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Toxic gases
Human Toxicology, J. Descotes (Ed.) © 1996 Elsevier Science B.V. All rights reserved
ggi
Ph. Hantson, F.J. Baud and R. Garnier
26. Toxic gases
Acute exposure to toxic inhalants under occupational or accidental circumstances may lead to a large variety of clinical manifestations, some of them being particularly life-threatening. The chronic effects of acute exposure have not been fully characterized. In this review, toxic gases will be classified according to the mechanism of injury, either as irritant or as asphyxiant. The clinical manifestations following fume or smoke exposure will be presented briefly.
IRRITANT GASES Ammonia Ammonia is widely used in the industry and as a household cleaner. Mixing ammonia with hypochlorite bleaches results in the formation of chloramine causing partially reversible pneumonitis. The inhalation of ammonia vapors causes irritation of the eyes and respiratory tract. Dyspnea with bronchospasm, cough, hemoptysis, chest pain are the main clinical features. Mucosal burns develop along the tracheobronchial tree [1]. Hypoxemia with pulmonary edema and altered mental status often complicates exposure to concentrated ammonia vapors. Persistent pulmonary damage may follow an apparent clinical improvement [2]. Other symptoms include irritant effects with nausea, vomiting, burning sensation, swelling of the lips, mouth and larynx. No reliable data exist regarding the effects of prolonged exposure to ammonia gas [3]. According to available data, ammonia seems not to be carcinogenic. Bromine Bromine gas is very corrosive to the eyes, skin and respiratory tract. Pulmonary toxicity seems to be even more severe than that of chlorine gas and may also evolve to chemical pneumonitis and ARDS [4]. Neurologic and gastrointestinal manifestations can also be encountered. Dermatitis and burns may result from inhalation exposure.
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Toxicity following chronic exposure may be similar to t h a t observed after ingestion of excessive amounts of bromides. A mild degree of spermatogenesis suppression and impaired reproductive performance were observed in a recent series of eight patients following accidental exposure to bromine vapor [5]. Chlorine a n d h y d r o g e n chloride Acute chlorine gas exposure is commonly due to the manipulation of household cleaning agents. Chlorine gas is converted to hydrochloric acid and active oxygen. Chlorine gas is corrosive to mucous membranes. Nose, throat and eye irritation is frequent. Burning, chest pain, suffocation, coughing are typical findings following mild to moderate exposure. Severe pulmonary edema is usually seen 12-24 hours after massive exposure and respiratory arrest is possible [6]. Delayed airway hyperresponsiveness has been noted after acute exposure [7]. This pattern was mainly identified among nonsmoking subjects in a recent study [8]. Hydrogen chloride shares the same corrosive properties as chlorine. Respiratory effects may range from irritation or even ulceration of the upper airways to reversible respiratory obstruction; laryngospasm, non-cardiogenic pulmonary edema and hemorrhage were infrequently observed. Inconsistent alterations of pulmonary function were reported following chronic or prolonged exposure. Long-term sequelae of acute exposure are less documented. Fluorine Fluorine is also considered as an irritant and may cause major cutaneous burns. Eye, nose and respiratory tract irritation is frequent. Pulmonary complications are usually severe with bronchospasm and pulmonary edema [9]. Osteosclerosis has been reported following very long occupational or environmental exposure [10]. No teratogenic effects have been observed in mice. Iodine Iodine is available in solid forms or in vapors. Liquid formulations of iodine are still widely used as antiseptic preparations. Iodine is metabolized to iodide which can be stored as th3rroglobulin in the thyroid gland [11]. Iodine is toxic by ingestion or inhalation. Corrosive properties directly result in severe gastroenteritis with cardio-circulatory collapse, CNS manifestations or renal failure. Inhalation of iodine vapors may lead to irritation of the respiratory tract. Hypoor hyperthyroidism may develop following long-term iodine exposure (topical applications of povidone iodine). There is also evidence that iodides diffuse across the placenta and into the breast milk. N i t r o g e n derivatives N i t r o u s oxide (N2O) is an inorganic gas widely used for clinical anesthesia and as propellant in the industry. Acute toxicity following N2O inhalation is
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due to asphyxia, with fatahties reported among sniffing abusers [12]. Recent reports showed t h a t prolonged anesthesia with N2O in normal patients is devoid of clinical side effects [13]. Conflicting data exist concerning teratogenicity in humans. A greater incidence of spontaneous abortion in exposed dental assistants has been reported. Occupational exposure to high levels of nitrous oxide may adversely affect women's fertility [14]. Animal studies suggest t h a t N2O is a potential carcinogen. N i t r o g e n oxides. Nitrous oxide fumes are mixtures of varying proportions of five oxides: nitric oxide (NO), nitrogen trioxide (N2O3), nitrogen dioxide (NO2), nitrogen tetroxide (N2O4) and nitrogen pentoxide (N2O5). Silo-filler's disease results also from the decomposition following fermentation of nitrous acid into a mixture of nitrogen oxides. Pulmonary damages are mainly observed following acute or chronic exposure to nitrogen oxides. Coughing, shortness of breath on exertion or at rest, chest pain and hemoptysis were present in an outbreak of N02-induced respiratory illness among ice hockey players [15]. Delayed pulmonary edema (4 to 24 hours) is commonly encountered [16]. Respiratory manifestations include bronchospasm and bronchiolitis obliterans, the late-onset form of which is more severe and hardly reversible [17]. Emphysema may occur after low and chronic exposure. Increased airway responsiveness to low levels of NO2 in asthmatic subjects is controversial [18]. Other symptoms include fatigue, headache and nausea. JVIethemoglobinemia may occur in the presence of NO or higher oxides of nitrogen. The teratogenic, genotoxic and carcinogenic effects of NO or NO2 have only been recently reported in animals. Ozone Ozone can be produced either by ultraviolet light action on oxygen, by photochemical reactions or in the industry. Ozone has a high oxidative capacity affecting cell membranes. Its toxic effects may result from the formation of peroxides and free radicals. Ozone acts primarily as an irritant for the eyes, throat and respiratory tract. Respiratory manifestations include dyspnea, edema, bronchitis, bronchiolitis and alterations of pulmonary function tests with increased pulmonary resistances [19]. The effects of ozone on airway resistance when combined with other air pollutants is still a matter of debate. Long-term effects have not yet been fully explored but epidemiological studies have provided evidence t h a t chronic exposure to photochemical oxidants may deteriorate lung function [20]. Bronchiolitis and bronchitis have been reported in animals following chronic exposure. Ozone could be genotoxic due to its radiomimetic properties. Teratogenicity has been observed in animal models following exposure to high concentrations. However, cytogenetic effects on h u m a n lymphocytes could not be demonstrated [21].
