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DEFENDING THE CONTROLLED TRIAL
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EFFECTS OF INHALED SOLVENT VAPOURS LARGE quantities of organic solvents are used in industry, especially where plastics are involved, yet we know very little about their effects on performance. Most of those now in general use have narcotic properties, but there is no convincing evidence that they have any harmful long-term effects; examples are trichlorethylene, 1,1,1-trichlorethane, toluene, xylene, and styrene (vinyl benzene). Good industrial practice calls for reduction in exposure to any of these to a minimum, on general grounds, but the case becomes even stronger if it can be shown that excessive exposure impairs productivity through the behavioural effects of the material. Cherry and co-workers’ have looked at men who were exposed to styrene used as a resin solvent in the building of glass-fibre boats. Their performance was compared, in behavioural tests at the beginning and end of the working day, with that of a non-exposed group. Exposure was measured from diffusion buttons, blood styrene concentrations were measured at the end of the working day, and all urine passed between the end of work and bedtime was collected and its content of mandelic acid (a metabolite of styrene) estimated. The exposed men were divided into a high blood styrene group (3-5pLmol/1) and low blood styrene group (5-4 mol/1). Cherry et al. found no convincing changes in most of the objective tests of performance, but those workers with high blood styrene reported greater subjective feelings of physical and mental tiredness at the end of the day, and had consistently slower reaction times, in both the morning and the afternoon. In all three groups, scores in the tests worsened through the day, but deterioration was greatest in the high styrene group. Cherry and co-workers do not claim that these findings afford strong evidence that styrene adversely affects performance. Slow reaction times and subjective tiredness may sometimes be factors in the causation of accidents, but productivity or the quality of the product are not necessarily affected. They point out that, with a constant level of atmospheric styrene, more will be absorbed by the people doing the heaviest physical work, and the tiredness described by the subjects could just as well be due to this as to high blood styrene; and they admit the possibility that none of the workers examined was exposed to sufficient styrene to produce acute effects on performance. Further similar studies, not only on styrene but also on other widely used organic solvents, would certainly fill a gap in current knowledge of industrial toxicology.
DEFENDING THE CONTROLLED TRIAL THE foundation of modern scientific therapeutics-the controlled clinical trial-will survive the attacks lately made upon it. It will take something considerably more penetrating than a West German decision no longer to demand such investigations for drug registration purposes or the doubts and musings of a few clinicians, lawyers, and professional
ethicists to diminish the status of this important scientific tool. All the same, clinical pharmacologists are sensitive to the criticisms, and a year ago they organised a select international gathering in Oxfordshire, the consensus from whichI is an excellent defence, on scientific grounds (which is easy) and on ethical grounds (less so), ofthe randomised controlled clinical trial. The seventeen participants do not quite get round the awkward paradox set by the notion that there are two sorts of ethics in medicine, the collective and the individual-a dilemma that public health specialists will readily recognise. The answer provided is the familiar one: it is no less ethical in the face of uncertainty, to choose, on the basis of statistical methods than on hunches and experience. But some critics look at it differently. The scenario may seem old-fashioned but the patient says, or implies, "I am in your hands, what do you recommend"; and his physician thinks, and may even say, "Of possibilities A, B, and C there is no clear-cut choice, but for you at this time and at this hospital under my care I would on balance recommend ...". The following week, having agreed to take part in a trial, he would have to look in a coded envelope before deciding; and the patient and even his doctor may still not know what is in the tablets. If the patient is to surrender his right to participate in the treatment decision and his right to the doctor’s clinical judgment then we need a special style of informed consent-an important aspect of the problem, but one that the Ditchley Park conference deemed not "immediately relevant to the scientific/ ethical issues considered".
APPROPRIATE-TECHNOLOGY BLOOD COMPONENTS IN most parts of the developing world blood for transfusion is very scarce and the separate components are virtually unobtainable. Recruitment of donors meets ethnic, cultural, and educational barriers; many of those who do volunteer must be rejected because of malnutrition, malaria, or hookworm anaemia; and, even when recruited, donors are easily lost because of poor liaison. In developed countries, one of the prime activities of a blood-transfusion service is the harvesting of plasma and labile blood components. The aim is to collect over half the donations into multiple plastic packs for further processing. This is the system which developing countries usually try to copy; and they come to grief because the technology and infrastructure are lacking. There is also the enormous expense of refrigerated centrifuges, freezing cabinets, and skilled maintenance personnel. Yet, for lack of blood products, obstructed labour and postpartum hxmorrhage are likely to be fatal and people with severe haemophilia seldom live more than three years. Imported material is no answer: in some countries a bottle of imported albumin concentrate costs half the annual income of an average rural family. On p. 724 Dr Lovric and his colleagues describe a method which might cope with at least part of the demand for these blood components. A local supply, even a limited one, produced by this "appropriate technology", could be of immense value to the rural poor who cannot meet the expense of materials from outside.
