Document 2JRMaK49dmE4Zmb7odLkMBpDp

The Diagnosis of Lead Poisoning in the Light of i;ont Information Robert A* Lohoe Ft on the Kettering Laboratory of Applied Physiology of the University of Cincinnati, Clnclnm> fcl, Ohio* The large fussier of rooently published articles on load poison'lig testifies to a greatly heightened Interest 'n what nuat be listed as one of our oldest clinical problems* Unfortunately, the amount of light which has been shed upon the probleat does not correlate r >closely ' th fc>ie volume of the literary output* Indeed, It would soon that an actonpt on the part of the practitioner of rsdioine to examine and interpret the current literature would result almost Inevitably In 3uch disc our ngnent and confusion os to cause him to return to time* honored concepts and procedures* Kven the casual reader will note tha ^ t x&iny of the articles published recently deal primarily with laboratory methods of dlapnoenron ti*e apparent assumption that the underlying.; patho! ogled physiology of load Intoxication has been completely elucidate and nay, therefore, be taken for grunted, or ttmt it; need not be taken into account In the Interpretation of findings* on night bo led to believe that laboratory procedures may be substituted for clinical study* In fact there is an Insistent demand, not only In tadlco*logal but in general practice, for a laboratory test which, standing alone, will have a positive diagnostic atrfniricance* There is good roue on, therefore, to concern* laboratory cll^^osis, and to appraise in a aonewhat cautious and critical man er the extent to which laboratory observations and the interpretation* which are derived from then tnay e aocepted as trustworthy In view of the imposai i 11.'fcy of reviewing the literature even in a curaory xaantser, or even of mentioning many matter* which are of physiology cal importance, in the short time available, I shall attempt to clarify a few point* which seem to be of immediate practical importance to the problem of diagnosis* Normal Lewd .Metabolism The ingestion (and probably the inhalation), absorption, and excretion of lead have been shown to be normal phenomena of human life* (la,b,c,d).* The limit* of the normal value* for lead ingestion and for lead excretion in the feoe* and urine of persons in the United State* may be defined in substantially absolute toma,(2)* The values for the blood, spinal fluid and tissue* are not so Satisfactorily established, in that the full range of normal variability is inadequately defined (!&,2)* ^Thts is particularly true in the oaae of the akin, and unfortunately so, since ^unwarranted clinical slgnlfloanee haiT|recently/ been attributed to apparent variations in the lead content of thm tlssue*( 3) *) The evidence indicate* that within the somewhat incompletely defined pbyaiologioal limits, & state of dynamic equilibrium is maintained In which little or no pro gressive lead accumulation in the tissues occurs, but, rather, lv.take and output come into approximate balance after a certain Level of absorption into the tissues has been reached, (lb)* uch data as have appeared to Indicate that there Is a tendency toward progressive accumulation in the tissues, ohiefly the skeleton, show that the actual concentration difference between youth and old age are alight, - so alight, indeed as to require further procf that they exceed the limits of ohanoe variation* (l*.)* So evidence has been developed to show that unusual amounts of lead accumulate In the tissues or are retained1_in00th1qd. 4tisz sues except as the result of an pabnormal intake* There ure* to be suro, significant variations In absorption and operation frora day to day* but when compared with the metabolism of the more camion metallic constituents of living materiel, the normal metabolism of lead is remarkably stabile* v,1bother or not lead is physloloo'icnlly useful Is a matter for conjecture* but regardless of the eventual answer to this question the concept of lead as an accumu lative poison, without referonoe to quantity* has received a rude shock* Obviously* hereafter* when we refer to the poisonous properties oi' ler-d in animal or human metabolism, we shall have to makes use of quantitative terns* This point of view necessarily alters the significance of what lias long - eon regarded as an important element in the diagnosis of plumbisi nnmol;:, the history of exposure, The* discovery of a potential 3ouroe of exposure, without reference to lfcn intensity, has often been a signal fojr the cessation of further clinical study of a patient, Such lapses of judgement have been encouraged on the one hand by the fact that the clinical manifestations of lead intoxication are many* varied, and largely non-specific, and on the other by the belief that the absorption of any quantity of lead, however small, might cause illness if xpo ure were prolonged or if an unusual susceptibility