109: Toxic Alcohols
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109: Toxic Alcohols Sage W. Wiener HISTORY AND EPIDEMIOLOGY Methanol was a component of the embalming fluid used in ancient Egypt. Robert Boyle first isolated the molecule in 1661 by distilling boxwood, calling it spirit of box.29 The molecular composition was determined in 1834 by Dumas and Peligot, who coined the term “methylene” from the Greek roots for “wood wine.”202 Industrial production began in 1923, and today most methanol is used for the synthesis of other chemicals. Methanol containing consumer products that are commonly encountered include model airplane and model car fuel, windshield washer fluid, solid cooking fuel for camping and chafing dishes, photocopying fluid, colognes and perfumes, and gas line antifreeze (“dry gas”). Methanol is also used as a solvent by itself or as an adulterant in “denatured” alcohol.138Most reported cases of methanol poisoning in the United States involve ingestions of one of the above products, with more than 60% involving windshield washer fluid,58 although most inhalational exposures involve carburetor cleaner.87 In a Tunisian series, ingested cologne was the most common etiology.30 In a Turkish series, cologne was also most common, accounting for almost 75% of ingestions.129 Perfume was one of several exposures in a patient with methanol poisoning in a report from Spain,173 and methanol poisoning from cologne has also been reported in India.12 There are sporadic epidemics of mass methanol poisoning, most commonly involving tainted fermented beverages.23,130These epidemics are a continuing problem in many parts of the world.16,146,153,166,187,218,257 Ethylene glycol was first synthesized in 1859 by Charles-Adolphe Wurtz and first widely produced as an engine coolant during World War II, when its precursor ethylene oxide became readily available.70 Today its primary use remains as an engine coolant (antifreeze) in car radiators. Antifreeze used in gas tanks generally contains methanol. Because of its sweet taste, it is often consumed unintentionally by animals and children. Aversive bittering agents may be added to ethylene glycol containing antifreeze to try to prevent ingestions by making the antifreeze unpalatable, an approach required by law in two states. However, there is no evidence that this strategy is effective, and comparisons in poison center data between ethylene glycol ingestions where bittering agents were required and where they were not have revealed no significant differences in frequency or volume of ingestion, or any other outcome variable (Chap. 135).253,254 Isopropanol is primarily available as rubbing alcohol. Typical household preparations contain 70% isopropanol. It is also a solvent used in many household, cosmetic, and topical pharmaceutical products. Perhaps because it is so ubiquitous, inexpensive, and with a common name that contains the word “alcohol”, isopropanol ingestions are the most common toxic alcohol exposure reported to poison centers in the United States,36typically in cases where it was used as an ethanol substitute (Chap. 136). CHEMISTRY Alcohols are hydrocarbons that contain a hydroxyl (-OH) group. The term “toxic alcohol” traditionally refers to alcohols other than ethanol that are not intended for ingestion. In a sense, this is arbitrary, since all alcohols are toxic, causing inebriation and end organ effects if taken in excess. The most common clinically relevant toxic alcohols are methanol and ethylene glycol (1,2-ethanediol). Ethylene glycol contains two hydroxyl groups; molecules with this characteristic are termed diols or glycols because of their sweet taste. Other common toxic alcohols include isopropanol (isopropyl alcohol or 2-propanol), benzyl alcohol (phenylmethanol), and propylene glycol (1,3-propanediol). Primary alcohols, such as methanol and ethanol, contain a hydroxyl group on the end of the molecule (the terminal carbon), whereas secondary alcohols, such as isopropanol, contain hydroxyl groups bound to middle carbons. Glycol ethers are glycols with a hydrocarbon chain bound to one or 1 2 1 more of the hydroxyl groups (forming the basic structure R O-CH2-CH2-O-R or R O-CH2-CH2-CH2- OR2). Glycol ethers commonly encountered include ethylene glycol butyl ether (also known as 2- butoxyethanol, ethylene glycol monobutyl ether, or butyl cellosolve), ethylene glycol methyl ether (2- methoxyethanol), and diethylene glycol (2,2′-dihydroxydiethyl ether). Poisoning with these compounds may clinically resemble toxic alcohol poisoning, and diethylene glycol is discussed in detail in Special Considerations: SC7. TOXICOKINETICS/TOXICODYNAMICS Alcohols are rapidly absorbed after ingestion74,88 but are not completely bioavailable because of metabolism by gastric alcohol dehydrogenase (ADH), as well as by first-pass hepatic metabolism. Occasionally, delayed or prolonged absorption may occur.68 Although methanol may also be absorbed in significant amounts by inhalation, poisoning by this route is uncommon. In workers exposed to methanol fumes from industrial processes for up to 6 hours at concentrations of 200 ppm (Occupational Health and Safety Administration {OSHA} permissible exposure limit {PEL}), there was no significant accumulation of methanol or its metabolite formate.148 Another study showed that with methanol use in the semiconductor industry, ambient methanol concentrations generally do not approach this OSHA limit even in a room with poor ventilation due and with no local exhaust ventilation.80 Surprisingly, concentrations far in excess of the OSHA PEL can be present within the passenger compartment of a car when using the windshield wipers with methanol-containing windshield washing fluid.21 No cases of human poisoning are reported from this type of exposure, probably because these concentrations are not sustained over a long time. Two patients with occupational inhalational exposure aboard a tanker carrying methanol developed consequential toxicity, including the death of one; both patients reportedly used appropriate personal protective equipment.139 Additionally, cases of inhalational poisoning are reported with intentional inhalation of methanol as a drug of abuse, typically in the form of carburetor cleaning fluid (“huffing”) (Chap. 84), and with massive exposures of rescue workers responding to the scene of an overturned rail car filled with methanol.14,75,87,158,244,250 Two case series suggest that patients who present after chronic inhalation of methanol have good clinical outcomes with folate and ADH blockade alone and without need for hemodialysis,20,158 although in another series, patients with inhalational exposure were as likely to require dialysis as patients with methanol ingestion.87 Transdermal methanol exposure can be consequential if exposure is prolonged.131 Ethylene glycol has low volatility and is not reported to cause poisoning by inhalation. In one study, human volunteers inhaled vaporized ethylene glycol at a concentration of 1340 to 1610 ppm for 4 hours to simulate an industrial exposure. Afterward, the volunteers had detectable but not clinically significant concentrations of ethylene glycol and its metabolites.242 Most alcohols have some dermal absorption, although isopropanol and methanol are able to penetrate the skin much better than ethylene glycol.63,154,248 Most reported cases of toxic alcohol poisoning by this route involve infants57 because of their greater body surface area–to– volume ratio, and likely this also involved simultaneous inhalation. One reported case of transdermal methanol poisoning involved a 51 year-old woman, but details of the exposure were not reported.230Another case involved a 52 year-old woman who reportedly frequently massaged with methanol containing cologne and spirit over the course of 3 days. That patient suffered significant visual and neurologic sequelae despite aggressive treatment with ethanol and hemodialysis.2 One methanol fatality was deemed to be caused by transdermal absorption (in addition to blunt trauma) when high tissue methanol concentrations were measured in the absence of detectable methanol in the gastrointestinal tract,15 but inhalational exposure could also conceivably have contributed. When human volunteers were exposed to 100% ethylene glycol applied to a 66 cm2 area of skin under an occlusive dressing for 6 hours, detectable but not clinically significant amounts were absorbed.242 Once absorbed, alcohols are rapidly distributed to total body water. In human volunteers given an oral dose of methanol on an empty stomach, the measured volume of distribution was 0.77 L/kg, with a distribution half-life of about 8 minutes.88 This is only slightly longer than the absorption half- life, so serum concentrations typically peak soon after ingestion and then begin to fall. Without intervention, toxic alcohols are metabolized through successive oxidation by ADH and aldehyde dehydrogenase (ALDH), each of which is coupled to the reduction of NAD+to NADH. Methanol is metabolized to formaldehyde, then to formic acid (Fig. 109–1). Ethylene glycol has two hydroxyl groups that are serially oxidized by ADH and ALDH, producing, in turn, glycoaldehyde, glycolic acid, glyoxylic acid, and finally oxalic acid (Fig. 109–2). Like ethanol, this metabolism follows zero-order kinetics, with a rate that is reported to be about 10 mg/dL/h.50,118,169 Additionally, this rate is apparently unchanged in chronic ethanol users.97,98 Alternate minor metabolic pathways such as catalase exist for methanol and ethylene glycol. FIGURE 109–1. Major pathway of methanol metabolism.