Journal of environmental pathology and toxicology最新文献

Linoleic acid administered intravenously was highly toxic to the rat lung. The severity of the toxicity paralleled the dosage administered and was characterized by generalized, irreversible damage to alveolar wall structures. Although evidence of tissue damage was not apparent or minimal by light microscopy, ultrastructural studies disclosed extensive degeneration and necrosis of septal wall components with 15 minutes following injection of low dosages of linoleic acid. Degeneration of endothelial cells was most severe suggesting that these cells were the target of injury resulting in impaired vascular integrity, interstitial and alveolar edema, and degeneration of type 1 pneumocytes. Fragmentation and stripping of endothelium from capillary basement membranes was uniformly present and was in some instances associated with platelet aggregation indicative of early thrombosis. These studies suggest that this toxic effect on septal capillaries leading to increased permeability and alveolar edema may be a contributing factor to death occurring from free fatty acid toxicity in the human.

The memory response of lymphocytes to antigen was altered in mice exposed to lead, cadmium, or methylmercury. Both lead (1300 ppm) and methylmercury(10 ppm) impaired the memory response while cadmium (300 ppm) stimulated memory. Memory was significantly affected only at the largest dosages where toxic signs were generally detected. The lower dosages did not affect the memory of lymphocytes which produce antibody. These data suggest that the T lymphocyte rather than the B lymphocyte is the cell affected when the secondary immune response is altered after exposure to subclinical amounts of these environmental contaminants.

To study the long term effects of estrogenic diets, 2160 virgin female C3H/Hel mice, having a high titer to the mammary tumor virus factor (MMTV), were fed diets containing 0, 10, 100, 500, or 1000 ppb diethylstilbestrol (DES) or 100, 1000, or 5000 ppb 17 beta-estradiol (E2) from 6 to 110 weeks of age; 1368 virgin female C3HeB/FeJ mice, having a low titer to the MMTV, were fed diets containing 0, 10, 1000, or 500 ppb DES from 6 to 136 weeks. In estrogen-treated mice, the incidence of cervical adenosis and of mammary hyperplastic alveolar nodules was increased and the time to development of mammary adenocarcinomas was shortened. These changes tended to increase with dose and time and appeared earlier in the C3H/HeJ mice. Other tumors observed included 32 cervical and 20 endometrial adenocarcinomas, 16 cervical granular cell myoblastomas, 12 peritoneal mesotheliomas involving the uterus, 2 cervical and 4 vaginal squamous cell carcinomas, 2 ovarian teratomas, 6 osteosarcomas, 25 pheochromocytomas and 3 thyroid carcinomas. Of these tumors, 1 cervical and 2 endometrial adenocarcinomas, and 4 pheochromocytomas occurred in C3HeB/FeJ control mice at 104-130 weeks; none occurred in C3H/HeJ controls. This study indicates that the MMTV facilitates the development of mammary lesions in C3H mice, that estrogens predispose C3H mice to endometrial and cervical adenocarcinomas, and that cervical adenosis may be a precursor of cervical adenocarcinoma in C3H mice and serve as an early indicator of the potential uterine carcinogenicity of a test compound. It supports the view that the C3H mouse may serve as an animal model for uterine adenocarcinomas and adenosis in women exposed to estrogens.

The principle water-soluble metabolite of DDT in mammals has been shown to be DDA (bis(p-chlorophenyl)acetic acid). Previous studies suggested that DDA was secreted by the renal proximal tubule and was reabsorbed at an unspecified site in the nephron. Since DDA has been known to produce alterations in cellular functions, the present study examined the possibility that the renal transport of DDA was capable of causing acute nephrotoxicity. When 100 mg/kg of DDA was infused iv into the rat during a 90 min period, there was a significant decrease (congruent to 20%) in the glomerular filtration rate (GFR) after 110 min from the start of administration. During these experiments, there was no change in the mean arterial blood pressure (MABP), urine flow rate (V), renal clearance of tetraethylammonium (CTEA) or fractional reabsorption of Na (FRNa). After 200 mg/kg of DDA was infused iv into the rat during a 90 min period, there was a 60% decrease in the GFR, CTEA and V. However, the decrease in renal function was accompanied by a dramatic reduction in MABP (125 to 60 mmHg). To determine whether DDA could have produced acute renal failure when the perfusion pressure was kept constant, isolated kidney experiments were performed. In these experiments, DDA (1.0 mM) was present in a dextran perfusate and the perfusion pressure was kept constant at 90 mmHg. During these experiments, the GFR, V and FRNa were decreased significantly. The results indicated that a high perfusate concentration of DDA caused acute renal failure in the isolated kidney which was produced even when the perfusion pressure was kept constant. In conclusion, DDA produced renal failure in vivo which was associated with a reduction in renal perfusion pressure; however, perfused kidney experiments indicated that DDA could have caused a direct effect on nephron function.

