Evoked potential alterations in methylmercury chloride toxicity

The present study was designed to assess the sensitivity of evoked potential techniques to detect alterations in offspring exposed to methylmercury chloride (MMC) at different developmental periods. Recordings were obtained from the visual cortex (VEP) and lateral geniculate (LGP) in 30-day old offspring. Results revealed decreased VEP latencies for peaks N1, P1, and P2 in offspring from mothers exposed either during gestation, or nursing and in offspring exposed directly to MMC for 9 days after weaning. Although not significant, a similar trend was observed in the LPG. It is suggested that the decreased latencies may be a result of compressed brain development.     

Long-term toxicity study quillaia extract in rats

Tannic acid fixation reveals differences in the number of protofilaments between microtubules (MTs) in the nematode Caenorhabditis elegans. Most cells have MTs with 11 protofilaments but the six touch receptor neurons (the microtubule cells) have MTs with 15 protofilaments. No 13-protofilament (13-p) MT has been seen. The modified cilia of sensory neurons also possess unusual structures. The cilia contain nine outer doublets with A subfibers of 13 protofilaments and B subfibers of 11 protofilaments and a variable number of inner singlet MTs containing 11 protofilaments. The 15-p MTs but not the 11-p MTs are eliminated by colchicine-treatment or by mutation of the gene mec-7. Concomitantly, touch sensitivity is also lost. However, whereas colchicine treatment leads to the loss of all MTs from the microtubule cells, mutations in mec-7 result in the partial replacement of the 15-p MTs with 11-p MTs. Benzimidazoles (benomyl and nocodazole) have more general effects on C. elegans (slow growth, severe uncoordination, and loss of processes from the ventral cord) but do not affect the 15-p MTs. Benomyl will, however, disrupt the replacement 11-p MTs found in the microtubule cells of mec-7 mutants. The 11-p and 15-p MTs also respond differently to temperature and fixation conditions. It is likely that either type of MT will suffice for the proper outgrowth of the microtubule cell process, but only the 15-p MT can function in the specialized role of sensory transduction of the microtubule cells.     

Chronic effects of methylmercury in rats. I. Biochemical aspects

The effect of a pre-coronary angioplasty education and counselling program on knowledge and psychological status of patients and on knowledge and quality of life/coping status of their spouses was evaluated. Forty patients and their spouses participated in a pre-coronary angioplasty education and counselling program and 40 served as controls. Knowledge, psychological status and quality of life/coping status were assessed prior to coronary angioplasty and at a mean of four and 11 months post-coronary angioplasty. At four months, improved knowledge and reduced anxiety were found for patients in the experimental group. At 11 months, spouses in the experimental group showed continued improvement in quality of life compared to those in the control group. It was concluded that pre-coronary angioplasty education and counselling can impact favourably upon knowledge in patients and quality of life in spouses.     

Teratogenicity study of magnesium chloride hexahydrate in rats

Teratogenicity of magnesium chloride hexahydrate (MgCl2.6H2O) was examined in rats. Magnesium chloride hexahydrate dissolved in distilled water was given to pregnant Wistar rats by gavage once a day from day 6 through 15 of pregnancy at doses of 0, 200, 400 and 800 mg/kg/day. The pregnant rats were sacrificed on day 20 of pregnancy and their fetuses were examined for malformation. Magnesium chloride hexahydrate caused no increased incidences of fetal malformation, and no toxic signs in the pregnant rats and the fetuses. It was concluded that magnesium chloride hexahydrate has no teratogenicity in rats when given by gavage. The no observed adverse effect level was estimated to be over 800 mg/kg/day for both pregnant rats and rat fetuses.     

Twenty-six-week oral toxicity study of benzalazine in rats

A 26-week toxicity study by oral gavage administration was performed in Sprague-Dawley rats with benzalazine (2-hydroxy-5-[(4-carboxyphenyl) azo] benzoic acid, CAS 64896-26-0), a new agent for the treatment of ulcerative colitis and Crohn's disease of the large intestine, as a part of a safety evaluation program. Dosages of 0 (control), 300, 900 and 2700 mg/kg b.w./d were selected for this study. Except slight changes in the urinary status (decreased pH value and increased specific gravity) from 900 mg/kg b.w./d p.o. onwards, which were probably substance related, no further intolerance reactions were observed. The urine had a dark-yellow colour which was probably an indication of metabolites of benzalazine or benzalazine itself which were excreted via the urine. Behaviour, external appearance, body weight gain, food and water consumption, haematology, clinical biochemistry, organ weight analysis, macroscopic and microscopic examinations revealed no substance-related influence. Therefore, on the basis of the results obtained, it is concluded that the non-toxic dose level in this study is considered to be 300 mg benzalazine/kg b.w./d p.o. following daily administration for 26 weeks.     

