SEQUESTERING AGENTS AND BILE SALTS

1023 weapon against many respiratory virus illnesses for which vaccines are unlikely to be successful. If the early promise of antitumour activity is fulfilled, a new series of powerful drugs will indeed be in prospect. a

TUBERCULOSIS IN THE LABORATORY THE life of the pathologist or bacteriologist is obviously less dangerous than that of a deep-sea diver Casual consideration suggests or a circus acrobat. that it is no more " nasty, brutish and short " than that of any other member of our profession. There 1 was some surprise, therefore, in 1957 when Reid pointed out that such statistics as were available to him indicated that the hospital pathologist and his assistants were about four times more likely to die of tuberculosis (and suicide) than those of comparable grades in the Post Office.I His evidence was certainly strong enough to justify concern, and an immediate result was a report2 from the Public Health Laboratory Service detailing practical measures to limit tuberculous infection in the laboratory. Since then there have been changes. There are fewer patients with tuberculosis, and fewer specimens from them reach the laboratory. Because of the range and complexity of the tests to which tubercle bacilli are now submitted, there has been a laudable tendency to concentrate this work in specialised institutions which have the experience and equipment to lessen the hazards. Nevertheless the danger still persists, and the Department of Health and Social Security has thought it wise to issue a revised edition3 of the P.H.L.S. report for general distribution. The changes are not extensive but they bring to light many details of methods which have been improved in the interval. It would be folly to offer employment in the laboratory to anyone who is tuberculin-negative. An X-ray of the chest should be taken at least annually, and this practice should include clerical as well as laboratory staff. The report might have included a word on the imperative need for the speedy reporting of accidents. The unwritten history of several laboratories holds stories of prolonged and fatal infections arising from such accidents as the slip of a hypodermic needle, not reported at the time from a sense of shame. Nowadays there can be few laboratories handling tuberculous material which do not make use of a ventilated cabinet for the operations which seem to be most dangerous. The directions for the care and maintenance of these in this report are not entirely for that matter, are the specifications of some of the models which are on the market. The essential is a continuous flow of clean air sufficient to carry any effluvia either through a filter or to the outside air under all circumstances. Since filters get clogged and electric motors fail, supervision and maintenance must get careful attention. Since such cabinets are desirable for work with many infectious parasites the Department might consider the issue of

satisfactory. Nor,

inclusive technical memorandum on their and use and offer some help in their maintendesign ance. Most of the other advice in this report is admirable, but the action to be taken when a centrifuge tube breaks while spinning seems casual. It is very well to say that " the bowl, bucket and contents " of the centrifuge are to be disinfected, but the methods are left to the imagination-and the line between disinfection and eyewash is thin. One difficulty for the authors of these reports is that the technical processes likely to disperse viable tubercle bacilli can only be guessed and have been identified by a-priori reasoning. The guesses seem sound, but they remain unproven. At the time of Reid’s inquiry there was a little evidence, numerically insufficient for serious consideration, that it was more dangerous to do a necropsy on a tuberculous patient than to examine his sputum. Experience leads to the suspicion that the postmortem-room porter has an especially dangerous job, and we hope that he is always included in the tally for an annual X-ray.

a

more

SEQUESTERING AGENTS AND BILE SALTS BILE salts are sterols of great physiological importance. They have both hydrophilic and hydrophobic groups which confer detergent properties, so they play a key part in fat absorption. They are excreted into the bile as glycine or taurine conjugates and in both man and laboratory animals the conjugated bile salts are actively reabsorbed in the ileum 1; but significant amounts of unconjugated bile acids are reabsorbed by passive diffusion in the human jejunum.2 The reabsorbed bile salts return via the portal blood to the liver whence, together with newly synthesised bile salts, they are re-excreted. This enterohepatic circulation is remarkably efficient. The normal bile-salt pool is about 4 g. and the total pool probably circulates about six times a day.Such bile salts as do escape to the colon undergo bacterial deconjugation and dehydroxylation and are reabsorbed to contribute to the bile-salt pool. Thus less than 5 % of the bile salts is lost in the faeces per cycle.4 Bile-acid synthesis is increased when there is interruption of the enterohepatic circulation, but the capacity of the liver to improve the bile-acid synthesis-rate is limited and is incapable of increasing beyond four to six fold.55 Loss of function in the terminal ileum, either through disease or surgical resection, causes a break in the enterohepatic circulation of the bile salts and a corresponding increase in bile-salt synthesis and turnover. Another result is the passage of large amounts of bile salts into the colon. For reasons which are not understood, bile salts in excess in the colon have a cathartic action, inhibiting water transport, stimulating mucus Thus severe secretion, and influencing motility. diarrhoea may result, cholegenic diarrhoea ", and the "

3.

Borgström, B., Lundh, G., Hofmann, A. F. Gastroenterology, 1963, 45, 229. Hislop, I. G., Hofmann, A. F., Schoenfield, L. J. J. clin. Invest. 1967, 46, 1070. Borgström, B., Dahlquist, A., Lundh, G., Sjovall, J. ibid. 1957, 36,

4. 5.

Meihoff, W. E., Kern, F. Jr. ibid. 1968, 47, 261. Hofmann, A. F. Gastroenterology, 1966, 50, 56.

1. 2.

1. Reid, D. D. Br. med. J. 1957, ii, 10. 2. Mon. Bull. Minist. Hlth Lab. Serv. 1957, 16, 64. 3. Precautions against Tuberculous Infection in the Diagnostic Labcratory. October, 1970. Department of Health and Social Security.

H.M.(70)60.

1521.

