Document YjLVMe0jrkwoNGj3Q0oJnvXj0

9-IN ICA L SIGNIFICANCE OF HEMATOLOGIC CHANGES IN LEAD ABSORPTION AND LEAD POISONING WILLARD MACHLE, M.D. NEW YORK ANY discussion of the clinical significance of changes in the blood in relation to absorption of lead and lead intoxication can be kept brief for two reasons: First, the facts as to clinical significance have been established and confirmed,1 and second, the status of knowledge as to pathogenesis of the changes is so equivocal and ill defined as to be of limited general interest. Any merit which added discussion may have, therefore, will be that of emphasis by restatement, in an endeavor to direct the clinical effort to the patient himself and to the more definitive analytic data. Recent studies of Kench, Gillam and Lane *12 and the observations of Falconer34are in support of the thesis that the basic hematologic dis turbance in lead poisoning is an interference in the formation of .proto porphyrin brought about by depression in cellular activity rather than by blocking of the formation of the iron-porphyrin complex. This interference results in nonutilization of protoporphyrin and consequent porphyrinuria, disturbed synthesis of hemoglobin with hypochromic anemia and an increased hemoglobin metabolism.* At one time or another almost all elements of the blood picture have been studied for their possible significance as criteria of lead intoxication. All deviations were found to be nonspecific. Two changes, however, occur with sufficient frequency and of such an order, of magnitude as to be useful, though not definitive, diagnostic aids. These are punctate basophilia (or stippling) and reduction in hemoglobin. STIPPL IN G Stippling, the hematologic change most commonly thought of in connection with plumbism, is, like polychromasia, essentially an abnor- Preser.ted in a Conference on Lead Poisoning at the Seventh Annual Congress on Industrial Health, Boston, Sept. 30, 1946. 1. Kehoe, R. A., and others: Report of the Committee on Lead Poisoning, New York, American Public Health Association, 1943. 2. Kench, J. E .; Gillam, A. E., and Lane, R. E .: Biochem. J. 36:384, 1942. 3. Falconer, E. H .: Am. J. M. Sc. 203:857, 1942. 4. (a) Pfeil, E .: Ang. Chem. 53:374, 1940. (6) Mangeri, S .: Med. d. lavoro 31:97, 1940. (c) Robscheit-Robbins, F. S., and Whipple, G. H .: J. Exper. Med. 63:767, 1936. 150 mality chrom well e cells a while appeal ular.si ofth e th e ifij agents -is-n't.a'Usimo'-smjn? :rsu the,,bl' norma ficahct The?fi mcthd( etc.'.'w thejc and-' tl status' thik& pi m are gj\ values are' evi A few under!; thresh 0. ltd mustb 'S,j giftung, 1919.fel zk e. m s. 71:266; 15:257, 8.'1 9. 1 M ACHLE--LEAD POISONING mality in the behavior of the erythrocytes to stains. That both poly- chromasia and stippling are manifestations of reticulation has been fairly well established by the fact that the proportions of polychromatophilic cells and stippled cells are largely determined by the method of staining,5 while the surii of the two elements parallels the reticulocyte' count. It appears probable,5 though not certain, that persistence of the same retic ular substance i$Responsible for all three types of cells, since the form of the reticular material in supravital specimens does not indicate whether the fixed, stained cell_ will be stippled or polychromatophilic. Toxic agents, siich as lead and phenylhydrazinej influence the basic reticulum a- \ in some unknown fashion, this alteration being evidenced in the abnormal ,rJ & staining reactions.55". . v . .. .. .. . - TV. : > i" ..... Significance of Stippling.--Since stippling is not a specific change in ' * ; .W ''1' the blood unique in lead absorption and is commonly present in the ;r.;t normal, nonexposed population1 and since no characteristic morpho logic differences in stippling occur, it is evident, that any clinical signi- , ficance that obtains .will be determined by quantitative relationships. The first requisite for this is a method of measurement that will give reproducible results characteristic for .the method. No, standardized method is yet established. It is known that the stain, the time, the />H, etc., will affect the counts,5 and there is, moreover, good evidence that the manner of preparation of specimens, the temperature, the humidity and the time' of drying will influence the results profoundly. This V" ' status of affairs is responsible in large part for the divergence, in values that have been reported for nonexposed groups and greatly limits the practical value of what can be a useful tool. For example, in table 1 are given a number of values reported for nonexposed normal and dis- `V-'v eased persons and exposed groups. It may be seen that the ranges in values are extremely wide.