pharmaceuticals, tobacco products, or nicotine containing plants may also lead to poisoning. Smoking excessive amounts of tobacco has also led to poisoning; a case was reported where two brothers smoked 17 and 18 pipes of tobacco in succession and were both fatally poisoned. Spilling an extremely high concentration of nicotine onto the skin can result in intoxication or even death since nicotine readily passes into the bloodstream following skin contact. The recent rise in the use of electronic cigarettes, many forms of which are designed to be refilled with nicotine-containing "e-liquid" supplied in small plastic bottles, has renewed interest in nicotine overdoses, especially the possibility of young children ingesting the liquids. A 2015 Public Health England report noted an "unconfirmed newspaper report of a fatal poisoning of a two-year old child" and two published case reports of children of similar age who had recovered after ingesting e-liquid and vomiting. They also noted case reports of suicides by nicotine, where adults drank liquid containing up to 1,500 mg of nicotine. They recovered (helped by vomiting), but an ingestion apparently of about 10,000 mg was fatal, as was an injection. They commented that "Serious nicotine poisoning seems normally prevented by the fact that relatively low doses of nicotine cause nausea and vomiting, which stops users from further intake." Four adults died in the US and Europe, after intentionally ingesting liquid. Two children, one in the US in 2014 and another in Israel in 2013, died after ingesting liquid nicotine. The discrepancy between the historically stated 60-mg dose and published cases of nicotine intoxication has been noted previously (Matsushima et al. 1995; Metzler et al. 2005). Nonetheless, this value is still widely accepted over the 500 mg figure as the basis for safety regulations of tobacco and other nicotine-containing products (such as the EU wide TPD, set at a maximum of 20 mg/ml. Pathophysiology The symptoms of nicotine poisoning are caused by effects at nicotinic cholinergic receptors. Nicotine is an agonist at nicotinic acetylcholine receptor which are present in the central and autonomic nervous systems, and the neuromuscular junction. At low doses nicotine causes stimulatory effects on these receptors, however, higher doses or more sustained exposures can cause inhibitory effects leading to neuromuscular blockade. It is sometimes reported that people poisoned by organophosphate insecticides experience the same symptoms as nicotine poisoning. Organophosphates inhibit an enzyme called acetylcholinesterase, causing a buildup of acetylcholine, excessive