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5. Lung damaging agents

Chlorine

5.1 Chlorine is a yellow-green gas at room temperature and pressure with a pungent, irritating odour. It is denser than air, and tends to accumulate at ground level. Chlorine is an extremely common agent of considerable commercial importance, being used extensively in the production of chlorinated organic polymers, solvents and other organic chemicals. (1)

5.2 Chlorine, the first chemical to be used as a warfare agent during the First World War, was released by German Forces in April 1915 at the Ypres salient. The line was being held by the First Canadian Division, which bore the brunt of the casualties, resulting in several cases of 'irritable heart', bronchitis, 'gastric symptoms', haemoptysis, asthma and 'neuroses'. (2)

5.3 It is now recognised that acute exposure to chlorine causes symptoms of mucus membrane irritation, cough, haemoptysis, chest tightness and dyspnoea. Physical examination following exposure to high concentrations may reveal tachypnoea, hypoxia and wheezing.(1), (3)

5.4 There is no specific antidote for chlorine exposure and management is largely supportive, involving evaluation and support of breathing and circulation, establishment of IV access, administration of supplemental oxygen, bronchodilators and standard treatment of coma, hypotension and seizures. (4) Corticosteroids have also been given and their use is reviewed in the case studies below.

5.6 We think it is important to point out that in cases of significant lung injury caused by exposure to chlorine and other compounds, supported ventilation, preferably with supplementary oxygen, is of vital importance. Positive pressure ventilation is an established approach in such cases.

Case studies

5.7 There are several reports of accidental exposure to chlorine in the literature. Andelson and Kaufman described a 29-year old man and his 27 year old wife who were accidentally exposed to chlorine in their home. Both presented with respiratory distress, cyanosis and hypotension. Despite receiving supplemental oxygen (100%), prednisone and penicillin, both patients died. The concentration of chlorine in these cases is unknown in this small study and the only conclusion that can be drawn is that both patients died, despite intervention. (5)

5.8 In a similar study, two sisters were exposed to an unspecified dose of chlorine following an accident. Case 1 presented with a severe cough and chest pain. A chest X-Ray revealed bilateral pulmonary infiltrates; supplemental oxygen was given and the patient discharged a few days later. Spirometry at one year was consistent with both obstructive and restrictive airways dysfunction.

5.8 Case 2 allegedly received similar exposure and presented with mucosal irritation, hoarseness, dyspnoea and coughing. Supplemental oxygen and hydrocortisone 100mg IV followed by prednisone 60 mg orally at 8 hours were given. The patient subsequently improved and was discharged. Spirometry was reported to be normal at one year.6 This is again a small, noncontrolled, study, making it difficult to ascertain the efficacy of the treatment regime. In addition, it may be that case 2 received a lower exposure than her sister, which would also explain the more favourable outcome.

5.9 Following a laboratory accident, two teenage children were exposed to chlorine. One casualty received a bronchodilator, frusemide and dexamethasone, whilst the other received 'corticosteroids' only.(7) Again, assessing the efficacy of treatment is extremely difficult.

5.10 There have also been a number of chemical incidents involving chlorine release reported in the literature. Following the accidental release of 300 litres of chlorine in Saragossa, Spain, in 1981, 164 people required symptomatic treatment. This included supplemental oxygen and1 mg Urbason/kg body weight. A follow up study at 5 years revealed no persistent symptoms. The criteria for administration of treatment are not clear and thus the efficacy of treatment cannot be ascertained. (8)

5.11 Similar limitations apply to a report of thirteen children presenting to an Accident & Emergency department following exposure to chlorine at a swimming pool. Again, treatment regimes varied, with all receiving humidified oxygen and a bronchodilator, whilst only 4 received methylprednisolone (9)

5.12 Chronic exposure to chlorine has been investigated in construction workers with a confirmed diagnosis of reactive airways dysfunction syndrome (RADS). A questionnaire distributed to 71 such workers revealed that 58 had persistent respiratory symptoms and that 4 had received corticosteroid treatment. However, some of the patients in this study had a previous history of non-occupational asthma, making the interpretation of the data difficult (10).

