Document YG79BRxYb6jGDge1D4Gwv1K1D

y> CyiM^tk '4 tsfa TOXICITY OF INDUSTRIAL METALS SECOND EDITION ETHEL BROWNING, M.D. Formerly H.M. Medical Inspector of Factories; Adviser on Toxicology to the Courtauld Organization J. i ,; 1 NEW YORK APPLETON-CENTURY-CROFTS Division of Meredith Corporation LONDON BUTTERWORTHS N36938 .3 '- &'*it" y.^Sr&^^'dSV.&'-w'V^sV^ CHAPTER 20 LEAD l e a d is one of the oldest metals to have served mankind. Even before Roman : times lead water pipes were used and in 1285 the first cistern of lead was constructed in the City of London. King Henry HI " in the twenty-first year of his reign " granted permission to the citizens of London to convey i water from the Town of Teyboume by pipes of lead into their city (Stow, 1945). Lead mining is of great antiquity, for the conditions in which it was worked have been described by many historians and archaeologists. OCCURRENCE Lead ores are found in U.S.A., England, Germany, Mexico, Spain, New South Wales and South America. The most abundant lead-containing ore is galena, in which it occurs as the sulphide, PbS, and from which commercial lead is chiefly obtained. It is also found in cerussite (the carbonate), anglesite (the sulphate), crocojsite (the chromate), wulfenite (the molybdate), pyroxnorpbite (the phosphate), matloddte (the chloride) and vanadinite (the vanadate). It is present in plants and soils in very small amounts; fixation by the clay ofnormal soil converts added lead to insoluble inactive compounds, but very acid soils increase the solubility and soluble compounds are toxic to plants except in very low concentrations (Gilbert, 1957). ! I PROPERTIES Lead is a bluish-grey metal witha bright metallic lustre when cut. In moist air it becomes coated with a film, probably an oxide, ultimately converted Into a basic carbonate. It is not tough enough to be hammered into foil or drawn into wife but can be pressed into pipes or rolled into thin sheets. It is fairly rapidly dissolved by nitric acid, and is soluble, to some extent, in - organic acids such as acetic and food" acids, and by water in pipes if the water holds nitrates, ammonium salts and carbon dioxide in solution. The presence of carbonates from limestone or chalk prevents this process by the formation of a film on the interior of the pipes which protects the lead from further action. Atomic weight, 207; specific gravity, 11-25-11-4; melting point, 327C.; boiling point, 1620C. The maximum allowable concentrations are: metallic lead, 0-2 mg. per c.m.; lead arsenate, 0-15 mg. per c.m. INDUSTRIAL USES INORGANIC COMPOUNDS AND METALLIC LEAD (1) In "the manufacture of pipes, cisterns, roof coverings, etc. and in the metallizing of lead wires. (2) In the chemical industry for containers for sulphuric acid, evaporation pans, etc. m >& ; vf-- (3) In the i (4) In stor; (5) In vari' (6) In paii chromates, si (7) In flint (8) In the lead poisonir longer report where the pn solubility re! symptoms ar (9) In the (10) In thi (11) Incei (12) As N lead in the f used as barr on pipes, cor and pressure considerably The severi been estimati orhisassock of molten le solder and t storage batte weighing of harmful exp and steel ten It may be (Question C amounts to i ORGANIC Tetraethyl " anti-knock intoxication considered 1 motor fuel, 1 of petrol en; The metabc regard to i1 influence be DUP050313183 toman id was ty-first ronvey (Slow, it was , New ig ore lercial glesite pyros (the e clay t veiy plants moist /erted oil or It is it, in if the The y the from 7C.; are: i the ition LEAD ITS (3) In the manufacture of lead shot, bullets, linotype metal, etc. (4) In storage batteries, as accumulator plates. (5) In various alloys, with antimony, tin, copper, etc. (6) In paints, varnishes and pigments, as litharge, red lead, white lead, chromates, sulphate and titanatc. (7) In Sint glass and vitreous enamelling as a lead or lead-potash silicate. (8) In the pottery industry as a low-solubility lead glaze or frit. Cases of lead poisoning from these low-solubility glazes in the pottery industry are no longer reported, but in Italy, in a factory making glazed tiles for mosaic work; where the proportion of lead in the frit was as high as 10-40 per cent and the solubility relatively high, many workers were admitted to hospital with symptoms and signs oflead intoxication (D'Onofrio, 1949). (9) In the manufacture of litharge rubber. (10) In the manufacture of insecticides (lead arsenate). (11) In certain plastics, as the borate. (12) As Noise Barriers. It has recently been proposed (Fader, 1966) that lead in the form of sheet lead and/or lead-loaded flexible plastic should he used as barriers to industrial noise. Either could be hung above ceilings or on pipes, conduits, gas turbines and air ducts to prevent the noise from fluids and pressure of air and gases. This procedure has been found to reduce considerably the peak intensity ofnoise. The severity of the inorganic lead hazard in-the various processes has been estimated by Elkins (1959). Fromthe results of investigations by himself or his associates he considers that the most severe hazard occurs in the spraying: of molten lead and lead paint; in the grinding or power sanding of lead or solder and the pouring of leaded iron and steel; in certain operations in storage battery manufacture; the operation of wire patenting, the mixmg and weighing of lead powders. Lead smelting and burning are also sources of harmful exposure, while soldering, lead casting, brush painting, linotyping; and steel tempering are regarded as relatively non-hazardous. It may be of interest to note a statement given in answer to a question (Question Clinic, 1967) that lead silicate dust can be absorbed in sufficient amounts to produce lead intoxication. ORGANIC COMPOUNDS Tetraethyl lead (PKCyajj) is the chief organic compound used, as an " anti-knock " addition to motor fuels. It gives rise to a syndrome of intoxication quite different from that of inorganic lead (see p. 178) and is considered hazardous during the process of manufacture or mixing with motor fuel, but not in the handling of dilute solutions or in the exhaust gases of petrol engines. METABOLISM The metabolism of lead follows closely that of calcium, particularly with regard to its deposition in and mobilization from bone. Many factors influence both of these in a similar manner. When bone marrow activity DUP05031 31 84 ,^V:iVff^^;*^'*"gBfe,>g 174 TOXICITY OF INDUSTRIAL METALS is increased, as in leukaemia or severe anaemia, calcium mobilization may take place, causing hypercalcaemia and osteolysis. In these conditions lead may also be liberated and give rise to an increased lead content of the blood even when there has been no undue exposure to lead. Thus, when an excessive amount of lead has been deposited in bone, either from ingestion or from industrial exposure, and has remained immobilized for years, inter current factors causing mobilization may cause a sudden outbreak of clinical symptoms of lead poisoning. Lead is not among the metals considered essential to the nutrition of ani mals or human beings; it is classified by Schroeder (1957) as " one of the trace metals with organic specificities ", Certain foods contain significant and more than average amounts--bread, meats, tinned foods and vegetables (Kehoe et a1933), and according to Schroeder, the daily intake from ex posures to the "functions of civilization" (lead pipes, food containers, articles soldered with lead, insecticides) is about 0-4 mg. Lead is present in practically all organs and tissues. According to Kehoe (1949) the average gross quantity of lead in the body of the normal human adult in the U.S.A. varies according to the body weigjit^from 100 to 400 mg. In Japan, the average total body content of lead has been estimated as about ! 78 mg. in adolescence and 131 mg. in old age, the difference being probably t accounted for by variations in constitution, mode of life and food (Horiucbi ] et al., 1959). The bones contain the highest concentration, but file actual amounts vary considerably according to various investigators. Horiuchi and t co-workers, expressing the values in terms of micrograms per 100 g., give tables of these differing results both for adult and also for foetal bones, attributing the variation to different methods of analysis. Their own estimations of adult bone, while showing much higher levels than in the soft tissues, show a wide variation in individual specimens, the amounts f rangingfrom 215 to 1,240 pg. per 100 g. for ribs, from242 to 890 pg. for verte brae, and from 311 to 2,980 pg. for femurs. By comparison, Hansmann and t Perry (1940) give an average value of 870 pg. for ribs, and Tompsett and Anderson (1935) 710 pg. for vertebrae. In the soft tissues a similar dis crepancy appears in the various estimations, but all are agreed that the liver and kidneys contain the largest amounts. For the liver these range from an average of 173 pg. per 100 g. (Tompsett and Anderson) to 190 pg. (Horuichi and co-workers) and 79 pg. (Kehoe et al., 1933). In blood, Kehoe gives a range of 0-01-0-05 mg. per 100 g.; Bessman and Layne (1955) 0 to 0-3 mg.; Tompsett and Anderson an average of 0 05. This variability naturally depends to a great extent on the fact that a single blood sample gives only the concentration of lead at that time, while the lead discharged into the blood stream in unusual amounts Is constantly being removed from the circulation, re-distributed and excreted. The most recent opinion, that of Egli et al. (1957), considers 0-05 mg. per 100 g. the " tolerance limit. " for the appearance of lead poisoning. Teisinger (1965) believes that when the level of lead in the urine is 3 mg. per 24 hours, symptoms of poisoning appear with some frequency and that excretion within the range of 0-8 to 1 mg. per L per 24 hours should be regarded as the permissible maximum. ABSOR Absorj ingested only 10 | secretion evolved, has been passages Absor cance th absorbec enter thr khis, 19' EXCRI Lead : In nom faecal le and oth which e: relativel and Ant urine at of lead above f able in< absorpt sidered tion by observe taminai estimat the ski: deliben with th lead; ir increas in lead Hefou the lun severity those < expectt associa presenl W;f DUP050313185 LEAD 175 ABSORPTION [ 1 Absorption from the gastro-intestinal tract is very small. Most of the lead ingested passes through and is excreted in the faeces. Kehoe(I960) states that only 10 per cent or .less actually reaches the tissues, blood, body fluids and secretions. In workers exposed to lead processes where dust or fume is evolved, a certain 'amount is absorbed from the respiratory passages after it has been retained there, but some is either exhaled or trapped in the upper passages and subsequently swallowed. Absorption of inorganic lead by the skin is not generally of great signifi cance though' according to Fatty (1958) lead acetate and lead oleate can be absorbed in appreciable amounts. Lead tetraethyl, on the other hand, can enter through the skin both in liquid and vapour form (Marchenko and Beili- khis, 1946).. '' EXCRETION I s1 i Lead is excreted both in the urine and also to a greater extent, in the faeces. In normal persons who show no evidence of lead accumulation the daily faecal lead intake is almost equivalent to the amount ingested from the food and other usual sources. In such persons an equilibrium is established in which excretion keeps pace with absorption and urinary excretion is small and relatively constant at levels varying from 0-0! to 0 08 mg. per 1. (Tompsett and Andersen, 1935, give their results in amounts per diem (average0 05 mg. for urine and 0-22 mg. for faeces) because, in the case of urine, the concentration of lead varies with the volume secreted.) When lead isvingested in amounts above that normally contained in food and beverages it produces a measur able increase in the rate of urinary excretion during the period of active absorption and for some time afterwards. A level of 0-15 mg. per 1. is con sidered by Egfi et al. (1957) as the " threshold " for lead intoxication. Excre tion by the sweat was not considered a possibility by some of the earlier observers who regarded any lead found on the skin as a mere surface con tamination. In 1954, however, Shiels, using sensitive methods of analysis, estimated the amount of lead deposited on pads of cotton wool attached to the skin of the chest of persons suffering from lead poisoning or having deliberately ingested lead acetate. Comparing the amount of lead deposited with that of controls, he found it significantly greater in those exposed to lead; in the case of ingested lead the amount during the period of ingestion increased from 0-012 mg. per 1.. to 0-024 and 0-05 mg. Retention by the lungs, in lead workers, ship breakers and controls was studied by Mehani in 1966. He found that 39-47 per cent by weight of the inspired lead was retained in the lungs of lead-exposed workers but varied with several factors, including severity ofeffort at work, and size of the particles, a considerable portion of those of 3fi and more being retained in the mouth and throat and either expectorated or swallowed and excreted in the faeces. The retention was not associated with the depth of breathing, and the final conclusion was that in present working conditions, with an average atmospheric concentration of 9 <3 DUP050313186 176 TOXICITY