Subchronic oral toxicity in guinea pigs of soot from a polychlorinated biphenyl-containing transformer fire

We have previously described the acute po toxicity in guinea pigs of soot from a transformer fire at the State Office Building in Binghamton, New York. The soot was determined to contain polychlorinated biphenyls, biphenylenes, dibenzodioxins, and dibenzofurans. The present study evaluates soot toxicity in guinea pigs receiving 0, 0.2, 1.9, 9.3, or 46.3 ppm soot in the feed for 90 days or 231.5 ppm for 32 days. At 231.5 ppm, body weight loss, thymic atrophy, bone marrow depletion, skeletal muscle and gastrointestinal tract epithelial degeneration, and fatty infiltration of hepatocytes were observed. Mortality had reached 35% by Day 32 (when survivors were killed), with total soot consumption of approximately 400 mg/kg. At 46.3 or 9.3 ppm soot, a reduced rate of body weight gain was observed, and at 46.3 ppm, the mortality by Day 90 was 30%. Relative (to body) thymus weights were decreased in both groups, while relative spleen weights were increased at 46.3 ppm soot only. Salivary gland interlobular duct squamous metaplasia and focal lacrimal gland adenitis were detected histopathologically, while bone marrow depletion was noted only in females at the higher dose. Diminished serum alanine aminotransferase (ALT) activity in both sexes and decreased serum sodium levels in male and potassium levels in female animals were detected at both dose levels. decreased gamma-glutamyl transferase activity and red blood cell count and elevated serum creatinine and triglycerides were observed only in animals fed 46.3 ppm soot. At 1.9 ppm soot, salivary gland duct metaplasia was observed in both sexes, along with decreased relative thymus weights, ALT activity, and serum sodium levels in male animals only. No effects attributable to soot exposure were noted in animals receiving 0.2 ppm soot for 90 days. Total average soot consumption for male and female animals in the 0.2, 1.9, 9.3, and 46.3 ppm dosage groups was 1.2, 12, 55, and 275 mg/kg, respectively. Although many of the observed effects were typical of acute exposure of guinea pigs to the Binghamton soot or to polychlorinated aromatic hydrocarbons in general, salivary gland duct metaplasia has not been previously reported. Toxic effects of this subchronic exposure were observed at lower total doses than with acute exposure, although variations in absorption due to the effects of different vehicles (aqueous in the acute study versus the feed in this study) could account for some or all of this difference.     

Acute toxicity, subchronic dermal toxicity, and delayed contact sensitization evaluations of dicyclopentenyloxyethyl methacrylate in rabbits and guinea pigs

The subchronic dermal toxicity of dicyclopentenyloxethyl methacrylate (DPOMA) was evaluated in young adult New Zealand White rabbits, and its potential to produce delayed contact sensitization was evaluated in Harley guinea pigs by a modified Buehler's closed patch technique. In addition, studies were conducted to evaluate the acute systemic toxicity of DPOMA in rats (oral) and rabbits (dermal), and its eye and skin irritancy in rabbits. In the subchronic dermal toxicity study, 4 groups of rabbits were treated percutaneously with DPOMA at 0 (acetone), 10, 107, and 1067 (undiluted) mg/kg X day in a volume of 1 ml/kg, over a 4-wk period. The application sites were unoccluded. No deaths occurred, and no signs of systemic toxicity were observed. No treatment-related effects were seen on body weights, hematology, clinical chemistry, urinalysis, organ weights, or histopathology (except the treated skin). The only treatment-related effect was slight to moderate skin irritation in the mid- and high-dose groups. The severity of skin irritaton was dependent on the number of applications and the concentration of DPOMA. Maximal skin irritation occurred after 1 wk. No skin irritation was seen in the control and low-dose group. In the DCS study, guinea pigs received 6 induction doses of 0.5 ml 100% DPOMA and were challenged with 0.5 ml of 50% (w/v) DPOMA in acetone 2 wk after the last induction treatment. No erythema or edema was observed in any of the challenged guinea pigs in either the treated and control groups. These acute toxicity studies indicate that DPOMA is practically nontoxic by a single exposure via both oral and dermal routes (the oral LD50 in rat and dermal LD50 in rabbits were greater than 5.0 g/kg body weight), slightly irritating to the skin, and inconsequentially irritating to the eyes. The no-observed-effect level (NOEL) for systemic toxicity of DPOMA applied repeatedly to rabbits skin is at least 1067 mg/kg X d. DPOMA is not a strong or moderate skin sensitizer in guinea pigs.     