5.13 The utilisation of animal models has allowed quantifiable chlorine concentrations to be applied under carefully controlled conditions and for treatment regimes to be scrutinised. In one such study, eighteen premedicated and anaesthetised pigs were subjected to 140 ppm of chlorine gas for 10 minutes. The treatment group (beclomethasone dipropionate) had significantly higher Pa02 and ventilation to perfusion ratio and less histological damage than the control group.(11)

5.14 A similar study exposed 24 anaesthetised juvenile female pigs to a higher concentration of chlorine, namely 400 ppm for 10 minutes. Likewise, steroid intervention (budesonide 0.1 mg/kg) given within 30 minutes of exposure was associated with more favourable cardio-respiratory symptoms and lower wet lung weights at autopsy.(12)

5.15 These studies support a protective role for corticosteroid intervention following experimental chlorine injury, at least in pigs. The exposure of anaesthetised pigs under controlled experimental conditions, however, differs markedly from the likely exposure of casualties to chlorine either following an industrial accident or a deliberate release scenario. Caution is therefore required in extrapolating the data to man.

5.16 The findings in pigs are supported by studies in rats exposed to 1500 ppm chlorine for 5 minutes. The dexamethasone-treated group revealed significantly reduced pulmonary airway resistance and methacholine induced bronchoconstriction, as compared to the control group.(13)

Phosgene

5.17 Phosgene is a colourless gas at room temperature and pressure. It has a boiling point of 8.20C, making it extremely volatile at room temperature. Initial exposure results in immediate coughing and choking, headache, lachrymation, tightness of the chest and nausea and vomiting. This is frequently followed by a period of 2-24 hours during which the patient appears well and symptom free. This is followed by coughing, dyspnoea, tachypnoea and cyanosis, as a consequence of a phosgene-induced increase in alveolar pulmonary capillary permeability, resulting in delayed pulmonary oedema. The prognosis is good if casualties survive more than 48 hours.(14)

5.18 Phosgene was first synthesised by Davy in 1812, but prepared as a chemical weapon by Haber during the First World War. It was first used by German Forces on the 19th December, 1915, when 88 tons were released, resulting in 1069 casualties and 120 deaths. Phosgene was subsequently utilised by the allies and accounted for 85% of all deaths attributed to chemical warfare during this campaign.(15)

5.19 Phosgene is also used in industry in organic synthesis, dye manufacture, in pharmaceuticals, agro-chemicals, synthetic foams, resins and polymers. It is therefore readily available and this, coupled to its recognised toxicity, makes it suitable for use as a terrorist chemical warfare agent.

5.20 There is no specific antidote for phosgene exposure and treatment is supportive, including evaluation of the airway, administration of supplemental oxygen, ronchodilators, adrenaline for children with stridor and dopamine for hypotension, bradycardia and renal impairment. (4) Codeine phosphate may be beneficial for phosgene induced coughing; high doses may exacerbate respiratory depression.(14) Steroid therapy in phosgene exposure remains unproven.(16)

5.21 As phosgene is capable of reacting with cellular sulphydryl groups, reduce glutathione (GSH) redox state and increase arachidonic acid mediator production and lipid peroxidation, (17) several workers have focused on agents increasing cellular GSH levels as a means of preventing lipid peroxidationinduced pulmonary oedema.