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Phosgene Phosgene is a highly toxic gas produced by the burning of chlorinated hydrocarbons or the action of ultraviolet radiation on such compounds. Phosgene reacts with water to form hydrochloric acid and carbon dioxide. It is considered as an irritant to the skin, eyes and respiratory tract. Following exposure to high concentrations, severe pulmonary complications may develop including pulmonary edema and bronchoconstriction. Delayed onset pulmonary edema with fatal respiratory failure has been reported [22]. Non-cardiogenic pulmonary edema may also be related to an increased pulmonary vascular permeability [23]. Phosgene can also impair renal and hepatic function by depleting glutathione stores [24]. Chronic exposure may lead to pulmonary fibrosis and emphysema [25]. Sulfur derivatives Sulfur dioxide (SO2) is formed by the combustion of sulfur-containing materials and is considered as an important air pollutant (acid rain). SO2 is irritating to the mucosa of the nasophar3nix and respiratory tract. Respiratory symptoms are prominent with pulmonary edema and bronchoconstriction. Asthmatic patients are more susceptible and bronchial hyperactivity may persist for several years [26]. Obstructive and restrictive lung disease, chronic bronchitis may also develop after an acute exposure. Other symptoms include conjunctival irritation and dermal frostbite. There is no evidence of teratogenic or direct carcinogenic effects due to SO2 which could be a promoter in combination with benzo(a)pyrene or arsenic. Sulfuric acid. Fuming sulfuric acid is a solution of sulfur trioxide in sulfuric acid. It is also present in mist and acid rain. Sulfuric acid is corrosive to the mucous membranes and respiratory tract. Inhalation of sulfuric acid mist causes a reflex increase in respiratory rate and bronchoconstriction. Overacute exposure produces severe bronchospasm and non-cardiogenic pulmonary edema [27]. ASPHYXIANT GASES Carbon monoxide Carbon monoxide (CO) is produced by the incomplete combustion of carboncontaining materials in poorly ventilated rooms. Inhalation and even ingestion of methylene chloride can also produce delayed CO poisoning. CO intoxication should be determined from the patient's mental and cardiovascular status rather than carboxyhemoglobin level. In severe poisoning, arterial pH, bicarbonate levels, serum CPK activity and chest X-ray should be monitored.
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Acute and chronic effects of CO poisoning are due to tissue h5^oxia. The most sensitive organs to oxygen deprivation are the central nervous system (CNS) and the myocardium. Infants, pregnant women, elderly people or patients with a previous history of myocardial insufficiency or chronic obstructive pulmonary disease are particularly at risk. CNS depression may evolve to irreversible coma. Residual and delayed neurologic effects may occur after acute CO poisoning. Alteration of cognitive functions is the main feature. The incidence of delayed neurological sequelae is correlated to the initial level of consciousness and duration of coma. Myocardial insufficiency may be aggravated or precipitated by CO [28]. Pulmonary edema and adult respiratory distress syndrome have been observed. Other symptoms include psychiatric, gastrointestinal and metabolic disorders. The value of hyperbaric oxygen was assessed in a recent prospective study. Pregnant women were excluded from this study. In patients without initial impairment of consciousness, the value of hyperbaric oxygen was not greater than normobaric oxygen. In patients with initial impairment of consciousness, two sessions of hyperbaric oxygen were not more efficient t h a n one session in the prevention of late neurological sequelae [29]. Potential effects of long-term exposure to low concentrations remain controversial. CO is teratogenic and embryotoxic at high maternal carboxyhemoglobin concentrations [30]. An increase in fetal death has been reported in a recent survey [31]. Carbon dioxide Hypoxia from reduced oxygen concentration in inspired air is the consequence of acute exposure to simple asphyxiant gases. Symptoms appear usually when oxygen concentration is less than 15%. In 1985, the Lake Nyos disaster was responsible for numerous deaths. It was due to a massive liberation of C02as a suffocating aerosol leading to immediate asph3^ia. Survivors had lost consciousness for several hours; some complained of cough, headache and wealiness [32,33]. Exposure to lower concentrations results in h3^erventilation and headache due to cerebral vasodilatation. Cyanide derivatives There are various sources of cyanide formation. The most toxic forms by inhalation are hydrogen cyanide (HCN), cyanogen [(CN)2], and its halides, and cyanide salts. Cyanide can also be released by hepatic metabolism from various nitrile compounds resulting in delayed cyanide poisoning. Calcium cyanide, isocyanates and metal cyanides do not share the same toxic properties and act mainly as irritants. Symptoms following acute poisoning depend upon the extent of and time since exposure. Cyanide exposure may produce death within minutes. Hyperpnea, tachycardia, h3^ertension and central nervous system (CNS) stimu-
