Special Article
Drug Safety 5 (5): 359-383, 1990 0114-5916/90/0009-0359/$12.50/0 © Adis International Limited All rights reserved. MEDT03305
An Introduction to the Clinical Toxicology of Volatile Substances R.J. Flanagan, M. Ruprah, T.J. Meredith and J.D. Ramsey Poisons Unit, Guy's Hospital, London, Division of Toxicology and Environmental Health, Department of Health, I London, and Toxicoiogy Unit and Department of Clinical Epidemiology, St George's Hospital Medical School, London, England
Contents
Summary ..................................................................................................................................... 359 I. Volatile Substance Abuse ..................................................................................................•.... 361 1.1 Modes of Abuse of Volatile Substances ......................................................................... 361 1.2 Prevalence of Abuse ............. ;.......................................................................................... 363 1.3 Mortality from Abuse ...................................................................................................... 364 1.4 Morbidity from Abuse ..................................................................................................... 364 I.S Treatment of Chronic Abusers and Strategie& for Prevention ..................................... 36S 2. Oinical Toxicology of Volatile Substances ................. _....................................................... 367 2.1 Acute Poisoning ............................................................................................................... 367 2.1.1 Clinical Features and Treatment ........................................................................... 367 2.1.2 Toluene and Butane ................................................................................................ 368 2.1.3 Chlorinated Hydrocarbons ..................................................................................... 368 2.1.4 Solvent Ingestion ..................................................................................................... 369 2.2 Chronic Toxicity of Volatile Compounds ..................................................................... 369 2.2.1 Oinical Sequelae of Long Term Toluene Exposure ............................................ 370 2.2.2 Clinical Sequelae of Long Term Exposure to Chlorinated Solvents .................. 372 3. Pharmacokinetics of Volatile Substances ............................................................................. 373 3.1 Absorption, Distribution and Elimination .................................................................... 373 3.2 Metabolism ....................................................................................................................... 375 4. Diagnosis of Poisoning Due to Volatile Substances ........................................................... 375 4.1 Clinical and Circumstantial Evidence ............................................................................ 375 4.2 Role of Toxicological Analyses ....................................................................................... 375 4.2.1 Blood Toluene Concentrations and Oinical Features of Toxicity ..................... 378 4.2.2 Blood I,I,I-Trichloroethane Concentrations and Clinical Features of Toxicity .................................................................................. 379 S. Conclusions .................................................................................................................. 379
Summary
Acute poisoning with organic solvents and other volatile compounds now usuillly follows deliberate inhalation (volatile substance abuse) or ingestion of these compounds.
I The contents of this article represent the authors' views alone and in no way commit the Department of Health.
Drug Safety 5 (5) 1990
360
Solvents from adhesives, typewriter correction and dry cleaning fluids, cigarette lighter refills (butane) and aerosol propellants are commonly abused. The major risk is that of sudden death. Arrhythmias leading to cardiac arrest are thought to cause most deaths, but anoxia, respiratory depression and vagal stimulation leading to cardiac arrest may also contribute, as may indirect causes such as aspiration of vomit or trauma. In the United Kingdom (UK), 3.5 to 10% of young people have at least experimented with volatile substance abuse and mortality is more than 100 per annum. The products abused are cheap and readily available despite legislation designed to limit supply. Volatile substance abuse is not illegal and only a minority of abusers are known to progress to heavy alcohol or illicit drug use. Prevention of abuse by education,"ot only of children but also of parents, teachers, retailers and health care workers, is important in limiting the problem. However, volatile substance abuse-related deaths are still increasing in the UK despite many measures aimed at prevention. Clinically, volatile substance abuse is characterised by a rapid onset of intoxication and rapid recovery. Euphoria and disinhibition may be followed by hallucinations, tinnitus, ataxia, confusion, nausea and vomiting. It is important not to further alarm the patient if signs of serious toxicity are present, since a cardiac arrest may be precipitated. Further exposure should be prevented and the patient resuscitated and given supplemental oxygen if necessary. Cardiac arrhythmias should be treated conventionally and respiratory failure managed supportively. Long term exposure to n-hexane is associated with the development of peripheral neuropathy, while prolonged abuse (notably of toluene or chlorinated solvents) can cause permanent damage to the central nervous system, heart, liver, kidney and lungs. Knowledge of the routes of absorption, distribution and excretion of volatile compounds, and of the rates governing these processes, is important in understanding the rate of onset, intensity and duration of intoxication, and rate of recovery after volatile substance abuse. In addition, such knowledge is helpful when the clinician is attempting to interpret the results of toxicological analyses performed on samples (blood, other tissues, urine) from such patients. Many volatile substances are partly metabolised, the metabolites being eliminated in exhaled air or in urine. Although metabolism normally results in detoxification, enhanced toxicity may also result as with carbon tetrachloride, chloroform, dichloromethane, n-hexane, trichloroethylene and possibly halothane. Identification of volatile substance abusers can be difficult, but the hair, breath and clothing may smell of solvent, and empty containers may be found. Perioral eczema ('glue-sniffer's rash') from direct contact with glue poured into a plastic bag occurs rarely. Headspace gas chromatography of blood can detect exposure to many compounds but not to complex mixtures such as petrol; detection of metabolites is only useful with a few compounds, notably toluene, trichloroethylene and xylene. Prevalence studies suggest that volatile substance abuse is increasing worldwide yet the UK is the only country to collate and regularly publish data on abuse-related deaths. Such data, although difficult to collect, are important in identifying and monitoring the problem. A coordinated approach to the collation of analogous data on an international basis would be valuable in monitoring the efficacy of preventative programmes.