Secalonic acid D is an acutely toxic and teratogenic mycotoxin, produced by Penicillium oxalicum in corn. Two rodent mutagenicity tests, the dominant lethal test designed to evaluate male germ cell mutations and the micronucleus test designed to evaluate somatic cell mutations, were conducted in mice to assess the carcinogenic potential of secalonic acid D. Data obtained indicate that the positive control compound triethylene melamine (TEM) induced dominant lethal mutations during weeks 1 through 4 after administration to male mice and also resulted in a greatly increased population of micronucleated polychromatic (immature) erythrocytes in bone marrow of treated male mice. Secalonic acid D, however, failed to induce dominant lethal mutations but produced a slight but statistically significant increase in the number of micronucleated polychromatic erythrocytes in mouse bone marrow at maximally tolerated doses. It is concluded that secalonic acid D may e weakly mutagenic in a mouse somatic cell mutation system.

A series of naphthalene diols, quinones, and related compounds were examined for their ability to inhibit mixed-function oxidase in liver microsomes obtained from rats which had been pretreated with 3-methylcholanthrene (3-Mc) or phenobarbital (PB). Using benzo(a)pyrene monooxygenase as a measure of mixed-function oxidase activity, it was found that phenanthrene-9, 10-quinone was the most active compound tested with a K1 = 0.79 microM. Phenanthrene-9, 10-quinone did not affect cytochrome c reductase but did inhibit aminopyrine N-demethylase and p-nitroanisole-O-demethylase in both 3-MC and PB-induced microsome with almost identical inhibition constants. 1,2-Naphthoquinone exerted similar effects as phenanthrene-9,10-quinone on cytochrome c reductase, aminopyrine N-demethylase and p-nitroanisole-O-demethylase. Both quinones stimulated NADPH oxidase activity but the extent of this stimulation did not explain their inhibition of microsomal oxidation. Kinetic studies using benzo(a)-pyrene monooxygenase with phenanthrene-9, 10-quinone and 1,2-naphthoquinone indicated that they were noncompetitive with benzo(a)pyrene and mixed noncompetitive with NADPH. Both of these quinones inhibited benzo(a)pyrene induced oncogenic transformation in C3H10T1/2CL8 cells in culture in a dose response manner, presumably by inhibition of the cellular microsomal enzyme which activate benzo(a)pyrene. Phenanthrene-9, 10-quinone and 1,2-naphthoquinone seem to inhibit microsomal oxidative processes by interaction at the level of cytochrome P-450 possibly with a cytochrome P-450-substrate-oxygen complex.

Ad-3 mutants induced by hycanthone, lucanthone and their indazole analogs, IA-3, IA-4 and IA-5 were studied to characterize the genetic alterations produced by these agents in Neurospora crassa. The results of genetic analysis indicate that, in marked contrast to past experiments with chemical mutagens on heterokaryon 12, all of these antischistosomal agents induce a very high frequency of multilocus deletions.

Four lots of 200 rainbow trout embryos were exposed to 200 ml solutions of aqueous 0.5 ppm aflatoxin B1 (AFB1) for 1 hr, and 4 lots of 200 rainbow trout embryos were sham-treated for 1 hr. After hatching and swimup, 100 fry from each group were selected for a feeding trial. Two groups of AFB1-treated and 2 groups of sham-treated fry were fed a control diet, while corresponding groups of AFB1-treated and sham-treated fry were fed the control diet plus 100 ppm Aroclor 1254 for 1 year. Samples were taken at 9 and 12 mon to monitor tumor incidence, Aroclor 1254 accumulation and histopathology. At the end of 12 mon, the liver cancer incidences in the combined AFB1-treated, control diet groups and the AFB1-treated, Aroclor 1254 diet groups were essentially the same. 65.8% and 63.9%, respectively. One trout in the sham-control, Aroclor 1254 diet group had a single liver cancer, but the sham-control, control diet group had none. The Aroclor 1254 fed groups had significantly higher liver to body weight ratios at 12 noon but not at 9 mon. Levels of accumulated Aroclor 1254 were similar to those reported previously, approximately 75 ppm on a whole fish basis at 12 mon. Glycogen depletion of hepatocytes and splenic hyperemia were the only tissue changes induced by Aroclor 1254.

When amikacin was administered to Fischer rats at a dose of 120 mg/kg/day for up to 14 days, renal proximal tubule cells became vacuolated, but BUN and creatinine remained normal. Renal cortical drug levels rose steadily throughout the treatment period. When, in a second trial of the same duration, the drug dose was tripled, focal proximal tubular necrosis, then regeneration, occurred and the animals became azotemic. Tissue drug concentrations peaked and began to decline during the treatment period, having reached levels more than three times higher than achieved at the lower dose. Ultrastructural changes were similar to those observed with other aminoglycosides. The results indicate that amikacin is less nephrotoxic than gentamicin and more toxin than tobramycin and netilmicin in the Fischer rat.

This article summarizes the results of experimental studies on teratogenesis associated with exposure to benzene by oral, parenteral or inhalation routes. Administration of benzene to pregnant experimental animals did not produce marked developmental effects in the fetus at concentrations which did not cause concomitant maternal toxicity. Thus, at maternally nontoxic levels, benzene does not constitute a teratogenic hazard.