Nephrotoxicity of sodium arsenate in dogs.

Nephrotoxicity of sodium arsenate was evaluated in dogs to determine the pathophysiologic basis for renal lesions caused by this heavy metal. Examination of biopsy specimens indicated that the low dose of the As salt (0.73 mg/kg of body weight) produced histologic changes consisting of mild degeneration and vacuolation of renal tubular epithelium. Vacuolation involved mainly the ascending thick portion of the nephron. Clinical pathologic changes were not demonstrable at this dosage level according to glomerular filtration rate (creatinine clearance), fractional reabsorption of sodium, potassium, and chloride; plasma osmolar and free water clearance; and urinalysis. The medium dose (7.33 mg/kg) resulted in alterations determined by urinalysis, but did not markedly affect other clinical pathologic measurements. Histopathologic changes were equal to or greater than those seen with the low dose. Tubular necrosis was observed in the cortical portion of the nephron and the ascending thick limb. The high dose (14.66 mg/kg) consistently produced marked changes in all parameters evaluated. Clinical pathologic alterations were compatible with acute tubular necrosis involving all segments of the nephron. Histologically, moderate glomerular sclerosis and severe tubular necrosis were observed. During recovery from the high dose of As, a gradual compensatory healing process was observed that was evident in all clinical pathologic parameters and was confirmed from sequential renal biopsy specimens.

Metabolism and renal handling of sodium arsenate in dogs.

Renal handling of sodium arsenate was studied in 5 dogs. Using a low dose (0.73 mg/kg of body weight) of sodium arsenate given IV, variable arsenite concentrations were detected in plasma and urine. Using a medium dose (7.33 mg/kg), the renal tubule cells were determined to be the probable sites of reabsorption of arsenate, reduction of arsenate to arsenite, and secretion or diffusion of the latter into urine. However, using a high dose (14.66 mg/kg), despite a similar pattern of reduction of arsenate to arsenite, marked reabsorption of arsenite into plasma took place instead of secretion or diffusion into urine. Because of reabsorption, the amount of arsenite in plasma (18.4 +/- 3.5% of the total As) was about 3 times higher than that measured during the medium dose experiment (6.0 +/- 1.0%). During the clearance experiments which lasted 110 minutes, only 40% to 45% of the arsenate infused was excreted in urine, and a minimal amount of dimethylarsinic acid (DMAA) was detected. In contrast, by the next day, DMAA was the major metabolite excreted in urine. This excretion of As as DMAA was partly due to delayed excretion of 55% to 60% As that was stored in the body and was subsequently metabolized.

Occupational exposures to pesticides containing organoarsenicals in California.

The only organic arsenicals used in agriculture are methanearsonic acid (MSMA) and its sodium and ammonium salts and dimethylarsinic acid (cacodylic acid) and its sodium salt. They have an oral LD50 in the rat of 700-1,000 mg/kg and are classified as toxicity category 3 pesticides. During the three-year period 1975, 1976 and 1977 in California there were 34 reports by physicians of injury due to exposure to pesticides containing organic arsenicals of which nine resulted in systemic symptoms and the remainder being eye and skin irritations. There appeared to be prompt recovery from these exposures. They were caused primarily by use of faulty equipment, not using due care in its operation, poor work practices and improper use of protective equipment. There is no evidence that this group of chemicals is carcinogenic in animals or man.

Tissue distribution and binding of radioactivity in mouse after intravenous administration of [14C]3-chloro-p-toluidine.

The avicide [14C]3-chloro-p-toluidine (CPT) HCL, ring labeled, was injected intravenously to mice. The radioactivity associated with this compound was found to be unevenly distributed in different parts of the body. It leaves the plasma, as well as many tissues, with 2 elimination rate constants, the fast and the slow. The faster component of the [14C]CPT decay curve of the plasma was similar to the faster components of the decay curves of brain, lung, heart, intestine, testicle and kidney. The retention half-life of the radioactivity for the slower component of the decay curve varied a great deal from tissue to tissue, being shortest (14.55 h) in the intestine and longest (326 h) in the adipose tissue. Of the 10 tissues examined, a substantial amount of [14C]CPT radioactivity was found to be covalently bound only to liver, kidney, lung and RBC protein. There was no cause and effect relationship between the covalent binding of radioactivity and the tissue pathology, since no remarkable histopathological lesions were found in the liver and kidney of treated mice. The tissue retention of [14C]CPT radioactivity did not parrallel the covalent binding of the compound to tissue protein. The covalent binding of [14C]CPT radioactivity to RBC was suggestive of the conversion of the parent compound into a reactive metabolite responsible for the generation of methemoglobin in mice. The percent distribution of radioactivity in subcellular fractions of liver and kidney correlated with the amount of protein associated with subcellular fractions. The 102 000 g supernatant fraction of the liver contained the highest proportion of radioactivity, both in terms of absolute percent radioactivity as well as specific activity (dpm/mg of protein). This was also true for the 102 000 g supernatant fraction of the kidney. The majority of radioactivity in the 102 000 g supernatant fraction of liver appears to be bound to one or more polypeptide sized proteins with a mol. wt. of approx. 1000--2000.