1. Anon. The scientific and ethical basis of the clincal evaluation of medicines
1. Cherry
N, Waldron HA, Wells GG, Wilkinson RT, Wilson HK, Jones S. An
investigation of the
acute
behavioural effects of styrene
workers. Br J Indust Med 1980; 37: 234-40.
on
factory
Report of international conference, held as a guest conference at the Ditchley Foundations, Ditchley Park, England, 13-16 September 1979. Eur J Clin Pharmacol 1980; 18: 29-34. an
EFFECTS OF INHALED SOLVENT VAPOURS LARGE quantities of organic solvents are used in industry, especially where plastics are involved, yet we know very little about their effects on performance. Most of those now in general use have narcotic properties, but there is no convincing evidence that they have any harmful long-term effects; examples are trichlorethylene, 1,1,1-trichlorethane, toluene, xylene, and styrene (vinyl benzene). Good industrial practice calls for reduction in exposure to any of these to a minimum, on general grounds, but the case becomes even stronger if it can be shown that excessive exposure impairs productivity through the behavioural effects of the material. Cherry and co-workers’ have looked at men who were exposed to styrene used as a resin solvent in the building of glass-fibre boats. Their performance was compared, in behavioural tests at the beginning and end of the working day, with that of a non-exposed group. Exposure was measured from diffusion buttons, blood styrene concentrations were measured at the end of the working day, and all urine passed between the end of work and bedtime was collected and its content of mandelic acid (a metabolite of styrene) estimated. The exposed men were divided into a high blood styrene group (3-5pLmol/1) and low blood styrene group (5-4 mol/1). Cherry et al. found no convincing changes in most of the objective tests of performance, but those workers with high blood styrene reported greater subjective feelings of physical and mental tiredness at the end of the day, and had consistently slower reaction times, in both the morning and the afternoon. In all three groups, scores in the tests worsened through the day, but deterioration was greatest in the high styrene group. Cherry and co-workers do not claim that these findings afford strong evidence that styrene adversely affects performance. Slow reaction times and subjective tiredness may sometimes be factors in the causation of accidents, but productivity or the quality of the product are not necessarily affected. They point out that, with a constant level of atmospheric styrene, more will be absorbed by the people doing the heaviest physical work, and the tiredness described by the subjects could just as well be due to this as to high blood styrene; and they admit the possibility that none of the workers examined was exposed to sufficient styrene to produce acute effects on performance. Further similar studies, not only on styrene but also on other widely used organic solvents, would certainly fill a gap in current knowledge of industrial toxicology.
DEFENDING THE CONTROLLED TRIAL THE foundation of modern scientific therapeutics-the controlled clinical trial-will survive the attacks lately made upon it. It will take something considerably more penetrating than a West German decision no longer to demand such investigations for drug registration purposes or the doubts and musings of a few clinicians, lawyers, and professional
ethicists to diminish the status of this important scientific tool. All the same, clinical pharmacologists are sensitive to the criticisms, and a year ago they organised a select international gathering in Oxfordshire, the consensus from whichI is an excellent defence, on scientific grounds (which is easy) and on ethical grounds (less so), ofthe randomised controlled clinical trial. The seventeen participants do not quite get round the awkward paradox set by the notion that there are two sorts of ethics in medicine, the collective and the individual-a dilemma that public health specialists will readily recognise. The answer provided is the familiar one: it is no less ethical in the face of uncertainty, to choose, on the basis of statistical methods than on hunches and experience. But some critics look at it differently. The scenario may seem old-fashioned but the patient says, or implies, "I am in your hands, what do you recommend"; and his physician thinks, and may even say, "Of possibilities A, B, and C there is no clear-cut choice, but for you at this time and at this hospital under my care I would on balance recommend ...". The following week, having agreed to take part in a trial, he would have to look in a coded envelope before deciding; and the patient and even his doctor may still not know what is in the tablets. If the patient is to surrender his right to participate in the treatment decision and his right to the doctor’s clinical judgment then we need a special style of informed consent-an important aspect of the problem, but one that the Ditchley Park conference deemed not "immediately relevant to the scientific/ ethical issues considered".
APPROPRIATE-TECHNOLOGY BLOOD COMPONENTS IN most parts of the developing world blood for transfusion is very scarce and the separate components are virtually unobtainable. Recruitment of donors meets ethnic, cultural, and educational barriers; many of those who do volunteer must be rejected because of malnutrition, malaria, or hookworm anaemia; and, even when recruited, donors are easily lost because of poor liaison. In developed countries, one of the prime activities of a blood-transfusion service is the harvesting of plasma and labile blood components. The aim is to collect over half the donations into multiple plastic packs for further processing. This is the system which developing countries usually try to copy; and they come to grief because the technology and infrastructure are lacking. There is also the enormous expense of refrigerated centrifuges, freezing cabinets, and skilled maintenance personnel. Yet, for lack of blood products, obstructed labour and postpartum hxmorrhage are likely to be fatal and people with severe haemophilia seldom live more than three years. Imported material is no answer: in some countries a bottle of imported albumin concentrate costs half the annual income of an average rural family. On p. 724 Dr Lovric and his colleagues describe a method which might cope with at least part of the demand for these blood components. A local supply, even a limited one, produced by this "appropriate technology", could be of immense value to the rural poor who cannot meet the expense of materials from outside.
1. Anon. The scientific and ethical basis of the clincal evaluation of medicines
1. Cherry
N, Waldron HA, Wells GG, Wilkinson RT, Wilson HK, Jones S. An
investigation of the
acute
behavioural effects of styrene
workers. Br J Indust Med 1980; 37: 234-40.
on
factory
Report of international conference, held as a guest conference at the Ditchley Foundations, Ditchley Park, England, 13-16 September 1979. Eur J Clin Pharmacol 1980; 18: 29-34. an