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lation may be seen in the early phase of cyanide poisoning before the stage of global depression. Cyanosis is only a late finding. Metabolic acidosis and elevated serum lactate levels are commonly noted. Victims of cyanide poisoning either die acutely or recover fully. Parkinsonian symptoms and dystonia have been reported after ingestion of cyanide salts [34]. Methyl isocyanate acts mainly as an irritant gas, and the fatalities in the Bhopal disaster were due to acute respiratory distress occurring in the area close to the factory. Chronic cyanide exposure may produce various neurological disorders (headache, optic neuropathy, myelopathy). Effects on the thyroid gland (decreased iodine uptake) and on vitamin Bi2/folate metabolism have also been suspected. Dermatitis and respiratory tract irritation are also possible. Potassium cyanide has been associated with teratogenic and genotoxic effects in animals. Chromosomal abnormalities, spontaneous abortions and malformative syndromes have been demonstrated following the Bhopal tragedy [35]. H y d r o g e n sulfide Hydrogen sulfide is a highly toxic gas which is produced by decomposition of sulfur compounds. It can be encountered in a large variety of industrial processes. At low vapor concentrations, hydrogen sulfide is irritant for the eyes, nose, respiratory and gastrointestinal tract. At higher concentrations, it produces neurological impairment with dizziness, headache and loss of consciousness [36]. Mortality following exposure to very high concentrations has been reported to reach 6% [37]. Respiratory paralysis, tachycardia with ECO ischemic changes, hypotension, cyanosis, asphyxial convulsions occur in fatal cases. Anoxic effects would be related to the inhibition of cytochrome oxidase enzymes. Lactic acidosis is a common observation following hydrogen sulfide poisoning. Delayed neuropsychiatric sequelae have been also reported after acute hydrogen sulfide poisoning [38]. Phosphine Phosphine is a highly toxic gas produced by different phosphide salts (aluminium, calcium, zinc) following exposure to moisture. Phosphine is mainly used as fumigant or rodenticide. Toxicity occurs either following ingestion or inhalation. Organs with high oxygen requirements are especially sensitive, including the brain, kidneys, heart and liver. Mortality following aluminium phosphide poisoning remains particularly high [39]. The cardiovascular and respiratory complications are often life-threatening and include cardiac arrhythmias, shock and also delayed pulmonary edema. Symptoms of chronic poisoning include anemia, bronchitis, gastro-intestinal and neurosensorial disturbances [40].
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OTHER TOXIC GASES Metal f u m e fever Metal fume fever is produced by inhaling metal oxides produced by heating various metals, the most common being zinc and copper. Non-specific symptoms including fever, dry throat, pyrexia, myalgias, weakness or dyspnea are commonly reported; a metallic taste is inconstant. Recovery is usually complete within 24 to 48 hours with no chronic impairment [41]. P o l y m e r fume fever When polytetrafluoroethylene (Teflon®) is heated up to 315-375°C under conditions of insufficient ventilation, an influenza-like syndrome called polymer fume fever can develop. Polymer fume fever is usually self-limiting with a complete resolution within 48 hours. Symptoms may start up to 12 hours following exposure and are usually less severe than in metal fume fever. They include hyperpyrexia, mild tachycardia and hypertension, chest discomfort with respiratory tract irritation and weakness. Interestingly, no fatalities have been reported and there is no evidence of long-term effects [42]. P r o d u c t s of c o m b u s t i o n Symptoms following fire hazards often combine effects of irritants (acrolein, ammonia, chlorine, hydrogen chloride, nitrogen dioxide, phosgene, sulfur dioxide) and asphyxiants (carbon monoxide and cyanide). Smoke, heat and flame may all play a deleterious role. Thermal injury mainly affects the upper airways and can be used as a marker for significant smoke exposure. Smoke is composed of a particulate fraction and gases. Toxic gas production depends on oxygen supply, temperature, rate of heating and material. Cardiovascular, respiratory and central nervous systems may be variably affected. Early recognition of signs of severe exposure to CO and CN is of primary importance, since specific therapy can be added to the general supportive measures, even at the scene of fire [43,44].
REFERENCES 1. 2. 3. 4.
Millea TP, Kucan JO, Smoot EC (1989) Anhydrous ammonia injuries. J. Burn. Care Rehahil, 10, 448-453. Arwood R, Hamond J, Ward GO (1985) Ammonia inhalation. J. Trauma, 25, 444-447. Swotinsky RB, Chase KH (1990) Health effects of exposure to ammonia: scant information. Am. J. Indust. Med., 17, 515-521. Kraut A, Lilis R (1988) Chemical pneumonitis due exposure to bromine compounds. Chest, 94, 208-210.