Organic solvents and other volatile compounds are used extensively in industry and in the laboratory. Long term exposure to solvent vapour may thus occur during the manufacture and use of a variety of products (table I). Morbidity and mortality from exposure to volatile substances is not a new problem: many cases of jaundice occurred
when I, I ,2,2-tetrachloroethane was used for 'doping' (waterproofing) fabric-covered aircraft during World War I, and chloroform anaesthesia was associated with cardiac arrhythmias and hepatorenal necrosis after prolonged use (Meredith et al. 1989). Today, if anaesthesia is excluded, acute poisoning with volatile substances usually follows deliberate
Clinical Toxicology of Volatile Substances
inhalation of vapour in order to become intoxicated ['glue sniffing', solvent abuse, volatile substance abuse (VSA»). In addition, patients who ingest solvents or solvent-containing products, either by accident or deliberately, and the victims of industrial and domestic mishaps, provide further groups which may exhibit acute toxicity due to these compounds. Finally, chloroform and other volatile compounds are still used in the course of crimes such as rape and murder (McGee et a!. 1987).
1. Volatile Substance Abuse Many early anaesthetics (diethyl ether, chloroform, nitrous oxide) were first used recreationally by such eminent people as Coleridge, Southey and Wedgwood (Brecher 1974). More recently, abuse of trichloroethylene (Baader 1927) and petrol (Clinger & Johnson 1951) has been recorded and volatile substance abuse has now been reported from most parts of the world. Solvents from adhesives, notably toluene, typewriter correcting fluids and thin- , Table I. Some uses of volatile substances Manufacture of/use as
Areas of use
Adhesives Aerosol propellants Anaesthetics Chemical warfare agents Detergents Drugs Explosives Fire extinguishers Fuels Inks Laboratory chemicals Lubricants Paints, enamels and lacquers Paint thinners Perfumes Pesticides Refrigerants Resins Rubber Sealants Stains, dyes and varnishes Waxes
Agriculture Art studios Chemical industry Degreasing Dry cleaning Fat processing Food processing Laboratory work Leather japanning Medicine/dentistry Painting/paint stripping Printing Wood preservation
36'
ners (often I,I,I-trichloroethane), other halogenated solvents, hydrocarbons such as'those found in petrol (gasoline) and cigarette lighter refills (butane), and aerosol propellants (tables II; III) are among the compounds which may be abused in this way (Cohen 1981; Hayden et al. 1976; McHugh 1987; Ramsey et a!. 1989). In addition to the volatile compounds discussed above, amyl and butyl nitrites are misused for their vasodilator properties, often by male homosex1,l8ls. The health hazards associated with the abuse of these compounds have-heen reviewed by Haverkos and Dougherty (1988). Vapour-phase poisoning with acetonitrile and methanol, for example, may also be encountered, often in an occupational setting, but such compounds are not normally abused. Deliberate inhalation of noxious gases such "as chlorine has also been described (Rafferty 1980), but again such substances are not normally abused and are not considered further here. l.l Modes of Abuse of Volatile Substances
The physical form of a product often determines the mode of abuse; deep breathing thrQp.gh the nose and mouth is usually involved, not simply 'sniffing'. Adhesives are usually poured into plastic bags such as empty potato crisp (chip) packets. The top is then gathered together and placed over the mouth and the vapour inhaled. Exhaled air is rebreathed and hypercapnia and hypoxia may add to the effects of the solvent (Watson 1981). cans of glu~i may be heated to increase the yield of solvent. Liquids may be poured on to fabric (a coat sleeve or handkerchief) or into cutaway plastic bottles, such as empty detergent or bleach containers, and the vapour inhaled directly. Plastic bags may be filled from aerosol cans, fire extinguishers or gas cylinders; these products may also be sprayed or released under bedclothes, or inhaled directly. Aerosols are usually liquid or solid suspensions supplied in cans containing a liquefied propellant gas; at room temperature I volume of liquid propellant may generate 200 to 360 volumes of va- , pour. The, intended use of the product is immaterial, although those with a high proportion of
362
Table II. Volatile COl)'lpounds which may be abused by inhalation Aliphatic hydrocarbons Acetylene n-Butane8 Isobutane (2-methylpropane)8 n-Hexane b Propane 8 Alicyclic/aromatic hydrocarbons Cyclopropane (trimethylene) Toluene (toluol, methylbenzene, phenylmethane) Xylene (xylol, dimethylbenzene)C Mixed hydrocarbons Petrol (gasoline)d Petroleum ethers6 Halogenated compounds Bromochlorodifluoromethane (BCF) Carbon tetrachloride (tetrachloromethane) Chlorodifluoromethane (halon 22, propellant 22, 'Freon 22') Chloroform (trichloromethane) Dichlorodifluoromethane (halon 12, propellant 12, 'Freon 12') Dichloromethane (methylene chloride) 1,2-Dichloropropane (propylene dichloride) Enflurane (2-chloro-1 ,1,2-triftuoroethyl difluoromethyl ether) Ethyl chloride (monochloroethane) Halothane (2-bromo-2-chloro-1,1 ,1-trifluoroethane) lsoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) Methoxyflurane (2,2-dichloro-1,1-difluoroethyl methyl ether) Tetrachloroethylene (perchloroethylene) 1,1 ,1-Trichloroethane (methylchloroform, 'Genklene') Trichloroethylene ('trike' , 'Trilene') Trichlorofluoromethane (halon 11 , propellant 11 , 'Freon 11') 1,1,2-Trichlorotriftuoroethane (halon 113) Oxygenated compounds Acetone (dimethyl ketone) Butanone (butan·2-one, methyl ethyl ketone, MEK) Diethyl ether (ethoxyethane) Dimethyl ether (DME, methoxymethane) Ethyl acetate Methyl acetate Methyl isobutyl ketone (MIBK, isopropyl acetone) Methyl tert.-butyl ether (MTBE) Nitrous oxide (dinitrogen monoxide, laughing gas) a b
c d e
Components of liquefied petroleum gas (LPG). Commercial 'hexane: is a mixture of n-hexane and n-heptane with small amounts of some higher aliphatic hydrocarbons. Mainly o-xylene (1,3-dimethylbenzene). Boiling range 40-2000C, atmospheric pressure. Mixtures of pentanes, hexanes, etc., with specified boiling ranges (for example 40-60°C).