existed* There can he littlo excuse for such reasoning in the future* The history of lend exposure* if it is to be tnkeir'aeriously, h u s thrive son quantitative manning* It is not enough to know the trad or occupation of the patient* Industrial conditions change rapidly* Ltnd haxards exist in trades supposedly free of exposure* and conversely, cone potentially dangerous occupations are so safeguarded as to be free of significant exposure* 'The clinical history of exposure, to bs useful, must therefore be precise and apeeiric in developlng a basis for an estimation of the oxtent of exposure either in relation to other exposure conditions which are well known to the examiner, or in terms of the effects of the exposure upon other persons similarly 01 543 occupied There Is at least one type of potential- lend OX) enure to shlch the ei.ovc reaorvatlona should not apply In practice, despite their validity in principle. There is every re'-son for suspecting the existence of significant and dangerous lead exposure in the case of children with a history of pica* The occurrence of lend-oontulning commodities and the use of load paints on furniture, toys, and other objects, within the reach of small children is much too common to ignore. 'The existence of symntoie even slightly suggestive of plumbisa should result In prompt investigation! of the child and hio surroundings. Abnormal head Metabuliag The limits beyond which human lend absorption comes to be aa&oclated with injurious effects cannot !.r, defined precisely at present, and until certain details of the behavior of lead are understood more clearly it la not likely that the question will To answered satisfactorily. * Certain criteria, which are in line with sound clinical practice in other fields, nay he adopted. Industry provides nany and varied examples of / group -xpoauro to load compounds. Careful study of representative groups of expused persons will eventually give a clear indication of the quantita tive relationships which exist between ex osurs, absorption, distribution '\ within the tissues, excretion, ^nd intoxication. It is probable that long before w# have learned the details of the physiological stechun* sms which are responsible for lead intoxication in any individual, wo shall have a clear idea of the types and degrees of lead exposure and absorption which are associated with the production of intoxication 41thin the group, iioreovor we shall know the range of the concentrations of lend, in excreta, blood, spinal fluid, and tissues, which arc associated with the occurrence of illness among a definite proportion of human beings. Doubtless, also. In the process of obtaining theoo practically useful data, much will have been learned of the nature of the mechaniems involved. pe?U 01 544 It la not to bo supposed that vie are entirely lucking in information of the type described move. A very j;refc amo-nt of work has been done in thia direction* What must be realized la that only a beginning has been made, and that e are almost though not quite in the dark aa to the actual mechaniezaa of lead intoxication* . t ia alao true, unfortunat-ly, thAtt the various methods which have been used in obtaining the available data have been so lacking in uniformity, and so variable in their sensitivity, that the respective seta of results cannot be put on an absolute basis for comparison or clinical use* Ambiguities of thia type are being eliminated in some of the more reoent studies but they are still a s urce of confusion* Therefore the clinician may well be somewhat cautious in his interpretation of the infwrmefcion which he receives from the laboratory* i'or present purpose*, we must regard findings beyond the range of normal values as a;normal in the sense that they Indicate the occurrence of an unusual and therefore pragmatically abnormal load metabolism* JJq r) cloan-cut correlation has been shown to exist between the occurrence of clinical symptoms, and the occurrence of a specific concentration of load in the excreta, or in any tissue or oody fluid* h. if the presence of symptoms* However, they have not do term ned fa.iequutftly the rang of variability of' tho lo*5d concentration in the blood of normal individuals, and their dictum cannot, th^roi'ore, be accepted as established However it has been 3hown that load at sorption, us evidenced by the lend content of the blood and certain other tissues, as well as alimentary and urinary lead excretion vary; mensureably in accordance wltn the severity of exposure to load compounds* (6)# Abnormally high findings may thus be regarded only as evidence of abnormal lead exposure* On the other hand, despite the fact of variable individual response to lead absorpt! on, there Is a threshold of absorption (evidenced by excreftl w) above wnich so e proportion of exposed persona become ill, trio clinical severe fcy of the in absorption. (6). Therefor, although