5.22 Sciuto et al investigated the effect of N-acetyl cysteine (NAC) on anaesthetised male New Zealand rabbits exposed to 1500 ppm of phosgene. Compared to animals treated with phosgene alone, NAC-treated rabbits had significantly smaller increases in pulmonary wet weight, lower leukotriene levels and higher glutathione levels. This suggests that NAC may protect against phosgene-induced pulmonary oedema by maintaining GSH levels and inhibiting production of inflammatory leukotrienes. (18)

5.23 This group of workers also investigated the protective effect of butylated hydroxyanisole (BHA) pre-treatment on phosgene-induced pulmonary oedema under controlled conditions. BHA was found to significantly prolong survival, raise lung GSH levels and to significantly reduce pulmonary wet weight with respect to controls. (17) As pre-treatment is an unlikely option for the treatment of casualties subjected to a deliberate release scenario, the data must be interpreted with caution.

5.24 Post-exposure administration of a GSH-repleting agent has been investigated in anaesthetised guinea pigs. It was found that in administration of 5,8,11,14-eicosatetraynoic acid (ETYA) 5 minutes after exposure to phosgene at 44ppm prevented GSH depletion and significantly reduced the lung wet weight/dry weight ratio as compared to a group that received phosgene only. (19) It is to be noted that only 5 minutes elapsed between exposure to phosgene and the administration of ETYA; such a short delay between exposure and administration is unlikely to be met in exposed casualties. The effect of longer time delays between exposure and administration would have been more meaningful.

Mustard Gas

5.25 At room temperature, sulphur mustard is a yellow oily volatile liquid, with a faint odour of garlic. It is a powerful vesicant, resulting in erythema of the skin and subsequent formation of large fluid filled blisters. Inhalation of vapour may result in bronchitis, necrosis of the respiratory epithelium and broncho-pneumonia. There is no specific antidote for mustard. The mainstay of management is based upon physiotherapy, oxygen supplementation, antibiotics and mechanical ventilation. (20)

5.26 Several workers, however, have investigated the ability of drugs to prevent sulphur mustard-induced pulmonary injury. The GSH-dependent detoxification of sulphur mustard in particular has been investigated.

5.27 NAC has been reported to prevent increases biochemical parameters in lavage fluid following exposure of anaesthetised rats to sulphur mustard. LDH, GGT and albumin levels did not vary significantly from control values at 12 hours, suggesting reduction of cellular injury and transudation. Although this study is encouraging, it should be noted that NAC was co-administered with sulphur mustard and this again is an unlikely time frame for exposed casualties.(21) By contrast, however, exposure of rat lung slices to benzenethiols (Mustard scavengers) and cysteine esters (GSH precursors) did not produce a protective effect. (22)

5.28 In a study on a human bronchial-epithelium cell line (16HBE14o-), it was found that NAC and L-thiocitrulline (L-TC, a l-arginine analogue) prevented sulphur and nitrogen-mustard induced cellular injury, as determined by a cytological colourimetric assay. More effective protection against sulphur mustard was provided by a drug combination including L-TC, NAC, the antioxidant dimethylthiourea, the nucleophile hexamethylenetetramine and the anti-gelatinase antibiotic doxycycline (DOX). (23) It is noteworthy that both DOX and NAC are already available in clinical practice and thus could be used to treat mustard contaminated casualties.

Conclusions

5.29 There are no specific antidotes for the treatment of casualties exposed to chlorine, phosgene or mustards. Management is, therefore, supportive.

5.30 Cortico-steroid therapy has been given to casualties accidentally exposed to chlorine. Clinical data regarding efficacy are inconclusive, as the numbers given steroids have been small and the indications for administration unclear. There have been no controlled clinical studies. There is a stronger evidence base from animal studies, particularly from porcine and rodent models.

5.31 Lung Injury induced by phosgene and mustard appears to be mediated by GSH depletion, lipid peroxidation, free radical generation and subsequent cellular toxicity. There is limited evidence to suggest that repletion of GSH reduces and/or prevents lung damage by these agents.

References

(1). Das R, Blanc PD. Chlorine gas exposure and the lung: a review. Toxicol Ind Health 1993; 9: 439-455.

(2). The After Effects of Chlorine Gas Poisoning.' Meakins, JC & Priestley, JG. The Canadian Medical Association Journal(1919) 9: 968-974.