OF INDUSTRIAL METALS lead of2 mg. per 10 c.m. the amount retained per shift would be less than half the amount which can be tolerated without producing evidence of ill-health. STORAGE Before 1924, when Minot and Aub made a special investigation of the storage of lead in bone, its presence in bone was considered relatively unimportant compared with its widespread distribution in the soft tissues. It then became apparent that while in the softer tissues the deposited lead Is loosely held and decreases in amount with time, the highest concentration remains in the bones (Fairhall and Miller, 1941). The trabeculae have been found especially rich in lead, and while the epiphyseal portion is particularly rich in the early stage of absorption, deposition occurs throughout the compact tissue on all surfaces over which blood passes, first, according to Fairhall (1943) in colloidal form, and finally as segregated crystalline masses localized in dumps around the Haversian canals in the compact and cancel lous tissue. Thus the more recently absorbed lead is stored in a situation from which it can be readily mobilized (Brown, 1946). LEAD IN THE FOETUS | In mothers unexposed to lead the distribution of lead in foetal tissues and 1 organs appears to follow that of the adult; in bones it tends to increase with i their development. On the basis of their analyses of foetal tissues, placenta and umbilical blood (Horiuchi and co-workers, 1959), and by the observations of earlier workers (including Legge and Goadby (1912) that long term over-exposure of the mother may be followed by toxic effects on the j foetus), it is believed that lead passes from the mother through the placenta :) to the foetus, since the lead content of the bones increases with the develop ment of the foetus at the expensp of its blood lead; the bones, with their l harmless deposition oflead at this time, may have a protective function in this > respect. \ TOXICOLOGY i j ' Although symptoms now known to be those of lead poisoning appeared very | early in the history of its use--Hippocrates in 370 n.c. described a severe | - attack of colic in a man extracting metals, and the ancient Egyptians well I understood the properties of lead as a homicidal agent--the recognition of I an associationbetween symptoms of poisoning and the use of lead in industry j was long delayed. Industrial poisoning in lead miners must have occurred in | the appalling conditions in which they are known to have worked, but the | " Miners' sickness " described by Paracelsus in the sixteenth and Pansa in i the seventeenth centuries was not specifically correlated with their exposure | to lead. It was not until 1831 that Thackrah first definitely associated lead with the ill-health of miners. " Miners of lead," he stated, " suffer consider ably from their employ," and went on to describe the high rate of mortality among them though without giving details of the symptoms which caused it. A more favourable opinion of the health of the lead miners of Derbyshire was given by Wiliam Webb (1857), but he noted that " a miner can generally be pointed out by his pallid face In the same year Jackson, while stating that th> colica i their s' severes acute 5 reports 11 out based A.notht revealc The the pol in Grc Legge Absor; so grea based accoun series c with le tamina many t to lead someth The manife in indu has bet niques aids to lead. 1957)v mildest rneanti is kept that im excess' poison! the Lis Injuries elude " lead.or specific Factor! workin Betu the Chi to 55, DUP050313187 n half leolth. of the itivcly issues, lead is ration e been ;uiarly ut the iing to misses :anceluation es and >e with iacenta 3serva: longon the Iacenta sveloph their . in this id very severe ns well lion of idustry irred in but the ansa in iposure ed lead msiderortality used it. lire was -ally be stating LEAD 177 that the miners of Arkendale and Swaledale " are not liable either to paralysis, colica pictonum or lead poisoning ", asserted that miners absorb lead through their skin and lungs. Actually, lead mining itself has never produced the severest cases of lead poisoning, and recent investigations have revealed few acute symptoms. In the Moroccan lead mines, for example, Rodier (1948) reported that no acute lead poisoning had been observed, and that while 11 out of 50 examined showed " signs of intoxication ", the diagnosis was based only on the presence of punctate basophilia of 2,500 per million. Another survey by Belden and Garber (1949) of men handling galena also revealed rio evidence of intoxication by lead. The whole problem of lead poisoning, not only in the mines but also m the potteries, the painting industry and other fields of use of lead in industry in Great Britain, received its most serious attention up to that time when Legge and Goadby (1912) published their book" Lead Poisoning and Lead Absorption ". The preventive measures and statutory legislation which have so greatly reduced the incidence of severe lead poisoning in Britain have been based essentially on their work. In America, the most detailed historical account of lead poisoning is that of Gtrey P. McCord (1953 and 1954) in a series of articles in Industrial Medicine and Surgery, vote. 22,23. They deal with lead poisoning as it relates to early cases of poisoning from food con tamination, medicines, cosmetics, paints, and ceramic grazes, mining, and many other aspects, and draw an interesting picture of the effects ofexposure to lead in earlier times as compared with the present knowledge, gained by sometimes bitter experience. The picture has indeed changed to a very great extent. Some of the severe manifestations, especially encephalopathy, arc practically never encountered in industry, and the distinction between lead intoxication and lead absorption has been made much more factual by the development of laboratory tech niques for the estimation of lead in air, blood and urine; these are not only aids to diagnosis but also to the control of the health of those exposed to lead. This aspect is well summarized by Bloomfield (cited by Johnstone, 1957) when he says " Lead intoxication rarely occurs at all and only in its mildest manifestations among regularly employed industrial workers if the mean urinary lead concentrations of representative groups of such workmen is kept below 0 01 mg. per 1. and if the exposure is controlled so uniformly that individual results are generally below 015 mg. per 1. and very rarely in excess of 0 -2 mg. per L". The fall in the incidence of cases notified as lead poisoning is as striking as the decrease of severity of its manifestations. In the List of Diseases prescribed under the National Insurance (Industrial Injuries) Act, 1946, the occupations in which lead poisoning is involved in clude " the use or handling of or exposure to the fumes, dust or vapour of lead or a compound of lead, or a substance containing lead " and there are 6 specified processes concerned with lead manufacture in which, under the Factories Acts (Section 58) women and young persons are prohibited from working. Between 1900 and 1958 the number of cases listed in the Annual Report of the ChiefInspector of Factories had fallen from 1058, with 38 deaths in 1900 to 55, none fatal, in 1958. The highest incidence was in the painting of DUP050313188 178 TOXICITY OF INDUSTRIAL METALS buildings (15) and shipbuilding (11). In electric accumulator works, apart pounds was. from the industrial poisoning occurring in workers in battery manufacture 1900 and 19 and repair, the hazard of this industry was emphasized by a non-industrial 1940 only tv outbreak among children in Rotherham in 1954, as the result of using dis somewhat d carded battery casings as domestic fuel (Gillet, 1955). Lead poisoning was it emphasizi ': i 1 not suspected as the cause of death in 2 children until 2 further cases were diagnosed; a full investigation of 232 children exposed to risk then revealed all necessar the different 55 cases of lead poisoning or lead absorption. poisoning a; The most hazardous compounds of lead in industrial use are those of ! high solubility. Lead chromate and sulphide are undoubtedly less toxic than more favoui rarely accon the more soluble acetate, chloride and oxide, but Elkins (1959) states that The case ret chronic industrial lead poisoning is caused as readily by the dust of lead out the reps sulphate, carbonate or metallic lead as by these soluble compounds. The exposure to c i fact that many operations such as soldering and linotyping, involving molten ; lead, have not produced a high incidence of intoxication is because the had failed t process the} temperature at which the vapour pressure oflead produces a high atmospheric institute hyj ; concentration (500C.) is not necessarily reached in such processes. The heavy risk d real risk arises not from the fume itself but from the dust oflead oxide which of encephal forms on the surface of the molten metal. This applies to the process of weakness at 'ii " wire patenting ", which is generally regarded as a " low toxicity " operation. tremor of ti i This is so if adequate precautions are taken to keep the surface of molten the right ar lead (through which the wire passes) free from dust; to prevent the accumula fusion and tion of dust in the workroom, and to avoid careless handling and un pected whet ? hygienic measures. Where these precautions are not observed, severe cases of that of anat *i poisoning have occurred. INORGANIC LEAD POISONING marked pur 4-5 per cen count of 10 fluid were a The clinical picture of lead poisoning is so well recognized and the subject has blood 0-33 : been so widely investigated during the past fifty years that a complete account ties bad dis; of all its aspects would necessitate a whole volume devoted to this one was some c\ metal. Only those aspects relevant to the modern concept of lead poisoning in tins con: and absorption will therefore be dealt with, together with the most important ingested lea references needed to fill in the picture. fatal; it is s An excellent review of the symptoms and physical signs was given by developmer Professor Lane (1949) in the Milroy Lectures delivered before the Royal Colic.--! College of Physicians in 1947. and in fact It must again be emphasized that there is a clear distinction between lead of the empl poisoning and lead absorption, and that organic lead compounds give a level of leac different pathological picture from that of inorganic lead. that in case in those wh '-s SYMPTOMS OF INORGANIC LEAD POISONING sider that tl The chief early symptoms of intoxication are fatigue, disturbance of sleep, and constipation. More prolonged and severe exposure may be followed by colic, anaemia and neuritis. The most acute and severe effect of all, very rarely seen nowadays from industrial exposure in adults (but still occurring occasionally in children from ingestion), is encephalopathy. Encephalopathy.--Encephalopathy from exposure to inorganic lead com but by altei Anaemia, red cell coi millions pet a colour ini The mos DUP050313189 or works, apart ry manufacture i non-industrial jit of using dis1 poisoning was rther cases were sk then revealed sc are those of y less toxic than i959) states that he dust of lead impounds. The nvolving molten i is because the iigh atmospheric processes. The lead oxide which o the process of city " operation, irface of molten nt the accumulaindling and und, severe cases of d the subject has omplete account >ted to this one >flead poisoning most important is was given by icfore the Royal ion between lead mpounds give a sTG urbance of sleep, y be followed by fleet of all, very ut still occurring rganic lead com- ' LEAD 179 ; \ poundswasreported with somefrequency inBritain 50 to 60yearsago. Between ; ; .i V.' ; T900 and 1909,262 cases were recorded; betweenl939 and 1948 only five; in 1940 only two, and since then only one (Hay, 1950). This case may justify a j< y i; . somewhat detailed description, not only on account of its rarity, bat because it emphasizes, so dearly the fact that such a case is likely to occur only when ' y all necessary precautions have been neglected. It also exemplifies some of > ; ,the differences which exist between the cerebral syndrome of inorganic lead \ ' poisoning and that caused by tetraethyl lead; the inorganic lead prognosis is more favourable, its effects are less permanent and more subjective, and it is rarely accompanied by the objective signs of loss ofvision, paresis and aphasia. ; , '/jJThft case recorded by Hay was that of a man employed as a cooper, carrying : r 1 but the repair of barrels which had contained white lead. The conditions of : yv exposure to lead were exceptionally bad, and owing to the fact that the firm ,. had failed to notify the Factory Department that they were engaged in this ('{ process they had for some time escaped supervision and had not attempted to j y institute hygienic measures of any kind. Two of the four men exposed to this heavy risk developed lead poisoning but only in one were the symptoms those , v ;' ' of encephalopathy. This man's chief complaints were headache, anorexia, weakness and loss of weight during the last 6 months. He showed a fine tremor of the lips and hands, slight bilateral papilloedema, loss of power in the right arm and unsteady gait. Later he developed diplopia, mental con fusion and excitement, and hallucinations. Lead poisoning was-only sus pected when a blue line on the gums was observed. His blood picture was that of anaemia: red blood cells 3-5 millions per cam, haemoglobin 9-7 g., marked punctate basophilia (16,000 per million) and a reticulocyte count of 4-5 per cent. The cerebrospinal fluid was under high pressure, with a cell count of 10 per c.mm. The lead content of urine, blood and cerebrospinal . fluid were afl above normal, the urinary lead at its highest 0 -48 mg. per 1., the 1 blood 0-33 per 100 g. After 6 months all physical and biological abnormali ties had disappeared except for a slightly excessive blood lead level, but there was some evidence of residual intellectual deterioration. It may he of interest in this connection to note that the encephalopathy of children who have ingested lead compounds is more severe in its manifestations, and is frequently fatal; it is sometimes followed in those who survive by permanently retarded development (Williams et al., 1952). Colic.