Liver morphology in guinea pigs fed pyrolysis products of a polychlorinated biphenyl transformer fluid continuously for 90 days

After a fire involving a transformer, the State Office Building in Binghamton, New York, was contaminated with soot containing polychlorinated biphenyls, biphenylenes, naphthalenes, dioxins, and dibenzofurans. The toxicity of the soot and its effect on liver morphology after prolonged (subchronic) exposure were determined for both sexes of Hartley guinea pigs, which were fed soot continuously for 90 days. By light microscopy the observed alterations of the liver were predominantly centrilobular; they included hepatocyte hypertrophy, steatosis, increased glycogen and iron, focal necrosis, and bile duct proliferation with fibrosis. Cytoplasmic vacuoles and acidophilic hyalin-like bodies were observed. Electron microscopy of hepatocytes showed proliferated smooth endoplasmic reticulum (SER), cytoplasmic vacuoles, concentric membrane arrays (CMAs), glycogen bodies, and microdroplets of fat, often without limiting membranes. The vacuoles frequently contained membrane fragments and had a halo-like periphery composed of proliferated membranes. Cell debris, membrane fragments, and small CMAs were observed in the sinusoids. Membrane fragments were also observed in the bile canaliculi and bile ducts. Intoxicated bile duct cells contained more cytoplasmic myelin whorls and altered mitochondria. In contrast to the previously reported study of a single dose, these liver alterations showed a strong dose dependence, emphasizing the importance of time and method of administration. The cytoplasmic vacuoles, which were not pronounced in the previous study, are here a prominent alteration, probably originating from outpouchings of canaliculi and sinusoidal membranes. A hypothesis for the mechanism of hepatocyte detoxification based on the proliferated SER and ejection of membrane fragments is proposed.     

Liver morphology in guinea pigs administered either pyrolysis products of a polychlorinated biphenyl transformer fluid or 2,3,7,8-tetrachlorodibenzo-p-dioxin

A transformer cooled and insulated with a mixture of 65% Aroclor 1254 and 35% chlorinated benzenes located in the Binghamton State Office Building in Binghamton, New York, was involved in a fire, which produced soot containing polychlorinated biphenyls, biphenylenes, dioxins, and dibenzofurans. A single dose of either soot or 2,3,7,8-tetrachlorodibenzo-p-dioxin in aqueous methyl cellulose was administered by gavage to Hartley guinea pigs of both sexes. The liver tissue was examined 42 days after administration. By light microscopy hypertrophy of hepatocytes, steatosis, focal necrosis, and cytoplasmic hyalin-like bodies were observed as a result of both treatments. Bile duct proliferation (adenofibrosis) was observed only in the guinea pig groups administered soot. These animals also showed proliferation of the smooth endoplasmic reticulum, concentric membrane arrays (CMA), mitochondrial alterations, decreased rough endoplasmic reticulum, and autophagolysosomes by electron microscopy. The CMAs, which corresponded to the hyalin-like bodies, surrounded lipid droplets and cytoplasmic matrix containing mitochondria and degenerating organelles.     

Acute respiratory toxicity following inhalation exposure to soman in guinea pigs

Respiratory toxicity and lung injury following inhalation exposure to chemical warfare nerve agent soman was examined in guinea pigs without therapeutics to improve survival. A microinstillation inhalation exposure technique that aerosolizes the agent in the trachea was used to administer soman to anesthetized age and weight matched male guinea pigs. Animals were exposed to 280, 561, 841, and 1121 mg/m³ concentrations of soman for 4 min. Survival data showed that all saline controls and animals exposed to 280 and 561 mg/m³ soman survived, while animals exposed to 841, and 1121 mg/m³ resulted in 38% and 13% survival, respectively. The microinstillation inhalation exposure LCt₅₀ for soman determined by probit analysis was 827.2 mg/m³. A majority of the animals that died at 1121 mg/m³ developed seizures and died within 15-30 min post-exposure. There was a dose-dependent decrease in pulse rate and blood oxygen saturation of animals exposed to soman at 5-6.5 min post-exposure. Body weight loss increased with the dose of soman exposure. Bronchoalveolar lavage (BAL) fluid and blood acetylcholinesterase and butyrylcholinesterase activity was inhibited dose-dependently in soman treated groups at 24 h. BAL cells showed a dose-dependent increase in cell death and total cell counts following soman exposure. Edema by wet/dry weight ratio of the accessory lung lobe and trachea was increased slightly in soman exposed animals. An increase in total bronchoalveolar lavage fluid protein was observed in soman exposed animals at all doses. Differential cell counts of BAL and blood showed an increase in total lymphocyte counts and percentage of neutrophils. These results indicate that microinstillation inhalation exposure to soman causes respiratory toxicity and acute lung injury in guinea pigs.     