Overexpression of manganese-superoxide dismutase prevents methylmercury toxicity in HeLa cells

HeLa cells were stably transformed with plasmid constructs that allowed constitutive expression of antioxidant enzymes such as catalase, glutathione peroxidase (GSH-Px), Cu,Zn-superoxide dismutase (Cu,Zn-SOD) or Mn-superoxide dismutase (Mn-SOD) to examine the involvement of reactive oxygen generation in methylmercury toxicity. Overexpression of catalase, GSH-Px or Cu,Zn-SOD did not affect the sensitivity of HeLa cells against methylmercury. However, the sensitivity of HeLa cells against methylmercury was decreased by overexpression of Mn-SOD, an enzyme localized in matrix of mitochondria and which decomposes superoxide anions. These results suggest that formation of superoxide anions in the mitochondria might be involved in the mechanism of the cytotoxicity of methylmercury.     

Toxicity evaluation of petroleum blending streams: inhalation subchronic toxicity/neurotoxicity study of a light alkylate naphtha distillate in rats

A 13-wk inhalation study was conducted with Sprague-Dawley CD rats (12/sex/group) were exposed by inhalation for 13 weeks to a light alkylate naphtha distillate (LAND-2, C4-C10; average molecular weight 89.2) at actual average concentrations of 0 (room air), 668, 2220, or 6646 ppm, 6 h/d, 5 d/wk; 12 additional rats/sex in the control and high dose groups were held after final exposure for a 4-wk recovery period. The highest exposure concentration was 75% of the lower explosive limit. Standard parameters of subchronic toxicity were measured throughout the study; at necropsy, organs were weighed and tissues processed for microscopic evaluation. Neurotoxicity evaluations consisted of motor activity (MA) and a functional operational battery (FOB) measured pretest, during 5, 9, and 14 wk of the study, and after the 4-wk recovery period. Whole-body perfusion and microscopic examination of selected organs and nervous tissue from the control and high dose rats were conducted at the end of exposure. No test-related mortality or effects on physical signs, body weight, or food consumption were observed. Statistically significant increases in absolute and relative kidney weights in high-exposure males correlated with microscopically observed hyaline droplet formation and renal nephropathy, effects in male rats that are not toxicologically significant for humans. Increased liver weights in both sexes at the highest dose had no microscopic correlate and appeared reversible after the 4-wk recovery period. Exposure to LAND-2 at any dose did not produce neurotoxicity measured by MA, FOB, or neuropathology. The no-observed-effects level (NOEL) for LAND-2 was 2220 ppm for subchronic toxicity and > or =26646 ppm for neurotoxicity.     

Testicular toxicity of allyl chloride

This study deals with the review of the literature regarding the indirect blood pressure measurement in normal pregnant women. It shows the changes that happened with the blood pressure due to pregnancy. Polemical aspects in the procedure of blood pressure measurement are discussed; for example, which one of the Korotkoff phases (4 or 5) that better represent the diastolic blood pressure and the use of Ambulatory Blood Pressure Monitoring in pregnancy. The recommendations from different societies are emphasized (American Heart Association, British Hypertension Society, Australasian Society, National High Blood Pressure Education Program and World Health Organization).     

Long-term study of chronic oral aluminum exposure and spatial working memory in rats.

The authors report an effort to advance animal models that mimic the cognitive decline of Alzheimer's disease. Rats were trained and repeatedly tested in a spatial delayed matching-to-position paradigm in the water maze, with the location of the submerged platform changing between, but not within, days. After Trial 1 (random search) and intertrial intervals of 30 s or 1 hr, memory was tested in Trial 2. Young rats quickly acquired this task and were repeatedly tested after different intervals over 7 months, with a slight increase in performance toward the end of testing, but no difference in latencies between delays. Oral long-term treatment of 1 group with 0.1 % aluminum caused no delay-dependent working memory deficit. This testing protocol may enable between- and within-subject long-term assessment of spatial working memory before and after drug treatment and may prove useful in animal models of progressive cognitive decline. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Subchronic toxicity study of liquid paraffin in F344 rats

A 13-week oral toxicity study of liquid paraffin was carried out in F344 rats at the dose levels of 5, 2.5, 1, 0.5, 0.2 and 0% in the powdered diet to select a suitable dose range for a 2-year carcinogenicity study. Each group consisted of 10 males and 10 females. No animals showed decrease in body weights and food intakes in any group, and all animals were surviving at the end of the experiment. Changes indicating obvious toxicity of liquid paraffin were not observed in the hematological-, serum biochemical- and histopathological-examinations. Based on these data, a concentration of 5% or more in the diet was considered as the maximum tolerable dose of liquid paraffin for both sexes in F344 rats.     