there Is no clinical Jusfcifleatioi for the assumption that abnormal analytical results prove tho existence of lead intoxication, the demonstration of abnormal findings within the range of values whioh have been shown to occur among exposed persons some of whoa have developed lead intoxication establishes the potential clinical sig nificance of the exposure! tho higher tho level of load absorption and excretion, the more certain is its potential significance. There is no certainty, however, that symptoms shown by the person in question are due to lead. Indeed, tho diagnosis of lecd Intoxication can be made with reasonable certainty only on the basis of symptom and signs of illness whi coincide nltft the known clinicnl picture of lend Intoxlcafcion. Thus far we have spoken of abnormal lead metabolism as though 'the relationship between absorption, distribution in the tissues, and ex cretion remained unaltered by an Increased level of ingestion or inhalation, i.e. as though it represented the normal type of equilibrium maintained at a higher level. There are certain evidences that tills Is not tho case, but that there la a type of lead metabolism which in Itself is pathological. Apparently the urinary lead excretion does not Increase proportionally with increased lead exposure, beyond a certain point. (6). Various hypotheses might be advanced in explanation of this phenomenon, as a working basis for further study, but regardless of the explanation It would appear that this is an indication of a ohange in the metabolic pattern, - a change associated with a progressive accumulation of lead within the organism. There is little adequate evidence that such accumulation Is associated with a change ir^he manner of distribution of lead in the tissues of the body, but further lnv s tlgation Is needed to settle this Important quo* ion. Additional evidence of a qualitative change in the character of 7 the equ' Hr rium 1 etwron h* ;h levels of lend conoentrn* l /n in the tiasties and the lea-; concentration In the excretions Is to bo found In the fact that the urinary excretory rate drops rapidly for a tire after the cess^tl of severe exposure* and then continues at a much lo er but still diminish!! rate for a with the severity of the previous exposiire (7) * apparently until the normal relationship between lead intaki lead content of tissues* and lead output has been re-established* Evidently when the rate of absorption is high* some of the lead is distributed Into the tissues in such a way as to be released less readily than that which is involved in a normal or only slightly inoroased rate of absorption* Aub has provided evidence that a more active calcium and lead metabolism takes place in the fenestrated portion of certain bones as compared with their solid portlon*(8)* It way be that such differences exert & profound Influence upon the manner in which varying concentrations of circulating lead come to ha deposited in the skeleton* Vfhatover may be its Cause* the sharp decline in the excretory r^te after ttyr cessation of severe exposure must be reckoned with in diagnostic practice* Thus conclusive evidence of abnormal lead absorption in the form of a significantly heightened excrotor rate Is most readily found within a short time after the cessation of ab- normal exposure. Che longer the interval between the cessation of exposure and the examination of the excreta* the greater will bo the difficulty in interpreting the results* Eventually all evidence will disappear* and not even the analysis of the tissues can be relied upon to show that nn abnormal exposure had occurred* (7) On the other hand only n sl'ght increase in lead absorption results In the prompt elevation of the rate of lead excretion (1 b)* so that the analytical study of the excreta carrier out in close time relation to a suspected exposure will establish the algs nlfioance or inaignificsnoe of the exposure* In our experience* the excret rate always continues at nn elevated level for some tine after the sub- 0aicienoe of active aymptona of intoxication. ;>adlola~lc and lilcroscootc Kvldences of /ibncrmal Lord. Absorption* It la evident from the foregoing paragraphs that analytical procedure# are useful aa diagnostic measures only to the extent that they are means of estimating the significance of exposure to land compounds. They have the advantage over other clinical methods of being entirely specifla, and this advantage gives them a unique usefulness, Ho diaoussl of the laboratory signs of abnormal lead absorption would io complete, however, without referring to recently discovered radiologic evidence, and to the widely accepted but somewhat ill-defined aignlfiance of certain blood changes. ark, (9) end a 1'ttle later Vogt, (10) directed attention to a sharply defined line of Increased density at the margin of maximal growth in the bones of children, associated with