Intro
Naphthalene is a toxic substance. Toxic effects vary from individual to individual (in adults, ingestion of 6 grams has led to significant toxicity or no symptoms at all; in children, in whom absorption occurs rapidly, a reported dose of 2 grams has been fatal) and they act at a both local and a systemic level. The systemic effects of naphthalene occur chiefly in the erythrocytes with haemolysis, with subsequent blocking of renal tubules by precipitated haemoglobin. Haemolysis is more likely to occur in individuals with a hereditary deficiency of glucose-6-phosphate dehydrogenase, sickle cell anaemia and sickle cell trait. Besides that, Naphthalene has noxious effects on others targets such as the gastroenteric system, the liver (hepatic necrosis may occur), the urinary system, the brain and the eye (cataract). Local effects are not that serious. It's all about the skin (Contact Dermatitis) and the cornea (corneal lesion).
Chemical Structure
Naphthalene, also known as naphthalin, is a crystalline, aromatic, white, solid hydrocarbon (PAH: Polycyclic Aromatic Hydrocarbon) with formula C10H8 and the structure of two fused benzene rings. It is best known as the traditional, primary ingredient of moth balls.
It is volatile, forming an inflammable vapour, and readily sublimes at room temperature, producing its characteristic odour. It's insoluble in water, somewhat soluble in methanol/ethanol, soluble in organic solvents and very soluble in ether, chloroform, or carbon disulfide.
More details are here
Routes of absorption and related Symptoms
• Oral: Poisoning may occur after ingestion of large doses of Naphthalene. Ingestion of naphthalene-containing mothballs is a common occurrence in children. In vivo studies suggest that Naphthalene is transferred in intestinal epithelium by diffusion, which appears extensively governed by the physicochemical properties of PAHs, particularly lipophilicity, and it arrives in the portal blood mostly unchanged. For this reason, it is different from other PAHs (such as Benzo(a)pyrene) which are extensively metabolized by gut’s mucosal cells. Sources
Ingestion gives rise to abdominal cramps, nausea, vomiting and diarrhoea. Some additional signs and symptoms of naphthalene ingestion include headache, profuse sweating, tachycardia, respiratory distress, listlessness, confusion. In some cases ingestion of naphthalene may also cause arrhythmias, convulsions and coma and could possibly be fatal
• Inhalation: Naphthalene toxicity can occur by vapor inhalation. Some of the common signs and symptoms of an acute inhalation exposure to naphthalene include headache, confusion, nausea, vomiting and profuse perspiration.
• Dermal: Systemic reactions, such as jaundice and haemolysis have occurred after dressing infants in clothing stored with naphthalene moth balls suggesting that percutaneous absorption may occur. Dermal absorption, especially in infants maybe significant and further enhanced by prior application of oils. Dermal exposure to naphthalene causes mild skin irritation, however, some individuals may be more sensitive to naphthalene and dermal contact may give rise to severe dermatitis. Ocular exposure to naphthalene has been seen to result in eye irritation, corneal damage, lens opacities and the formation of cataracts. More studies about the naphthalene-induced cataract are reported here
• Transplacental: Effects of toxicity can be observed in the newborn following transplacental transfer of naphthalene or its oxidation products. Antepartum maternal naphthalene inhalation from mothballs may cause in most neonates either cardiovascular or parenchymal lung disease. A minority could have methemoglobinemia, readily detectable by the persistent chocolate-brown appearance of the blood when exposed to air. A specific case report is described here
Metabolism
Naphthalene is metabolized in the liver to yield a variety of hydroxy and methylthio derivatives. The metabolism of naphthalene has been extensively studied in experimental animals. The metabolism of naphthalene forms a number of reactive metabolites, which may be responsible for its toxicity, including 1,2-naphthalene oxide, 1,2-naphthoquinone and 1,4-naphthoquinone. The initial stage of naphthalene metabolism is the formation of the epoxide, 1,2-naphthalene oxide by cytochrome P450 (CYP) oxidation. The epoxide is relatively unstable and can undergo spontaneous rearrangement to 1-naphthol or 2-naphthol, which can be conjugated to either glucuronides or sulphates and excreted in the urine. The 1-naphthol metabolite is the most common of the two formed and alternatively to conjugation, it may undergo further metabolism by CYP 450 into 1,4-naphthoquinone resulting in toxicity and adduct formation. 1,2-naphthalene oxide may be further converted first by epoxide hydrolase (to yield 1,2-dihydroxynaphthalene) and then by dihydrodiol dehydrogenase (to yield 1,2-naphthoquinone, a known cataractogenic agent).
