Microscopic Changes In Liver Research Articles

Pathological and structural study of cardiac striated muscle and quadriceps along with the study of microscopic changes in liver, kidney and lung tissue following short-term and long-term resistance exercises in male rats

Background. Resistance exercise is a method designed to increase muscle strength and endurance, leading to beneficial physiological changes in various tissues. The aim of this study is to investigate the pathological and structural effects of short-term and long-term resistance training on various tissues of male rats, including cardiac striatum, quadriceps, liver, kidney, and lung tissue. Methods. Forty male Wistar rats were randomly divided into four groups: one-month control, four-month control, one-month exercise, and four-month exercise. After the exercise period, the animals were anesthetized and dissected to separate various tissues, which were then treated with formalin and prepared for analysis. Results. The study findings showed that liver tissue did not show significant histopathological changes in response to exercise. However, in the heart tissue, mild hyperemia and hypertrophy of muscle cells were observed in the exercise groups compared to the control groups. In the quadriceps muscle, hypertrophy was observed to a lesser extent in the one-month exercise group and to a greater extent in the four-month exercise group. There was a significant difference in the diameter of the muscle cells of the quadriceps muscle between the one-month and four-month exercise groups, indicating the beneficial effects of long-term exercise. Additionally, an increase in the size of the epithelial tissue of the urinary tubes was observed in both exercise groups, which indicates an increase in kidney function due to exercise. Conclusion. Overall, the results of this study show that resistance exercise can lead to beneficial physiological changes in various tissues, especially with long-term exercise. Understanding these changes can increase our knowledge about the benefits of exercise. Practical Implications. Resistance exercises, through actions such as hyperemia, hypertrophy of muscle cells, and hypertrophy of the epithelial tissue of urinary tubes, improve the efficiency of the heart, kidneys and muscles during sports exercises, especially with long-term exercise.

PATHOMORPHOLOGY OF CANDIDAMYCOSIS IN THE LIVER OF REPTILES

The article describes our studies on the study of pathomorphological changes in the liver of reptiles with disseminated candidosis. The aim of the research is to study the pathomorphology of mycosis caused by fungi of Candida genus, the features of macroscopic and microscopic changes in liver under the influence of this type of parasitic fungus. The study is aimed at analyzing changes in the hepatobiliary system of reptiles with Candida infection. Pathoanatomical, cytological and histological diagnostic methods were used in the course of the study, with application of: PAS-reaction, Gamorry-Grocott, by Mallory, Van Gieson and Diff-Quikk. Consideration of the issues of pathomorphological manifestation of mycoses, in particular candidosis in the liver of reptiles, was carried out at the Department of Morphology and Expertise of Ural State Agrarian University in 2013 in 2021. To describe the manifestation of yeast-like fungal infections in the liver, we performed a pathoanatomical autopsy of 90 reptiles with a preliminary diagnosis of mycosis, followed by selection, fixation and histological examination of the affected liver according to the generally accepted method. Laboratory research methods were carried out by inoculating biological material on Sabouraud nutrient medium to confirm the diagnosis. We detected changes characteristic of granulomatous process in the liver with candidosis. Granulomas were located both on the surface of the organ and inside. They were pale gray in color, clearly limited, ranging in size from 0.05 to 0.5 cm. The liver parenchyma was loosened, the liver was enlarged, the edges were blunt, the color was from dark red to dark brown. Areas of necrosis with threads of pseudomycelium were revealed in granuloma localization during histological examination of the liver parenchyma. Sinusoidal capillaries were filled with blood in the surrounding tissue, and the vessels in the triad area underwent the processes of mucoid and fibrinoid swelling. Processes of granular, sometimes fatty degeneration were revealed in the parenchyma of the organ.

Nonclinical Safety Profile of Revusiran, a 1st-Generation GalNAc-siRNA Conjugate for Treatment of Hereditary Transthyretin-Mediated Amyloidosis.

