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MAN-MADE MINERAL FIBRES—A SAFE ALTERNATIVE TO ASBESTOS?
1125
In one of his last research projects, Sir Hans Krebs showed with his co-workers that the antifungal action of benzoate occurs only in an acidic environment and is due to acidification of the cell interior. The detailed mechanism is as follows. The yeast cell membrane is permeable to undissociated benzoic acid, but impermeable to the benzoate ion. In an acidic medium the undissociated form predominates, and enters the cell until the concentrations inside and outside become equal. However, neutralisation of the undissociated form within the cell causes a shift of the pH of the intracellular water. A change of more than 1 pH unit occurs at benzoic acid concentrations that are used in food preservatives and antifungal therapy. This is sufficient to inhibit one of the many enzymes in the fermentation pathway, phosphofructokinase, causing an accumulation of fructose-6-phosphate which is the substrate for this enzyme. Intermediates beyond the stage of phosphofructokinase decrease and, as a result, ATP falls, thus restricting yeast growth. This mechanism explains the efficacy of Whitfield’s ointment, containing 6% benzoic acid and 3% salicylic acid (as free acids)-a remedy devised empirically by Whitfield. Other acids with antifungal effects include salicylic acid, medium-chain saturated and unsaturated fatty acids, sorbic acid, and undecylenic acid; these likewise cause an acidification of intracellular water. Their common features are a lipophilic undissociated form, a hydrophilic anion, and a pK value that cause the acid to be present in extracellular water, partly in the undissociated form. Under these conditions neutralisation by intracellular buffers causes acidification of the cell, inhibition of a key enzyme of fermentation, and subsequent restriction of yeast growth. Perhaps this information on the oldest known antifungal agent will help in the search for new and more specific remedies.
MAN-MADE MINERAL FIBRES—A SAFE ALTERNATIVE TO ASBESTOS? A MAJOR obstacle to control of occupational carcinogens arises from the long latent period between exposure and effect. This means that assessment of the present levels of risk to man must invariably be based on past exposures. The argument that cases of cancer arising today reflect the appalling conditions prevalent in the past, and not the "safe" environment of today, is heard regularly when occupational diseases are identified in industries with long exposure history, and when people argue for stricter control of those
industries.
,
If evidence that a new material is carcinogenic is clear only many years after exposure, how can we hope to define sensible control limits? The question arises with man-made mineral fibre (MMMF). The materials, which constitute the main alternatives to asbestos, include "mineral wool" and "fibrous glass", as well as fine or very fine glass fibre. In view of the asbestos story, one might at first think that any alternative must be safer. However, because the risks associated with asbestos exposure seem to reflect physical rather than chemical properties, MMMF needs urgent scrutiny. In 1976 an international workshop, convened at the WHO Regional Office for Europe in Copenhagen, was
told of a programme of research to be supported and coordinated by the Joint European Medical Research Board. A scientific and technical committee was formed. The recommended programme of research included detailed environmental of manufacturing plants, surveys development of methods for assessing fibrous dusts, studies of patterns of mortality and morbidity of employees exposed to MMMF, animal studies on the digestion and elimination of fibres and their fibrogenic and oncogenic effects, and explication of their physical and chemical properties in vitro. A second meeting was held in Copenhagen in April last year, and the report has just been published.’ This meeting, attended by scientists and representatives of government, industry, and labour discussed evidence on the possible hazards. The meeting aimed to provide the best possible assessment of current scientific knowledge of the biological effects of MMMF and of what further research should be recommended. It emerged from the conference that exposure to MMMF during its manufacture and use is generally low compared with exposure to asbestos. Health has not been affected to a readily detectable extent, with the exception of transient skin and upper respiratory irritation. On the other hand, some possible long-term effects were reported that had not been recognised before, either because they had not been looked for or because previous methods had not been sufficiently sensitive to detect them. The uncertainty attached to the findings of mortality studies is epitomised by the statement that "... there is as yet insufficient evidence from mortality studies reported at the Conference to establish that MMMF are innocent; nor are there sufficient data to establish confidently that exposure to MMMF production plants has an effect on mortality". Few people have been studied thirty or more years after first employment with MMMF. In the European study there were 17 deaths from lung cancer in this group compared with 8’87 expected. While the 95% confidence limits on the standard mortality ratio (from 110 to 296) excludes 100, the mortality could be raised only marginally; and, if so, the excess might be explained by confounding factors such as cigarette smoking patterns. The meeting heard that there was still no evidence of clinically important respiratory disease in workers exposed long term. Also, work in animals had revealed no hazard of mesothelioma from inhalation of ordinary types of MMMF-possibly because of their higher solubility than that of asbestos. The procedures for developing this collaborative research programme are encouraging. The scientists have largely preserved their status as independent researcherssomething that has not always been possible in the sphere of occupational cancer. The parallel to asbestos should, however, serve as a warning. The recommendations for extending the research programme should be taken very seriously, as should the preliminary evidence of long-term effects in man. While the evidence for high risk is not strong, we might ask whether the evidence regarding the carcinogenicity of asbestos would have been any stronger if it had been based on similar studies of men exposed to similar conditions. We are assured that, for the men studied, exposure to MMMF "was generally low to very low". Those concerned with industrial hygiene would be wise, nonetheless, to consider enforcing even higher standards. 1. WHO/IARC
7 Krebs
HA, Wiggins D, Stubbs M, Sols A, Bedoya F. Studies on the mechanism of the antifungal action of benzoate. Biochem J 1983, 214: 657-63.
Biological effects of man-made mineral fibres. Report on a World Health Organisation and International Agency for Research on Cancer Meeting (EURO Rep Studies 81). Copenhagen: WHO, 1983.
