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FILE NAME: Sprayed Asbestos (SPRA) DATE: 1953 July DOC#: SPRA012 DOCUMENT DESCRIPTION: Medical Journal Article - The Prevention of the Dust Diseases -im lancet] ORIGINAL ARTICLES [july 11, 1953 In 1912 an excellent translation of this hook was made by ^ THE PREVENTION OF, THE DUST Herbert Hoover, a mining engineer, and his wife. This DISEASES * A. I. G. McLaughlin , M.D. Sydney, F.R.C.P. H.M. MEDICAL INSPECTOR OF FACTORIES sir Malcolm Morris, who was on the staff of St. Mary's Hospital for over 20.years, was a pioneer in public health as well as being a great dermatologist. In the galaxy of great names for which the hospital is notable, he holds a high place and his contributions both to dormatology and publio health are of enduring value. It is oomrnon knowledge th at dermatitis causos more eases of ill health aud lost time in industry than any of the other diseases of occupation. But it can bo said that tlio , diseases of the lungs caused by dust are inoro dangerous than the industrial dermatoses. The pneumoconioses . often cause death, whereas skin lesions, though they are 1 disabling, are rarely fatal. Again, the lung diseases caused by dust are harder to diagnose, and in the early stages at least they give no outward sign of the patho l logical process going on inside the chest. A disease of the skin has this advantage, that it can be seen, even by the novice, as soon as it appears. But the pneumo conioses come on like a thief in the night, or rather, like a thief who plies his trade for days, nights, and years before he is finally caught. And by that time the damage is done. It is like closing tho stable door after the horse 'M itsostcololesne.,thIendtdroyrinwghtioleptrheevehnotrtsheeisdusstitlldiisneatshees wsteabalime; or while1the man is still in good health. And in this discourse, I shall describe some of tho ways in which was tho same Herbert Hoover, who later became President of the United States. But the outstanding name among the early doctors was Bernardino Ramazzini, an Italian who in 1700 published tho first textbook {Be Morbia Artificum) on occupational dlseasoB, based on first-hand observations of varied occupations and tho maladies which arise from them. Ramazzini is justly called the father of occupa tional medicine; and it was ho who taught that when seeing a patient for the first time one should not only ask him where his pain is, but what his job is.j' Even today tliore are doctors who do not got details of their patients' occupations. Ramazzini quotes the account of the uooropsioa oarried out in 1049 by Diomorbroock on stone cutters, " in whose lungs lio found Buch heaps of sand, that in running the knife through tho pulmonary vesicles he thought he was cutting some sandy body." This is tlio first account of the pathology of silicosis, as it is now called. In spite of this, the earlier doctors confused tho dust fibroses of the lungs with tuberculosis. But we have to bear in mind that the tubercle bacillus was not dis covered until 1882, and that the study of pathology was not put on a firm basis until the early part of the 19th century. As a point of historical interest, it might be added that Sir Malcolm Morris was present at the first demonstration of the tubercle bacillus iu Koch's laboratory in Berlin in 1882 (Lancet 1924). The 19th century was notable for the rise of the idea that inhalation of large quantities of dust of any kind can damage the lungs hut that some dusts are more harmful than others. It was our first great English writer on the occupational diseases who emphasised this. He we are trying to close the door. was Charles Turner Thackrah, a doctor in Leeds who in Historical 1831 published his hook on the Effecte of Arts, Trades and Professions. The title goes on--" and of civic states and if Before dealing with the prevention of the pneumo- habits of living on health and longevity, with suggestions oonioses, I ought to say something about them. For, for the removal of many of the agents which produce in order to prevent a disease, it is obvious that one must disease, aud shorten the duration of life." He noted that first know that it exists, and the causes of it. bricklayers and limeworkors were long-lived and that * To us in the 20th century it may seem strange that at sandstone masons usually died before they reached the > any time it was not known th at dust, w h eu inhaled into age of 40. But he was not quite clear in his mind how the lungs, could damage them. But it took a long time before this fact was established, and though the history I Rnmazzim's motto was " Modiei menus plebeios curantis est interrogare rjuas artos oxorceant.M of the pneumoconioses goes back as far as Hippocrates (about 400 B.C.) and perhaps earlier, they