Revusiran is a 1st-generation short interfering RNA targeting transthyretin conjugated to an N-acetylgalactosamine ligand to facilitate delivery to hepatocytes via uptake by the asialoglycoprotein receptors. Revusiran, in development for the treatment of hereditary transthyretin-mediated amyloidosis, was discontinued after an imbalance in deaths in the “ENDEAVOUR” phase 3 clinical trial. Nonclinical safety assessments included safety pharmacology, acute and repeat-dose toxicity, genotoxicity, and carcinogenicity. There were no effects on cardiovascular or respiratory function in monkeys after single doses of up to 100 mg/kg. No neurological effects were noted in monkeys in repeat-dose studies up to 300 mg/kg. Revusiran was well tolerated in repeat-dose mouse (weekly doses) and rat and monkey (five daily doses followed by weekly doses) toxicity studies. The no observed adverse effect level (NOAEL) in rats was 30 mg/kg based on reversible microscopic changes in liver that were accompanied by correlating elevations in clinical chemistry at higher doses. Dose-limiting toxicity was absent in monkeys, and the NOAEL was 200 mg/kg. There was no evidence of genotoxicity in vitro or in vivo at limit doses or carcinogenicity in a 2-year study in rats at doses up to 100 mg/kg. Overall, these results demonstrate that revusiran had a favorable nonclinical safety profile.

MONOSODIUM GLUTAMATE-INDUCED LIVER MICROSCOPIC AND BIOCHEMICAL CHANGES IN MALE RATS, AND THE POSSIBLE AMENDMENT OF QUERCETIN

The safety of using monosodium glutamate (MSG) as a food flavour enhancer has generated much controversy locally and globally. Quercetin (QU), a natural compound of multiple origins, has broad biopharmacological effects as an antioxidant and a hepatoprotective substance. Therefore, the present study was designed to investigate the modulatory effect of oral doses of QU on the microscopic liver changes and liver oxidative stress induced by MSG. Thirty male albino rats were divided into five groups, each of six rats: group I received distilled water, group II received corn oil, group III was administered QU (14 mg/kg body weight), group IV was treated with aqueous MSG (15 mg/kg body weight), and group V was given MSG (15 mg/kg body weight) simultaneously with QU (14 mg/kg body weight), orally and daily for 30 days. Numerous deleterious histological and ultrastructural changes were induced by MSG in concomitant with a significant increase in the activities of serum aminotransferases (ALT and AST) and the level of hepatic lipid peroxidation, while decreases in superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, as well as reduced glutathione (GSH) concentration were also recorded. QU administration amended the liver histological lesions and ultrastructural changes induced by MSG via decreasing significantly the level of hepatic lipid peroxidation and the leakage of serum aminotransferases, and improving the hepatic antioxidant defence system. In conclusion, QU showed a hepatoprotective activity against the potential toxicity of MSG food flavour.

Use of yeast (Pichia kudriavzevii) as a novel feed additive to ameliorate the effects of aflatoxin B1 on broiler chicken performance.

The aim of this study was to evaluate the efficacy of autochthonous Pichia kudriavzevii as a novel bioadsorbent for aflatoxin B1 (AFB1). The selection of this yeast was based on the AFB1 adsorption capacity previously demonstrated in vitro (Magnoli et al. 2016). One-day-old Cobb broilers (n=160) were randomly assigned to four dietary treatments (T1: basal diet (B); T2: B + 0.1% yeast; T3: B + AFB1, 100μg/kg; T4: B + 0.1% yeast + AFB1, 100μg/kg). Performance parameters (average daily weight gain body, average daily consumption, feed conversion ratio, carcass weight, and dead weight), biochemical parameters (albumin, globulin, and albumin/globulin), liver pathological changes, and AFB1 residual levels in the liver and excreta were evaluated. Significant differences (P<0.05) in performance parameters were observed among treatments and controls: T3 group showed the lowest average daily body weight gain value while in T4 group, the value of this parameter increased significantly (P<0.05). T3 and T4 groups showed the lowest and highest values for average daily feed consumption, respectively. The feed conversion ratio (FC) showed no significant differences among treatments. T3 group showed the lowest dead weight and carcass weight compared with T1 group. The biochemical parameters showed no significant differences among treatments. T3 group showed macroscopic and microscopic liver changes compared to the control. Aflatoxin B1 levels (μg/g) were detected in broiler livers and showed significant differences among treatments (P<0.05). In conclusion, native P. kudriavzevii incorporation (0.1%) in broiler diets containing AFB1 was shown to be effective in ameliorating the adverse effects of AFB1 on production.