- Similar, smaller, differences in magnitude are evident in the proposals for threshold values for lead intoxication. A few such are given in table 2. The authors' comments reflect the i p a " f . uncertainty which exists when one attempts the establishment of any threshold value. It follows that the clinical significance of a single stippled cell count must be interpreted in the light of method, associated disease, etc. With 5. (at Schmidt, P., and Weyrauch, F .: Ueber die Diagnostic der Bleivergiftung, Jena, Gustav Fischer, 1933. (6) Pappenheim, A .: Folia haemat. 24:1, 1919. (c) Whitby, L. E. H., and Britten, C. J. C .: Lancet 1:1173, 1933. 6. Rosegger, H .: Klin. Wchnschr. IS: 158, 1936. 7. (a) Kehoe and others.1 (b) Footnote 5. (c) Rosegger. (d) Falconer, E. H .: Ann. Int. Med. 12:1429, 1939. (e) Teleky, L .: Munchen. med. Wchnschr. 71:266, 1924. (/) Kehoe, R. A .; Thamann, F., and Cholak, J . : J. Indust. Hyg. 15:257, 1933. (g) Sanders, L. W .: ibid.; 25:38, 1943. 8. Kehoe.1 Pappenheim.5b Whitby and Britten.5 9. Bruckner, H .: Arch. Hyg. 98:95, 1927; OCCUPATIONAL MEDICINE the same method, however, repeated counts on persons and groups are useful indexes of magnitude of lead absorption, especially when sudden and progressive increases in counts occur. The erratic character of the T a b l e 1.---Means and Ranges in Values of Stippled Cells per Million Erythrocytes A uthor S tain Number M ean Ranges . v /, S am p le: Brown, E. W .: J . In d u st Hyg. 4 3 :1 1 3 , 1926 a n d S m lrn o w a ............. T* - M ayers ,or . . . . . . . . . . . . . . . . . ..V.i'. F a lc o n e r 74 F a lc o n e r 74 S a n d e rs 7* W right S a n d e rs 7* N elson, L o ckw o o d a n d Mac- - k a y 101,<v-v V>.\ . * L a n e *> . . . . . . . . . . I . . ; N elson, W . T .: M. J . A ustralia 1 X310, 1931 . Nelson, W. T .: M. J . A ustralia lx 3 1 0 r 1931 -.t 'f v* . O '. K ehoe, T h a m a n n a n d 'C h o Iak 7 r ` M-B F a lc o n e r 74 J-Q F a lc o n e r 74 S a n d e rs 7* F a lc o n e r 74 S a n d e rs 7* N elson, Lockw ood a n d Mack a y 10` N elson, L ockw ood an d Mac*ay N e lso n ,. L ockw ood an d Mac- . kay lo r ` 65 N o rm a l 'su b je c ts . -- . . . .N onexposed w o rk m ro ja liS B sfl ... a tlp p lln g ; o n ly w l t o j d y J i y S g a V *ne:n!a 0 1 N o rm al rtib!eetL only^v-.'* 1 a tlp p le ie e E .fo a a ii.^ 'jjtS a (MOO.. ' N o r m a l / ( D b J e e M ^ t O S M l ^ j y ha4iio.'tlppllngr^*ti" f c ^ S 3 ......' - Nonerpoaed p a tie n 1 ti^ S S j 06,000. . N o n ex p o sed ! - ery workera; BO% hp&t&SAgJa - >. > . ' n o 0-2,6 0 0 fe M edical tn d a n t p * ? v # 5^ M V t o d n o * a tlp p lln H 'j5?f;r^iS-?1 256 937 : 0-7,000V; N o n e x p o a e d 'w o r k e r a / ' -1 223 . . . :> * 0-2,000- . N o m a l n b } e rt ; h a d n o -'jiU p p U n r ' . . . r 0-4,000 ~ H e a lth y ';m e n ; . . . . :; I . 0-7,200 . N o n ex p o aed c le rk s: ; 24% h a d n o - a tI p p ^ * 7 d V L . 6 0 960 - 0-6,000. r N a tiv e In d ia n a; ^ A . w o m en .a n d 1'c h lld jrm v '" ,;^ * r 4 - P a tJ e n t /w ltb b n t r J a s d ^ ^ M `J-vfy 5 exposure;:- 1 .27,000 --62,000' 11 Peaxtpi eonsut r,ew lth o u t - > a d ^ W i ? j 3 ? 0-1,400' H a z a rd o u s * e x p o s u r a t v r ^ * ^ ^ '; 45% h a d tfo . . . . . . ' - P a in t m anufacture^ 6-7,200 H a z a r d o u s e x p o s u r e ^ '?-, .. 100% ;J i a d 's t l p p l l n c 69 4,335 0-20,000l^-' S lig h t e xpoossuurree- - to .; 'lea d 'r..'-- Jc.Jrjr 14,220 0-20,000 S to rag e bttery*,r5-- ' ' ' . ' ' ' w o rk e rs ; `-V S 'tsfS -z -1.2.. 36,382 ,t ,i i P e r s o n a w ith *M adv& . polaonln e - * - .& f i? * M ethylene blue. 7* ' f Jenner-QIemsa counterstain. T a b l e 2.