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5. Potashnik G, Carel R, Beimaker J, Levine M (1992) Spermatogenesis and reproductive performance following human accidental exposure to bromine vapor. Reprod. Toxicol, 6, 171-174. 6. Heidemann SM, Goetting MG (1991) Treatment of acute hypoxemic respiratory failure caused by chlorine exposure. Pediatr. Emerg. Care, 7, 87-88. 7. Schwartz DA, Smith DD, Lakshminarayan S (1990) The pulmonary sequelae associated with accidental inhalation of chlorine gas. Chest, 97, 820-825. 8. Kennedy SM, Enarson DA, Janssen RG, Chan-Yeung M (1991) Lung health consequences of reported accidental chlorine gas exposures among pulpmill workers. Am. Rev. Respir. Dis., 143, 74-79. 9. Finkel M (1983) Hamilton & Hardy's Industrial Toxicology, 4th Edition, John Wright, PSG., Boston; 180-183. 10. Nemeth L, Zsogon E (1989) Occupational skeletal fluorosis. Clin. Rheumatol., 3, 81-88. 11. Dela Cruz F, Brown DH, Leiken JB et al (1987) Iodine absorption after topical administration. West. J. Med., 146, 43-45. 12. Chadly A, Marc B, Barres D et al (1989) Suicide by nitrous oxide poisoning. Am. J. Forens. Med. Pathol, 10, 330-331 13. Lampe GH, Wauz LZ, Donegan J H et al (1990) Effects on outcome of prolonged exposure of patients to nitrous oxide. Anesth. Analg., 71, 586-590. 14. Rowland AS, Baird DD, Weinberg OR et al (1992) Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. A^. Engl J. Med., 327, 993-997. 15. Hedberg K, Hedberg CW, Ther C et al (1989) An outbreak of nitrogen dioxide-induced respiratory illness among ice hockey players. JAMA, 262: 3014-3017. 16. Douglas WW, Hepper NGG, Colby TV (1989) Silo-Filler's disease. Mayo Clin. Proc, 64, 291-304. 17. Epler GR (1989) Sillo-Filler's disease: a new perspective. Mayo Clin. Proc, 64, 368-370. 18. Rubinstein I., Bigby BG, Reiss TF, Broushey HA (1990) Short-time exposure to 0.3 ppm nitrogen dioxide does not potentiate airway responsiveness to sulfur dioxide in asthmatic subjects. Am. Rev. Respir. Dis., 141, 381-385. 19. Hazucha MJ, Bates DV, Bromberg PA (1989) Mechanism of action of ozone on the h u m a n lung. J. Appl. Physiol, 67, 1535-1541. 20. Folinsbee LJ, Horvath SM (1986) Persistance of the acute effects of ozone exposure. Aviat. Space Environ. Med., 57, 1136-1143. 21. Victorin K (1992) Review of the genotoxicity of ozone. Mutat. Res., 277, 221-238. 22. Bardley BL, Unger KM (1982) Phosgene inhalation: a case report. Texas Med., 78, 51-53. 23. Kennedy TP, Michael JR, Hoidal JR et al (1989) Dibutyryl cAMP, aminophylline, and beta adrenergics agonists protect against pulmonary edema caused by phosgene. J. Appl Physiol, 67, 2542-2552. 24. Lheureux P, Leduc D, Askenasi R (1993) Toxic gases and vapors exposures. JEUR, 6, 35-48. 25. Sittig M (1985) Handbook of Toxic and Hazardous Chemicals and Carcinogens, 2nd ed. Noyes Publications, Park Ridge, NJ. 26. Rabinovitch S, Greyson MD, Weiser M et al (1989) Clinical and laboratory features of acute sulfur dioxide inhalation poisoning: two year follow up. Am. Rev. Respir. Dis., 139, 556-558.
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27. Knapp MJ, Bunn WB, Stave GM (1991) Adult respiratory distress syndrome from sulfuric acid fume inhalation. South. Med. J., 84, 1031-1033. 28. Allred EN, Bleecker ER, Chaitman BR et al (1991) Effects of carbon monoxide on myocardial ischemia. Environ. Health Perspect., 91, 89-132. 29. Raphael JC, Elkilarrat D, Jars-Guincestre MC et al (1989) Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet, ii, 417-419. 30. Norman CA, Halton DM (1990) Is carbon monoxide a workplace teratogen? A review and evaluation of the literature. A/iin. Occup. Hyg., 34, 335-347. 31. Mathieu-Nolf M, Mathieu D, Monso-Germain M et al (1992) Acute carbon monoxide poisoning during pregnancy (abstract). EAPCCT, 15th Congress, Istanbul, Turkey. 32. Freeth S (1992) The deadly cloud hanging over Cameroon. New Scientist, 15, 23-27. 33. Wagner GN, Clark MA, Kownigsberg ES et al (1988) Medical evaluation of the victims of the 1985 Lake Nyos disaster. J. Forensic ScL, 33, 899-909. 34. Valenzuela R, Court J, Godoy J (1992) Delayed cyanide induced dystonia. J. Neurol. Neurosurg. Psychiatr., 55, 198-199. 35. Goswani FIK, Chandorkar M, Bhaftacharya K et al (1990) Search for chromosomal variations among gas-exposed persons in Bhopal. Hum. Genet, 84, 172-176. 36. Glass DC (1990) A review of the health effects of hydrogen sulfide exposure. Ann. Occup. Hyg., 34, 323-327 37. Burnett WW, King EG, Grace M et al (1977) Hydrogen sulfide poisoning: review of 5 years' experience. Canad. Med. Assoc. J., 177, 1277-1280. 38. Tvedt B, edland A, Skyberg K, Forberg O (1991) Delayed neuropsychiatric sequelae after acute hydrogen sulfide poisoning. Affection of motor function, memory, vision and hearing. Acta Neurol. Scand., 84, 348-351. 39. Singh RB, Singh RG, Singh U (1991) Hypermagnesemia following aluminium phosphide poisoning. Int. J. Clin. Pharmacol. Ther. Toxicol., 29, 82-85. 40. Sax M, Lewis RJ (1989) Dangerous properties of industrial materials, 7th edition, pp. 2768-2769. Van Nostrand Reinhold, New York. 41. Proctor NH, Hughes J P , Fischman ML (1988) Chemical Hazards of the Workplace, 2nd edition, pp. 418-419. J.B. Lippincott Co, Philadelphia, PA. 42. Offermann PV, Finley CJ (1992) Metal fume fever - A review. Ann. Emerg. Med., 21, 872-875. 43. Baud FJ, Barriot P, Toffis V et al (1991) Elevated bloood cyanide concentrations in victims of smoke inhalation. A^. Engl. J. Med., 325, 1761-1766. 44. Shiono H, Maseda C, Akane A et al (1991) Rapid and sensitive quantitation of cyanide in blood and its application to fire victims. Am. J. Forens. Med. Pathol.,12, 50-53.
ggi
Ph. Hantson, F.J. Baud and R. Garnier
26. Toxic gases
Acute exposure to toxic inhalants under occupational or accidental circumstances may lead to a large variety of clinical manifestations, some of them being particularly life-threatening. The chronic effects of acute exposure have not been fully characterized. In this review, toxic gases will be classified according to the mechanism of injury, either as irritant or as asphyxiant. The clinical manifestations following fume or smoke exposure will be presented briefly.