--This is sometimes so severe as to simulate an acute appendicitis, and in fact has been so diagnosed and surgically treated when the nature of the employment has been overlooked. That colic does not depend on the level of lead in the blood was shown by Vigliani and Zurlo (1951) who found that in cases with active colic it was 0-138 mg. per 1. as compared with 0-116 in those who had had an attack some few days or weeks before. They con sider that the colic is caused not by involvement of the intestinal tissue itself but by alterations in the autonomic system. Anaemia.--Anaemia is not usually severe but is hypochromic. The total red cell count in cases of moderate severity is generally between 4 and 4J millions per cm with a haemoglobin level between 70 and 80 per cent and a colour index of about 0 -8 per cent. The most specific feature of the blood picture is a high level of punctate !' (' \ DUP05031 3190 180 TOXICITY OF INDUSTRIAL METALS basophilia; there is also polychromasia and usually an increase in the number of reticulocytes. The extent of the haemolytic breakdown of red cells has been shown in animals by the deposition of iron in the spleen (Goldblatt and Goldblatt, 1956). This increased rate of red cell destruction has been regarded by some observers as the result of damage to the peripheral cell, its envelope having been rendered brittle by the action of lead in the circulating blood (Aub et al., 1925). The actual mechanism of tins action has been suggested to be that of contact of the plasma lead causing increased fragility of the corpuscles. In vitro experiments by Clarkson and Kench (1958), however, have led them to conclude that in vivo plasma lead will cause only minimal changes in the fragility of circulating red cells and that all the injurious effects (inhibition of haem synthesis, and morphological changes such as punctate basophilia) will have already been produced in precursor cells developing in the bone marrow. Other observers, including McFadzean and Davis (1949) and Baikie and Valtis (1954) suggest that the increase in cell destruction is associated with the elimination of the immature and presumably defective cells; Baikie and Valtis have shown, in animals poisoned with lead, that the oxygen consumption of stippled cells and reticulocytes is higher than that of the mature cell, and they discuss the hypothesis advanced by Rimington (1938) that lead interferes with the elaboration of haem by blocking an enzymic process in its synthesis. The results of an investigation by Eriksen (1955), using the radioactive tracer technique, on the other hand, appear to indicate that lead interferes with protoporphyrin synthesis but has no effect on the iron incorporation. The actual mechanism of the action of lead as a haemolytic agent remains in the realm of conjecture at present. Changes in the bone marrow,---There have been a number of reports on the condition of the bone marrow in lead poisoning, especially with reference to the morphological characteristics of the erythropoietic cells. Beritic and Vandekar (1956) found a marked tendency to an increased production of erythrocytes in the bone marrow in a group of persons suffering from lead poisoning. The most characteristic feature was the presence of a large number of stippled erythroblasts (values as high as 371 per 1,000) and of nuclear abnormalities, these findings being recently confirmed by David (1959). He noted morphological changes in the erythroblasts which included a typical formation of the nuclei (karyorrhexis, deformation, polypoidosis), the presence of paraerythroblasts, variation In cell size, and deficient haemoglobin content. Siderocytes, sideroblasts and reticuloendothelial cells, present in numbers considerably above the normal, contained an abnormally large amount of iron, suggesting a disturbance of the iron metabolism of these cells, and the plasma frequently showed discrete basophilic stippling. As in the case of the mechanism of the action of lead in changes in the peripheral Wood cells, there is still uncertainty as to the true cause of these changes in the bone marrow, but most recent observers believe that the initial effect of lead is a primary hyperstimulation, followed by a delay in maturation; the anaemia, of a haemolytic character, is a secondary feature. Pcripl hands ai rence an by <3^,, When v. muscles raay beo Df the ft due to p. Tremo iead wor The K manifest jn cases particles it must 1 tartar fre present i sulphide where it from the mouths. only a fe jf there i months i Premn healthy manifest of lead v. been pu He foum decalcifu action is the bone phospha POSSH Chron standing heavy cx conseque generally and vase 1941; an the renal rhages a tormina t as a vase '55 ysgfrjww"'jy-*?*?,1 DUP050313191 i the number red cells has :n (Goldblatt by some ob: having been I (Aub et al., to be that of rpuscles. In ; led them to anges in the '.inhibition of sophilia) win one marrow. 1 Baikie and ated with the Baikie and en consumpmature cell, 18) that lead process in its : radioactive ad interferes corporation, it remains in ports on the reference to Beritid and oduction of g from lead : of a large ,000) and of 1 by David ich included slypoidosis), id deficient ithelial cells, i an abnormctabolism basophilic mges in the use of these at the initial maturation; LEAD 181 Peripheral neuritis (lead palsy).--Actual paralysis of the muscles of the hands and feet--wrist-drop and foot-drop--is now a relatively rare occur rence among lead workers though some weakness of the musdes, evidenced by decrease of strength of the hand grip, can still occasionally be observed. When wrist drop does occur the paralysis usually begins In the extensor muscles of the fingers, at first in the right hand of right-handed persons, and may become bilateral. It is accompanied by wasting of the posterior musdes of the forearm and is not associated with sensory disturbance. Foot-drop, due to paralysis of the extensor musdes of the toes, is even less common. Tremor.--A fine tremor, or fibrillary twitching, used to be a feature among lead workers but is rarely seen in modem industry. The lead line (Burtonian or " blue line ")--This sign is regarded as a manifestation of excessive absorption of lead though it is not always present in cases of true intoxication. It consists of a deposit of dark blue-grey particles in the substance of the gum, in a line about 1 mm. from the margin. It must be distinguished from the discoloration ofpyorrhoea, carbon-carrying tartar from neglected teeth, and from the dark patches on the gums frequently present in coloured workers. It is -believed to be caused by patches of lead sulphide, the lead having been brought by the blood stream to the gum, where it is converted to the sulphide by the sulphuretted hydrogen arising from the decomposition of protein foods, particularly in unhealthy or unclean mouths. In some cases the " line " is not fully developed, but consists of only a few granules around one or two teeth; these may clear in a few.weeks if there is no further absorption, whereas the gross blue line may remain for months after cessation of exposure. Premature loss of teeth.---The fact that many lead workers lose apparently healthy teeth at an early age has led some observers to regard this as a manifestation of lead poisoning. Confirmatory evidence of the association of lead with changes in the jawbone that canlead to loosening of the teeth has been put forward by Koelsch (1959) in a series of animal experiments. He found that the jawbones of rabbits poisoned with lead carbonate showed decalcification, erosion and progressive osteoclasis. The mechanism of this action is attributed to a demineralization caused by chemical displacement of the bone calcium by lead carried in the blood as colloidal secondary lead phosphate and deposited as tertiary phosphate. POSSIBLE LATE SEQUELAE OF LEAD POISONING Chronic kidney disease and arteriosclerosis in lead workers of many years* standing was believed by the early observers (who saw many more cases of heavy exposure to lead than is possible to-day) to be a direct though delayed consequence of their occupational exposure. In America this view is not . generally held. Animal experiments have certainly shown that lead is a renal and vascular poison (Calvery, 1938; Fishberg, 1939; Fairhall and Miller, 1941; and others). These observers have recorded degenerative changes in the renal tubules and vascular lesions, in the form of multiple minute haemor rhages and thickening of the walls of the blood vessels of the type usually terminating in nephrosclerosis. From this evidence lead would be regarded as a vascular poison with an effect on the renal circulation which in human ... .q;' DUP050313192 182 TOXICITY OF INDUSTRIAL METALS beings would eventually develop into the condition known as " chronic Bright's disease This was the view of Legge and Goadby (1912) and of Oliver (1914), who said that interstitial nephritis had come to be regarded as the typical renal lesion of lead poisoning. With this view Lane (1949) was in agreement. He stated that during the last 15 years he had seen 9 deaths from hypertension with renal failure in lead workers who had formerly had severe exposure and whose death had occurred at the relatively early average age of 48-52. Histological examina tion of the kidneys showed a picture varying from that of benign hyper tension with progressive renal damage to one similar to the malignant phase of arteriolar necrosis. * Albuminuria is not a frequent finding in lead workers, though in the investigation of Dreessen el al. (1941) a statistically significant higher in cidence was present in. lead workers, especially in those exposed to higher . concentrations. Lane found only a trace of albumin in 3 out of 56 storage battery workers, this being present also in two controls. ' No actual rise in blood pressure of workers in the accumulator industry (still one of those carrying a major lead hazard), has been demonstrated by Belknap (1936), Dreessen et al. (1941) or by Lane, who believe that this absence of significant change shows that their exposure has not reached a dangerous level and that the disappearance of chronic Bright's disease in lead workers is due to the improvement of conditions in modem lead industries and in 1963, in an investigation, together with Dingwall Fordyce, of a large group of pensioners and present employees of storage battery workers, they, reported a highly significant excess of deaths from cerebro vascular disorders; these men had been heavily exposed for many years. This view appears to be supported by the studies of Henderson and Inglis (195?) in Australia, which showed that though 63 per cent of the cases could not be allotted to any known cause of renal disease, they had a history of childhood plumbism and excessive amounts of lead in the bones. The contro versy on this subject is however not yet ended; it was stated in 1965 by Prerovi ska and Roth after biochemical examination of 50 lead workers that they I found no proof of a hazard of premature arteriosclerosis, and they confirmed ; their opinion by the results of experiments on rabbits, where they found no 1 evidence ofatherosclerotic changes in vessels or organs. i | LEAD ABSORPTION j The danger of continual absorption of lead in amounts which do not of i themselves cause clinical symptoms and signs of poisoning is that a point , ' may be reached when the " threshold levd " for potential poisoning can be exceeded, and then an intercurrent factor may produce a metabolic disturb, ance which has the appearance of toxic manifestations. \ DIAGNOSIS OF EXCESSIVE LEAD ABSORPTION l Estimation of the level at which lead absorption has become potentially > dangerous usually depends upon examination of the blood for anaemia, i punctate basophilia and reticulocytosis, of the urine and faeces for a raised . j lead content, and of the urine for its coproporphyrin level. :r I Blood cxamin usually mild', w: and a haemogtt f sometimes acco from the pallor seen in worker ** leaden " tingi nose and tempi the skin of the * PUNCTATE B. i lead absorptioi f both in experi human beings also in haemo extent detracte ; numbers in le even though t made it a usef actual numbei ' been subject - differences ha dark-ground E fight, gives a great and len when some v; smears were present than i basophilia gb subjects, but i (dark-ground i work even ifi Lane (193! : punctate cell! an excessive often appear granulated b cells, which i dark-ground levd in a gr value in the ; dividual coi I reservation l symptoms o signs of acul ` BASOPHIUi ! and McCorc S tag basophi j The red cells DUP050313193 is "chronic 912) and of regarded as : during the il failure in : death had al examinanign hypergnant phase >ugh in the t higher ind to higher ' 56 storage or industry instrated by ve that this t reached- a s disease in lodem lead ill Fordyce, age battery >m cerebronany years, t and Inglis cases could a history of Thecontroi by Prerovrs that they y confirmed :y found no a do not of hat a point ning can be ilic disturb- potentially w anaemia, for a raised | LEAD 183 t Blood examinations.