Subchronic inhalation toxicity study of a water-dispersible polyester in rats

AQ55 is a high molecular weight, water-dispersible, amorphous polyester used in applications where the exclusion of solvents and conventional surfactants is desirable, such as water-based adhesives, coatings, emulsions, paint primers, cosmetics and detergents. Potential health effects were evaluated in rats exposed by inhalation for about 13 wk to mean concentrations of 0, 2.4, 19.6 or 199 mg/m3 AQ55 polymer. No mortality occurred and body weights were unaffected. Mean relative liver weights in all treated male groups were slightly higher than control weights, but were not judged to be treatment related. Absolute liver weights and all other organ weights except lung weights were normal. Haematology, clinical chemistries and gross pathology were unremarkable. Exposure-related changes in the 199 mg/m3 groups included increased mean absolute and relative lung weights, accumulations of macrophages and acute inflammatory cells in alveolar and bronchial lumina, and increased numbers of macrophages in sinusoids of peribronchial lymph nodes. Minor accumulation of macrophages in alveolar lumina was the only exposure-related change in the 19.6 mg/m3 group. No exposure-related effects were seen in the 2.4 mg/m3 group. AQ55 produced no systemic toxicity, and aerosols of AQ55 do not appear to be toxic to pulmonary tissues following subchronic inhalation exposure.     

Dose-response assessment for developmental toxicity. III. Statistical models

Although quantitative modeling has been central to cancer risk assessment for years, the concept of dose-response modeling for developmental effects is relatively new. The benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpoints for determining reference doses and reference concentrations. Statistical models appropriate for representing the unique features of developmental toxicity testing have been developed and applied (K. Rai and J. Van Ryzin, 1985, Biometrics 41, 1-9; L. Kupper, C. Portier, M. Hogan, and E. Yamamoto, 1986, Biometrics 42, 85-98; R. Kodell, R. Howe, J. Chen, and D. Gaylor, 1991, Risk Anal. 11, 583-590). Generalizations of those models (designated the RVR, LOG, and NCTR models, respectively) account for the correlations among observations in individual fetuses or implant within litters; the potential for variables other than dose, such as litter size, to affect the probability of adverse outcome; and the possibility of a threshold dose below which background response rates are unaltered. The generalized models were applied to a database of 607 endpoints with significant dose-related increases in response rate. It was determined that the models were generally capable of fitting the observed dose-response patterns, with the LOG model appearing to be superior with respect to fit. A significant contributor to the ability of the LOG model to fit the data was its flexibility with respect to the representation of the dependence of response probability on litter size, a trait not shared by the other two models. Litter size appeared to be a significant covariable for predicting response rates, even when intralitter correlation was accounted for by assuming a beta-binomial distribution for the observations among individual fetuses. In contrast, a threshold dose parameter did not appear to be necessary to adequately describe the observed dose-response patterns. BMD estimates (corresponding to 5% additional risk) from all three models were similar to one another and to BMDs estimated from other, generic dose-response models (not specifically designed for developmental toxicity testing) that modeled average proportion of fetuses affected. The BMDs at the 5% level of risk were similar to no observed adverse effect levels determined by statistical tests of trend. Greater emphasis on and further examination of dose-response modeling for developmental toxicity testing are needed; biologically based approaches that consider the continuum of developmental effects induced in such tests should be encouraged.     

Histopathological studies on the toxicity of ochratoxin A in rats. I. Acute oral toxicity