IRRITANT GASES Ammonia Ammonia is widely used in the industry and as a household cleaner. Mixing ammonia with hypochlorite bleaches results in the formation of chloramine causing partially reversible pneumonitis. The inhalation of ammonia vapors causes irritation of the eyes and respiratory tract. Dyspnea with bronchospasm, cough, hemoptysis, chest pain are the main clinical features. Mucosal burns develop along the tracheobronchial tree [1]. Hypoxemia with pulmonary edema and altered mental status often complicates exposure to concentrated ammonia vapors. Persistent pulmonary damage may follow an apparent clinical improvement [2]. Other symptoms include irritant effects with nausea, vomiting, burning sensation, swelling of the lips, mouth and larynx. No reliable data exist regarding the effects of prolonged exposure to ammonia gas [3]. According to available data, ammonia seems not to be carcinogenic. Bromine Bromine gas is very corrosive to the eyes, skin and respiratory tract. Pulmonary toxicity seems to be even more severe than that of chlorine gas and may also evolve to chemical pneumonitis and ARDS [4]. Neurologic and gastrointestinal manifestations can also be encountered. Dermatitis and burns may result from inhalation exposure.
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Chapter 26 — Toxic gases
Toxicity following chronic exposure may be similar to t h a t observed after ingestion of excessive amounts of bromides. A mild degree of spermatogenesis suppression and impaired reproductive performance were observed in a recent series of eight patients following accidental exposure to bromine vapor [5]. Chlorine a n d h y d r o g e n chloride Acute chlorine gas exposure is commonly due to the manipulation of household cleaning agents. Chlorine gas is converted to hydrochloric acid and active oxygen. Chlorine gas is corrosive to mucous membranes. Nose, throat and eye irritation is frequent. Burning, chest pain, suffocation, coughing are typical findings following mild to moderate exposure. Severe pulmonary edema is usually seen 12-24 hours after massive exposure and respiratory arrest is possible [6]. Delayed airway hyperresponsiveness has been noted after acute exposure [7]. This pattern was mainly identified among nonsmoking subjects in a recent study [8]. Hydrogen chloride shares the same corrosive properties as chlorine. Respiratory effects may range from irritation or even ulceration of the upper airways to reversible respiratory obstruction; laryngospasm, non-cardiogenic pulmonary edema and hemorrhage were infrequently observed. Inconsistent alterations of pulmonary function were reported following chronic or prolonged exposure. Long-term sequelae of acute exposure are less documented. Fluorine Fluorine is also considered as an irritant and may cause major cutaneous burns. Eye, nose and respiratory tract irritation is frequent. Pulmonary complications are usually severe with bronchospasm and pulmonary edema [9]. Osteosclerosis has been reported following very long occupational or environmental exposure [10]. No teratogenic effects have been observed in mice. Iodine Iodine is available in solid forms or in vapors. Liquid formulations of iodine are still widely used as antiseptic preparations. Iodine is metabolized to iodide which can be stored as th3rroglobulin in the thyroid gland [11]. Iodine is toxic by ingestion or inhalation. Corrosive properties directly result in severe gastroenteritis with cardio-circulatory collapse, CNS manifestations or renal failure. Inhalation of iodine vapors may lead to irritation of the respiratory tract. Hypoor hyperthyroidism may develop following long-term iodine exposure (topical applications of povidone iodine). There is also evidence that iodides diffuse across the placenta and into the breast milk. N i t r o g e n derivatives N i t r o u s oxide (N2O) is an inorganic gas widely used for clinical anesthesia and as propellant in the industry. Acute toxicity following N2O inhalation is
Chapter 26 — Toxic gases
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due to asphyxia, with fatahties reported among sniffing abusers [12]. Recent reports showed t h a t prolonged anesthesia with N2O in normal patients is devoid of clinical side effects [13]. Conflicting data exist concerning teratogenicity in humans. A greater incidence of spontaneous abortion in exposed dental assistants has been reported. Occupational exposure to high levels of nitrous oxide may adversely affect women's fertility [14]. Animal studies suggest t h a t N2O is a potential carcinogen. N i t r o g e n oxides. Nitrous oxide fumes are mixtures of varying proportions of five oxides: nitric oxide (NO), nitrogen trioxide (N2O3), nitrogen dioxide (NO2), nitrogen tetroxide (N2O4) and nitrogen pentoxide (N2O5). Silo-filler's disease results also from the decomposition following fermentation of nitrous acid into a mixture of nitrogen oxides. Pulmonary damages are mainly observed following acute or chronic exposure to nitrogen oxides. Coughing, shortness of breath on exertion or at rest, chest pain and hemoptysis were present in an outbreak of N02-induced respiratory illness among ice hockey players [15]. Delayed pulmonary edema (4 to 24 hours) is commonly encountered [16]. Respiratory manifestations include bronchospasm and bronchiolitis obliterans, the late-onset form of which is more severe and hardly reversible [17]. Emphysema may occur after low and chronic exposure. Increased airway responsiveness to low levels of NO2 in asthmatic subjects is controversial [18]. Other symptoms include fatigue, headache and nausea. JVIethemoglobinemia may occur in the presence of NO or higher oxides of nitrogen. The teratogenic, genotoxic and carcinogenic effects of NO or NO2 have only been recently reported in animals. Ozone Ozone can be produced either by ultraviolet light action on oxygen, by photochemical reactions or in the industry. Ozone has a high oxidative capacity affecting cell membranes. Its toxic effects may result from the formation of peroxides and free radicals. Ozone acts primarily as an irritant for the eyes, throat and respiratory tract. Respiratory manifestations include dyspnea, edema, bronchitis, bronchiolitis and alterations of pulmonary function tests with increased pulmonary resistances [19]. The effects of ozone on airway resistance when combined with other air pollutants is still a matter of debate. Long-term effects have not yet been fully explored but epidemiological studies have provided evidence t h a t chronic exposure to photochemical oxidants may deteriorate lung function [20]. Bronchiolitis and bronchitis have been reported in animals following chronic exposure. Ozone could be genotoxic due to its radiomimetic properties. Teratogenicity has been observed in animal models following exposure to high concentrations. However, cytogenetic effects on h u m a n lymphocytes could not be demonstrated [21].