Drug Safety 5 (5) 1990
propellant, such as 'pain relief (topical analgesic) sprays, deodorants and fly sprays, rather than those with little (shaving foam, for example) are preferred. If some constituents are not respirable, for example aluminium chlorhydrate in antiperspirants, then the product may be first bubbled through water or sprayed into a plastic bag and the aerosol allowed to settle. Misuse of salbutamol (albuterol)or beclomethasone-containing aerosols has been attributed to abuse of the propellant (Brennan 1983; Pratt 1982; Thompson et al. 1983), even by a 4year-old child (O'Callaghan & Milner 1988). Domestic ('natural') gas is rarely abused, primarily because the principal component, methane, is not narcotic. However, the fuel gases used in cigarette lighters, small blow torches and camping gas stoves consist of n-butane with smaller amounts of isobutane and propane (known as 'butane'). They are available in small, inexpensive packs and are very attractive to misusers. Gas from larger containers (sometimes propane) is also abused. However, these latter containers usually need a valve to regulate the gas supply, whereas cigarette lighter refills may be misused by simply clenching the nozzle between the teeth and pressing to release the contents. This latter mode of abuse is well illustrated in the paper by Hansen and Knudsen (1988) and carries the risk of a jet of fluid cooled to below - 20·C causing bums to the throat and lungs. The consequent mucosal oedema may cause respiratory difficulties, while rapid chilling of the larynx may cause death from vagal stimulation leading to bradycardia and cardiac arrest. Petroleum distillates such as white spirit and paraffin (kerosene) are not volatile enough to be abused by inhalation. Petrol (gasoline), however, is relatively volatile and is often abused, especially in less developed communities (Daniels & Latcham 1984; Rischbieth et al. 1987; Watson DS 1986). As might be expected with abuse of very flammable materials, petrol 'sniffing' is associated with an increased risk of explosion and fire (Cole et al. 1986). Lead poisoning from alkyl leads used as 'antiknock' agents is a common complication (Chessare & Wodarcyk 1988; Coulehan et al. 1983; McCracken 1987).
Clinkal Toxicology of Volatile Substances
1.2 Prevalence of Abuse
In the UK from 1984 to 1986, a mean prevalence of previous or current volatile substance abuse of 5.9% was reported in adolescent schoolchildren in London (Chadwick et al. 1989). The proportion of abusers ranged from 0.5 to 9.6% over the 16 schools surveyed, with no marked sex difference. However, if subjects who had never been 'intoxicated' were excluded, the mean prevalence·fell to 3.6%. Similarly, in a survey in South Wales in 1985, of 4766 pupils aged 11 to 19 years, 6.1 % had tried volatile substance abuse and a further 0.7% were current users; 3 pupils (0.1 %) 'sniffed' every day (Cooke et a1. 1988). O( those who had experimented, 58% had already 'sniffed' by age 13 years. Two other studies reported higher prevalence rates but the criteria used to select the schools surveyed are unclear (Diamond et a1. 1988; Swadi 1988). Thus, it seems that 3.5 to 10% of young people (both males and females) in the United Kingdom have at least experimented with volatile substance abuse and current users comprise some 0.5 to 1% of the secondary school population. Similar, if not slightly higher, figures have been reported from other countries within the past 10 years. Thus, some 10% of young people aged 15 to 20 years in Oslo, Norway, had 'sniffed' volatile substances at some stage (Lavik 1987). It has been estimated that 7 to 12% of high school pupils in the US have 'sniffed' at least once and that about 4% do so regularly (Sharp & Korman 1981). Similar findings were reported by Coulehan et al. (1983) in a study of Navajo adolescents. A mean prevalence of 10% was reported in 1977 in Mexico, but the rate of increase was estimated at 0.7% per year (Costero & Barroso 1977). Of 1836 students aged 9 to 18 years from a low socioeconomic background in Sao Paulo, Brazil, some 24% had abused volatile substances at some stage; 4.9% had 'sniffed' within the last month (Carlini-Cotrim & Carlini 1988). The substances most commonly abused were 'lan~-perfume' (a mixture of chloroform and diethyl ether) [36%], acetone (34%), petrol (32%), fingernail polish (31%) and glue (25%). In Singapore, arrests of inhalant abusers (mostly aged 15 to 19
363
Table III. Some products which may be abused by inhalation Product
Major volatile components
Adhesives balsa wood cement contact adhesives cycle tyre repair adhesive PVC cement
Ethyl acetate Toluene, hexane and esters Toluene and xylenes Trichloroethylene
Aerosols air freshener deodorants, antiperspirants fly spray hair lacquer paint Anaesthetics/analgesics gaseous liquid local
Halons, butane dimethyl ether Halons, butane dimethyl ~ 'Halons, butane dimethyl ether Halons, butane dimethyl ether Halons, butane
and/or and/or and/or and/or and esters
Nitrous oxide, cyclopropane Diethyl ether, halothane, enflurane, isoflurane Halons 11 and 12, ethyl chloride
Commercial dry cleaning and degreasing agents
1,1,1-Trichloroethane, tetrachloroethylene, trichloroethylene (rarely carbon tetrachloride,"1,2dichloropropane)
Domestic spot removers and dry cleaners
1,1,1-Trichloroethane, tetrachloroethylene, trichloroethylene
Fire extinguishers
BrOmochlorodiftuoromethane, halons 11 and 12
Fuel gases cigarette lighter refills butane propane
n-Butane, isobutane and propane n-Butane, isobutane and propane Propane and butanes
Nail varnish/nail varnish remover
Acetone and esters
.Paints/paint thinners
Butanone, esters, hexane, toluene, xylene
Paint stripper
Dichloromethane and toluene
Surgical plaster/chewing gum remover
Trichloroethylene
Typewriter .correction fluids/ thinners
1,1,1-Trichloroethane
364