1024

syndrome has been called " cholerheic enteropathy ".6 The sequence of events in the cycle suggested that removal of bile salts from the colon might bring clinical improvement. So cholestyramine was used to treat this syndrome. Cholestyramine is a quaternary ammonium anion-exchange resin with a polystyrene polymer skeleton. As the chloride salt, it binds bile acids, exchanging chloride for bile acid, and thereby sequestering bile acids in the gut, preventing their reabsorption, and promoting their excretion.’7 It has proved useful in treating the pruritus of biliary obstruction. Cholestyramine has been given with great benefit to certain patients who had diarrhoea after ileal resection: although there was predictably an increase in fxcal fat, it was moderate and caused no difficulty.8 An unexplained observation is that when the length of ileum resected exceeded 100 cm. the patients failed to respond to

cholestyramine.

Another agent which, it has been claimed, absorbs bile acids is lignin, a substance found as a reinforcing fibre in plants. It is amorphous polymeric material formed by units which are phenylpropane derivatives.99 The absorbing action is thought to be due to hydrophobic bonding and the absorptive ability may increase with increased methylation of the hydroxyl moieties on the phenylpropane units in the lignin. Diarrhoea precipitated by small-bowel resection is reported to have stopped after the administration of lignin. 10 As some of the preparations of cholestyramine are unpleasant to take, the hope was that lignins would provide an acceptable alternative for sequestering bile salts. Unfortunately the latest news is that lignin may not be as effective as the earlier work indicated. In a comparison between cholestyramine and lignin given to patients with post-ileectomy diarrhoea, cholestyramine controlled the diarrhoea and lignin was less effective. Moreover lignin did not seem to bind significantly to conjugate bile salts.11-

IRRADIATION OF FOOD

THE safe preservation of food, drugs, cosmetics, and other materials in the environment presents difficulties. Certain products such as wood smoke, salt, sodium nitrate, sodium nitrite, sulphur dioxide, alcohol, and acetic acid have been used as preservatives for a long time and are widely considered as GRAS (" generally regarded as safe "), but this does not ensure that they Sodium nitrite with acetic acid are free from hazard. forms nitrous acid, which can deaminate cytosine residues of nucleic acid and act as a mutagen.12,13 Sodium bisulphite has now been shown to deaminate R.N.A.14 which suggests that sulphur dioxide and sodium bisulphite should be subjected to further

long-term biological

tests.

Hofmann, A. F. ibid. 1967, 52, 752. Tennent, D. M., Siegel, H., Zanetti, M. E., Kuron, G. W., Ott, W. M., Wolf, F. J. J. Lipid Res. 1960, 1, 469. 8. Hofmann, A. F., Poley, J. R. New Engl. J. Med. 1969, 281, 397. 9. Eastwood, M. A., Hamilton, D. Biochim. biophys. Acta, 1968, 152, 165. 10. Eastwood, M. A., Girdwood, R. M. Lancet, 1968, ii, 1170. 11. Heaton, K. W., Heaton, S. T., Barry, R. E. Advance Abstracts of 4th World Congress of Gastroenterology, 1970; p. 447. 12. Orgel, L. E. Adv. Enzymol. 1965, 27, 289. 13. Freese, E. in Molecular Genetics (edited by J. N. Taylor); vol. I, p. 207. New York, 1963. 14. Shapiro, R., Cohen, B. I., Servis, R. E. Nature, 1970, 227, 1047. 6. 7.

Heating, cooling, and exposure to light are physical preserving food and sterilising surgical instruments, domestic food containers, and other materials. Ionising radiations, either from the radiomethods of

cxsium-137 or from sophisticated and effective means food or instruments. The irradiation of

active elements cobalt-60

machines,

or

are more

of sterilising

special diets for patients particularly susceptible to infection has been used in Britain for some years. The uses of irradiation in this way and for the sterilisation of instruments have obvious advantages and there Sterilisation of food that may seems little risk. contain anaerobic bacteria requires doses of the order of 5 megarads. Irradiation to this extent changes the flavour of food; and meat treated in this way has been described as tasting of " wet dog ". It is thought that some canned meat sterilised by this means has been issued to American armed forces. Smaller doses of about 100,000 rads increase the " shelf life" of foods and have been called " pasteurisation doses ". Treatment of this kind could be of value in increasing the availability of fruit, vegetables, meat, and other

perishable products. Atomic-energy authorities in many countries are anxious to find peaceful uses for radioactive materials, and the treatment of food seems a good outlet. There has thus been some pressure to use these methods and much effort has been expended, but many of the biological experiments which, it was hoped, would justify the use of irradiated food were badly planned and performed. The main hazards expected from irradiated food seem to be mutagenicity and carcinogenicity. Unfortunately the chemical changes brought about in food are not sufficiently understood to make biochemical interpretation of the effects possible. Some experiments 16 have shown that irradiated food and food components have mutagenic and cytotoxic properties under in-vitro conditions. There is no positive evidence that any irradiated food or food component is carcinogenic, but few have been effectively tested.

Doses of 10,000 to 75,000 rads to food will control infestation by insects in stored grain and in groundwheat products and prevent sprouting of certain vegetables, particularly potatoes and onions. An expert committee xe has recommended the temporary acceptance of irradiation of wheat and wheat products, with doses up to 75,000 rads and of potatoes and onions with doses up to 15,000 rads. The biological data on onions were unsatisfactory, partly because a high intake of onions, irradiated or not, was toxic to the animals. These irradiation procedures have been used in countries without producing any toxic effects. Even though the chemical changes are unknown, irradiation is probably less dangerous than chemical additives used to produce the same effects. The publication of the W.H.O. report 16 might lead to increased use of ionising radiations in the foodprocessing and other industries. some

15. Schubert, J. Bull. Wld Hlth Org. 1969, 41, 873. 16. Tech. Rep. Ser. Wld Hlth Org. 1970, no. 451. Wholesomeness of Irradiated Food, with special reference to Wheat, Potatoes, and

Onions.