were not charted with accuracy until about 30 years ago. Even TABLE I -- DUST DISEASES OF THE LUNGS pow there is a great deal to be learned about them. Progress iu knowledge is usually associated with great names; hut one should not forget those workers who made no great splash in history. Tho building-up of knowledge has been likened to a coral island, into tho ` formation of which go the lives of many individual Ho ' organisms. So it is with our knowledge of the occupational ' diseases. One of the great names iu occupational medieiue, an,' after Hippocrates, was Paracelsus, also called Bombast. .est , He, in 1530, published a bonk on industrial diseases in um which he described the chronic lung diseases of miners as pulmonary consumption and asthma. He thought that these diseases were due mainly to the influence of the Diseases 1. Chronic fibroses 2, Aot pneumon itis, oedema and/ or bronchiolitis 3. Asthma Dust or fumo Silica Asbestos Coul Talc Bauxite uud corundum Beryllium 5 * : i a Vanadium xidea Bagodsc (sugar-cane) Wood (e.g., Western red cedar) Varietios Silicosis Asbestos Is Coal pneumoconiosis Talo pneumoconiosis Shaver's disease Beryllium . granulomatosis Manganese pneumonia Beryllium pneumon itis &c. Bagassosls . astral bodies, but he added that the " climate of the mines might have something to do with them. I daresay f that in writing about the climate he included dust as one of the possible causes, hut he did not say so. The next Seeds Grain Feathers Wool Doublo aalta.of platinum 'great name was Georgius Agricola who, in a book called Gum acacia E i lie Metallica (1558), said that the inhalation of MOOITOBlve " dusts predisposed worker to a diwense characterised by exhaustion, coughing, and " that difficulty of breathing which the Greeks called asthma." 4, ('amor AramioOhroinattvs Mickel carbonyl (f) AflbeBtos Radioactivo emanations ( Based on the Malcolm Morris memorial lecture given under the auspices of the Chadwick Trust at St. Mary's Hospital, . London, on Dec. 9, 1952. 6778 5. Chronic bronchitis Cotton and emphysema Flax aud other dusts Byssinosis B i 5 0 3HE lancet] ORIGINAL ARTICLES much the taking of alcohol had to do with these pulmon ary diseases. He was against alcohol (in the same way th at President Coolidge was against sin) and no doubt he had good reason to be, because it was quite cheap in those days. ' . Two other great English names in the history of the pneumoconioses are T. B. Peacock and E. H. Greenliow. Peacock, a physician on the staff of St. Thomas's Hospital, first established between I860 and 1800 the existence of "miners' disease as an entity and distinguished it clinically from pulmonary tuberculosis. Greenliow (1860, 1861), who was attached to the Middlesex Hospital, carried out the first largo field investigation into the dusty industries such as the potteries, metal trades, cutlery making, tin and copper mining, coal-mining, lead mining, cotton, flax, Bilk and woollen manufacture, hosiery ami lace making, glove-making, and agriculture. In the 'Transactions of the Pathological Society of London (1860-00) are to be found excellent clinical and pathological descriptions by both these doctors of the disease which was later to be called silicosis by Visconti in 1870. They even found the dust of free silica in the lungs and examined it under polarised light. For about 40 years after this excellent work nothing much was done about the dust diseases. But with the turn of the century a new interest began to be taken in F i g , I---D u st o f q u a rt o r fro o tiiie a show ing c ry sta llin e s tr u c tu r e ( x 450). the problem, not ouly in this country, but also in other parts of the world. It is significant that about the same time there was a quickening of the tempo of life in general. The horse began to give way to the motor-car, and soon there came the first aeroplane. Then too there was the telegraph and the telephone and all those " comforts '' of present-day life which give us little or no time to think. In the factories and in the mines, there was a speeding-up of output. Hand labour began to be replaced by the machine. In the cotton industry the change had come a little earlier. But the air-hammer or the pneumatic tool began to be used more extensively in the early part of the century for such jobs as mining, quarrying, and the cleaning of castings in foundries. There is also the ( spray gun, which is used to 6pray paint, glazes, metals, j and asbestos, and was introduced with the idea of j speeding up the work. This, from a health point of view, I is a dangerous instrument, because it is very difficult | to control the spray and to prevent its inhalation by the I workers. If there is one thing certain about increased speed of production in industry, it is that a dusty process