronic Oral Toxicity Study of Diisopropyl Methylphosphonate in Mink

Diisopropyl methylphosphonate (DIMP), produced during manufactureof the chemical agent GB (Sarin), is a groundwater contaminantat Rocky Mountain Arsenal, Colorado. DIMP was fed for 90 daysto dark brown "Ranch Wild" mink housed under controlled indoorconditions. One-year-old mink, 10 of each sex, were fed 0, 50,450, 2700, 5400, or 8000 ppm in standard ranch diet. ActualDIMP consumption was 0, 8, 73, 400, 827, and 1136 mg/kg bodywt/day, respectively. Two additional groups of 10 served as"pair-fed" controls. Body weight and food intake were recordedweekly. Complete blood count and 15 chemical analytes were measuredat Weeks 0, 3, 7, and 13. Necropsy and microscopic examinationwere performed on all mink. No clinical morbidity or deathsoccurred. Both sexes fed 8000 ppm ate approximately 20% lessand weighed approximately 20% less than the controls; 5400 ppmfemales had a 10% weight decrement. Plasma cholinesterase (ChE)decreased in the top three dose groups starting at Week 3. At13 weeks, decrements were approximately 50% but returned tonormal after 1 week without DIMP. Erythrocyte ChE was not reduced.Heinz bodies occurred in 10–15% of RBCs in 50% of 8000ppm mink at 13 weeks, and 0.1–2.0% of RBCs in 25% at 2700ppm. There were mild decreases in RBC count, hematocrit, andhemoglobin, and increases in reticulocyte count, at the 5400and 8000 ppm doses. All recovered within 3 weeks after DIMPwas with drawn. 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 (approximately73 mg DIMP/kg body wt/day). Compared to reports of similar studiesof DIMP in rats and dogs, these mink displayed no unique speciessusceptibility.     

Tumors of the Bladder, Kidney, and Intestine of F344 Rats and Liver of B6C3F1 Mice Administered o-Nitroanisole in Feed

Tumors of the Bladder, Kidney, and Intestine of F344 Rats andLiver of B6C3F₁ Mice Administered o-Nitroanisole in Feed. IRWIN,R. D., CHHABRA, R., EUSTIS, S., PINTER, A., AND PREJEAN, J.D. 1996). Fundam. Appl. Toxicol. 30, 1–12. o-Nitroanisole, a mutagenic intermediate used in the manufactureof azo dyes, was administered in feed for 2 years at concentrationsof 0, 222, 666, or 2000 ppm to groups of 60 male and 60 femaleF344 rats. No significant increase in neoplasms occurred inthese groups of rats. Additional (stop exposure) groups of 60male and 60 female F344 rats received diets containing 0, 6000,or 18,000 ppm for 27 weeks followed by maintenance on controldiets for up to an additional 77 weeks. Survival of the stopexposure groups was reduced because of the development of chemicalrelated neoplasms of the urinary bladder. After 13, 28, 40,and 65 weeks on study, 10 rats per group were necropsied andevaluated for the presence of chemical associated lesions. Hyperplasiaof the epithelium of the urinary bladder was significantly increasedat all interim evaluations. A transitional cell carcinoma wasobserved at the 13-week evaluation in one male rat that received18,000 ppm and thereafter transitional cell neoplasms of thebladder were present in male and female rats at each interimevaluation. Adeno matous polyps of the large intestine weresignificantly increased in groups that received 6000 or 18,000ppm. In addition carcino mas of the large intestine were presentin four males and two females that received 18,000 ppm. Hyperplasiaof the transitional epithelium of the renal pelvis was significantlyincreased in groups of rats that received 6000 or 18,000 ppmand transitional cell papillomas were observed in three malesand one female that received 18,000 ppm. Transitional cell carcinomasof the kidney occurred in one male that received 6000 ppm andsix males and one female that received 18,000. Groups of 60male and 60 female B6C3F₁, mice received dietary concentrationsof 0, 666, 2000, or 6000 ppm o-nitroanisole for 2 years. Nostop exposure study was conducted with mice. The only neoplasticresponse observed in mice was in the liver of males; hepatocellularadenomas or carcino mas were increased in groups of male micethat received 2000 or 6000 ppm. No increase in neoplasms associatedwith chemical exposure occurred in female mice.     

