American Journal of Therapeutics 13, 277–280 (2006)

Lindane Neurotoxicity in Childhood

Anjum Singal and Gurvinder P. Thami*

Lindane (gamma-benzene-hexachloride) has been widely used as an antiscabetic and a

pediculicidal agent for the past 50 years with reasonably good efficacy. After its initial use as a
first-line therapy, there have been several reports of its neurotoxicity, especially among infants and
young children. Literature review reveals that the risk of its neurotoxicity is minimal if used
properly and strictly according to the prescribed recommendations. However, following availability
of other safer and equally efficacious alternatives, it is now being regarded as a second-line therapy
for scabies and pediculosis.

Keywords: lindane, gamma-benzene-hexachloride, scabies, neurotoxicity, safety, pediculosis

INTRODUCTION parasites including Pediculus humanus, Phthirus pubis,

Lindane (gamma-benzene-hexachloride), an insecticide
belonging to chlorinated hydrocarbon family, is one of
the 8 isomers of 1-6 hexachlorocyclohexane.1 First
synthesized by Michael Faraday in 1825, this chlorine
analogue of mucoinositol is presently in use as a
technical grade insecticide in variable concentrations or
as 1% solution, cream, or shampoo for the treatment of
scabies and lice infestation in humans.1 Following
excessive percutaneous absorption and accidental
ingestion of lindane, there have been some toxicity
problems. Review of lindane toxicity with special
reference to its neurotoxicity reveals several case
reports and series in the literature chiefly affecting
infants and young children. However, its judicious use
with strict adherence to prescribed safety precautions
can prevent its toxicity in most patients.
PHARMACOLOGY IN HUMANS
AND ANIMALS
Lindane is a powerful insecticide and parasiticide
with a rapid action against the majority of external
Department of Dermatology and Venereology, Government
Medical College Hospital, Chandigarh, India.
*Address for correspondence: Department of Dermatology and
Venereology, Government Medical College Hospital, Sector 32 B,
Chandigarh, 160030 India. E-mail: thamigp@yahoo.com
1075-2765 r 2006 Lippincott Williams & Wilkins
and Sarcoptes scabiei. It affects the nervous
system of parasites after getting absorbed through
their surface chitin, leading to seizures and death.2
Besides this, it also stimulates production of leuko-
triene C4 and arachidonic acid, the exact relevance of
which is not known with respect to its pharmacologic
effects.3
There are few data regarding its pharmacokinetics
in humans. Lindane is readily absorbed after oral
ingestion, inhalation, or topical application. Being
highly lipid soluble, it gets readily absorbed through
the skin in amounts varying from 9% without
occlusion to as high as 80% when used under
occlusion, absorption being highest within 8 hours of
application. It is metabolized in the liver, stored in the
fat and other lipophilic tissues such as white matter of
the brain, and is rapidly eliminated through the
body.4 Based on the urinary excretory data, its half-life
has been estimated to be approximately 12 hours.2
Metabolism and hence elimination, however, are
slower in children compared with adults.3
HUMAN TOXICITY
Lindane was used as an insecticide since 1942, while
its therapeutic role as an antiscabetic was esta-
blished in 1948.1,5 The frequency of its use as a
therapeutic modality in the treatment of scabies and
pediculosis in the United States alone has been more
than a million prescriptions in the past year.6,7
278
Humans are exposed to its toxic effects through
accidental ingestion, inhalation, or increased percuta-
neous absorption. Most of the adverse effects are
encountered when it is not used properly according to
the recommendations; however, one fifth of the
patients may experience these even when the drug
is used appropriately.6,8 The incidence of adverse
events is incalculable, presumably due to under-
reporting. A total 17 deaths have been reported, of
which 3 deaths have been confirmed to be due to
lindane use not in accordance with the product label,
including multiple topical applications or oral inges-
tion.8 Of the remaining 14 deaths associated with
lindane, but not confirmed, in 9 cases, its use was
again not in accordance with the product label. Most
commonly, patients often reapplied lindane because
of continued itching despite 1 application.
Various animal studies have shown lethal dose of
lindane (LD50) for warm-blooded animals in the range
of 50–60 mg/kg body weight depending on its portal
of entry.1 Absorption via the cutaneous route has been
found to be at least 9.3% through forearm skin and
100% through scrotal skin.9,10 The first suggestion
that major toxicity and death could be caused by
exposure to lindane through the skin was reported as
early as 1953.11
Acute toxicity occurs within 30 minutes of exposure
via the oral route and is characterized by features
such as nausea, vomiting, paraesthesias, giddiness,
tremors, ataxia, apprehension, excitability, disorienta-
tion, convulsions, coma, respiratory failure, and
sometimes death.2,12 Chronic lindane exposure in
humans has resulted in depressed liver function,
altered menstruation, and cardiac arrhythmias.
Rarely, immunologically mediated hemopoietic de-
pression or blood dyscrasias may be induced.1
Necropsy studies of fatal lindane toxicity have
revealed fatty infiltration of liver, degeneration of
cardiac muscle, and necrosis of vessels of lungs,
kidneys, and brain.1 Besides systemic effects, topical
application can result in irritant contact dermatitis,
eczematization, urticaria, and rarely alopecia.
Neurotoxicity is the most frequently observed
adverse effect of lindane due to its predilection for
the lipid-rich white matter of the brain. Lindane levels
in the brain have been found to be 10 times
greater than in blood following a single topical
application of 1% lindane lotion.13 Infants and
young children seem to be more prone as most cases
of neurotoxicity reported in the literature pertain
to this age group. According to the FDA, of all
the adverse events reported, 70% are neurologic
events including seizure, dizziness, headache, and
paraesthesia.8
American Journal of Therapeutics (2006) 13(3)
Singal and Thami
Although the exact mechanism of lindane neuro-