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Phosgene Phosgene is a highly toxic gas produced by the burning of chlorinated hydrocarbons or the action of ultraviolet radiation on such compounds. Phosgene reacts with water to form hydrochloric acid and carbon dioxide. It is considered as an irritant to the skin, eyes and respiratory tract. Following exposure to high concentrations, severe pulmonary complications may develop including pulmonary edema and bronchoconstriction. Delayed onset pulmonary edema with fatal respiratory failure has been reported [22]. Non-cardiogenic pulmonary edema may also be related to an increased pulmonary vascular permeability [23]. Phosgene can also impair renal and hepatic function by depleting glutathione stores [24]. Chronic exposure may lead to pulmonary fibrosis and emphysema [25]. Sulfur derivatives Sulfur dioxide (SO2) is formed by the combustion of sulfur-containing materials and is considered as an important air pollutant (acid rain). SO2 is irritating to the mucosa of the nasophar3nix and respiratory tract. Respiratory symptoms are prominent with pulmonary edema and bronchoconstriction. Asthmatic patients are more susceptible and bronchial hyperactivity may persist for several years [26]. Obstructive and restrictive lung disease, chronic bronchitis may also develop after an acute exposure. Other symptoms include conjunctival irritation and dermal frostbite. There is no evidence of teratogenic or direct carcinogenic effects due to SO2 which could be a promoter in combination with benzo(a)pyrene or arsenic. Sulfuric acid. Fuming sulfuric acid is a solution of sulfur trioxide in sulfuric acid. It is also present in mist and acid rain. Sulfuric acid is corrosive to the mucous membranes and respiratory tract. Inhalation of sulfuric acid mist causes a reflex increase in respiratory rate and bronchoconstriction. Overacute exposure produces severe bronchospasm and non-cardiogenic pulmonary edema [27]. ASPHYXIANT GASES Carbon monoxide Carbon monoxide (CO) is produced by the incomplete combustion of carboncontaining materials in poorly ventilated rooms. Inhalation and even ingestion of methylene chloride can also produce delayed CO poisoning. CO intoxication should be determined from the patient's mental and cardiovascular status rather than carboxyhemoglobin level. In severe poisoning, arterial pH, bicarbonate levels, serum CPK activity and chest X-ray should be monitored.
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Acute and chronic effects of CO poisoning are due to tissue h5^oxia. The most sensitive organs to oxygen deprivation are the central nervous system (CNS) and the myocardium. Infants, pregnant women, elderly people or patients with a previous history of myocardial insufficiency or chronic obstructive pulmonary disease are particularly at risk. CNS depression may evolve to irreversible coma. Residual and delayed neurologic effects may occur after acute CO poisoning. Alteration of cognitive functions is the main feature. The incidence of delayed neurological sequelae is correlated to the initial level of consciousness and duration of coma. Myocardial insufficiency may be aggravated or precipitated by CO [28]. Pulmonary edema and adult respiratory distress syndrome have been observed. Other symptoms include psychiatric, gastrointestinal and metabolic disorders. The value of hyperbaric oxygen was assessed in a recent prospective study. Pregnant women were excluded from this study. In patients without initial impairment of consciousness, the value of hyperbaric oxygen was not greater than normobaric oxygen. In patients with initial impairment of consciousness, two sessions of hyperbaric oxygen were not more efficient t h a n one session in the prevention of late neurological sequelae [29]. Potential effects of long-term exposure to low concentrations remain controversial. CO is teratogenic and embryotoxic at high maternal carboxyhemoglobin concentrations [30]. An increase in fetal death has been reported in a recent survey [31]. Carbon dioxide Hypoxia from reduced oxygen concentration in inspired air is the consequence of acute exposure to simple asphyxiant gases. Symptoms appear usually when oxygen concentration is less than 15%. In 1985, the Lake Nyos disaster was responsible for numerous deaths. It was due to a massive liberation of C02as a suffocating aerosol leading to immediate asph3^ia. Survivors had lost consciousness for several hours; some complained of cough, headache and wealiness [32,33]. Exposure to lower concentrations results in h3^erventilation and headache due to cerebral vasodilatation. Cyanide derivatives There are various sources of cyanide formation. The most toxic forms by inhalation are hydrogen cyanide (HCN), cyanogen [(CN)2], and its halides, and cyanide salts. Cyanide can also be released by hepatic metabolism from various nitrile compounds resulting in delayed cyanide poisoning. Calcium cyanide, isocyanates and metal cyanides do not share the same toxic properties and act mainly as irritants. Symptoms following acute poisoning depend upon the extent of and time since exposure. Cyanide exposure may produce death within minutes. Hyperpnea, tachycardia, h3^ertension and central nervous system (CNS) stimu-
