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Toxicological properties of phosphorothioate and related esters present as impurities in technical organophosphorus insecticides.

O,O,S-Trimethyl phosphorothioate, an impurity in several technical organophosphorus insecticides, when administered orally to rats at single doses as low as 15 mg/kg caused delayed mortality, with death occurring 4-22 d after treatment. Delayed toxic signs were also observed in mice, but mice were generally less sensitive than rats. O,O,S-triethyl phosphorothioate and O,S,S-trimethyl phosphorodithioate induced the same signs of intoxication at slightly higher doses. Rats treated with O,O,S-trimethyl phosphorothioate refused food and water within 24 h after treatment and did not eat or drink until the time of death. Neither injection of nutrient solution nor atropine served to reduce or block intoxication. However, the isomeric O,O,O-trimethyl phosphorothioate was a potent antagonist of the toxicity of O,O,S-trimethyl phosphorothioate. As little as 1% of the O,O,O-trimethyl isomer protected rats from the intoxicating effects of the O,O,S-trimethyl isomer at doses as high as 200 mg/kg. Rat serum carboxylesterase and cholinesterase were inhibited for prolonged periods after a single oral dose of O,O,S-trimethyl phosphorothioate, but the duration of inhibition was significantly less when the toxicant contained 1% O,O,O-trimethyl isomer.

Animals↗

Effect of lead acetate on neurobehavioral development of rats.

We investigated the effects of lead exposure during the pre- and postnatal period on the neurobehavioral development of female Wistar rats (70-75 days of age, 120-150 g) using a protocol of lead intoxication that does not affect weight gain. Wistar rats were submitted to lead acetate intoxication by giving their dams 1.0 mM lead acetate. Control dams received deionized water. Growth and neuromotor development were assessed by monitoring daily the following parameters in 20 litters: body weight, ear unfolding, incisor eruption, eye opening, righting, palmar grasp, negative geotaxis, cliff avoidance and startle reflex. Spontaneous alternation was assessed on postnatal day 17 using a T maze. The animals' ability to equilibrate on a breaker rim was measured on postnatal day 19. Lead intoxication was confirmed by measuring renal, hepatic and cerebral lead concentration in dams and litters. Lead treatment hastened the day of appearance of the following parameters: eye opening (control: 13.5 +/- 0.6, N = 88; lead: 12.9 +/- 0.6, N = 72; P < 0.05), startle reflex (control: 13.0 +/- 0.8, N = 88; lead: 12.0 +/- 0.7, N = 72; P < 0.05) and negative geotaxis. On the other hand, spontaneous alternation performance was hindered in lead-exposed animals (control: 37.6 +/- 19.7; lead: 57.5 +/- 28.3% of alternating animals; P < 0.05). These results suggest that lead exposure without concomitant undernutrition alters rat development, affecting specific subsets of motor skills.

Analysis of Variance↗

The rate of 2,5-hexanedione intoxication, not total dose, determines the extent of testicular injury and altered microtubule assembly in the rat.

Charles River CD rats (220 g) were intoxicated with 1.0, 0.5, or 0.25% 2,5-hexanedione (2,5-HD) in the drinking water for a total of 21, 35, or 69 days, respectively. All rats received a total dose of 131 +/- 2 mmol/kg 2,5-HD at dose rates ranging from 1.9 to 6.1 mmol/kg/day. Rats were sacrificed 4 weeks after ending intoxication to evaluate the extent of testicular injury. An exposure rate of 6.1 mmol 2,5-HD/kg/day produced uniformally low testis weights (49% of control) and severe germ cell depletion, while exposure at 1.9 mmol/kg/day gave normal testis weights and histology. Exposure at the intermediate dose rate of 3.8 mmol 2,5-HD/kg/day produced an intermediate degree of testicular injury. In a separate experiment, testis pyrrole content and microtubule assembly behavior were measured in rats exposed to 2,5-HD at the various dose rates for 3 weeks. The rate of intoxication determined the extent of biochemical abnormality. Rats exposed to 1.0, 0.5, or 0.25% 2,5-HD had microtubule nucleation times 55, 63, and 72% of control and pyrrole contents equivalent to 2.14, 1.40, and 1.18 nmol 2,5-dimethylpyrrole/mg testis protein. These data demonstrate that 2,5-HD-induced testicular injury, unlike the nervous system toxicity, is dependent upon the rate of intoxication independent of total dose.

Animals↗

The ability of two commercially available quick test kits to detect drug-facilitated sexual assault drugs in beverages.