Biochemical and histopathological ultrastructural changes caused by ZnO nanoparticles in mice

Five week-old mice were divided into a vehicle control group, and groups exposed to ZnO nanoparticles at low (0.5 g/kg), middle (1 g/kg), high (3 g/kg), and exceptionally high-dose (5 g/kg). After the first, second, third, and fourth weeks’ of exposure, blood biochemistry, histopathology, and electron microscopic ultrastructural changes in liver, kidney and spleen were investigated. Increased alkaline phosphatase activities were observed in all treated mice being statistically significant at higher dose. No changes were observed in the serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, creatinine, blood urea nitrogen, and lipid levels. During the first and second weeks of the treatment, effects on the cytoarchitecture of liver, kidney, and spleen were not perceived while during the third and fouth weeks of treatment sporadic mild effects were seen. Ultrastructural electron microscopic changes in liver, kidney, and spleen were not observed for the low-dose group on the first, second, third, and fourth weeks, suggesting that exposure to ZnO nanoparticles at low dose is safe. Long-term (i.e., more than 28 days) exposure to the exceptionally high-dose resulted in sporadic changes in nuclear chromatin condensation, irregular nuclear membrane, polymorphic mitochondria, mitochondrial swelling, and vacuolation. ZnO nanoparticles could be well tolerated and no death occurred in any group of treated mice.

Effect of low levels of aflatoxin B1 on performance, biochemical parameters, and aflatoxin B1 in broiler liver tissues in the presence of monensin and sodium bentonite

Aflatoxins (AF) are a major problem in broiler production and are significant economic and public health burdens worldwide. A commercial sodium bentonite (Na-B) adsorbent was used to prevent the effect of AF [50 µg of aflatoxin B₁ (AFB₁)/kg of feed] in broiler productivity, biochemical parameters, macroscopic and microscopic liver changes, and AFB₁ liver residues. The influence of Na-B (0.3%) and monensin (MON, 100 mg/kg), alone or in combination, was investigated in depth. The dietary treatments were as follows: treatment (T) 1: basal diet (B); T2: B + MON; T3: B + Na-B; T4: B + Na-B + MON; T5: B + AFB₁; T6: B + AFB₁ + Na-B + MON; T7: B + AFB₁ + MON; T8: B + AFB₁ + Na-B. Birds were fed dietary treatments for 28 d (d 18 to 46). No significant differences (P < 0.05) were observed among treatments with respect to broiler performance, biochemical parameters, or relative liver weights. With the exception of T8, all livers showed histopathological alterations, with accumulation of fat vacuoles. The normal appearance of livers from T8 showed the protective effect of Na-B against aflatoxicosis. The residual AFB₁ levels in livers from T5 to T8 ranged from 0.2 to 1.0 ng/g and were higher in livers from T6 (P < 0.05). Results of this study indicate a competition between AFB₁ and MON for adsorption sites on Na-B when feed contains low levels of the toxin, indicating a nonselective adsorption capacity of this particular Na-B. In addition, significant levels of AFB₁ in livers indicate that this determination is an important technique not only for diagnosis of aflatoxicosis in broilers, but also for quality control of avian products.