--Anaemia, if unassociated with clinical symptoms, is usually mild, with a total red cell count of not less than 4,000,000 per cm and a haemoglobin level of 75-80 per cent Even when mild, however, it is sometimes accompanied by a noticeable and characteristic pallor; tins differs from the pallor of severe anaemia not due to lead and from that sometimes seen in workers in hot, airless conditions, in that it has a peculiar greyish " leaden " tinge and is often associated with a pinched appearance round the nose and temples. Lane suggests that it is due to spasm of the capillaries of ; the skin of the face. I p u n c t a t e b a s o p b il ia.--The nature and significance of stippled cells in lead absorption has been the subject of a voluminous literature. It occurs ' both in experimental animals (McFadzean and Davis, 1949) and also in human beings ingesting or inhaling lead compounds. The fact thatifocciirs also in haemolytic anaemias unrelated to lead intoxication has ta a certain extent detracted from its specificity for lead, but its presence in much greater , numbers in lead poisoning, and in practically all workers exposed to lead, even though they exhibit no clinical symptoms and no severe anaemia, has i made it a useful diagnostic aid in lead absorption. The relation between the. actual numbers of basophil cells and the degree of lead absorption has also ; been subject to much variation of opinion. Undoubtedly some of these i differences have arisen from the fact that examination of blood smears by dark-ground illumination, a much less fatiguing procedure than by transmitted light, gives a considerably higher punctate count--approximately twice as great and Jensen (1965) has stated that he has failed to find basophilic cells when some variations are used in preparing the blood smear. When thick smears were made and dried slowly, a greater number of basophils were present than in thin rapidly dried smears. The actual level at which punctate j basophilia gives warning of impending lead intoxication differs in individual subjects, but most observers now consider anything above 10,000 per million (dark-ground method) a danger signal and an indication for suspension from | work even if unaccompanied by symptoms or physical signs. Lane (1931) made a distinction between fine and coarse granules in the i punctate cells, the fine granules indicating a less severe effect and the coarse * an excessive and rapid absorption. He has also noted that polychromasia ` often appears before punctate basophilia. (By transmitted light, very finely granulated basophil cells may easily be counted in error as polychromatic ' cells, which may partly account for the lower count by this method than by dark-ground fllumination). Lane has also suggested that a raised average level iu a group of exposed workers is a significant finding and of greater value in the control of absorption and the diagnosis of plumblsm than in dividual counts. With this statement some observers would make the , reservation that individuals with high basophil counts and with no clinical ` symptoms other than moderate anaemia sometimes unexpectedly develop signs of acute Intoxication within a short time of their examination. b a s o p h il ic a g g r e g a t io n t es t .--This test, described by McCord et al. (1924) and McCord et al. (1935) depends on the enumeration ofall red cells contain ing basophilic material, including reticulocytes and polychromatic cells. The red cells are haemolysed and the " clumped " basophilic material stained o DUP050313194 Ik . i1 i vi^/V^.-- 184 TOXICITY OF INDUSTRIAL METALS ' l. ',/) ..V .7,* X^X-'M '/ > with Romanovsky stain; the percentage relationship between the aggregations On the unfixed portion and the total number of red cells in the fixed portion is calculated. In healthy individuals this percentage is on the average 0- 85 per cent; findings above 2 per cent are said to suggest the possibility of Ly Ell so< wi' approaching lead poisoning or its early presence. It is not always positive av :;'V/<-" in chronic lead poisoning. r e t ic u l o c y t e c o u n t s .--Some observers regard a mild reticulocytosis as pc to a measure of lead absorption on the grounds that it is a feature ofhaemolytic anaemia (Fleckel and Tschernow, 1930). It is even less specific to lead than pa vv'^f; punctate basophilia and should not be regarded as a method of diagnosis in individual cases, though it is a useful aid in the group control proposed by . * ur. Tr t5 Lane. Dreessen ei al. (1941) point out that if a patient has a high stippled count there is a strong probability that he will also have high reticulocyte fai in< ,'i.'!'i,: I' .*:' i. '.'& and polychromatophilic levels. They found that in men with a low lead exposure (up to 0-74 mg. per c.m. of lead) the reticulocyte count averaged 1- 7 per cent; it rose with increasing exposure and length of employment to ea tei oc 3-9 per cent in men employed for 15 years in an atmospheric concentration of over 3 mg. per c.m. I an of s id er o c y t e c o u n t .--Sidcrocytes are erythrocytes containing fragments of ; kr non-haematin iron which can be stained by a'dipyridine and potassium thiocyanate. According to Case (1945) these are " ageing " cells and should di: of be found in increased numbers in haemolytic conditions where there is a (F <.i high rate of erythrocyte destruction. He estimates the percentage in normal is blood as 0 -5 to 0-8, and found It increased from 10 to 30 per cent in 4 cases of m lead poisoning. b l o o d l e a d LEVEL.--The level of lead in blood does not increase as much in lead absorption as does that of urine, but it fluctuates less widely (Elkins, 1959). The actual level indicative of absorption considered dangerous has been given varying values by different observers, as does the range of normal ar ct ot H values (see p. 174). According to Patty (1949) 0-07-0-08 mg. per 100 g. are indicative of non-harmful absorption, and between 0-08 and 0-15 mg. per 100 g. of dangerous absorption. A lower value (0-05 mg. per 100 g.) is given by Egli et al. (1957) as the " tolerance limit " for intoxication. j pl es e> ti< Lead content of urine and faeces.--As already observed (p. 175) faecal excretion of lead is greater than urinary excretion; it represents mainly lead swallowed with secretions from the upper respiratory passages and from contamination of the hands. Thus the faecal lead output, while giving a rough picture of the lead exposure, is not a direct measure of the absorption. It has been estimated, however, that lead exposure is safe if it does not give an average daily faecal lead excretion ofmore than 0-6 mg. and that the threshold for potential poisoning may be exceeded if it is not in excess of 1-4 mg. (Kehoe et al. (1933). Urinary lead increases rapidly with even moderate absorption. According to Elkins (1959) there may be an increase from the normal average of about 0-03 mg. per I., to 0-10-0-15 within a few weeks. He considers levels between 0*15 and 0-2 mg. per 1. as " borderline " and above 0-2 mg. as indicative of harmful exposure, while others, including Egli et al. (1957) and Lynch (1949) agree that 0-15 mg. per L represents the "bottom level for exposure"; ; j | P< tc c< at te 9, o Cl tl 9 u ii o \\ If DUP050313195 itions rtion erage ity of skive sis as olylic than ptosis cd by ppled ocyte ' lead raged :nt to -ation cits of ssium hould j is a ormal scsof much Ikins, is has ormal g. are 8- Per given faecal / lead from ing a ption. ivc an :shold 4 mg. irding about tween ivc of [1949) LEAD 185 Lynch regards 0-3 mg. per 1. as the "top level indicating absorption". Elkins states that " lead levels in excess of 04 mg. per 1. are usually associated, sooner or later, with some degree of lead intoxication ". He also states that with regard to the correlation between urinaiy and blood lead levels, the average level in the blood corresponding to 0-2 mg. per L of urine is 0 07 mg. per 100 g. of blood and a blood lead level of 0-9 mg. per 100 g. is comparable to 0-3 mg. per L of urine. Coproporphyrinuria.--There is a normal range of daily excretion of copro porphyrin, depending on constitution, diet and activity--0-120 y in the urine and 150-400 y in the faeces, (Dobriner et al,, 1937). Cantarow and Trumper (1955) give the normal daily level in the urine as 160 y and in the faeces 300-400 y. In animals and human beings lead absorption results in an increased excretion of protoporphyrin in the urine, and this is considered an earlier indication of lead absorption than punctate basophilia (De Langen and ten Berg, 1948). Such an increased excretion is not specific to lead poisoning; it occurs also in poisoning by mercury, organic arsenicals, some organic solvents and aromatic amines, and in some diseases such as Weil's disease, cirrhosis of the liver and obstructive jaundice (Watson, 1952). It is not definitely known whether the porphyrinuria of lead poisoning differs from that of the disease porphyria (Singer, 1953), but in lead poisoning there is an increase, of coproporphyrin HI, in which it differs from true haemolytic anaemia (HolacSk and PSnickovi, 1957) and to a smallerextent ofuroporphyrin, which, is found in large amounts in conditions where there is stress on the bone marrow(Kench et al, 1952). A correlation between the concentration of coproporphyrin in the urine and that of the lead in blood and urine of industrial lead workers (and in children suffering from acute lead poisoning) has been recorded by several observers (Maloof, 1950; Shiels et al., 1953; Bashour, 1954; Chisholm and Harrison, 1956) and it; is generally agreed that estimation of the copropor phyrin content of the urine is a valuable supplement to urine or blood lead estimations. Meek et al. (1948), although their results of examining workers exposed to lead fumes did not show complete correlation between the excre tion of lead and that of coproporphyrin in the urine, considered the copro porphyrin test as a " potential laboratory tool ". An attempt by Wyllie (1955) to correlate the urinary coproporphyrin values with the punctate basophil count showed that with mild exposure the coproporphyrinuria increased from an average value of 3 y to 120 y per 100 ml., with a punctate count of 1,000 or less per million red cells, to 1,300 y per 100 ml. when the punctate count rose to 9,800. The uroporphyrin values, estimated by the spectrophotometric method of Rimington and Svensson (1950) also increased, as did the ratio between coproporphyrin and uroporphyrin; with punctate counts of 1,000 per million this ratio is seldom greater than 2/1, but as the stippled cells increased to 9,800 the ratio rose as high as 6/1. In Bashour's (1954) investigation, both urinary and blood porphyrins were increased, though only 5 of the 44 exposed individuals showed clinical symptoms of lead poisoning. The daily urinary coproporphyrin averaged nearly ten times the normal while the blood values were only slightly above. The blood lead concentration was above the normal level in 39 individuals. Elkins states that a high coproporphyrin level (above T.r.M, o DUP050313196 __ fnfi^*^^*!a~-*f!?