AIMS: Assessment of the sensitivity and specificity of two commercially available 'drug-facilitated sexual assault' drug detector kits, Drink Guard and Drink Detective. DESIGN: Experimental. SETTING: Laboratory. MEASUREMENTS: Gamma hydroxybutyrate (GHB) sodium salt, ketamine hydrochloride, temazepam, flunitrazepam and diazepam were dissolved (Tween added to benzodiazepine solutions) as separate stock solutions and added to 330 ml samples of cola (Pepsi Max), beer (Stella Artois), 'alcopop' (Bacardi Breezer) and placebo (distilled water). The doses used are reported to be common in cases of intoxication. Each kit was tested 10 times for each drink/drug combination. Two blind, independent observers scored each test (presence/absence of drug) in accordance with kit instructions; chi 2 was used to compare the proportion of times raters scored tests correctly and incorrectly. Sensitivity and specificity were calculated overall, for each drink, and sensitivity was calculated for each drug. Inter-observer agreement was evaluated using the kappa statistic. FINDINGS: While both raters were able to score significantly more tests correctly than incorrectly using Drink Detective, and one rater scored similarly using Drink Guard, the overall sensitivity of Drink Detective and Drink Guard was 69.0% (95% CI 64.2-73.5%) and 37.5% (95% CI 30.1-45.5%), respectively. Sensitivity was drink-dependent. Drink Detective was unable to detect our dose of GHB in water, with all tests scored negatively by both raters for this drink/drug combination (n = 20 negative scores). Overall, specificity was 76.6% (95% CI 71.5-81.0%) and 87.9% (95% CI 83.0-91.6%) for Drink Guard and Drink Detective, respectively, but was affected by the beverage. Inter-rater agreement was poor for Drink Guard (kappa = 0.278 +/- 0.069) but excellent for Drink Detective (kappa = 0.894 +/- 0.245). Inter-observer agreement was drug-dependent. CONCLUSIONS: Use of drug detector kits by the public in the night-time environment needs further investigation and may create a false sense of security (false negatives) and undue concern (false positives) among kit users.

Benzodiazepines↗

Developmental toxicity of subcutaneously administered meso-2,3-dimercaptosuccinic acid in mice.

meso-2,3-Dimercaptosuccinic acid (DMSA) is a water-soluble effective antidote for the treatment of heavy-metal intoxications. Information concerning the developmental toxicity of DMSA, however, has not been available. In order to determine the potential developmental toxicity of DMSA, pregnant Swiss mice were given 0, 410, 820, or 1640 mg DMSA/kg/day subcutaneously on Days 6-15 of gestation. Maternal effects included a significant reduction in weight gain during the exposure and postexposure periods at 1640 mg/kg/day. Food consumption was similar to controls at all doses levels except for the high dose group in the post-treatment period. Results of hematological and serum biochemical analyses in the DMSA-treated groups were comparable to those of the controls. However, in light of the pronounced effects on maternal weight gain the dose of 1640 mg/kg/day would be maternally toxic. Significant increases in the number of resorptions and the incidence of stunting were found, along with a significant decrease in the number of live fetuses per litter, when the 1640 mg/kg/day group was compared with the controls. Significant reductions in fetal body weight and fetal body length means were also found when the 820 and 1640 mg/kg/day groups were compared with the controls. Consequently, these results indicate that DMSA would be embryo-toxic to mice at 1640 mg/kg/day and fetotoxic at 820 mg/kg/day. In contrast, very slight fetotoxicity was observed at 410 mg/kg/day. Gross external, internal soft tissue, and skeletal examinations of the fetuses revealed that DMSA was teratogenic in the mouse when given subcutaneously at 820 and 1640 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Hair cell regeneration in the chicken cochlea following aminoglycoside toxicity.

Hair cell loss in the avian cochlea partially recovers following both acoustic trauma and aminoglycoside intoxication. DNA labeling with tritiated thymidine has shown that the restoration of cell number following acoustic trauma results from the production of new hair cells by mitotic division. The purpose of the present study was to determine if mitosis also contributes to the recovery of hair cell number which occurs following aminoglycoside intoxication. Chickens received daily injections of either gentamicin sulfate or distilled water for 10 consecutive days. During the latter 7 days of this period, all birds were also injected with [3H]thymidine. Following postinjection survival periods of 3 or 6 days, one papilla from each bird was processed for autoradiography and the other for scanning electron microscopy (SEM). Incorporation of [3H]thymidine was seen over hair cells and support cells in experimental papillae in regions of hair cell loss. No labeling was seen outside of damaged regions or in the papillae of control birds. SEM showed that damaged regions in experimental birds contained cells similar in appearance to developing auditory hair cells in avian embryos. These results show that the restoration of hair cell number following aminoglycoside toxicity results from the production of new cells by mitosis.

Animals↗

The effect of zinc supply on cadmium-induced changes in the tibia of rats.