In one of his last research projects, Sir Hans Krebs showed with his co-workers that the antifungal action of benzoate occurs only in an acidic environment and is due to acidification of the cell interior. The detailed mechanism is as follows. The yeast cell membrane is permeable to undissociated benzoic acid, but impermeable to the benzoate ion. In an acidic medium the undissociated form predominates, and enters the cell until the concentrations inside and outside become equal. However, neutralisation of the undissociated form within the cell causes a shift of the pH of the intracellular water. A change of more than 1 pH unit occurs at benzoic acid concentrations that are used in food preservatives and antifungal therapy. This is sufficient to inhibit one of the many enzymes in the fermentation pathway, phosphofructokinase, causing an accumulation of fructose-6-phosphate which is the substrate for this enzyme. Intermediates beyond the stage of phosphofructokinase decrease and, as a result, ATP falls, thus restricting yeast growth. This mechanism explains the efficacy of Whitfield’s ointment, containing 6% benzoic acid and 3% salicylic acid (as free acids)-a remedy devised empirically by Whitfield. Other acids with antifungal effects include salicylic acid, medium-chain saturated and unsaturated fatty acids, sorbic acid, and undecylenic acid; these likewise cause an acidification of intracellular water. Their common features are a lipophilic undissociated form, a hydrophilic anion, and a pK value that cause the acid to be present in extracellular water, partly in the undissociated form. Under these conditions neutralisation by intracellular buffers causes acidification of the cell, inhibition of a key enzyme of fermentation, and subsequent restriction of yeast growth. Perhaps this information on the oldest known antifungal agent will help in the search for new and more specific remedies.
MAN-MADE MINERAL FIBRES—A SAFE ALTERNATIVE TO ASBESTOS? A MAJOR obstacle to control of occupational carcinogens arises from the long latent period between exposure and effect. This means that assessment of the present levels of risk to man must invariably be based on past exposures. The argument that cases of cancer arising today reflect the appalling conditions prevalent in the past, and not the "safe" environment of today, is heard regularly when occupational diseases are identified in industries with long exposure history, and when people argue for stricter control of those
industries.
,
If evidence that a new material is carcinogenic is clear only many years after exposure, how can we hope to define sensible control limits? The question arises with man-made mineral fibre (MMMF). The materials, which constitute the main alternatives to asbestos, include "mineral wool" and "fibrous glass", as well as fine or very fine glass fibre. In view of the asbestos story, one might at first think that any alternative must be safer. However, because the risks associated with asbestos exposure seem to reflect physical rather than chemical properties, MMMF needs urgent scrutiny. In 1976 an international workshop, convened at the WHO Regional Office for Europe in Copenhagen, was
told of a programme of research to be supported and coordinated by the Joint European Medical Research Board. A scientific and technical committee was formed. The recommended programme of research included detailed environmental of manufacturing plants, surveys development of methods for assessing fibrous dusts, studies of patterns of mortality and morbidity of employees exposed to MMMF, animal studies on the digestion and elimination of fibres and their fibrogenic and oncogenic effects, and explication of their physical and chemical properties in vitro. A second meeting was held in Copenhagen in April last year, and the report has just been published.’ This meeting, attended by scientists and representatives of government, industry, and labour discussed evidence on the possible hazards. The meeting aimed to provide the best possible assessment of current scientific knowledge of the biological effects of MMMF and of what further research should be recommended. It emerged from the conference that exposure to MMMF during its manufacture and use is generally low compared with exposure to asbestos. Health has not been affected to a readily detectable extent, with the exception of transient skin and upper respiratory irritation. On the other hand, some possible long-term effects were reported that had not been recognised before, either because they had not been looked for or because previous methods had not been sufficiently sensitive to detect them. The uncertainty attached to the findings of mortality studies is epitomised by the statement that "... there is as yet insufficient evidence from mortality studies reported at the Conference to establish that MMMF are innocent; nor are there sufficient data to establish confidently that exposure to MMMF production plants has an effect on mortality". Few people have been studied thirty or more years after first employment with MMMF. In the European study there were 17 deaths from lung cancer in this group compared with 8’87 expected. While the 95% confidence limits on the standard mortality ratio (from 110 to 296) excludes 100, the mortality could be raised only marginally; and, if so, the excess might be explained by confounding factors such as cigarette smoking patterns. The meeting heard that there was still no evidence of clinically important respiratory disease in workers exposed long term. Also, work in animals had revealed no hazard of mesothelioma from inhalation of ordinary types of MMMF-possibly because of their higher solubility than that of asbestos. The procedures for developing this collaborative research programme are encouraging. The scientists have largely preserved their status as independent researcherssomething that has not always been possible in the sphere of occupational cancer. The parallel to asbestos should, however, serve as a warning. The recommendations for extending the research programme should be taken very seriously, as should the preliminary evidence of long-term effects in man. While the evidence for high risk is not strong, we might ask whether the evidence regarding the carcinogenicity of asbestos would have been any stronger if it had been based on similar studies of men exposed to similar conditions. We are assured that, for the men studied, exposure to MMMF "was generally low to very low". Those concerned with industrial hygiene would be wise, nonetheless, to consider enforcing even higher standards. 1. WHO/IARC
7 Krebs
HA, Wiggins D, Stubbs M, Sols A, Bedoya F. Studies on the mechanism of the antifungal action of benzoate. Biochem J 1983, 214: 657-63.
Biological effects of man-made mineral fibres. Report on a World Health Organisation and International Agency for Research on Cancer Meeting (EURO Rep Studies 81). Copenhagen: WHO, 1983.