Document pvmwd8D7ZXRXJ4jjdO6NJkGd

O' '3 V Fd (.'i>www Toucal Vol |4, pp 64I-W4 Pcr^umon Prtf5s J*9"^ Printed m Gicdt Britain \ Information Section ARTICLES OF GENERAL INTEREST VINYL CHLORIDE DISEASE- AN IMMUNE COMPLEX DISORDER? A recent publication (Ward et al, Br. nwd. ./, 1976. 1, 936) suggests that vinyl chloride disease or, more strictly, the vinyl chloride syndrome may be the new est recruit to the ever-growing band of immune com plex disorders. An immune complex disorder is a form of tissue damage resulting from the building up of aggregates consisting of antigen and antibody. The aggregates form a lattice-type complex which, under certain con ditions. precipitates out of the fluid phase and is de posited in the microvasculature, particularly at sites rich in capillary networks such as the skin and kid ney. The deposited complexes fix a substance called complement, and this results in the production of a local inflammatory reaction. Complement exists in the serum as nine individual proteins which are biolo gically inert; on activation, the components bind to one another in a sequential fashion, during which process some of the single components become biolo gically active, acquiring properties that influence capillary permeability and the movement of inflam matory cells. The activation of the complement sequence can cer tainly be brought about by antigen-antibody com plexes, but aggregated immunoglobulin and certain chemical compounds can also start the process. It is important, therefore, when assessing the changes pro duced in this connexion by vinyl chloride, to remember that the demonstration of complement ac tivation does not mean unequivocally that it is due to deposits of immune complexes. The vinyl chloride syndrome, like the classic im mune complex disorder systemic lupus erythematosus (SLE), consists of lesions in many organ systems. It is reasonable to postulate that there may be an underlying pathological process which could account for the different clinical manifestations and, by com parison with SLE, such a process could be a hyper sensitivity response mediated by immune complexes. Dr. Ward and her colleagues had the opportunity to examine 58 patients referred from a single vinyl chloride polymerization plant. The patients were divided by clinical criteria into four distinct groups. Group 1 consisted of nine patients with overt signs and symptoms of vinyl chloride disease (Cited in F.C.T. 1976, 14, 347). Group 2 contained 19 patients described as "moderately disabled and multisymptomatic". Group 3 was the largest group, consisting of 25 patients with complaints reflecting a variety of symptoms but with very few clinical signs, while group 4 patients, five in all, were asymptomatic. The immunological findings relevant to the claim that vinyl chloride disease is an immune complex dis order were the demonstration of mixed cryoglobulins, the reputed complement changes and the demons tration of IgG and C3 in the small vessels of the skin and muscles. Cryoglobulins are precipitated when the serum of some patients is cooled to 4 C, and the pre cipitates can be collected by centrifugation, solubi lized and subjected to immunoelectrophoresis to determine their content. Although cryoprecipuates are usually found in immune complex disorders, they are by no means pathognomonic because it is very difficult to show that the precipitates are composed of aggregates of antigen and antibody. The unmunoelectrophoretic analysis earned out by Dr. Ward could give no information on the nature of a putative antigen. Low serum levels of C4 and C3 and the in vivo conversion of C, indicate that complement is being activated. Immune complexes can consume comple ment. and changes of charge reflecting complement activation are often found in immune complex dis orders but, again, they are not pathognomonic. It is important, when exogenous chemical substances are suspected antigens, to check that they are not anti complementary in their own right. The demonstration by direct immunofluorescence of IgG. Cj., C3 and fibrinogen in the lumen of vessels is good evidence in favour of deposited immune com plexes. Unfortunately. Dr. Ward did not publish photographs of the fluorescence, and as this particular procedure is difficult to interpret, good photographs would help to convince any sceptic. The remaining immunological findings are not im pressive and do not add much to the evidence incri minating immune complexes in the aetiology of vinyl chloride disease. What is impressive is the close corre lation between the positive immunological findings and the clinical groupings, positive results being recorded in 88. 58, 8 and 0% in groups 1. 2. 