Nasopharyngeal removal of ozone in rabbits and guinea pigs

In estimating pollutant concentrations responsible for observed pulmonary effects, nasopharyngeal removal of the pollutant plays an important role. The nasopharyngeal removal of ozone (O3) in anesthetized male guinea pigs and male and female rabbits was determined by drawing O3 through the isolated upper airways at a constant flow rate which approximated the animal's respiratory minute volume. The tracheal O3 concentration in rabbits and guinea pigs was markedly similar and was linearly related to the chamber concentration of O3 over a range of 196--3920 micrograms/m3 (0.1--2.0 ppm O3). Regression analyses showed that O3 removal in the nasopharyngeal region is approximately 50% in both species. Both rabbit sexes responded similarly over the concentration range studied. Exposures of guinea pigs to O3 concentrations between 3920 and 5880 micrograms/m3 (2.0 and 3.0 ppm) showed that, at these higher concentrations, relatively more O3 is removed by the upper airways.     

Skin toxicity of propranolol in guinea pigs.

The skin toxicities of propranolol were studied in guinea pigs. In the primary and cumulative skin irritation studies, the skin reactions and the histopathological changes were observed in all animals treated with propranolol, and those tended to increase with the increase of propranolol dosage. The skin reactions increased with the application times of propranolol up to 7 days in the cumulative skin irritation study. In the skin sensitization, the phototoxicity and the skin photosensitization studies, no skin reactions were observed in any animals used in the studies. These results indicate that propranolol caused skin irritation, but was negative for skin sensitization, phototoxicity and skin photosensitization in guinea pigs.     

Acute toxicity of T2 toxin in rats, mice, guinea pigs, and pigeons

The acute intravenous, intragastric, subcutaneous, intraperitoneal and intratracheal toxicity of T2 toxin has been studied in rats, mice, guinea-pigs, and pigeons. The acute LD50 values obtained varied between 1.0 and 14 mg X kg-1, there being little difference between the various routes in any given species. T2 caused vomiting in pigeons at doses of one fifth or less the LD50. In rats doses of 3.0 and 5.0 mg X kg-1 T2 produced lymphopenia, reticulocytosis, and in the highest dose groups normoblastaemia. Additionally, changes in plasma alkaline phosphatase and aspartate aminotransferase activities were seen. Histological changes were observed in lymphoid organs and were most severe in the thymus, lymph nodes, and Peyer's patches. The spleen was less severely affected. Gastrointestinal changes consisting of dead and dying lymphoid cells throughout the lamina propria were seen together with, in some cases, mucosal ulceration. The time course of the development and of the reversal of the changes was followed.     

Acute toxicity of polychlorinated dibenzofurans in CF-1 mice

Eight-week-old CF-1 mice, male and female, were given synthesized polychlorinated dibenzofurans (PCDF) orally, sc, or ip as a single exposure. The oral LD50 was approximately 200 mg/kg in males and 400 mg/kg in females. In mice that died, hepatomegaly and atrophy of the thymus were consistent findings; subcutaneous edema and dermal alterations also occurred frequently. In surviving mice, the liver showed small necrotic foci accompanied by cellular infiltrates in sections stained with hematoxylin and eosin. Ultrastructural alterations of hepatocytes 30 days after exposure consisted of a marked increase in lipid droplets and moderate hypertrophy of smooth-surfaced endoplasmic reticulum. From these results, it was concluded that the nature of toxic responses to PCDF was similar to that associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin.     

Immunosuppressive activity of a polychlorinated diphenyl preparation on the humoral immune response in guinea pigs

Three groups of 12 female albino guinea pigs were fed 0, 10 and 50 ppm Aroclor 1260 (PCB) for 8 wk. In half of the animals a function test of the immunological system was carried out: tetanus toxoid injection was used to study the humoral response. At the end of the experiment cellulose acetate electrophoresis was used to determine the serum proteins, including the γ-globulin level. The number of γ-globulin-containing cells in popliteal lymph nodes was determined semiquantitatively with the direct fluorescent antibody technique. Both these techniques seemed to be sensitive parameters for the immunosuppressive action of PCB in the tetanus toxoid-stimulated animals.     

The toxicity of Azadirachta indica leaves in goats and guinea pigs

The effects produced by the administration of aqueous suspensions of the green or dried leaves of Azadirachta indica, a common tropical plant, were investigated in goats and guinea pigs. At doses of 50 or 200 mg/kg given orally over a period of up to eight weeks, the plant produced a progressive decrease in body weight, weakness, inappetence, and loss of condition. There were also decreases in heart, pulse and respiratory rates. Diarrhea was observed in animals given the fresh leaves. In goats, the higher doses of the plant leaves produced tremors and ataxia during the last few days of treatment. No statistically significant hematological changes were observed after dosing the animals with A indica leaves, although there was a tendency towards lowered erythrocyte counts, packed cell volume and hemoglobin concentration. The treatments caused significant rises in the plasma activity of aspartate transferase, sorbitol dehydrogenase, and concentrations of cholesterol, urea, creatinine and potassium. No significant changes in the plasma concentration of sodium, chloride or bilirubin were detected. On necropsy of treated goats there were areas of hemorrhagic erosions. The hearts appeared flappy and in some animals there were hydropericarium. Histopathologically, there was evidence of various degrees of hemorrhage, congestion, and degeneration in the liver, kidney, lung, duodenum and brain. Degeneration of the seminiferous tubules was also seen.(ABSTRACT TRUNCATED AT 250 WORDS)     