toxicity is not known, it is believed to act through
neuronal inhibition of ‘‘g-aminobutyric acid (GABA)
transmission along with altered intracellular calcium
levels and excitatory amino acid transmission in the
brain.14,15
REVIEW OF LITERATURE
Lindane toxicity as a result of percutaneous absorp-
tion was first reported in 1953 in a group of 79 persons
folio whig exposure to a 40% mixture of its isomers
applied to the household environment including bed
covers, clothes, and body surfaces. Initial symptoms
of lassitude, vertigo, headache, myalgia, intestinal
colic, diarrhea, and stomatitis were followed by
neurologic symptoms in the form of mental confu-
sion, dysarthria, and convulsions.11
From 1960 to 1977, there were only 26 case reports
of 1% lindane toxicity despite its extensive use in
more than 24 million applications in a period of
17 years.16 Kramer et al16 critically evaluated these
reports from published literature and formulated an
operational criteria to determine whether the sus-
pected drug is causative in producing an adverse
drug reaction. Using a branched logic decision format,
they scored 6 axes of detisional strategy, ie, previous
general experience with the drug, alternative etiologic
agents used, timing of events, drug levels and
evidence of overdose, and dechallenge and recha-
llenge and categorized these reports into definite,
probable, possible, and unlikely. Of 13 cases of
seizures reported, none scored as definite, 6 were
probable, 5 were possible, and 2 were unlikely.
Ginsberg et al 17 noted a 3- to 20-fold variation
in lindane level in infants and children at each of the
8 sampling times reported. Feldmann and Maibach9
observed a similar individual variation of transcuta-
neous absorption in adult volunteers. Pramanik and
Hansen18 reported a case with lindane blood levels
17 times greater than expected following a single
application in a 4-month-old infant. Malnutrition has
been implicated as a risk factor for developing toxicity
with lindane application by both Pramanik and
Hansen18 and Hall and Hall.19 Moreover, lindane
levels have been reported to be higher in those with
reduced body fat level.9 Boyd and Chen20 showed
that cachectic rats whose growth had been stunted by
a protein-deficient diet were twice as susceptible to
the toxic effects of topical lindane when compared
with normally fed animals. Solomon et al13 demon-
strated a 10-fold greater concentration of lindane in
guinea pig brain than in blood after a single
Lindane Neurotoxicity in Childhood
application of 1% lindane. It has been suggested that
the brain may be one of the few lipid-rich areas of the
body in a fat-depleted malnourished patient in which
lipid-soluble lindane may preferentially accumulate.18
Davies et al21 reported a fatal case of lindane
neurotoxicity in an infant who was given a hot water
bath prior to 2 consecutive nightly applications kept
for a longer time than recommended. Hall and Hall19
reported a case of severe long-term lindane poisoning
in which the patient developed neurotoxicity along
with skin and gastrointestinal changes following
3 repeated applications of lindane.
A few case reports of neurotoxicity among adults
include an 18-year-old girl who developed general-
ized tonic-clonic convulsions after a hot water bath.22
Besides this, there have been a few reports of
neurotoxicity following its accidental ingestion as
well.21
CURRENT STATUS AND
RECOMMENDATIONS FOR
LINDANE USE
Although lindane has been in use since 1951, it
became ‘a second-line therapy since 1995 because of
the availability of safer first-line alternatives like
permethin and malathion.6,8 According to the FDA,
because lindane products have benefits that outweigh
risks when used as directed, their use should be
restricted to those who have either failed to respond
to adequate doses, or are intolerant of, other approved
therapies of scabies and pediculosis.6,8 Following
precautions can help decrease the incidence of lindane
toxicity in general and neurotoxicity in particular. 23
1. Application immediately after a hot bath or on
wet skin should be avoided as epidermal hydra-
tion and vasodilatation facilitates its absorp-
tion.1,16,24
2. Longer application periods than recommended
should be avoided as a 6-hour application period
is as effective as longer periods.12,18,24,25
3. Repeated applications within a short span of time
should be avoided as frequent applications may
lead to cumulative toxicity.1,16,24
4. Oils or oil-based preparations should not be
simultaneously used as these increase lindane
absorption.6,8,23
5. Thumb sucking and licking in children after
application should not be allowed as oral inges-
tion increases the systemic levels of lindane.16,24
6. Extreme caution should be exercised in predis-
posing situations like infancy, childhood, preg-
279
nancy, weight less than 50 kg, massively
excoriated skin, epidermal barrier dysfunction
(eg, atopic dermatitis, psoriasis, ichthyosis), mal-
nourishment, etc.1,16,18–20,24–27
7. Lindane is contraindicated in all neonates, chil-
dren with history of seizures, and in adults with
known seizure disorders. It should be used
cautiously in those at risk due to their lowered
threshold of seizures (eg, people taking HIV
treatments, antipsychotics, bupropion, systemic
steroids, quinolone antibiotics or antimalarials
and people with head injuries or intracranial
lesions, eating disorders, or benzodiazepine or
ethanol abuse).6,8
8. Use of occlusive diapers, shower caps, or tight
clothes should be avoided after lindane applica-
tion as they lead to increased percutaneous
absorption.6,8
9. Breast-feeding women should pump and
discard milk for at least 24 hours after using
lindane.6
10. Pharmacists should not dispense more than
2 fluid ounces of lindane as this quantity is
usually sufficient for its single local application.6
CONCLUSION
Despite the fact that epicutaneous absorption of 1%
formulation of lindane has been found to have led to
several cases of neurotoxicity and death, an appro-
priate application still carries a minimal risk. Strict
adherence to prescription recommendations and
precautions can further safeguard renewed status of
lindane as a second-line drug for scabies and
pediculosis.
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