will become more dusty ; and that there will be a greater incidence of the dust diseases, if attention is not given at the same time to increased control of dust. But quite Fig. 2--Q u a rtz crystals and ag g reg ates o f iro n oxide fum e (la rg e black i a re a s ) In a fo u n d ry d u s t cloud ( x 1000). . often the efforts at dust control are inadequate and do not keep pace with the increased speed of production. For instance, silicosis and silico-tuberculosis did not become a problem in haematite mining until the intro duction of the pneumatic drill. Stewart and Faulds (1031) say th at luematile mining has been carried on in Cumberland since the timo of the Homan occupation. " It was formerly considered a healthy trade, but evidence is accumulating to show that in this respect a definite change for-the worse has taken place. The miners themselves believe that the trouble started with the introduction of the dry mechanical drill in 1013." Previously the ore bad been obtained by the old " hammer and jumper " method. Meiklejohn (1951, 1052a and b), in liis history of lung diseases of coalminers in Great Britain, points out that mechanical cutting and conveying of coal was introduced early in the present century. The change from hand cutting of coal led to an increased dustiness of the air iu the mines, not only at tile coal face but generally through-, out the workings. He quotes 1I.M. Chief Inspector off Mines (Bryan 1950) as saying : " There is no doubt that one result of the adoption of many of the present methods of machine mining is that the production of dust in mines lias increased in recent years and is still increasing. If we are to get rid of the scourge of pneumoconiosis, this process must be reversed." MeCallum (1052) also thinks that mechanised coal-getting lias increased the prevalence of pneumoconiosis in the Durham coalfield and 11that future developments in the coalfield will intensify dust production and tlie risks of pneumoconio sis unless dust suppression methods are considerably extended." F if. 3--D u it of d ia to m a c .o u , e a r th o r k ia ia lg u h r ; a non-cry,tallinC , , fo rm of freo ofIlea ( x 300). 1 J 2* * <c e t ] ORIGINAL ARTICLE8 [July 11, 1953 51 je use of the pneumatic tool instead of hand methods . the fettling of steel castings has also increased the isk ofsilicosis in this occupation {McLaughlin et al. 1950). Dust and Dust Diseases It is commonly thought that the dust diseases are confined to a small group of fibroses of the lung caused by the inhalation of inorganic dusts such as silica, asbestos, and coal. That this is not so was clearly shown by Collis in liis Milroy lectures in 1915. Ho pointed out that au excessive mortality from all respiratory diseases was experienced by dwellers in dusty atmospheres, an excess which increases with age und with the amount of dust present. In Loudon al that time 050 tons of dust a year came down over a square mile, whereas in an agri cultural district it was 195 tons, a figure which is big enough In all conscience. It is interesting to note also, that the inorganio content of the lungs, which largely comes from inhaled dust, also increases with age, Radio logists sometimes have difficulty in distinguishing in chest films the shadows thrown by dust deposits from the abnormal shadows seen in films of old people. It does not often occur to them that tho changes associated with age might in fact he partly or even mainly caused by dust deposits in the lungs. The types of pulmonary disease caused by dust are shown in table i. Fi|< Dut of tale o r F ren ch chalk, com p o t ad o f plat and a mall ' \ p ro p o r tio n q f fibre ( x 1060). ,w' Ttf Tvill he seen th at these diseases fall into five broad groups i chronic fibrosis; acute pneumonia, oedema, and bronchiolitis ; asthma ; cancer ; and chronio bronchitis and emphysema. There is also a sixth group which hardly comes under the heading of diseaso--namely, tho abnormal X-ray appearances seen In those workers who have been inhaling the radio-opaque dusts such as iron or its oxides (Biderosis), barium (baritosis), tiu (stannosis), and emery. Such cates usually present au abnormal X-ray picture without clinical evidence of disease or disability. Even these six groups do not complete the list, but it will he enough to show that a wide range of pulmonary diseases can be caused by the inhalation of dust, which may he both organic and inorganic. It should be remembered, too, that dusts can convey infections such as anthrax and tuberculosis, and indeed pulmoi^ry anthrax (wool-sorters' disease) is a well- defined occupational malady, now fortunately rare in ' ius country. 