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lation may be seen in the early phase of cyanide poisoning before the stage of global depression. Cyanosis is only a late finding. Metabolic acidosis and elevated serum lactate levels are commonly noted. Victims of cyanide poisoning either die acutely or recover fully. Parkinsonian symptoms and dystonia have been reported after ingestion of cyanide salts [34]. Methyl isocyanate acts mainly as an irritant gas, and the fatalities in the Bhopal disaster were due to acute respiratory distress occurring in the area close to the factory. Chronic cyanide exposure may produce various neurological disorders (headache, optic neuropathy, myelopathy). Effects on the thyroid gland (decreased iodine uptake) and on vitamin Bi2/folate metabolism have also been suspected. Dermatitis and respiratory tract irritation are also possible. Potassium cyanide has been associated with teratogenic and genotoxic effects in animals. Chromosomal abnormalities, spontaneous abortions and malformative syndromes have been demonstrated following the Bhopal tragedy [35]. H y d r o g e n sulfide Hydrogen sulfide is a highly toxic gas which is produced by decomposition of sulfur compounds. It can be encountered in a large variety of industrial processes. At low vapor concentrations, hydrogen sulfide is irritant for the eyes, nose, respiratory and gastrointestinal tract. At higher concentrations, it produces neurological impairment with dizziness, headache and loss of consciousness [36]. Mortality following exposure to very high concentrations has been reported to reach 6% [37]. Respiratory paralysis, tachycardia with ECO ischemic changes, hypotension, cyanosis, asphyxial convulsions occur in fatal cases. Anoxic effects would be related to the inhibition of cytochrome oxidase enzymes. Lactic acidosis is a common observation following hydrogen sulfide poisoning. Delayed neuropsychiatric sequelae have been also reported after acute hydrogen sulfide poisoning [38]. Phosphine Phosphine is a highly toxic gas produced by different phosphide salts (aluminium, calcium, zinc) following exposure to moisture. Phosphine is mainly used as fumigant or rodenticide. Toxicity occurs either following ingestion or inhalation. Organs with high oxygen requirements are especially sensitive, including the brain, kidneys, heart and liver. Mortality following aluminium phosphide poisoning remains particularly high [39]. The cardiovascular and respiratory complications are often life-threatening and include cardiac arrhythmias, shock and also delayed pulmonary edema. Symptoms of chronic poisoning include anemia, bronchitis, gastro-intestinal and neurosensorial disturbances [40].
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OTHER TOXIC GASES Metal f u m e fever Metal fume fever is produced by inhaling metal oxides produced by heating various metals, the most common being zinc and copper. Non-specific symptoms including fever, dry throat, pyrexia, myalgias, weakness or dyspnea are commonly reported; a metallic taste is inconstant. Recovery is usually complete within 24 to 48 hours with no chronic impairment [41]. P o l y m e r fume fever When polytetrafluoroethylene (Teflon®) is heated up to 315-375°C under conditions of insufficient ventilation, an influenza-like syndrome called polymer fume fever can develop. Polymer fume fever is usually self-limiting with a complete resolution within 48 hours. Symptoms may start up to 12 hours following exposure and are usually less severe than in metal fume fever. They include hyperpyrexia, mild tachycardia and hypertension, chest discomfort with respiratory tract irritation and weakness. Interestingly, no fatalities have been reported and there is no evidence of long-term effects [42]. P r o d u c t s of c o m b u s t i o n Symptoms following fire hazards often combine effects of irritants (acrolein, ammonia, chlorine, hydrogen chloride, nitrogen dioxide, phosgene, sulfur dioxide) and asphyxiants (carbon monoxide and cyanide). Smoke, heat and flame may all play a deleterious role. Thermal injury mainly affects the upper airways and can be used as a marker for significant smoke exposure. Smoke is composed of a particulate fraction and gases. Toxic gas production depends on oxygen supply, temperature, rate of heating and material. Cardiovascular, respiratory and central nervous systems may be variably affected. Early recognition of signs of severe exposure to CO and CN is of primary importance, since specific therapy can be added to the general supportive measures, even at the scene of fire [43,44].
REFERENCES 1. 2. 3. 4.
Millea TP, Kucan JO, Smoot EC (1989) Anhydrous ammonia injuries. J. Burn. Care Rehahil, 10, 448-453. Arwood R, Hamond J, Ward GO (1985) Ammonia inhalation. J. Trauma, 25, 444-447. Swotinsky RB, Chase KH (1990) Health effects of exposure to ammonia: scant information. Am. J. Indust. Med., 17, 515-521. Kraut A, Lilis R (1988) Chemical pneumonitis due exposure to bromine compounds. Chest, 94, 208-210.