Organophosphate pesticide poisoning.

A total of 118 workers from a 120-person grape picking crew became ill in early September 1976. Of these (108 men and 10 women), 85 received medical attention and three of the 85 were admitted to hospital. The symptoms were typical for organophosphate poisoning. Average plasma and red cell cholinesterase values for the affected workers were depressed more than 60 percent. Most were treated with atropine and some were also treated with 2-PAM (pralidoxime). The exposure to residues of the organophosphate pesticides dialifor (Torak((R))) and phosalone (Zolone((R))) occurred in one grower's vineyards near Madera, California. It appeared that workers had been allowed into recently-treated areas before the expiration of the required 30-day safety interval for dialifor, and that excessive skin exposure to residues of this pesticide had resulted. The clinical management of these cases and the occupational surveillance of the workplace became quite complex. The grower sustained significant losses of grapes during the period in which some of his vineyards were under quarantine and he had to pay substantial medical expenses as well as a fine for violating state regulations concerning the proper use of pesticides. Organophosphate pesticides decay more slowly under hot, dry weather conditions than they do when rainfall is frequent. California has imposed a number of specific safety intervals to be observed after the application of these pesticides to certain crops. If, in violation of these regulations, workers are permitted to enter fields too soon, poisoning can occur.

Hexachlorobenzene II. Effects on growing lambs of prolonged low-level oral exposure to hexachlorobenzene (HCB).

Fifty growing male (castrated) lambs were exposed to hexachlorobenzene in the diet at levels of 0, 0.01, 0.1 and 1.0 ppm for 90 days. They were then moved to clean quarters and the study continued for an additional 210 days. Growth rates, certain plasma enzyme activities and hepatic microsomal enzyme activities were studied to detect subclinical effects related to the exposure. A 19-day acute exposure at 100 ppm was done and the same parameters except for growth rate, measured. Hematocrit and plasma protein concentrations were also monitored. No significant changes were seen in the growth rates (90 days exposure), in the plasma enzymes alkaline phosphatase, glutamic oxaloacetic transaminase, glucose 6-phosphate dehydrogenase or succinic dehydrogenase, or in the hematocrit or plasma protein concentrations after either the 90-day or 19-day exposures. However, in vivo metabolism of antipyrine was increased in both the 1.0 ppm (90-day) and the 100 ppm (19-day), but was significantly increased (p less than 0.01) in only the 100-ppm exposure. Additionally, hepatic microsomal N-demethylase was increased significantly by the 90-day exposure at 1.0 ppm and the 19-day exposure at 100 ppm, but the hepatic microsomal O-demethylase was significantly increased only after the 1.0-ppm exposure. Histopathologic examination of tissues (brain, lung, myocardium, large and small intestines, liver, kidneys, adrenals, mesenteric lymph nodes) collected from animals sacrificed at 90 days and at the termination of the study (300 days) revealed no lesions suggestive of harmful HCB exposure.

Hexachlorobenzene I. Uptake, distribution and excretion of hexachlorobenzene (HCB) in growing lambs.