The relationship among microsomal enzyme induction, liver weight, and histological change in cynomolgus monkey toxicology studies

The purpose of this investigation was to examine the relationship among hepatic microsomal enzyme induction, liver weight, histological evidence of hepatic injury, and serum clinical chemistry markers of hepatic origin in the cynomolgus monkey. We report here the results from independent toxicology studies for 10 investigative drug candidates representing four therapeutic classes. Study conditions were selected to elicit target organ toxicity. We found that six of the 10 compounds altered cytochrome P450-associated activities in both male and female monkeys, two in females only, and one altered similar activities in males only. Frequently, significant treatment-related elevations in NADPH cytochrome c reductase and ethylmorphine N-demethylase were noted. When the results from all 10 studies were pooled, 14 cytochrome P450-associated activities were significantly increased and five were decreased in males compared to 15 significantly increased and three decreased in the females. Treatment-associated liver weight increases were noted in four studies. Except for hepatocellular hypertrophy in one study, no significant treatment-related microscopic changes in liver and no elevations of serum biomarkers commonly associated with liver toxicity were observed in any of the studies that demonstrated significant hepatic enzyme induction. Compared to parallel rat studies, one compound was an inducer only in monkeys and one was an inducer only in rats. Significant elevations of microsomal drug-metabolizing enzymes in the cynomolgus monkey liver are not accompanied by substantial hepatic changes except for hepatomegaly. These alterations in the hepatic drug-metabolizing enzyme system were benign based the absence of histopathological lesions and serum biomarkers of hepatobiliary toxicity.

Dimethoate-induced effects on antioxidant status of liver and brain of rats following subchronic exposure

Dimethoate, an organophosphate pesticide, is used in controlling the pests of a variety of crops. The study was carried out to understand the role of dimethoate in inducing oxidative stress leading to generation of free radicals and alterations in antioxidant enzymes and scavengers of oxygen free radicals. The effects of subchronic exposure of dimethoate in the production of oxidative stress were evaluated in male Wistar rats in the present study. Dimethoate was administered orally at doses 0.6, 6, and 30 mg/kg for 30 days in these rats. The results indicated an increase in levels of hepatic Cytochrome P450, lipid peroxidation, catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase in liver and brain at doses 6 and 30 mg/kg. There were no significant changes in the level of glucose-6-phosphate dehydrogenase activity except in liver at 30 mg/kg. A decrease in glutathione was observed at 30 and 6 mg/kg in both liver and brain. Glutathione- S-transferase increased at 30 and 6 mg/kg in liver and 30 mg/kg in brain. Erythrocyte acetylcholinesterase was inhibited at 30 and 6 mg/kg doses. Dose-dependent histopathological changes were seen in both liver and brain. This study concludes that oxidative stress due to dimethoate may be ascribed to induction of Cytochrome P450, inhibition of AChE and disturbance in activities of GSH and GST enzymes causing lipid peroxidation and histological and electron microscopic changes in liver and brain.

Relative bio-availability and utilisation of phosphatic fertilisers as sources of phosphorus in broilers and layers