--Proposed Threshold Vdlues for Stippled Cells per Million Etythrocytes%$;_')w A uthor S c h m id t, d t e d b y F a lc o n e r 74 S c h m id t a n d W e y ra n ch B*........ S c h n ltte r, d t e d b y F a lc o n e r 7d. K eboe a n d o t h e r s 1................'.., S a n d e rs 7* ........ ....................... . S a n d e rs 7r ......... .................... S a n d e rs 71 F a lc o n e r 74 V alu e 'in d ic a tiv e o f lntoxfcation" , ' .t -vA "Pathognom onic for intoxication^ " v; " S u g g est* In creased a b s o r p t i o n " '; ;. V " S uggests increased ab so rp tio n b y groups" "Requires additional evidence to a tta in d ia g n o stic significance" : . ^ : ;"..'C "Defines lead intoxleatlon" -^):YvV.--S - "H igh probability of being due to le a d 7 In to x ic a tio n " - : stippled cell response and the dangers of relying on results of a single sampling, even in groups, have been well demonstrated, by Sanders,7*. who found a normal mean value (480 per million) and ranges, for one yfC ii sibld'ti i OD1 M ACHLE--LEAD POISONING month, in a group of 20 men with hazardous exposure (as evidenced by a mean urinary concentration of lead for the group of 0.128 mg. per liter).' These results may be compered with mean stippled cell counts of 2,912 per million (ranges 6 to 7,200) obtained eight months before, when the urinary excretion of lead for the group was 0.191 mg. per liter. Critical evaluation of the best information at hand 10 makes it pos sible to elaborate certain' sfftqments as to the validity and clinical sig nificance of stipplingl . .'?* -'V''')-. V (a) Stippling and polychromasia are the result of the reactions of reticular substance to stains, and are indications of activity of the marrow. (b) Alterations of the reticular substance, especially the alteration caused by lead, will lead to increases in stippling. (c) Stippled cells are present in nonexposed, normal persons at times in numbers up to 7,000 per million. In diseases other than lead poisoning (hepatic cirrhosis, pulmonary disease) and especially in the blood dyscrasias, stippled cell counts as high as 50,000 per million may occur without associated lead exposure. Single counts therefore may have value only when critically applied. ; (d) Hazardous lead absorption usually but not always causes ele vations in stippled cell counts; when'it does, the relationship is general and direct but erratic and with wide ranges of variation for single observations. . -. . (e) The greatest value of stippled cell counts derives from recurring observations on groups of exposed workmen and comparison of these results with previous values for the group and with values for nonexposed controls. Repeated observations .in individuals are of more limited usefulness when used as an index of hazardous absorption or as a diagnostic or prognostic criterion in lead'intoxication. \ (/) No critical stippled cell level for hazardous lead exposure can be set. Considerable experience with a uniform, method in. a given situation may enable prediction of likelihood of occurrence of cases of intoxication in groups. Any threshold value, however, cannot be applied elsewhere owing to the pronounced influence of technic on the counts. (g) High stippled cell counts occur with great frequency in active, lead poisoning. Absence of stippling in cases of suspected poisoning is good evidence that some agent other than lead is responsible. 10. (o) Kehoe.1 (6) Schmidt and Weyrauch.51 (c) Whitby and Britten.5* (d) Falconer.711 (e) Sanders.7^ (/) Mayers, M. R .: J. Indust Hyg. 8:222, 1926. (g) Kogan, B., and Smimowa, L .: ibid. 9:43S, 1927. (h) Lane, R. E .: ibid. 13:276, 1931. (i) Nelson, W. T .; Lockwood, L., and Mackay, K .: M. J . Aus tralia 2:317, 1932. OCCUPATIONAL MEDICINE (/i) There is urgent need for a standardized method for quantitation of the altered reticular substance. HYPOCHROMIC ANEMIA jf Hypochromic anemia, with reduction in mean corpuscular hemoglobin and porphyrinuria, is believed by some 4* b to be the most sensitive index of hazardous lead exposure, and where it is possible to repeat examina tions at frequent intervals it is undoubtedly an excellent index of the general health of the worker. Despite