(3). Beach FXM, Jones ES, Scarrow GD. Respiratory effects of chlorine gas. Br J Ind Med 1969; 26: 231-236.

(4). Agency for Toxic Substances & Disease Registry (ATSDR).

(5). Adelson L, Kaufman J. Fatal chlorine poisoning: report of two cases with cliniopathological correlation. Am J Clin Pathol 1971; 56: 430-442.

(6). Chester EH, Kaimal PJ, Payne CB, Kohn PM. Pulmonary injury following exposure to chlorine gas: possible beneficial effects of steroid treatment. Chest 1977; 72: 247-50.

(7). Edwards IR, Temple WA, Dobbinson TL. Acute chlorine poisoning from a high school experiment. N Z Med J 1983: 96: 720-721.

(8). Fleta J, Calvo C, Zuninga J, Castellano M, B ueno M. Human Toxicol 1986; 5: 99-100.

(9). Sexton JD, Pronchik DJ. Chlorine inhalation: the big picture. Clin Toxicol 1998; 36:87-93.

(10). Bherer L, Cushman R, Courteau JP, Quevillon M, Cote G, Bourbeau J, L'Archeveque J, Cartier A, Malo JL Survey of construction workers repeatedly exposed to chlorine over a three to six month period in a pulpmill: II. Follow up of affected workers by questionnaire, spirometry and assessment of bronchial responsiveness 18 to 24 months after exposure ended. Occup Environ Med 1994; 51: 225-228.1

(11). Gunnarsson M, Walther SM, Seidal T, Lennquist S. Effects of inhalation of corticosteroids immediately after experimental chlorine gas lung injury. J Trauma 2000; 48:101-107.

(12). Wang J,  Zhang, L, Walther SM. Inhaled budesonide in experimental chlorine gas chlorine gas injury: influence of time interval between injury and treatment. Intensive Care Med 2002; 28: 352-357.

(13). Demnati R, Fraser R, Martin JG, Plaa G, Malo JL. Effects of dexamethasone on functional and pathological changes in rat bronchi caused by high acute exposure to chlorine. Toxicol Sci 1998; 45: 242- 246.

(14). Evison D, Hinsley D, Rice, P. Chemical Weapons. BMJ 2002; 324: 332-335.

(15). Maynard RL. A Medical Review of Chemical Warfare Agents. 1989 2nd. Edition.

(16). Diller WF. Therapeutic strategy in phosgene poisoning. Toxicol Ind Health 1985; 1: 93-99.

(17). Sciuto AM, Moran TS. BHA diet enhances the survival of mice exposed to phosgene. Inhalation Toxicol 1999; 11: 855-871.

(18). Sciuto AM, Strickland PT, Kennedy TP, Gurtner GH. Protective effects of N-acetyl cysteine treatment after phosgene exposure in rabbits. Am J Respir Crit Care Med 1995; 151: 768-772.

(19). Sciuto AM. Post-treatment with ETYA protects against phosgeneinduced lung injury by amplifying the glutathione to lipid peroxidation ratio. Inhalation Toxicol 2000; 12: 347-356.

(20). Willems JL. Clinical management of mustard gas casualties. Ann Med Militaris (Belg) 1989 3; (suppl 1): 1-61.

(21). Anderson DR, Byers SL, Vesely KR. Treatment of sulfur mustard (HD)- induced lung injury J.Appl Toxicol 2000; 20,: S129-S132.

(22). Langford AM, Hobbs MJ, Upshall DG, Blain PG, Williams FM. The effects of sulphur mustard on glutathione levels in rat lung slices and the influence of treatment with arylthiols and cysteine esters. Human Exp Toxicol 1996 15: 619-624.

(23). Rappeneau, S, Baeza-Squiban, A, Marano F & Calvert J Efficient protection of human bronchial epithelial cells against sulfur and nitrogen mustard cytotoxicity using drug combinations. Toxicol Sci 2000; 58: 153-160.

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