the local deposition of abnormal amounts of lead. Their further observations have provided a means for the prompt detection of abnormal lead absorption In the case of young children. The density produced by lead deposition Is not so specific in / character as to differentiate it In every instance from those which may result from other pathologic processes, but it may be so striking in an otherwise apparently normal bone as to call attention to previously unsuspected lead absorption* The character of the line changes with the lapse of time, becoming leas intense ns the lead is given up by the bone after discontinuance of exposure, and also becoming more widely separated from the active growth area aa the latter moves progressively forward. Mo such line Is formed in adult bones, so that the usefulness of the procedure is limited to the study of children. Positive findings must be interpreted with the same degree of caution that is required In the case of other indications of abnormal lead absorption* Moreover It is to be doubted if negative findings cun bo accepted as proof that no recent significant abeorptlon of lead has occurred. This Is especially to be 1 015 4 8 taken into account In view of the occr.sii.tial case of acute lend Intoxica tion from the accidental Ingestion of large amounts of lead. Tb numerous blood changes associate d with, abnormal lead abaorpt; have boon the subject of extensive inquiry and abundant controversy for many years* The grantor portion of the present disagreement is concerned with Che significance of variations in the numbers of various types of erythrocytes* The reticulocytes have been shown to undergo changes in number under the influence of leed absorption* Likewise basophilic stlppll of the erythrocytes hns long been known ns an accompaniment of lend absorption and intoxication* Various methods for staining and counting one or the other or both of these type cells have been devised and recommended, and a large number of experimentalists and eliniclans, working with widely variant methods and groups of patients, have set up standards for the differenbinti of normal fron abnormal findings* It would be difficult if not impossible to bring any order out of the chaoe which has resulted, or to harmonize the diametrically opposed points of view into a generally acceptable state ment of the facts* Accordingly I shall mention only a few opinions, and 3hall confine myself largely to the presentation of the results which have been obtained by L. * handers, of the lettering Laboratory, through the consistent use of one simple clinical method as applied to the study of the occurrence of stippled erythrocytes in the blood of normal and abnormal individuals* Lehman (11) believes that stippling of the erythrocytes occurs in what Is usually regarded as significant numbers in conditions other than lead poisoning or the well recognised anemias* He believes that he has demonstrated that exposure to humid atmosphere, alcohol, and cement dust results in the production of Increased stippling* The majority of "experi mental workers deny the occurrence of more than a vein? amall number of stippled cells In normal blood* Those who admit their normal occurreno# ID np.t up a nsxirhl limit of fron 100 to 500 per million. Dohwars (12) maintain# that "considerable quernblties are never found in the renlly healthy". Koch (13) regards 100 stippled ery throe:; tea pep million aa suaplci jua ot plurabism, and 500 per million na diagnostic. Helm (li*.} abates that stippling Is not found in oases other than lead Intoxication, severe anemias, and grave Intoxications. fchmidfc (15) has established a figure of IDO per million as useful confirmatory evidence of lend intoxlda tion and 1000 per million as shoving a ''deep seated condition". An Incompleted study of our data accumulated over a period of ten years, vhtoh Is nov being made by Tba, Sanders, shoes that the presence of sfcipoled erythrocytes is of frequent occurrence In the blood of persons who are apparently normal dnd healthy, and who are free from abnormal lend nbaorotlon. In a aeries of 78U persons whose carefully taken histories showed no evidenoe of occupational lead exposure, the mean number of stlppl erythrocytes per million was found to be 339*18 vith a probable statistical error of 9?2, and a standard deviation of 405.6 (equivalent to about 1 3tippled erythrocyte lc ovary 12 fields where each field contains approxt* riately 250 erythrocytes)j ufc of theae nen gave results varying from loij.0 to IkhO per million erythrocytes, over 2# ran from I520 to 1920 per million, nnd the upper limit was near bOOO per million. It follows from these observations that the mere occurrence of atlpled erythrocytes in the blood is not indicative of abnormal lend absorption and that the aero demonstration of stippling has no diagnostic value. The range of normal vain os must be established for any method of examination of the blood, and the method itself must be so standardized aa to yield consistent and comparable results. Our data on persona abnormally exposed to lead and to certain .fcher agents have not been so worked up as to Justify a complete statement of their significance. Nevertheless certain facts which have a bearing upon diagnosis, have become obvious from the nature of the individual results. 