make a.c.e. mixture. in 1848, hannah greener, a 15-year-old girl who was having an infected toenail removed, died after being given the anaesthetic. her autopsy establishing the cause of death was undertaken by john fife assisted by robert mortimer glover. a number of physically fit patients died after inhaling it. in 1848, however, john snow developed an inhaler that regulated the dosage and so successfully reduced the number of deaths. the opponents and supporters of chloroform disagreed on the question of whether the medical complications were due to respiratory disturbance or whether chloroform had a specific effect on the heart. between 1864 and 1910, numerous commissions in britain studied chloroform but failed to come to any clear conclusions. it was only in 1911 that levy proved in experiments with animals that chloroform can cause cardiac fibrillation. despite this, between 1865 and 1920, chloroform was used in 80 to 95% of all narcoses performed in the uk and german-speaking countries. in germany, the first comprehensive surveys of the fatality rate during anaesthesia were made by gurlt between 1890 and 1897. in 1934, killian gathered all the statistics compiled until then and found that the chances of suffering fatal complications under ether were between 1:14,000 and 1:28,000, whereas under chloroform the chances were between 1:3,000 and 1:6,000. the rise of gas anaesthesia using nitrous oxide, improved equipment for administering anaesthetics and the discovery of hexobarbital in 1932 led to the gradual decline of chloroform narcosis. criminal use chloroform has been used by criminals to knock out, daze, or even murder victims. joseph harris was charged in 1894 with using chloroform to rob people. serial killer h. h. holmes used chloroform overdoses to kill his female victims. in september 1900, chloroform was implicated in the murder of the u.s. businessman william marsh rice. chloroform was deemed a factor in the alleged murder of a woman in 1991 when she was asphyxiated while sleeping. in 2002, 13-year-old kacie woody was sedated with chloroform when she was abducted by david fuller and during the time that he had her, before he shot and killed her. in a 2007 plea bargain, a man confessed to using stun guns and chloroform to sexually assault minors. use of chloroform as an incapacitating agent has become widely recognized, bordering on clichéd, due to the popularity of crime fiction authors having criminals use chloroform-soaked rags to render victims unconscious. however, it is nearly impossible to incapacitate someone using chloroform in this manner. it takes at least five minutes of inhaling an item soaked in chloroform to render a person unconscious. most criminal cases involving chloroform also involve another drug being co-administered, such as alcohol or diazepam, or the victim being found to have been complicit in its administration. after a person has lost consciousness due to chloroform inhalation, a continuous volume must be administered, and the chin must be supported to keep the tongue from obstructing the airway, a difficult procedure typically requiring the skills of an anesthesiologist. in 1865 as a direct result of the criminal reputation chloroform had gained, the medical journal the lancet offered a "permanent scientific reputation" to anyone who could demonstrate "instantaneous insensibility", i.e. losing consciousness instantaneously, using chloroform. safety exposure chloroform is known to form as a by-product of water chlorination, along with a range of other disinfection by-products, and as such is commonly present in municipal tap water and swimming pools. reported ranges vary considerably but are generally below the current health standard for total trihalomethanes of 100μg/l. nonetheless, the presence of chloroform in drinking water at any concentration is considered controversial by some. historically, chloroform exposure may well have been higher due to its common use as an anaesthetic, as an ingredient in cough syrups, and as a constituent of tobacco smoke where ddt had previously been used as a fumigant. pharmacology it is well absorbed, metabolized, and eliminated rapidly by mammals after oral, inhalation, or dermal exposure. accidental splashing into the eyes has caused irritation. prolonged dermal exposure can result in the development of sores as a result of defatting. elimination is primarily through the lungs in the form of chloroform and carbon dioxide; less than 1% is excreted in the urine. chloroform is metabolized in the liver by the cytochrome p-450 enzymes, by oxidation to chloromethanol and by reduction to the dichloromethyl free radical. other metabolites of chloroform include hydrochloric acid and digluathionyl dithiocarbonate, with carbon dioxide as the predominant end product of metabolism. like most other general anesthetics and sedative-hypnotic drugs, chloroform is a positive allosteric modulator for the gabaa receptor. chloroform causes depression of the central nervous system (cns), ultimately producing deep coma and respiratory center depression. when ingested, chloroform caused symptoms similar to those seen following inhalation. serious illness has followed ingestion of 7.5 g (0.26 oz). the mean lethal oral dose for an adult is estimated at 45 g (1.6 oz). the anesthetic use of chloroform has been discontinued because it caused deaths due to respiratory failure and cardiac arrhythmias. following chloroform-induced anesthesia, some patients suffered nausea, vomiting, hyperthermia, jaundice, and coma due to hepatic dysfunction. at autopsy, liver necrosis and degeneration have been observed. chloroform has induced liver tumors in mice and kidney tumors in mice and rats. the hepatotoxicity and nephrotoxicity of chloroform is thought to be due largely to phosgene. conversion to phosgene chloroform converts slowly in air to the extremely poisonous phosgene (cocl2), releasing hcl in the process. 2 chcl3 + o2 → 2 cocl2 + 2 hcl to prevent accidents, commercial chloroform is stabilized with ethanol or amylene, but samples that have been recovered or dried no longer contain any stabilizer. amylene has been found ineffective, and the phosgene can affect analytes in samples, lipids, and nucleic acids dissolved in or extracted with chloroform. phosgene and hcl can be removed from chloroform by washing with saturated aqueous carbonate solutions, such as sodium bicarbonate. this procedure is simple and results in harmless products. phosgene reacts with water to form carbon dioxide and hcl, and the carbonate salt neutralizes the resulting acid. suspected samples can be tested for phosgene using filter paper (treated with 5% diphenylamine, 5% dimethylaminobenzaldehyde in ethanol, and then dried), which turns yellow in phosgene vapour. there are several colorimetric and fluorometric reagents for phosgene, and it can also be quantified with mass spectrometry. regulation chloroform is suspected of causing cancer (i.e., possibly carcinogenic, iarc group 2b) as per the international agency for research on cancer (iarc) monographs. it is classified as an extremely hazardous substance in the united states as defined in section 302 of the u.s. emergency planning and community right-to-know act (42 u.s.c. 11002), and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities. bioremediation of chloroform some anaerobic bacteria use chloroform for their respiration, termed organohalide respiration, converting it to dichloromethane.