3 and 4, respectively. The fact that there is such a close cor relation clearly suggests that the clinical manifes tations of the disease are either caused by immune complexes of some type or cause the formation of immune complexes; vinyl chloride could be the causa tive agent in either case. There is no evidence in Dr. Ward's paper, however, to show that vinyl chloride induces monomer-specific antibodies. The data could be explained by postulating that vinyl chloride acts biochemically to produce tissue damage, w hich secon darily leads to an auto-allergic response w ith immune complex formation between `self-component- antigens and antibody. The distinction depends on whether vinyl chloride functions as an antigenic determinant, a point that may appear academic, since the net result is a disease brought about by immune-complex depo sits, but is important if the mechanism of action is BOR 010147 642 Articles of general interest to be understood. Furthermore an understanding of the processes leading to the formation of immune complexes could influence the clinical management of the disabled patients and the monitoring of indivi duals at risk. Dr. Ward and her colleagues are to be congratu lated on pointing towards a possible aetiology of this disturbing syndrome. Their results must obviously be .confirmed, preferably by an independent group, but this could prove difficult in view of the geographical localization of the patients. [H. Amos--BIBRA] ADDING TO THE HEXACHLOROPHENE PICTURE When first introduced as a bacteriostatic agent in soap and cosmetics and as a therapeutic means of controlling the gram-positive populations of bacteria on normal human skin, hexachlorophene (HCP) was considered innocuous apart from its ability to induce allergic dermatitis or photosensitivity in a small pro portion of the population. In 1971, however, the FDA published a study indicating that HCP could produce central nervous system degeneration when fed to rats over relatively short periods (Cited in F.C.T. 1972, 10. 275). and demonstrations that HCP could be absorbed in significant amounts into the blood stream of infants bathed daily with a 3% formulation (ibid 1972. 10. 114) raised the question of its safety for this use. Subsequent studies have been discussed from time to time in this Journal, and in this article we consider further aspects of HCP toxicity reported since our last review (ibid 1974, 12. 563). Absorption in mm Gillespie et al. IJ. Hyg., Camb. 1974, 73, 3111 stud ied the data from a maternity hospital in which dust ing powder containing &33'0 HCP was routinely applied to the umbilical stump and trunk of neonates. The HCP content of blood from mothers before deli very' and from infants at birth and at the age of 8 days was measured. In all but one instance, in which HCP was assumed to have been derived from the use of HCP-containing toilet preparations before deli very. HCP was absent or barely detectable in mater nal and umbilical cord blood. Concentrations of HCP in blood from 8-day-old infants ranged from zero to 0T66/ig'ml. with a mean of 0-066 ,ug/ml. and were thus well below those known to produce toxic effects in animals Nevertheless, the authors suggest that HCP treatment should generally be confined to use in hospitals and under medical supervision during the first 7-10 days of life. It should be used w ith caution on low-birth-weight babies and not at all on infants with burnt or excoriated skin. Absorption of HCP by adults after daily wholebody washings with a 3",', HCP preparation contain ing a detergent was determined by Calesmck i-r uJ, (Toxic, appl. Pharmac. 1975. 32. 204). In 50 adult volunteers, blood HCP was measured initially and after 3 weeks during which all known sources of HCP were avoided. Two detergent-based products, each containing 3% HCP, were then applied daily to the whole body surface excluding the scalp, as a 3-minute application of 30 ml (900mg HCP) with enough water for adequate lathering. Blood samples were obtained at 7-day intervals for up to 4 weeks after the end of treatment or until the concentration of HCP had returned to its pre-trial value. Among the 43 subjects who completed over 6 weeks of the trial, the blood concentration of HCP exceeded 1-3 ug/ml in four, two using each preparation, during weeks 4 or 5. Pooled .data showed a mean HCP peak during weeks 3-5 of 0-5-0-66 ug/ml, falling during weeks 6-8 to 0-33-0-51 yig. ml and returning to the pretreatment level of 0 009-0 012 /tg/ml within 2-3 weeks of the ces sation of applications. These findings suggested that the chronic blood concentration of more than 1 gg HCP/ml required to produce neurological damage in rats is higher than that likely to result from repeated whole-body washing of adults with 3% HCP deter gent preparations. In a further absorption study in adults (Bye et al. Br. J. Derm. 1975. 93. 209), Ultralanum, an ointment containing corticosteroid with 1-4% HCP, xvas applied to six adults in quantities of 15-60g/week for periods ranging from 2 weeks to 17 months. Plasma concentrations of 0-03-0-30 gg/ml were found but there was no clinical evidence of toxicity. No cor relation could be found between plasma-HCP levels and the total treatment periods. The possibility that infants may ingest HCP in milk has also been investigated (West et al. Bull. env. con tain. 4 Toxicol. (L'.S.) 1975, 13, 167). Six samples of human milk, collected before restrictions on the hos pital use of HCP were enforced, contained HCP in concentrations of <2-9-5 ppb (b = 10*), with a mean of 5-7 ppb. Five milk samples obtained after restric tions were in force showed no HCP in two, <2 ppb in two and 8-3 ppb in the fifth. It was concluded that these concentrations of HCP, in the low ppb range, probably did not constitute a hazard to infants, although it would be interesting to study nursing mothers who. for good medical reasons, continue to use HCP preparations topically. Human poisoning A tentative correlation hetween encephalopathy in infants and the hospital treatment of neonates with HCP emulsions has been attempted by Shuman or al. (Pediatrics. Springfield 1974, 54. 689), who exam ined brain specimens from 248 children who died below the age of 5 years. In 17 children, vacuolar encephalopathy was seen and was related to a history I 3 | t i i BOR 010148