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659. Skin reactions induced by drugs
506
THE C H E M I C A L ENVIRONMENT
658. Chronic exposure to sulphur dioxide Skalpe, I. O. (1964). Long-term effects of sulphur dioxide exposure in pulp mills. Brit. J. industr. Med. 21, 69. Sulphur dioxide (SO2) is widely used in industry and there is a great deal of interest in its chronic toxicity by inhalation. The limit allowed in most countries is 5 ppm (Barnes, Brit. med. J. 1961, ii, 1097) but few controlled clinical studies have been reported until now. The present investigation covered workers at 4 pulp mills in Norway. Workers were examined by the author himself and those exposed to 2-36 ppm SOz were compared with those who were not. Parameters recorded were cough, sputum production, dyspnoea, vital capacity (VC) and the maximum expiratory flow rate (MEFR). Since older workers were likely to have been exposed far longer than younger workers and as the VC and the MEFR decrease with age, the subjects examined were divided into two groups: the under 50 group had an average duration of exposure of 6.8 yr while that of the over 50 group was 20.3 yr. Since no significant difference in the incidence of cigarette smokers was found between the exposed workers and the controls, smoking was not taken into account. The results show strikingly that the frequency of cough, expectoration and dyspnoea on exertion was significantly higher among the exposed workers than the controls; the difference was more marked among the younger workers. In the under 50 group 62 % of exposed workers had a chronic cough compared with 0.6 % of controls. Among all workers examined, 56 % of those exposed to SOz coughed regularly compared with 13 % of controls; 46 % of exposed workers were troubled by chronic production of sputum compared with 5 % of controls; and 22 % of exposed workers readily became out of breath as compared with 5 of controls. No difference was seen between exposed and control groups in regard to VC but the MEFR of the younger exposed workers (509 1/min) was substantially lower than that of the controls (551 1/min). There cart be no doubt from this well-conducted, clearly presented and convincing investigation that chronic exposure to SO2 is very likely to lead to respiratory disorders. 659. Skin reactions induced by drugs Sternberg, T. H. & Bierman, S.M. 1963). Unique syndromes involving the skin. induced by drugs, food additives and environmental contaminants. Arch. Derm. 88, 779. Drugs and certain food additives and contaminants may give rise to reactions in man which simulate naturally-occurring disease and assume almost any clinical pattern. This paper focuses attention on the increasing role played by drugs and other compounds in the pathogenesis of rare syndromes involving the skin. It has been known for some time that certain drugs, such as sulphonamides, may induce syndromes resembling spontaneouslyoccurring collagen disease. The clinical picture of systemic lupus erythematosus (SLE) is induced in about 10% of hypertensive patients on long-term treatment with hydralazine. The hydralazine lupus syndrome does have some distinguishing features and is usually reversible following withdrawal of the drug, although sometimes the condition persists for several years. Syndromes resembling SLE have been associated with a variety of structurally and pharmacologically dissimilar drugs. While it is possible that external factors may provoke pre-existent SLE, intrinsic mechanisms, particularly a specific hypersensitivity, axe apparently involved in the appearance of this form of drug-induced disease. The usual explanation put forward is that the drugs induce an allergic response by combining with body proteins to form haptens. Among pigmentary diseases induced by various compounds are: a syndrome resembling the congenital disease oehronosis, induced by resorcinol or 'carbolic acid'; methaemoglobinaemia in premature babies due to marking ink on nappies; or the same condition in children or young adults, arising from the ingestion of sodium nitrite or the use of an
COSMETICS AND TOILETRIES
507
enema containing hexachlorophene; hair colour change due to mephenesin carbamate; and tooth pigmentation in young children following prolonged therapy with chlortetraeycline or oxytetracycline. A most extraordinary reaction is the syndrome simulating malignant'lymphoma, with many of the features of serum sickness, produced by drugs used in the treatment of epilepsy or tuberculosis. Adverse drug reactions sometimes result in clinical patterns simulating congenital skin diseases, such as the triparanol-induced ectodermal syndrome resembling congenital ichthyosis, and a facial haemangioma induced by thalidomide. Most drug-induced syndromes are comparatively infrequent because of limited exposure to drugs, but the greater use of food additives in the diet of large populations increases the possibility of outbreaks of epidemic proportions, such as the incidence of a syndrome resembling exanthema infectiosa in Germany and Holland in 1958 and 1960, which was claimed to be due to a margarine emulsifier (Cited in F.C.T. 1963, 1, 92), and outbreaks of porphyria cutanea tarda which occurred in Turkey as a result of widespread consumption of wheat treated with hexachlorobenzene (Cited in F.C.T. 1963, 1, 126). While the large scale of these outbreaks facilitated the speedy establi~hm,ent of their cause, less spectacular reactions are more difficult to recognize, and the authors make a plea for more effort in the clinical evaluation of food additives and contaminants, particularly with regard to their long-term effects. [Readers will recall our previous reviews on the Dutch margarine sickness (Cited in F.C.T. 1964, 2, 90) which lead to very different conclusions. The authors wonder why there has been only one isolated report of angiitis due to the "insecticide" (sic) dichlorophenoxyacetic acid, when the "ubiquity of exposure to insecticides" would lead one to expect this to be a more common occurrence. May we respectfully suggest that the authors "brush up" on their facts, from sources other than Rachel Carson ("Silent Spring"), W. Longwood ("The Poisons in Your Food") and W. C. Hueper.]