-*i/Tr'i'i'^*n j s- 186 TOXICITY OF INDUSTRIAL METALS 1 mg. per 1. of urine) together with a urinary or blood lead value indicative of patholog' harmful exposure, is a warning which should not be ignored. The " toler pass thrc ance limit " recommended by Egli et al. (1957) based on a study of workers in initial ris accumulator and lead colour factories, where about two-thirds of these wor copropoi kers had a urinary coproporphyrin level greater than 6 y per 100 ml., is 6-8 y chromic per 100 ml., though none showed the complete picture of lead intoxication. counts, The factors involved in the porphyrinuria of lead poisoning are still not the urine completely understood. Some investigators (c.g. Kcnch et al., 1952) have for A.L. attributed it to a breakdown of the iron-porphyrin (protoporphyrin) in the nicians. e haemoglobin molecule, with increased red cell destruction and bone marrow hyperactivity--in other words to a haemolytic action of lead; others, such as Vanotti (1954) consider it an inhibition of the utilization of iron in the synthesis of haemoglobin, with formation of porphyrin type HI, a non-ironcontaining blood pigment. The most recent and, according to Goldblatt 1 i He ha: levels is cent, have than 12-i and Goldblatt (1956), most reliable view is that " the porphyrins excreted in poisoning, in disease, and in the normal organism derive not from the 75 (is- pe levels ex per 100g breakdown of haemoglobin but from the processes of synthesis of haemo globin ". : Estim; A diagnostic criterion in the form of the presence in the urine of amino- ! photomc laevulic acid has been suggested by Kramer and Selander (1965) on the mended grounds that it may be correlated with the amount of metabolically active ' combine lead, and therefore oflead intoxication. | blood es Versenate (Ca^EDTA), has in recent years been suggested by several ' agent m authorities as a reliable test for excessive absorption of lead, both in lead ; samples workers and in non-industrially exposed persons. (Leckie and Thompsett I .in HNO (1958), Albahary, Truhaut and Boudene (1958), Teisinger and Srbova (1959), Mettu Williams, Leigh and Matthews (1966). Some of these have found that estimate intravenous injections have produced the highest excretion of lead, while mostcoi others have given an oral dose of 1 g. ofversenate at 10 p.m. and estimated the survey < total lead in the urine in two early morning tests. Leckie and Thompsett discusse found that one group of laboratory workers with no known exposure to ! . results c lead showed, on the basis of haemoglobin level, stipple cell count, copro ' potentia porphyrinuria and lead in urine, no changes sufficient to indicate more than ! Holzapf small absorption, while all workers with lead, who were considered on these j one in a findings to show excessive absorption, showed after versenate administration ' groupsi urinary lead levels of over 760it per 1. and Teisinger (1965) has stated that Estimat! persons exposed to lead whose blood picture shows punctate basophilia of 12-50 m more than 1,000 per million, porphyrinuria of more than 0-150 mg. per L had rev- and a lead blood level of more than 0-70 mg. per cent show an excretion rate group a of lead of more than 1-7 mg. per L after EDTA, while those suffering from anaemia excrete an average of 5-05 mg. per 24 hours. He summarizes the value of the versenate test by stating that when at least two of the more widely used tests are positive, the mobilization test would not be useful, but that it is suitable for dubious cases, and also in order to decide whether the patient, after an episode of lead poisoning, should resume work with lead. Hie various tests for lead absorption have also been exhaustively discussed tion tw< poisonii and hei statistic adminis present, atmosp' by Rainsford (1968), who states that there is sometimes a very incomplete .1 correlation between them, but that this is more apparent than real, since the i V DUP050313197 LEAD 187 f pathological findings suggest that a worker exposed to a lead hazard can pass through several stages before developing overt phunbism, namely an 1 initial rise in the blood-lead level followed by a rise in urinary excretion of coproporphyrin and aminolaevulin and these may be followed by a hypo / chromic anaemia combined with a rise in the reticulocyte and punctate counts. He points out that the coproporphyrinuria test is only reliable when t the urine has a specific gravity of more than 1,008, and that this test and that A for A.L.A. are time-consuming procedures needing highly qualified tech-' e nidans. v He has also shown that the relationship between haemoglobin and blood- e levels is that all specimens with haemoglobin levels of less than 13-0 g. per cent have blood-lead levels exceeding 50 ftg. per 100 g. while those with less i. than 12-0 g. of haemoglobin per cent have blood-lead levels of more than t 75 ftg. per 100 g., though in his investigation some workers with haemoglobin a levels exceeding 14-9 per cent had blood-lead levels of more than 100 ftg. per 100 g. Estimation of lead in Mood and mine by Atomic Absorption Spectro photometry has been described by Slavin and Sprague (1964) and recom e mended as being less time-consuming than other methods, especially when e combined with a chelating agent, but they issue a warning that in the case of blood estimation there may be a potential error; for example, the chelating tl agent may not recover all the organically bound lead, or that in the blood d samples lead may be lost in the precipitate unless the blood had been dissolved :t in HNO*. >, Methods of estimation.--There are many methods in present use for the it estimation of lead in air, blood and urine, and for coproporphyrinuria. The e most complete and exhaustive account of theseis given by Marmet (1958) in his e survey of three accumulator and two colour factories in Switzerland. He tt discusses the advantages of the methods used by himself, and correlates the o results of the various tests with each other and with the extent of the existing i- potential hazard. Similar conclusions have been reached by Reinhold and n Holzapfel (1967) as the results of their investigation of two groups ofworkers, ;e one in a ceramic works and the other in a factory producing lead colours. Both n groups were given 1 g. of CaNa2EDTA twice daily over a period of one year. it Estimation of the lead in air in the colour factory gave values of 6-750 to >f 12-50 mg. per c.m., indicating a high lead risk. A preliminary investigation 1. had revealed a blue line on the gums of one female worker in the ceramic :e group and anaemia In one of the colour grinders. At the end of the investiga n tion two other grinders showed signs interpreted as early symptoms of lead ic poisoning, and the lead line of the girl in the ceramic group had not improved c and her blood picture had deteriorated. Only in two cases was there a it statistically acceptable improvement. It was concluded that while EDTA 1C administration is valuable when clear symptoms of early lead intoxication are i. present, the only true prophylaxis of lead poisoning is a lead-free working :d atmosphere. :e ic I o DUP050313198  jp** - :i H 1S8 TOXICITY OF INDUSTRIAL METALS *6 :3i PROPHYLAXIS AND PREVENTION OF LEAD POISONING This preventive measure of control of lead exposure is emphasized by Berg and Zenz (1967) in a non-ferrous foundry, based on environmental, hygienic and clinical measures. These consisted of atmospheric analyses, engineering adjustments in the melting and pouring areas in the form of mechanically exhausted hoods, prohibition of eating and drinking in the work places, urine analyses and coproporphyrin tests. Berg and Zenz state that no cases of outright lead Intoxication occurred during these preventive procedures. A <s TREATMENT OF LEAD POISONING Practically all the former suggested remedies for lead poisoning (admini stration of citrates, calcium and BAL) have now been superseded by the method of chelation. This was introduced by Bessman et at. (1952) to the Conference on Lead Poisoning at the Massachusetts General Hospital that year, following the preliminary report of a case treated by this method. The case, a 3 year old child, having eaten paint from window sills for the past 8 months, had suddenly developed convulsions. On the 9th day after admission to hospital, he was given 50 mg', of calcium EDTA intravenously in 50 ml. of 5 per cent glucose solution. In view of developing oliguria and high blood pressure, and since little was then known about the effects of versenate, the treatment was discontinued for the next 2 days, when for the first time punctate basophilia appeared, with a 4 per cent reticulocytosis. With improvement ofthe renal symptoms, but resumption of the encephalitic signs, treatment was re-started with gradually increasing doses. After a total dose of 6-5 gm. during 12 days the improvement was so marked that it was finally discontinued, with no further appearance of symptoms. Since that time the efficacy of versenate treatment both in children and adults has been established and supported by a large number of investigations in Europe and America.. The first report in Great Britain was published by Giles et at. (1955), the mode of action and chemical characteristics having been investi gated by Kacpinski et at. (1953). EDTA, tetracetic acid, or versenate, is a synthetic polyaminoacid, only slightly soluble in water and most organic solvents, but soluble in dilute mineral acids. It forms salts with alkali metal bases and the solubility ofthese salts in water increases as the acidic groups of EDTA are neutralized one after another. The importance of this substance from the point of view of therapy of metallic poisoning, especially lead, is its ability to form inner complexes with many metals, called chelates, which are stable and watersoluble; it has therefore a " sequestering " action on metals. In the case of lead stored in the body the calcium complex of EDTA, calcium disodium versenate, is used in order to prevent the removal of calcium to an extent which might cause hypocalcaemia. Its formula is as follows: This si withou blood < soft tis: Effec of treai symptc basopb anincr opinioi AXLE versern symptc colic is to Sait other i URIN is rapi intrave urine, Karpir 2 mg. and T< with 0 been r 2g.pr 70 mg PUNt marke a rapii DUP050313199 INDUSTRIAL METALS i > PREVENTION OF LEAD ISONING ol of lead exposure is emphasized by Berg foundry, based on envirbhip.tntai,1 hygienic sisted of atmospheric analyses/engineering souring areas in the form of mechanically ating and drinking in the work places, urine ts. Berg and Zenz state that mo cases of sd during these preventive procedures. (OISONING ' -' ested remedies for lead poisoning (adminiI BAL) have now been superseded by the introduced by Bcssman et al, (1952) to the it the Massachusetts General Hospital that report of a case treated iby./this method. ;ving eaten paint from window sills for the veloped convulsions. On the 9th day after ven 50 mg. of calcium EDTA intravenously olution. In view of developing oliguria and little was then known about the effects of continued for the next 2 days, when for the ippeared, with a 4 per cent reticulocytosis. ymptoms, but resumption of the encephalitic i with gradually increasing doses. After a days the improvement was so marked that it io further appearance of symptoms. Since to treatment both in children and adults has ay a large number ofinvestigations in Europe n Great Britain was published by Giles et al. chemical characteristics having been investi- irsenate, is a synthetic polyaminoacid, only nost organic solvents, but soluble in dilute & alkali metal bases and the solubility ofthese acidic groups of EDTA are neutralized one t of this substance from the point of view of . especially lead, is its ability to form inner called chelates, which are stable and waterluestering " action on metals. In the case of ilcium complex of EDTA, calcium disodium prevent the removal of calcium to an extent mia. Its formula is as follows: LEAD 189 This stable and soluble Iead-versenate complex is excreted in the urine without significant toxic effects and with great relief of symptoms and signs of blood disturbance. It is believed that most of the lead is excreted from the soft tissues and that lead deposited in the bones is less readily accessible. Effects of Versenate Therapy.--All observers are agreed upon three results of treatment of lead poisoning by calcium disodium versenate--alleviation of symptoms, rapid increase in urinary lead excretion and decrease in punctate basophilia. A decrease in coproporphyrinuria has also been recorded, and an increase in the level of lead in the blood, though there is some difference of opinion on the latter point. ' a l l ev ia t io n o f s y mpt o ms .--The most strikingly favourable results of versenate treatment have been observed in those cases where encephalitic symptoms have been prominent, as in children who have ingested lead, but colic is also rapidly relieved, in some cases within 2 days. Anaemia, according to Saita and Moreo (1957) does not respond with the same certainty as the other phenomena of intoxication, though the punctate basophilia does. u r in a r y l e a d e x c r et io n ,--The increase in excretion of urinary lead is rapid and very marked. Elkins (1959) states that CaEDTA when given intravenously will cause a ten to thirty-fold increase in the lead content of the urine, and comparable results have been obtained by many other observers. Karpinski et al. (1953) recorded an increase in a 24-hour specimen from 2 mg. on the second day of treatment to 4 mg. on the seventh, and Leckie and Tompsett (1958) an excretion of over 1-5 mg. in 24 hours as compared with 0-32 mg. and 0-65 mg. in controls. Even higher levels of excretion have been reported by Saita and Moreo (1957); they state that a daily dosage of 2 g. produced a lead elimination in the urine as high as 20 mg. daily, and up to 70 mg. in 9 days of treatment. p u n c t a t e b a s o p h il ia .--A sharp drop in punctate basophilia is another marked feature of versenate treatment. Markus and Spencer (1955) recorded a rapid fall in the punctate count of three vitreous enamellers, one of whom DUP050313200 Sii&i: 190 TOXICITY OF INDUSTRIAL METALS showed 11,200 per million before treatment, and Belknap (1952) and many others have reported similar results. c o p r o p o r p h y r in u r ia .--A reduction in coproporphyrin excretion was noted by Ruotolo and Elkins (1954) and by Saita and Moreo (1957); the latter did not find a corresponding reduction in the protoporphyrin of the blood. l e ad m b l o o d .