Mechanism of

action and
toxicity of
organochloride.
Presented by
Areeba Sajjad
roll 05
 Mechanism of action and toxicity.
» In general, the mechanism of action of organochlorine insecticides is not
yet fully understood.
» The DDT-type insecticides alter the transport of sodium and potassium ions
across axonal membranes, resulting in an increased negative after-potential
and prolonged action potentials. As a result, repetitive firing and a
spontaneous train of action potentials occur. Specifically, DDT inhibits the
activation of sodium channels and the activation of potassium
conductance. The mechanism of cyclodienes involved in hyperexcitation of
the CNS and convulsions has been explained based on their structural
resemblance to the bicyclic γ-aminobutyric acid (GABA) receptor
antagonist picrotoxin.

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 Contd.

» The mammalian GABA receptor is coupled to an intrinsic chloride

ion channel and is the primary mediator of neuronal inhibition in
the brain. Like picrotoxin, cyclodienes block the inhibitory action
of GABA. Heptachlor (and its toxic metabolite heptachlor
epoxide) and related organochlorines are also reported to target
dopaminergic neurons in the striatum by releasing dopamine,
which appears to play a role in the etiology of idiopathic
Parkinson's disease (Kirby et al., 2001). In another study, Dutheil
et al. (2010) investigated interaction between ABCB1 gene and
professional exposure to organochlorine insecticides in
Parkinson's disease.
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 Toxicity in humman

» Some of the organochlorine insecticides have the potential to induce

placental toxicity. Many organochlorines and their metabolites are known
to be found in the placenta and cord blood and cross the placental barrier
(Sala et al., 2001; Herrero-Mercado et al., 2010). Shen et al. (2005)
determined the content of many organochlorine pesticides in human
placentas. The average number of pesticides found per placenta was 18.5
from a total of 27. Wojtowicz et al. (2007) reported that DDT and its
metabolite DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] caused
inhibition of estradiol secretion (due to direct action on aromatase activity),
with concomitant stimulation of progesterone secretion in human term
placental explants, which can be attributed to adverse pregnancy
outcomes.
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 Toxicity in animals.

» In animal studies, pregnant Swiss mice exposed to lindane at

different stages of pregnancy produced various toxicological
effects, including fetotoxicity and reproductive failure (Sircar and
Lahiri, 1989). Lindane exposure during early pregnancy (days 1–4)
caused total absence of any implantation, during mid-pregnancy
(days 6–12) caused total resorption of fetuses, and during late
pregnancy (days 14–19) caused the death of all pups within 12 h to
5 days after parturition. In addition, lindane can cause
reproductive failure by causing a deficiency of steroid hormones
(estrogen and progesterone).

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