Chronic fenthion toxicity in laying hens.

White leghorn laying hens were exposed to weekly dermal applications of either 1 mg fenthion/kg (FEN; low dose) or 4 mg FEN/kg (high dose) for 24 w with the objective of evaluating chronic FEN toxicity. Four of 24 hens at the high dose exhibited transitory loss of proprioception, perching ability, and righting reflex after 8 to 16 w exposure. All hens receiving the high dose lost the ability or desire to jump from a box during the latter half of the FEN exposure period. Inhibition of serum cholinesterase and brain acetylcholinesterase was greater in the high-dose hens. Brain neuropathy target esterase was not inhibited. Behavioral changes were not correlated with changes in brain concentrations of enzymes or neurotransmitters or their metabolites. Muscle fiber abnormalities were more common in the high-dose hens. Muscle electrical activity was recorded electromyographically via telemetry. Fibrillation (denervation) potentials were absent, but amplitude times duration values for motor unit potentials of the peroneus longus muscle for 5 of the 6 4-w evaluation intervals were higher in the high-dose hens. This EMG response suggested presence of a mild neuropathy which was supported by results of ultrastructural examinations of the sciatic nerve. The low dose initially produced 8% stimulation of egg production while the high dose inhibited egg production 10% during the latter 16 w of the study and reduced body weight 8% during this period.

Release and metabolism of dopamine in a clonal line of pheochromocytoma (PC12) cells exposed to fenthion.

The effects of an organophosphate (OP) pesticide, fenthion (FEN), on the release and metabolism of dopamine were evaluated in a clonal line of rat pheochromocytoma (PC12) cells. HPLC was used to determine media concentrations of DA and the DA metabolites norepinephrine (NE), 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA). The FEN formulation solvent did not significantly affect DA metabolism. In the first study, cultures were treated with 10(-5) or 10(-6) M FEN or 10(-5) M neostigmine, a non-OP acetylcholinesterase inhibitor. Concentrations of both catecholamines were elevated in cultures treated with 10(-5) M FEN by 2.8-fold for DA and 3.5-fold for NE. Neostigmine effects were of smaller magnitude and DA was decreased after 24 hr. Cultures were also treated with depolarizing levels of K+, but the effect of FEN was not altered, suggesting that FEN does not act by increasing DA release. In the second study, the effect of 10(-6) M FEN was evaluated in cultures treated with the DA uptake inhibitor benztropine, the monoamine oxidase (MAO) inhibitor pargyline, or the catechol-O-methyltransferase (COMT) inhibitor tropolone. Inhibitor effects were consistent with their known mechanisms of action. In all cultures treated with FEN, the ratio HVA/DOPAC was decreased after 3 and 6 hr of exposure. A decrease in HVA/DOPAC was also observed in cultures treated with neostigmine and tropolone. In combination with pargyline, FEN decreased DA in contrast to its usual effect of increasing DA. Neither the stimulation of DA release nor the inhibition of DA uptake affected the observed action of FEN in PC12 cultures.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxic effects of organophosphates on nerve cell growth and ultrastructure in culture.

Organophosphates (OP) comprise one of the major classes of pesticides in use today. It is well accepted that the primary site of action of the OPs is at cholinergic synapses. However, it has been suggested that OPs may have direct neural effects as well. In this study, cultured chick dorsal root ganglia (DRG) were used to study the effect of fenthion (FEN), an OP pesticide, on isolated nerve cell growth and ultrastructure. Light microscopic evaluation revealed a dose-response relationship between the concentration of FEN (10(-2) M to 10(-5) M) and severity of morphologic changes. Cultured explants were treated with a lower concentration of FEN (10(-6) M) and morphologic alterations were compared to those observed in explants treated with 10(-6) M paraoxon, a more acutely toxic OP, or 10(-6) M neostigmine, a non-OP inhibitor of acetyl-cholinesterase. Based on both light and electron microscopy, neostigmine had no observed effect on cell morphology except for an inhibition of the extension of neurites by DRG cells. In contrast, explants treated with OPs exhibited a significant alteration in cell morphology. Initial lesions were observed first in the neurites and pseudopodia and consisted of vacuolization, loss of tubular structures, retraction of pseudopodia, and cell membrane disruption at the growth cone. Lipid accumulations were observed within the cytoplasm of treated cells. The effects of paraoxon on DRG cell morphology were significantly more severe than the effects of FEN, and lipid vacuoles observed in paraoxon-treated cells were several times larger than those observed in FEN-treated cells (5-10 microns in diameter vs. 0.5-1.0 microns in diameter). Results show that OPs have a direct effect on DRG nerve cells in culture, consistent with an alteration in cell membrane integrity. Cultured DRG cells can be useful in the evaluation of toxicologic effects.