years) increased from 24 in 1980 to 763 in 1984 (Teck-Hong 1986). It is clear that volatile substance abuse is a significant, probably increasing, problem in many developed and less developed countries. Several factors contribute to its popularity. The products abused are cheap and readily available. Furthermore, the containers, for example those of typewriter correction fluid and thinners, are convenient and either easily concealed or their possession ostensibly legitimate. Volatile substance abuse is often a group activity and peer-group pressure is probably a factor in encouraging the persistence of the practice. It has been suggested that toluene users are more likely to 'sniff in a group setting, possibly because of the longer duration of intoxication with this compound (Evans & Raistrick 1987a). Unlike underage drinking, abuse of volatile compounds is not illegal, at least in the UK, and both the onset of effects and recovery can be rapid (section 2.1), a distinct advantage over alcohol because a child who 'sniffs' after school can still return home sober. This is especially true with aerosol propellants and butane. 1.3 Mortality from Abuse The major risk associated with volatile substance abuse is that of sudden death. Bass (1970) reported 110 such deaths in the US from abuse of aerosol propellants and chlorinated solvents during the I 960s. Further series of fatalities have been noted again from the US (Carlton 1976; Garriott & Petty 1980) and from Scandinavia (Edh et al. 1973; Kringsholm 1980). In the UK, sudden deaths from volatile substance abuse have been monitored systematically since 1970 (Anderson et al. 1985) and have increased from between 2 and 4 per yeaI' in the early 1970s to 133 in 1988 (fig. I); the trend is still upward. Deaths occurred in all social classes and in all parts of the UK. The age at death ranged from II to 76 years, but most deaths (72%) occurred in adolescents aged less than 20 years (fig. 2). In contrast to the results of prevalence studies, most deaths (90%) occurred in males. In 19% of cases there was no evidence that the de-
Drug Safety 5 (5) 1990
ceased had abused volatile substances before. Nevertheless, the death rate from volatile substance abuse in the UK is relatively low, given the number of abusers indicated by prevalence studies. The compounds encountered in abuse-related deaths in the UK are: fuel gases, mainly butane (approximately 30% of cases); solvents from adhesives (approximately 20%); other solvents, notably I,I,'I-trichloroethane (approximately 30%); and aerosol propellants (halons and/or butane) [approximately 20%]. The precise mode of death is seldom clear, but indirect effects such as trauma, aspiration of vomit and asphyxia associated with the use of a plastic bag predominate in deaths associated with solvents from adhesives (fig. 3). On the other hand, 4 modes of 'direct' acute volatile substance abuse-related death can be recognised: anoxia, vagal stimulation, respiratory depression and cardiac arrhythmias (Shepherd 1989). Of these, cardiac arrhythmias leading to cardiac or cardiorespiratory arrest are probably the most common cause of death. Sudden alarm, exercise or sexual activity may precipitate an arrhythmia since volatile substance abuse sensitises the heart to circulating catecholamines; in many volatile substance abuse-related deaths the immediate ante mortem event was fright and running (Bass 1970; Carlton 1976). There are no published data on deaths related to volatile substance abuse from other countries which are comparable with those available in the UK, although individual cases and small series of deaths are reported regularly. This is unfortunate because such statistics may provide a crude measure of prevalence and can thus help to assess the efficacy of preventative programmes. However, changes in the population at special risk must not be neglected. In the UK at least the adolescent population is set to decline in number by some 10 to 20% over the next few years (data from Government Actuary's Department, London). 0
1.4 Morbidity from Abuse Local chronic sequelae of the abuse of volatiles include recurrent epistaxis, halitosis, oral and nasal
Clinical Toxicology of Volatile Substances
365
160 134
140 118
120 100 til
.r::
80
63
90
20-30
5
42.1
As components of li
Drug Safety 5 (5): 359-383, 1990 0114-5916/90/0009-0359/$12.50/0 © Adis International Limited All rights reserved. MEDT03305
An Introduction to the Clinical Toxicology of Volatile Substances R.J. Flanagan, M. Ruprah, T.J. Meredith and J.D. Ramsey Poisons Unit, Guy's Hospital, London, Division of Toxicology and Environmental Health, Department of Health, I London, and Toxicoiogy Unit and Department of Clinical Epidemiology, St George's Hospital Medical School, London, England
Contents
Summary ..................................................................................................................................... 359 I. Volatile Substance Abuse ..................................................................................................•.... 361 1.1 Modes of Abuse of Volatile Substances ......................................................................... 361 1.2 Prevalence of Abuse ............. ;.......................................................................................... 363 1.3 Mortality from Abuse ...................................................................................................... 364 1.4 Morbidity from Abuse ..................................................................................................... 364 I.S Treatment of Chronic Abusers and Strategie& for Prevention ..................................... 36S 2. Oinical Toxicology of Volatile Substances ................. _....................................................... 367 2.1 Acute Poisoning ............................................................................................................... 