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5. Potashnik G, Carel R, Beimaker J, Levine M (1992) Spermatogenesis and reproductive performance following human accidental exposure to bromine vapor. Reprod. Toxicol, 6, 171-174. 6. Heidemann SM, Goetting MG (1991) Treatment of acute hypoxemic respiratory failure caused by chlorine exposure. Pediatr. Emerg. Care, 7, 87-88. 7. Schwartz DA, Smith DD, Lakshminarayan S (1990) The pulmonary sequelae associated with accidental inhalation of chlorine gas. Chest, 97, 820-825. 8. Kennedy SM, Enarson DA, Janssen RG, Chan-Yeung M (1991) Lung health consequences of reported accidental chlorine gas exposures among pulpmill workers. Am. Rev. Respir. Dis., 143, 74-79. 9. Finkel M (1983) Hamilton & Hardy's Industrial Toxicology, 4th Edition, John Wright, PSG., Boston; 180-183. 10. Nemeth L, Zsogon E (1989) Occupational skeletal fluorosis. Clin. Rheumatol., 3, 81-88. 11. Dela Cruz F, Brown DH, Leiken JB et al (1987) Iodine absorption after topical administration. West. J. Med., 146, 43-45. 12. Chadly A, Marc B, Barres D et al (1989) Suicide by nitrous oxide poisoning. Am. J. Forens. Med. Pathol, 10, 330-331 13. Lampe GH, Wauz LZ, Donegan J H et al (1990) Effects on outcome of prolonged exposure of patients to nitrous oxide. Anesth. Analg., 71, 586-590. 14. Rowland AS, Baird DD, Weinberg OR et al (1992) Reduced fertility among women employed as dental assistants exposed to high levels of nitrous oxide. A^. Engl J. Med., 327, 993-997. 15. Hedberg K, Hedberg CW, Ther C et al (1989) An outbreak of nitrogen dioxide-induced respiratory illness among ice hockey players. JAMA, 262: 3014-3017. 16. Douglas WW, Hepper NGG, Colby TV (1989) Silo-Filler's disease. Mayo Clin. Proc, 64, 291-304. 17. Epler GR (1989) Sillo-Filler's disease: a new perspective. Mayo Clin. Proc, 64, 368-370. 18. Rubinstein I., Bigby BG, Reiss TF, Broushey HA (1990) Short-time exposure to 0.3 ppm nitrogen dioxide does not potentiate airway responsiveness to sulfur dioxide in asthmatic subjects. Am. Rev. Respir. Dis., 141, 381-385. 19. Hazucha MJ, Bates DV, Bromberg PA (1989) Mechanism of action of ozone on the h u m a n lung. J. Appl. Physiol, 67, 1535-1541. 20. Folinsbee LJ, Horvath SM (1986) Persistance of the acute effects of ozone exposure. Aviat. Space Environ. Med., 57, 1136-1143. 21. Victorin K (1992) Review of the genotoxicity of ozone. Mutat. Res., 277, 221-238. 22. Bardley BL, Unger KM (1982) Phosgene inhalation: a case report. Texas Med., 78, 51-53. 23. Kennedy TP, Michael JR, Hoidal JR et al (1989) Dibutyryl cAMP, aminophylline, and beta adrenergics agonists protect against pulmonary edema caused by phosgene. J. Appl Physiol, 67, 2542-2552. 24. Lheureux P, Leduc D, Askenasi R (1993) Toxic gases and vapors exposures. JEUR, 6, 35-48. 25. Sittig M (1985) Handbook of Toxic and Hazardous Chemicals and Carcinogens, 2nd ed. Noyes Publications, Park Ridge, NJ. 26. Rabinovitch S, Greyson MD, Weiser M et al (1989) Clinical and laboratory features of acute sulfur dioxide inhalation poisoning: two year follow up. Am. Rev. Respir. Dis., 139, 556-558.
Chapter 26 — Toxic gases
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27. Knapp MJ, Bunn WB, Stave GM (1991) Adult respiratory distress syndrome from sulfuric acid fume inhalation. South. Med. J., 84, 1031-1033. 28. Allred EN, Bleecker ER, Chaitman BR et al (1991) Effects of carbon monoxide on myocardial ischemia. Environ. Health Perspect., 91, 89-132. 29. Raphael JC, Elkilarrat D, Jars-Guincestre MC et al (1989) Trial of normobaric and hyperbaric oxygen for acute carbon monoxide intoxication. Lancet, ii, 417-419. 30. Norman CA, Halton DM (1990) Is carbon monoxide a workplace teratogen? A review and evaluation of the literature. A/iin. Occup. Hyg., 34, 335-347. 31. Mathieu-Nolf M, Mathieu D, Monso-Germain M et al (1992) Acute carbon monoxide poisoning during pregnancy (abstract). EAPCCT, 15th Congress, Istanbul, Turkey. 32. Freeth S (1992) The deadly cloud hanging over Cameroon. New Scientist, 15, 23-27. 33. Wagner GN, Clark MA, Kownigsberg ES et al (1988) Medical evaluation of the victims of the 1985 Lake Nyos disaster. J. Forensic ScL, 33, 899-909. 34. Valenzuela R, Court J, Godoy J (1992) Delayed cyanide induced dystonia. J. Neurol. Neurosurg. Psychiatr., 55, 198-199. 35. Goswani FIK, Chandorkar M, Bhaftacharya K et al (1990) Search for chromosomal variations among gas-exposed persons in Bhopal. Hum. Genet, 84, 172-176. 36. Glass DC (1990) A review of the health effects of hydrogen sulfide exposure. Ann. Occup. Hyg., 34, 323-327 37. Burnett WW, King EG, Grace M et al (1977) Hydrogen sulfide poisoning: review of 5 years' experience. Canad. Med. Assoc. J., 177, 1277-1280. 38. Tvedt B, edland A, Skyberg K, Forberg O (1991) Delayed neuropsychiatric sequelae after acute hydrogen sulfide poisoning. Affection of motor function, memory, vision and hearing. Acta Neurol. Scand., 84, 348-351. 39. Singh RB, Singh RG, Singh U (1991) Hypermagnesemia following aluminium phosphide poisoning. Int. J. Clin. Pharmacol. Ther. Toxicol., 29, 82-85. 40. Sax M, Lewis RJ (1989) Dangerous properties of industrial materials, 7th edition, pp. 2768-2769. Van Nostrand Reinhold, New York. 41. Proctor NH, Hughes J P , Fischman ML (1988) Chemical Hazards of the Workplace, 2nd edition, pp. 418-419. J.B. Lippincott Co, Philadelphia, PA. 42. Offermann PV, Finley CJ (1992) Metal fume fever - A review. Ann. Emerg. Med., 21, 872-875. 43. Baud FJ, Barriot P, Toffis V et al (1991) Elevated bloood cyanide concentrations in victims of smoke inhalation. A^. Engl. J. Med., 325, 1761-1766. 44. Shiono H, Maseda C, Akane A et al (1991) Rapid and sensitive quantitation of cyanide in blood and its application to fire victims. Am. J. Forens. Med. Pathol.,12, 50-53.