Archives of toxicology
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Archives of toxicology · Apr 2007
Effects of combined, multiple stressors on pyridostigmine-induced acute toxicity in rats.
A number of studies have evaluated the possibility that stress-induced changes in blood-brain barrier permeability enhanced the central effects of the carbamate acetylcholinesterase inhibitor, pyridostigmine. We previously found relatively little evidence of stress-induced changes in the acute toxicity of pyridostigmine in rats using a variety of restraint, forced running and forced swimming stress conditions. In this study, we evaluated the effects of sequential pre-exposure to multiple stressors on the acute toxicity of pyridostigmine. ⋯ Cholinesterase activity was significantly inhibited in blood (47-50%) and diaphragm (80%) following pyridostigmine exposure regardless of stress conditions. Slight but significant inhibition (11-15%) of cerebellar cholinesterase activity was observed following pyridostigmine exposure, but inhibition was not influenced by stress. We conclude that while acute lethality from pyridostigmine may be increased by combined, multiple stressors, increased lethality does not appear due to enhanced cholinergic toxicity or via increased cholinesterase inhibition in either central or peripheral tissues.
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Archives of toxicology · Nov 2006
Cerebral acetylcholine and choline contents and turnover following low-dose acetylcholinesterase inhibitors treatment in rats.
Male Sprague-Dawley rats were treated for 3 weeks with (1) regular tap drinking water plus subcutaneous (s.c.) saline (0.5 ml/kg) injections three times/week, (2) pyridostigmine bromide (PB) in drinking water (80 mg/L) plus s.c. saline injections three times/week, (3) regular tap drinking water plus s.c. sarin (0.5 x LD(50)) injections three times/week, or (4) PB in drinking water plus s.c. sarin injections three times/week. Repeated doses of sarin, in the presence or absence of PB, were devoid of acute toxicity during the three-week treatment period. Two, 4, and 16 weeks post-treatment, animals were given an intravenous pulse injection of choline labeled with 4 deuterium atoms (D4Ch) followed, after 1 min, by microwave fixation of the brain in vivo. ⋯ Statistically significant differences among brain regions were found for D0Ch, D4Ch, D0ACh and D4ACh at 2, 4 and 16 weeks post-treatment. However, differences in the values of these parameters between control and drug treatments were found only for D0ACh and D0Ch at 2 and 4 weeks, but not at 16 weeks post-treatment. In conclusion, the results from these experiments do not support a delayed or persistent alteration in cholinergic function after exposure to low doses of PB and/or sarin.
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Archives of toxicology · Nov 2005
Use of the dog as non-rodent test species in the safety testing schedule associated with the registration of crop and plant protection products (pesticides): present status.
The results from a survey of the expert information that is publicly accessible on the use of the dog as test species during the regulatory evaluation of agricultural chemicals and pesticides are reported. Methods that are being used or considered in order to reduce the number of dogs used for this purpose are described. Regulatory evaluation aims at establishing threshold values for safe human exposure; it is based on no-observed-adverse-effect levels (NOELs) determined in animal studies. ⋯ Chronic tests using dogs would then only be required if the test compound belongs to a new class of chemicals that has never been tested before. Thus, the report concludes that, according to current scientific knowledge, the routine 12-month studies in dogs are no longer required for agricultural chemicals and pesticides, and international regulations should be changed accordingly. Active international support of such measures is welcomed, from both an economical and an animal welfare perspective.
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Archives of toxicology · Jun 2005
Respiratory effect of acute and subacute exposure to endotoxin-contaminated metal working fluid (MWF) aerosols on Sprague-Dawley rats.
Male Sprague-Dawley rats were exposed to a water-soluble metal working fluid (MWF) (5% v/v) contaminated with endotoxins (10,000 eu/ml or 100,000 eu/ml) at 10 mg/m3 for six hours per day for three days (acute exposure) or two weeks (subacute exposure). The geometric mean diameter of the MWF aerosols was 1.56 microm, and the airborne endotoxin concentrations ranged from 1,231 to 2,173 eu/m3 (10,000 eu/ml in the bulk MWF) for the low dose and 19,263-27,386 eu/m3 (100,000 eu/ml in the bulk MWF) for the high dose. Minimal effects were observed after exposure to 10 mg/m3 of the MWF without endotoxins for three days or two weeks. ⋯ The level of endotoxin-specific IgE in the serum obtained from the rats exposed to the MWF with endotoxins increased dose-dependently, while the levels of total immunoglobulins (IgG(1), IgG(2a) and IgE) and endotoxin-specific IgG(1) and IgG(2a) remained unchanged. Accordingly, the current results indicate that lung inflammation can be immediately induced by acute or subacute exposure to an MWF contaminated with endotoxins, and macrophages would appear to play a role in the induction of inflammation along with B-cell functions rather than T-cell functions, after subacute exposure to an MWF with endotoxins. In addition, endotoxin-specific IgE is an early marker for endotoxin exposure in the workplace.
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Archives of toxicology · Dec 2004
ReviewEthylene glycol: an estimate of tolerable levels of exposure based on a review of animal and human data.
Upon ingestion ethylene glycol (EG, monoethylene glycol) is rapidly absorbed from the gastrointestinal tract, and depending on the severity of exposure signs of toxicity may progress through three stages. Neurological effects characterize the first step consisting of central nervous depression (intoxication, lethargy, seizures, and coma). The second stage, usually 12-24 h after ingestion, is characterized by metabolic acidosis due to the accumulation of acidic metabolites of EG, primarily glycolic acid (GA), contributing to the ensuing osmolal and anion gaps. ⋯ However, human data from case reports are generally insufficient for the determination of a clear dose-response relationship and quantification of threshold doses for systemic toxicity, in particular renal effects, is limited. As toxicity is largely a consequence of metabolism of EG to GA, it is important to note that no signs of renal injury have developed at initial plasma glycolate concentrations of up to 10.1 mM (76.7 mg/dl). Plasma EG levels of 3.2 mM (20 mg/dl) are considered the threshold of toxicity for systemic exposure, if therapeutic strategy is based on the EG concentration alone.