INTERACTION STUDIES BETWEEN LINDANE (GAM MA LIN -20®) AND DIMETHOATE (ROGOR®) IN VIVO AND IN VITRO
INTERACTION STUDIES BETWEEN LINDANE (GAM MA LIN -20®) AND DIMETHOATE (ROGOR®) IN VIVO AND IN VITRO
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Date
1998-09
Authors
GADAKA , MADU ADAMU
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Abstract
The toxicity of lindane and dimethoale has been studied individually and in combination in
laboratory animals both in vivo and in vitro. Effects of lindane pretreatmenl on the toxicity
of dimethoate was examined in acute and sub-chronic toxicity studies. The median lethal
dose (LD50) for lindane and dimethoate were determined in wister strain rats by
intraperitoneal route as 29.5 mg/kg and 185 mg/kg respectively. Symptoms of poisoning for
lindane (hyper-excitation, tremor, conclusions) and dimethoate (swaying gait, respiratory
distress, convulsion) were dose-dependent in severity.
Lindane (1mg/kg, i.p) daily administration for seven days increaesd dimethoate LD50 in
rats by 29.5%. The survival time in mice exposed to lethal dose of dimethoate (400 mg/kg)
was also increased by 27.5% compared to control. Antidotal therapy trial against acute
lindane poison was also carried out in mice using diazepam, phenobarbitone and phenytoin.
All three agents produced dose-dependent alleviation of symptoms and as well increased
survival rates. The highest trial dose of phenytoin (40 mg/kg). phenobaritone (20 mg/kg)
and diazepam (10 mg/kg) resulted in 50%, 62.5% and 75% survival rales respectively. The
control group produced 12.5% survival rate.
EEG studies in rats showed desynchronization of the reticular formation (RF;) wave pattern
due to lindane which effect was potentialed by dimethoale. Lindane-induced
desynchronization was reversed by diazepam and phenytoin.
Twelve weeks sub-chronic toxicity studies in rats investigated the effect of combined
exposure to weekly lindane (10 mg/kg, i.p) and daily dimethoate (10, 25, 50. 75 mg/kg
feed) oral administration. Control group receive normal Iced and no lindane treatment. At
intervals of four weeks, rats were killed blood samples collected for enzyme assay, serum
albumin and total bilirubin were determined. Liver, kidney and intestines were removed for
histopathologic examinations.
Serum transaminase (AST and ALT) activities showed general elevation in the dimethoatefed
compared to control animals. Furthermore, AST and ALT activities were slightly higher
in lindane-frce compared to lindane-treated dimethoate sub-groups throughout the twelve
weeks exposure period. Serum AST activities were significantly (P < 0.05 - P - 0.01)
higher in the dimethoate-fed animals in the presence and absence of lindane at four and
eight weeks exposure, while activities were insignificantly laised at twelve weeks. Serum
ALT activities on the other hand were significantly elevated (P < 0.02 - P < 0.001) at eight
and twelve weeks while activities showed insignificant eleva'ion at four weeks exposure
compared to control values. Activities of serum ALT were significantly raised (P < 0.05 - P
< 0.001) at four weeks but dropped significantly (P < 0.05 - P - 0.01) below control activity
at eight weeks. Activity returned to control levels at twelve weeks exposure.
Serum albumin levels showed an insignificant decrease over control value at four weeks.
However, significantly lower levels (P < 0.05 - P < 0.001) were observed at eight and
twelve weeks exposure. No clear pattern was however, observed between lindane-free and
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lindane-treated groups in the serum.albumin levels. Levels for total bilirubin showed a
gradual increase with duration of exposure, being insignificantly different from control at
four weeks and significantly (P < 0.02 - P < 0.001) elevated at twelve weeks. Values for
total bilirubin were higher in the presence of lindane treatment.
Histopathologic examination after twelve weeks exposure period revealed no lesions in the
kidneys and the intestines at all dose levels. However, the liver revealed various degree of
fatty degeneration, the ocurrence of which showed correlation in extent of damage to period
of exposure, rather than dimethoate dose or lindane treatment.
Experiments using isolated rabbits ileum and rat phrenic nerve-diaphragm preparations
showed a biphasie response by lindane, with stimulation at low doses and inhibition at high
dose. Dimethoate dose-dependently potentiated cholinergic responses at both nicotinic and
muscarinic receptors. Dimethoate (8 ng/ml) response was augmented by physosligmine (2.6
ng/ml) and antagonized by atropine (2 ng/ml), while d-tubocurarine (1.3 ng/ml) attenuated
both dimethoate (60 ng/ml) and lindane (4.3 ng/ml) response at the neuromuscular junction.
Lindane (6.4 ng/ml) attenuated dimethoate (8 ng/ml-) response and attenuated both
spontaneous rabbit ileum and nerve twitch responses. The effect of lindane was augmented
by d-tubocurarine (1.3 ng/ml) and attenuated by lignocaine (16.8 ng/ml). Lignocaine
similarly attenuated dimethoate (60 ng/ml) response on the nerve.
The findings of these studies suggest some degree of protection provided by lindane against
dimethoate toxicity. The protective effect of lindane was pronounced in acute dimethoate
administration and less so in sub-chronic concurrent exposure. The in vitro results indicate
antagonism of dimethoate response by lindane. Combined pesticides exposure, therefore,
need not necessarily imply exaggerated toxicity.
Description
A thesis in the department of PharmacoIogy and Clinical Pharmacy, Faculty of
Pharmaceutical Sciences, Ahmadu Bello University', Zaria, submitted to the
Postgraduate School in partial fulfillment of the requirement for the award of
degree of Doctor of Philosophy.
Ahmadu Bello University, Zaria.
SEPTEMBER. 1998.
Keywords
INTERACTION,, STUDIES,, LINDANE,, (GAM MA LIN -20®), DIMETHOATE, (ROGOR®), VIVO,, VITRO.