1. Different concentrations of non-phytate phosphorus (NPP, 2·5, 3·0, 3·5, 4·0 and 4·5 g/kg diet) were given to broilers (8 to 42 d of age) to establish regressions between dietary NPP concentration and body weight gain and tibia ash content. Second and third experiments were conducted to study the feasibility of utilisation of different phosphatic fertilisers [ammonium phosphate (AP), ammonium polyphosphate (APP), single super phosphate (SSP), NPK (17:17:17, NPK) and NP (28:28:0, NPK)] in commercial broilers (8 to 42 d) and White Leghorn layers (252 to 364 d). 2. Phosphatic fertilisers were incorporated both in broiler (10 g calcium and 4·5 g NPP/kg) and layer (35 g calcium and 3·5 g NPP/kg) diets by replacing dicalcium phosphate (DCP) in toto. 3. The logarithmic curves obtained for predicting the body weight gain and tibia ash content at different levels of NPP used in experiment 1 were Y = 156·27 + 2468·8 log X (r 2 = 0·958) and Y = 530·82 + 144·26 log X (r 2 = 0·916), respectively. 4. Body weight gain and food intake in broilers given APP- or NP-supplemented diets were comparable to these in the DCP-fed group. Feeding of NPK, AP or SSP resulted in significant depression in weight gain and food intake and high excreta moisture content. Food/gain, Ca and P contents in tibia ash and serum were not influenced by the use of phosphatic fertilisers as P sources in broiler diets. 5. Tibia ash content in broilers fed on diets containing fertilisers was either similar to or significantly higher than that in the DCP-fed group. Broilers on AP or SSP retained more P and had higher tibia ash content than those on DCP. AP, SSP or NPK caused degenerative and necrotic changes in liver, kidney and intestine of broilers. 6. Relative bio-availability of P from APP or NP was better for body weight gain than AP, SSP or NPK, while the reverse was true for bone calcification. 7. APP and NP gave hen-d egg production similar to that of DCP-fed layers. Food intake was significantly reduced in layers fed on diets containing fertilisers. However, food/egg mass, egg weight and serum Ca and inorganic P contents were not influenced by inclusion of fertilisers in layer diets. 8. Except for AP, inclusion of fertilisers in layer diets reduced shell weight and shell thickness compared with the DCP-fed group. However, no apparent eggshell defects were found which could be attributable to diet. 9. Results of these experiments suggest that APP and NP can be used as the sole source of P both in broiler and layer diets, replacing DCP in toto. However, when utilising these P sources in layers, due attention should be given to shell quality. Fertilisers containing high F (AP and SSP) or K (NPK) reduced performance in broilers and layers and caused microscopic changes in liver, kidney and intestine in broilers.

Man-made vitreous fibres and lung cancer

<dm:abstracts xmlns:dm="http://www.elsevier.com/xml/dm/dtd"><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" view="all" class="author" id="aep-abstract-id1"><ce:section-title>Publisher Summary</ce:section-title><ce:abstract-sec view="all" id="aep-abstract-sec-id1"><ce:simple-para id="fsabs076" view="all">This chapter reviews the glyphosate. Glyphosate is a broad-spectrum, post-emergent systemic herbicide with activity on essentially all annual and perennial plants. Glyphosate is poorly absorbed both dermally and via oral exposure, and it is not biotransformed. It has been shown that glyphosate does not bioaccumulate. Animal studies indicate that glyphosate is essentially nontoxic via acute oral and dermal exposure, and that glyphosate salts are nonirritating to the eyes and skin. Glyphosate does not produce dermal sensitization in guinea pigs. In repeated dose studies in laboratory animals, treatment-related effects included reduced body weight gain, increased liver weights, degenerative ocular lens changes, and microscopic liver changes, but only at very high dose levels. Glyphosate-based formulations are used worldwide in virtually every phase of agricultural, industrial, silvicultural, and residential weed control. Due to low solubility in water, glyphosate is typically formulated into commercial products in the form of a salt. Large amounts of glyphosate-based herbicides are occasionally deliberately ingested to attempt suicide and may result in serious gastrointestinal, cardiovascular, pulmonary, and possibly death. Glyphosate has very low acute toxicity and is not mutagenic.</ce:simple-para></ce:abstract-sec></ce:abstract></dm:abstracts>