--There is some disagreement as to whether versenate treatment increases the level oflead in the blood. According to Manville and Moser (1955) the blood lead is not appreciably affected by EDTA, but KarpinsM et al. (1953) observed a prompt rise following versenate therapy. They considered this to indicate the mobilization of lead from extravascular tissues; as treatment progressed the blood lead level at first declined and then rose again, suggesting that there were storage places for lead in the body not easily reached by versenate. Mode of administration and dosage of versenate.--There appears to be no doubt that the intravenous method of administration is more rapid and more efficacious than the oral, but, if the efficacy is based on the production of increased elimination of lead there is some evidence that oral therapy can produce this effect. Naturally the effect of oral therapy is less striking since, according to Elkins (1959) possibly less than 1 per cent of the ingested EDTA is absorbed. Other authorities have estimated the absorption at much higher levels, Teisinger and Srbova (1956) at 2-6 per cent; Foreman et al. (1953) at 1$ per cent in t r a v e n o u s d o s ao e.--There still exists some difference of opinion as to the optimum dosage. Leckie and Tompsett (1958) investigated 8 men em ployed in the process known in Great Britain as " wire patenting ". Only one man had acute symptoms of lead poisoning; in the remainder excessive lead absorption was diagnosed principally on an increased urinary coproporphy rin, varying from 4 to 100 y per 100 ml. It was found that the most satisfactory urinary excretion of lead was obtained by giving 0-5 g. over 3 hours twice daily in four-day courses. As the second course, separated by 3 days from the first, produced less than half the excretion of the first, it was assumed that the available lead was being rapidly eliminated. In order to discover whether there was a further quantity which would become gradually available, an identical course was given 7 weeks later. This produced 7 mg. of lead as compared with 8-4 mg. from the second course. The unfortunate result of a case reported by Bessman et al. (1954) when a patient after an initial improvement following her first dose of EDTA relapsed and died from cerebral oedema suggested that this one dose did not lower the concentration of intracellular lead sufficiently to. prevent the redistribution on withdrawal of the chelating agent. Leckie and Tompsett advise therefore that in severe cases the therapy should be given continuously for at least 48 hours before resuming the intermittent dosage. By the inter mittent method the optimum daily dose is 2 g., and this should be given in an intravenous infusion of saline over 6 hours daily, in 5-day courses separated by 3 or 4 days. o r a l a d min is t r a t io n .--In animals poisoned with lead it has been stated by Ricders (1954) that while feeding with EDTA calcium disodium does not LEAD cause a significant increase in the combin lead, it does cause a marked shift from fae A comparison of oral with intravenous Sidbury et al. (1953) showing that oral adr lead excretion, and this has been confirn Bell et al. (195 and others. The shift ft also been confirmed, hut tins is not ap administration. Bell and co-workers f intravenous administration, in mert suffe The actual elimination of lead by urine a administration of 3 g. over a period of 1 to lead, caused a 2 to 3-fold total incrc: thirds of that produced by intravenous ft ORAL THERAPY AS A PROPHYLACTIC ME CaEDTA given by mouth might be a uscf exposed to lead (Savicevid et al., 1959). 1 view. He points out that the end result favour of the urinary would probably be: of lead from the body and that even if tl the rate, the quantities involved in the coi probably be too small to he of practical . would be required to maintain the effect Savicevid et al. base their strong reconu laxis on actual cases of lead poisoning t (2 g. drily) of a CaEDTA preparation. Toxic effects of EDTA.--Possible tori kidneys, the bone marrow, the cardiac have been suggested. On the kidneys, t Cottier (1957) was the result of an error per kg. body weight was followed by a i On the bane marrow, Belknap (1952 the blood-forming elements in one of 3 < with marked success. Signs of regenc days after cessation of treatment Sucl and Moreo (1957). They state that th treated for lead poisoning by calcium ve treatment; only in patients with colic v hyperplasia and this was regarded as i episode. No change in the erythrocyti Savicevid and co-workers in their cases In the heart, Bradley and Powell (195 cardiogram in 4 out of 5 child patic between the second and fourth day of tp 75 mg. per kg. body weight per day in The question of interference with th the assumption that copper and iron (Teisinger and Ficerova-Bergerova, 195 of about 70 g. by mouth no fall in hae **><.*> DUP050313201 or INDUSTRIAL METALS ore treatment, and Belknap (1952) and many suits. eduction in coproporphyrin excretion was (1954) and by Saita and Moreo (1957); the iding reduction in the protoporphyrin of the ;ome disagreement as to whether verbenate lead in the blood. According to Manville and is not appreciably affected by EDTA, but ;d a prompt rise following versenate therapy, e the mobilization of lead from extravascular [ the blood lead level at first declined and then e were storage places for lead in the body not losage of versenate.--There appears to be no hod of administration is more rapid and more if the efficacy is based on the production of here is some evidence that oral therapy can the effect of oral therapy is less striking since, ibly less than 1 per cent of the ingested EDTA have estimated the absorption at much higher 156) at 2-6 per cent; Foreman et al. (1953) at 2 still exists some difference of opinion as to md Tompsett (1958) investigated 8 men emGreat Britain as " wire patenting ". Only one id poisoning; in the remainder excessive lead :ipally on an increased urinary coproporphy- per .100 ml. It was found that the most >f lead was obtained by giving 0-5 g. over 3 ourses. As the second course, separated by less than half the excretion of the first, it was i was being rapidly eliminated. In order to rther quantity which would become gradually as given 7 weeks later. Hus produced 7 mg. ig. from the second course, ase reported by Bessman el al. (1954) when a vement following her first dose of EDTA il oedema suggested that this one dose did intracellular lead sufficiently to prevent the 1 the chelating agent. Leckie and Tompsett iscs the therapy should be given continuously tming the intermittent dosage. By the interlily dose is 2 g., and this should be given in ! over 6 hours daily, in 5-day courses separated limals poisoned with lead it has been stated ding with EDTA calcium disodium does not LEAD 191 cause a significant increase in the combined faecal and urinary excretion of lead, it does cause a marked shift from faecal to urinary lead. A comparison of oral with intravenous therapy in children was made by Sidbury et al. (1953) showing that oral administration did cause an increase in lead excretion, and this has been confirmed by Bradley and Powell (1954), Bell et al. (1956) and others. The shift from faecal to urinary excretion has also been confirmed, but this is not apparently an effect specific to oral administration. Bell and co-workers found that it occurred also with intravenous administration, in men suffering from chronic lead poisoning. The actual elimination of lead by urine and faeces combined, following oral administration of 3 g. over a period of 10 days while away from exposure to lead, caused a 2J to 3-fold total increase in excretion, amounting to two- thirds of that produced by intravenous therapy. o r a l t h e r a p y a s a p r o p h y l a c t ic me a s u r e .--It has been suggested that CaEDTA given by mouth might be a useful prophylactic measure for workers exposed to lead (Savicevifi ef al., 1959). Kehoe (1955) is not in favour of this view. He points out that the end result of a decreased faecal excretion in favour of the urinary would probably be a lowering of the rate of elimination of lead from the body and that even if there should be an overall increase in the rate, the quantities involved in the conditions of potential exposure would probably be too small to be of practical significance; also continuous dosage would be required to maintain the effect. Savicevid et al. base their strong recommendation ofthis method of prophy laxis on actual cases of lead poisoning treated by oral medication of tablets (2 g. daily) of a CaEDTA preparation. Toxic effects of EDTA.--Possible toxic effects of versenate therapy on the kidneys, the bone marrow, the cardiac muscle and the electrolyte balance have been suggested. On the kidneys, the toxic effect reported by Vogt and Cottier (1957) was the result of an error in dosage. A daily dose of 600 mg. per kg. body weight was followed by a necrotizing nephrosis. On the bone marrow, Belknap (1952) recorded a transient depression of the blood-forming elements in one of 3 cases which he had treated by EDTA with marked success. Sighs of regenerative hyperplasia were observed 19 days after cessation of treatment. Such an effect has been denied by Saita and Moreo (1957). They state that the bone marrow function of patients treated for lead poisoning by calcium versenate was satisfactory at the end of treatment; only in patients with colic was there a decrease of erythroblastic hyperplasia and this was regarded as normal towards the end of an acute episode. No change in the erythrocyte or haemoglobin level was noted by Savicevid and co-workers in their cases treated by oral CaEDTA. In the heart, Bradley and Powell (1954) noted slight changes in the electro cardiogram in 4 out of 5 child patients, but they became normal again between the second and fourth day oftreatment. These children had received 75 mg. per kg. body weight per day in divided doses at six-hour intervals. The question of interference with the electrolyte balance has arisen from the assumption that copper and iron are excreted together with the lead (Teisinger and Ficerova-Bergerova, 1958). The fact that with a total dosage of about 70 g. by mouth no fall in haemoglobin was observed led Savicevid SitejgSpfW11 "V DUP050313202 'Hove***-*** 192 TOXICITY OF INDUSTRIAL METALS to consider that such a disturbance of iron and copper metabolism was improbable. ORGANIC LEAD POISONING--TETRAETHYL LEAD The organic lead compound of chief industrial importance is tetraethyl lead, which is used as an " anti-knock " addition to motor fuels, not in its pure form but as " ethyl fluid ", a mixture of49-63 per cent of TEL with ethylene bromide, dibromide or dichloroethane. According to Marchenko and Beilikhis (1946) ethyl fluid is added to motor fuel in amounts of 2-6 c.c. to 1 kg., corresponding to 1 -5-8 parts by weight ofTEL, to 1,000 parts by weight of fueL PROPERTIES Pure TEL (Pb(CaH5)4) is a clear oily liquid with a sweetish odour. It is practically insoluble in water but readily soluble in many organic solvents, and in fats and lipids. It is strongly decomposed, with liberation of heat, by halogens and their solutions, and by concentrated nitric and sulphuric acid, not by weak mineral acids and alkalis. It has a very high volatility--at 18C. air saturated with its vapour contains about 5 mg. per 1. Specific gravity, 1-64; boiling point, about 200C.; at 135C. it begins to decompose slowly. METABOLISM Absorption.--Owing to the high volatility of TEL, absorption is most commonly by inhalation but the liquid is readily absorbed from the gastro intestinal tract and also from the skin. Animal experiments have shown that the greater part of the lead absorption from a single application to the skin takes place during the first hour. Distribution and excretion.