367 2.1.1 Clinical Features and Treatment ........................................................................... 367 2.1.2 Toluene and Butane ................................................................................................ 368 2.1.3 Chlorinated Hydrocarbons ..................................................................................... 368 2.1.4 Solvent Ingestion ..................................................................................................... 369 2.2 Chronic Toxicity of Volatile Compounds ..................................................................... 369 2.2.1 Oinical Sequelae of Long Term Toluene Exposure ............................................ 370 2.2.2 Clinical Sequelae of Long Term Exposure to Chlorinated Solvents .................. 372 3. Pharmacokinetics of Volatile Substances ............................................................................. 373 3.1 Absorption, Distribution and Elimination .................................................................... 373 3.2 Metabolism ....................................................................................................................... 375 4. Diagnosis of Poisoning Due to Volatile Substances ........................................................... 375 4.1 Clinical and Circumstantial Evidence ............................................................................ 375 4.2 Role of Toxicological Analyses ....................................................................................... 375 4.2.1 Blood Toluene Concentrations and Oinical Features of Toxicity ..................... 378 4.2.2 Blood I,I,I-Trichloroethane Concentrations and Clinical Features of Toxicity .................................................................................. 379 S. Conclusions .................................................................................................................. 379
Summary
Acute poisoning with organic solvents and other volatile compounds now usuillly follows deliberate inhalation (volatile substance abuse) or ingestion of these compounds.
I The contents of this article represent the authors' views alone and in no way commit the Department of Health.
Drug Safety 5 (5) 1990
360
Solvents from adhesives, typewriter correction and dry cleaning fluids, cigarette lighter refills (butane) and aerosol propellants are commonly abused. The major risk is that of sudden death. Arrhythmias leading to cardiac arrest are thought to cause most deaths, but anoxia, respiratory depression and vagal stimulation leading to cardiac arrest may also contribute, as may indirect causes such as aspiration of vomit or trauma. In the United Kingdom (UK), 3.5 to 10% of young people have at least experimented with volatile substance abuse and mortality is more than 100 per annum. The products abused are cheap and readily available despite legislation designed to limit supply. Volatile substance abuse is not illegal and only a minority of abusers are known to progress to heavy alcohol or illicit drug use. Prevention of abuse by education,"ot only of children but also of parents, teachers, retailers and health care workers, is important in limiting the problem. However, volatile substance abuse-related deaths are still increasing in the UK despite many measures aimed at prevention. Clinically, volatile substance abuse is characterised by a rapid onset of intoxication and rapid recovery. Euphoria and disinhibition may be followed by hallucinations, tinnitus, ataxia, confusion, nausea and vomiting. It is important not to further alarm the patient if signs of serious toxicity are present, since a cardiac arrest may be precipitated. Further exposure should be prevented and the patient resuscitated and given supplemental oxygen if necessary. Cardiac arrhythmias should be treated conventionally and respiratory failure managed supportively. Long term exposure to n-hexane is associated with the development of peripheral neuropathy, while prolonged abuse (notably of toluene or chlorinated solvents) can cause permanent damage to the central nervous system, heart, liver, kidney and lungs. Knowledge of the routes of absorption, distribution and excretion of volatile compounds, and of the rates governing these processes, is important in understanding the rate of onset, intensity and duration of intoxication, and rate of recovery after volatile substance abuse. In addition, such knowledge is helpful when the clinician is attempting to interpret the results of toxicological analyses performed on samples (blood, other tissues, urine) from such patients. Many volatile substances are partly metabolised, the metabolites being eliminated in exhaled air or in urine. Although metabolism normally results in detoxification, enhanced toxicity may also result as with carbon tetrachloride, chloroform, dichloromethane, n-hexane, trichloroethylene and possibly halothane. Identification of volatile substance abusers can be difficult, but the hair, breath and clothing may smell of solvent, and empty containers may be found. Perioral eczema ('glue-sniffer's rash') from direct contact with glue poured into a plastic bag occurs rarely. Headspace gas chromatography of blood can detect exposure to many compounds but not to complex mixtures such as petrol; detection of metabolites is only useful with a few compounds, notably toluene, trichloroethylene and xylene. Prevalence studies suggest that volatile substance abuse is increasing worldwide yet the UK is the only country to collate and regularly publish data on abuse-related deaths. Such data, although difficult to collect, are important in identifying and monitoring the problem. A coordinated approach to the collation of analogous data on an international basis would be valuable in monitoring the efficacy of preventative programmes.