COSMETICS AND TOILETRIES 660. Safety-in-use of household detergents Snyder, F. H., Opdyke, D. L., Griffith, J. F., Rubenkoenig, H. L., Tusing, T. W. & Paynter, O. E. (1964). Toxicologic studies on household synthetic detergents. I. Systemic effects. Toxicol. appl. Pharmacol. 6, 133. Opdyke, D. L., Snyder, F. H. & Rubenkoenig, H. L. (1964). Toxicologic studies on household synthetic detergents. I[. Effects on the skin and eyes. ibid 6, 141. Although many toxicity studies have been performed using specific ingredients of household synthetic detergents (Cited in F.C.T. 1964, 2, 280), the experiments described in these 2 papers are believed to be the first carried out on a complete household product. The authors have evaluated the toxicological risk from both the systemic and the topical aspects. The two formulations examined were similar, each consisting of 50 % condensed phosphate, 13 % sodium sulphate, 6% sodium silicate and 11% aesthetic additives and water content. Detergent I had sodium alkylbenzene sulphonate and detergent II, sodium alkylbenzene sulphonate and sodium alkyl sulphate in equal parts, as the active surfaetant ingredients. The acute oral toxicity in rats for I and II showed an LDso range of 2.2-7.5 g/kg, i.e. of the same order as sodium bicarbonate and table salt. Oral doses of 0.4 g/kg of either product caused prompt emesis in dogs, but doses of 5 g/kg showed no additional evidence of toxicity except slight transient diarrhoea. Groups of male and female rats fed 0-5 ~o of I or II in the diet for up to 2 yr exhibited no evidence of toxic effects as judged by haemoglobin
THE C H E M I C A L ENVIRONMENT
658. Chronic exposure to sulphur dioxide Skalpe, I. O. (1964). Long-term effects of sulphur dioxide exposure in pulp mills. Brit. J. industr. Med. 21, 69. Sulphur dioxide (SO2) is widely used in industry and there is a great deal of interest in its chronic toxicity by inhalation. The limit allowed in most countries is 5 ppm (Barnes, Brit. med. J. 1961, ii, 1097) but few controlled clinical studies have been reported until now. The present investigation covered workers at 4 pulp mills in Norway. Workers were examined by the author himself and those exposed to 2-36 ppm SOz were compared with those who were not. Parameters recorded were cough, sputum production, dyspnoea, vital capacity (VC) and the maximum expiratory flow rate (MEFR). Since older workers were likely to have been exposed far longer than younger workers and as the VC and the MEFR decrease with age, the subjects examined were divided into two groups: the under 50 group had an average duration of exposure of 6.8 yr while that of the over 50 group was 20.3 yr. Since no significant difference in the incidence of cigarette smokers was found between the exposed workers and the controls, smoking was not taken into account. The results show strikingly that the frequency of cough, expectoration and dyspnoea on exertion was significantly higher among the exposed workers than the controls; the difference was more marked among the younger workers. In the under 50 group 62 % of exposed workers had a chronic cough compared with 0.6 % of controls. Among all workers examined, 56 % of those exposed to SOz coughed regularly compared with 13 % of controls; 46 % of exposed workers were troubled by chronic production of sputum compared with 5 % of controls; and 22 % of exposed workers readily became out of breath as compared with 5 of controls. No difference was seen between exposed and control groups in regard to VC but the MEFR of the younger exposed workers (509 1/min) was substantially lower than that of the controls (551 1/min). There cart be no doubt from this well-conducted, clearly presented and convincing investigation that chronic exposure to SO2 is very likely to lead to respiratory disorders. 659. Skin reactions induced by drugs Sternberg, T. H. & Bierman, S.M. 1963). Unique syndromes involving the skin. induced by drugs, food additives and environmental contaminants. Arch. Derm. 88, 779. Drugs and certain food additives and contaminants may give rise to reactions in man which simulate naturally-occurring disease and assume almost any clinical pattern. This paper focuses attention on the increasing role played by drugs and other compounds in the pathogenesis of rare syndromes involving the skin. It has been known for some time that certain drugs, such as sulphonamides, may induce syndromes resembling spontaneouslyoccurring collagen disease. The clinical picture of systemic lupus erythematosus (SLE) is induced in about 10% of hypertensive patients on long-term treatment with hydralazine. The hydralazine lupus syndrome does have some distinguishing