--The distribution of TEL in file tissues after absorption differs, at least in the initial stages, from that of inorganic lead, as does its final site of deposition. Kehoe and Thamann (1931) found that in rabbits, following skin absorption, the absorbed TEL became decomposed in the tissues and after a period of 3 to 14 days both its distribution and excretion followed quantitatively that of water-soluble lead compounds. The site of greatest concentration, however, unlike that of inorganic lead, is the brain. It is known from animal experiments that there is very little deposi tion of inorganic lead in the brain, even when given intravenously (Ginsberg and WeatheraU, 1948), and Goldblatt and Goldblatt (1956) found no cumula tion in the brain of animals inhaling lead compounds even when there was extensive damage to the kidneys. In animals and human beings poisoned with TEL, lead in both volatile and also non-voiatile form has been found particu larly in the brain. Thus, Norris and Gettler (1925), examining the tissues of 4 fatal cases of poisoning occurring during the manufacture of TEL, found a volatile lead compound (estimated by a colorimetric micro method) in the brains of 2 of these and values for both volatile and non-volatile lead up to 12-21 fig. per g. It is believed that the volatile organic lead compounds have a special predilection for lipoid and nerve tissue and on the basis of animal Li experiments Goldblatt and Goldblatt which overt signs of encephalopathy n In the liver of animals subjected to TEL vapour, lead has been demonst 1956); they used a special technique, and measured the infra-red absorptior by vacuum distillation. TOXICOLOGY The majority of fatal cases of tetn been non-occupational in origin; fro excessive inhalation of the compound of contaminated food or drink. Mai drinking of contaminated beverages higher rate than in cases due to inhal: skin. It is not generally considered that tl of cars using ethyl fluid, to the passersthe concentration of TEL is not in < author, however (Fatzer, 1953), has pi complaints of muscular pain, heada diarrhoea and constipation, sleep dish: dystonia ", that inhalation of exhaust petrol can be responsible for these disti tion has usually arisen from the clean tained leaded petrol. The sludge in I centrations of 1 per cent or over. Acc possible for men exposed to the air i lethal dose of TEL in half an hour, whi of exposure in one day or successive illness. SYMPTOMS OF POISONING The symptoms and time of onset va of exposure. With a heavy single exp hours and the symptoms rapidly pri exposure there may be a latent period the symptoms may differ from those of In fatal cases acute mental disturb tions, convulsions and coma usually pi a few days. Less severe cases also s excitement, agitation and disorientati nausea and vomiting. Between the ; may be periods of depression and ap good once the critical period, within a and restoration may be complete will uncommon. In mild cases the con dreams, restlessness, loss of appetite a. DUP050313203 'fW/ifP-. INDUSTRIAL METALS ince of iron and copper metabolism was ONmG--TETRAETir^:LEAD icfindustrial importance is'letrafettiyl lead, " addition to motor fuels, not in its pure ure of 49-63 per cent of TEL with ethy! ne icthane. According to Marchenko and ;d to motor fuel in amounts of 2-6 c.c. to ; by weight of TEL, to 1,000 parts by weight ir oily liquid with a sweetish odour. It is readily soluble in many organic solvents, ;ly decomposed, with liberation of heat, by by concentrated nitric and Sulphuric acid, alkalis. It has a very high volatility---at ir contains about 5 mg. per I.`\ oint, about 200^.; at 135C. it begins to :a b o l is m h volatility of TEL, absorption is most iquid is readily absorbed from the gastrokin. Animal experiments have shown that ition from a single application to the skin e distribution of TEL in the tissues after initial stages, from that of inorganic lead, Kehoe and Thamann (1931) found that in i, the absorbed TEL became decomposed of 3 to 14 days both its distribution and hat of water-soluble lead compounds, n, however, unlike that of inorganic lead, is I experiments that there is very little deposieven when given intravenously (Ginsberg iattand Goldblatt (1956) found no cumula ting lead compounds even when there was a animals and human beings poisoned with' 1 non-volatile form has been found particund Gettler (1925), examining the tissues of g during the manufacture of TEL, found a 1 by a colorimetric micro method) in the both volatile and non-volatile lead up to t the volatile organic lead compounds have id nerve tissue and on the basis of animal ~j&M* Mii**<iSiaaaiadg6,. - LEAD 193 experiments Goldblatt and Goldblatt (1956) suggest that the critical level at which overt signs of encephalopathy may appear is 2-3 jug. per g. in the brain. In the liver of animals subjected to inhalation of air nearly saturated with TEL vapour, lead has been demonstrated in small amounts (Stevens et al., 1956); they used a special technique, with pentane as the extraction solvent, and measured the infra-red absorption spectrum of the solution concentrated by vacuum distillation. TOXICOLOGY The majority of fatal cases of tetraethyl lead intoxication reported have been non-occupational in origin; from misuse, accidental.spillage causing excessive inhalation of the compound in its undiluted state, or from ingestion of contaminated food or drink. Marchenko and Beiiikhis (1946) state that drinking of contaminated beverages caused 72-2 per cent of fatalities, a higher rate than in cases due to inhalation. It can also be absorbed by the skin. It is not generally considered that there is any risk of poisoning to drivers of cars using ethyl Quid, to the passers-by, or even to garage attendants where the concentration of TEL is not in excess of 0-1 per cent One German author, however (Fatzer, 1953), has put forward arguments, based on vague complaints of muscular pain, headache, nasal inflammation, alternating diarrhoea and constipation, sleep disturbance and other signs of " vegetative dystonia ", that inhalation of exhaust gases from automobiles using leaded petrol can be responsible for these disturbances. In industrial cases intoxica tion has usually arisen from the cleaning of storage tanks which have con tained leaded petrol. The sludge in these tanks may contain TEL in con centrations of 1 per cent or over. According to Kitzmiller et al. (1954), it is possible for men exposed to the air in such tanks to inhale and absorb a lethal dose ofTEL in half an hour, while in less severe conditions a few hours of exposure in one day or successive days may cause serious or even fatal illness. SYMPTOMS OF POISONING The symptoms and time of onset vary with the time, degree and duration of exposure. With a heavy single exposure the onset may be within several hours and the symptoms rapidly progressive; with repeated intermittent exposure there may be a latent period of 2 to 3 weeks; with slight exposure the symptoms may differ from those of an anxiety state. In fatal cases acute mental disturbance, with delirium, mania, hallucina tions, convulsions and coma usually precede death, which may occur within a few days. Less severe cases also show mental confusion, sleeplessness, excitement, agitation and disorientation, sometimes also abdominal pain, nausea and vomiting. Between the attacks of mania and delirium there may be periods of depression and apathy. The prognosis for recovery is good once the critical period, within a week or two of the onset, has passed, and restoration may be complete within 4-10 weeks, but relapses are not uncommon. In mild cases the complaints include insomnia, with bad dreams, restlessness, loss of appetite and gastro-intestinal disturbance; they a .. DUP050313204 194 TOXICITY OF INDUSTRIAL METALS usually disappear within a few weeks. Symptoms of this kind were described by Muller (1954) in 4 men employed in the recovery of lead scrap used for the production of TEL. TISSUE LEAD IN TEL POISONING The presence of lead, in both volatile and also non-volatile form, has been demonstrated in the tissues, particularly the brain, of animals and human beings poisoned with TEL. In the experiments of Kehoe and Thamann (1931), it was found that the greater part of the lead absorption from a single application of TEL to the skin of rabbits took place during the first hour and was distributed in the tissues, initially differently from that of water-soluble lead compounds, but later became decomposed in the tissues, and after a period of 3 to 14 days both distribution and excretion followed quantitatively that of water-soluble lead compounds. In human beings, Norris and Gettler (1925), examining the tissues of 4 fetal cases occurring during the manufacture of TEL, found in the brains of 2 of these, volatile and non-volatile lead in amounts up to 12-21 pg. per g. It is known from animal experiments that when inorganic lead is given even intravenously there is very little deposition in the brain (Ginsberg and Weatherall, 1948); Goldblatt and Goldblatt (1956) also found no accumula tion in the brains of animals given lead by inhalation, even when there was extensive damage to the kidneys. It appears that the volatile organic lead compounds have a special predilection for lipoid and nerve tissue. Goldblatt and Goldblatt suggest that the critical level in the brain, at which encephalopathy may appear, is 2-3 /xg. per g. In the liver of rats subjected to inhalation of air nearly saturated with TEL the presence of lead in small amounts has been demonstrated by Stevens et al. (1956). LEAD CONTENT OF BLOOD AND URINE IN TEL POISONING The blood level is not consistently altered in TEL poisoning. In the series of cases described by Kitzmiller et al. (1954), even in those of great severity, the blood lead levels were only slightly above the normal (0-060-07 mg. per 100 g.) and in those of Miiller the values were normal in subjects with varying degrees of intoxication. The urinary lead excretion is more definitely affected; in both the above series the level was above normaL Elkins (1959) suggests levels of "maximum allowable concentration" and of " harmful exposure " as 0-08 mg. per 1. and 0-15 mg. per 1. respectively. The urinary coproporphyrin is apparently not a reliable index of early TEL poisoning. TREATMENT OF TEL WITH CaEDTA While there is no definite evidence of the therapeutic efficiency of chelate treatment in organic lead poisoning, Kitzmiller et al. found that when given intravenously in doses of 1 g. per 30 pounds of body weight CaEDTA did cause a varying increase in the excretion of urinary lead, but not in the level of lead in the blood. In one severe case the urinary lead rose from 0-3-2% mg. per 1. at one period 2 days later, falling again to 0-26 mg. per 1. at the end ofa LEAD week and to lower values when treatment was well tolerated. BIBLIOGRAPHY AND RE Albahary, C, Truhaut, R., and Boud&ie, C. (1958) le Test de la Plomburie provoquee par le Yc Archs. Mol. prof. Med. trot., 19,121. Aub, J. C., Fairhall, L. T., Minot, A. and Rezniki Medicine (Baltimore), 4,1. Baikie, A. G., and Valtis, D. J. (1954). " The C Experimental Lead Poisoning." Brit. J. expo Basliour, F. A. (1954); " Urinary Uroporphyrin, phyrin Excretion in Lead Exposed Workers." Belden, E. A., and Garber, L. F. (1949). " Health /. industr. Hyg31, 347. Belknap, E. L. (1936). "Clinical Studies on D Blood Pressure Observations." Ibid., 18,380. -- (3 952). " EDTA in the Treatment of Lead 1 21, 305. Bell,' P. F., Gilliland, J. C., Boland, J. R., and Su Oral EDTA CaDisodium on Urinary and 3 indust. Hlth., 13,366. Berg, B. A., and Zenz, C. (1967). " Environment Exposure in a Non-ferrous Foundry." Amer. Beritid, T., and Vandekar, M. (1956). " Erythrop Poisoning." Blood, 11,114. Bessman, S. P., and Layne, E. C (1955). " Dete Urine." J. Lab. din. Med., 45,159. -- Ried, H., and Rubin, M. (1952). "Treatme CaDisodium Versenate." Med. Ann. D. C., 2 -- Rubin, M., and LeiVdn, S. (1954). " Treat Pediatrics, 14, 201. Bradley, J. E., and Powetl, A. M. (1954). "Oral Children." J. Pediat., 45,297. Brown, A (1946). " The Lead Content of Bloo< Processes in Bone." Quart. J. Med., 15,77. Calvery, H. O. (1938). " Chronic Effects of Ingestt med. Ass., Ill, 1722. Cantarow, A., and Trumper, M. (1955). Clinical Bic W. B. Saunders Co. Case, R. A. M. (1945). " Siderocytes in Haemolyt 271. Chisholm, J. I., and Harrison, H. E. (1956). porphyrin Excretion and its Relation to EDTA Acute Lead Intoxication." J. din. Invest., 35, Clarkson, T. W., and Kench, J. B. (1958). " Sedii Human Erythrocytes in vitro after Exposure Industr. Med., 15, 115. David, A. (1959). " Das Knochenmark be! Gewer' Arch. Gewerbepath. Gewerbrhyg., 17, 329. De Lan-en, and ten Berg, J. A. G. (1948). " Porpl of Lead Poisoning." Acta. med. scand., 130,3 Dingwali-Fordyce, I., and Lane, R. E. (1963). Workers." Brit. J. industr. Med., 20,311. D'Onofrio, V. (1949). " II Satumismo nelPIndt industr., 18, 155. Dobriner, K., Strain, W. H., and Localio, S. A. (1937 of Coproporphyrin and Total Coproporphyrin Soc. exp. Biol. (N.Y.)., 36,752. DUP050313205 4 DUSTRIAL METALS Symptoms of this kind were described in the recovery of lead scrap used for ONING He and also non-volatile form, has been, arly the brain, of animals and human experiments of Kehoe and Thamann art of the lead absorption from a single rits took place during the first hour and r differently from that of water-soluble lecomposed in the tissues, and after a n and excretion followed quantitatively tier (1925), examining the tissues of 4 facture of TEL, found in the brains of id in amounts up to 12-21 jug. per g. It hat when inorganic lead is given even position in the brain (Ginsberg and Idblatt (1956) also found no accumulalead by inhalation, even When there It appears that the volatile organic Jilection for lipoid and nerve tissue, the critical level in the brain, at which S. per g. lation of air nearly saturated with TEL ts has been demonstrated by Stevens ND URINE IN TEL POISONING f altered in TBL poisoning. In the r et al. (1954), even in those of great >nly slightly, above the normal (0-06iller the values were normal in subjects The urinary lead excretion is more s series the level was above normal, timum allowable concentration " and :r I. and 0-15 mg. per 1. respectively, 'arently not a reliable index of early CaEDTA >f the therapeutic efficiency of chelate itamiller et al. found that when given pounds of body weight CaEDTA did m of urinary lead, but not in the level the urinary lead rose from 0-3-2-2 mg. again to 0-26 mg. per 1. at the end of a LEAD 195 week and to lower values when treatment was discontinued. The drug was well tolerated. BIBLIOGRAPHY AND REFERENCES Aibahary, C., Truhaut, R, and Boudene, C. (1958). " Depistage de Satumisme par le Test de la Plomburie provoquee par le Versenate de Calcium Disodique." AubA,Jr.cChs.,.FMaairth.parIlo, fL..MTe.,dM. trinaov.t,,1A9.,1S2.,1a.tid Reznikoff, I. (1925). " Lead Poisoning." BaikMie,edAic.inGe.,(BaanldtimVoarleti)s,,4D,1..J. (1954). " The 02 Consumption of the Blood in Experimental Lead Poisoning." Brit. J. exper. Path., 