4 .. Dusts and Fumes Tg understand the dust diseases it is necessary to know a good deal about the chemical and physical properties of dusts and fumes, the behaviour of dust clouds, and he reaction between them and the tissues of tho respira tory tract. Intensive research during the past 91 years Fig. S---D ut cloud fro m bestos b o a rd in g bow ing bosto (fibres) ' and a m o rp h o u s c e m e n t d u s t ( 150). has given us a great deal of information on these matters, and a few points may bo mentioned here. Both dusts and fumes are composed of particles which, when airborne, can he inhaled into the lungs. Dusts, which may be organic and inorganic (or animal, vegetable, and mineral) are mechanically formed by vigorous action such as grinding, rubbing, crushing, drilling, hammering, and sawing, and in general are of the same chemical composition as the substances from which they come. Fumes (the term Is often used incorrectly) are the result of condensation of particles from the gaseous state, and in industry are usually the oxides' formed from hot or boiling metals. Iron oxide, for instance, when it comes hot off the welding are is a fume, hut when it is in the form of rust knocked oft' an iron girder it is a dust. In a dust cloud (fig. 1) the particles remain separate, hut in a fume they tend to flocculate and form large masses composed of very small particles. It has been shown that most of the particles of dust or fume which get into tho lung tissue are about 3 p or less in diameter, and it is often assumed that anything larger cannot get into the alveoli. But these structures measure up to 100 p across and there seems to he no reason why particles much larger than 3 p cannot get into them. The factor which determines the size of dust particles found in the lungs is tho diameter of the lymphatic channels, through which they are taken by phagocytes. It is true, however, that many of tho larger particles are trapped in the nose and the upper respiratory passages. Fig. 6--L e a th e r dut c o m p o u d m ain ly o f non*strlpd m iiicU -flbr (<1M0) 52 vu m l a n o k t] OBIQINAL ARTICLES [JULY 11, 1953 TABLE XI-- DEATH FROM ALL TYPES OF PNEUMOCONIOSIS IN ENGLAND AND WALES 1040-51 f- " Industry 1940 1941 1942 1943 1944 1946 1946 1947 1948 1940 1950 1951 Totals 1 Potteries .. .. .. 53 45 47 41 32 41 49 54 48 63 73 02 608 Sandstone .. .. . . 109 69 54 77 57 65 61 55 68 51 29 71 779 Grinding ot m etals, See, . . 41 26 26 21 24 22 32 27 26 37 22 21 325 Refractories ,. ., 16 12 7 7 6 9 g 10 13 13 8 a 117 j Miscellaneous Coalmining .. .. .. 7 . . 232 5 7 5 196 230 270 13 311 19 3S7 14 421 20 577 27 639 25 756 70 840 129 937 347 5308 ! Other mining .. .. 64 40 46 43 39 40 51 50 49 64 42 51 579 Asbestos .. ., ,. 11 17 n g 10 11 16 15 15 17 12 18 161 Cotton (byasluosls) ,, 6 7 1 1 3 4 a 7 11 s 05 ; 533 423 434 485 493 604 055 81g 893 1033 1113 ' 13U5 8789 Npn-ocoupational .. . . 650 461 443 493 531 529 503 CIO 051 554 7) 732 0907 Fnoh dust oluud Las its uwu eharuotorislio appearance uudor tlm miorosenpe. In fig. 1 is shown dm dust of quurtz or free silica, it is composed of small crystals which romain separate in the dust cloud. l!y contrast, the appearance of iron oxide fume h shown in lig. 2. The large black masses are made up of hundreds of small particles. Fig. 3 shows the microscopic appearances of kieselguhr or diatomite, a lion-crystalline form of free silica. Fig. 4 shows the dust of talc or French chalk, which is composed of plates and a few libres, while in fig. 5 asbestos dust is seen to be made up mainly of fibres. Leather dust is shown in fig. 6 to bo made up of non8triped muscle-fibres ; wood dust (fig. 7) has characteristic transverse striatious. The Body's Defence Mechanisms Against Dust If a man's lungs are healthy they can deal with a good deal of dust or fume without becoming damaged. The body's defence mechanisms against dust are briolly ; (a) the vibrissaj of the nose, which uet as a partial filter for the larger particles ; (b) the mucous secretions of the nose and the upper respiratory passages, in which a large proportion of the particles is trapped and then expelled by (c) the wave-like action of tho cilia of the nasal and bronchial epithelium. Below the respiratory bronchioles, whore there are no cilia, (<l) the phagocytes come into play. They engulf the dust panicles ami take them up to the area of ciliary action, or into the lung lymphatics. Recent work has cast doubt on'the hypo thesis that dust is taken into the lung parenchyma by phagocytic action, but the fact remains that dust does get into the luugs, whatever may be tbe exact method of locomotion. . Tbe concentration of dust which can bo inhaled without danger varies according to the nature of the dust and also to the length of time that a man is breathing it. Again, the intermittent exposure to high concentrations of dust may be more dangerous than exposure to lower concen trations