无细胞耻垢分枝杆菌疫苗对豚鼠的长期毒性研究

目的:观察无细胞耻垢分枝杆菌疫苗对豚鼠的长期毒性。方法:48只豚鼠随机均分成无细胞耻垢分技杆菌疫苗低、中、高剂量组(疫苗用量分别为50,250和500μg·kg-1)和阴性对照组,每周1次,连续7周肌内注射疫苗,阴性对照组给予等体积的生理氯化钠溶液。在实验前、中、末期(n=12)和恢复期(n=4)观察动物体重、白蛋白和球蛋白比值、抗疫苗抗体IgG和总IgE的含量;在实验末期和恢复期对豚鼠作病理组织学检查和骨髓细胞学检查。结果:阴性对照组豚鼠抗疫苗抗体IgG始终为阴性,疫苗组豚鼠注射疫苗后抗疫苗抗体IgG阳转;各组豚鼠在整个实验过程中体重稳定增加,白蛋白和球蛋白比值未见明显改变,血清IgE均为阴性;各脏器未见病理性损害和免疫复合物沉积,各脏器系数与阴性对照组比较未见统计学差异;骨髓各系造血细胞未见抑制现象。结论:无细胞耻垢分枝杆菌疫苗对豚鼠无长期毒性。     

Acute toxicity of polychlorinated naphthalenes and their effect on cytochrome P450

Polychlorinated naphthalenes (PCNs) are able to induce cytochrome P-450-dependent microsomal mono-oxygenase activities in vivo and in vitro. The aim of this study was to investigate the toxicity of a PCN mixture, and its effect on the levels of cytochrome P-450 in rats. The animals were intragastrically administered a mixture of PCNs in single doses of 250, 500 and 1000 mg/kg b.w. Dissection of animals was performed 24, 72 and 240 hours after administration. After PCN administration (all doses) the body weight loss (up to 30% in comparison with the control group, 240 hours after administration) and an increase of relative liver mass (about 126-153% of controls, 72 hours after administration) were observed. The exposure to PCN evoked an increase in the level of total cytochrome P-450 as well as the activity of CYP 1A (mediated 7-ethoxyresorufin O-deethylation) at all time points. The maximum activity of CYP 1A (about 12- to 15-fold increase in comparison with the control group) was observed 72 hours after dosing. Malondialdehyde (MDA), determined in the liver, showed a high increase and 240 hours after administration, the level of MDA was about one order of magnitude greater in comparison with control.     

Subchronic vaginal toxicity studies of Alcide Allay gel and liquid in guinea pigs

Alcide Allay, an antimicrobial preparation produced in gel and liquid forms, was evaluated for vaginal toxicity in guinea pigs. 1.0 g/kg Allay gel or placebo was administered intravaginally once per day over a 30 day period while 2.5 g/kg Allay liquid (containing either of two concentrations of sodium chlorite and lactic acid as active ingredients) or placebo was applied vaginally three times per day for 10 days. At the conclusion of the studies, hematology, blood and urine clinical chemistry tests and necropsies were performed. RBC, HGB, HCT, MCHC and direct bilirubin increased while CO2, SGPT and CPK decreased in blood after Allay liquid treatment. Creatinine, urea nitrogen and uric acid in urine were statistically reduced in the liquid groups. Hematology and clinical chemistry parameters were within the normal range of values reported in the literature for guinea pigs, indicating no clinical significance due to drug treatment. Significant differences in organ body/weight ratios were observed between controls and Allay gel and liquid groups. However, only the livers in the gel study and the vaginas in both studies were changed histologically.     

Studies of foetal death and foetal weight in guinea pigs fed polychlorinated biphenyls (PCB)

Pregnant guinea pigs were fed a total dose of 100 mg of the commercial PCB preparation Clophen A50 during days 16 to 60 of gestation. This treatment caused severe foetal, but no maternal, death. Contrarily, a total dose of 25 mg or 100 mg of 2,2',4,4',5,5'-hexachlorobiphenyl (HCB) did not cause foetal death in the guinea pig. The prenatal growth rate was increased by a total dose of 25 mg, but not by 100 mg, of HCB.