features and is usually reversible following withdrawal of the drug, although sometimes the condition persists for several years. Syndromes resembling SLE have been associated with a variety of structurally and pharmacologically dissimilar drugs. While it is possible that external factors may provoke pre-existent SLE, intrinsic mechanisms, particularly a specific hypersensitivity, axe apparently involved in the appearance of this form of drug-induced disease. The usual explanation put forward is that the drugs induce an allergic response by combining with body proteins to form haptens. Among pigmentary diseases induced by various compounds are: a syndrome resembling the congenital disease oehronosis, induced by resorcinol or 'carbolic acid'; methaemoglobinaemia in premature babies due to marking ink on nappies; or the same condition in children or young adults, arising from the ingestion of sodium nitrite or the use of an
COSMETICS AND TOILETRIES
507
enema containing hexachlorophene; hair colour change due to mephenesin carbamate; and tooth pigmentation in young children following prolonged therapy with chlortetraeycline or oxytetracycline. A most extraordinary reaction is the syndrome simulating malignant'lymphoma, with many of the features of serum sickness, produced by drugs used in the treatment of epilepsy or tuberculosis. Adverse drug reactions sometimes result in clinical patterns simulating congenital skin diseases, such as the triparanol-induced ectodermal syndrome resembling congenital ichthyosis, and a facial haemangioma induced by thalidomide. Most drug-induced syndromes are comparatively infrequent because of limited exposure to drugs, but the greater use of food additives in the diet of large populations increases the possibility of outbreaks of epidemic proportions, such as the incidence of a syndrome resembling exanthema infectiosa in Germany and Holland in 1958 and 1960, which was claimed to be due to a margarine emulsifier (Cited in F.C.T. 1963, 1, 92), and outbreaks of porphyria cutanea tarda which occurred in Turkey as a result of widespread consumption of wheat treated with hexachlorobenzene (Cited in F.C.T. 1963, 1, 126). While the large scale of these outbreaks facilitated the speedy establi~hm,ent of their cause, less spectacular reactions are more difficult to recognize, and the authors make a plea for more effort in the clinical evaluation of food additives and contaminants, particularly with regard to their long-term effects. [Readers will recall our previous reviews on the Dutch margarine sickness (Cited in F.C.T. 1964, 2, 90) which lead to very different conclusions. The authors wonder why there has been only one isolated report of angiitis due to the "insecticide" (sic) dichlorophenoxyacetic acid, when the "ubiquity of exposure to insecticides" would lead one to expect this to be a more common occurrence. May we respectfully suggest that the authors "brush up" on their facts, from sources other than Rachel Carson ("Silent Spring"), W. Longwood ("The Poisons in Your Food") and W. C. Hueper.]
COSMETICS AND TOILETRIES 660. Safety-in-use of household detergents Snyder, F. H., Opdyke, D. L., Griffith, J. F., Rubenkoenig, H. L., Tusing, T. W. & Paynter, O. E. (1964). Toxicologic studies on household synthetic detergents. I. Systemic effects. Toxicol. appl. Pharmacol. 6, 133. Opdyke, D. L., Snyder, F. H. & Rubenkoenig, H. L. (1964). Toxicologic studies on household synthetic detergents. I[. Effects on the skin and eyes. ibid 6, 141. Although many toxicity studies have been performed using specific ingredients of household synthetic detergents (Cited in F.C.T. 1964, 2, 280), the experiments described in these 2 papers are believed to be the first carried out on a complete household product. The authors have evaluated the toxicological risk from both the systemic and the topical aspects. The two formulations examined were similar, each consisting of 50 % condensed phosphate, 13 % sodium sulphate, 6% sodium silicate and 11% aesthetic additives and water content. Detergent I had sodium alkylbenzene sulphonate and detergent II, sodium alkylbenzene sulphonate and sodium alkyl sulphate in equal parts, as the active surfaetant ingredients. The acute oral toxicity in rats for I and II showed an LDso range of 2.2-7.5 g/kg, i.e. of the same order as sodium bicarbonate and table salt. Oral doses of 0.4 g/kg of either product caused prompt emesis in dogs, but doses of 5 g/kg showed no additional evidence of toxicity except slight transient diarrhoea. Groups of male and female rats fed 0-5 ~o of I or II in the diet for up to 2 yr exhibited no evidence of toxic effects as judged by haemoglobin