It has been determined that zinc supplementation (240 microg Zn/ml) during (for 12 weeks) or after (for 2 weeks) cadmium exposure (50 microg Cd/ml for 12 weeks) can prevent the accumulation and toxic action of Cd in the tibia of rats. The exposure to Cd led to disturbances in bone metabolism reflected by changes in the chemical composition of bone and decreased bone mineral density (osteomalacian changes). The Zn supply in conditions of Cd intoxication completely prevented the Cd-induced increase in percentage of water content and decrease in tibia ash weight, ash weight/dry weight, non-org. comp./org. comp., Zn content and concentration. Moreover, Zn partly protected from the decrease in Ca concentration and content, percentage of non-organic components content, Ca/wet weight, Ca/ash weight and Ca/dry weight. Zn administered after Cd exposure partly, but not completely, protected from Cd-induced decrease in percentage of non-organic components content, Ca/wet weight as well as Ca content and concentration. This protective effect on bone was most evident when Zn was administered during Cd exposure. But Zn, independently of the manner of its administration, did not prevent Cd accumulation in the tibia. Our results suggest that Zn supply in conditions of simultaneous exposure can prevent Cd-induced bone loss to some extent, and used after Cd treatment can give therapeutic benefits.

Animals↗

Rupture of the heart in a burn patient: a case report of free wall rupture of the left ventricle.

A 63-year-old male was burned when in a state of alcoholic intoxication, he fell head first into a bathtub filled with hot water and received burns covering 40 per cent BSA. Despite surgical wound debridement, a severe sepsis continued and a sudden cardiac arrest occurred. Autopsy revealed a large volume of blood in the pericardial space. The heart was ruptured through a myocardial abscess in the posterior wall of the left ventricle. The principle cause of his death was attributed to acute cardiac tamponade following cardiac rupture through a myocardial abscess.

Abscess↗

Effects of glucose on chemically induced acute hepatic failure in rats.

TOPIC: Acute hepatic failure (AHF) is a physiopathological entity difficult to reproduce experimentally but necessary to evaluate new therapies such as bioartificial liver (BAL) or hepatocyte transplantation (HcTX). Two main animal models are available: surgical or chemical induction of an AHF. Many authors have assessed BAL or HcTX with such models and observed increased survival rate in the treated groups. However, during AHF, severe hypoglycemia takes place. Some authors have shown that adjunction of glucose in beverage after surgically induced AHF may induce by itself an improvement of survival rate. METHOD: The purpose of the present study is to test if the adjunction of glucose leads to the same effect in an AHF chemically induced by D-Galactosamine (D-Gal). A group of animals (rats) receiving glucose 20% as beverage immediately after intoxication (Group 1), is compared with a control group receiving tap water (Group 2). RESULTS: The required dose to achieve AHF is 2.75 g/kg body weight (Gr. 0). Survival rates are as follows: Gr. 1: Day 3:20%; day 5: 10%; day 8: 0%. Gr. 2: Day 3: 0%. The difference in survival rate is not statistically significant between the two groups. Liver enzymes peak at 24 hours, then return to normal values; blood sugar levels show no difference between groups. Histological examination of Gr. 0 animals surviving and sacrificed on day 28 shows restitutio ad integrum of hepatic structure. CONCLUSION: Glucose adjunction does not alter survival rate. We can conclude that this particular model of AHF is reliable.

Animals↗

Moderate alcohol dose and chronic obstructive pulmonary disease: not a cause of hypoventilation.

Six patients with chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second, 1.01 +/- 0.08 L [mean +/- SEM] ) were given either 1 mL of 100% alcohol per kilogram of body weight in an aqueous solution or a similar volume of water in a crossover design on consecutive days. All subjects became intoxicated and the peak alcohol concentration was 137 +/- 11 mg/dL, 40 minutes after ingestion. No significant difference was found in either PaO2 or PaCO2 between the alcohol and control period. A significant decrease in arterial pH occurred following alcohol (P less than .05), and represented a mild metabolic acidosis. Alcohol ingestion resulted in an increase in oxygen consumption (P less than .05) and carbon dioxide production (P less than .05) but no change in respiratory rate. It appears that small to moderate amounts of alcohol will not cause marked changes in oxygen tension or alveolar hypoventilation in patients with severe COPD who do not have marked hypercapnia. Nevertheless, other effects of alcohol on the cardiopulmonary system and the concomitant use of sedatives have to be considered before condoning the use of alcohol.

Aged↗

Chronic interstitial nephropathy in patients on long-term lithium treatment.

One-hundred and ten patients treated with lithium for more than six months were studied in order to determine the prevalence of lithium induced nephropathy. Eighteen of 69 patients (26 per cent) who had been treated for more than two years presented a chronic interstitial nephropathy characterized by a marked decrease in renal concentrating ability with a disproportionate preservation of glomerular filtration rate. Histologically, increased amounts of fibrotic tissue in the medulla and the cortex were found together with tubular atrophy. In 40 per cent of the patients who underwent renal biopsy, cystic formations in the cortex were found. The impairment of renal concentrating ability could be related to the duration of lithium treatment and the degree of tubular damage correlated with the degree of impairment of renal concentrating ability. Lithium induced, chronic nephropathy is a rather common complication of long-term lithium treatment and reduces the patients capacity to regulate water and electrolyte metabolism. As water and electrolyte loss appears to precede the slowly progressing lithium intoxication, the main hazard of lithium induced nephropathy is lithium intoxication.