The uptake, distribution, and excretion of hexachlorobenzene (HCB) was studied in young male (castrated) lambs. Lambs were exposed for 90 days at a dietary concentration of 0, 0.01, 0.1 and 1.0 ppm. Tissue concentration of HCB were monitored by periodic omental biopsy and by post-slaughter collection of tissues at 90 and at 300 days. Blood samples were collected by venipuncture each time that biopsies or sacrifice occurred. Findings of the 300 days duration study were: (1) the growth rate of the exposed lambs was unaffected by the exposure to the dietary HCB, (2) adipose tissue concentrations reached a level approximately ten times that in the diet at the end of the 90-day exposure period, (3) HCB concentration was higher in the omental fat than in the perirenal fat at 90 days but not at 300 days, (4) a good portion of the apparent decresae in HCB in the fat following cessation of exposure is due to dilution (by increasing carcass fat), (5) the apparent half-life of HCB was approximately 90 days and was not dose-dependent at the exposure rates studied, and (6) the highest HCB concentrations in other tissues were in the brain and liver. The study demonstrated that the omental biopsy provides an excellent means of estimating body fat burden of this lipid soluble pesticide, although it tends to provide an overestimate during actual dietary exposure. The finding that the bioconcentration of and the depletion from the adipose tissues were independent of dose enables prediction of the degree to which food animals might become contaminated if allowed to feed on HCB-contaminated pastures or feed stuffs, and of the time which will be required for such residues to decrease to negligible levels. This predictive ability is of obvious benefit to both the food animal producer and the consumer. Since the HCB is apparently much more stable in the body than is indicated by the depletion half-life of 90 days in these growing lambs, it follows that environmental contamination of grazing lands or animal feeds is of far greater consequence for adult animals which would not be likely to experience the growth dilution of carcass residues.

The effect of a low energy diet on the concentration of DDT in the adipose tissue of turkeys.

Turkey hens which had completed a breeding season and contained DDT in their fat were divided into 2 groups of 20 hens each. One group was fed a high wheat control diet throughout a 6 week period while another group was fed a low energy diet for 3 weeks and then the control diet for 3 weeks. Biopsy samples of adipose tissue taken initially and at 3 weeks and carcass adipose tissue samples of 6 weeks were analyzed for DDT and DDE. Total DDT concentration in adipose tissue increased when the hens were fed the low energy diet but decreased again when fed the control diet so that the overall change in DDT concentration over the 6 week period was not different for the two groups. The biopsy technique used in this study was successful in greatly reducing variability and improving precision.

Mobilization of leucocytes and subsequent release of histamine and lysosomal enzymes into the peritoneal and pleural cavities of rats by actinomycin D (dactinomycin).

1. The effects of intraperitoneal injections of actinomycin D on the temporal characteristics of the accumulation of the inflammatory exudate and cells into the peritoneal and pleural cavities were studied in male Sprague Dawley rats. 2. A measurable quantity of the exudate appeared in both cavities within 24 h and reached maxima in the peritoneal and pleural cavities on the fourth and third days, respectively. Thereafter, the accumulated volume of liquid decreased progressively in the peritoneal cavity but stayed more or less at about the same level in the pleural cavity until the sixth day. 3. The pooled peritoneal and pleural exudates contained neutrophils, macrophages, mast cell and eosinophils. The leucocyte infiltration occurred in two phases, the maximum cell numbers being found on the third and fifth days. A precipitous fall in the number of leucocytes occurred on the fourth day. Neutrophils and macrophages accounted for 85-95% of the total number of leucocytes. 4. The supernatant of the inflammatory exudate after centrifugation at 3,000 g contained histamine and the soluble lysosomal enzyme proteins, acid phosphatase and beta-glucuronidase until the sixth day following the initial dose of actinomycin D. 5. It is suggested that the release of lysosomal enzymes in the exudate, subsequent to leucocyte mobilization and the release of histamine from the mast cells, are probably involved in the genesis of inflammatory conditions induced by actinomycin D.

In vivo hemolytic potency and binding of chlorpromazine to plasma protein and erythrocytes of rat and dog (38579).

It was demonstrated by equilibrium dialysis that dog red cells have a greater ability to bind chlorpromazine than rat red cells. Dog plasma was shown to have a greater ability to bind chlopromazine than rat plasma although this difference was not statistically significant. In the presence of CPZ (10-3M), the 50% hemolysis time of dog red cells suspended in homologous plasma or in 0.9% buffered NaCl solution was much greater than that of rat red cells treated in the same manner. The 50% hemolysis time of dog red cells suspended in homologous plasma was considerably shortened when they were suspended in rat plasma. Conversely, an increase in the 50% hemolysis time was obtained when rat red cells were suspended in dog plasma. Several possibilities for the slower rate of CPZ-induced hemolysis of dog red cells as compared to rat has been discussed in the present report.