this, the consensus leads one to the conclusion that hypochromic anemia is even less specific than stip pling-, since it so frequently results from environmental factors, under nutrition and disease. Moreover, the degree of reduction in hemoglobin is never great, and the mean levels for groups do not always relate well to the magnitudes of exposure.11 Even in cases of lead intoxication during the acute episode, individual hemoglobin and erythrocyte values fall within ranges like those of nonexposed workmen.12 I may state, then, that though reduction in the hemoglobin content of erythrocytes may be an early index of hazardous lead absorption, the reductions which occur are usually slight, not closely related to magnitude of exposure and not differentiated from hypochromic anemia arising from other common causes. Hemoglobin concentration, like weight, is best employed as an index of the general state of health and nutrition. OTHER CHANGES Significant changes in leukocytes and platelets do not occur except in severe acute intoxication and when large therapeutic doses of lead are given 13 and are neither noteworthy nor specific. In clinically active poisoning, leukocyte counts are usually within normal limits.12 Erythropoietic activity of the marrow is evidenced by the appearance of reticulocytes in the peripheral blood (normally from 0 to 2 per cent of erythrocytes). It is to be expected that any agent, such as lead, which affects hemoglobin metabolism will cause changes in reticulocytes. The qualitative changes (stippling and polychromasia) have been mentioned in a preceding section. In addition, increases in the" absolute numbers of reticulocytes are commonly seen with lead absorption. Some reports suggest a rather close correlation between reticulocyte counts and order and duration of exposure when large groups are studied.11 In individuals and small groups, however, reticulocyte counts appear to be a no more sensitive and significant index than does stippling. This is in keeping with the common observation of the erratic character of reticulocyte responses both after therapy and as a result of action of harmful agents.14 Since 11. Dreesen, W. C .: J. Indust. Hyg. & Toxicol. 25:50, 1943. 12. Ashe, W. F .: J. Indust. Hyg. & Toxicol. 25:55 1943. 13. Falconer.3 Brookfield, R. W .: J. Path. & Bact 31:277, 1928. 14. Minot. G. R., and Castle, W. B .: Lancet 2:319, 1935.' MACHLE--LEAD POISONING 155 ion stippling is a manifestation oT altered reticular material the vagaries of the two will be associated. Correspondingly, the technic for basophilic aggregation of McCord,15 which enumerates reticulocytes as well as other basophilic material in the erythrocytes, would be expected to give related >in values, possibly moresfnsitive, but not more specific. ex Corpuscular fragilfty'.jn lead absorption at one time received con .a- siderable attention, and both increased 5,1and decreased fragility has been he reported in cases of lead intoxication. No recent, well controlled studies to have been reported. In view of the problems of interpretation of cor P- puscular fragility tests, and the varying criteria used for lead intoxi .T- cation on which statements have been based, it is my opinion that in determinations of corpuscular fragility are of less diagnostic value than ell are simpler technics such as the technic for stippled cell counts. in es CONCLUSIONS e, 1. Lead interferes with synthesis of protoporphyrin and alters the es reticular substance, but there are no specific hematologic changes in :h lead absorption. d 2. Basophilic stippling becomes significant with respect to lead n absorption when subject to the following conditions: (a) with employ is ment of a uniform method for which normal ranges of values have been defined, (b) when repeated frequently on groups and used as an index of trends in exposure, (c) as supportive evidence in the diagnosis of lead intoxication and (d) in the exclusion of lead intoxication. 3. Other hematologic changes are more variable and less character istic than is the stippling. Room 714, Chrysler Building, 40S Lexington Avenue (17). 15. McCord, C. P .; Holden, F. R., and Johnston, J . : Am. J. Pub. Health 25:1089, 1935.