Muscular dystrophy in a litter of golden retriever dogs.

Clinicopathologic findings from two golden retriever dogs with an inherited, progressive, degenerative muscle disease that were studied until 27 and 40 months of age are described. Initial clinical signs included stilted gait and simultaneous advancement of their pelvic limbs. Further gait restriction and muscle hypertrophy eventually occurred. Serum creatine kinase was dramatically elevated (greater than 10,000 U/L). There were persistent "spontaneous" high-frequency discharges (pseudomyotonia) on electromyographic evaluation. Features of both muscle fiber degeneration (hyaline fibers, myophagocytosis) and regeneration (small basophilic fibers) were seen on light microscopy. Similar ultrastructural changes (fiber hypercontraction, increased myoblasts) were present. On morphometric histochemical evaluation, mean fiber diameter of both type 1 and 2 fibers was increased compared with controls in two of three muscles examined. There was no apparent fiber type predominance. Scattered ragged red fibers were seen, but this appeared to be a nonspecific finding of either muscle fiber regeneration or degeneration. These findings and potential contributing pathophysiologic mechanisms are discussed in relation to Duchenne muscular dystrophy.

Neuromuscular effects of chronic exposure to fenthion in dogs and predictive value of electromyography.

Chronic exposure to organophosphates (OP) can result in nonspecific neurologic signs in both man and animals. Improved methods are needed to predict toxicity and to better characterize neuromuscular effects. In this study, dogs were exposed to an OP (fenthion) by weekly dermal application of a 20% solution at a dosage of 44 mg/kg. This dosage does not produce signs of acute OP toxicity in dogs, although plasma cholinesterase (ChE) levels are significantly decreased. Electromyograms (EMG) were used to monitor motor unit potential (MUP) activity at minimal and submaximal contractile effort in four different muscles. At 1-month intervals, muscle biopsies were obtained and plasma ChE levels were determined. At 3 months, hyperreflexia and/or mild proprioceptive deficits were observed. The dosage was reduced to 22 mg/kg for the remaining 3 months of the study. At the end of this 6-month study, nerve and muscle biopsies were obtained. Mean plasma ChE levels were decreased (preexposure value of 1775 IU/liter to low of 310 IU/liter) and correlated with duration of exposure and change in dosage level. Fourier analysis of EMG indicated some increase in higher frequency components of the power spectrum with time, and analysis of individual MUPs revealed a significant (p less than 0.05) increase in the product of the amplitude times the duration of the potentials in all muscles examined. Biopsy results were supportive of EMG findings of altered neuromuscular function and loss of small motor units. The EMG changes were most consistent in the gastrocnemius muscle and were detected prior to development of clinical signs. These results indicate that EMG can be useful in monitoring OP exposure and predicting toxicity.

Pharmacokinetics of gentamicin in cats given Escherichia coli endotoxin.

Nineteen cats were given 3 mg of gentamicin sulfate/kg of body weight by rapid IV, SC, or IM injection for baseline values. Serum concentration of gentamicin vs time data were analyzed using a noncompartmental model based on statistical moment theory. One week later, each cat was given 0.5 microgram of Escherichia coli endotoxin/kg, IV. After cats had an increase in rectal temperature of at least 1 C, 3 mg of gentamicin/kg was administered by the same route used the previous week. Serum concentration of gentamicin vs time data were analyzed, and pharmacokinetic values were compared with base-line values. For IV studies, the half-life (t1/2) of gentamicin and the mean residence time were significantly different (P less than 0.05) compared with base line, whereas the total body clearance and apparent volume of distribution at steady state were not. The harmonic mean +/- pseudo SD for the t1/2 of gentamicin after IV administration was 76.8 +/- 12.6 minutes for base line and was 65.2 +/- 12.2 minutes in the same cats given endotoxin. The t1/2 of gentamicin after SC administration was 74.6 +/- 6.2 minutes for base line and was 65.2 +/- 13.6 minutes in the same cats given endotoxin. After IM administration, the t1/2 of gentamicin was 60.3 +/- 10 minutes for base line and was 59.7 +/- 13.6 minutes in the same cats given endotoxin. After IV administration of gentamicin, the arithmetic mean +/- SD for the mean residence time was 102.4 +/- 16.1 minutes for base line vs 79.2 +/- 18.4 minutes in the same cats given endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)