Occupational hypersensitivity to mollusc shell dust

<dm:abstracts xmlns:dm="http://www.elsevier.com/xml/dm/dtd"><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" view="all" class="author" id="aep-abstract-id1"><ce:section-title>Publisher Summary</ce:section-title><ce:abstract-sec view="all" id="aep-abstract-sec-id1"><ce:simple-para id="fsabs076" view="all">This chapter reviews the glyphosate. Glyphosate is a broad-spectrum, post-emergent systemic herbicide with activity on essentially all annual and perennial plants. Glyphosate is poorly absorbed both dermally and via oral exposure, and it is not biotransformed. It has been shown that glyphosate does not bioaccumulate. Animal studies indicate that glyphosate is essentially nontoxic via acute oral and dermal exposure, and that glyphosate salts are nonirritating to the eyes and skin. Glyphosate does not produce dermal sensitization in guinea pigs. In repeated dose studies in laboratory animals, treatment-related effects included reduced body weight gain, increased liver weights, degenerative ocular lens changes, and microscopic liver changes, but only at very high dose levels. Glyphosate-based formulations are used worldwide in virtually every phase of agricultural, industrial, silvicultural, and residential weed control. Due to low solubility in water, glyphosate is typically formulated into commercial products in the form of a salt. Large amounts of glyphosate-based herbicides are occasionally deliberately ingested to attempt suicide and may result in serious gastrointestinal, cardiovascular, pulmonary, and possibly death. Glyphosate has very low acute toxicity and is not mutagenic.</ce:simple-para></ce:abstract-sec></ce:abstract></dm:abstracts>

Thirteen-Week Inhalation Toxicity of 2- and 4-Chloronitrobenzene in F344/N Rats and B6C3F1 Mice

Toxicity studies were performed by exposing F344/N rats and B6C3F1 mice to 2- and 4-chloronitrobenzene (CNB) by whole-body inhalation 6 hr/day, 5 days/week, for 13 weeks. Animals were evaluated for clinical chemistry (rats), hematology (rats), histopathology, and body/organ weights. Exposure concentrations were 0, 1.1, 2.3, 4.5, 9, and 18 ppm for 2-CNB and 0, 1.5, 3, 6, 12, and 24 ppm for 4-CNB. All rats in the 2-CNB study survived until the end of the study. Two male mice in the 18-ppm group in the 2-CNB study, however, died during Week 12; no deaths attributable to 4-CNB exposure occurred in rats or mice. In both studies, the mean body weight gains of exposed animals were similar to those of the respective controls. In rats, inhalation exposure to 2- or 4-CNB resulted in methemoglobinemia leading to a regenerative anemia and a variety of tissue changes secondary to the oxidative erythrocyte injury. In the 2-CNB study, methemoglobinemia resulted in a normocytic, normochromic, responsive anemia, whereas with 4-CNB, the methemoglobinemia was more severe and resulted in a macrocytic, hyperchromic, responsive anemia. Alterations of erythrocyte morphology were observed in both studies; changes included Heinz bodies, poikilocytes, and polychromasia. In rats, both isomers caused increases in serum activities of alanine aminotransferase and sorbitol dehydrogenase and increased bile acid concentrations. Microscopic liver changes included hemosiderin deposition in Kupffer cells (rats and mice exposed to 4-CNB), hepatocytomegaly (mice), and cytoplasmic basophilia (rats). Hepatocellular necrosis and chronic inflammation observed in mice were rather specific to the 2-CNB isomer, as only slight evidence of focal necrosis in the liver was observed in mice exposed to 4-CNB. Splenic lesions included hemosiderin accumulation, capsular fibrosis, and increased hematopoietic cell proliferation. Increased bone marrow hemosiderin and hematopoietic cell proliferation and kidney tubule hemosiderin deposition were also observed. Other findings, attributed to chemical exposure but not to the hematotoxicity, were described. Lesions included hyaline droplet nephropathy and degeneration of the testis in male rats exposed to 4-CNB, inflammation of the harderian gland in rats exposed to 4-CNB, hyperplasia of the nasal cavity epithelium in rats exposed to 2-CNB, and hyperplasia of the forestomach epithelium in mice exposed to 4-CNB; these lesions have not been described previously in studies with these chemicals. Based on the exposure concentrations evaluated, A no-observed-adverse-effect level (NOAEL) for histopathological injury in mice was 4.5 ppm for 2-chloronitrobenzene and 6 ppm for 4-chloronitrobenzene; a NOAEL was not determined for rats.