Organic solvents and other volatile compounds are used extensively in industry and in the laboratory. Long term exposure to solvent vapour may thus occur during the manufacture and use of a variety of products (table I). Morbidity and mortality from exposure to volatile substances is not a new problem: many cases of jaundice occurred
when I, I ,2,2-tetrachloroethane was used for 'doping' (waterproofing) fabric-covered aircraft during World War I, and chloroform anaesthesia was associated with cardiac arrhythmias and hepatorenal necrosis after prolonged use (Meredith et al. 1989). Today, if anaesthesia is excluded, acute poisoning with volatile substances usually follows deliberate
Clinical Toxicology of Volatile Substances
inhalation of vapour in order to become intoxicated ['glue sniffing', solvent abuse, volatile substance abuse (VSA»). In addition, patients who ingest solvents or solvent-containing products, either by accident or deliberately, and the victims of industrial and domestic mishaps, provide further groups which may exhibit acute toxicity due to these compounds. Finally, chloroform and other volatile compounds are still used in the course of crimes such as rape and murder (McGee et a!. 1987).
1. Volatile Substance Abuse Many early anaesthetics (diethyl ether, chloroform, nitrous oxide) were first used recreationally by such eminent people as Coleridge, Southey and Wedgwood (Brecher 1974). More recently, abuse of trichloroethylene (Baader 1927) and petrol (Clinger & Johnson 1951) has been recorded and volatile substance abuse has now been reported from most parts of the world. Solvents from adhesives, notably toluene, typewriter correcting fluids and thin- , Table I. Some uses of volatile substances Manufacture of/use as
Areas of use
Adhesives Aerosol propellants Anaesthetics Chemical warfare agents Detergents Drugs Explosives Fire extinguishers Fuels Inks Laboratory chemicals Lubricants Paints, enamels and lacquers Paint thinners Perfumes Pesticides Refrigerants Resins Rubber Sealants Stains, dyes and varnishes Waxes
Agriculture Art studios Chemical industry Degreasing Dry cleaning Fat processing Food processing Laboratory work Leather japanning Medicine/dentistry Painting/paint stripping Printing Wood preservation
36'
ners (often I,I,I-trichloroethane), other halogenated solvents, hydrocarbons such as'those found in petrol (gasoline) and cigarette lighter refills (butane), and aerosol propellants (tables II; III) are among the compounds which may be abused in this way (Cohen 1981; Hayden et al. 1976; McHugh 1987; Ramsey et a!. 1989). In addition to the volatile compounds discussed above, amyl and butyl nitrites are misused for their vasodilator properties, often by male homosex1,l8ls. The health hazards associated with the abuse of these compounds have-heen reviewed by Haverkos and Dougherty (1988). Vapour-phase poisoning with acetonitrile and methanol, for example, may also be encountered, often in an occupational setting, but such compounds are not normally abused. Deliberate inhalation of noxious gases such "as chlorine has also been described (Rafferty 1980), but again such substances are not normally abused and are not considered further here. l.l Modes of Abuse of Volatile Substances
The physical form of a product often determines the mode of abuse; deep breathing thrQp.gh the nose and mouth is usually involved, not simply 'sniffing'. Adhesives are usually poured into plastic bags such as empty potato crisp (chip) packets. The top is then gathered together and placed over the mouth and the vapour inhaled. Exhaled air is rebreathed and hypercapnia and hypoxia may add to the effects of the solvent (Watson 1981). cans of glu~i may be heated to increase the yield of solvent. Liquids may be poured on to fabric (a coat sleeve or handkerchief) or into cutaway plastic bottles, such as empty detergent or bleach containers, and the vapour inhaled directly. Plastic bags may be filled from aerosol cans, fire extinguishers or gas cylinders; these products may also be sprayed or released under bedclothes, or inhaled directly. Aerosols are usually liquid or solid suspensions supplied in cans containing a liquefied propellant gas; at room temperature I volume of liquid propellant may generate 200 to 360 volumes of va- , pour. The, intended use of the product is immaterial, although those with a high proportion of
362
Table II. Volatile COl)'lpounds which may be abused by inhalation Aliphatic hydrocarbons Acetylene n-Butane8 Isobutane (2-methylpropane)8 n-Hexane b Propane 8 Alicyclic/aromatic hydrocarbons Cyclopropane (trimethylene) Toluene (toluol, methylbenzene, phenylmethane) Xylene (xylol, dimethylbenzene)C Mixed hydrocarbons Petrol (gasoline)d Petroleum ethers6 Halogenated compounds Bromochlorodifluoromethane (BCF) Carbon tetrachloride (tetrachloromethane) Chlorodifluoromethane (halon 22, propellant 22, 'Freon 22') Chloroform (trichloromethane) Dichlorodifluoromethane (halon 12, propellant 12, 'Freon 12') Dichloromethane (methylene chloride) 1,2-Dichloropropane (propylene dichloride) Enflurane (2-chloro-1 ,1,2-triftuoroethyl difluoromethyl ether) Ethyl chloride (monochloroethane) Halothane (2-bromo-2-chloro-1,1 ,1-trifluoroethane) lsoflurane (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) Methoxyflurane (2,2-dichloro-1,1-difluoroethyl methyl ether) Tetrachloroethylene (perchloroethylene) 1,1 ,1-Trichloroethane (methylchloroform, 'Genklene') Trichloroethylene ('trike' , 'Trilene') Trichlorofluoromethane (halon 11 , propellant 11 , 'Freon 11') 1,1,2-Trichlorotriftuoroethane (halon 113) Oxygenated compounds Acetone (dimethyl ketone) Butanone (butan·2-one, methyl ethyl ketone, MEK) Diethyl ether (ethoxyethane) Dimethyl ether (DME, methoxymethane) Ethyl acetate Methyl acetate Methyl isobutyl ketone (MIBK, isopropyl acetone) Methyl tert.-butyl ether (MTBE) Nitrous oxide (dinitrogen monoxide, laughing gas) a b
c d e
Components of liquefied petroleum gas (LPG). Commercial 'hexane: is a mixture of n-hexane and n-heptane with small amounts of some higher aliphatic hydrocarbons. Mainly o-xylene (1,3-dimethylbenzene). Boiling range 40-2000C, atmospheric pressure. Mixtures of pentanes, hexanes, etc., with specified boiling ranges (for example 40-60°C).