Adult↗

Effects of chronic lead exposure on release of endogenous catecholamines: a preliminary communication.

The release of endogenous dopamine and norepinephrine from six brain regions (cortex, hippocampus, hypothalamus, striatum, s. nigra, n. accumbens-o. tubercle) of chronically lead-exposed rats was compared to release from controls. Prenatal and postnatal chronic lead intoxication was induced by 1000 ppm lead acetate in the drinking water of dams 70 days prior to mating and throughout gestation and lactation. Offspring were also maintained on 1000 ppm lead acetate until sacrificed at approximately 60 days of age. Release was measured in vitro from tissue minces prepared from both lead-exposed and control rats. There were no significant differences in spontaneous or potassium-stimulated norepinephrine release between lead-exposed and control rats. Potassium and amphetamine both stimulated striatal dopamine release; however, no marked differences between lead-exposed and control tissue were seen. Potassium-stimulated release of dopamine from the nucleus accumbens-olfactory tubercle area was increased in the lead-exposed animals. This is interesting in light of the postulated role of the n. accumbens in the central regulation of motor activity and the reported alterations in activity in lead-exposed rodents.

Animals↗

[Effect of n-nitrosodimethylamine (NDMA) on activity of selected enzymes in blood serum of the rat].

Changes in the activity of GOT, GPT, AP and GGTP in blood of rats intoxicated by low doses of N-Nitrosodimethylamine (NDMA) are presented. A significant increase in the activity of GOT and GPT was found after single doses (20 micrograms/kg b.w.) of NDMA as well as a significant increase in the activity of GOT, GPT, AP and GGTP after a prolonged intoxication per os by doses of 20 micrograms/dm3 given in drinking water.

Administration, Oral↗

The role of bile and digestive juices in cadmium effect on the absorption processes in rat small intestine.

The effects of bile and digestive juices was studied on the intestinal absorption of water, sodium and glucose in the small intestine of rats after their intoxication with one dose of cadmium 1.33 mg/kg of body weight injected intravenously. The investigations were carried out on 60 rats by the method of intestinal perfusion. The obtained results showed that cadmium inhibited the intestinal absorption of these substances. Bile and digestive juices abolished partially this effect during their physiological secretion. After administration of cholagogues no protective role of bile and digestive juices was observed alleviating the toxic effects of cadmium, and the intestinal absorption was even more reduced.

Animals↗

Natural and acquired resistance of mice to infection by airborne Klebsiella pneumoniae after subchronic intoxication by cadmium administered orally.

Mice daily ingested about 22 mg of cadmium per kg of body weight in drinking water for 30 days. On the 30th day, the liver and kidneys of the mice contained about 18 micrograms of Cd2+ per g of fresh organ. A group of these mice was immunized against Klebsiella pneumoniae using two injections of vaccine, the first on the 7th day and the second on the 14th day of intoxication. On the 28th day, the non-immunized and the immunized mice were infected via a respiratory route by one lethal dose 50% of K. pneumoniae (the LD50 for the immunized mice was 2.4 times higher than the LD50 for the non-immunized mice). Comparison with the non-intoxicated control mice showed that the ingestion of Cd2+ did not significantly modify the natural resistance or the acquired resistance of the mice to the infection by airborne K. pneumoniae.

Animals↗

[High aluminum concentrations in well water of southern Lower Saxony sandy soil areas caused by acid precipitation--evaluation from the public health and ecologic viewpoint].

Decades of acid precipitation have caused soil acidification in regions with low neutralizing capacity of industrial countries, thus mobilizing aluminium from clay minerals into soil solution and ground water. In the southern sandy heath-land of Lower Saxony all the wells with pH values lower than 4.5 showed aluminium contents higher than 2.0 mg/l. 66.7% of the specimens within the pH-range 4.5 to 5.0 and 20% of the specimens within the pH-range 5.0 to 5.5 had aluminium levels of more than 0.2 mg/l, that is the maximum permissible limit value of the drinking water regulation. High contents of aluminium in drinking water are objectionable from the hygienic point of view, as they may cause intoxications in infants and patients with impaired renal function. In addition to this, the involvement of aluminium in the pathogenesis of severe degenerative disorders of the central nervous system cannot be excluded, such as Alzheimers disease, amyotrophic lateral sclerosis and Parkinsons dementia.

Acid Rain↗