Magnetic fields

<dm:abstracts xmlns:dm="http://www.elsevier.com/xml/dm/dtd"><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" view="all" class="author" id="aep-abstract-id1"><ce:section-title>Publisher Summary</ce:section-title><ce:abstract-sec view="all" id="aep-abstract-sec-id1"><ce:simple-para id="fsabs076" view="all">This chapter reviews the glyphosate. Glyphosate is a broad-spectrum, post-emergent systemic herbicide with activity on essentially all annual and perennial plants. Glyphosate is poorly absorbed both dermally and via oral exposure, and it is not biotransformed. It has been shown that glyphosate does not bioaccumulate. Animal studies indicate that glyphosate is essentially nontoxic via acute oral and dermal exposure, and that glyphosate salts are nonirritating to the eyes and skin. Glyphosate does not produce dermal sensitization in guinea pigs. In repeated dose studies in laboratory animals, treatment-related effects included reduced body weight gain, increased liver weights, degenerative ocular lens changes, and microscopic liver changes, but only at very high dose levels. Glyphosate-based formulations are used worldwide in virtually every phase of agricultural, industrial, silvicultural, and residential weed control. Due to low solubility in water, glyphosate is typically formulated into commercial products in the form of a salt. Large amounts of glyphosate-based herbicides are occasionally deliberately ingested to attempt suicide and may result in serious gastrointestinal, cardiovascular, pulmonary, and possibly death. Glyphosate has very low acute toxicity and is not mutagenic.</ce:simple-para></ce:abstract-sec></ce:abstract></dm:abstracts>

The occurrence of somatomedin C in daunorubicin-induced cardiomyopathy in rabbits

Toxicity studies were performed by exposing F344/N rats and B6C3F1 mice to 2- and 4-chloronitrobenzene (CNB) by whole-body inhalation 6 hr/day, 5 days/week, for 13 weeks. Animals were evaluated for clinical chemistry (rats), hematology (rats), histopathology, and body/organ weights. Exposure concentrations were 0, 1.1, 2.3, 4.5, 9, and 18 ppm for 2-CNB and 0, 1.5, 3, 6, 12, and 24 ppm for 4-CNB. All rats in the 2-CNB study survived until the end of the study. Two male mice in the 18-ppm group in the 2-CNB study, however, died during Week 12; no deaths attributable to 4-CNB exposure occurred in rats or mice. In both studies, the mean body weight gains of exposed animals were similar to those of the respective controls. In rats, inhalation exposure to 2- or 4-CNB resulted in methemoglobinemia leading to a regenerative anemia and a variety of tissue changes secondary to the oxidative erythrocyte injury. In the 2-CNB study, methemoglobinemia resulted in a normocytic, normochromic, responsive anemia, whereas with 4-CNB, the methemoglobinemia was more severe and resulted in a macrocytic, hyperchromic, responsive anemia. Alterations of erythrocyte morphology were observed in both studies; changes included Heinz bodies, poikilocytes, and polychromasia. In rats, both isomers caused increases in serum activities of alanine aminotransferase and sorbitol dehydrogenase and increased bile acid concentrations. Microscopic liver changes included hemosiderin deposition in Kupffer cells (rats and mice exposed to 4-CNB), hepatocytomegaly (mice), and cytoplasmic basophilia (rats). Hepatocellular necrosis and chronic inflammation observed in mice were rather specific to the 2-CNB isomer, as only slight evidence of focal necrosis in the liver was observed in mice exposed to 4-CNB. Splenic lesions included hemosiderin accumulation, capsular fibrosis, and increased hematopoietic cell proliferation. Increased bone marrow hemosiderin and hematopoietic cell proliferation and kidney tubule hemosiderin deposition were also observed. Other findings, attributed to chemical exposure but not to the hematotoxicity, were described. Lesions included hyaline droplet nephropathy and degeneration of the testis in male rats exposed to 4-CNB, inflammation of the harderian gland in rats exposed to 4-CNB, hyperplasia of the nasal cavity epithelium in rats exposed to 2-CNB, and hyperplasia of the forestomach epithelium in mice exposed to 4-CNB; these lesions have not been described previously in studies with these chemicals. Based on the exposure concentrations evaluated, A no-observed-adverse-effect level (NOAEL) for histopathological injury in mice was 4.5 ppm for 2-chloronitrobenzene and 6 ppm for 4-chloronitrobenzene; a NOAEL was not determined for rats.