35,434. Bashour, F. A. (1954). " Urinary Uroporphyrin, Porphobiltnogen and Copropor- phyrin Excretion in Lead Exposed Workers." J. Lab. din. Med., 44,764, Belden, E. A., and Garber, L. F. (1949). " Health of Workers Exposed to Galena." BelkJn.aipn,dEus.trL. .H(y1g9.3,63)1. , 3"4C7.linical Studies on Lead Absorption in the Human; Blood Pressure Observations." Ibid., 18,380. -- (1952). " EDTA in the TreatmentofLead Poisoning." Industr, Med. Stirg., Bell,2P1.,3F0.5, .Gilliland, J. C, Boland, J. R., and Sullivan, B. R. (1956). " Effect of Oral EDTA CaDisodium on Urinary and Faecal Lead Excretion." Arch, Bergi,nBdu. sAt. J,Baltnhd., Z13e,n3z6, 6C. . (1967). " Environmental and clinical Control of Lead Exposure in a Non-ferrous Foundry." Amer. ind. Hyg. Ass. J., 28,175. Beritid, T., and Vandekar, M. (1956). " Erythropoietic Cell Morphology in Lead BesSPmoaisno, Sni.nPg..", anBdloLoady, n1e1,,1E1.4C. . (1955). " Determination of Lead in Blood and --UrRiniee.d", HJ..,Laanbd.Rcluinb.inM, eMd..,(4159,521)5.9." Treatment ofLead Encephalopathy with --CaRDuisboind,iuMm.,VearnsdenLaeteik."in, MS.ed(1.9A5n4n).. D".TCre.,a2tm1,e3n1t2o. f Lead Encephalopathy." Bra' dPleeyd,iaJt.riBcs.,, 1a4n,d2P01o.well, A. M. (1954). " Oral EDTA in Lead Intoxication in BiowCnh,ilAdr.e(n1.9"46J)..Pe"dTiahte., L4e5a,2d97C.ontent of Blood and its Relation to Rarefying CSalvPerroyc, eHss.eOs.i(n19B3o8n)e. ."" CQhuraornt.icJ.EMffeecdts.,o1f5I,n7g7e.sted Lead and Arsenic." J.Amer. Ganmtaerod.wA,Ass-.,,aInldlT,r1u7m22p.er, M. (1955). Clinical Biochemistry, p.534. Philadelphia; CaseW, R. .BA. .SMau.n(d1e9rs45C).o. " Siderocytes in Haemolytic Diseases." J. Path. Bact., 57, Chis2h7o1lm. , J. J., and Harrison, H. E. (1956). "Quantitative Urinary Coproporphyrin Excretion and its Relation to EDTA Administration in Children with ClarkAscount,eTL.eWad.,InatnodxicRaetaiocnh.,"J. 1B..d(i1n9.5I8n)v.es"t.,S3e5d,i1m1e3n1t.ation Rate and Fragility of Human Erythrocytes in vitro after Exposure to Lead Chloride." Brit. J. DaviIdn,dAust(r1.9M59e)d.., "15D,a1s1K5.nochenmark bei Gewerblicher Bleivergiftung." C. D. De LAarncghe.nG, eavniderbteenpaBteh.rgG, eJw. Aer.bGrh.y(g1.,91478,).32"9.Porphyrin in Urine as First Symptom DingowfaLlle-FaodrPdyociseo,nIin,,g.a"ndAcLtaan. em,eRd..scEa. n(t1,916330)., 37". A Follow-up Study of Lead D'OnWoofrrikoe,rsV.". (1B9r4it9.)J. . in"dIuIstSr.aMtuemd.i,s2m0o,31n1e.llTndustria Ceramica." Bass. Med. Dobirnindeurs,tKr.,.,ISSt,ra15in5,.W. H.,and Localio, S. A. (1937). " Quantitative Measurement of Coproporphyrin and Total Coproporphyrin I Excretion in Animals." Proc. Soc. exp. Biol. (N.Y.)., 36, 752. f f'3 IS DUP050313206 <^k- ^w^g'fr^S^S^tfj^^g^S^^^aaSe^BEfl^aSssis^aesiKa^fi^h'^jx^&L. 196 TOXICITY OF INDUSTRIAL METALS Drecssen, W. C, Edwards, T. I., and Reinhardt, W. H. (1941). " The Control ofthe Lead Hazard in the Storage Battery Industry." U.S. Treas. publ. HIth. Bull. No. 262. Egli, R.( Grandjean, E., Marmet, J., and Kapp, H. (1957). " Der Verbreitung det Chronischen Bleivergiftung in Akkumulatorea und Bleifarben Fabriken." Schweiz med. Wschr., 87,1171. Elkins, H. B. (1959). The Chemistry of Industrial Toxicology. New York; John Wiley and Sons. Eriksen, L. (1955). " Effect of Lead on the in vitro Biosynthesis of Heme and Free Erythrocyte Porphyrins." Scand. /. din. Lab. Invest., 7, 80. Fader, B. (1966). " Practical Designs for Noise Barriers based on Lead." Amer. bid. Hyg. Ass. J., 27,520. Fairhall, L. T. (1943). " The Identification and Localisation of Lead in Bone Tissue." U.S. Treas. Pub. Hltlu Rep., No. 58. 209. -- and Miller, J. W., (1941). " The Deposition and Removal of Lead in the Soft Tissues." Ibid. 56,1641. Fatzer,R.(19S3). "Anzeichen von Bleivergiftung?" Schwelz.Med. fPicftr.,83.631. Fishberg, A. M. (1939). Hypertension and Nephritis. London; Baillifere, Tindall and Cox. Fleckel, L M. and Tschernow, I. G. (1930). " Zur Friibdiagnosis der Bleivergif i tung." Z. Cew-Hyg., 17,65. Foreman, H., Vier, M.,and Magell, M. (1953). " Metabolism ofCU-labelled EDTA in the Rat." J. biol. Chem., 203, 1045. Gilbert, F. A. (1957). Mineral Nutrition and the Balance oflife. Univ. Oklahoma Press. Giles, H. McC., Moore, C. J., and Still, B. M. (1955). " Treatment of Lead Poison ing with CaDisodium Versenate." Lancet, 1,183. fGillet, J. A. (1955). " An Outbreak of Lead Poisoning in Rotherham." Ibid., 1, /. 1118. Ginsberg, M., and Weatherall, M. (1948). " Acute Distribution of Intravenously Administered Lead Acetiite in Normal and BAL-treated Rabbits." Brit. J. Pharmacol., 3,223. Goldbiatt, M. W., and Goldblatt, J. (1956). "Industrial Carcinogenesis and Toxicology" in Industrial Medicine and Hygiene. Ed. E. R. A. Merewether. London; Butterworth. Hansmann, G. H., and Perry, M.C. (1940). " Lead Absorption and Intoxication in Man." Arch. Path. (Chicago), 30, 226. Hay, W. (1950). " Lead Encephalopathy in a Cooperage." Brit. J. industr. Med., 7,177. Henderson, D. A., and Inglis, J. A. (1957). " The Lead Content ofBone in chronic Bright's Disease." Australas. Ann. Med., 6,145. HolacSk, V, and PeniSkovi, M. (1957). " Excretion of Urinary Coproporphyrin in Lead Poisoning." Brit. J. industr. Med. 14, 198. Horiuchi, K., Horiguchi, S., and Suckane, M. (1959). " Studies on the Industrial Lead Poisoning." Osaka C. med. J., 5,41. Jackson, T. H. (1857). "Diseases of Miners of Arkendale and Swaledale." Brit, med. J., p. 619. Jensen, (1965), cited in EditoriaL "Basophilic Stippling in Lead Poisoning." J. occup. Med., 8,343. Johnstone,R. T. (1957). "A Re-examination ofthe Picture ofPlumbism." Industr. Med. Surg., 26, 323. Karpinski, F. E., Rieders, F., and Girsh, L. S. (1953). " CaDisodium Versenate in the Therapy of Lead Encephalopathy." J. Pediat., 42,687. Kehoe, R. A. (1949). Industrial LeadPoisoning in Industrial Hygiene and Toxicology, Vol. II Patty, F. A., New York; Interscience Publishers Inc. { -- (1955). " Misuse of EDTA CaDisodium for Prophylaxis of Lead Poisoning." J. Amer. med Ass., 157, 341. Kehoe, R. A. (1960). " The Metabolism of Lead in Health and Disease. Harben I Lecture, pp. 30 and 39. LEAD -- and Thamann, F. (1931). " Behaviour o --TEL." Amer. J. Hyg., 13,478. -- -- and Cholak,J. 1933. "OnNormal A' J. industr. Hyg., 15,257. Kench, J. E., Lane, R. E., and Varley, H. (1952 Lead Poisoning." Brit. J. industr. Med., 9, Kitzmiller, K. V., Cholak, J., and Kehoe, R. A Lead (TEL) Intoxication with CaEDTA." , Koelsch, F. (1959). " Bleivergiftung und Zahnau Kramer, K,, and Sdander, S. (1965). " Studies between different Laboratory Tests." Brit. J Lane, R. E. (1931). " Punctate Basophilia in C Hyg., 13, 276. -- (1936). "The Prevention of Industrial PI -- (1949). "The Care of the Lead Worker." -- (1965). " The clinical Aspects ofPoisonir Ann. occup. Med., 8,31. Leckie, W. J. H., and Tprapsett, S. L. (1958). " EDTA (Versene)in ExcessiveInorganic Lead Legge, T. M., and Goadby, K. W, (1912). he London and New York; Longmans, Green Lynch, J. G. B. (1949). " The Problem of Lead 60, 495. McCord, C. P. (1953). " Lead and Lead Poisi Med. Surg., 22, 573. -- (1954). Ibid, 23,27. -- Holden, F. R., and Johnston, J. (1935). the Lead Poisoning Epidemicof 1934-35." . -- Munster, D. K., and Rehm, M. (1924). in Lead Poisoning." J. Amer. med. Ass., 8 McFadzean, H. J. S., and Davis, L. J. (1949). Poisonmg." Quart. J. Med., 18, 57. Maloof, C. C. (1950). " Role of Porphyrins industr. Hyg., 1, 296. Manville, L. D., and Moser, R. (1955). " R< Workers exposed to Lead." Arch, industr. Marchenko, E. N., and Beilikhis, G. A. (1946). Tetraethyl Lead," Gig. i Sanit., 11,17. Markus, A. C., and Spencer, A. G. (1955). " T with CaDisodium Versenate." Brit. med.. Marmet, J. (1958). Industrietoxicolagische (Thesis), Zurich; Eidgenossischen Technisc Meek, S. F., Mooney, T., and Harrold, G. < Lead Poisoning." Industr. Med. Surg., 17 Mehani, S. (1966). " Lead Retention by the Ann. occup. Hyg., 9,165. Minot, A. S,, and Aub, J. C. (1924). " The Organism." J. industr. Hyg., 6,149. Muller, K. (1953). " Zur Kasuistik der BIcitctr Norris, C,, and Gettler, A. O. (1925). " Poise med. Ass., 85, 818. Oliver, T. (1914). Lead Poisoning. London; I Patty, F. A. (1949). " The Significance of Lead Surg., 18, 368. -- (1958). Industrial Hygiene and Toxico York; Interscience Publishers Inc. Prerovska, I., and Roth, Z. (1965). " Einfiuss rungen in der Ader-Wand und Serum in I Gewerbepath-, Gewerbehyg, 21,256. t t DUP050313207 F INDUSTRIAL METALS J Reinhardt, W. H. (1941). "The Control of the iaitery Industry." U.S. Treas. publ. Hlth. iw.l. f.. and Kapp, H. (1957). " Der Verbreitung der n Akkumulatoren und Bleifarbcn Eabrikcn." istry of Industrial Toxicology. New York; John id on the in vitro Biosynthesis of Heme and Tree .mi/. /. din. Lab. Invest., 7,80. igns for Noise Barriers based on Lead." Amer. Icntification and Localisation of Lead in Bone 'tit. Rep., No. 58.209. " The Deposition and Removal of Lead in the i Bleivergiftung?" Schweiz.Med. IFic/ir.,83,631. tsion and Nephritis. London; BaiJli&e, Timiail . G. (1930). " Zur Frfihdiagnosis der Blcivcrgif- I. M. (1953). " Metabolism ofCL-labelled EDTA 203, 1045. utrition and the Balance ofLife. Univ. Oklahoma 1 Still, B. M. (1955). " Treatment of Lead Poisonate." Lancet, 1,183. eak of Lead Poisoning in Rotherham." ibid., 1, 4. (1948). " Acute Distributioii of Intravenously in Normal and BAL-treated Rabbits." Brit. J. att, J. (1956). " Industrial Carcinogenesis and iedicine and Hygiene. Ed. E. R. A. Mcrcwcthcr. .C. (1940). 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Lead Poisoning and Lead Absorption. London and New York; Longmans, Green and Co. Lynch, J. G. B. (1949). " The Problem of Lead Poisoning." Canad. mad. Ass. J., McC6o9rd,4,9C5.. P. (1953). " Lead and Lead Poisoning in Early America." Industr. Med. Surg., 22, 573. ---- H(1o9l5d4e)n. , FIb.idR.,.,2a3n,2d7J.ohnston, J. (1935). " Basophilic Aggregation Test in theLead PoisoningEpidemic of 1934-35." Amer. J. publ. Hlth.,25,1089. -- Munsterj D. K., and Rehm, M. (1924). " The Basophilic Aggregation Test McFiandLzeeaand,PHo.isJo.nSin.,ga."ndJD. aAvmise,rL. .mJe.d(.1A9s4s9.),.82",S1i7g5n9if.icance of Stippling in Lead MaloPoofi,soCn.inCg.."(19Q5u0a).rt. "J.RMoeled.o, 1f 8P,o5r7p.hyrins in Occupational Diseases." Arch, Manivnidliues, trL. .HDyg.,.,a1n,d29M6o. ser, R. (1955). " Recent Developments in the Care of Workers exposed to Lead." Arch, industr. Hlth., 12, 528. Marchenko, E. N., and Beilikhis, G. A. (1946). 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Med. --Su(r1g9.,518)8., 3I6n8d.ustrial Hygiene and Toxicology, 2nd Ed., Vol. I, p. 162. New York; Xnterseience Publishers Inc. Prerovska, L, and Roth, Z. (1965). " Einfiuss von Blei auf biochemische Verande- rungen in der Ader-Wand und Serum in Hinblick auf Atherosklerosis." Arch, cimoerhenath-. Gewerbehyg, 21,256. DUP050313208 198 TOXICITY OF INDUSTRIAL METALS QuestionCliriic(l9S7). J. Occup. Med., 9,141. Rainsford, S. G.` (1968). " The Problem of Medical Supervision of Lead Workers. 1968." Royalnav. med-. ServiceJ. Reinbold, .R.,,and Holzapfel, G. (1967). "Investigation into the Long-term Prophylaxis by CaNa2EDTA in Workers exposed to Lead." Arch. Gewerbepath. Gewerbehyg.^23,155. Rieders, F. (1954).` " Effect of Oral Disodium Calcium EDTA on Urinary and Faecal Excretion of Lead in Rabbits." Fed. Proc., 13,397. Rimington, C.(l938). (Cited by Baikie and Valtis, 1954.) C. R. Lab. Carlsberg, ser. e/'m.,22,'454. -- and SvenssoivS. L. (1950). " Spectrophotometric Detennination of Uro porphyrin." ' Scand. J. elm. Lab. Invest., 2,209. Rodier, J. (1948).', ``Etude du Satumisme dans les Mines de Plomb Mantimes." Arch. Mai.'prof., 9,539. Ruotolo, B. P.JXV.', and Elkins, H. B. (1954). " Lead and Coproporphyrin Excretion of Patients treated with EDTA." Arch, inditstr. Hyg., 9, 205. Saita, G., and Moreo, L. (1957). " Mielogramma, Rjcambio Porforinico, Sideremia, nei Saturnisrho sotto Trattamento con Versenati di Calcio." Med. d. Lavoro., 48,130. Savicevid, M., Petrovid, L, Sleinkovif, M., and Djordjenid, S. (1959). "Unsere Erfahringen . mit Ca Daa EDTA (Mosatel-Bagget) bei chronischer Blei Exposition." Zbl. Arbeitsmed., 9, 6. Schroeder, H. A. (1956). " Trace Metals and Chronic Diseases." Advanc. Intern. Med., 8,259. Shiels, D. O. (1954). " Elimination of Lead in Sweat." Aust. Ann. Med., 3,225. -- Palmer, G. R., Cornish, P. E., and Kearley, E. J. (1953). " Porphyrinuria in Persons exposed to Lead Hazards." Med. J. Aust., 2,171. Sidbury, J. B., Bynum, J. C., and Fetz, L. L. (1953). " Effect of Chelating Agent on Urinary Lead Excretion." Proc. Soc. exp. Biol. (N. /.)., 82, 226. Singer, K. (1953). " Intermittent Porphyria." Metabolism, 2,280. Slavin, W., and Sprague, S. (1964). " The Determination of Trace Metals in Blood and Urine by Atomic Absorption Spectrophotometry." Atomic Absorption Newsletter, Perkin-Elmer Corporation. Norwalk, Connecticut. Stevens, C. D., Feldhake, C. J., and Kehoe, R. A. (1956). " Isolation from Liver of TEL after Inhalation." J. Pharmacol, exp. Titer., 117, 420.. Stow, J. (1945). The Survey ofLondon. London; J. M. Dent and Sons Ltd. Teisinger, J. (1965). " Practical Significance of Diagnostic Mobilisation of Lead." Scientific Reports on Industrial Hygiene and Occupational Diseases in Czecho slovakia, 10,71. -- and Ficerova-Bergerova, V. (1958). " Ueber den Einfiuss des zur Therapie der Bleivergjftung Angewendetes Ca-dinatrium Salzes der EDTA auf den Eisen und Kupferspiegel." Arch. 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