Elimination and excretion
1,2-dihydroxynaphthalene and 2-naphthol are excreted as glucuronides in the urine.
Conjugates of glutathione and cysteine are excreted in the bile.
Haemolytic anaemia caused by naphthalene
The International Agency for Research on Cancer (IARC) points out that acute exposure may cause haemolytic anaemia. The latter may occur in healthy humans (especially children), after ingesting mothballs or deodorant blocks containing naphthalene (usually accidentally, but sometimes with a suicidal aim). Over 400 million people have an inherited condition called Glucose-6-Phosphate-Dehydrogenase deficiency. Exposure to naphthalene is more harmful for these people and may cause hemolytic anemia at lower doses. In this case, poisoning may occur with inhalation and dermal contact too (babies who had contact with impregnate blankets or clothes).
Dermal absorption seems to be enhanced by prior application of ointments and other oily cosmetics.
Pathogenesis of Haemolytic anaemia
Assumption of naphthalene results in the formation of an epoxide metabolite that is probably responsible for haemolysis. Haemolysis mostly occurs in individuals with a hereditary deficiency of Glucose-6-Phosphate Dehydrogenase due to instability of erythrocyte glutathion. Toxicity may be in the newborn due to their inability to conjugate both naphthalene and bilirubin leading to kernicterus (it is a bilirubinic encephalopathy with bilirubin infiltration in some areas of the encephalon, especially the basal ganglia and the hippocampus).
Clinic of Haemolytic anaemia
There is fragmentation of red cells with anisocytosis and poikilocytosis, severe anaemia with nucleated red cells, leucocytosis and dramatic decreases in haemoglobin concentrations, haematocrit and red cell count. More severe reactions also include Heinz body formation, haemoglobinuria and mild methaemoglobinaemia. The haemolytic episode tend to be self limiting. Damage occurs most intensively in older cells, i.e. those approaching the normal life span of 100 to 120 days. Patients develop jaundice and the chief threat to life in young infants is kernicterus that carries a high mortality. In older children and adults the haemolytic crisis may be followed by acute renal failure.
Diagnosis
Diagnosis of naphthalene poisoning by ingestion is made from the history of exposure and the presence of clinical manifestations and signs and symptoms of haemolysis. If poisoning is due to inhalation or dermal absorption, medical history may result difficult and incomplete.
Biomedical analysis
Haematological findings may include a rapid fall in erythrocyte count, haemoglobin concentration and haematocrit followed by a temporary increase in reticulocytes and normoblasta in the peripheral blood. During a haemolytic crisis the fragility of the remaining cells is increased. Haemoglobin is present in the plasma. Red cells may contain Heinz bodies and the cells may be fragmented showing anisocytosis and poikilocytosis. Serum bilirubin is elevated. The urine may be wine coloured brown or black; the colour may vary from patient to patient or in the same patient during the course of illness. In most but not all persons with naphthalene induced haemolysis, a deficiency of G6PD can be demonstrated.
Management
In case of skin or eye contact, flush contaminated area with lukewarm gently running water for at least 20 minutes.
In case of inhalation, if acute symptoms are present remove source of contamination and/or move victim away from the source; make a proper assessment of airway, breathing and circulation; administer oxygen if patient cyanosed; perform cardio-pulmonary resusitation if appropriate; support ventilation using appropriate mechanical device.
In case of ingestion, if a significant amount is ingested and if no convulsions present, cautious gastric lavage can be considered; lavage is not likely to be effective if more than 2 hours have passed since ingestion.
Specific treatment
A severe anaemia due to haemolysis may require small repeated blood transfusions (preferably with red cells from a non-sensitive individual) until the haemoglobin concentration is 60 to 80% of normal. Corticosteroids appear to have been beneficial in a few cases of naphthalene haemolysis. Sodium bicarbonate orally is indicated to maintain alkaline urine.
Other useful web sites
www.beyondpesticides.org
www.inchem.org
www.hpa.org.uk
Gianluca Franco (matricola 242016)
Federico Bottino (matricola 239599)