01 550 - 11 Vifch due regard to the technique which we hnve oyed, the following conclusions nrt* justified. (a) There la a definite overlapping of the normal and abnormal range of stippling* duo to Tilde individual variability, loth among noraal and abnormal jrrou-s# (b) Lead absorption la hut ono of a number of f no tors which may cause an increase In the number of stippled erythrocytes without Inducing subjective illness# (e) Load absorption tends In the Individual case to cause increased sfcippli'g of the erythrocytes# ( 'e have seen as many as 19000 stippled cells per nllllcn erythrocytes In subjectively well lut leaded persons#) (d) Tho extent of the Increase produced by lead absorption la not necessarily related to the zmjyilfcude of the lead exposure, or to the rcta and magnitude of the lead absorption# (a) Thersi is no necessary oorrolatJ.cn between the nunr or of stippled erythrocytes and the onset or severity of load intoxication. (In active lead i. toxlcation wo have found up to ^3,000 per million erythrocytes) {?) In our experience, thus far, lead intoxicu *:i on Is always associated with the .presence of come degree of stippling, although In certain cases vrltfr1 abrupt onset following promptly upon a brief massive exposure. It may not appear promptly# Granting the validity of these conclusions, tbo examination of the blood f r stippling by methods of equivalent sensitivity to those which we have employed, la useful ns a nouns of excluding lor d v.v. a f a ter In suspected oases of loud Intoxication, when the results are negative*, and as a means of providing confirmatory evldenco when positive. R f ^ T-r-nCftB 1** K-Thoo, < A*, rfhnjnami, F, air; Cholak, J*j on the nornal air sorption and excretion of load* (a) I* Lead absorpt'un and excretion In primitive life, J. Induat. ilyg., 257 U955) (b) II* Lead absorption and lend excretion In nodorn Aiaof lean life, ibid* s *75 (1955) (c) III. The source* of normal lead absorption. Ibid, * 290 (192 (d) IV* Lead absorption and excretion in infants and children. Ibid, 1 t 501 (1935) (Footnote* Extensive reference to the literature of the subject may be found in this series of papers*) 2* Kehoe, !? A*, '.'hanamn, F*, and Cholak, J.* Nortel absorption and excretion of lead, J.A.M.A., loUt 90 (1935)* 3* Gaul, L.K., and Btaud, A.U.* Clinical opeotrosoopy* spectr(.metric analysis of biopay specimens obtained from oases of pluablsm and workmen In daily contact with lead paints, J* Nerv. and Kent* Dia., 51 t 2o5 (1 >55) Ik* Barth, .** lintorsuchungen Tiber den Blelgehalt der menechlichen Knochen, Virchows Arch* f* path* /.nat., 281 : li^u (1931) 5* Lifcencr, M*, and 7/eyrauoh, F.t Unterauchun. on fiber den Eleigehal't des Mutes und Kerns, seine ^exlahungen ztun Auf treten klini^bher , Krankheltserschelnungen sowie seine blngnoatlaehe r edeutung, r,rch*f* bewerbepath. u. Gewerbehyg., 4 * 74 (1935)* 7 6* Kehoe, F. A*, Thwaann, F* , and Cholak, J.* Lend absorption and excretion in certain lead trades, J* Indust. Hyg., 1^ * 306 (1955)* 7* Kohoe, >U A.,?hiuaann, F., and Cholak, J.i Lead absorption and excretion in relation to the diagnosis of lead poisoning, J* Indust* Hyg., * 320 (1955)* 8* 9* 10* 11. 12* Aub, J.C., Robb, G*p., and Fosameisl, i'*t L nd studies XVII. significance of bone trabeculae In the treatment of lend poisoning. Am. J. Pub. Health, 22 ; 325 (1932) Park, L* A.i Shadows produced by lead in the x-ray pictures of ths growing skeleton. Am* J* .is* Child*, ill t 485 (1951) Vogt, K.C.* A roentgen sign of pluniblsmt the lead line in growing bone. Am* J* Hoentgenol*, 2^ 8 550 (1950) Lehmann, H#t Ubber das Vorkoomen basophil granulierter brythrocyten beim Menachen ohne Bleielnwirkung ale Ursache, Aroh. f. Uyg., 102 t 111 (1929). dchwars, L.i basophil gekornte Krythrooyten, vemehrtes Porphyrin sowie andore Boobachtungen bei dor Burchunfcersuehung von Arbeitern vorschledener lietriebe nit : leigefRhrdung, Stschr. f. Hyp. u. Infektionakr*, 102 * 57 (1924)* 01 R5 13 13* Koch, * ur i-rnfis dar li&aatologlsohen ^la^nosaetellung bl iilelvilrkxui,;; Voraohlag etner r>tancim'dftfrbui)g dor i;ranulo|>olyo!ircsia ..ryti-roayum. Arch* f. Hyg., ^4 1 3O0 (1922*) li; Ho In do alaeo, /;gaae-L*/'onfc, and a *i Contribution a lfetude du antumioKo proteaalunel; 1 d^piafca^e nnr loa^ wothode la laboretoira, du praaafcumisB efi du saturnism confimai i ull, nod., iwia, s kii>5 (1922) 15. -cl-jsidt, Pm 1 Kouore :'csrachunen Sber da a ' wtien dar Blaiverglf tung. I'll in* UachP., 367 (1927) /