Traumatic spinal cord lesions in children are infrequent (2 to 5 per cent of all cases admitted to specialised paraplegic centres depending on whether the upper age limit is set at 10 or 15 years). Traffic accidents are responsible for at least 50 per cent of the lesions; playground accidents and various sports add another 35 per cent. A large proportion of the accidents have been found to be related to the child's normal desire for adventure and exploration. The segment most frequently involved in our own series of 18 cases was the cervical and upper thoracic spine. Histopathological studies have shown that splitting of the cartilaginous end-plate in the growth zone of the vertebrae is a common finding. Radiological signs of spinal trauma are less evident than in adults; they may be totally missing. Precise neurological assessment must rely on repeated examination and close clinical observation, especially in the comatous child with a head injury. Spinal cord involvement must be suspected and the child treated as a paraplegic until definite proof of a normal neurological status is available. Due to a highly labile water electrolyte balance in the early post-traumatic stage and considerable fluctuations in plasma volume and temperature regulation, permanent monitoring of the cardiovascular function, body temperature and diuresis is mandatory. In children below the age of 10, deep vein thrombosis and embolism are exceptional (sepsis creates a high-risk situation requiring anticoagulation). In the initial treatment of spinal injury only conservative measures should be considered; there are no indications for laminectomy, nor for spinal fusion. In the tetraplegic child below the age of 6, skull-traction should be avoided and immobilisation of the cervical segment achieved by bilateral padded head-rests.     

Brain aging in normotensive and hypertensive strains of rats. III. A quantitative study of cerebrovasculature

The mechanism of degradation of fructose-1,6-bisphosphate aldolase from rabbit muscle by the lysosomal proteinase cathepsin B was determined. Treatment of aldolase with cathepsin B destroys up to 90% of activity with fructose 1,6-bisphosphate as substrate, but activity with fructose 1-phosphate is slightly increased. Cathepsin L, another lysosomal thiol proteinase, and papain are also potent inactivators of aldolase, whereas inactivation is not caused by cathepsins D or H even at high concentrations, or by cathepsin B inhibited by leupeptin or iodoacetate. The cathepsin-B-treated aldolase shows no detectable change in subunit molecular weight, oligomer molecular weight or subunit interactions. Cathepsin B cleaves dipeptides from the C-terminus of th aldolase subunits. Four dipeptides are released sequentially: Ala-Tyr, Asn-His, Ile-Ser and Leu-Phe, and a maximum of five additional dipeptides may be released. There are indications that this peptidyldipeptidase activity of cathepsin B may be an important aspect of its action on protein substrates generally.     

Long-term memory facilitation in rats by posttraining epinephrine.

Effects of posttraining epinephrine (EPI) on retention of a massed (1 session, 30 trials) 2-way active avoidance task in rats were studied. The rats received an injection of 0.05 mg/kg EPI, 0.01 mg/kg EPI, or distilled water immediately after the training session. EPI did not improve retention 24 hrs after the training session (Exp 1) but enhanced retention 20 days after the training session (Exp 2). The group receiving the smaller dose of EPI had better retention than the group receiving the larger dose, indicating dose dependency. The authors suggest that the process of consolidation of massed 2-way active avoidance conditioning is long and elaborative. Posttraining EPI would facilitate this active process of consolidation, improving performance as consolidation goes on. This facilitation needs, at least under certain conditions, more than 24 hrs to be expressed as a higher level of performance on the retention test. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A 13-week subchronic toxicity study of josamycin in F344 rats

A 13-week subchronic toxicity study of josamycin was performed in male and female F344 rats to determine the maximum tolerable dose (MTD) for subsequent investigation of the carcinogenicity. As animals refused to take diet containing 5.0% josamycin in our preliminary study, dose levels in the present study were determined as 0, 0.16, 0.32, 0.63, 125 and 2.5% in diet. Rats were randomly allocated to 6 groups, each consisting of 10 males and 10 females. No animal died during the administration period and no group showed significant changes in body weight gain. Definite toxicity of josamycin was not noted in hematological and serum biochemical examinations. Histopathological examinations revealed no particular findings related to josamycin administration except cecal enlargement in the 1.25 and 2.5% groups. based on the results of the present study, it was concluded that the MTD of josamycin in 2.5% in diet, because the dietary dose level of 2.5% proved to exert no significant toxicological signs.     

A repeated-dose dermal toxicity study of hydrophobically modified hydroxypropyl methylcellulose in rats

A six-month repeated-dose dermal toxicity study followed by a 30-day recovery test of hydrophobically modified hydroxypropyl methylcellulose (HM-HPMC), a new cellulose derivative used as a thickener for topical pharmaceuticals, was conducted using rats. Aqueous paste of HM-HPMC was applied to the skin of rats once daily at dose levels up to 60 mg/kg/day, which was the highest dose that could be administered. Items checked included general signs, urinalysis, hematology, ophthalmology, and histopathology. One rat died during the administration period owing to a malignant tumor in the hemopoietic system, which was not attributed to the test substance. Statistically significant differences were found in some test results, but those were not dose-dependent and were considered to be incidental or spontaneous. It was concluded that the test substance was not toxic upon chronic dermal administration at dose levels up to 60 mg/kg/day.