Drug Safety 5 (5) 1990
propellant, such as 'pain relief (topical analgesic) sprays, deodorants and fly sprays, rather than those with little (shaving foam, for example) are preferred. If some constituents are not respirable, for example aluminium chlorhydrate in antiperspirants, then the product may be first bubbled through water or sprayed into a plastic bag and the aerosol allowed to settle. Misuse of salbutamol (albuterol)or beclomethasone-containing aerosols has been attributed to abuse of the propellant (Brennan 1983; Pratt 1982; Thompson et al. 1983), even by a 4year-old child (O'Callaghan & Milner 1988). Domestic ('natural') gas is rarely abused, primarily because the principal component, methane, is not narcotic. However, the fuel gases used in cigarette lighters, small blow torches and camping gas stoves consist of n-butane with smaller amounts of isobutane and propane (known as 'butane'). They are available in small, inexpensive packs and are very attractive to misusers. Gas from larger containers (sometimes propane) is also abused. However, these latter containers usually need a valve to regulate the gas supply, whereas cigarette lighter refills may be misused by simply clenching the nozzle between the teeth and pressing to release the contents. This latter mode of abuse is well illustrated in the paper by Hansen and Knudsen (1988) and carries the risk of a jet of fluid cooled to below - 20·C causing bums to the throat and lungs. The consequent mucosal oedema may cause respiratory difficulties, while rapid chilling of the larynx may cause death from vagal stimulation leading to bradycardia and cardiac arrest. Petroleum distillates such as white spirit and paraffin (kerosene) are not volatile enough to be abused by inhalation. Petrol (gasoline), however, is relatively volatile and is often abused, especially in less developed communities (Daniels & Latcham 1984; Rischbieth et al. 1987; Watson DS 1986). As might be expected with abuse of very flammable materials, petrol 'sniffing' is associated with an increased risk of explosion and fire (Cole et al. 1986). Lead poisoning from alkyl leads used as 'antiknock' agents is a common complication (Chessare & Wodarcyk 1988; Coulehan et al. 1983; McCracken 1987).
Clinkal Toxicology of Volatile Substances
1.2 Prevalence of Abuse
In the UK from 1984 to 1986, a mean prevalence of previous or current volatile substance abuse of 5.9% was reported in adolescent schoolchildren in London (Chadwick et al. 1989). The proportion of abusers ranged from 0.5 to 9.6% over the 16 schools surveyed, with no marked sex difference. However, if subjects who had never been 'intoxicated' were excluded, the mean prevalence·fell to 3.6%. Similarly, in a survey in South Wales in 1985, of 4766 pupils aged 11 to 19 years, 6.1 % had tried volatile substance abuse and a further 0.7% were current users; 3 pupils (0.1 %) 'sniffed' every day (Cooke et a1. 1988). O( those who had experimented, 58% had already 'sniffed' by age 13 years. Two other studies reported higher prevalence rates but the criteria used to select the schools surveyed are unclear (Diamond et a1. 1988; Swadi 1988). Thus, it seems that 3.5 to 10% of young people (both males and females) in the United Kingdom have at least experimented with volatile substance abuse and current users comprise some 0.5 to 1% of the secondary school population. Similar, if not slightly higher, figures have been reported from other countries within the past 10 years. Thus, some 10% of young people aged 15 to 20 years in Oslo, Norway, had 'sniffed' volatile substances at some stage (Lavik 1987). It has been estimated that 7 to 12% of high school pupils in the US have 'sniffed' at least once and that about 4% do so regularly (Sharp & Korman 1981). Similar findings were reported by Coulehan et al. (1983) in a study of Navajo adolescents. A mean prevalence of 10% was reported in 1977 in Mexico, but the rate of increase was estimated at 0.7% per year (Costero & Barroso 1977). Of 1836 students aged 9 to 18 years from a low socioeconomic background in Sao Paulo, Brazil, some 24% had abused volatile substances at some stage; 4.9% had 'sniffed' within the last month (Carlini-Cotrim & Carlini 1988). The substances most commonly abused were 'lan~-perfume' (a mixture of chloroform and diethyl ether) [36%], acetone (34%), petrol (32%), fingernail polish (31%) and glue (25%). In Singapore, arrests of inhalant abusers (mostly aged 15 to 19
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Table III. Some products which may be abused by inhalation Product
Major volatile components
Adhesives balsa wood cement contact adhesives cycle tyre repair adhesive PVC cement
Ethyl acetate Toluene, hexane and esters Toluene and xylenes Trichloroethylene
Aerosols air freshener deodorants, antiperspirants fly spray hair lacquer paint Anaesthetics/analgesics gaseous liquid local
Halons, butane dimethyl ether Halons, butane dimethyl ~ 'Halons, butane dimethyl ether Halons, butane dimethyl ether Halons, butane
and/or and/or and/or and/or and esters