Ovine White-Liver Disease (OWLD). Pathology

Microscopic liver changes could earliest be found after 1 month on OWLD pasture, and include extensive fatty change with large spherical vacuoles in hepatocytes, varying size of hepatocytes and nuclei, and formation of Councilman bodies. Later came ceroid deposits, biliary hyperplasia and mesenchymal proliferation. Changes occurred in all lambs which died or were killed due to OWLD, and altogether 83% of the lambs grazing OWLD pastures showed typical or suspect changes. Widespread haemosiderosis of the spleen was common. In severely affected lambs, sclerosis of the Peyer's patches and of the germinative centres of the intestinal lymph nodes were seen, as were neuronal atrophy and patchy microcavitation of areas in the brain stem. Four had polyvasculitis. Cobalt/vitamin B12 supplemented lambs showed no specific changes. Lambs which grew well on other pastures (H lambs), but which were subclinically Co/B12 deficient some years, showed no fulminant hepatic OWLD, but 15% developed some features seen in OWLD. They showed no extensive fatty change. Results indicate that OWLD is a manifestation of B12 deficiency worsened by factors triggering early hepatic fatty change resulting in a more severe liver damage with loss of intracellular homeostasis rendering the hepatocytes vulnerable to other elements, like copper.

Analysis of Fatalities from Acute Narcotism in a Major Urban Area

The incidence of acute, fatal narcotism in San Francisco was determined to be 3.2% of all deaths (10 882) subject to medical examiner's inquiry in a five-year period. Heroin was responsible for the greatest number of these cases, usually accompanied by alcohol or other abused drugs. The median concentration of the heroin metabolite, morphine, in the blood in fatal cases was 20 microgram/dL. Death from propoxyphene, the second most frequently encountered narcotic, was generally determined to be suicidal, while death from heroin was judged to be accidental. The highest rate occurred in black males between the ages of 21 and 30 years. The three most consistent findings were positive identification of the drug in the body (100% of the cases), pulmonary edema (90.4% of the cases), and microscopic liver changes (71.1% of the cases).

Zoalene Toxicity in Broiler Chickens

Toxic factors accidentally incorporated into commercial rations and causing pathology are rare in relation to the millions of tons of rations prepared for domestic animals. Some exceptions, each causing a typical gross and microscopic change, include the following: 1) A chlorinated naphthalene contaminating the lubricant of a cattle feed pelleting machine, causing hyperkeratosis in cattle (9,12). 2. An unidentified toxic factor present in some lots of oleic fatty acids, causing an endotheliosis in chickens and turkeys manifested by a hydropericardium and ascites (3,4,17,18,22). 3) A factor, thought to be a mycotoxin, in ground nut meals incorporated into poultry rations, causing a high mortality with gross and microscopic liver changes in turkey poults, ducks, and pheasants (1,8,12). 4) A chlorinated hydrocarbon used as a plasticizer in an epoxy resin paint (13), causing hydropericardium and ascites in young chickens. 5) Toxic proteins from soybean oil meal extracted with trichloroethylene, producing a hemorrhagic aplastic anemia in cattle (14,15). 6) Seeds of Crotalaria spectabilis, causing ascites and liver damage in young chickens and turkeys (2,19). 7) Histamine from decomposed fish meal, causing proventricular enlargement, gizzard erosions, and splenic atrophy (20,21). Zoalene (3,5-dinitro-ortho-toluamide; Dow Chemical Co., Midland, Michigan), for use as a coccidiostat, is limited in the