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In one of his last research projects, Sir Hans Krebs showedwith his co-workers that the antifungal action of benzoateoccurs only in an acidic environment and is due to acidi-fication of the cell interior. The detailed mechanism is asfollows. The yeast cell membrane is permeable to undis-sociated 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 outsidebecome equal. However, neutralisation of the undissociatedform within the cell causes a shift of the pH of the intracel-lular water. A change of more than 1 pH unit occurs at ben-zoic acid concentrations that are used in food preservativesand antifungal therapy. This is sufficient to inhibit one of themany enzymes in the fermentation pathway, phosphofructo-kinase, causing an accumulation of fructose-6-phosphatewhich is the substrate for this enzyme. Intermediates beyondthe stage of phosphofructokinase decrease and, as a result,ATP falls, thus restricting yeast growth. This mechanismexplains the efficacy of Whitfield’s ointment, containing 6%benzoic acid and 3% salicylic acid (as free acids)-a remedydevised empirically by Whitfield.Other acids with antifungal effects include salicylic acid,

medium-chain saturated and unsaturated fatty acids, sorbicacid, and undecylenic acid; these likewise cause an acidifica-tion of intracellular water. Their common features are a

lipophilic undissociated form, a hydrophilic anion, and a pKvalue that cause the acid to be present in extracellular water,partly in the undissociated form. Under these conditionsneutralisation by intracellular buffers causes acidification ofthe cell, inhibition of a key enzyme of fermentation, andsubsequent restriction of yeast growth. Perhaps this informa-tion on the oldest known antifungal agent will help in thesearch for new and more specific remedies.

MAN-MADE MINERAL FIBRES—A SAFEALTERNATIVE TO ASBESTOS?

A MAJOR obstacle to control of occupational carcinogensarises from the long latent period between exposure andeffect. This means that assessment of the present levels of riskto man must invariably be based on past exposures. Theargument 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 occupationaldiseases are identified in industries with long exposurehistory, and when people argue for stricter control of thoseindustries. ,

If evidence that a new material is carcinogenic is clear onlymany years after exposure, how can we hope to definesensible control limits? The question arises with man-mademineral fibre (MMMF). The materials, which constitute themain alternatives to asbestos, include "mineral wool" and"fibrous glass", as well as fine or very fine glass fibre. In viewof the asbestos story, one might at first think that anyalternative must be safer. However, because the risksassociated with asbestos exposure seem to reflect physicalrather than chemical properties, MMMF needs urgentscrutiny. In 1976 an international workshop, convened atthe WHO Regional Office for Europe in Copenhagen, was

7 Krebs HA, Wiggins D, Stubbs M, Sols A, Bedoya F. Studies on the mechanism of theantifungal action of benzoate. Biochem J 1983, 214: 657-63.

told of a programme of research to be supported andcoordinated by the Joint European Medical Research Board.A scientific and technical committee was formed. Therecommended programme of research included detailedenvironmental surveys of manufacturing plants,development of methods for assessing fibrous dusts, studiesof patterns of mortality and morbidity of employees exposedto MMMF, animal studies on the digestion and eliminationof fibres and their fibrogenic and oncogenic effects, andexplication 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 possiblehazards. The meeting aimed to provide the best possibleassessment of current scientific knowledge of the biologicaleffects of MMMF and of what further research should berecommended.

It emerged from the conference that exposure to MMMFduring its manufacture and use is generally low comparedwith exposure to asbestos. Health has not been affected to a

readily detectable extent, with the exception of transient skinand upper respiratory irritation. On the other hand, somepossible long-term effects were reported that had not beenrecognised before, either because they had not been lookedfor or because previous methods had not been sufficientlysensitive to detect them. The uncertainty attached to thefindings of mortality studies is epitomised by the statementthat "... there is as yet insufficient evidence from mortalitystudies reported at the Conference to establish that MMMFare innocent; nor are there sufficient data to establish

confidently that exposure to MMMF production plants hasan effect on mortality". Few people have been studied thirtyor more years after first employment with MMMF. In theEuropean study there were 17 deaths from lung cancer in thisgroup compared with 8’87 expected. While the 95% con-fidence limits on the standard mortality ratio (from 110 to296) excludes 100, the mortality could be raised onlymarginally; and, if so, the excess might be explained byconfounding factors such as cigarette smoking patterns. Themeeting heard that there was still no evidence of clinicallyimportant respiratory disease in workers exposed long term.Also, work in animals had revealed no hazard ofmesothelioma from inhalation of ordinary types of

MMMF-possibly because of their higher solubility thanthat of asbestos.The procedures for developing this collaborative research

programme are encouraging. The scientists have largelypreserved their status as independent researchers-

something that has not always been possible in the sphere ofoccupational cancer. The parallel to asbestos should,however, serve as a warning. The recommendations forextending the research programme should be taken veryseriously, as should the preliminary evidence of long-termeffects in man. While the evidence for high risk is not strong,we might ask whether the evidence regarding the carcino-genicity of asbestos would have been any stronger if it hadbeen based on similar studies of men exposed to similarconditions. We are assured that, for the men studied,exposure to MMMF "was generally low to very low". Thoseconcerned with industrial hygiene would be wise, none-theless, to consider enforcing even higher standards.

1. WHO/IARC Biological effects of man-made mineral fibres. Report on a World HealthOrganisation and International Agency for Research on Cancer Meeting (EURORep Studies 81). Copenhagen: WHO, 1983.