Hematologic Toxicity of AZT and ddC Administered as Single Agents and in Combination to Rats and Mice

Hematologic Toxicity of AZT and ddC Administered as Single Agentsand in Combination to Rats and Mice. THOMPSON, M. B., DUNNICK,J. K., SUTPHIN, M. E., GILES, H. D., IRWIN, R. D., AND PREJEAN,J. D. (1991). Fundam. Appl. Toxicol. 17, 159-176. Toxicity studiesof 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxycytidine(ddC) were conducted in F344/N rats and B6C3F, mice. The drugswere administered as single agents and in combination. In allstudies, animals were treated by oral gavage twice a day, 7days a week. In studies of the individual compounds, each wasadministered for 13 weeks at the following concentrations; AZTin rats, 0, 125, 250, 500, 1000 mg/kg and in mice, 0, 25, 50,100, 400, 1000 mg/kg; ddC in rats and mice, 0, 250, 1000, 2000mg/kg. Additional male rats and female mice that were treatedwith 0, 250, 1000, or 2000 mg/kg ddC and male and female micetreated with 0, 50, 400, 1000 mg/kg AZT were maintained for30 days after treatment was stopped (at 94 days) to evaluatethe reversibility of toxic effects. Hematologic variables weremeasured on Days 5, 23, and 94 (last day of dosing), and onDay 123 (after a 30-day period without treatment). AZT and ddCproduced dose-related, poorly regenerative, macrocytic anemiasas evidenced by decreases in erythrocyte counts, he-matocrits,and hemoglobin concentrations and increases in mean corpuscularhemoglobin and mean corpuscular volume. Bone marrow samplesin rats treated with AZT were hyperplastic whereas those inmice treated with AZT and rats and mice treated with ddC werehypoplastic. The hematologic toxicity of AZT was more severethan that of ddC. Generally, toxic effects of either chemicalwere greater in mice than in rats and more pronounced in femalethan in male animals. After 30 days without dosing, hematologiceffects either resolved or dramatically improved. In studiesin which ddC and AZT were administered in combination for 4weeks at concentrations of 0/0, 0/500, 500/0, 10/500, 100/500,500/500, and 500/1000 mg/kg ddC/AZT, there was macrocytic anemiain animals in the lower doses and marked microcytic anemia insurviving male mice in higher dose groups. Most female micedied in the 500/500 and 500/1000 mg/kg ddC/ AZT dose groups.At lower concentrations (100/500, 500/1000 mg/kg ddC/AZT), effectsof the two drugs were similar to those in the single drug studies.At higher concentrations (500/500 and 500/1000 mg/kg ddC/AZT),the combination treatment produced enhanced hematopoietic toxicity.These studies demonstrated the early and progressive time courseof toxicity of AZT and ddC, species differences in sensitivitiesand responses, and reversibility of effects after terminationof treatment. Based on these findings, a chronic toxicity studyis being conducted with AZT in mice.     

ERYTHROPOIETIN LEVELS IN CORD BLOOD OF CONTROL INFANTS AND INFANTS WITH RESPIRATORY DISTRESS SYNDROME

Erythropoietin levels (ESF) were measured in premature infants with and without the respiratory distress syndrome in an effort to define the role of intrauterine hypoxia in the genesis of the disease. No difference in levels could be detected between infants with and without the: respiratory distress syndrome. This suggests that either intrauterine hypoxia plays no role in the genesis of the respiratory distress syndrome or that the hypoxia is (1) of short duration, (2) of relatively long duration, or (3) remote with respect to the time of birth. The higher levels found in full-term infants suggested that hypoxia before birth is a more common feature of the term delivery than the premature delivery.     

Splenic Pseudocyst Associated with Hypersplenism

A patient with hypersplenism, who was found to have a splenic pseudocyst containing an organized hematoma, is described. There are only two patients with splenic pseudocyst and hypersplenism and an additional two patients with splenic cysts and hypersplenism reported in the world literature. The hypersplenism associated with splenic cysts and pseudocysts is explained on the basis of an expansion of the plasma volume and the total blood volume, an increased destruction of red blood cells and a pooling of blood in the enlarged spleen. The combined use of ultrasonography and computerized tomography has increased the accuracy of noninvasive diagnosis and made more invasive examinations unnecessary. When the ultrasound is technically unsuccessful or when it shows a mixed echo pattern, one should resort to computerized tomography with which it is possible, almost invariably, to differentiate between cysts and neoplasms.     

Sickle Cell Disease. A Serum Defect in the Thromboplastin Generation Test

1. A defective ability of sickle cell disease (SCD) serum to support thromboplastin generation was demonstrated.

2. The serum defect was associated primarily with homozygous SCD, although defects of varying severity were also noted in the heterozygous forms.

3. The deficiency appears to be due to an accelerated loss of thrombin orthrombin-like factors from serum.

Submitted on April 29, 1964 Accepted on November 1, 1964