Nitrous oxide, cyclopropane Diethyl ether, halothane, enflurane, isoflurane Halons 11 and 12, ethyl chloride
Commercial dry cleaning and degreasing agents
1,1,1-Trichloroethane, tetrachloroethylene, trichloroethylene (rarely carbon tetrachloride,"1,2dichloropropane)
Domestic spot removers and dry cleaners
1,1,1-Trichloroethane, tetrachloroethylene, trichloroethylene
Fire extinguishers
BrOmochlorodiftuoromethane, halons 11 and 12
Fuel gases cigarette lighter refills butane propane
n-Butane, isobutane and propane n-Butane, isobutane and propane Propane and butanes
Nail varnish/nail varnish remover
Acetone and esters
.Paints/paint thinners
Butanone, esters, hexane, toluene, xylene
Paint stripper
Dichloromethane and toluene
Surgical plaster/chewing gum remover
Trichloroethylene
Typewriter .correction fluids/ thinners
1,1,1-Trichloroethane
364
years) increased from 24 in 1980 to 763 in 1984 (Teck-Hong 1986). It is clear that volatile substance abuse is a significant, probably increasing, problem in many developed and less developed countries. Several factors contribute to its popularity. The products abused are cheap and readily available. Furthermore, the containers, for example those of typewriter correction fluid and thinners, are convenient and either easily concealed or their possession ostensibly legitimate. Volatile substance abuse is often a group activity and peer-group pressure is probably a factor in encouraging the persistence of the practice. It has been suggested that toluene users are more likely to 'sniff in a group setting, possibly because of the longer duration of intoxication with this compound (Evans & Raistrick 1987a). Unlike underage drinking, abuse of volatile compounds is not illegal, at least in the UK, and both the onset of effects and recovery can be rapid (section 2.1), a distinct advantage over alcohol because a child who 'sniffs' after school can still return home sober. This is especially true with aerosol propellants and butane. 1.3 Mortality from Abuse The major risk associated with volatile substance abuse is that of sudden death. Bass (1970) reported 110 such deaths in the US from abuse of aerosol propellants and chlorinated solvents during the I 960s. Further series of fatalities have been noted again from the US (Carlton 1976; Garriott & Petty 1980) and from Scandinavia (Edh et al. 1973; Kringsholm 1980). In the UK, sudden deaths from volatile substance abuse have been monitored systematically since 1970 (Anderson et al. 1985) and have increased from between 2 and 4 per yeaI' in the early 1970s to 133 in 1988 (fig. I); the trend is still upward. Deaths occurred in all social classes and in all parts of the UK. The age at death ranged from II to 76 years, but most deaths (72%) occurred in adolescents aged less than 20 years (fig. 2). In contrast to the results of prevalence studies, most deaths (90%) occurred in males. In 19% of cases there was no evidence that the de-
Drug Safety 5 (5) 1990
ceased had abused volatile substances before. Nevertheless, the death rate from volatile substance abuse in the UK is relatively low, given the number of abusers indicated by prevalence studies. The compounds encountered in abuse-related deaths in the UK are: fuel gases, mainly butane (approximately 30% of cases); solvents from adhesives (approximately 20%); other solvents, notably I,I,'I-trichloroethane (approximately 30%); and aerosol propellants (halons and/or butane) [approximately 20%]. The precise mode of death is seldom clear, but indirect effects such as trauma, aspiration of vomit and asphyxia associated with the use of a plastic bag predominate in deaths associated with solvents from adhesives (fig. 3). On the other hand, 4 modes of 'direct' acute volatile substance abuse-related death can be recognised: anoxia, vagal stimulation, respiratory depression and cardiac arrhythmias (Shepherd 1989). Of these, cardiac arrhythmias leading to cardiac or cardiorespiratory arrest are probably the most common cause of death. Sudden alarm, exercise or sexual activity may precipitate an arrhythmia since volatile substance abuse sensitises the heart to circulating catecholamines; in many volatile substance abuse-related deaths the immediate ante mortem event was fright and running (Bass 1970; Carlton 1976). There are no published data on deaths related to volatile substance abuse from other countries which are comparable with those available in the UK, although individual cases and small series of deaths are reported regularly. This is unfortunate because such statistics may provide a crude measure of prevalence and can thus help to assess the efficacy of preventative programmes. However, changes in the population at special risk must not be neglected. In the UK at least the adolescent population is set to decline in number by some 10 to 20% over the next few years (data from Government Actuary's Department, London). 0
1.4 Morbidity from Abuse Local chronic sequelae of the abuse of volatiles include recurrent epistaxis, halitosis, oral and nasal
Clinical Toxicology of Volatile Substances
365
160 134
140 118
120 100 til
.r::
80
63
90
20-30
5
42.1
As components of li