over a longer period. The harder the job is, the more deeply will a man have to bieatho, and in conse- tjucncc 1m will breathe more dust. Individuals, tuu, var ;' greatly in tlmir capacity to deal with dusts, and of tw men who have been working at ihe same job for U$ same length of time one may get a disease of the bin and the other may bo unaffected. This is one reason wlf 1 am not greatly impressed by the validity of what as known as the maximum allowable concentrations (f dusts (ii.a.O.), of which lists have been drawn up * various countries. The m.a.c.s seem to bo based on th1 assumption that man is a standardised machine, whio! clearly he is not. The reasons for the differences i '[ individual reaction to dust are pot accurately known, bv ...j it is likely that they depend on anatomical, physiologies j v and biochemical variations from one person to another. ! J ti COAL-MINING SILIC O S IS i PNEUMOCONIOSIS 387 421 l l l l l l l I , , o, 2 O' FACTORY PROCESSES H 167 171 157 la s 177 184 192 2 7 2 O 2rz *<n -w Fig. ft---C h a rt show ing~ trnds o f death fro m fibrosis of th e iun^ coalm iner and fa c to ry w o rk e rs d u rin g th e p e rio d 1940-SI incluiln is known, however, that previous damage to tbe lung a factor which leads to tbe retention of dust in them, any case, there are instances where people have sp ' long years in thu dusty trades and have died from cau other than tlie dust diseases. On the other hand, uu ' u thousands have died as a direct result of the inhabit ; *1 of dust. The Size of the Problem liow many deaths have occurred from the diseases 1 Our information is incomplete in many reap hut table n gives at least some idea ot the size o ff problem. It is based on figures supplied to tbe FacM Department by tbe Registrar-General, and it shows I number of deaths from fibrosis ot the lung from 1Mil 1951 inclusive. In all industries there were 8789 deaths from oecui tioual fibrosis of the lung in tbe 12-year period and it s be seen that tbe total yearly figures are going up. Ori tho same period (hero were 6907 deaths from u| ORIGINAL AKTIOUSS [july u , ies3 63 upational fibrosis of the lung. I t should be emphasised that the deaths oceurriug each year in the occupational group are the result of conditions which obtained in industry some years previously, possibly 10-20 years or even longer. About two-thirds of the total number of deaths occurred in coalminers, and the figures rose steeply from 232 in 1940 to 937 in 1951. It is likely that part of the increase is due to more accurate diagnosis or at least to greater interest in the pneumoconiosis problem amongst coalminers. In 'fig. 8 is shown a comparison, based on the crudeligures from table II between the deaths in coalminers and factory workers. In factory processes the yearly number of deaths was going down until 1943 but there has boon a slight rise in the later years. ' (ii'o be concluded) A FOLIC-ACID EXCRETION TEST . IN THE INVESTIGATION OF '^ INTESTINAL MALABSORPTION , ; 1 i R o n a ld H . G m m vooo M.B., rh .l). Edim, F.R.C.P.E., M.R.C.P. /SENIOR LECTURER IN MEDICINE IN TUB UNIVERSITY 0 j ,'; EDINBURGH ..'IN 1880 Mauson, having anglicised a similar Dutch word, described `` sprue " as a disease occurring in the tropics or subtropics or among persons who had previously resided in warm climates ; the disease was characterised by glossitis and stomatitis, by tho passage of pale copious loose fermenting stools, and by flatulence, wasting, and anemia. The phrase " the sprue syndrome" has been used in recent years to include the features found in idiopathic steatorrhcca of non-tropical origin and in {Bjiac disease ; since tho introduction of the fat-balance test of Cooke et ol. (194(5) it lias been extended to include cases where there is megaloblastic amemia and deficient absorption of fat hut little other clinical evidence of intestinal malabsorption, and the term " malabsorption syndrome has come into use. * Ip the diagnosis of sprue the fat-balance test is most useful, hut it suflers from the fact that the patient lias to be in a hospital where a suitable diet can be given, that all the food given must be consumed (or necessary corrections made), and that the stools must be collected lor several days, always a difiioult matter in general hospital wards. It has usually been considered rather surprising that ' the megaloblastic amemia of sprue can bo treated with folic acid administered by mouth. The seeming paradox of successfully treating a condition believed to be due to . malabsorption of hiemopoietic factors by giving these same substances orally lias led to the hypothesis th at the fyult in sprue is malabsorption of naturally occurring 1folic-acid conjugates rather than of folic acid itself. , ffn some instances it appears th at there is malabsorption , of vitamin B,,, since therapy with parenterally adminis. tered yittlmin Bu has been effective in a few patients,) a The present investigation indicates that there is, in 'fact, considerable deficiency of absorption of folic acid in Sprue, aud that advantage eau be taken of this to devise a test of folic-acid absorption and excretion for the diagnosis of malabsorption by the small intestine. The estimation of the folic-acid content of the urine Or Other body-fluids is usually done microbiologieally. The growth of a certain strain of a streptococcus or lactobacillua in a suitable medium depends on the mount of folio acid present in that medium. Thus it is .possible to set up tubes containing the medium with ^measured amounts of folic acid aud others containing the medium with various dilutions of urine, In both sets of tubes the amount of growth depends on the ' concentration of folic acid. The amount of growth is measured photo-dectrically after a suitable period of incubation, by estimation of turbidity in the medium, and the amount of folic acid in the urine may easily be calculated. Tho test has many difficulties but when it has been successfully initiated it is satisfactory, giving reproducible results. If further work confirms the value of the folic-acid excretion test, the diagnosis of sprue should, at least in some instances, be rendered easier in that special diet is not required, and specimens of urine can be sent for assay from other hospitals to laboratories in which folic-acid testj are being done. It is not yet possible to say whether a positive fat-balance test may he associated with a negative folic-acid excretion test in the " malabsorption syndrome." No cases of chronic pancreatic disease have been available for study. METHODS AND MATERIALS The folic acid used ill these tests, whether it was given by injection or by nmutli, was derived fruiu ampoules of ` Folvilo ' (Lederle Laboratories Ltd.). The ampoules were taken from hatches tested by us aud found to contain 16 mg. of folic apul per ml. Certuiu batches were rejected because their content proved to ho higher than that stated on the label. Must of tho ampoules were, in fact, taken from one batch, supplied by Dr. A. T. Mennie, of Lederle Laboratories Ltd., London. In any one patient the same hatch was used for all the tests. On two occasions, where the intention was to load the tissues by large doses (cases 33 and 37, table m) hospital stock ampoules were used. The dose was accurately measured in a tuberculin syringe. For tests of excretion following oral therapy this test dose was diluted with a small quantity of water. 24-hour collections of urine were made in brown bottles containing toluene and a phosphate buffer of pH 0-8. The greatest possible care was taken to ensure that the urines were total 24-huur specimens, Recovery experi ments in which folic acid was added to urine gave completely satisfactory results. The uriues were kept iu a refrigerator at 40, aud readings were usually made within 3 days. All the readings were made at least in duplicate. Folic acid was estimated by the method of Teply and Elvelijem (1945), Streptococcus jaiculis R being used as the test organism. Tho tubes were incubated at 37C for about 1(5 hours, and readings were made by turbidity estimations iu a Spekkcr photo-electric ahsorptiometer. No correction need be made for the resting urinary content of folio acid, since iu ten normal persons the mean urinary folic-acid content corrected for citrovorum factor was only L7 pg. (range 012 -3 0 pg.) per 24 hours. - Urinary citrovorum factor was estimated iu most instances, since citrovorum factor is also a growth factor for Strep, fmcalis, the organism used in tho folic-acid assay. Citrovorum factor was estimated by a modification of the method of Sauborlich and Baumann (1948), with Leucouostoc citrovorum as the test organism. Ileie, too, turbidity readings were made after incubation at 37t! for about 1(5 hours. The mean resting urinary content of citrovorum factor in ten normal persons was 0-84 pg. (range : negligible amount--3-3 pg.) per 24 hours. No correction has been made for this in the citrovorumfactor readings, which are included only for biochemical interest. It will lie seen that a small proportion of the folic acid administered iu those investigations was excreted as citrovorum factor or as a substance with similar micro biological properties, bud the figures given for folic-acid execution have not been corrected for this, because such a correction would in no way alter the conclusions. Sevcial oi the patients were in hospitals in outlying districts where it was impossible to make as full investi gations as would have been preferred. In some instance.-, it was necessary to collect the urine at the patients' homes.